Compound containing multi-fused ring structure

Abstract

Belongs to the field of medicinal chemistry, and relates to a compound containing a multi-fused ring structure, in particular to a compound shown as a formula (I), a stereoisomer or pharmaceutically acceptable salt thereof, a preparation method thereof or a pharmaceutical composition thereof, and application of the compound in preparation of medicines for treating diabetes or obesity related diseases. # imgabs0 #

Description

Compounds containing multiple fused ring structures

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits to Chinese patent application No. 202310802212.0 filed with the State Intellectual Property Office of China on June 30, 2023, Chinese patent application No. 202311497217.3 filed with the State Intellectual Property Office of China on November 3, 2023, and Chinese patent application No. 202410808056.3 filed with the State Intellectual Property Office of China on June 20, 2024, and the contents of the above applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of pharmaceutical chemistry and relates to compounds containing a multi-condensed ring structure, stereoisomers thereof or pharmaceutically acceptable salts thereof, preparation methods thereof, or pharmaceutical compositions thereof, and use thereof in preparing drugs for treating diabetes or obesity-related diseases. Background Art

[0004] Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose concentrations and associated with significant morbidity and mortality. Obesity is considered a significant risk factor for T2DM, with approximately 85% of T2DM patients being overweight or obese. Glucagon-like peptide-1 (GLP-1) is an incretin secreted by L cells in the small intestine as nutrients pass through the digestive tract. GLP-1 is known to exert multiple physiological effects through the GLP-1 receptor, such as promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing food intake. Although GLP-1 analogs have been commercialized as diabetes treatments and are considered one of the most effective diabetes treatments due to their efficacy in lowering HbA1c and reducing weight, GLP-1 analogs must be administered via subcutaneous injection, resulting in poor patient compliance. The development of non-peptide small molecule GLP-1 receptor agonists to improve patient compliance is of great significance and has become a research hotspot in the field of diabetes.

[0005] Summary of the Invention

[0006] The present application provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0007] in,

[0008] X 1 、X 2 are independently selected from C or N;

[0009] Y 1 、Y2 、Y 3 or Y 4 are independently selected from CH, C or N;

[0010] R 1 Selected from C 11-15 Cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, 11-15 membered heterocyclic group, the C 11-15 Cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, 11-15 membered heterocyclic group is a tricyclic ring, the C 11-15 Cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, 11-15 membered heterocyclic group may be optionally independently replaced by one or more R a replace;

[0011] Or, R 1 Selected from C 3-7 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered heterocyclic group, said R 1 By a C 2-4 Alkynyl substitution, R 1 further optionally independently represented by one or more R a Substitute, the C 2-4 The alkynyl group may be optionally substituted with one or more R b replace;

[0012] Each R a are independently selected from deuterium, halogen, =O, deuterated C 1-6 Alkyl, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the deuterated C 1-6 Alkyl, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 The alkylene group is optionally independently replaced by one or more R c1 Substitution; said C 3-6Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R d1 replace;

[0013] Each R 2 are independently selected from halogen, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 The alkylene group is optionally independently replaced by one or more R c2 Substitution; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R d2 replace;

[0014] Alternatively, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms C 4-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic group, the C 4-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-6 membered heterocyclyl are optionally independently substituted by one or more R d3 replace;

[0015] Each R 3 are independently selected from deuterium, halogen, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 The alkylene group is optionally independently replaced by one or more R c3 Substitution; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R d4 replace;

[0016] R 4 Selected from H, deuterium, halogen, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylene, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 The alkylene group is optionally independently replaced by one or more R c4 replace;

[0017] Each R 5 are independently selected from halogen, -CN, -OH, -SH, -NH2, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl, the C 1-6 Alkyl NH-, (C 1-6Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 The alkyl group is optionally independently substituted with one or more R c5 replace;

[0018] R' and R" are independently selected from H, halogen, -CN, -OH, -SH, -NH2, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 The alkyl group is optionally independently substituted with one or more R c6 replace;

[0019] Alternatively, R' and R" together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with one or more R d5 replace;

[0020] Each are independently selected from a single bond or a double bond;

[0021] Each R b are independently selected from deuterium, halogen, -CN, -OH, -NH2, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted independently with one or more substituents selected from deuterium, halogen, OH, CN or NH2;

[0022] Each R c1 、R c2 、R c3 、R c4 、R c5 and R c6 are independently selected from deuterium, halogen, -CN, -OH or -NH2;

[0023] Each R d1 、R d2 、R d3 、R d4 and R d5 are independently selected from deuterium, halogen, -CN, -OH, =O, -NH2, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted independently with one or more substituents selected from deuterium, halogen, OH, CN or NH2;

[0024] q is selected from 0, 1, 2, 3 or 4;

[0025] n is selected from 0, 1, 2, 3 or 4;

[0026] m is selected from 0, 1, 2, 3 or 4.

[0027] In some embodiments, "substituted with one or more" is each independently selected from 1, 2, 3, 4, 5, or 6 substitutions.

[0028] In some embodiments, "substituted by one or more" is each independently selected from 1, 2, 3, 4, or 5 substitutions.

[0029] In some embodiments, "substituted by one or more" is each independently selected from 1, 2, 3, or 4 substitutions.

[0030] In some embodiments, "substituted by one or more" is each independently selected from substituted by 1, 2, or 3.

[0031] In some embodiments, the "hetero" in the heteroaryl or heterocyclyl group is each independently selected from oxygen, sulfur and nitrogen heteroatoms, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), and the sulfur atom is optionally oxidized to S(O) or S(O)2, and other variables are as defined herein.

[0032] In some embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spiro bicyclic ring, or a monocyclic bridged bicyclic ring.

[0033] In some embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring or a monocyclic spiro bicyclic ring.

[0034] In some embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spiro bicyclic ring, or a monocyclic bridged bicyclic ring, wherein the monocyclic ring and the structural unit connected.

[0035] In some embodiments, the aromatic ring in the tricyclic ring and the structural unit connected.

[0036] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spiro bicyclic ring or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is an aromatic ring, and the monocyclic ring and the structural unit connected.

[0037] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spiro bicyclic ring or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is a benzene ring or a 5-6 membered heteroaromatic ring, and the monocyclic ring and the structural unit connected.

[0038] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spiro bicyclic ring or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 N atoms, and the monocyclic ring and the structural unit connected.

[0039] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spiro bicyclic ring or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is a benzene ring or a 6-membered heteroaromatic ring containing 1-2 N atoms, and the monocyclic ring and the structural unit connected.

[0040] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spiro bicyclic ring or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, and the monocyclic ring and the structural unit connected.

[0041] In other embodiments, the tricyclic ring is selected from a monocyclic fused bicyclic ring, a monocyclic spiro bicyclic ring or a monocyclic bridged bicyclic ring, wherein the monocyclic ring is a benzene ring or a pyridine ring, and the monocyclic ring and the structural unit connected.

[0042] In this application, R 1 Neutral structural unit When the connected rings are aromatic, R 1 is defined as an aryl or heteroaryl group.

[0043] In some embodiments, R 1 Selected from C 11-15 Aryl or 11-15 membered heteroaryl, the C 11-15 The aryl or 11-15 membered heteroaryl is a tricyclic ring, wherein the C 11-15 Aryl or 11-15 membered heteroaryl may be optionally independently substituted with one or more R a replace.

[0044] In some embodiments, R 1 Selected from Benzo C 7-11 Fused bicycloalkyl, benzo 7-11 membered fused biheterocyclic group, benzo 7-11 membered fused biheteroaryl, pyrido C 7-11 Fused bicycloalkyl, pyrido 7-11 membered fused biheterocyclic group, pyrido 7-11 membered fused biheteroaryl, pyrimido C 7-11 Fused bicycloalkyl, pyrimido 7-11 membered fused biheterocyclic group, pyrimido 7-11 membered fused biheteroaryl, pyridazinone C 7-11 Fused bicycloalkyl, pyridazine 7-11 membered fused biheterocycloalkyl, pyridazine 7-11 membered fused biheteroaryl, pyrazine C 7-11 Fused bicycloalkyl, pyrazino 7-11 membered fused biheterocycloalkyl, pyrazino 7-11 membered fused biheteroaryl, benzo C 7-11 Spirobicycloalkyl, benzo C 7-11 Spirobiheterocyclic, pyridoC 7-11 Spirobicycloalkyl, pyrido C 7-11 Spirobiheterocyclic, pyrimidoC 7-11 Spirobicycloalkyl, pyrimido C 7-11 Spirobiheterocyclic, pyridazinyl 7-11 Spirobicycloalkyl, pyridazinone C 7-11 Spirobiheterocyclic group, pyrazino C 7-11 Spirobicycloalkyl or pyrazinoC 7-11 Spirobiheterocyclic group, the R 1 may be optionally independently replaced by one or more R a replace.

[0045] In some embodiments, R 1 Selected from Benzo C 7-9 Fused bicycloalkyl, benzo 7-9 membered fused biheterocyclic group, benzo 7-9 membered fused biheteroaryl, pyrido C 7-9 Fused bicycloalkyl, pyrido 7-9 membered fused biheterocyclic group, pyrido 7-9 membered fused biheteroaryl, pyrimido C 7-9Fused bicycloalkyl, pyrimido 7-9 membered fused biheterocyclic group, pyrimido 7-9 membered fused biheteroaryl, pyridazinone C 7-9 Fused bicycloalkyl, pyridazine 7-9 membered fused biheterocycloalkyl, pyridazine 7-9 membered fused biheteroaryl, pyrazine C 7-9 Fused bicycloalkyl, pyrazino 7-9 membered fused biheterocycloalkyl, pyrazino 7-9 membered fused biheteroaryl, benzo C 7-9 Spirobicycloalkyl, benzo C 7-9 Spirobiheterocyclic, pyridoC 7-9 Spirobicycloalkyl, pyrido C 7-9 Spirobiheterocyclic, pyrimidoC 7-9 Spirobicycloalkyl, pyrimido C 7-9 Spirobiheterocyclic, pyridazinyl 7-9 Spirobicycloalkyl, pyridazinone C 7-9 Spirobiheterocyclic group, pyrazino C 7-9 Spirobicycloalkyl or pyrazinoC 7-9 Spirobiheterocyclic group, the R 1 may be optionally independently replaced by one or more R a replace.

[0046] In some embodiments, R 1 Selected from benzo 7-9 membered fused diheterocyclic group, benzo 7-9 membered fused diheteroaryl group, benzo C 7-9 Spirobicycloalkyl, benzo C 7-9 Spirobiheterocyclic or pyridoC 7-9 Spirobicycloalkyl, the R 1 may be optionally independently replaced by one or more R a replace.

[0047] In some embodiments, R 1 Selected from benzo 7-9 membered fused diheterocyclic group, benzo 7-9 membered fused diheteroaryl group, benzo C 7-9 Spirobicycloalkyl, benzo C 7-9 Spirobiheterocyclic or pyridoC 7-9 Spirobicycloalkyl, the R 1 Neutral structural unit The connected ring is a benzene ring or a pyridine ring; the R 1 may be optionally independently replaced by one or more R a replace.

[0048] In some embodiments, R 1 Selected from benzo 7-9 membered fused diheterocyclic group, benzo C 7-9 Spirobicycloalkyl or benzo C 7-9 Spirobiheterocyclic group, the R 1 may be optionally independently replaced by one or more R a replace.

[0049] In some embodiments, R 1 Selected from benzo 7-9 membered fused diheterocyclic group, benzo C 7-9 Spirobicycloalkyl or benzo C 7-9 Spirobiheterocyclic group, the R 1 Neutral structural unit The connected ring is a benzene ring; the R 1 may be optionally independently replaced by one or more R a replace.

[0050] In some embodiments, R 1Selected from benzo 5-membered cycloalkyl fused 3-membered cycloalkyl, benzo 5-membered cycloalkyl fused 4-membered cycloalkyl, benzo 5-membered cycloalkyl fused 5-membered cycloalkyl, benzo 6-membered cycloalkyl fused 4-membered cycloalkyl, benzo 6-membered cycloalkyl fused 5-membered cycloalkyl, benzo 5-membered cycloalkyl fused 3-membered heterocyclic group, benzo 5-membered cycloalkyl fused 4-membered heterocyclic group, benzo 5-membered cycloalkyl fused 5-membered heterocyclic group, benzo 6-membered cycloalkyl fused 4-membered heterocyclic group, benzo 6-membered cycloalkyl fused 5-membered heterocyclic group, benzo 5-membered heterocyclic group condensed 3-membered cycloalkyl, benzo 5-membered heterocyclic group condensed 4-membered cycloalkyl, benzo 5-membered heterocyclic group condensed 5-membered cycloalkyl, benzo 6-membered heterocyclic group condensed 4-membered cycloalkyl, benzo 6-membered heterocyclic group condensed 5-membered cycloalkyl, benzo 5-membered heterocyclic group condensed 3-membered heterocyclic group, benzo 5-membered heterocyclic group condensed 4-membered heterocyclic group, benzo 5-membered heterocyclic group condensed 5-membered heterocyclic group, benzo 6-membered heterocyclic group condensed 4-membered heterocyclic group, benzo 6-membered heterocyclic group condensed 5-membered heterocyclic group, benzo 5-membered heteroaryl condensed 3-membered cycloalkyl, benzo 5-membered heteroaryl fused 4-membered cycloalkyl, 5-membered heteroaryl fused 5-membered cycloalkyl, 5-membered heteroaryl fused 6-membered cycloalkyl, 6-membered heteroaryl fused 4-membered cycloalkyl, 6-membered heteroaryl fused 5-membered cycloalkyl, 5-membered heteroaryl fused 3-membered heterocyclic group, 5-membered heteroaryl fused 4-membered heterocyclic group, 5-membered heteroaryl fused 5-membered heterocyclic group, 5-membered heteroaryl fused 6-membered heterocyclic group, 6-membered heteroaryl fused 4-membered heterocyclic group, 6-membered heteroaryl fused 5-membered heterocyclic group 6-membered heterocyclic group, benzo 5-membered cycloalkyl fused 5-membered heteroaryl, benzo 6-membered cycloalkyl fused 5-membered heteroaryl, benzo 5-membered cycloalkyl fused 6-membered heteroaryl, benzo 5-membered heterocyclic group fused 5-membered heteroaryl, benzo 6-membered heterocyclic group fused 5-membered heteroaryl, benzo 5-membered heterocyclic group fused 6-membered heteroaryl, pyrido 5-membered cycloalkyl fused 3-membered cycloalkyl, pyrido 5-membered cycloalkyl fused 4-membered cycloalkyl, pyrido 5-membered cycloalkyl fused 5-membered cycloalkyl, pyrido 6-membered cycloalkyl fused 4-membered cycloalkyl, Pyrido 6-membered cycloalkyl fused 5-membered cycloalkyl, pyrido 5-membered cycloalkyl fused 3-membered heterocyclic group, pyrido 5-membered cycloalkyl fused 4-membered heterocyclic group, pyrido 5-membered cycloalkyl fused 5-membered heterocyclic group, pyrido 6-membered cycloalkyl fused 4-membered heterocyclic group, pyrido 6-membered cycloalkyl fused 5-membered heterocyclic group, pyrido 5-membered heterocyclic group fused 3-membered cycloalkyl, pyrido 5-membered heterocyclic group fused 4-membered cycloalkyl, pyrido 5-membered heterocyclic group fused 5-membered cycloalkyl, pyrido 6-membered heterocyclic group fused 4-membered cycloalkyl, pyrido 6-membered heterocyclic group fused 5-membered cycloalkyl, pyrido 5-membered heterocyclic group fused 3-membered heterocyclic group, pyrido 5-membered heterocyclic group fused 4-membered heterocyclic group, pyrido 5-membered heterocyclic group pyrido 5-membered heterocyclic group, pyrido 6-membered heterocyclic group condensed 4-membered heterocyclic group, pyrido 6-membered heterocyclic group condensed 5-membered heterocyclic group, pyrido 5-membered heteroaryl condensed 3-membered cycloalkyl, pyrido 5-membered heteroaryl condensed 4-membered cycloalkyl, pyrido 5-membered heteroaryl condensed 5-membered cycloalkyl, pyrido 5-membered heteroaryl condensed 6-membered cycloalkyl, pyrido 6-membered heteroaryl condensed 4-membered cycloalkyl, pyrido 6-membered heteroaryl condensed 5-membered cycloalkyl, pyrido 5-membered heteroaryl condensed 3-membered heterocyclic group, pyrido 5-membered heteroaryl condensed 4-membered heterocyclic group, pyrido 5-membered heteroaryl condensed 5-membered heterocyclic group, pyrido 5-membered heteroaryl condensed 6-membered heterocyclic group, pyrido 6-membered heteroaryl condensed 4-membered heterocyclic group,pyrido 6-membered heteroaryl fused 5-membered heterocyclic group, pyrido 5-membered cycloalkyl fused 5-membered heteroaryl, pyrido 6-membered cycloalkyl fused 5-membered heteroaryl, pyrido 5-membered cycloalkyl fused 6-membered heteroaryl, pyrido 5-membered heterocyclic group fused 5-membered heteroaryl, pyrido 6-membered heterocyclic group fused 5-membered heteroaryl, pyrido 5-membered heterocyclic group fused 6-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 5-membered cycloalkyl, benzo 6-membered cycloalkyl spiro 4-membered cycloalkyl, benzo 6-membered cycloalkyl spiro 5-membered cycloalkyl, benzo 5-membered Cycloalkyl spiro 3-membered heterocyclic group, benzo 5-membered cycloalkyl spiro 4-membered heterocyclic group, benzo 5-membered cycloalkyl spiro 5-membered heterocyclic group, benzo 6-membered cycloalkyl spiro 4-membered heterocyclic group, benzo 6-membered cycloalkyl spiro 5-membered heterocyclic group, benzo 5-membered heterocyclic spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic spiro 4-membered cycloalkyl, benzo 5-membered heterocyclic spiro 5-membered cycloalkyl, benzo 6-membered heterocyclic spiro 4-membered cycloalkyl, benzo 6-membered heterocyclic spiro 5-membered cycloalkyl, benzo 5-membered heterocyclic spiro 3-membered heterocyclic group, benzo 5-membered heterocyclic spiro 4-membered heterocyclic group, benzo 5-membered heterocyclic spiro 5-membered heterocyclic group, benzo 6-membered heterocyclyl spiro 4-membered heterocyclyl, benzo 6-membered heterocyclyl spiro 5-membered heterocyclyl, benzo 5-membered heteroaryl spiro 3-membered cycloalkyl, pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, pyrido 5-membered cycloalkyl spiro 4-membered cycloalkyl, pyrido 5-membered cycloalkyl spiro 5-membered cycloalkyl, pyrido 6-membered cycloalkyl spiro 4-membered cycloalkyl, pyrido 6-membered cycloalkyl spiro 5-membered cycloalkyl, pyrido 5-membered cycloalkyl spiro 3-membered heterocyclyl, pyrido 5-membered cycloalkyl spiro 4-membered heterocyclyl, pyrido 5-membered cycloalkyl spiro 5-membered heterocyclyl, pyrido 6-membered cycloalkyl spiro 4-membered heterocyclyl ... pyrido 5-membered heterocyclyl spiro 3-membered cycloalkyl, pyrido 5-membered heterocyclyl spiro 4-membered cycloalkyl, pyrido 5-membered heterocyclyl spiro 5-membered cycloalkyl, pyrido 6-membered heterocyclyl spiro 4-membered cycloalkyl, pyrido 6-membered heterocyclyl spiro 5-membered cycloalkyl, pyrido 5-membered heterocyclyl spiro 3-membered heterocyclyl, pyrido 5-membered heterocyclyl spiro 4-membered heterocyclyl, pyrido 5-membered heterocyclyl spiro 5-membered heterocyclyl, pyrido 6-membered heterocyclyl spiro 4-membered heterocyclyl, pyrido 6-membered heterocyclyl spiro 5-membered heterocyclyl or pyrido 5-membered heteroaryl spiro 3-membered cycloalkyl, wherein R, 1 may be optionally independently replaced by one or more R a replace.

[0051] In other embodiments, R 1 is selected from benzo 5-membered heteroaryl fused 5-membered heterocyclic group, benzo 5-membered heteroaryl fused 6-membered heterocyclic group, benzo 5-membered heterocyclic group fused 5-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic group spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic group spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered heterocyclic group, pyrido 5-membered heteroaryl fused 5-membered cycloalkyl or pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, wherein R 1 may be optionally independently replaced by one or more R a replace.

[0052] In other embodiments, R 1 is selected from benzo 5-membered heteroaryl fused 5-membered heterocyclic group, benzo 5-membered heteroaryl fused 6-membered heterocyclic group, benzo 5-membered heterocyclic group fused 5-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic group spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic group spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered heterocyclic group, pyrido 5-membered heteroaryl fused 5-membered cycloalkyl or pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, wherein R 1 Neutral structural unit The connected ring is a benzene ring or a pyridine ring; the R 1 may be optionally independently replaced by one or more R a replace.

[0053] In some embodiments, R 1 is selected from benzo 5-membered heteroaryl fused 5-membered cycloalkyl, benzo 5-membered heteroaryl fused 5-membered heterocyclyl, benzo 5-membered heteroaryl fused 6-membered heterocyclyl, benzo 5-membered heterocyclyl fused 5-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered heterocyclyl or pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, wherein R 1 may be optionally independently replaced by one or more R a replace.

[0054] In some embodiments, R 1 is selected from benzo 5-membered heteroaryl fused 5-membered cycloalkyl, benzo 5-membered heteroaryl fused 5-membered heterocyclyl, benzo 5-membered heteroaryl fused 6-membered heterocyclyl, benzo 5-membered heterocyclyl fused 5-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered heterocyclyl or pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, wherein R 1 Neutral structural unit The connected ring is a benzene ring or a pyridine ring; the R 1 may be optionally independently replaced by one or more R a replace.

[0055] In some embodiments, R 1 is selected from benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl or benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, wherein R 1 may be optionally independently replaced by one or more R a replace.

[0056] In some embodiments, R 1 is selected from benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl or benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, wherein R 1 Neutral structural unit The connected ring is a benzene ring; the R 1 may be optionally independently replaced by one or more R a replace.

[0057] In some embodiments, R 1 Selected from The R 1 may be optionally independently replaced by one or more R a replace.

[0058] In some embodiments, R 1 Selected from The R 1 may be optionally independently replaced by one or more R a In other embodiments, R 1 Selected from The R 1 may be optionally independently replaced by one or more R a replace.

[0059] In some embodiments, R 1 Selected from The R 1 may be optionally independently replaced by one or more R a replace.

[0060] In other embodiments, R 1 Selected from The R 1 may be optionally independently replaced by one or more R a replace.

[0061] In other embodiments, R 1 Selected from The R 1 may be optionally independently replaced by one or more R a replace.

[0062] In some embodiments, R 1 is selected from phenyl or 5-6 membered heteroaryl, said R 1 By a C 2-4 Alkynyl substitution, R 1 further optionally independently represented by one or more R a Substitute, the C 2-4 The alkynyl group may be optionally substituted with one or more R b replace.

[0063] In some embodiments, R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein R 1 By a C 2-4 Alkynyl substitution, R 1 further optionally independently represented by one or more R a Substitute, the C 2-4 The alkynyl group may be optionally substituted with one or more R b replace.

[0064] In some embodiments, R 1 is selected from phenyl or pyridyl, said R 1 By a C 2-4 Alkynyl substitution, R 1 further optionally independently represented by one or more R a Substitute, the C 2-4 The alkynyl group may be optionally substituted with one or more R b replace.

[0065] In some embodiments, R 1 is selected from phenyl or pyridyl, said R 1 is substituted by an ethynyl or propynyl group, R 1 further optionally independently represented by one or more R a Substituted, the ethynyl or propynyl group may be optionally replaced by one or more R b replace.

[0066] In some embodiments, R 1 is selected from phenyl or pyridyl, said R 1 is substituted by an ethynyl or 1-propynyl group, R 1 further optionally independently represented by one or more R a Substituted, the ethynyl or propynyl group may be optionally replaced by one or more R b replace.

