Compound serving as GLP-1r agonist

Abstract

The present invention relates to a compound serving as a GLP-1R agonist and a use thereof in the preparation of a drug for treating and / or preventing GLP-1 receptor-mediated diseases.

Description

Compounds as GLP-1R agonists Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to GLP-1R agonists. Background Technology

[0002] GLP-1 is primarily secreted by intestinal L cells. When the intestines are stimulated by nutrients, large amounts of GLP-1 are secreted. GLP-1's function depends on its receptor, GLP-1R. GLP-1R is widely distributed throughout various tissues of the body, not just limited to pancreatic tissue. In pancreatic α cells, GLP-1 reduces glucagon secretion, while in pancreatic β cells, it promotes insulin secretion. Both work together to lower blood sugar, making GLP-1R an important target for diabetes treatment. Furthermore, GLP-1 promotes β-cell proliferation while protecting them from endoplasmic reticulum stress-induced cell death. In the intestine, GLP-1 stimulates the division and proliferation of crypt cells, promoting intestinal growth. Intestinal intraepithelial lymphocytes, under the influence of GLP-1, can reduce inflammatory responses and protect intestinal tissue. In the brain, GLP-1 can reduce appetite and decrease addictive behaviors towards certain foods, thus potentially being used to treat obesity. GLP-1R is also expressed in the cardiovascular system. GLP-1 can increase heart rate and cardiac output, thus having a cardioprotective function. Currently, GLP-1 analogs have been developed as effective therapeutic agents for diabetes and obesity. Recently, liraglutide and semaglutide have demonstrated reduced liver fat and promoted NASH regression in clinical trials, indicating potential efficacy against NASH.

[0003] However, due to the peptide nature of GLP-1 analogs, improving their metabolic stability and bioavailability is challenging, and there are currently no available small molecule GLP-1 receptor agonists on the market. Therefore, developing a class of small molecule GLP-1 receptor agonists with good metabolic stability and bioavailability has broad application prospects. Summary of the Invention

[0004] One or more embodiments of this application provide compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, isotopic compounds, deuterated derivatives, metabolites, or prodrugs thereof.

[0005] in

[0006] Y1 and Y2 are each independently selected from bonds, CR, CHR, and C(R)2;

[0007] Y3 is selected from CR and C(R)2;

[0008] X1 is selected from C, CH, and N;

[0009] X2 is selected from CR, C(R)2, N, NR, O, and S;

[0010] X3 and X7 are each independently selected from C, CH, and N;

[0011] X4, X5, and X6 are each independently selected from CR, C(R)2, N, and NH;

[0012] L1 is selected from

[0013] L2 is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with 1 to 6 substituents selected from the group consisting of: deuterium, halogen, =O, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl;

[0014] Or, two carbon atoms on the same atom 1-6 Alkyl formation C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CH2O(C 3-6 cycloalkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy;

[0015] R is independently selected from H, deuterium, halogen, -OH, -CN, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2- 6-olefin, C 2-6 The alkynyl group is optionally substituted by 1 to 6 substituents selected from the group consisting of deuterium and halogens;

[0016] R1 is selected from H, deuterium, halogens, -OH, -CN, -NR7R8, -NO2, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -C(=NH)NR7R8, -OC(=O)NR7R8, -NR9C(=O)NR7R8, -NR9C(=NH)NR7R8, -NR9C(=O)OR7, -NR7C(=O)R8, -SO2R7, -S(=O)(NR7)R8, -N=S(=O)R7R8, -NR7SO2R8, -SO2NR7R8, -S(O)(NR7)NR8R9, -NR7SO2NR8R9, -P(=O)R7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, or S, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S, C 2-6 alkenyl and C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl, C 2-6 alkenyl, C 2-6 The alkynyl group may optionally be substituted by 1 to 6 substituents selected from the group consisting of: deuterium, halogen, oxo (=O), -OH, -NH2, -CN, -COOH, -C(O)OC. 1-3 Alkyl, -C(O)OC 3-6 cycloalkyl, -C(O)NH-C 1-3 Alkyl group, -C(O)NH-C 3-6 Cycloalkyl, -C(O)N-(C 1-3 Alkyl)2、-SO2C 1- 3alkyl, -SO2C 3-6 cycloalkyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-3 alkyl;