[0067] In some embodiments, each R a are independently selected from halogen, =O, deuterated C 1-5 Alkyl, -OH, -CN, NH2, C 1-5 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-5 Alkoxy, C 1-5 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the deuterated C 1-5 Alkyl, C 1-5 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C1-5 Alkoxy or C 1-5 Alkoxy C 1-3 The alkylene group is optionally independently replaced by one or more R c1 Substitution; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R d1 replace.

[0068] In some embodiments, each R a are independently selected from halogen, =O, deuterated C 1-3 Alkyl, -OH, -CN, NH2, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl or 3-5 membered heterocyclic group, the deuterated C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy or C 1-3 The alkoxymethylene groups are optionally independently substituted with one or more R c1 Substituted; the cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl or 3-5 membered heterocyclic group is optionally independently replaced by one or more R d1 replace.

[0069] In some embodiments, each R a are independently selected from halogen, =O, deuterated C 1-3 Alkyl, C 1-3 Alkyl or C 3-6 Cycloalkyl, the deuterated C 1-3 Alkyl or C 1-3 The alkyl group is optionally independently substituted with one or more R c1 Substitution; said C 3-6 Cycloalkyl is optionally independently substituted with one or more R d1 replace.

[0070] In some embodiments, each R aare independently selected from F, Cl, Br, I, =O, -CD3, -C2D5, -OH, -CN, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, methoxymethylene, ethoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl or phenyl, and the methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, methoxymethylene or ethoxymethylene is optionally and independently replaced by one or more R c1 Substituted; the cyclopropyl, cyclobutyl, cyclopentyl or phenyl group is optionally independently replaced by one or more R d1 replace.

[0071] In some embodiments, each R a are independently selected from F, Cl, Br, I, =O, -CD3, -C2D5, -OH, -CN, methyl, ethyl, propyl, methoxymethylene, ethoxymethylene, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, propyl, methoxymethylene or ethoxymethylene is optionally and independently replaced by one or more R c1 Substituted; the cyclopropyl, cyclobutyl or cyclopentyl are optionally independently replaced by one or more R d1 replace.

[0072] In some embodiments, each R a are independently selected from F, Cl, Br, =O, -CD3, -C2D5, methyl, ethyl, propyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl and propyl groups are optionally independently replaced by one or more R c1 Substituted; the cyclopropyl, cyclobutyl or cyclopentyl are optionally independently replaced by one or more R d1 replace.

[0073] In some embodiments, each R a Each is independently selected from F, methyl, =O, -CD3 or cyclopropyl.

[0074] In some embodiments, each R a are independently selected from methyl or =0.

[0075] In some embodiments, each R a are independently selected from F or methyl.

[0076] In some embodiments, R 1 Selected from The R 1 may be optionally substituted independently by 1, 2 or 3 substituents selected from F, methyl, =O, -CD3 or cyclopropyl. 1Selected from The R 1 It may be optionally substituted independently with 1, 2 or 3 substituents selected from F, methyl, =0, -CD3 or cyclopropyl.

[0077] In other embodiments, R 1 Selected from The R 1 It may be optionally substituted independently with 1, 2 or 3 substituents selected from F, methyl, =0, -CD3 or cyclopropyl.

[0078] In other embodiments, R 1 Selected from The R 1 It may be optionally substituted independently with 1, 2 or 3 substituents selected from F, methyl, =0, -CD3 or cyclopropyl.

[0079] In some embodiments, R 1 Selected from In other embodiments, R 1 Selected from

[0080] In some embodiments, R 1 Selected from

[0081] In other embodiments, R 1 Selected from

[0082] In other embodiments, R 1 Selected from

[0083] In some embodiments, each R b Each is independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally substituted independently with one or more substituents selected from deuterium, halogen, OH, CN or NH2.

[0084] In some embodiments, each R b Each independently selected from C 1-3 Alkoxy, the C 1-3 Alkoxy groups are optionally substituted independently with one or more substituents selected from deuterium, halogen, OH, CN or NH2.

[0085] In some embodiments, each R b are independently selected from F, Cl, Br, I or methoxy.

[0086] In some embodiments, each R b are independently selected from methoxy.

[0087] In some embodiments, R 1 is selected from phenyl or pyridyl, said R 1 is substituted by an ethynyl or propynyl group, R 1 Further optionally independently substituted by 1, 2 or 3 substituents selected from F or methyl, the ethynyl or propynyl group may be optionally substituted by 1, 2 or 3 methoxy groups.

[0088] In some embodiments, R 1 is selected from phenyl or pyridyl, said R 1 is substituted by a 1-propynyl group, R 1 Further optionally independently substituted with 1, 2 or 3 F, the 1-propynyl group may be optionally substituted with 1 methoxy group.

[0089] In some embodiments, R 1 Selected from

[0090] In some embodiments, R 1 Selected from

[0091] In some embodiments, each R 2 are independently selected from halogen, -OH, -CN, C 1-5 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-5 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-5 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-5 Alkoxy is optionally independently substituted with one or more R c2 Substitution; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R d2 replace.

[0092] In some embodiments, each R 2 are independently selected from halogen, -OH, -CN, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 3-5Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-5 membered heterocyclic group, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-3 Alkoxy is optionally independently substituted with one or more R c2 Substitution; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R d2 replace.

[0093] In some embodiments, each R 2 are independently selected from halogen, C 1-3 Alkyl, or C 3-5 Cycloalkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c2 Substitution; said C 3-6 Cycloalkyl is optionally independently substituted with one or more R d2 replace.

[0094] In some embodiments, each R 2 are independently selected from F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl or cyclopentyl, and the methyl, ethyl or propyl group is optionally independently replaced by one or more R c2 Substituted; the cyclopropyl, cyclobutyl or cyclopentyl are optionally independently replaced by one or more R d2 replace.

[0095] In some embodiments, each R 2 are independently selected from F, methyl or cyclopropyl, the methyl group being optionally independently replaced by one or more R c2 Substituted; the cyclopropyl group is optionally independently replaced by one or more R d2 replace.

[0096] In some embodiments, each R 2 are independently selected from F, methyl or cyclopropyl.

[0097] In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, the C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl are optionally independently substituted by one or more R d3 replace.

[0098] In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms C 5-6Cycloalkyl or 5-6 membered heterocyclic group, the C 5-6 Cycloalkyl or 5-6 membered heterocyclic group is optionally independently substituted by one or more R d3 replace.

[0099] In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms C 5-6 Cycloalkyl, the C 5-6 Cycloalkyl is optionally independently substituted with one or more R d3 replace.

[0100] In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms a cyclopentyl, pyrrolyl, tetrahydrofuranyl or tetrahydrothienyl group, wherein the cyclopentyl, pyrrolyl, tetrahydrofuranyl or tetrahydrothienyl group is optionally independently replaced by one or more R d3 In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms a cyclopentyl group, which is optionally independently substituted with one or more R d3 replace.

[0101] In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms a cyclopentyl group.

[0102] In this application, R on two adjacent carbon atoms 2 It should be understood that the structural unit formed by forming a cyclopentyl group together with the carbon atom to which it is connected is R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it is understood that the structural unit formed is

[0103] In some embodiments, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms a cyclopentyl group, and the resulting structural unit is

[0104] In some embodiments, q is selected from 0, 1, 2, or 3.

[0105] In some embodiments, q is selected from 1, 2, or 3.

[0106] In some embodiments, q is selected from 2.

[0107] In some embodiments, q is selected from 3.

[0108] In some embodiments, the structural unit Selected from

[0109] In some embodiments, the structural unit Selected from

[0110] In some embodiments, the structural unit Selected from

[0111] In some embodiments, the structural unit Selected from

[0112] In some embodiments, the structural unit Selected from

[0113] In some embodiments, the structural unit Selected from

[0114] In some embodiments, X 1 、X 2 One of them is selected from C, and the other is selected from N.

[0115] In some embodiments, the structural unit Selected from

[0116] In some embodiments, the structural unit Selected from

[0117] In some embodiments, Y 1 、Y 2 、Y 3 are independently selected from C or N, Y 4 Selected from CH.

[0118] In some embodiments, Y 1 、Y 2 、Y 3 At least one selected from N, Y 4 Selected from CH.

[0119] In some embodiments, Y 1 Selected from C, Y 2 Selected from N, Y 3 Selected from C, Y 4 Selected from CH.

[0120] In some embodiments, Y 1 Selected from C, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from CH.

[0121] In some embodiments, Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from C, Y 4 Selected from CH.

[0122] In some embodiments, the structural unit Selected from

[0123] In some embodiments, the structural unit Selected from

[0124] In some embodiments, each R 3 are independently selected from deuterium, halogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl groups are optionally independently substituted with one or more R c3 Substitution; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R d4 replace.

[0125] In some embodiments, each R 3 are independently selected from deuterium, halogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c3 replace.

[0126] In some embodiments, each R 3 are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c3 replace.

[0127] In some embodiments, each R 3 are independently selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl or propyl group is optionally independently replaced by one or more R c3 Substituted; the cyclopropyl, cyclobutyl or cyclopentyl are optionally independently replaced by one or more R d4 replace.

[0128] In some embodiments, each R 3 are independently selected from methyl, ethyl or propyl, and the methyl, ethyl or propyl group is optionally replaced by one or more R c3 replace.

[0129] In some embodiments, the R 3 Selected from methyl.

[0130] In some embodiments, n is selected from 0, 1, 2, or 3.

[0131] In some embodiments, n is selected from 1, 2, or 3.

[0132] In some embodiments, n is selected from 1.

[0133] In some embodiments, R 4 Selected from H, deuterium, halogen, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy is optionally independently substituted with one or more R c4 replace.

[0134] In some embodiments, R 4 Selected from H or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c4 replace.

[0135] In some embodiments, R 4 is selected from H or methyl, said methyl being optionally replaced by one or more R c4 replace.

[0136] In some embodiments, R 4 Selected from H or methyl.

[0137] In some embodiments, R 4 Selected from H.

[0138] In some embodiments, R 4 Selected from methyl.

[0139] In some embodiments, R 5 Selected from halogen, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3Alkoxy is optionally independently substituted with one or more R c5 replace.

[0140] In some embodiments, R 5 Selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c5 replace.

[0141] In some embodiments, R 5 Selected from methyl.

[0142] In some embodiments, m is selected from 0, 1, 2, or 3.

[0143] In some embodiments, m is selected from 0, 1 or 2.

[0144] In some embodiments, m is selected from 0.

[0145] In some embodiments, m is selected from 1.

[0146] In some embodiments, R' and R" are each independently selected from H, deuterium, halogen, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy is optionally independently substituted with one or more R c6 replace.

[0147] In some embodiments, R' and R" are each independently selected from H or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c6 replace.

[0148] In some embodiments, R' and R" are each independently selected from H or methyl, the methyl group being optionally replaced by one or more R c6 replace.

[0149] In some embodiments, R' and R" are both selected from methyl.

[0150] In some embodiments, R' and R" together with the carbon atom to which they are attached form C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl is optionally independently substituted with one or more R d5 replace.

[0151] In some embodiments, R' and R" together with the carbon atom to which they are attached form a cyclopropyl group, which is optionally independently replaced by one or more R d5 replace.

[0152] In some embodiments, R' and R" together with the carbon atom to which they are attached form a cyclopropyl group.

[0153] In some embodiments, each R c1 、R c2 、R c3 、R c4 、R c5 and R c6 are independently selected from halogen, -CN, -OH or -NH2.

[0154] In some embodiments, each R c1 、R c2 、R c3 、R c4 、R c5 and R c6 are independently selected from F, -CN, -OH or -NH2.

[0155] In some embodiments, each R c1 、R c2 、R c3 、R c4 、R c5 and R c6 are independently selected from F or OH.

[0156] In some embodiments, each R c1 、R c2 、R c3 、R c4 、R c5 and R c6 are independently selected from F.

[0157] In some embodiments, each R d1 、R d2 、R d3 、R d4 and R d5 are independently selected from halogen, -CN, -OH, -NH2, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 Alkoxy groups are optionally substituted independently with one or more substituents selected from halogen, OH, CN or NH2.

[0158] In some embodiments, each R d1 、R d2 、R d3、R d4 and R d5 Each is independently selected from F, -CN, -OH, -NH2, methyl or methoxy, and the methyl or methoxy is optionally substituted independently with one or more substituents selected from F, OH, CN or NH2.

[0159] In some embodiments, each R d1 、R d2 、R d3 、R d4 and R d5 Each is independently selected from F, -CN, -OH, -NH2, methyl or methoxy.

[0160] In some embodiments, each R d1 、R d2 、R d3 、R d4 and R d5 are independently selected from F or methyl.

[0161] In some embodiments, each R d1 、R d2 、R d3 、R d4 and R d5 are independently selected from F.

[0162] The compound of formula (I) of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (IA), (IB), (IC) or (ID), its stereoisomer or pharmaceutically acceptable salt thereof,

[0163] Among them, R 1 、R 2 、R 3 、R 4 、R 5 , R', R", q, n or m are as defined for the compound of formula (I).

[0164] The compound of formula (I) of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-J), (II-K) or (II-L), its stereoisomer or pharmaceutically acceptable salt thereof,

[0165] in, R 1 、R 2 、R 3 、R4 、R 5 , R′, R", R a , q, n or m are as defined for the compound of formula (I);

[0166] r is selected from 0, 1, 2, 3 or 4;

[0167] X is selected from C or N;

[0168] X 3 、X 4 、X 5 or X 6 are independently selected from C or N;

[0169] X 7 、X 8 、X 9 、X 10 or X 11 are independently selected from C, CH or N.

[0170] In some embodiments, X is selected from C. In some embodiments, X is selected from N.

[0171] In some embodiments, X 3 Selected from N, X 4 、X 5 or X 6 are independently selected from C or N.

[0172] In some embodiments, X 3 、X 6 Selected from N, X 4 、X 5 Selected from C.

[0173] In some embodiments, X 3 、X 4 Selected from N, X 5 、X 6 Selected from C.

[0174] In some embodiments, X 7 and X 11 One of them is selected from N, and the other is selected from C.

[0175] In some embodiments, X 7 and X 9 Selected from N, X 11 Selected from C, X 8 and X 10 Selected from CH.

[0176] In some embodiments, r is selected from 0, 1 or 2.

[0177] In some embodiments, r is selected from 0 or 2.

[0178] The present application also provides a compound of formula (I'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0179] Among them, X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、 R 1 、R 2 、R 3 、R 4 、R 5 , R', R", q, n or m are as defined for the compound of formula (I).

[0180] The compound of formula (I) of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (I-A'), (I-B'), (I-C') or (I-D'), its stereoisomer or pharmaceutically acceptable salt thereof,

[0181] Among them, R 1 、R 2 、R 3 、R 4 、R 5 , R', R", q, n or m are as defined for the compound of formula (I).

[0182] The compound of formula (I) of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (II-A'), (II-B'), (II-C'), (II-D'), (II-E'), (II-F'), (II-G'), (II-H'), (II-I'), (II-J'), (II-K') or (II-L'), its stereoisomer or pharmaceutically acceptable salt thereof,

[0183] in, R 1 、R 2 、R 3 、R 4 、R 5 , R′, R", R a , q, n or m are as defined for the compound of formula (I);

[0184] r is selected from 0, 1, 2, 3 or 4;

[0185] X is selected from C or N;

[0186] X 3 、X 4 、X 5 or X 6 are independently selected from C or N;

[0187] X 7 、X 8 、X 9 、X 10 or X 11 are independently selected from C, CH or N.

[0188] In some embodiments, X, X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 or X 11 The definitions of are as described above for the compounds of formula (II-D), (II-F) and (II-J).

[0189] The compound of formula (I) of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (III-A), its stereoisomer or pharmaceutically acceptable salt thereof,

[0190] Among them, X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、 R 1 、R 2 、R 3 、R 4 、R 5 , R′, R″ and q are as defined for the compound of formula (I).

[0191] The compound of formula (I) of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (III-A'), formula (III-B') or formula (III-C'), its stereoisomer or pharmaceutically acceptable salt thereof,

[0192] Among them, X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、 R1 、R 2 、R 3 、R 4 、R 5 , R′, R″ and q are as defined for the compound of formula (I).

[0193] The compound of formula (I) of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (IV-A), its stereoisomer or pharmaceutically acceptable salt thereof,

[0194] Among them, X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、 R 1 、R 2 、R 3 、R 4 , R′, R″ and q are as defined for the compound of formula (I).

[0195] The compound of formula (I) of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (IV-A'), formula (IV-B') or formula (IV-C'), its stereoisomer or pharmaceutically acceptable salt thereof,

[0196] Among them, X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、 R 1 、R 2 、R 3 、R 4 , R′, R″ and q are as defined for the compound of formula (I).

[0197] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0198] In another aspect, the present disclosure provides the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0199] On the other hand, the present disclosure also provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0200] On the other hand, the present disclosure also provides a method for treating various GLP-1 related diseases, comprising administering a therapeutically effective amount of the above-mentioned compound of the present disclosure, its stereoisomers, its pharmaceutically acceptable salts or pharmaceutical compositions thereof to a mammal, preferably a human, in need of such treatment.

[0201] On the other hand, the present disclosure also provides the use of the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of drugs for treating various GLP-1 related diseases.

[0202] On the other hand, the present disclosure also provides uses of the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment of various GLP-1 related diseases.

[0203] On the other hand, the present disclosure also provides the above-mentioned compound of the present disclosure, its stereoisomers, its pharmaceutically acceptable salts, or pharmaceutical compositions thereof for treating various GLP-1 related diseases.

[0204] In some embodiments, the GLP-1 related diseases are selected from diabetes or obesity.

[0205] The compounds disclosed herein have good in vitro and in vivo agonist activity (eg, GLP-1 enzyme agonist activity in vitro) and metabolic stability (eg, liver microsomal metabolic stability) related to GLP-1.

[0206] definition

[0207] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0208] When a covalent bond in certain structural units or groups in the present disclosure is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group as long as it does not violate the valence bond connection rules.

[0209] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0210] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0211] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3 It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0212] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0213] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0214] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L' in A-L'-Z represents a covalent bond, it means that the structure is actually AZ.

[0215] When a substituent's bond crosses two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, the bonds on either side of Ring A may be bonded to any two different atoms on Ring A.

[0216] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0217] The term "alkyl" refers to a group of the formula C n H 2n+1 The hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The alkyl group may be straight or branched, for example, it may be "C 1-12 Alkyl" or "C 1-6 Alkyl" etc. For example, the term "C 1-12"Alkyl" refers to an alkyl group containing 1 to 12 carbon atoms, including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 and any combination of these. 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. For another example, the term "C 1-3 The term "alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).

[0218] The term "deuterated C 1-n "Alkyl" refers to an alkyl group substituted with 1 to 2n+1 deuterium atoms. The definition of alkyl is as described above. The maximum number of deuterium atoms that can be substituted depends on the maximum number of hydrogen atoms that can exist in the alkyl group itself. The position of substitution can be arbitrary. For example, the term "deuterated C 1-3 The term "alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl) substituted by 1 to 7 deuterium atoms, wherein the methyl group may be substituted by 1, 2 or 3 deuterium atoms; the ethyl group may be substituted by 1, 2, 3, 4 or 5 deuterium atoms; and the n-propyl and isopropyl groups may be substituted by 1, 2, 3, 4, 5, 6 or 7 deuterium atoms.

[0219] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms, for example, "C 2-12 Alkenyl" or "C 2-6 Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0220] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms, for example, "C 2-12 Alkynyl" or "C 2-6Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl (e.g., 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH)), butynyl (e.g., 1,3-butadiynyl (-C≡CC≡CH)), and the like.

[0221] The term "alkoxy" refers to an -O-alkyl group.

[0222] The term "alkylthio" refers to an -S-alkyl group.

[0223] The term "cycloalkyl" refers to a fully saturated or partially saturated cyclic hydrocarbon that can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, and the like. For example, C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl.

[0224] The term "heterocyclyl" refers to a non-aromatic or partially non-aromatic ring that is fully saturated or partially saturated and can exist as a monocyclic, bridged, fused or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 13-membered ring (e.g., a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered or 13-membered ring), a 10 to 13-membered ring, or an 11 to 13-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Non-limiting examples of heterocyclyl include, but are not limited to, spiro[cyclopropane-1,3'-dihydroindole]yl, 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazinyl, 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolyl, 1',3'-dihydrospiro[cyclopropane-1,2'-indene]yl, phenyl, pyridinyl, 1,3-dihydrospiro[indene-2 ,3'-oxetane] group, spiro[cyclobutane-1,3'-dihydroindole] group, spiro[cyclopropane-1,1'-isoindolinyl] group, spiro[cyclopenta[c]pyridine-5,1'-cyclopropane] group, spiro[cyclopropane-1,3'-indolyl] group, 5H-imidazo[5,1-a]isoindolyl or 2,3-dihydro-1H-cyclopenta[3,4]pyrazolo[1,5-a]pyridinyl, etc.

[0225] The term "aryl" refers to an aromatic carbocyclic group, and in addition to an aromatic moiety, it may include a non-aromatic moiety. The ring may be a monocyclic ring or a dicyclic or tricyclic ring formed by a phenyl ring and an aromatic moiety or a non-aromatic moiety. For example, an aryl group may have 6-20 carbon atoms, 6-15 carbon atoms, 6-14 carbon atoms, 6-12 or 6-11 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetralin, isochromanyl, 2,4-dihydro-1H-isoquinoline-3-one group or spirocyclic [cyclopropane-1,2'-indene]-1'(3'H)-one group.

[0226] The term "heteroaryl" refers to a monocyclic or polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring which may contain non-aromatic moieties in addition to the aromatic moiety. The ring may be a monocyclic ring or a bicyclic or tricyclic ring formed by a benzene ring or a monocyclic heteroaryl ring with an aromatic or non-aromatic moiety. Preferred heteroaryls have a single 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered) or multiple fused rings containing 6 to 15, in particular 6 to 12, ring atoms (e.g., 6, 7, 8, 9, 10, 11, or 12 ring atoms). Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, pyridopyrrolyl, or spiro[cyclopropane-1,3'-indolinyl]-2'-onyl.

[0227] The term "alkylene" refers to a divalent group formed by removing a hydrogen from any position of an alkyl group, for example, the term "C 1-3 "Alkylene" refers to an alkylene group containing 1 to 3 carbon atoms, including but not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-).

[0228] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0229] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed key

[0230] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.

[0231] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0232] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0233] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0234] The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0235] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0236] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0237] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0238] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0239] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0240] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0241] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F.123 I. 125 I and 36 Cl et al.

[0242] Certain isotopically-labeled compounds of the present disclosure (e.g., those labeled with 3H and 14C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0243] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of this disclosure.

[0244] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0245] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0246] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0247] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0248] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0249] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0250] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0251] The therapeutic dose of the disclosed compounds may depend on, for example, the specific use of the treatment, the manner in which the compound is administered, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compounds may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0252] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0253] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0254] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as the amino groups in the present disclosure). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0255] In some embodiments, the compounds of the present disclosure can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0256] This disclosure uses the following abbreviations:

[0257] Among them, R 1 、R 2 、R 3 、R 4 、R 5 ,q,X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 , R' or R" are as defined above, and Z is a leaving group, including but not limited to F, Cl, Br, I, etc.

[0258] This disclosure uses the following abbreviations:

[0259] NaHMDS stands for sodium bis(trimethylsilyl)amide; DCM stands for dichloromethane; and MeOH stands for methanol.

[0260] For the sake of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0261] Example 1

[0262] Step 1: Synthesis of intermediate 1-2

[0263] 5'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-dihydroindole]-2'-one (500 mg) and N,N-dimethylformamide (7 mL) were mixed. Sodium hydride (126 mg, 60% dispersion in mineral oil) was added under ice-cooling. The reaction was stirred for 30 minutes. Methyl iodide (0.055 mL) was added dropwise to the reaction mixture. The reaction mixture was transferred to room temperature and stirred for 1.5 hours. The reaction mixture was poured into a mixture of ethyl acetate (30 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 450 mg of intermediate 1-2.

[0264] MS (ESI, [M+H] + )m / z:252.05.

[0265] 1 H-NMR (500MHz, DMSO-d6): δ7.43 (dd, J=8.3, 2.0Hz, 1H), 7.28 (d, J=2.0Hz, 1H), 7 .03(d,J=8.2Hz,1H),3.20(s,3H),1.69(q,J=3.8Hz,2H),1.52(q,J=3.8Hz,2H).

[0266] Step 2: Synthesis of intermediate 1-3

[0267] A mixture of intermediate A-1 (250 mg), intermediate 1-2 (186 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (40.3 mg), potassium carbonate (235 mg), cuprous iodide (21.57 mg) and N-methylpyrrolidone (4 mL) was placed in an oil bath at 120°C under nitrogen protection and stirred overnight. The reaction solution was cooled to room temperature and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated, and purified by concentration column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 0.3 g of intermediate 1-3.

[0268] MS (ESI, [M+H] + )m / z:613.37.

[0269] 1H-NMR (500MHz, DMSO-d6): δ7.49 (dd, J=8.4, 2.2Hz, 1H), 7.24 (d, J=1.9Hz, 1H), 7 .15(t,J=5.9Hz,2H),7.10(d,J=6.3Hz,2H),6.91(s,1H),5.18-5.03(m,1H),4.3 7-4.13(m,1H),3.23(s,3H),3.19-3.06(m,1H),2.77-2.61(m,2H),2.19(d,J=1. 7Hz,6H),1.68-1.63(m,2H),1.58-1.53(m,2H),1.43(s,9H),1.22-1.18(m,3H).

[0270] Step 3: Synthesis of intermediate 1-4

[0271] Intermediate 1-3 (0.28 g), dichloromethane (2 mL), and 4N hydrochloric acid in dioxane solution (2 mL) were mixed and stirred at room temperature for 1 hour. Stirring was stopped and the mixture was concentrated under reduced pressure to obtain 0.24 g of intermediate 1-4.

[0272] MS (ESI, [M+H] + )m / z:513.1.

[0273] Step 6: Synthesis of Compound 1 and Compound 1-A

[0274] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.576 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.236 g) were stirred for 5 minutes, followed by the addition of Intermediate 1-4 (0.125 g) and the reaction was stirred at 30°C. The reaction solution was poured into water (50 mL), extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 95:5) to obtain Compound 1. Compound 1 was separated by chiral HPLC (column: REFLECT I-Cellulose B, 30×250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 25:75; flow rate: 40 mL / min) to obtain Compound 1-A (43 mg).

[0275] Compound 1-A: R t =1.34 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6×100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40°C)

[0276] HRMS: (ESI, [M+H] + )m / z:906.4130.

[0277] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.58-7.31(m,3H),7.30-7.03(m,6H),7.01 -6.68(m,2H),5.61-5.49(m,1H),4.46-4.29(m,1H),3.77-3.66(m,2H),3.66-3.58(m, 1H),3.28-3.15(m,4H),3.08-2.98(m,1H),2.94-2.83(m,1H),2.29-2.13(m,6H),1.8 4-1.62(m,6H),1.58-1.50(m,4H),1.42-1.37(m,2H),1.27(s,3H),1.25-1.13(m,8H).

[0278] Example 2

[0279] Step 1: Synthesis of intermediate 2-1

[0280] 5'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-dihydroindole]-2'-one (500 mg) and N,N-dimethylformamide (8 mL) were mixed. Sodium hydroxide (126 mg, 60% dispersion in mineral oil) was added under ice-cooling. The mixture was stirred for 10 minutes, followed by deuterated iodomethane (457 mg). The mixture was allowed to return to room temperature and react for 2 hours. Upon completion of the reaction, the reaction mixture was poured into saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 400 mg of intermediate 2-1.

[0281] MS (ESI, [M+H] + )m / z:255.08.

[0282] 1 H-NMR (500MHz, DMSO-d6): δ7.42(dd,J=8.3,2.0Hz,1H),7.28(d,J=2.0Hz,1H),7.02(d,J=8.2Hz,1H),1.72-1.67(m,2H),1.54-1.49(m,2H).

[0283] Step 2: Synthesis of intermediate 2-2

[0284] Intermediate A-1 (250 mg), intermediate 2-1 (188 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (40.3 mg), potassium carbonate (235 mg), cuprous iodide (21.57 mg) and N-methylpyrrolidone (6 mL) were mixed and reacted at 120°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (petroleum ether:ethyl acetate = 70:30) to obtain 260 mg of intermediate 2-2.

[0285] MS (ESI, [M+H] + )m / z:616.39.

[0286] 1 H NMR (500MHz, DMSO-d6): δ7.49(dd,J=8.4,2.2Hz,1H),7.24(d,J=2.1Hz,1H),7.19-7.14(m,2H),7.10(d,J=6.2Hz,2H),6.96-6.87(m,1 H),2.79-2.61(m,2H),2.19(d,J=2.0Hz,6H),1.69-1.62(m,2H),1.58-1.53(m,2H),1.44(s,9H),1.38-1.22(m,3H),1.21-1.14(m,3H).

[0287] Step 3: Synthesis of intermediate 2-3

[0288] Intermediate 2-2 (260 mg) was mixed with 4N hydrochloric acid dioxane solution (5 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 230 mg of intermediate 2-3.

[0289] Step 4: Synthesis of intermediate 2-4 and compound 2

[0290] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 2-3 (0.148 g) was added thereto and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 70 mg of intermediate 2-4. The intermediate 2-4 was separated by chiral HPLC (column: CHIRAL ART Cellulose-SB, 30×250 mm, 5 μm, mobile phase: ethanol-dichloromethane (1:1):n-hexane=30:70, flow rate: 38 mL / min) to give compound 2 (35 mg).

[0291] Compound 2: Rt = 2.80 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 mL / min; column temperature: 40°C)

[0292] HRMS: (ESI, [M+H] + )m / z:909.4328.

[0293] 1 H NMR(500MHz,DMSO)δ11.73(s,1H),7.56-7.48(m,2H),7.45-7.32(m,2H),7.29-7.23(m,2H),7.2 0(s,1H),7.16-7.13(m,2H),6.94(s,2H),5.63-5.50(m,1H),4.44-4.33(m,1H),3.73-3.68(m,2H ),3.67-3.56(m,1H),3.18(s,1H),3.06-3.00(m,1H),2.93-2.85(m,1H),2.22(s,6H),1.76-1.6 5(m,6H),1.64-1.59(m,2H),1.57-1.47(m,6H),1.39(d,J=6.3Hz,2H),1.24(s,4H),1.18(s,3H).

[0294] Example 3

[0295] Step 1: Synthesis of intermediate 3-1

[0296] 5'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-dihydroindole]-2'-one (500 mg) and toluene (50 mL) were mixed, and cyclopropylboronic acid (360 mg), 4-dimethylaminopiperidine (800 mg), copper acetate (440 mg) and 2M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (1.1 mL) were added in sequence. The mixture was heated to 95°C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:2) to obtain 0.5 g of intermediate 3-1.

[0297] MS (ESI, [M+H] + )m / z:278.09.

[0298] 1 H-NMR (500MHz, DMSO-d6): δ7.43(dd,J=8.3,2.0Hz,1H),7.25(d,J=2.0Hz,1H),7.10(d,J=8.3Hz,1H),2.73 (tt,J=7.0,3.8Hz,1H),1.65(q,J=3.7Hz,2H),1.49(q,J=3.7Hz,2H),1.06-0.95(m,2H),0.85-0.73(m,2H).

[0299] Step 2: Synthesis of intermediate 3-2

[0300] Intermediate A-1 (250 mg), intermediate 3-1 (250 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (50 mg), potassium carbonate (250 mg), cuprous iodide (25 mg) and N-methylpyrrolidone (5 mL) were mixed, and the mixture was placed in an oil bath at 120°C under nitrogen protection and stirred for reaction overnight. The reaction solution was cooled to room temperature and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (30 mL), and the organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated, and separated and purified by concentration column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 0.3 g of intermediate 3-2.

[0301] MS (ESI, [M+H] + )m / z:639.33.

[0302] 1H-NMR (500MHz, DMSO-d6): δ7.49 (dd, J=8.4, 2.3Hz, 1H), 7.24 (d, J=8.4Hz, 1H), 7.20 (d ,J=2.1Hz,1H),7.15(d,J=3.2Hz,1H),7.10(d,J=6.3Hz,2H),6.91(s,1H),5.12(s,1H), 4.21(s,1H),3.15(s,1H),2.80-2.61(m,3H),2.19(s,6H),1.67-1.57(m,2H),1.51(q,J =3.4Hz,2H),1.43(s,9H),1.19(d,J=5.8Hz,3H),1.07-0.99(m,2H),0.86-0.78(m,2H).

[0303] Step 3: Synthesis of intermediate 3-3

[0304] Intermediate 3-2 (0.3 g) and 4N hydrochloric acid dioxane solution (3 mL) were mixed and stirred at room temperature for 1 hour. Stirring was stopped and the mixture was concentrated under reduced pressure to obtain 0.26 g of intermediate 3-3.

[0305] MS (ESI, [M+H] + )m / z:539.32.

[0306] Step 4: Synthesis of intermediate 3-4 and compound 3

[0307] Intermediate B-1 (0.12 g), N,N-dimethylformamide (4 mL), triethylamine (0.068 g), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.14 g) were stirred for 5 minutes, followed by the addition of Intermediate 3-3 (0.16 g) and the reaction was stirred at 30°C. The reaction solution was poured into water (50 mL), extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 95:5) to obtain Intermediate 3-4. Intermediate 3-4 was separated by chiral HPLC (column: Pre-packed REGIS IB, 30 × 250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 30:70; flow rate: 40 mL / min) to obtain 85 mg of compound 3.

[0308] Compound 3: Rt = 2.02 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 30:70; flow rate: 2.0 mL / min; column temperature: 40°C)

[0309] HRMS: (ESI, [M+H] + )m / z:932.4280.

[0310] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.55-7.49(m,2H),7.42-7.36(m,1H),7.28-7.13(m,6H),6.95(s,2H) ,5.55(d,J=6.0Hz,1H),4.38(d,J=9.5Hz,1H),3.72(d,J=10.4Hz,2H),3.63(t,J=11.2Hz,1H),3.53-3.39(m,1H ),3.24-3.11(m,1H),3.03(t,J=11.9Hz,1H),2.88(d,J=15.6Hz,1H),2.81-2.69(m,2H),2.22(s,6H),1.73-1.6 2(m,6H),1.56-1.51(m,4H),1.39(d,J=6.9Hz,2H),1.19-1.12(m,6H),1.03(t,J=7.3Hz,3H),0.89-0.78(m,4H).

[0311] Example 4

[0312] Synthesis of compound 4:

[0313] Intermediate 1-4 (133 mg), N,N-dimethylformamide (5 mL), triethylamine (492 mg), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (277 mg) were mixed and stirred for 5 minutes. Intermediate B-2 (100 mg) was then added and stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (DCM:MeOH = 95:5) to obtain Intermediate 4-1. Intermediate 4-1 was separated by chiral HPLC (column: REGIS IB, 30×250 mm, 10 μm; mobile phase: n-hexane:dichloromethane:ethanol = 70:15:15; flow rate: 40 mL / min) to obtain 40 mg of compound 4.

[0314] Compound 4: Rt = 3.89 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 60:40; flow rate: 2.0 mL / min; column temperature: 40°C)

[0315] HRMS: (ESI, [M+H]+)m / z:892.3949.

[0316] 1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),7.57–7.38(m,3H),7.34–7.05(m,6H),7.00 -6.90(m,1H),6.85-6.71(m,1H),5.50(s,1H),4.47-4.30(m,1H),3.72(d,J=8.9Hz ,2H),3.55(d,J=36.8Hz,1H),3.23(s,3H),3.09-2.98(m,1H),2.89-2.75(m,1H), 2.20(d,J=10.8Hz,6H),1.76-1.51(m,9H),1.36-1.22(m,10H),1.21-1.16(m,3H).

[0317] Example 5

[0318] Step 1: Synthesis of intermediate 5-2

[0319] 6'-Bromospiro[cyclopropane-1,3'-dihydroindole]-2'-one (0.5 g) was dissolved in N,N-dimethylformamide (10 mL). Cesium carbonate (1.38 g) and iodomethane (0.17 mL) were added sequentially. The mixture was heated to 80°C and stirred for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The residue was filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 0.51 g of intermediate 5-2.

[0320] MS (ESI, [M+H+2] + )m / z:254.02.

[0321] 1 H-NMR (500MHz, CDCl3): δ7.15 (dd, J=7.9, 1.7Hz, 1H), 7.04 (d, J=1.8Hz, 1H), 6. 69(d,J=7.9Hz,1H),3.27(s,3H),1.75(q,J=4.1Hz,2H),1.51(q,J=4.2Hz,2H).

[0322] Step 2: Synthesis of intermediate 5-3

[0323] Combine Intermediate 5-2 (0.14 g), Intermediate A-1 (0.2 g), cuprous iodide (17.25 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (25.8 mg), potassium carbonate (125 mg), and N-methylpyrrolidone (5 mL). Heat the mixture to 130°C and stir under nitrogen for 6 h. Dilute with water and ethyl acetate, extract with ethyl acetate, and wash the organic layer with water, then with saturated aqueous NaCl, and dry over anhydrous sodium sulfate. Filter and concentrate, separate, and purify by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 0.18 g of Intermediate 5-3.

[0324] MS (ESI, [M+H] + )m / z:613.38.

[0325] 1 H-NMR (500MHz, CDCl3): δ7.26 (s, 1H), 7.09 (d, J = 6.2Hz, 2H), 7.05 (d, J = 7.4Hz, 1H), 6.87(d,J=7.9Hz,1H),6.68(d,J=3.2Hz,1H),6.29(s,1H),5.43-5.16(m,1H),4.59- 4.21(m,1H),3.31(s,3H),3.23-3.06(m,1H),2.82-2.75(m,2H),2.22(d,J=2.2Hz,6 H),1.77(q,J=4.2Hz,2H),1.54(q,J=4.1Hz,2H),1.50(s,9H),1.32(d,J=6.7Hz,3H).

[0326] Step 3: Synthesis of intermediate 5-4

[0327] Intermediate 5-3 (0.17 g) was mixed with 6N hydrochloric acid in dioxane (1 mL) and stirred at room temperature for 1 h. After concentration and evaporation of the solvent, saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration and concentration were performed to obtain 0.11 g of intermediate 5-4.

[0328] MS (ESI, [M+H] + )m / z:513.36.

[0329] Step 4: Synthesis of intermediate 5-5

[0330] Intermediate B-1 (0.08 g) and N,N-dimethylformamide (2 mL) were mixed, followed by triethylamine (44 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (110 mg). After stirring for 10 minutes, Intermediate 5-4 (0.082 g) was added, and the mixture was stirred at 40°C for 2 hours. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 98:2) to obtain 60 mg of Intermediate 5-5. Intermediate 5-5 was separated by chiral HPLC (CHIRALART Cellulose-SB column, 30×250 mm, 10 μm; mobile phase: n-hexane:dichloromethane:ethanol = 72:21:7; flow rate: 40 mL / min) to obtain 17 mg of Compound 5.

[0331] Compound 5: Rt = 2.08 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 30:70; flow rate: 2.0 mL / min; column temperature: 40°C)

[0332] HRMS: (ESI, [M+H] + )m / z:906.4103.

[0333] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.53(s,1H),7.41-7.32(m,3H),7.31-7.24(m,2H),7.17-7.11( m,3H),7.00-6.95(m,2H),5.57(d,J=6.8Hz,1H),4.38(d,J=13.9Hz,1H),3.71(d,J=8.9Hz,2H),3.24(s,3 H),3.09-3.03(m,1H),2.89(d,J=16.7Hz,1H),2.22-2.18(m,7H),1.64-1.62(m,2H),1.55-1.53(m,2H),1 .40(d,J=6.4Hz,2H),1.36-1.33(m,4H),1.30(s,2H),1.27(s,3H),1.24(s,4H),1.18(s,3H),1.15(s,2H).

[0334] Example 6

[0335] Step 1: Synthesis of intermediate 6-1

[0336] Intermediate A-2 (700 mg), intermediate 1-2 (506 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (132 mg), potassium carbonate (640 mg), cuprous iodide (88 mg), and N-methylpyrrolidone (10 mL) were mixed and reacted at 120°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.75 g of intermediate 6-1.

[0337] MS (ESI, [M+H] + )m / z:625.42

[0338] Step 2: Synthesis of intermediate 6-2

[0339] Intermediate 6-1 (0.75 g) and 4N hydrochloric acid dioxane solution (10 mL) were mixed and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.65 g of intermediate 6-2.

[0340] Step 3: Synthesis of intermediate 6-3 and compound 6

[0341] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 6-2 (0.15 g) was added and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 90 mg of intermediate 6-3. The intermediate 6-3 was separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 30:70; flow rate: 40 mL / min) to give compound 6 (40 mg).

[0342] Compound 6: Rt = 5.58 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 60:40; flow rate: 2.0 mL / min; column temperature: 40°C)

[0343] HRMS: (ESI, [M+H] + )m / z:918.4083.

[0344] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.57-7.50(m,2H),7.42-7.36(m,2H),7.32-7.26(m,4H),7.26-7.22(m ,2H),6.93-6.87(m,2H),5.58-5.51(m,1H),4.41-4.34(m,1H),3.73-3.70(m,2H),3.66-3.58(m,1H),3.26-3.23 (m,3H),3.21(s,1H),3.05-3.00(m,1H),2.92-2.87(m,1H),2.11-2.00(m,2H),1.72-1.64(m,6H),1.63-1.59(m, 2H),1.58-1.51(m,6H),1.41-1.38(m,2H),1.34-1.33(m,3H),1.30(s,3H),0.99-0.96(m,2H),0.60-0.55(m,2H).

[0345] Example 7

[0346] Step 1: Synthesis of intermediate 7-2

[0347] 3-Oxopiperazine-1-carboxylic acid tert-butyl ester (3.52 g) and N,N-dimethylformamide (80 mL) were mixed, sodium hydride (0.960 g, 60% dispersion in mineral oil) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. 2-Fluoro-4-bromonitrobenzene (3.52 g) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 2.29 g of intermediate 7-2.

[0348] 1 H-NMR (500MHz, CDCl3) δ7.93 (d, J=8.5Hz, 1H), 7.64 (dd, J=8.5, 2.0Hz, 1H), 7.52 (d, J=2.0Hz,1H),4.32-4.14(m,2H),4.00-3.86(m,2H),3.85-3.67(m,2H),1.51(s,9H).

[0349] Step 2: Synthesis of intermediate 7-3

[0350] Intermediate 7-2 (1.7 g), acetic acid (34 mL), and iron powder (1.2 g) were mixed and heated to 120°C under nitrogen for 1 hour. After the reaction, the reaction solution was cooled to room temperature, filtered through celite, and the filtrate was directly concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.26 g of intermediate 7-3.

[0351] MS (ESI, [M+H] + )m / z:352.14.

[0352] Step 3: Synthesis of intermediate 7-4

[0353] Intermediate 7-3 (1.26 g) was mixed with 4N aqueous hydrochloric acid (12 mL). Under nitrogen, the mixture was heated to 100°C for 1 hour. After the reaction, the reaction solution was poured into saturated sodium bicarbonate solution to adjust the pH to 8-9. Dichloromethane (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain 0.64 g of intermediate 7-4.

[0354] MS (ESI, [M+H] + )m / z:252.13.

[0355] 1 H-NMR (500MHz, DMSO-d6): δ7.74(d,J=1.5Hz,1H),7.49(d,J=8.5Hz,1H),7.30( dd,J=8.5,2Hz,1H),4.03(t,J=5.5Hz,4H),3.18(t,J=5.5Hz,2H),2.87(s,1H).

[0356] Step 4: Synthesis of intermediate 7-5

[0357] Intermediate 7-4 (0.22 g), methanol (7 mL), 37% formaldehyde aqueous solution (0.354 g), and acetic acid (0.150 mL) were mixed and stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (0.925 g) was added and stirred at room temperature for 12 hours. After the reaction, the reaction solution was poured into saturated sodium bicarbonate solution and extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.2 g of intermediate 7-5.

[0358] MS (ESI, [M+H] + )m / z:266.13.

[0359] 1 H-NMR (500MHz, DMSO-d6): δ7.76(d,J=2Hz,1H),7.51(d,J=8.5Hz,1H),7.32(dd,J=8 .5,2Hz,1H),4.13(t,J=5.5Hz,2H),3.74(s,2H),2.92(t,J=5.5Hz,2H),2.44(s,3H).

[0360] Step 5: Synthesis of intermediate 7-6

[0361] Intermediate A-1 (200 mg), intermediate 7-5 (181 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (32.2 mg), potassium carbonate (188 mg), cuprous iodide (17.25 mg) and N-methylpyrrolidone (5 mL) were mixed and reacted at 120°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.245 g of intermediate 7-6.

[0362] MS (ESI, [M+H] + )m / z:627.48.

[0363] 1 H-NMR (500MHz, DMSO-d6): δ7.74(s,1H),7.63(d,J=8.5Hz,1H),7.40(dd,J=8.5,2.5Hz,1H), 7.26(d,J=3Hz,1H),7.12(d,J=6Hz,2H),6.95(s,1H),5.22-5.05(m,1H),4.36-4.18(m,1H), 4.14(t,J=5.5Hz,2H),3.77(s,2H),3.20-3.05(m,1H),2.94(t,J=5.5Hz,2H),2.77-2.71(m, 1H),2.70-2.62(m,1H),2.45(s,3H),2.20(d,J=1.5Hz,6H),1.44(s,9H),1.22-1.18(m,3H).

[0364] Step 6: Synthesis of Intermediate 7-7

[0365] Intermediate 7-6 (0.24 g), dichloromethane (2 mL) and 4N hydrochloric acid dioxane solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.2 g of intermediate 7-7.

[0366] MS (ESI, [M+H] + )m / z:527.34.

[0367] Step 7: Synthesis of intermediates 7-8 and compound 7

[0368] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 7-7 (0.151 g) was added and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.12 g of intermediate 7-8. The above intermediate 7-8 was chirally resolved by supercritical fluid chromatography (chromatographic column: CHIRALART Cellulose-SB, 20×100 mm, 5 μm; mobile phase: carbon dioxide:ethanol (0.1% ammonia water) = 68:32; flow rate: 60 mL / min) to obtain 54 mg of compound 7.

[0369] Compound 7: Rt = 2.97 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 mL / min; column temperature: 40°C)

[0370] HRMS: (ESI, [M+H] + )m / z:920.4379.

[0371] 1H NMR (500MHz, DMSO-d6) δ11.74(s,1H),7.78(s,1H),7.65(d,J=8.5Hz,1H),7.53(s,1H),7.44-7.38(m,2H),7. 29-7.24(m,2H),7.20-7.14(m,2H),6.97-6.91(m,2H),5.62-5.55(m,1H),4.42-4.34(m,1H),4.19-4.12(m,2H ),4.08-3.92(m,1H),3.79-3.76(m,2H),3.73-3.70(m,2H),3.66-3.56(m,1H),3.24-3.15(m,1H),3.06-3.00( m,1H),2.96-2.92(m,2H),2.45(s,3H),2.23(s,6H),1.80-1.75(m,1H),1.73-1.64(m,4H),1.62-1.57(m,2H), 1.55-1.49(m,2H),1.41-1.39(m,1H),1.28-1.22(m,6H),1.18(s,3H).

[0372] Example 8

[0373] Step 1: Synthesis of intermediate 8-2

[0374] 2-Pyrrolidone (0.426 g) and N,N-dimethylformamide (15 mL) were mixed, and sodium hydride (0.273 g, 60% dispersion in mineral oil) was added under ice-cooling. The mixture was stirred at room temperature for 10 minutes. 2-Fluoro-4-bromonitrobenzene (1 g) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain 0.83 g of intermediate 8-2.