[0017] R2 is selected from C 3-12 Cycloalkyl groups, containing 1-4 3-12 membered heterocyclic groups selected from N, O or S heteroatoms, C 6- 12Aryl groups and 5-12 heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally surrounded by 1-6 R groups. 21 replace;

[0018] R 21 Selected from H, deuterium, halogens, -OH, -CN, oxo (=O), -NR7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2- 6-olefin, C 2-6 The alkynyl group is optionally substituted by 1 to 6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl containing 1-4 heteroatoms selected from N, O or S, and halogenated 3-6 membered heterocyclic alkyl containing 1-4 heteroatoms selected from N, O or S;

[0019] R3 is selected from C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, C 6- 12 Aryl groups and 5-12 heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally surrounded by 1-6 R groups. 31 Replace; or

[0020] R3 is selected from C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, C 6- 14 Aryl groups and 5-14 heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14Aryl and 5-14 heteroaryl groups are optionally surrounded by 1-6 R groups. 31 replace;

[0021] R 31 Selected from H, deuterium, halogens, -OH, -CN, -NO2, oxo (=O), -NR7R8, =NR7, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -NR7C(=O)R8, -SO2R7, -S(=O)(NR7)R8, -NR7SO2R8, -SO2NR7R8, -S(=O)(=NR7)NR8R9, -NR7SO2NR8R9, -P(=O)R7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 6-12 aryl, comprising 1-4 5-12 membered heteroaryl groups selected from N, O and S heteroatoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally substituted by 1-6 substituents selected from the following group: deuterium, halogen, -OH, -CN, -NO2, oxo (=O), -NR7R8, =NR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR7R8, -NR7C(O)R8, -SO2R7, -S(O)(NR7)R8, -NR7SO2R8, -SO2NR7R8, -S(O)(NR7)NR8R9, -NR7SO2NR8R9, -P(O)R7R8, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, halogenated 4-6 membered heterocyclic groups, phenyl groups, halophenyl groups, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S, haloated 5-6 membered heteroaryl groups, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C 3-6Cycloalkyl, deuterated 4-6-membered heterocyclic groups, deuterated phenyl, and deuterated 5-6-membered heteroaryl groups;

[0022] Or, two Rs 31 Together with the atoms attached to it, they form C 5-10 Cycloalkyl, 4-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, or 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 5-10 Cycloalkyl, 4-10-membered heterocyclic, phenyl, and 5-10-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -CN, -NO2, oxo (=O), -NR7R8, =NR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR7R8, -NR7C(O)R8, -SO2R7, -S(O)(NR7)R8, -NR7SO2R8, -SO2NR7R8, -S(O)(NR7)NR8R9, -NR7SO2NR8R9, -P(O)R7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, oxo (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, and halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, and deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C 1-6 Alkylamino, deuterated C 3-6 Cycloalkyl groups, containing 1-4 deuterated 4-6 membered heterocyclic groups selected from N, O and S heteroatoms;

[0023] R4 is selected from H, deuterium, halogens, -CN, oxo (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1- 6-alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy;

[0024] Alternatively, two R4 atoms attached to the same carbon atom can form an exocyclic double bond (=CR). 41 R 42 C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy;

[0025] Alternatively, R4 and R1 together with the atoms they are attached to form C. 5-10 Cycloalkyl, 5-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, phenyl, or 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, wherein the C 5-10 Cycloalkyl, 5-10-membered heterocyclic, phenyl, and 5-10-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -CN, -NO2, oxo (=O), -NR7R8, =NR7, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl or deuterated C 1-6Alkoxy;