[0375] MS (ESI, [M+H] + )m / z:285.02.

[0376] 1 H-NMR (500MHz, DMSO-d6): δ7.91(d,J=8.5Hz,1H),7.89(d,J=2Hz,1H),7.70(dd ,J=8.5,2Hz,1H),3.93(t,J=7Hz,2H),2.41(t,J=8.0Hz,2H),2.17-2.11(m,2H).

[0377] Step 2: Synthesis of intermediate 8-3

[0378] Intermediate 8-2 (0.7 g), acetic acid (20 mL), and iron powder (0.7 g) were mixed and heated to 120°C under nitrogen for 4 hours. After the reaction, the reaction solution was cooled to room temperature, filtered through celite, and the filtrate was directly concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.5 g of intermediate 8-3.

[0379] MS (ESI, [M+H] + )m / z:237.12.

[0380] 1 H-NMR (500MHz, DMSO-d6): δ7.71(d,J=2Hz,1H),7.48(d,J=8.5Hz,1H),7.26(dd ,J=8.5,2Hz,1H),4.10(t,J=7Hz,2H),2.94(t,J=7.5Hz,2H),2.65-2.59(m,2H).

[0381] Step 3: Synthesis of intermediate 8-4

[0382] Intermediate A-1 (200 mg), intermediate 8-3 (0.129 g), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (32.2 mg), potassium carbonate (188 mg), cuprous iodide (17.25 mg) and N-methylpyrrolidone (5 mL) were mixed and reacted at 120°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.25 g of intermediate 8-4.

[0383] MS (ESI, [M+H] + )m / z:598.39.

[0384] 1H-NMR (500MHz, DMSO-d6): δ7.76-7.70(m,1H),7.66-7.57(m,1H),7.34(d,J=7Hz,1 H),7.25(d,J=3Hz,1H),7.12(d,J=6Hz,2H),6.97(s,1H),5.22-5.06(m,1H),4.36- 4.18(m,1H),4.12(t,J=7Hz,2H),3.21-3.08(m,1H),2.99-2.90(m,2H),2.77-2.71 (m,1H),2.69-2.59(m,3H),2.20(d,J=1.5Hz,6H),1.44(s,9H),1.23-1.19(m,3H).

[0385] Step 4: Synthesis of intermediate 8-5

[0386] Intermediate 8-4 (0.25 g), dichloromethane (2 mL) and 4N hydrochloric acid dioxane solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.2 g of intermediate 8-5.

[0387] MS (ESI, [M+H] + )m / z:498.40.

[0388] Step 5: Synthesis of intermediate 8-6 and compound 8

[0389] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.277 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 8-5 (0.130 g) was added and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.12 g of intermediate 8-6. The intermediate 8-6 was chirally resolved by supercritical fluid chromatography (chromatographic column: CHIRALART Cellulose-SB, 20×100 mm, 5 μm; mobile phase: carbon dioxide:ethanol (0.1% ammonia water) = 53:47; flow rate: 60 mL / min) to obtain 30 mg of compound 8.

[0390] Compound 8: Rt = 3.57 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 mL / min; column temperature: 40°C)

[0391] HRMS: (ESI, [M+H] + )m / z:891.4119.

[0392] 1 H NMR(500MHz,DMSO-d6)δ11.74(s,1H),7.75(s,1H),7.64-7.59(m,1H),7.53(s,1H),7.41-7.34(m,2H),7.29-7.24(m,2 H),7.19-7.14(m,2H),7.00-6.91(m,2H),5.62-5.55(m,1H),4.42-4.35(m,1H),4.17-4.11(m,2H),3.76-3.67(m,2H), 3.22-3.16(m,1H),3.08-3.00(m,1H),2.99-2.93(m,2H),2.92-2.85(m,1H),2.68-2.59(m,3H),2.22(s,6H),1.82-1.7 5(m,1H),1.71-1.64(m,4H),1.62-1.57(m,2H),1.55-1.52(m,2H),1.41-1.39(m,1H),1.28-1.22(m,6H),1.18(s,3H).

[0393] Example 9

[0394] Step 1: Synthesis of intermediate 9-2

[0395] Sodium hydride (0.995 g, 60% dispersion in mineral oil) and N,N-dimethylformamide (10 mL) were mixed and stirred in an ice-water bath under nitrogen for 10 minutes. A solution of 6-bromoindanone (1 g) and 1,2-dibromoethane (3.12 g) in N,N-dimethylformamide (10 mL) was added dropwise. After the addition was complete, the mixture was stirred and maintained at the temperature. The reaction was stopped and the reaction solution was poured into water (150 mL). The resulting solution was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 0.69 g of intermediate 9-2.

[0396] 1H-NMR (500MHz, DMSO-d6): δ7.90(s,1H),7.65(d,J=7.9Hz,1H),7.59(d,J=8.0Hz,1H),3.25(s,2H),1.24(d,J=10.1Hz,4H).

[0397] Step 2: Synthesis of intermediate 9-3

[0398] Intermediate A-1 (250 mg), intermediate 9-2 (175 mg), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40.3 mg), potassium carbonate (235 mg), cuprous iodide (21.57 mg), and N-methylpyrrolidone (4 mL) were mixed. The mixture was stirred in an oil bath at 120°C under nitrogen protection and reacted overnight. The reaction was stopped, the reaction solution was cooled to room temperature, poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain 0.27 g of intermediate 9-3.

[0399] MS (ESI, [M+H] + )m / z:598.34.

[0400] 1 H-NMR (500MHz, DMSO-d6): δ7.99(s,1H),7.84(d,J=8.5Hz,1H),7.75(d,J=8.4Hz,1H),7.48(d,J=3.3Hz,1H),7.11(d,J=6.3Hz,2H),7.07(s,1H), 5.21-5.01(m,1H),4.39-4.11(m,1H),3.27(s,2H),3.22-3.04(m,1H),2 .77-2.62(m,2H),2.18(d,J=1.3Hz,6H),1.44(s,9H),1.27-1.18(m,7H).

[0401] Step 3: Synthesis of intermediate 9-4

[0402] Intermediate 9-3 (0.25 g), dichloromethane (2 mL) and 4N hydrochloric acid dioxane solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.21 g of intermediate 9-4.

[0403] MS (ESI, [M+H] + )m / z:498.0.

[0404] Step 4: Synthesis of intermediate 9-5, compound 9-A and compound 9-B

[0405] Intermediate B-1 (0.14 g), N,N-dimethylformamide (5 mL), triethylamine (0.806 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.330 g) were mixed and stirred for 5 minutes. Intermediate 9-4 (0.170 g) was then added and the mixture was stirred at room temperature. The reaction mixture was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 95:5) to obtain 130 mg of Intermediate 9-5. The intermediate 9-5 was separated by chiral HPLC (column: REFLECT I-Cellulose B, 30×250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:4):n-hexane = 25:75; flow rate: 40 mL / min) to give compound 9-A (26 mg) and compound 9-B (30 mg), respectively.

[0406] Compound 9-A: R t = 2.59 min (UPCC conditions: chromatographic column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40°C)

[0407] HRMS: (ESI, [M+H] + )m / z:891.4030.

[0408] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.06-7.74(m,3H),7.57-7.37(m ,3H),7.28-6.94(m,5H),5.65-5.53(m,1H),4.46-4.31(m,1H),3.79-3.59( m,3H),3.29(s,3H),3.10-2.98(m,1H),2.94-2.85(m,1H),2.23-2.15(m,6 H),1.83-1.47(m,8H),1.44-1.37(m,2H),1.28(s,3H),1.25-1.15(m,10H).

[0409] Compound 9-B: R t= 2.03 min (UPCC conditions: chromatographic column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40°C)

[0410] HRMS: (ESI, [M+H] + )m / z:891.4026.

[0411] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.07-7.68(m,3H),7.56-7.37(m, 3H),7.29-6.85(m,5H),5.64-5.54(m,1H),4.48-4.32(m,1H),3.77-3.59(m, 3H),3.30-3.13(m,3H),3.09-2.99(m,1H),2.96-2.86(m,1H),2.24-2.13(m, 6H),1.83-1.46(m,8H),1.43-1.36(m,2H),1.27(s,3H),1.25-1.14(m,10H).

[0412] Example 10

[0413] Step 1: Synthesis of intermediate 10-2

[0414] 1-Bromo-2-fluoro-4-iodobenzene (2 g), cuprous iodide (0.076 g), bistriphenylphosphine palladium dichloride (0.140 g), diisopropylamine (20 mL), and tert-butyldimethyl(propyl-2-yn-1-yloxy)silane (1.359 g) were mixed and stirred at room temperature overnight. The reaction solution was added to a mixture of ethyl acetate (30 mL) and water (40 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (2×30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 98:2) to obtain 1.8 g of intermediate 10-2.

[0415] 1 H-NMR (500MHz, DMSO-d6): δ7.60(t,J=7.8Hz,1H),7.32(dd,J=9.5,2.0Hz,1H),7.09(dd,J=8.3,1.9Hz,1H),4.42(s,2H),0.76(s,9H),-0.00(s,6H).

[0416] Step 2: Synthesis of intermediate 10-3

[0417] Intermediate 10-2 (1.8 g), tetrabutylammonium fluoride (1 M, 10.49 ml) and tetrahydrofuran (10 mL) were mixed and stirred at room temperature for 1 hour. The reaction system was directly spin-dried and purified by column chromatography (dichloromethane:methanol=100:0) to obtain 1.67 g of intermediate 10-3.

[0418] MS (ESI, [M+H] + )m / z:228.23.

[0419] 1 H-NMR (500MHz, DMSO-d6): δ7.79-7.72(m,1H),7.49(dd,J=9.5,1.9Hz,1H),7.26(dd,J=8.3,1.9Hz,1H),5.42(s,1H),4.39-4.30(m,2H).

[0420] Step 3: Synthesis of intermediate 10-4

[0421] Intermediate 10-3 (500 mg), tetrahydrofuran (10 mL), and sodium hydride (175 mg, 60% dispersion in mineral oil) were mixed, and the reaction system was placed in an ice-water bath. Methyl iodide (372 mg) was added dropwise to the reaction solution. The reaction mixture was transferred to room temperature and stirred for 2 hours. The reaction solution was quenched with water and added to a mixture of ethyl acetate (30 mL) and water (40 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (2×30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 320 mg of intermediate 10-4.

[0422] 1 H-NMR (500MHz, DMSO-d6): δ7.77-7.71(m,1H),7.52(dd,J=9.5,1.9Hz,1H),7.26(dd,J=8.2,2.1Hz,1H),4.33(s,2H),3.33(s,3H)

[0423] Step 4: Synthesis of intermediate 10-5

[0424] Cuprous iodide (21.57 mg), potassium carbonate (235 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (40.3 mg), intermediate A-1 (250 mg), intermediate 10-4 (210 mg), and N-methylpyrrolidone (4 mL) were added to the reaction system under nitrogen atmosphere and then placed in an oil bath at 130°C for 3 hours. The reaction solution was added to a mixture of ethyl acetate (30 mL) and water (40 mL), and the two phases were separated. The aqueous phase was extracted with ethyl acetate (2×30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was then purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 220 mg of intermediate 10-5.

[0425] MS (ESI, [M+H] + )m / z:604.33.

[0426] Step 5: Synthesis of intermediate 10-6

[0427] Intermediate 10-5 (210 mg, 0.348 mmol), dichloromethane (2 mL), and 4M dioxane hydrochloride (1.5 mL) were mixed and stirred at room temperature for 2 hours. The reaction system was concentrated under reduced pressure to obtain 190 mg of intermediate 10-6.

[0428] MS (ESI, [M+H] + )m / z:504.26.

[0429] Step 6: Synthesis of intermediate 10-7 and compound 10-A and compound 10-B

[0430] Intermediate B-1 (100 mg), N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (236 mg), and triethylamine (418 mg) were stirred for 5 minutes, followed by the addition of Intermediate 10-6 (123 mg) and stirring at room temperature for 3 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (30 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by high-pressure preparative chromatography to afford 80 mg of compound 10-7. Compound 10-7 was separated by chiral HPLC (column: REGIS IB, 30×250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 27:73; flow rate: 42 mL / min) to afford compounds 10-A (26 mg) and 10-B (30 mg).

[0431] Compound 10-A: Rt = 2.790 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 50:25:25; flow rate: 2.0 mL / min; column temperature: 40°C)

[0432] HRMS: (ESI, [M+H] + )m / z:897.3933.

[0433] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.59(t,J=8.6Hz,2H),7.53(s,1H),7.45(d,J=8.3Hz,1H),7 .40(d,J=8.6Hz,1H),7.26(d,J=8.4Hz,1H),7.17-7.06(m,3H),6.95(d,J=10.8Hz,2H),5.57(d,J=7.1 Hz,1H),4.36(s,2H),3.72(d,J=9.5Hz,3H),3.65-3.60(m,1H),3.2-3.15(m,1H),3.02(d,J=12.3Hz,1H),2.22(d,J=15.4Hz,6H),1.99 (s,1H),1.75-1.63(m,4H),1.57-1.47(m,2H),1.41(d,J=6.7Hz,3H),1.29(d,J=12.2Hz,5H),1.24(d,J=6.7Hz,3H),1.21-1.12(m,5H).

[0434] Compound 10-B: Rt = 2.169 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 50:25:25; flow rate: 2.0 mL / min; column temperature: 40°C)

[0435] HRMS: (ESI, [M+H] + )m / z:897.3928.

[0436] 1H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.60(d,J=9.6Hz,2H),7.53(s,1H),7.44(d,J=8.3Hz,1H),7.40(d,J=8.5Hz,1H) ,7.26(d,J=8.6Hz,1H),7.15(d,J=6.3Hz,2H),7.09(s,1H),6.95(d,J=13.0Hz,2H),5.63-5.52(m,1H),4.36(s,2H),3.72( d,J=9.6Hz,2H),3.65-3.59(m,1H),3.35(s,3H),3.20-3.15(s,2H),3.02(d,J=12.6Hz,1H),2.90(t,J=15.9Hz,1H),2.22( d,J=15.4Hz,6H),1.69-1.65(m,J=8.9Hz,3H),1.53-1.48(m,2H),1.29-1.27(m,6H),1.24-1.23(m,3H),1.18-1.16(m,5H).

[0437] Example 11

[0438] Step 1: Synthesis of intermediate 11-2

[0439] 2-Bromo-5-iodopyridine (2 g), cuprous iodide (0.040 g), bistriphenylphosphine palladium dichloride (0.198 g), tetrahydrofuran (30 mL), triethylamine (10.86 g), and propyne (0.367 g) were mixed and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into a mixture of ethyl acetate (30 mL) and water (40 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 97:3) to obtain 1.2 g of intermediate 11-2.

[0440] MS (ESI, [M+H] + )m / z:196.05.

[0441] 1 H-NMR (500MHz, DMSO-d6): δ8.41(d,J=2.4Hz,1H),7.75(dd,J=8.3,2.5Hz,1H),7.64(d,J=9.0Hz,1H),2.08(s,3H).

[0442] Step 2: Synthesis of intermediate 11-3

[0443] Intermediate A-1 (370 mg), intermediate 11-2 (246 mg), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (69 mg), cuprous iodide (32 mg), potassium carbonate (232 mg), and N-methylpyrrolidone (4 mL) were mixed, purged with nitrogen, and heated in an oil bath at 130°C with stirring for 3 hours. The reaction solution was added to a mixture of ethyl acetate (30 mL) and water (40 mL), and the two phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 1:1) afforded 420 mg of intermediate 11-3.

[0444] Step 3: Synthesis of intermediate 11-4

[0445] Intermediate 11-3 (450 mg), dichloromethane (2 mL), and 4N hydrochloric acid in dioxane solution (2 mL) were mixed and stirred at room temperature for 1 hour. Stirring was stopped and the mixture was concentrated under reduced pressure to obtain 347 mg of intermediate 11-4.

[0446] MS (ESI, [M+H] + )m / z:457.30.

[0447] Step 4: Synthesis of intermediate 11-5 and compound 11-A and compound 11-B

[0448] Intermediate 11-4 (132 mg), Intermediate B-1 (100 mg), triethylamine (492 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (277 mg), and N,N-dimethylformamide (5 mL) were mixed and stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 70 mg of 11-5. The intermediate 11-5 was separated by chiral HPLC (column: REFLECT I-Cellulose B, 30×250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:3):n-hexane = 20:80; flow rate: 40 mL / min) to give compound 11-A (15 mg) and compound 11-B (12 mg), respectively.

[0449] Compound 11-A: R t=1.58 min (UPCC conditions: chromatographic column: CHIRALPAK IB-3, 4.6×100 mm, 3 μm; mobile phase: carbon dioxide:ethanol:isopropanol=40:30:30; flow rate: 2.0 mL / min; column temperature: 40°C).

[0450] HRMS: (ESI, [M+H] + )m / z:850.3866

[0451] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.53-7.88(m,2H),7.63-6.67(m,9H),5.76-5.54(m,1H),4.51-4.35(m,1H),3.76-3.51(m,3H) ),3.24-3.14(m,1H),3.08-2.99(m,1H),2.96-2.85(m,1H),2.24-2.14(m,6H),2.11-2.04(m,3H),1.80-1.44(m,8H),1.34(s,3H),1.24 -1.17(m,8H).

[0452] Compound 11-B: R t =1.31 min (UPCC conditions: chromatographic column: CHIRALPAK IB-3, 4.6×100 mm, 3 μm; mobile phase: carbon dioxide:ethanol:isopropanol=40:30:30; flow rate: 2.0 mL / min; column temperature: 40°C).

[0453] HRMS: (ESI, [M+H] + )m / z:850.3867

[0454] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.56-7.91(m,2H),7.66-6.64(m,9H),5.76-5.52(m,1H),4.50-4.33(m,1H),3.83-3.54(m,3H),3.26-3 .15(m,1H),3.09-2.96(m,1H),2.96-2.84(m,1H),2.28-2.14(m,6H),2.1 3-2.03(m,3H),1.81-1.45(m,8H),1.37-1.32(m,3H),1.25-1.17(m,8H).

[0455] Example 12

[0456] Step 1: Synthesis of intermediate 12-2

[0457] Sodium hydride (1.167 g, 60% dispersion in mineral oil) was added to a mixture of tetrahydrofuran (60 mL) and ethanol (20 mL) at 0°C and stirred for 10 minutes. Intermediate 12-1 (5 g) and diethyl malonate (2.336 g) were then added to the reaction mixture, and the mixture was allowed to react at room temperature for 4 hours. The reaction mixture was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 4.3 g of intermediate 12-2.

[0458] 1 H-NMR (500MHz, DMSO-d6): δ7.45(d,J=1.8Hz,1H),7.34(dd,J=8.0,1.9Hz,1H),7.19(d ,J=8.1Hz,1H),4.15(q,J=7.1Hz,4H),3.49(s,2H),3.43(s,2H),1.17(t,J=7.1Hz,6H).

[0459] Step 2: Synthesis of intermediate 12-3

[0460] Intermediate 12-2 (0.5 g), THF (6 mL), and lithium borohydride (0.064 g) were mixed and reacted at room temperature overnight. The reaction solution was poured into saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 0.24 g of intermediate 12-3.

[0461] 1 H-NMR (500MHz, DMSO-d6): δ7.34(s,1H),7.25(d,J=8.0Hz,1H),7.10(d,J=8.0H z,1H),4.62(t,J=5.3Hz,2H),3.34(d,J=5.3Hz,4H),2.71(s,2H),2.65(s,2H).

[0462] Step 3: Synthesis of intermediate 12-4

[0463] Intermediate 12-3 (1 g) and tetrahydrofuran (15 mL) were mixed, and sodium hydride (0.187 g, 60% dispersion in mineral oil) was added at 0°C for half an hour. Then, p-toluenesulfonyl chloride (0.741 g) was added and the reaction continued for 1.5 hours. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 1.2 g of intermediate 12-4.

[0464] 1 H-NMR (500MHz, DMSO-d6): δ7.76(d,J=8.3Hz,2H),7.46(d,J=8.0Hz,2H),7.34 -7.25(m,2H),7.08(d,J=8.0Hz,1H),4.94(s,1H),3.97(d,J=4.3Hz,2H),3.28(s,2H),2.77 -2.58(m,4H),2.42(s,3H).

[0465] Step 4: Synthesis of intermediate 12-5

[0466] Intermediate 12-4 (500 mg) and tetrahydrofuran (10 mL) were mixed, and sodium hydride (97 mg, 60% dispersion in mineral oil) was added at 0°C. The mixture was reacted in an oil bath at 70°C overnight. The reaction mixture was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 0.19 g of intermediate 12-5.

[0467] 1 H-NMR (500MHz, DMSO-d6): δ7.43-7.38(m,1H),7.33-7.27(m,1H),7.17(d,J=8.0Hz,1H),4.52(s,4H),3.21(s,2H),3.15(s,2H).

[0468] Step 5: Synthesis of intermediate 12-6

[0469] Intermediate A-1 (0.1 g), dichloromethane (1 mL), and 4N hydrochloric acid in dioxane solution (1 mL) were mixed and reacted at room temperature for 1 hour. Stirring was stopped and the mixture was concentrated under reduced pressure to obtain 0.1 g of intermediate 12-6.

[0470] MS (ESI, [M+H] + )m / z:342.19.

[0471] Step 6: Synthesis of Intermediate 12-7

[0472] Intermediate 12-6 (0.25 g), N,N-dimethylformamide (4 mL), Intermediate B-1 (0.251 g), N,N-diisopropylethylamine (0.358 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.253 g) were mixed and reacted at room temperature overnight. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 0.2 g of Intermediate 12-7.

[0473] MS (ESI, [M+H] + )m / z:735.44.

[0474] Step 7: Synthesis of intermediate 12-8 and compound 12-A and compound 12-B

[0475] Intermediate 12-7 (0.2 g), N-methylpyrrolidone (4 mL), 12-5 (0.130 g), potassium carbonate (0.113 g), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.015 g) and cuprous iodide (10.37 mg) were heated to 130°C under nitrogen for 3 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was sanded and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 80 mg of intermediate 12-8. The intermediate 12-8 was separated by chiral HPLC (chromatographic column: REGIS IB, size: 30×250 mm, 10 μm; mobile phase: n-hexane: dichloromethane: ethanol = 70:15:15; flow rate: 40 mL / min) to give compound 12-A (29 mg) and compound 12-B (25 mg), respectively.

[0476] Compound 12-A: R t = 2.22 min (UPCC conditions: chromatographic column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40°C)

[0477] HRMS: (ESI, [M+H] + )m / z:893.4172.

[0478] 1H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.55-7.28(m,5H),7.27-7.06(m,4H),7 .02-6.77(m,2H),5.63-5.49(m,1H),4.61-4.50(m,4H),4.43-4.34(m,1H),3.77-3 .57(m,3H),3.27-3.11(m,5H),3.08-3.00(m,1H),2.95-2.84(m,1H),2.26-2.14(m ,6H),1.87-1.44(m,8H),1.40-1.35(m,2H),1.29-1.27(m,3H),1.25-1.17(m,6H).

[0479] Compound 12-B: R t =1.76 min (UPCC conditions: chromatographic column: CHIRALPAK IB-3, 4.6×100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol = 40:30:30; flow rate: 2.0 mL / min; column temperature: 40°C)

[0480] HRMS: (ESI, [M+H] + )m / z:893.4167.

[0481] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.58-7.28(m,5H),7.27-7.07(m,4H),6 .99-6.75(m,2H),5.62-5.52(m,1H),4.61-4.50(m,4H),4.45-4.33(m,1H),3.79-3 .56(m,3H),3.27-3.12(m,5H),3.07-2.97(m,1H),2.92-2.83(m,1H),2.26-2.16(m ,6H),1.81-1.46(m,8H),1.40-1.35(m,2H),1.29-1.26(m,3H),1.24-1.15(m,6H).

[0482] Example 13

[0483] Step 1: Synthesis of intermediate 13-1

[0484] 6'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2'-one (0.5 g) and N,N-dimethylformamide (5 mL) were mixed and cooled in an ice-water bath. Sodium hydroxide (0.13 g, 60% dispersion in mineral oil) was added portionwise. After addition, the ice-water bath was removed, the mixture was allowed to warm to room temperature and stirred for 10 minutes. The mixture was then cooled in an ice-water bath and deuterated iodomethane (0.46 g) was added. After addition, the ice-water bath was removed, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 0.53 g of intermediate 13-1.

[0485] 1 H-NMR (500MHz, DMSO-d6): δ7.31(d,J=1.8Hz,1H),7.18(dd,J=7.9,1.8Hz,1H),6.98(d,J=7.9Hz,1H),1.65-1.61(m,2H),1.55-1.50(m,2H).

[0486] Step 2: Synthesis of intermediate 13-2

[0487] Intermediate A-1 (0.2 g), N-methylpyrrolidone (4 mL), Intermediate 13-2 (0.19 g), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.032 g), potassium carbonate (0.19 g), and cuprous iodide (0.017 g) were mixed and heated to 130°C under nitrogen for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 0.13 g of Intermediate 13-2.

[0488] MS (ESI, [M+H] + )m / z:616.42.

[0489] 1H-NMR (500MHz, DMSO-d6): δ7.35(s,1H),7.30(d,J=3.4Hz,1H),7.27(dd,J=8.1,2.0Hz,1H),7.14-7.07(m,3H),6.97(s,1H),5.14(s, 1H),4.21(s,1H),3.14(s,1H),2.80-2.70(m,2H),2.19(s,6H),1.66-1.60(m,2H),1.56-1.51(m,2H),1.44(s,9H),1.22-1.16(m,3H).

[0490] Step 3: Synthesis of intermediate 13-3

[0491] Intermediate 13-2 (0.13 g), dichloromethane (2 mL), and 4N hydrochloric acid in dioxane solution (2 mL) were mixed, stirred at room temperature for 1.5 hours, and concentrated under reduced pressure to obtain 0.11 g of intermediate 13-3.

[0492] MS (ESI, [M+H] + )m / z:516.36.

[0493] Step 4: Synthesis of intermediate 13-4 and compound 13

[0494] Intermediate B-1 (0.08 g), N,N-dimethylformamide (2 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.22 g), and triethylamine (0.39 g) were mixed and stirred at room temperature for 5 minutes. A solution of Intermediate 1-3 (0.12 g) in N,N-dimethylformamide (1 mL) was then added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to afford 80 mg of Intermediate 13-4. Intermediate 13-4 was separated by chiral HPLC (chromatographic column: REGIS IB, 30×250 mm, 10 μm; mobile phase: n-hexane-ethanol (80:20): dichloromethane = 1:1; flow rate: 40 mL / min) to obtain compound 13 (38 mg).

[0495] Compound 13: Rt = 2.077 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide:methanol = 30:70; flow rate: 2.0 mL / min; column temperature: 40°C)

[0496] HRMS: (ESI, [M+H]+ )m / z:909.4308.

[0497] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.57-7.46(m,1H),7.43-7.23(m,5H),7.20-7 .06(m,3H),7.04-6.77(m,2H),5.77-5.53(m,1H),4.46-4.32(m,1H),3.80-3.54(m,3H) ,3.24-3.12(m,1H),3.08-2.96(m,1H),2.95-2.85(m,1H),2.26-2.15(m,6H),1.82-1.4 5(m,12H),1.43-1.36(m,2H),1.35-1.30(m,2H),1.29-1.25(m,4H),1.19-1.15(m,3H).

[0498] Example 14

[0499] Step 1: Synthesis of intermediate 14-1

[0500] Combine 6-bromo-7-fluoroindoline-2,3-dione (8.4 g), ethanol (150 mL), and 85% hydrazine hydrate solution (1.5 mL). Under nitrogen, heat the mixture to 85°C for 1 hour. After the reaction is complete, cool the reaction mixture to room temperature and filter. Combine the filter cake, ethanol (150 mL), and potassium tert-butoxide (12 g). Under nitrogen, heat the mixture to 85°C for 2 hours. After the reaction is complete, pour the reaction mixture into water, add 2N aqueous hydrochloric acid (50 mL) to adjust the pH to 2-3, filter, and dry the filter cake to obtain 4.2 g of intermediate 14-1.

[0501] MS (ESI, [MH] - )m / z:227.95.

[0502] 1 H-NMR (500MHz, DMSO-d6): δ11.03 (s, 1H), 7.24-7.19 (m, 1H), 7.01 (d, J = 7.5Hz, 1H), 3.55 (s, 2H).

[0503] Step 2: Synthesis of intermediate 14-2

[0504] A 2N solution of lithium diisopropylamide in tetrahydrofuran (8.69 ml) was added to a mixture of Intermediate 14-1 (1 g) and tetrahydrofuran (20 ml) at -40°C. The mixture was stirred for 30 minutes. 1,2-Dibromoethane (2.45 g) was then added to the reaction mixture, and the mixture was allowed to react at room temperature for 12 hours. The reaction mixture was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 0.27 g of Intermediate 14-2.

[0505] 1 H-NMR (500MHz, DMSO-d6): δ11.24 (s, 1H), 7.24-7.19 (m, 1H), 6.81 (d, J = 8.0Hz, 1H), 1.66-1.64 (m, 2H), 1.56-1.52 (m, 2H).

[0506] Step 3: Synthesis of intermediate 14-3

[0507] Intermediate 14-2 (0.27 g), N,N-dimethylformamide (5 mL), iodomethane (0.19 g), and cesium carbonate (0.68 g) were mixed and heated to 80°C under nitrogen for 1 hour. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (petroleum ether:ethyl acetate = 90:10) to obtain 0.13 g of intermediate 14-3.

[0508] 1 H-NMR (500MHz, DMSO-d6): δ7.29-7.26(m,1H),6.85(d,J=8.0Hz,1H),3.38(d,J=3.0Hz,3H),1.70-1.68(m,2H),1.59-1.57(m,2H).

[0509] Step 4: Synthesis of intermediate 14-4

[0510] Intermediate A-1 (200 mg), intermediate 14-3 (0.13 g), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (32 mg), potassium carbonate (188 mg), cuprous iodide (17.25 mg), and N-methylpyrrolidone (5 mL) were mixed and reacted at 100°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.14 g of intermediate 14-4.

[0511] MS (ESI, [M+H] + )m / z:631.39.

[0512] 1 H-NMR (500MHz, DMSO-d6): δ7.12 (d, J=6.5Hz, 2H), 7.08-7.04 (m, 1H), 6.99-6 .97(m,2H),6.92(s,1H),5.19-5.04(m,1H),4.39-4.14(m,1H),3.40(d,J=2. 5Hz,3H),3.23-3.06(m,1H),2.75-2.69(m,1H),2.67-2.62(m,1H),2.23(s,6 H),1.72-1.70(m,2H),1.62-1.59(m,2H),1.44(s,9H),1.21(d,J=7.0Hz,3H).

[0513] Step 5: Synthesis of intermediate 14-5

[0514] Intermediate 14-4 (0.14 g), dichloromethane (2 mL) and 4N hydrochloric acid in dioxane solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.11 g of intermediate 14-5.

[0515] MS (ESI, [M+H] + )m / z:531.31.

[0516] Step 6: Synthesis of compound 14

[0517] Intermediate B-3 (0.07 g), N,N-dimethylformamide (4 mL), triethylamine (0.47 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.19 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 14-5 (0.1 g) was added thereto and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.048 g of compound 14.

[0518] HRMS: (ESI, [M+H] + )m / z:924.4014.

[0519] 1H-NMR(500MHz,DMSO-d6)δ11.73(s,1H),7.53(s,1H),7.42-7.39(m,1H),7.37-7.36(m,1H),7.29-7.24(m,1H),7.19-7.1 5(m,2H),7.12-7.09(m,1H),7.01(s,1H),6.94(s,2H),5.59-5.52(m,1H),4.42-4.34(m,1H),3.72-3.70(m,2H),3.41(s, 3H),3.25-3.14(m,1H),3.07-2.99(m,1H),2.93-2.85(m,1H),2.75-2.70(m,1H),2.25(s,6H),1.75-1.71(m,2H),1.69-1 .64(m,2H),1.64-1.60(m,2H),1.52-1.49(m,2H),1.43-1.38(m,3H),1.34(s,3H),1.30(s,3H),1.24(s,3H),1.18(s,3H).

[0520] Example 15

[0521] Step 1: Synthesis of intermediate 15-1

[0522] A 2N solution of lithium diisopropylamide in tetrahydrofuran (15.7 mL) was added to a mixture of 6-bromo-5-fluoroindolin-2-one (1.8 g) and tetrahydrofuran (6 mL) at -60°C and stirred for 30 minutes. 1,2-Dibromoethane (4.41 g) was then added to the reaction mixture, and the mixture was allowed to react at room temperature for 12 hours. The reaction mixture was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to obtain 0.72 g of Intermediate 15-1.

[0523] MS (ESI, [MH] - )m / z:253.96.

[0524] 1 H-NMR (500MHz, DMSO-d6): δ10.64(s,1H),7.16-7.12(m,1H),7.10-7.07(m,1H),1.67-1.62(m,2H),1.54-1.49(m,2H).

[0525] Step 2: Synthesis of intermediate 15-2

[0526] Intermediate 15-1 (0.7 g) was mixed with N,N-dimethylformamide (15 mL). Sodium hydroxide (0.33 g, 60% dispersion in mineral oil) was added under ice-cooling. The reaction mixture was stirred for 30 minutes. Methyl iodide (1.94 g) was added dropwise to the reaction mixture. The reaction mixture was transferred to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 1:4) to obtain 0.40 g of intermediate 15-2.

[0527] MS (ESI, [M+H] + )m / z:269.87.

[0528] 1 H-NMR (500MHz, DMSO-d6): δ7.41(d,J=6.0Hz,1H),7.20(d,J=8.5Hz,1H),3.20(s,3H),1.73-1.66(m,2H),1.59-1.53(m,2H).

[0529] Step 3: Synthesis of intermediate 15-3

[0530] Intermediate A-1 (400 mg), intermediate 15-2 (367 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (90 mg), potassium carbonate (376 mg), cuprous iodide (50 mg), and N-methylpyrrolidone (10 mL) were mixed and reacted at 100°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (petroleum ether:ethyl acetate = 3:2) to obtain 0.52 g of intermediate 15-3.

[0531] MS (ESI, [M+H] + )m / z:631.43.

[0532] 1H-NMR (500MHz, DMSO-d6): δ7.24(d,J=9.5Hz,1H),7.22-7.19(m,1H),7.12(d,J= 6.5Hz,2H),6.98(d,J=3.0Hz,1H),6.91(s,1H),5.19-5.03(m,1H),4.37-4.14(m, 1H),3.22(s,3H),3.17-3.07(m,1H),2.76-2.70(m,1H),2.69-2.62(m,1H),2.22( s,6H),1.74-1.70(m,2H),1.60-1.55(m,2H),1.44(s,9H),1.22(d,J=6.0Hz,3H).

[0533] Step 4: Synthesis of intermediate 15-4

[0534] Intermediate 15-3 (0.25 g), dichloromethane (5 mL) and 4N hydrochloric acid in dioxane solution (5 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.22 g of intermediate 15-4.

[0535] MS (ESI, [M+H] + )m / z:531.32.

[0536] Step 5: Synthesis of compound 15

[0537] Intermediate B-3 (0.07 g), N,N-dimethylformamide (3 mL), triethylamine (0.47 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.2 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 15-4 (0.1 g) was added thereto and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.06 g of compound 15.

[0538] HRMS: (ESI, [M+H] + )m / z:924.4020.

[0539] 1H-NMR (500MHz, DMSO-d6): δ11.77(s,1H),7.52(s,1H),7.41-7.40(m,1H),7.28-7.26(m,2H),7.2 4-7.20(m,3H),7.03-6.99(m,1H),6.93-6.89(m,2H),5.61-5.51(m,1H),4.45-4.34(m,1H),3.76 -3.71(m,2H),3.23(s,3H),3.19-3.13(m,2H),3.04-3.00(m,1H),2.91-2.84(m,1H),2.24(s,6H) ,1.76-1.70(m,4H),1.60-1.56(m,4H),1.46-1.40(m,3H),1.30-1.26(m,6H),1.20-1.16(m,6H).

[0540] Example 16

[0541] Step 1: Synthesis of intermediate 16-1

[0542] At -78°C, a 2N solution of lithium diisopropylamide in tetrahydrofuran (9 mL) was added to a mixed solution of 6-bromo-4-fluorodihydro-2-one (1 g) and tetrahydrofuran (5 mL). The mixture was stirred at this temperature for 30 minutes. A solution of 1,2-dibromoethane (2.44 g) in tetrahydrofuran (5 mL) was then added dropwise. After the addition was complete, the mixture was slowly warmed to room temperature and stirred overnight. The reaction was terminated and the reaction solution was poured into a saturated ammonium chloride solution (100 mL). The resulting solution was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 0.54 g of intermediate 16-1.

[0543] MS (ESI, [MH] - )m / z:253.91.

[0544] 1 H-NMR (500MHz, DMSO-d6): δ10.91(s,1H),7.07(dd,J=9.3,1.5Hz,1H),6.93(d,J=1.5Hz,1H),1.78(q,J=4.0Hz,2H),1.48(q,J=3.9Hz,2H).

[0545] Step 2: Synthesis of intermediate 16-2

[0546] Intermediate 16-1 (540 mg) and N,N-dimethylformamide (11 mL) were mixed, and sodium hydride (132 mg, 60% dispersion in mineral oil) was added under ice-cooling. The reaction mixture was stirred for 30 minutes. Methyl iodide (935 mg) was added dropwise to the reaction mixture, and the reaction mixture was transferred to room temperature and stirred for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 500 mg of Intermediate 16-2.

[0547] MS (ESI, [M+H] + )m / z:269.98.

[0548] 1 H-NMR (500MHz, DMSO-d6): δ7.25(d,J=1.7Hz,1H),7.15(dd,J=9.3,1.5Hz,1H),3.21(s,3H),1.82(q,J=4.0Hz,2H),1.53(q,J=4.0Hz,2H).

[0549] Step 3: Synthesis of intermediate 16-3

[0550] Intermediate A-1 (500 mg), intermediate 16-2 (500 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (100 mg), potassium carbonate (300 mg), cuprous iodide (70 mg) and N-methylpyrrolidone (10 mL) were mixed, and the mixture was placed in a microwave at 150 ° C. under nitrogen protection and stirred for 1 hour. The reaction solution was cooled to room temperature and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (50 mL), and the organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated, and separated and purified by concentration column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 0.4 g of intermediate 16-3.

[0551] MS (ESI, [M+H] + )m / z:631.44.

[0552] 1H-NMR (500MHz, DMSO-d6): δ7.42(d,J=3.4Hz,1H),7.36-7.28(m,2H),7.11(d,J=6.3Hz,2H),7.03(s,1H),5.14(s,1H),4.22(s,1H) ,3.23(s,3H),3.19-3.02(m,1H),2.67(m,1H),2.19(s,6H),1.82(m,2H),1.53(q,J=3.9Hz,2H),1.44(s,9H),1.18(t,J=7.2Hz,4H).

[0553] Step 4: Synthesis of intermediate 16-4

[0554] Intermediate 16-3 (0.4 g), dichloromethane (2 mL), and 4N hydrochloric acid in dioxane solution (4 mL) were mixed and stirred at room temperature for 1 hour. Stirring was stopped and the mixture was concentrated under reduced pressure to obtain 0.2 g of intermediate 16-4.

[0555] MS (ESI, [M+H] + )m / z:531.32

[0556] Step 5: Synthesis of compound 16

[0557] Intermediate B-3 (0.15 g), N,N-dimethylformamide (4 mL), triethylamine (0.72 g), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.4 g) were mixed and stirred for 5 minutes. Intermediate 16-4 (0.2 g) was then added, and the mixture was stirred at 30°C overnight. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 80 mg of compound 16.

[0558] HRMS: (ESI, [M+H] + )m / z:924.4023.

[0559] 1H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.50(d,J=35.6Hz,2H),7.43-7.23(m,5H),7.16( d,J=6.1Hz,2H),6.95(s,1H),5.58(s,1H),4.39(d,J=10.2Hz,1H),3.71(d,J=8.2Hz,2H),3. 24(s,4H),3.04(d,J=10.2Hz,2H),2.89(d,J=14.8Hz,1H),2.25(s,6H),1.82(d,J=7.6Hz,2H ),1.69(d,J=12.5Hz,5H),1.58(d,J=31.6Hz,7H),1.39(d,J=6.4Hz,3H),1.21-1.10(m,6H).

[0560] Example 17

[0561] Step 1: Synthesis of Intermediate 17-1

[0562] 6'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2'-one (0.72 g), copper acetate (0.80 g), 4-dimethylaminopyridine (1.54 g), and toluene (20 mL) were mixed, followed by the dropwise addition of 2N sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.21 mL). The reaction mixture was stirred at 95°C for 16 hours and then cooled to room temperature. The reaction mixture was poured into ethyl acetate (30 mL) and water (70 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 350 mg of Intermediate 17-1.

[0563] 1 H-NMR (500MHz, DMSO-d6): δ7.28(d,J=1.8Hz,1H),7.18(dd,J=7.9,1.8Hz,1H),6.95(d,J=7.9Hz,1H),2.72 (tt,J=7.2,3.8Hz,1H),1.58(q,J=4.0Hz,2H),1.48(q,J=4.0Hz,2H),1.03-0.98(m,2H),0.82-0.77(m,2H).

[0564] Step 2: Synthesis of intermediate 17-2

[0565] Cuprous iodide (43.1 mg), potassium carbonate (391 mg), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (40.3 mg), Intermediate A-1 (250 mg), Intermediate 17-1 (205 mg), and N-methylpyrrolidone (5 mL) were mixed. The reaction mixture was stirred at 125°C under nitrogen for 16 hours and then cooled to room temperature. The reaction mixture was poured into ethyl acetate (20 mL) and water (30 mL). The two phases were separated, and the aqueous phase was extracted with 20 mL x 2. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 210 mg of Intermediate 17-2.

[0566] MS (ESI, [M+H] + )m / z:639.48.

[0567] Step 3: Synthesis of intermediate 17-3

[0568] Intermediate 17-2 (200 mg), dichloromethane (2 mL), and 4N hydrochloric acid in dioxane solution (4 mL) were mixed, stirred at room temperature for 1.5 hours, and concentrated under reduced pressure to obtain 180 mg of intermediate 17-3.

[0569] MS (ESI, [M+H] + )m / z:539.35.

[0570] Step 4: Synthesis of intermediate 17-4 and compound 17

[0571] Intermediate B-1 (114 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (317 mg), triethylamine (563 mg), and N,N-dimethylformamide (3 mL) were mixed and stirred at room temperature for 10 minutes. Intermediate 17-3 (160 mg) was then added and stirred at room temperature for 16 hours. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 60 mg of Intermediate 17-4. Intermediate 17-4 was separated by chiral HPLC (chromatographic column: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: ethanol / 0.1% ammonia water: n-hexane = 30:70, isocratic elution) to give compound 17 (18 mg).

[0572] Compound 17: Rt = 2.01 min (UPCC conditions: column: CHIRALPAK IB, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide:methanol / 0.1% ammonia water = 30:70; flow rate: 0.5 mL / min; column temperature: 40°C)

[0573] HRMS: (ESI, [M+H] + )m / z:932.4291.

[0574] 1 H NMR (500MHz, DMSO-d6): δ11.76(s,1H),7.51(d,J=17.9Hz,1H),7.40(dd,J=8.6,4.0Hz,1H),7.35(d,J=17.7Hz,2H),7.28-7.20(m,2H),7.1 7(d,J=6.7Hz,2H),7.09(s,1H),6.98(d,J=28.8Hz,2H),5.58(d,J=6.3Hz,1H),4.38(d,J=11.9Hz,1H),3.71(d,J=7.9Hz,2H),3.51(s,1H), 3.18(s,1H),3.03(t,J=12.1Hz,1H),2.89(d,J=16.5Hz,1H),2.75(s,1H),2.21(d,J=16.5Hz,5H),1.68(s,2H),1.59(d,J=3.5Hz,2H),1.50 (t,J=3.7Hz,2H),1.41(d,J=3.5Hz,2H),1.34(d,J=7.8Hz,3H),1.30(s,3H),1.28(s,2H),1.26(s,4H),1.23(s,4H),1.19(d,J=2.6Hz,4H).

[0575] Example 18

[0576] Step 1: Synthesis of intermediate 18-1

[0577] Intermediate A-2 (400 mg), intermediate 5-2 (320 mg), (1S,2S)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (64 mg), potassium carbonate (400 mg), cuprous iodide (38 mg) and N-methylpyrrolidone (8 mL) were mixed, and the mixture was placed in a microwave reaction at 140 ° C under nitrogen protection for 1 hour. The reaction solution was cooled to room temperature and poured into water (50 mL). The resulting solution was extracted with ethyl acetate (50 mL), and the organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated, and separated and purified by concentration column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 0.45 g of intermediate 18-1.

[0578] MS (ESI, [M+H] + )m / z:625.43.

[0579] 1 H-NMR (500MHz, DMSO-d6): δ7.37(s,1H),7.34(d,J=3.2Hz,1H),7.31-7.28(m,1H),7.27-7.23 (m,2H),7.11(d,J=7.9Hz,1H),6.98(s,1H),6.87(dd,J=6.8,2.5Hz,1H),5.13(s,1H),4.21(s ,1H),3.25(s,3H),3.19-3.00(m,1H),2.83-2.61(m,2H),2.10-2.01(m,1H),1.64(q,J=3.9Hz ,2H),1.53(q,J=3.7Hz,2H),1.43(s,9H),1.21-1.17(m,3H),0.95(m,2H),0.63-0.49(m,2H).

[0580] Step 2: Synthesis of intermediate 18-2

[0581] Intermediate 18-1 (0.45 g), dichloromethane (2 mL), and 4N hydrochloric acid in dioxane solution (10 mL) were mixed and stirred at room temperature for 1 hour. Stirring was stopped and the mixture was concentrated under reduced pressure to obtain 0.33 g of intermediate 18-2.

[0582] MS (ESI, [M+H] + )m / z:525.23.

[0583] 1H-NMR (500MHz, DMSO-d6): δ7.36(d,J=2.0Hz,1H),7.33(d,J=3.4Hz,1H),7.29(dd,J =8.0,2.1Hz,1H),7.27-7.22(m,2H),7.10(d,J=8.1Hz,1H),6.95-6.89(m,1H),6.89 -6.84(m,1H),4.10(s,1H),4.00(q,J=6.6Hz,1H),3.27(q,J=3.9Hz,1H),3.17(s,3H),2.98 -2.85(m,1H),2.77-2.60(m,2H),2.11-1.97(m,1H),1.63(q,J=4.0Hz,2H),1.53(q, J=3.8Hz,2H),1.13(d,J=6.6Hz,3H),0.95(dd,J=8.4,2.1Hz,2H),0.67-0.49(m,2H).

[0584] Step 3: Synthesis of intermediate 18-3 and compound 18

[0585] Intermediate B-1 (0.155 g), N,N-dimethylformamide (4 mL), triethylamine (0.075 g), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.18 g) were mixed and stirred for 5 minutes. Intermediate 18-2 (0.16 g) was then added and stirred at 30°C. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain Intermediate 18-3. The intermediate 18-3 was separated by chiral HPLC (mobile phase A: ethanol-dichloromethane (1:1), B: n-hexane, mobile phase A:B = 30%:70%, flow rate: 40 mL / min; column temperature: 25°C; chromatographic column: CHIRALART Cellulose-SB) to obtain 80 mg of compound 18.

[0586] Compound 18: Rt = 2.08 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm), mobile phase: carbon dioxide: methanol (0.1% ammonia) = 30:70; flow rate: 2 ml / min, column temperature: 40°C)

[0587] HRMS: (ESI, [M+H] + )m / z:918.4135.