[0026] R 41 R 42 Each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl;

[0027] R5 is selected from

[0028] R 51 R 52 Each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl;

[0029] R6 is selected from -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 3-12 Cycloalkyl, -L-containing 1-4 3-12 membered heterocyclic groups selected from N, O and S heteroatoms, -LC 6-12 aryl and -L-containing 1-4 5-12-membered heteroaryl groups selected from N, O and S heteroatoms, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally surrounded by 1-6 R groups. 61 replace;

[0030] R 61 Selected from H, deuterium, halogens, -OH, =O, -CN, -NR 6a R 6b C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 Alkyne, phenyl, or 5-10 heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 Alkyne, phenyl, or 5-10 heteroaryl groups are optionally surrounded by 1-6 R groups. 6e replace;

[0031] Or, two Rs 61 Together with the atoms attached to it, they form an exocyclic double bond (=CR). 6c R 6d C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy;

[0032] L is the key or can be chosen from -NR L -、-O-、-S-、C 1-6 Alkylene, -NR L -C 1-6 alkylene-, -C 1-6 Alkylene-NR L -、-OC 1-6 alkylene-, -C 1-6 alkylene-O-, wherein the C 1-6 The alkylene group is optionally substituted with 1 to 6 substituents selected from the group consisting of: deuterium, halogen, =O, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C 3-6 Cycloalkyl, or two carbon atoms on the same atom 1-6 Alkyl groups can form C groups optionally substituted with 1-6 halogens. 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms;

[0033] R 6a R 6b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, containing 1-4 4-6 membered heterocyclic groups selected from N, O, and S heteroatoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl;

[0034] R 6c R 6d Each is independently selected from the following groups: H, deuterium, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl;

[0035] R 6e Selected from deuterium, halogens, =O, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, containing 1-4 4-6 membered heterocyclic groups selected from N, O, and S heteroatoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl;

[0036] R L Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-10-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl;

[0037] R7, R8, and R9 are each independently selected from H, -CN, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 6-12 aryl, comprising 1-4 5-12 membered heteroaryl groups selected from N, O and S heteroatoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally substituted by 1-6 substituents selected from the following group: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl groups, 4-6 membered heterocycles containing 1-4 heteroatoms selected from N, O, and S, halogenated 4-6 membered heterocycles containing 1-4 heteroatoms selected from N, O, and S, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C 3-6 Cycloalkyl groups, containing 1-4 deuterated 4-6 membered heterocycles selected from N, O and S heteroatoms;

[0038] Alternatively, R7, R8, or R8, R9 attached to the same nitrogen atom can form a 4-6 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, and S, wherein the 4-6 membered heterocyclic group is optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl groups, 4-6 membered heterocycles containing 1-4 heteroatoms selected from N, O, and S, halogenated 4-6 membered heterocycles containing 1-4 heteroatoms selected from N, O, and S, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C3-6 Cycloalkyl groups, containing 1-4 deuterated 4-6 membered heterocycles selected from N, O and S heteroatoms;

[0039] n is 0, 1, 2, 3, 4, 5, or 6;

[0040] It can be a single bond or a double bond.

[0041] In one or more embodiments, the compound has a structure selected from the following formula:

[0042] Where: X1, X2, X3, X4, X5, X6, X7, R, R1, R2, R3, R4, R5, R6, Y1, Y2, L1, L2, n are defined as in equation (I).

[0043] In one or more embodiments, the compound has a structure selected from the following formula:

[0044] Where: X1, X2, X3, X4, X5, X6, X7, R, R1, R2, R3, R4, R5, R6, L1, L2, n are as defined in equation (I).

[0045] In one or more embodiments, It has a structure selected from the following:

[0046] in

[0047] R is independently selected from H, deuterium, halogen, -OH, -CN, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2- 6-olefin, C 2-6 The alkynyl group is optionally substituted by 0-6 substituents selected from the group consisting of deuterium and halogens;

[0048] m can be 0, 1, 2, 3, 4, 5, or 6.