[0588] 1H-NMR (500MHz, DMSO-d6): δ11.74(s,1H),7.53(s,1H),7.42-7.35(m,3H),7.29(dq,J =19.5,9.0Hz,5H),7.12(d,J=8.0Hz,1H),7.03-6.89(m,3H),5.65-5.49(m,1H),4.47 -4.31(m,1H),3.71(d,J=8.2Hz,3H),3.66-3.54(m,1H),3.24(s,3H),3.22-3.13(m,1H),3 .03(t,J=12.2Hz,1H),2.90(d,J=15.2Hz,1H),2.83-2.66(m,1H),2.13-1.95(m,2H),1.70 -1.61(m,6H),1.56-1.53(m,3H),1.40(d,J=5.9Hz,2H),1.20-1.13(m,6H),0.99(s,3H),0.60(dd,J=8.8,4.1Hz,3H).

[0589] Example 19

[0590] Step 1: Synthesis of intermediate 19-1 and compound 19

[0591] Intermediate B-2 (0.07 g) and N,N-dimethylformamide (2 mL) were mixed, followed by triethylamine (178 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (134 mg). After stirring for 10 minutes, Intermediate 5-4 (0.09 g) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 98:2) to obtain 60 mg of Intermediate 19-1. Intermediate 19-1 was isolated by chiral HPLC (mobile phase: n-hexane:ethanol = 80:20; flow rate: 40 mL / min; column temperature: 25°C; column: YMC CHIRALART Cellulose-SB 30×250) to obtain 20 mg of Compound 19.

[0592] Compound 19: Rt = 3.55 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm), mobile phase: carbon dioxide: methanol (0.1% ammonia) = 60:40; flow rate: 2 ml / min, column temperature: 40°C)

[0593] HRMS: (ESI, [M+H]+ )m / z:892.3960.

[0594] 1 H-NMR (500MHz, DMSO-d6): δ12.08(s,1H),7.48(d,J=10.0Hz,1H),7.40(d,J=8.7Hz,1H),7.38-7.35(m,1H),7.34-7.32(m,1H),7.29(d,J=7.9Hz,1 H),7.26(dd,J=8.6,2.5Hz,1H),7.22(d,J=8.5Hz,1H),7.17-7.10(m,2H) ,6.91-6.89(m,1H),6.70(s,1H),3.72(d,J=8.9Hz,2H),3.24(s,3H),3.08 -3.02(m,1H),2.86-2.79(m,1H),2.72(t,J=8.0Hz,1H),2.55-2.52(m,1H ),2.19(d,J=15.4Hz,6H),1.65-1.62(m,2H),1.53-1.51(m,2H),1.36-1.3 5(m,3H),1.34-1.33(m,2H),1.31-1.29(m,3H),1.28-1.27(m,3H),1.26- 1.25(m,2H),1.24-1.23(m,2H),1.23-1.22(m,2H),1.18(d,J=4.4Hz,2H).

[0595] Example 20

[0596] Step 1: Synthesis of intermediate 20-1 and compound 20

[0597] Intermediate B-2 (0.083 g), N,N-dimethylformamide (2 mL), triethylamine (0.265 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.109 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 6-3 (0.10 g) was added and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.12 g of intermediate 20-1. The intermediate 20-1 was separated by chiral HPLC (chromatographic column: Pre-packed REGIS IB, 30×250 mm, 10 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 30:70; flow rate: 40 mL / min) to obtain 33 mg of compound 20.

[0598] Compound 20: Rt = 7.47 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40°C)

[0599] HRMS: (ESI, [M+H] + )m / z:904.3973.

[0600] 1 H-NMR (500MHz, DMSO-d6): δ12.09(s,1H),7.52-7.43(m,2H),7.42-7.35(m,2H),7.34-7.18(m,4H),7.15-7.0 9(m,1H),7.03-6.97(m,1H),6.93-6.87(m,1H),6.85-6.65(m,1H),3.78-3.64(m,2H),3.24(s,1H),3.04(s,1H ),2.91-2.77(m,1H),2.10-1.96(m,1H),1.82(s,2H),1.75-1.58(m,6H),1.57-1.45(m,4H),1.37-1.34(m,3H) ,1.31-1.27(m,5H),1.26(s,3H),1.20-1.17(m,2H),1.02-0.91(m,2H),0.90-0.79(m,2H),0.66-0.50(m,2H).

[0601] Example 21

[0602] Step 1: Synthesis of Intermediate 21-1

[0603] A 2N solution of lithium diisopropylamide in tetrahydrofuran (46.7 mL) was added to a mixture of 5-bromo-2-oxindole (5 g) and tetrahydrofuran (50 mL) at -5°C and stirred for 30 minutes. 1,3-Dibromopropane (14.28 g) was then added to the reaction mixture and allowed to react at room temperature for 12 hours. The reaction mixture was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified on a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain 1.9 g of Intermediate 21-1.

[0604] MS (ESI, [M+H] + )m / z:251.98.

[0605] 1 H NMR (500MHz, DMSO-d6): δ10.34(s,1H),7.75(d,J=2.1Hz,1H),7.33(dd,J=8.2,2.1Hz ,1H),6.74(d,J=8.1Hz,1H),2.44-2.37(m,2H),2.36-2.29(m,2H),2.22-2.14(m,2H).

[0606] Step 2: Synthesis of intermediate 21-2

[0607] Intermediate 21-1 (0.7 g) was mixed with N,N-dimethylformamide (10 mL). Sodium hydroxide (0.14 g, 60% dispersion in mineral oil) was added under ice-cooling. The reaction mixture was stirred for 10 minutes. Methyl iodide (0.51 g) was added dropwise to the reaction mixture. The reaction mixture was transferred to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 88:12) to obtain 0.58 g of intermediate 21-2.

[0608] MS (ESI, [M+H] + )m / z:266.06.

[0609] 1H NMR (500MHz, DMSO-d6): δ7.82(d,J=2.0Hz,1H),7.45(dd,J=8.3,2.0Hz,1H),6.92(d, J=8.2Hz,1H),3.09(s,3H),2.46-2.39(m,2H),2.38-2.31(m,2H),2.25-2.17(m,2H).

[0610] Step 3: Synthesis of intermediate 21-3

[0611] Intermediate A-1 (220 mg), intermediate 21-2 (172 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (42.5 mg), potassium carbonate (207 mg), cuprous iodide (28.5 mg), and N-methylpyrrolidone (6 mL) were mixed and reacted at 130°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (petroleum ether:ethyl acetate = 55:45) to obtain 0.26 g of intermediate 21-3.

[0612] MS (ESI, [M+H] + )m / z:627.45.

[0613] 1 H NMR (500MHz, DMSO-d6): δ7.81(d,J=2.2Hz,1H),7.50(dd,J=8.4,2.2Hz,1H),7.27(d,J=3.2 Hz,1H),7.12(d,J=6.2Hz,2H),7.04(d,J=8.4Hz,1H),6.94(s,1H),5.14(s,1H),4.23(s,1H ),3.13(s,3H),2.77-2.72(m,1H),2.70(s,2H),2.48-2.41(m,2H),2.40-2.32(m,2H),2.20 (d,J=2.0Hz,6H),2.17(d,J=8.2Hz,2H),1.92-1.88(m,1H),1.44(s,9H),1.23-1.20(m,2H).

[0614] Step 4: Synthesis of intermediate 21-4

[0615] Intermediate 21-3 (0.25 g), dichloromethane (5 mL) and 4N hydrochloric acid dioxane solution (5 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.21 g of intermediate 21-4.

[0616] MS (ESI, [M+H] + )m / z:527.35.

[0617] Step 5: Synthesis of intermediate 21-5 and compound 21

[0618] Intermediate B-1 (100 mg), N,N-dimethylformamide (5 mL), triethylamine (0.678 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (277 mg) were mixed and stirred at room temperature for 5 minutes. Intermediate 21-5 (151 mg) was added and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 97:3) to obtain 0.18 g of intermediate 21-5. The intermediate 21-5 was separated by chiral HPLC (chromatographic column: CHIRAL ART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: ethanol-dichloromethane (3:2):n-hexane = 27:73; flow rate: 40 mL / min) to obtain 60 mg of compound 21.

[0619] Compound 21: Rt = 2.78 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 ml / min; column temperature: 40°C)

[0620] HRMS: (ESI, [M+H] + )m / z:920.4281.

[0621] 1H-NMR (500MHz, DMSO-d6): δ11.74(s,1H),7.83(s,1H),7.57-7.50(m,2H),7.42-7.38(m,1H),7.31(d,J=3.2Hz,1H),7.26(d,J=8 .4Hz,1H),7.19-7.15(m,2H),7.05(d,J=8.4Hz,1H),7.00-6.90(m,2H),5.64-5.52(m,1H),4.43-4.34(m,1H),3.74-3.69(m,2H) ,3.13(s,3H),3.11-3.06(m,1H),3.05-2.99(m,1H),2.92-2.86(m,1H),2.69(s,1H),2.47-2.41(m,2H),2.40-2.35(m,2H),2.23 (s,6H),2.21-2.18(m,2H),1.74-1.65(m,4H),1.62-1.48(m,5H),1.42(d,J=6.6Hz,2H),1.34(s,2H),1.30(s,2H),1.18(s,4H).

[0622] Example 22

[0623] Step 1: Synthesis of Intermediate 22-1

[0624] 4-Bromopyridine-2-carboxaldehyde (25 g), ethyl acrylate (26.9 g) and triethylenediamine (9.8 g) were mixed and stirred at room temperature overnight, then concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 34.2 g of intermediate 22-1.

[0625] MS (ESI, [M+H] + )m / z:286.04.

[0626] 1 H-NMR (500MHz, DMSO-d6): δ8.35(d,J=5.3Hz,1H),7.68(d,J=2.0Hz,1H),7.54(dd,J=5.2,2.0Hz,1H),6.22(s,1H ),6.06(d,J=5.7Hz,1H),5.90(t,J=1.5Hz,1H),5.48(d,J=5.7Hz,1H),4.16–3.99(m,2H),1.10(t,J=7.1Hz,3H).

[0627] Step 2: Synthesis of intermediate 22-2

[0628] Intermediate 22-1 (33.2 g) and dichloromethane (300 mL) were mixed and cooled in an ice-water bath. Pyridine (9.18 g) was added, followed by the slow dropwise addition of acetyl chloride (9.11 g). After addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (200 mL), and the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 35 g of intermediate 22-2.

[0629] MS (ESI, [M+H+2] + )m / z:330.04.

[0630] 1 H-NMR (500MHz, DMSO-d6): δ8.42(d,J=5.3Hz,1H),7.73(d,J=1.8Hz,1H),7.65(dd,J=5.3,1.9Hz,1 H),6.53(s,1H),6.37(s,1H),5.87(s,1H),4.12-4.08(m,2H),2.15(s,3H),1.14(t,J=7.1Hz,3H).

[0631] Step 3: Synthesis of intermediate 22-3

[0632] Intermediate 22-2 (39 g) and toluene (250 mL) were mixed and heated to 120°C overnight. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 6.4 g of intermediate 22-3.

[0633] MS (ESI, [M+H+2] + )m / z:270.05.

[0634] 1 H-NMR (500MHz, DMSO-d6): δ8.26(d,J=7.4Hz,1H),8.13(d,J=1.6Hz,1H),7.78(d,J=2.1Hz, 1H), 6.78 (dd, J=7.4, 2.1Hz, 1H), 6.74 (s, 1H), 4.27 (q, J=7.1Hz, 2H), 1.30 (t, J=7.1Hz, 3H).

[0635] Step 4: Synthesis of intermediate 22-4

[0636] Intermediate 22-3 (3.6 g), 1,4-dioxane (50 mL), pinacol borate (4.43 g), potassium acetate (2.64 g), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (0.49 g) were mixed and heated to 90°C under nitrogen overnight. Heating was stopped, and the mixture was cooled to room temperature. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 4.1 g of intermediate 22-4.

[0637] MS (ESI, [M+H] + )m / z:316.19.

[0638] 1 H-NMR (500MHz, DMSO-d6): δ8.24(d,J=7.0Hz,1H),8.16(d,J=1.7Hz,1H),7.88(s,1H) ,6.94(s,1H),6.74(dd,J=7.0,1.2Hz,1H),4.28(q,J=7.1Hz,2H),1.32-1.28(m,15H).

[0639] Step 5: Synthesis of intermediate 22-5

[0640] Intermediate 22-4 (4.1 g), 1,4-dioxane (2 ml), water (0.2 mL), a mixture of 6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate and 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (5.08 g), potassium carbonate (3.60 g), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (0.48 g) were heated to 90°C under nitrogen for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 3.6 g of intermediate 22-5.

[0641] MS (ESI, [M+H] + )m / z:300.19.

[0642] Step 6: Synthesis of Intermediate 22-6

[0643] Intermediate 22-5 (4.1 g) and methanol (80 mL) were mixed, 10% Pd / C (1.46 g) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The mixture was filtered and concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 2.6 g of intermediate 22-6.

[0644] MS (ESI, [M+H] + )m / z:302.20.

[0645] 1 H-NMR (500MHz, DMSO-d6): δ8.21(d,J=7.3Hz,1H),7.99(d,J=1.6Hz,1H),7.26-7.20(m,1H),6.62-6.61(m,2H),4.25(q,J=7.0Hz,2H),3 .73-3.64(m,2H),2.85(tt,J=12.4,3.6Hz,1H),1.72-1.65(m,2H),1.55-1.39(m,2H),1.29(t,J=7.1Hz,3H),1.24(s,3H),1.18(s,3H).

[0646] Step 7: Synthesis of Intermediate 22-7

[0647] Intermediate 22-6 (2.35 g), dimethyl sulfoxide (40 mL), iodoacetonitrile (3.91 g), and ferrous sulfate heptahydrate (1.08 g) were mixed and cooled in an ice-water bath. Hydrogen peroxide (4.78 mL) was added dropwise. After addition, stirring was continued for 2 hours. The reaction solution was poured into saturated sodium sulfite solution (100 mL) and ethyl acetate (100 mL). The layers were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 1 g of Intermediate 22-7.

[0648] MS (ESI, [M+H] + )m / z:341.27.

[0649] 1H-NMR (500MHz, DMSO-d6): δ8.26(d,J=7.4Hz,1H),7.35(s,1H),6.85(dd,J=7.4,1.9Hz,1H),6.76(s,1H),4.66(s,2H),4.31(q,J=7.1Hz,2H ),3.76-3.67(m,2H),2.92(tt,J=12.5,3.6Hz,1H),1.74-1.65(m,2H),1.57-1.42(m,2H),1.33(t,J=7.1Hz,3H),1.26(s,3H),1.19(s,3H).

[0650] Step 8: Synthesis of Intermediate 22-8

[0651] Intermediate 22-7 (0.31 g), tetrahydrofuran (6 mL), (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (0.38 g), and N,N-dimethylpropyleneurea (0.23 g) were mixed and cooled to 0°C in an ice-salt bath under nitrogen. A 1N solution of lithium bistrimethylsilylamide in tetrahydrofuran (5.46 mL) was then slowly added dropwise. After the addition, the mixture was stirred at 0°C for 1 hour. The reaction solution was poured into saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 0.51 g of the isomer. The isomers obtained above were prepared by HPLC (instrument: YMC high pressure preparative chromatograph; chromatographic column: Ultimate XB-C18, 30×250 mm, 10 μm; mobile phase: water-acetonitrile (35:65)) to obtain 0.19 g of intermediate 22-8.

[0652] Compound 22-8: Rt = 2.73 min (UPLC conditions: Column: Waters UPLC BEH C18 (50 × 2.1 mm, 1.7 μm), Mobile phase: 10 mM ammonium acetate buffer (with 0.1% glacial acetic acid)-acetonitrile (50:50):acetonitrile = 10:90, Flow rate: 0.6 mL / min, Column temperature: 40°C)

[0653] MS (ESI, [M+H] + )m / z:381.34.

[0654] 1H-NMR (500MHz, DMSO-d6): δ8.16(d,J=6.8Hz,1H),7.37(s,1H),6.87(dd,J=7.4,1.8Hz,1H),6.75(s,1H),4.37-4.26(m,2H),3.77- 3.65(m,2H),2.94(tt,J=12.3,3.6Hz,1H),1.70-1.67(m,4H),1.61-1.42(m,6H),1.34(t,J=7.1Hz,3H),1.26(s,3H),1.19(s,3H).

[0655] Step 9: Synthesis of Intermediate 22-9

[0656] Intermediate 22-8 (0.73 g), dimethyl sulfoxide (5 mL), hydroxylamine hydrochloride (0.67 g), and sodium bicarbonate (0.81 g) were mixed and heated to 65°C for overnight reaction. The reaction mixture was cooled to room temperature and poured into water (50 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.72 g of intermediate 22-9.

[0657] MS (ESI, [M+H] + )m / z:414.42.

[0658] Step 10: Synthesis of Intermediate 22-10

[0659] Intermediate 22-9 (0.72 g), dimethyl sulfoxide (7 mL), N,N'-carbonyldiimidazole (0.57 g), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.66 g) were mixed and stirred at room temperature for 3 hours. Stirring was stopped, and the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL). The aqueous phase was adjusted to pH 6-7 with 2N hydrochloric acid solution and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.6 g of intermediate 22-10.

[0660] MS (ESI, [M+H] + )m / z:440.31.

[0661] Step 11: Synthesis of Intermediate 22-11

[0662] Intermediate 22-10 (0.6 g), tetrahydrofuran (6 mL), water (1 mL), and potassium hydroxide (0.31 g) were mixed and heated to 70°C for 8 hours. Heating was stopped, the reaction mixture was cooled to room temperature, poured into water (80 mL), and extracted with ethyl acetate (20 mL). The aqueous phase was collected, the pH was adjusted to 4-5 with 2N hydrochloric acid solution, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.35 g of intermediate 22-11.

[0663] MS (ESI, [M+H] + )m / z:412.34.

[0664] 1 H-NMR (500MHz, DMSO-d6): δ12.58-11.62(m,2H),8.06-7.92(m,1H),7.36-7.23(m,1H),6.79-6.73(m,1H),6.72-6.63(m,1H) ),3.75-3.64(m,2H),2.96-2.85(m,1H),1.94-1.78(m,1H),1.76-1.63(m,3H),1.57-1.36(m,3H),1.25(s,6H),1.18(s,3H).

[0665] Step 12: Synthesis of intermediate 22-12 and compounds 22-A and 22-B

[0666] Intermediate 22-11 (0.1 g), Intermediate A-1 (0.15 g), N,N-dimethylformamide (3 mL), triethylamine (0.49 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g) were mixed and added. The mixture was stirred at room temperature for 4 hours. Stirring was stopped, and the reaction mixture was poured into water (50 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 65 mg of Intermediate 22-12. The intermediate 22-12 was prepared and separated by chiral HPLC (chromatographic column: REGIS IB, 30×250 mm, 10 μm; mobile phase: carbon dioxide:ethanol (containing 0.1% ammonia) = 65:35; flow rate: 80 mL / min) to obtain compound 22-A (25 mg) and compound 22-B (22 mg).

[0667] Compound 22-A: Rt = 2.06 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol (containing 0.1% ammonia) = 50:25:25; flow rate: 2.0 mL / min; column temperature: 40°C)

[0668] HRMS: (ESI, [M+H] + )m / z:906.4132.

[0669] 1 H-NMR (500MHz, DMSO-d6): δ11.91(s,1H),8.09-8.00(m,1H),7.58-7.48(m,1H),7.36-7.23(m,2H),7 .22-7.03(m,4H),6.98-6.43(m,3H),5.63(q,J=6.6Hz,1H),4.16-4.03(m,1H),3.78-3.64(m,2H),3. 52-3.41(m,1H),3.26-3.19(m,3H),3.02-2.83(m,2H),2.80-2.69(m,1H),2.25-2.13(m,6H),1.76-1 .63(m,4H),1.60-1.49(m,5H),1.38-1.34(m,3H),1.27-1.23(m,5H),1.19(s,3H),1.17-1.12(m,3H).

[0670] Compound 22-B: Rt = 1.74 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol (containing 0.1% ammonia) = 50:25:25; flow rate: 2.0 mL / min; column temperature: 40°C)

[0671] HRMS: (ESI, [M+H] + )m / z:906.4122.

[0672] 1H-NMR (500MHz, DMSO-d6): δ11.95(s,1H),8.10-8.00(m,1H),7.57-7.50(m,1H),7.37-7.24(m,2H),7 .22-6.92(m,5H),6.82-6.41(m,2H),5.63(q,J=6.7Hz,1H),4.19-3.99(m,1H),3.79-3.62(m,2H),3. 54-3.40(m,1H),3.27-3.19(m,3H),3.03-2.84(m,2H),2.83-2.71(m,1H),2.26-2.15(m,6H),1.76-1 .63(m,4H),1.61-1.51(m,5H),1.40-1.35(m,3H),1.28-1.21(m,5H),1.19(s,3H),1.17-1.11(m,3H).

[0673] Example 23

[0674] Step 1: Synthesis of Intermediate 23-1

[0675] Combine 4-bromo-7-fluoroindanone (1 g) and methanol (10 mL), cool in an ice-water bath, and add sodium borohydride (0.330 g) portionwise. Remove the ice bath after addition and stir at room temperature for 2 hours. Pour the reaction mixture into water (100 mL) and stir to precipitate a large amount of precipitate. Filter the filter cake and dry it in vacuo to obtain 0.7 g of Intermediate 23-1.

[0676] 1 H-NMR (500MHz, DMSO-d6): δ7.49 (dd, J=8.6, 4.4Hz, 1H), 7.04-6.96 (m, 1H), 5.43-5.38 (m, 1H), 5.36-5.29(m,1H),3.06-2.95(m,1H),2.81-2.66(m,1H),2.38-2.25(m,1H),1.96-1.85(m,1H).

[0677] Step 2: Synthesis of intermediate 23-2

[0678] Intermediate 23-1 (5 g) and dichloromethane (60 mL) were mixed and cooled to -78°C under nitrogen. Triethylsilane (7.55 g) and boron trifluoride etherate (8.23 mL) were then added dropwise. After addition, the mixture was naturally warmed to room temperature and stirred overnight. The reaction solution was poured into saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0) to obtain 4.3 g of intermediate 23-2.

[0679] 1 H-NMR (500MHz, DMSO-d6): δ7.40-7.34(m,1H),7.00-6.94(m,1H),3.01(t,J=7.6Hz,2H),2.90(t,J=7.6Hz,2H),2.09(p,J=7.6Hz,2H).

[0680] Step 3: Synthesis of intermediate 23-3

[0681] Intermediate 23-2 (2 g), tert-butyl carbazate (2.46 g), toluene (10 mL), sodium tert-butoxide (1.79 g), 5-di-tert-butylphosphino-1',3',5'-triphenyl-1'H-[1,4']dipyrazole (0.94 g), and palladium chloride (π-cinnamyl) dimer (0.24 g) were heated to 115°C under nitrogen for 5 hours. Heating was stopped, the mixture was cooled to room temperature, and the reaction solution was poured into water (100 mL). Extraction was performed with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 1.7 g of intermediate 23-3.

[0682] 1 H-NMR (500MHz, DMSO-d6): δ8.75(s,1H),7.02(s,1H),6.77(t,J=8.8Hz,1H),6.52-6.26( m,1H),2.82(t,J=7.5Hz,2H),2.73(t,J=7.5Hz,2H),2.03(p,J=7.6Hz,2H),1.41(s,9H).

[0683] Step 4: Synthesis of intermediate 23-5

[0684] Intermediate 23-3 (1.7 g), dichloromethane (20 mL), and trifluoroacetic acid (8.85 mL) were mixed and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue was redissolved in ethanol (20 mL). Intermediate 23-4 (1.52 g) and pyridine hydrochloride (0.074 g) were then added, and the mixture was heated to 85°C and stirred for 3 hours. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain 2.1 g of intermediate 23-5.

[0685] MS (ESI, [M+H] + )m / z:387.33.

[0686] 1 H-NMR (500MHz, DMSO-d6): δ7.13(dd,J=8.6,4.7Hz,1H),7.04(t,J=8.5Hz,1H),5.17-4.91(m,3H),4.21-3.98(m,1H),3.13 -2.90(m,3H),2.90-2.81(m,1H),2.80-2.69(m,1H),2.48-2.40(m,2H),2.10-2.00(m,2H),1.43(s,9H),1.27-1.20(m,3H).

[0687] Step 5: Synthesis of intermediate 23-6

[0688] Intermediate 23-5 (2.0 g) and tetrahydrofuran (60 mL) were mixed and cooled in an ice-water bath. Triethylamine (2.62 g) and triphosgene (1.55 g) were added. After addition, the mixture was naturally warmed to room temperature and stirred for 1 hour. Aminoacetaldehyde dimethyl acetal (2.72 g) was added and the mixture was naturally warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (40 mL x 3). The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain 1.38 g of intermediate 23-6.

[0689] MS (ESI, [M+H] + )m / z:518.4.

[0690] Step 6: Synthesis of Intermediate 23-7

[0691] Intermediate 23-6 (1.38 g), tetrahydrofuran (30 mL), and methanesulfonic acid (0.13 g) were heated to 60°C for 6 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 0.9 g of intermediate 23-7.

[0692] MS (ESI, [M+H] + )m / z:454.38.

[0693] Step 7: Synthesis of Intermediate 23-8

[0694] Intermediate 23-7 (0.4 g), Intermediate 1-2 (0.33 g), N-methylpyrrolidone (4 mL), potassium carbonate (0.37 g), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.063 g), and cuprous iodide (0.067 g) were mixed and heated to 130°C under nitrogen for 3 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 0.56 g of Intermediate 23-8.

[0695] MS (ESI, [M+H] + )m / z:625.42.

[0696] Step 8: Synthesis of Intermediate 23-9

[0697] Intermediate 23-8 (0.56 g), dichloromethane (5 mL), and 4N hydrochloric acid in dioxane (4 mL) were mixed, stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain 0.56 g of Intermediate 23-9.

[0698] MS (ESI, [M+H] + )m / z:525.35.

[0699] Step 9: Synthesis of intermediate 23-10 and compound 23

[0700] Intermediate B-1 (0.2 g), N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.55 g), and triethylamine (0.98 g) were mixed and stirred at room temperature for 5 minutes. A solution of Intermediate 23-9 (0.31 g) in N,N-dimethylformamide (1 mL) was then added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 65 mg of Intermediate 23-10. The intermediate 23-10 was separated by chiral HPLC (chromatographic column: REGIS IB, 30×250 mm, 10 μm; mobile phase: n-hexane-ethanol (70:30): dichloromethane = 2:1; flow rate: 40 mL / min) to obtain compound 23 (23 mg).

[0701] Compound 23: Rt = 3.31 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 50:50; flow rate: 2.0 mL / min; column temperature: 40°C)

[0702] HRMS: (ESI, [M+H] + )m / z:918.4122.

[0703] 1 H-NMR (500MHz, DMSO-d6): δ11.74(s,1H),7.59-7.22(m,5H),7.20-7.04(m,3H),7.02-6.93(m, 1H),6.92-6.65(m,2H),5.66-5.52(m,1H),4.44-4.31(m,1H),3.81-3.58(m,3H),3 .26-3.16(m,3H),3.08-2.99(m,1H),2.97-2.88(m,2H),2.88-2.81(m,2H),2.76-2 .69(m,1H),2.59-2.53(m,1H),2.10-1.89(m,3H),1.83-1.44(m,11H),1.39-1.37( m,1H),1.34-1.33(m,2H),1.25-1.23(m,4H),1.20-1.17(m,2H),1.16-1.12(m,2H).

[0704] Example 24

[0705] Intermediate 22-11 (0.1 g), Intermediate 6-2 (0.15 g), N,N-dimethylformamide (3 mL), triethylamine (0.49 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g) were added and stirred at room temperature overnight. Stirring was stopped, and the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was separated and purified by column chromatography (dichloromethane:methanol = 95:5) to obtain 65 mg of Intermediate 24-1. The intermediate 24-1 was separated by chiral HPLC (chromatographic column: REGIS IB, 30×250 mm, 10 μm; mobile phase: n-hexane:ethanol = 56:44; flow rate: 40 mL / min) to obtain compound 24 (21 mg).

[0706] Compound 24: Rt = 1.28 min (UPCC conditions: column: CHIRALPAK IB-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: ethanol: isopropanol (containing 0.1% ammonia) = 30:35:35; flow rate: 2.0 mL / min; column temperature: 40°C)

[0707] HRMS: (ESI, [M+H] + )m / z:918.4085.

[0708] 1 H-NMR (500MHz, DMSO-d6): δ11.97(s,1H),8.13-7.97(m,1H),7.60-7.51(m,1H),7.36-7.09(m,6H),7.07 -6.50(m,4H),5.78-5.54(m,1H),4.31-4.05(m,1H),3.83-3.65(m,2H),3.53-3.41(m,1H),3.27-3.18(m, 3H),3.04-2.88(m,2H),2.85-2.73(m,1H),2.10-1.98(m,1H),1.72-1.64(m,3H),1.61-1.51(m,5H),1.3 9-1.33(m,3H),1.28-1.22(m,6H),1.19(s,3H),1.17-1.11(m,3H),1.01-0.90(m,2H),0.64-0.51(m,2H).

[0709] Example 25

[0710] Step 1: Synthesis of intermediate 25-1

[0711] Pyridine-N-oxide (2 g) and dichloromethane (15 mL) were mixed, and benzoyl chloride (2.96 g) was added under ice-cooling. The reaction was stirred for 30 minutes, and 1-morpholinocyclopentene (4.19 g) was added. The mixture was heated to 40°C and reacted for 12 hours. After the reaction, the reaction solution was poured into a 20% aqueous hydrochloric acid solution. The pH of the aqueous phase was adjusted to 8-9 with a 5N aqueous sodium hydroxide solution. Dichloromethane (100 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain 1.56 g of intermediate 25-1.

[0712] MS (ESI, [M+H] + )m / z:162.12.

[0713] Step 2: Synthesis of intermediate 25-2

[0714] Intermediate 25-1 (1.37 g), methanol (60 ml), hydroxylamine hydrochloride (0.95 g), and potassium acetate (1.67 g) were mixed and stirred at 70°C for 1 hour. After the reaction, the reaction solution was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.43 g of intermediate 25-2.

[0715] MS (ESI, [M+H] + )m / z:177.32.

[0716] 1 H-NMR (500MHz, DMSO-d6): δ10.35(s,1H),8.49-8.45(m,1H),7.71-7.68(m,1H),7.28-7.26(m,1H),7.21-7.18(m,1H),3.85-3 .84(m,1H),2.55-2.52(m,1H),2.41-2.34(m,1H),2.18-2.09(m,1H),2.07-2.01(m,1H),1.93-1.89(m,1H),1.73-1.67(m,1H).

[0717] Step 3: Synthesis of intermediate 25-3

[0718] Intermediate 25-2 (1.43 g) and dichloromethane (20 mL) were mixed, and p-toluenesulfonyl chloride (1.70 g) and triethylamine (1.23 g) were added under ice-cooling. The mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was poured into water and extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 20:1) to obtain 0.68 g of intermediate 25-3.

[0719] MS (ESI, [M+H] + )m / z:159.12.

[0720] 1 H-NMR (500MHz, DMSO-d6): δ8.54-8.51(m,1H),7.46-7.42(m,1H),7.12-7.07(m,1H),6.70-6.66(m,1H),2.85-2.77(m,4H),2.48-2.42(m,2H).

[0721] Step 4: Synthesis of intermediate 25-4

[0722] Intermediate 25-3 (0.6 g), chloroform (12 mL), and liquid bromine (0.67 g) were mixed and reacted at 50°C for 12 hours. After the reaction, the reaction solution was poured into a saturated sodium sulfite solution and extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:1) to obtain 0.10 g of intermediate 25-4.

[0723] MS (ESI, [M+H] + )m / z:237.14.

[0724] 1 H-NMR (500MHz, DMSO-d6): δ8.89(s,1H),7.46(d,J=9.5Hz,1H),7.21(dd,J=9.5,2Hz,1H),2.83-2.74(m,4H),2.48-2.43(m,2H).

[0725] Step 5: Synthesis of intermediate 25-5

[0726] Intermediate A-1 (170 mg), intermediate 25-4 (100 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (27.4 mg), potassium carbonate (160 mg), cuprous iodide (14.67 mg), and N-methylpyrrolidone (5 mL) were mixed and reacted at 120°C under a nitrogen atmosphere for 12 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.183 g of intermediate 25-5.

[0727] 1 H-NMR (500MHz, DMSO-d6): δ8.96 (s, 1H), 7.59 (d, J = 9.5Hz, 1H), 7.39-7.37 (m, 1H ),7.31(d,J=3.5Hz,1H),7.11(d,J=6.5Hz,2H),6.98(s,1H),5.24-5.05(m,1H), 4.38-4.14(m,1H),3.24-2.98(m,1H),2.86-2.81(m,4H),2.76-2.72(m,1H),2.6 9-2.62(m,1H),2.49-2.44(m,2H),2.19(s,6H),1.44(s,9H),1.23-1.19(m,3H).

[0728] Step 6: Synthesis of Intermediate 25-6

[0729] Intermediate 25-5 (0.18 g), dichloromethane (2 mL) and 4N hydrochloric acid in dioxane solution (2 mL) were mixed and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.15 g of intermediate 25-6.

[0730] MS (ESI, [M+H] + )m / z:498.38.

[0731] Step 7: Synthesis of intermediate 25-7 and compound 25

[0732] Intermediate B-1 (0.1 g), N,N-dimethylformamide (5 mL), triethylamine (0.68 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 25-6 (0.13 g) was added and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.12 g of intermediate 25-7. The intermediate 25-7 was separated by chiral HPLC (chromatographic column: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: ethanol:n-hexane=43:57; flow rate: 40 mL / min) to obtain 26 mg of compound 25.

[0733] Compound 25: Rt = 4.57 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 x 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 60:40; flow rate: 2.0 ml / min; column temperature: 40°C)

[0734] HRMS: (ESI, [M+H] + )m / z:891.4098.

[0735] 1 H-NMR (500MHz, DMSO-d6): δ11.74(s,1H),8.98(s,1H),7.60(d,J=9.5Hz,1H),7.53(s,1H),7.44-7.39(m,2H),7. 35-7.33(m,1H),7.26(d,J=8.5Hz,1H),7.18-7.14(m,2H),7.02-6.93(m,2H),5.63-5.56(m,1H),4.41-4.35(m,1H ),3.73-3.69(m,2H),3.22-3.15(m,1H),3.07-3.02(m,1H),2.87-2.80(m,6H),2.48-2.42(m,2H),2.23(s,6H),1. 70-1.66(m,2H),1.60-1.56(m,2H),1.43-1.39(m,3H),1.28(s,3H),1.24(s,3H),1.18(s,3H),1.16-1.13(m,3H).

[0736] Example 26

[0737] Step 1: Synthesis of Intermediate 26-1

[0738] Cuprous iodide (42.0 mg), potassium carbonate (229 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (39.2 mg), Intermediate A-2 (250 mg), Intermediate 9-2 (196 mg), and N-methylpyrrolidone (4 mL) were mixed. The reaction mixture was heated to 130°C and stirred for 5 hours. The reaction mixture was poured into ethyl acetate (30 mL) and water (30 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 50:50) to obtain 190 mg of Intermediate 26-1.

[0739] MS (ESI, [M+H] + )m / z:610.41

[0740] Step 2: Synthesis of intermediate 26-2

[0741] Intermediate 26-1 (190 mg) and 4N hydrochloric acid in dioxane solution (10 mL) were mixed and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 130 mg of Intermediate 26-2.

[0742] MS (ESI, [M+H] + )m / z:510.34

[0743] Step 3: Synthesis of intermediate 26-3 and compound 26

[0744] Intermediate B-1 (100 mg), N,N-dimethylformamide (5 mL), triethylamine (492 mg), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (277 mg) were stirred for 5 minutes, then 26-3 (130 mg) was added and stirred at room temperature for 4 hours. The reaction solution was poured into water (50 mL), and the resulting solution was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated on a C18 preparative column (Xtimate C18, 21.2 × 250 mm, 5 μm; mobile phase: water (0.1% acetic acid): acetonitrile = 25:75, isocratic elution) to obtain 70 mg of intermediate 26-4. The intermediate 26-4 was separated by chiral HPLC (chromatographic column: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:1):n-hexane = 27:73, isocratic elution) to obtain 30 mg of compound 26.

[0745] Compound 26: Rt = 2.98 min (UPCC conditions: chromatographic column: CHIRALPAK IB, 4.6×100 mm, 3 μm; mobile phase: carbon dioxide: isopropanol (containing 0.1% ammonia water): ethanol = 50:25:25; flow rate: 0.5 mL / min; column temperature: 40°C).

[0746] HRMS: (ESI, [M+H] + )m / z:903.4006.

[0747] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),8.03(s,1H),7.88(d,J=8.4Hz,1H),7.78(d,J=8.4Hz,1H),7.5 4(s,1H),7.42-7.35(m,2H),7.32-7.21(m,4H),6.97-6.88(m,2H),5.58(d,J=6.7Hz,1H),4.39(s,1H),3. 72(d,J=10.2Hz,2H),3.24-3.17(m,2H),3.03-3.01(m,1H),2.91(d,J=15.4Hz,1H),2.74(t,J=7.5Hz,1H) ,2.10-1.96(m,2H),1.75-1.47(m,9H),1.44-1.09(m,13H),0.96(d,J=8.4Hz,2H),0.85(t,J=6.9Hz,3H).

[0748] Example 27

[0749] Step 1: Synthesis of Intermediates 27-1, 27-2, and 27-3

[0750] Intermediate A-3 (800 mg), intermediate 5-2 (548 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (258 mg), potassium carbonate (751 mg), cuprous iodide (173 mg), and N-methylpyrrolidone (12 mL) were mixed and reacted at 100°C under a nitrogen atmosphere for 4 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (petroleum ether:ethyl acetate = 1:1) to obtain 940 mg of intermediate 27-1. The intermediate 27-1 was separated by chiral HPLC (chromatographic column: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: ethanol: n-hexane = 43:57; flow rate: 40 mL / min) to obtain 450 mg of intermediate 27-2 and 460 mg of intermediate 27-3.

[0751] Intermediate 27-2: Rt = 3.73 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 40:60; flow rate: 2.0 ml / min; column temperature: 40°C)

[0752] MS (ESI, [M+H] + )m / z:613.44.

[0753] 1 H-NMR (500MHz, DMSO-d6): δ7.46(d,J=2.1Hz,1H),7.38(dd,J=8.1,2.0Hz,1H),7.33(d,J=3 .2Hz,1H),7.19(d,J=7.0Hz,2H),7.12(d,J=8.1Hz,1H),6.85(d,J=3.1Hz,1H),5.27(d,J=6 .0Hz,1H),4.31(s,1H),4.27-4.21(m,1H),4.11-4.03(m,1H),3.51(s,1H),3.24(s,3H),2. 17(d,J=2.1Hz,6H),1.66-1.62(m,2H),1.55-1.52(m,2H),1.45(s,9H),1.29-1.26(m,3H).

[0754] Intermediate 27-3: Rt = 4.78 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 40:60; flow rate: 2.0 ml / min; column temperature: 40°C)

[0755] MS (ESI, [M+H] + )m / z:613.43.

[0756] 1 H-NMR (500MHz, DMSO-d6): δ7.46(d,J=2.0Hz,1H),7.38(dd,J=8.1,2.0Hz,1H),7.33(d,J=3.2Hz ,1H),7.19(d,J=7.0Hz,2H),7.12(d,J=7.9Hz,1H),6.85(d,J=3.2Hz,1H),5.27(d,J=6.3Hz,1H) ,4.31(s,1H),4.24(dd,J=12.7,3.5Hz,1H),4.12-4.03(m,1H),3.51(d,J=1.1Hz,1H),3.24(s,3 H),2.17(d,J=2.1Hz,6H),1.67-1.62(m,2H),1.56-1.51(m,2H),1.45(s,9H),1.29-1.26(m,3H).

[0757] Step 2: Synthesis of intermediate 27-4

[0758] Intermediate 27-2 (0.2 g), dichloromethane (5 mL) and 4N hydrochloric acid in dioxane solution (5 mL) were mixed and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.16 g of intermediate 27-4.

[0759] MS (ESI, [M+H] + )m / z:513.34

[0760] Step 3: Synthesis of intermediate 27-5 and compound 27-A and compound 27-B

[0761] Intermediate B-1 (0.12 g), N,N-dimethylformamide (5 mL), triethylamine (0.393 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.22 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 27-4 (0.16 g) was added and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.2 g of intermediate 27-5. The intermediate 27-5 was separated by chiral HPLC (chromatographic column: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:3): n-hexane = 40:60; flow rate: 40 mL / min) to obtain 78 mg of compound 27-A and 80 mg of compound 27-B.

[0762] Compound 27-A: Rt = 1.09 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol / acetonitrile (1:1) (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40°C)

[0763] HRMS: (ESI, [M+H] + )m / z:906.4119.

[0764] 1 H-NMR (500MHz, DMSO-d6): δ12.16(s,1H),7.56-7.34(m,6H),7.30-7.17(m, 5H),7.12(d,J=7.2Hz,1H),6.95-6.81(m,3H),4.59-4.33(m,3H),3.89(s,1 H),3.77-3.63(m,3H),3.27-3.22(m,3H),3.11-2.98(m,2H),2.19(s,6H),1 .56-1.49(m,5H),1.46-1.38(m,4H),1.28(s,3H),1.23(s,3H),1.18(s,3H).

[0765] Compound 27-B: Rt = 1.44 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol / acetonitrile (1:1) (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40°C)

[0766] HRMS: (ESI, [M+H] + )m / z:906.4116.

[0767] 1 H-NMR (500MHz, DMSO-d6): δ12.15(s,1H),7.53-7.34(m,6H),7.31-7.18(m,5H),7.16-7.08(m,1H),6.96-6.78(m,3H),4.59-4.31(m,3H),3.89( s,1H),3.71(s,3H),3.25(s,3H),3.11-2.94(m,2H),2.19(s,6H),1.57- 1.49(m,5H),1.47-1.39(m,4H),1.30(s,3H),1.28(s,3H),1.26(s,3H).

[0768] Step 4: Synthesis of intermediate 27-6

[0769] Intermediate 27-3 (0.2 g), dichloromethane (5 mL) and 4N hydrochloric acid in dioxane solution (5 mL) were mixed and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 0.16 g of intermediate 27-6.

[0770] Step 5: Synthesis of intermediate 27-7 and compound 27-C and compound 27-D

[0771] Intermediate B-1 (0.12 g), N,N-dimethylformamide (5 mL), triethylamine (0.39 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.22 g) were mixed and stirred at room temperature for 5 minutes. Intermediate 27-6 (0.16 g) was added and stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 0.2 g of intermediate 27-7. The intermediate 27-7 was separated by chiral HPLC (chromatographic column: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: ethanol-dichloromethane (1:3): n-hexane = 40:60; flow rate: 40 mL / min) to obtain 74 mg of compound 27-C and 78 mg of compound 27-D.

[0772] Compound 27-C: Rt = 1.10 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol / acetonitrile (1:1) (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40°C)

[0773] HRMS: (ESI, [M+H] + )m / z:906.4132.

[0774] 1 H-NMR (500MHz, DMSO-d6): δ12.15(s,1H),7.47(d,J=5.8Hz,2H),7.44-7.32(m, 4H),7.31-7.18(m,5H),7.12(d,J=5.8Hz,1H),7.00-6.81(m,3H),4.58-4.31(m, 3H),3.95-3.82(m,1H),3.71(s,3H),3.25(s,3H),3.14-2.99(m,2H),2.19(s,6H ),1.59-1.51(m,5H),1.46-1.38(m,4H),1.28(s,3H),1.26(s,3H),1.23(s,3H).

[0775] Compound 27-D: Rt = 1.20 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6×100 mm, 3 μm); mobile phase: carbon dioxide: methanol / acetonitrile (1:1) (containing 0.1% ammonia) = 30:70; flow rate: 2.0 ml / min; column temperature: 40°C)

[0776] HRMS: (ESI, [M+H] + )m / z:906.4144.

[0777] 1 H-NMR (500MHz, DMSO-d6): δ11.68(s,1H),7.54-7.46(m,2H),7.42-7.34(m, 4H),7.29-7.16(m,5H),7.14-7.01(m,2H),6.90-6.82(m,2H),4.59(s,2H), 4.40(s,1H),4.14(s,1H),3.71(s,3H),3.25(s,3H),3.04(s,2H),2.19(s,6 H),1.66-1.59(m,5H),1.54(s,4H),1.35(s,3H),1.30(s,3H),1.26(s,3H).

[0778] Experimental Example 1: In vitro cell-level cAMP expression activity assay

[0779] HEK293 / CRE-Luc / GLP1R cells (manufacturer: GenScript Biotech Co., Ltd.) in good growth condition were taken, washed with PBS, trypsinized, and terminated with complete culture medium. The cells were collected into a centrifuge tube and the cell density was adjusted to 4×10 cells / mL using DMEM+2% FBS medium. 5 The cells were plated in a 96-well plate (100 μL / well) and incubated at 37°C for 1 h. After 1 h, the compound was added using a nanoliter pipette to a final concentration of 10 nM-0.0006 nM in two replicates, and a control was set up. After 6 h of incubation in a cell culture incubator, the detection reagent Luciferase (manufacturer: Novozymes Biotech, 50 μL / well) was added and the cells were allowed to stand at room temperature for 3 min to fully lyse the cells. Luminescence was detected using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the EC. 50 .

[0780] Some of the compounds disclosed herein have good in vitro cell cAMP expression activity, as shown in Table 1.

[0781] Table 1. In vitro cell cAMP expression activity of some compounds

[0782] Test Example 2: In vitro liver microsome stability assay

[0783] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), test compound, and NADPH + MgCl₂ solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), and test compound. The sample was added to an acetonitrile solution containing an internal standard for protein precipitation, and the supernatant was prepared and diluted for LC / MS / MS analysis. The in vitro liver microsomal stability of some compounds is shown in Table 2.

[0784] Table 2 In vitro liver microsome stability

[0785] Some compounds disclosed herein have good in vitro liver microsomal stability.

[0786] Experimental Example 3: Pharmacokinetic evaluation in mice

[0787] ICR mice weighing 18-22 g were randomly divided into 4 groups after acclimation for 3-5 days, with 9 mice in each group. The test compound was administered orally (IG) at a dose of 10 mg / kg and intravenously (IV) at a dose of 1 mg / kg.

[0788] The test animals (ICR mice) were fasted for 12 h before administration and given food 4 h after administration. They had free access to water before, during and after the experiment.

[0789] After oral administration, approximately 0.1 mL of blood was collected from the eye socket at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours. After intravenous administration, approximately 0.1 mL of blood was collected from the eye socket at 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours. Blood was collected at 3-4 time points per mouse, with 3 mice collected at each time point. Whole blood was collected and placed in a centrifuge tube containing EDTA-K2 and stored at 4°C. Plasma was separated by centrifugation within 1 hour at 4000 rpm for 10 minutes at 4°C. After collection, all plasma was immediately stored at -20°C until testing.

[0790] 30 μL of the plasma sample to be tested and the standard curve sample were aspirated, 300 μL of acetonitrile solution containing the internal standard (diazepam 20 ng / mL) was added, and the mixture was shaken and mixed for 5 min. The mixture was centrifuged at 13000 rpm for 10 min. 80 μL of the supernatant was taken and diluted with 80 μL of ultrapure water. The mixture was mixed and 2 μL was aspirated for liquid chromatography-mass spectrometry determination. The chromatogram was recorded.

[0791] The pharmacokinetic properties of some compounds in mice are shown in Table 3.

[0792] Table 3 Pharmacokinetic properties in mice

[0793] Some of the compounds disclosed herein have good pharmacokinetic properties in mice.

[0794] Example 4: Evaluation of hypoglycemic efficacy in mice

[0795] The experiment used GLP-1R humanized C57BL / 6J mice weighing 20-22g. The experiments were carried out after 3 days of adaptive feeding. All animals were fasted but not deprived of water until the end of the experiment. Blood was collected from the tip of the mouse tail.

[0796] The animals were fasted overnight, but not watered. The next day, blood was drawn from all animals for blood glucose testing. The animals were then randomly divided into a normal control group, a positive drug control group, and a test drug group based on blood glucose and body weight, with six animals in each group. The animals were then gavaged according to group. Five hours after administration, glucose solution (2g / kg) was injected intraperitoneally. Blood glucose concentrations were measured 0.25h, 0.5h, 1h, 2h, and 3h after glucose administration. Blood glucose levels were recorded throughout the experiment, and the area under the blood glucose-time curve (AUC0-180min Glu) was calculated.

[0797] The hypoglycemic efficacy of some compounds in mice is shown in Table 4.

[0798] Table 4 Evaluation of hypoglycemic efficacy in mice

[0799] Some compounds disclosed herein have good hypoglycemic effects in mice.

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, X 1 , X 2 are independently selected from C or N; Y 1 , Y 2 , Y 3 or Y 4 are independently selected from CH, C or N; R 1 Selected from C 11-15 Cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, 11-15 membered heterocyclic group, the C 11-15 Cycloalkyl, C 11-15 The aryl, 11-15 membered heteroaryl, 11-15 membered heterocyclic group is a tricyclic ring, and the C 11-15 Cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, 11-15 membered heterocyclic group may be optionally independently substituted with one or more R a replace; Or, R 1 Selected from C 3-7 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered heterocyclic group, said R 1 By a C 2-4 Alkynyl substitution, R 1 further optionally independently represented by one or more R a Substitute, the C 2-4 The alkynyl group may be optionally substituted with one or more R b replace; Each R a are independently selected from deuterium, halogen, =O, deuterated C 1-6 Alkyl, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the deuterated C 1-6 Alkyl, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 The alkylene group is optionally independently substituted with one or more R c1 Replacement; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl are optionally independently substituted with one or more R d1 replace; Each R 2 are independently selected from halogen, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 The alkylene group is optionally independently substituted with one or more R c2 Replacement; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl are optionally independently substituted with one or more R d2 replace; Alternatively, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms C 4-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic group, the C 4-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-6 membered heterocyclyl are optionally independently substituted with one or more R d3 replace; Each R 3 are independently selected from deuterium, halogen, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 The alkylene group is optionally independently substituted with one or more R c3 Replacement; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl are optionally independently substituted with one or more R d4 replace; R 4 Selected from H, deuterium, halogen, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylene, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 The alkylene group is optionally independently substituted with one or more R c4 replace; Each R 5 are independently selected from halogen, -CN, -OH, -SH, -NH2, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, Deuterium Generation C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 The alkyl group is optionally independently substituted with one or more R c5 replace; R' and R" are independently selected from H, halogen, -CN, -OH, -SH, -NH2, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 The alkyl group is optionally independently substituted with one or more R c6 replace; Alternatively, R' and R" together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with one or more R d5 replace; Each are independently selected from a single bond or a double bond; Each R b are independently selected from deuterium, halogen, -CN, -OH, -NH2, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted independently with one or more substituents selected from deuterium, halogen, OH, CN or NH2; Each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 are independently selected from deuterium, halogen, -CN, -OH or -NH2; Each R d1 , R d2 , R d3 , R d4 and R d5 are independently selected from deuterium, halogen, -CN, -OH, =O, -NH2, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted independently with one or more substituents selected from deuterium, halogen, OH, CN or NH2; q is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 11-15 Aryl or 11-15 membered heteroaryl, the C 11-15 The aryl or 11-15 membered heteroaryl is a tricyclic ring, wherein the C 11-15 The aryl or 11-15 membered heteroaryl group may be optionally independently substituted with one or more R a replace; Or, R 1 Selected from benzo C 7-11 Fused bicycloalkyl, benzo 7-11 membered fused biheterocyclic group, benzo 7-11 membered fused biheteroaryl, pyrido C 7-11 Fused bicycloalkyl, pyrido 7-11 membered fused biheterocyclic group, pyrido 7-11 membered fused biheteroaryl, pyrimido C 7-11 Fused bicycloalkyl, pyrimido 7-11 membered fused biheterocyclic group, pyrimido 7-11 membered fused biheteroaryl group, pyridazine C 7-11 fused bicycloalkyl, pyridazine 7-11 membered fused biheterocycloalkyl, pyridazine 7-11 membered fused biheteroaryl, pyrazine C 7-11 Fused bicycloalkyl, pyrazino 7-11 membered fused biheterocycloalkyl, pyrazino 7-11 membered fused biheteroaryl, benzo C 7-11 Spirobicycloalkyl, benzoC 7-11 Spirobiheterocyclic, pyridoC 7-11 Spirobicycloalkyl, pyridoC 7-11 Spirobiheterocyclic, pyrimidoC 7-11 Spirobicycloalkyl, pyrimidoC 7-11 Spirobiheterocyclic group, pyridazine 7-11 Spirobicycloalkyl, pyridazine 7-11 Spirobiheterocyclic, pyrazino 7-11 Spirobicycloalkyl or pyrazinoC 7-11 Spirobiheterocyclic group, said R 1 may be optionally independently represented by one or more R a replace; Or, R 1 Selected from benzo C 7-9 Fused bicycloalkyl, benzo 7-9 membered fused biheterocyclic group, benzo 7-9 membered fused biheteroaryl, pyrido C 7-9 Fused bicycloalkyl, pyrido 7-9 membered fused biheterocyclic group, pyrido 7-9 membered fused biheteroaryl group, pyrimido C 7-9 Fused bicycloalkyl, pyrimido 7-9 membered fused biheterocyclic group, pyrimido 7-9 membered fused biheteroaryl group, pyridazine C 7-9 fused bicycloalkyl, pyridazine 7-9 membered fused biheterocycloalkyl, pyridazine 7-9 membered fused biheteroaryl, pyrazine C 7-9 Fused bicycloalkyl, pyrazino 7-9 membered fused biheterocycloalkyl, pyrazino 7-9 membered fused biheteroaryl, benzo C 7-9 Spirobicycloalkyl, benzoC 7-9 Spirobiheterocyclic, pyridoC 7-9 Spirobicycloalkyl, pyridoC 7-9 Spirobiheterocyclic, pyrimidoC 7-9 Spirobicycloalkyl, pyrimidoC 7-9 Spirobiheterocyclic group, pyridazine 7-9 Spirobicycloalkyl, pyridazine 7-9 Spirobiheterocyclic, pyrazino 7-9 Spirobicycloalkyl or pyrazinoC 7-9 Spirobiheterocyclic group, said R 1 may be optionally independently represented by one or more R a replace; Or, R 1 Selected from benzo 7-9 membered fused diheterocyclic group, benzo 7-9 membered fused diheteroaryl group, benzo C 7-9 Spirobicycloalkyl, benzoC 7-9 Spirobiheterocyclic or pyridoC 7-9 Spirobicycloalkyl, the R 1 may be optionally independently represented by one or more R a replace; Or, R 1 Selected from benzo 7-9 membered fused diheterocyclic group, benzo 7-9 membered fused diheteroaryl group, benzo C 7-9 Spirobicycloalkyl, benzoC 7-9 Spirobiheterocyclic or pyridoC 7-9 Spirobicycloalkyl, the R 1 In and structural unit The connected ring is a benzene ring or a pyridine ring, and the R 1 Optional Independently by one or more R a replace; Or, R 1 Selected from benzo 7-9 membered fused diheterocyclic group, benzo C 7-9 Spirobicycloalkyl or benzoC 7-9 Spirobiheterocyclic group, said R 1 may be optionally independently represented by one or more R a replace; Or, R 1 Selected from benzo 7-9 membered fused diheterocyclic group, benzo C 7-9 Spirobicycloalkyl or benzoC 7-9 Spirobiheterocyclic group, said R 1 In and structural unit The connected ring is a benzene ring, and the R 1 may be optionally independently represented by one or more R a replace; Or, R 1 is selected from benzo 5-membered heteroaryl fused 5-membered heterocyclic group, benzo 5-membered heteroaryl fused 6-membered heterocyclic group, benzo 5-membered heterocyclic group fused 5-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic group spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic group spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered heterocyclic group, pyrido 5-membered heteroaryl fused 5-membered cycloalkyl or pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, wherein R 1 may be optionally independently represented by one or more R a replace; Or, R 1 is selected from benzo 5-membered heteroaryl fused 5-membered heterocyclic group, benzo 5-membered heteroaryl fused 6-membered heterocyclic group, benzo 5-membered heterocyclic group fused 5-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic group spiro 3-membered cycloalkyl, benzo 5-membered heterocyclic group spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered heterocyclic group, pyrido 5-membered heteroaryl fused 5-membered cycloalkyl or pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, wherein R 1 In and structural unit The connected ring is a benzene ring or a pyridine ring, and the R 1 may be optionally independently represented by one or more R a replace; Or, R 1 is selected from benzo 5-membered heteroaryl fused 5-membered cycloalkyl, benzo 5-membered heteroaryl fused 5-membered heterocyclyl, benzo 5-membered heteroaryl fused 6-membered heterocyclyl, benzo 5-membered heterocyclyl fused 5-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered heterocyclyl or pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, wherein R 1 may be optionally independently represented by one or more R a replace; Or, R 1 is selected from benzo 5-membered heteroaryl fused 5-membered cycloalkyl, benzo 5-membered heteroaryl fused 5-membered heterocyclyl, benzo 5-membered heteroaryl fused 6-membered heterocyclyl, benzo 5-membered heterocyclyl fused 5-membered heteroaryl, benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, benzo 5-membered heterocyclyl spiro 4-membered cycloalkyl, benzo 5-membered cycloalkyl spiro 4-membered heterocyclyl or pyrido 5-membered cycloalkyl spiro 3-membered cycloalkyl, wherein R 1 In and structural unit The connected ring is a benzene ring or a pyridine ring, and the R 1 may be optionally independently represented by one or more R a replace; Or, R 1 is selected from benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl or benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, wherein R 1 may be optionally independently represented by one or more R a replace; Or, R 1 is selected from benzo 5-membered cycloalkyl spiro 3-membered cycloalkyl or benzo 5-membered heterocyclyl spiro 3-membered cycloalkyl, wherein R 1 In and structural unit The connected ring is a benzene ring, and the R 1 may be optionally independently represented by one or more R a replace; Or, R 1 Selected from The R 1 may be optionally independently represented by one or more R a replace; Or, R 1 Selected from The R 1 may be optionally independently represented by one or more R a replace; Or, R 1 Selected from The R 1 may be optionally independently represented by one or more R a replace; Or, R 1 Selected from The R 1 may be optionally independently represented by one or more R a replace; Or, R 1 is selected from phenyl or 5-6 membered heteroaryl, said R 1 By a C 2-4 Alkynyl substitution, R 1 further optionally independently represented by one or more R a Substitute, the C 2-4 The alkynyl group may be optionally substituted with one or more R b replace; Or, R 1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein R 1 By a C 2-4 Alkynyl substitution, R 1 further optionally independently represented by one or more R a Substitute, the C 2-4 The alkynyl group may be optionally substituted with one or more R b replace; Or, R 1 is selected from phenyl or pyridyl, said R 1 By a C 2-4 Alkynyl substitution, R 1 further optionally independently represented by one or more R a Substitute, the C 2-4 The alkynyl group may be optionally substituted with one or more R b replace; Or, R 1 is selected from phenyl or pyridyl, said R 1 is substituted by an ethynyl or propynyl group, R 1 further optionally independently represented by one or more R a The ethynyl or propynyl group may be optionally substituted with one or more R b replace; Or, R 1 is selected from phenyl or pyridyl, said R 1 is substituted by an ethynyl or 1-propynyl group, R 1 further optionally independently represented by one or more R a The ethynyl or propynyl group may be optionally substituted with one or more R b replace; Or, R 1 is selected from phenyl or pyridyl, said R 1 is substituted by an ethynyl or propynyl group, R 1 further optionally independently substituted by 1, 2 or 3 substituents selected from F or methyl, and the ethynyl or propynyl group may be optionally substituted by 1, 2 or 3 methoxy groups; Or, R 1 is selected from phenyl or pyridyl, said R 1 is substituted by a 1-propynyl group, R 1 Further optionally independently substituted with 1, 2 or 3 F, the 1-propynyl group may be optionally substituted with 1 methoxy group.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R a are independently selected from halogen, =O, deuterated C 1-5 Alkyl, -OH, -CN, NH2, C 1-5 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-5 Alkoxy, C 1-5 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the deuterated C 1-5 Alkyl, C 1-5 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-5 Alkoxy or C 1-5 Alkoxy C 1-3 The alkylene group is optionally independently substituted with one or more R c1 Replacement; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl are optionally independently substituted with one or more R d1 Replace; each R b are independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally substituted independently with one or more substituents selected from deuterium, halogen, OH, CN or NH2; Or, each R a are independently selected from halogen, =O, deuterated C 1-3 Alkyl, -OH, -CN, NH2, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 alkoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl or 3-5 membered heterocyclic group, the deuterated C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy or C 1-3 The alkoxymethylene groups are optionally independently substituted with one or more R c1 The cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 5-6 membered heteroaryl or 3-5 membered heterocyclic group is optionally independently replaced by one or more R d1 replace; Or, each R a are independently selected from halogen, =O, deuterated C 1-3 Alkyl, C 1-3 Alkyl or C 3-6 Cycloalkyl, the deuterated C 1-3 Alkyl or C 1-3 The alkyl group is optionally independently substituted with one or more R c1 Replacement; said C 3-6 The cycloalkyl group is optionally independently substituted with one or more R d1 replace; Or, each R a are independently selected from F, Cl, Br, I, =O, -CD3, -C2D5, -OH, -CN, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, methoxymethylene, ethoxymethylene, cyclopropyl, cyclobutyl, cyclopentyl or phenyl, and the methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, methoxymethylene or ethoxymethylene is optionally and independently replaced by one or more R c1 Substituted; the cyclopropyl, cyclobutyl, cyclopentyl or phenyl group is optionally independently replaced by one or more R d1 replace; Or, each R a are independently selected from F, Cl, Br, I, =O, -CD3, -C2D5, -OH, -CN, methyl, ethyl, propyl, methoxymethylene, ethoxymethylene, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, propyl, methoxymethylene or ethoxymethylene is optionally and independently replaced by one or more R c1 Substituted; the cyclopropyl, cyclobutyl or cyclopentyl are optionally independently replaced by one or more R d1 replace; Or, each R a are independently selected from F, Cl, Br, =O, -CD3, -C2D5, methyl, ethyl, propyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl and propyl groups are optionally and independently replaced by one or more R c1 Substituted; the cyclopropyl, cyclobutyl or cyclopentyl are optionally independently replaced by one or more R d1 replace; Or, each R a Each is independently selected from F, methyl, =O, -CD3 or cyclopropyl; Or, each R a Each independently selected from methyl or =O; Or, each R a Each independently selected from F or methyl; Or, each R b Each independently selected from C 1-3 Alkoxy, the C 1-3 Alkoxy is optionally substituted independently with one or more substituents selected from deuterium, halogen, OH, CN or NH2; Or, each R b Each is independently selected from F, Cl, Br, I or methoxy; Or, each R b are each independently selected from methoxy.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently selected from halogen, -OH, -CN, C 1-5 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-5 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-5 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-5 The alkoxy group is optionally independently substituted with one or more R c2 Replacement; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl are optionally independently substituted with one or more R d2 replace; Or, each R 2 are independently selected from halogen, -OH, -CN, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-5 membered heterocyclic group, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-3 The alkoxy group is optionally independently substituted with one or more R c2 Replacement; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl are optionally independently substituted with one or more R d2 replace; Or, each R 2 are independently selected from halogen, C 1-3 Alkyl, or C 3-5 Cycloalkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c2 Replacement; said C 3-6 The cycloalkyl group is optionally independently substituted with one or more R d2 replace; Or, each R 2 are independently selected from F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl or propyl group is optionally independently replaced by one or more R c2 Substituted; the cyclopropyl, cyclobutyl or cyclopentyl are optionally independently replaced by one or more R d2 replace; Or, each R 2 are independently selected from F, methyl or cyclopropyl, the methyl being optionally independently replaced by one or more R c2 Substituted; the cyclopropyl group is optionally independently replaced by one or more R d2 replace; Or, each R 2 Each is independently selected from F, methyl or cyclopropyl; Alternatively, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, the C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl are optionally independently substituted with one or more R d3 replace; Alternatively, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms C 5-6 Cycloalkyl or 5-6 membered heterocyclic group, the C 5-6 Cycloalkyl or 5-6 membered heterocyclic group is optionally independently substituted by one or more R d3 replace; Alternatively, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms C 5-6 Cycloalkyl, the C 5-6 The cycloalkyl group is optionally independently substituted with one or more R d3 replace; Alternatively, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms a cyclopentyl, pyrrolyl, tetrahydrofuranyl or tetrahydrothienyl group, wherein the cyclopentyl, pyrrolyl, tetrahydrofuranyl or tetrahydrothienyl group is optionally independently substituted by one or more R d3 Substitution; or, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached, it forms a cyclopentyl group, which is optionally independently substituted with one or more R d3 replace; Alternatively, R on two adjacent carbon atoms 2 Together with the carbon atom to which it is attached it forms a cyclopentyl group.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 One of them is selected from C and the other is selected from N; Y 1 , Y 2 , Y 3 are independently selected from C or N, Y 4 Selected from CH; Or, Y 1 , Y 2 , Y 3 At least one selected from N, Y 4 Selected from CH; Or, Y 1 Selected from C, Y 2 Selected from N, Y 3 Selected from C, Y 4 Selected from CH; Or, Y 1 Selected from C, Y 2 Selected from C, Y 3 Selected from N, Y 4 Selected from CH; Or, Y 1 Selected from N, Y 2 Selected from C, Y 3 Selected from C, Y 4 Selected from CH.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 3 are independently selected from deuterium, halogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl groups are optionally independently substituted with one or more R c3 Replacement; said C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl are optionally independently substituted with one or more R d4 Substitution; said R 4 Selected from H, deuterium, halogen, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 The alkoxy group is optionally independently substituted with one or more R c4 Substitution; said R 5 Selected from halogen, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 The alkoxy group is optionally independently substituted with one or more R c5 replace; Or, each R 3 are independently selected from deuterium, halogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c3 replace; Or, each R 3 are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c3 replace; Or, each R 3 are independently selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl or propyl group is optionally independently replaced by one or more R c3 Substituted; the cyclopropyl, cyclobutyl or cyclopentyl are optionally independently replaced by one or more R d4 replace; Or, each R 3 are independently selected from methyl, ethyl or propyl, and the methyl, ethyl or propyl is optionally substituted by one or more R c3 replace; Alternatively, the R 3 Selected from methyl; Or, R 4 Select from H or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c4 replace; Or, R 4 is selected from H or methyl, the methyl group being optionally replaced by one or more R c4 replace; Or, R 4 Selected from H or methyl; Or, R 4 Selected from H; Or, R 4 Selected from methyl; Or, R 5 Selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c5 replace; Or, R 5 Selected from methyl.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R' and R" are independently selected from H, deuterium, halogen, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, deuterated C 1-3 Alkyl or C 1-3 The alkoxy group is optionally independently substituted with one or more R c6 replace; Alternatively, R' and R" are independently selected from H or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally independently substituted with one or more R c6 replace; Alternatively, R' and R" are independently selected from H or methyl, the methyl group being optionally replaced by one or more R c6 replace; Alternatively, R' and R" are both selected from methyl; Alternatively, R' and R" together with the carbon atoms to which they are attached form C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl is optionally independently substituted with one or more R d5 replace; Alternatively, R' and R" together with the carbon atom to which they are attached form a cyclopropyl group which is optionally independently substituted with one or more R d5 replace; Alternatively, R' and R" together with the carbon atom to which they are attached form a cyclopropyl group.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein q is selected from 0, 1, 2 or 3; or, q is selected from 1, 2 or 3; or, q is selected from 2; or, q is selected from 3; Optionally, m is selected from 0, 1, 2 or 3; or, m is selected from 0, 1 or 2; or, m is selected from 0; or, m is selected from 1; Optionally, n is selected from 0, 1, 2 or 3; or, n is selected from 1, 2 or 3; or, n is selected from 1.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 are independently selected from halogen, -CN, -OH or -NH2; Or, each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 Each is independently selected from F, -CN, -OH or -NH2; Or, each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 are independently selected from F or OH; Or, each R c1 , R c2 , R c3 , R c4 , R c5 and R c6 Each independently selected from F; Optionally, each of the R d1 , R d2 , R d3 , R d4 and R d5 are independently selected from halogen, -CN, -OH, -NH2, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted independently with one or more substituents selected from halogen, OH, CN or NH2; Or, each R d1 , R d2 , R d3 , R d4 and R d5 Each of the following is independently selected from F, -CN, -OH, -NH2, methyl or methoxy, wherein the methyl or methoxy is optionally substituted independently with one or more substituents selected from F, OH, CN or NH2; Or, each R d1 , R d2 , R d3 , R d4 and R d5 Each is independently selected from F, -CN, -OH, -NH2, methyl or methoxy; Or, each R d1 , R d2 , R d3 , R d4 and R d5 Each is independently selected from F or methyl; Or, each R d1 , R d2 , R d3 , R d4 and R d5 are independently selected from F.

10. A compound according to any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from a compound of formula (IA), (IB), (IC) or (ID), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 11. A compound according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-J), (II-K) or (II-L), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, r is selected from 0, 1, 2, 3 or 4; X is selected from C or N; X 3 , X 4 , X 5 or X 6 are independently selected from C or N; X 7 , X 8 , X 9 , X 10 or X 11 are independently selected from C, CH or N; Alternatively, X is selected from C; Alternatively, X is selected from N; Or, X 3 Select from N, X 4 , X 5 or X 6 are independently selected from C or N; Or, X 3 , X 6 Select from N, X 4 , X 5 Selected from C; Or, X 3 , X 4 Select from N, X 5 , X 6 Selected from C; Or, X 7 and X 11 One of them is selected from N, and the other is selected from C; Or, X 7 and X 9 Select from N, X 11 Selected from C, X 8 and X 10 Selected from CH; Alternatively, r is selected from 0, 1 or 2; Alternatively, r is selected from 0 or 2.

12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the compound of formula (I'), its stereoisomer or a pharmaceutically acceptable salt thereof:

13. A compound according to any one of claims 1 to 12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from a compound of formula (I-A'), (I-B'), (I-C') or (I-D'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 14. A compound according to any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (II-A'), (II-B'), (II-C'), (II-D'), (II-E'), (II-F'), (II-G'), (II-H'), (II-I'), (II-J'), (II-K') or (II-L'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, r is selected from 0, 1, 2, 3 or 4; X is selected from C or N; X 3 , X 4 , X 5 or X 6 are independently selected from C or N; X 7 , X 8 , X 9 , X 10 or X 11 are independently selected from C, CH or N; Or, X, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 or X 11 The definition is as described in the compounds of formula (II-D), (II-F) and (II-J) in claim 11.

15. A compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula (IV-A), a compound of formula (IV-A'), a compound of formula (IV-B') or a compound of formula (IV-C') or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 16. The following compound, its stereoisomer or its pharmaceutically acceptable salt:

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable excipient.

18. Use of the compound according to any one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating a disease associated with GLP-1.

19. A method for treating or preventing a disease associated with GLP-1, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 to a mammal, preferably a human, in need of such treatment.

20. Use of the compound according to any one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in treating GLP-1 related diseases.

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