[0049] In one or more embodiments, the compound has a structure selected from the group consisting of:

[0050] in

[0051] X1, X2, X3, X4, X5, X6, X7, R1, R2, R3, R5, R6, L2 are as defined in equation (I);

[0052] R4 groups are independently selected from H, deuterium, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 Alkoxy;

[0053] Alternatively, two R4 atoms attached to the same carbon atom can form an exocyclic double bond (=CR). 41 R 42 C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 Alkoxy;

[0054] R 41 R 42 Each element is independently selected from the following groups: H, deuterium, halogens, and C. 1-6 Alkyl and halogenated C 1-6 alkyl;

[0055] n is 0, 1, 2, 3, 4, 5, or 6. In one or more embodiments, the compound has the following structure:

[0056] R L21 Each element is independently selected from: H, deuterium, halogen, -CH2O(C) 3-6 cycloalkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C1-6 Alkyl and deuterated C 1-6 Alkoxy;

[0057] X1 and X7 are each independently selected from CH or N;

[0058] In one or more embodiments, R L21 Each is independently selected from: H, deuterium, methyl, ethyl, propyl, -CH2O-cyclopropyl; in one or more embodiments, one R in formula (VII) L21 One is H or deuterium, and the other is H, deuterium, methyl or -CH2O-cyclopropyl.

[0059] In one or more embodiments, the compound has the following structure:

[0060] In one or more embodiments, the compound has the following structure:

[0061] In one or more embodiments, the compound has the following structure:

[0062] In one or more embodiments, the compound has the following structure:

[0063] In one or more embodiments, R 211 R 212 and R 213 Selected from H, deuterium, halogens, -OH, -CN, oxo (=O), -NR7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally substituted by 1 to 6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 3-6 cycloalkyl, halogenated C 3-6Cycloalkyl, 3-6 membered heterocyclic alkyl containing 1-4 heteroatoms selected from N, O or S, and halogenated 3-6 membered heterocyclic alkyl containing 1-4 heteroatoms selected from N, O or S.

[0064] In one or more embodiments, R 211 R 212 and R 213 Each is independently selected from H, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, C 3-6 cycloalkyl or halogenated C 3-6 Cycloalkyl. In one or more embodiments, R 212 It is a halogen; in one or more embodiments, R 212 For F or -CF3.

[0065] In one or more embodiments, R 211 and R 213 Each is independently selected from H, D, or C. 1-3 alkyl.

[0066] In one or more embodiments, R 211 and R 213 At least one of them is C 1-3 alkyl.

[0067] In one or more embodiments, R 211 It is methyl or ethyl; in one or more embodiments, R 213 It is methyl or ethyl;

[0068] In one or more embodiments, X1 and X7 are independently CH and N; in one or more embodiments, X1 is CH and X7 is N; in one or more embodiments, X7 is CH and X1 is N.

[0069] In one or more embodiments, Y1 and Y2 are each independently selected from the key.

[0070] In one or more embodiments, Y3 is selected from -C(O)-.

[0071] In one or more embodiments, X1 is selected from C and CH.

[0072] In one or more embodiments, X2 is selected from CR and C(R)2.

[0073] In one or more embodiments, X3 is selected from C and CH.

[0074] In one or more embodiments, X7 is selected from C, CH, and N.

[0075] In one or more embodiments, X4, X5, and X6 are each independently selected from CR and C(R)2.

[0076] In one or more embodiments, L1 is selected from

[0077] In one or more embodiments, L2 is selected from -CH2-, -CH2-CH2-, and cyclopropyl.

[0078] In one or more embodiments, R is selected from C. 1-6 alkyl.

[0079] In one or more embodiments, R1 is H, D, -CN, -NO2, C 1-3 Alkyl groups, halogens, -NR7R8, -NR9C(=O)NR7R8, -NR9C(=O)OR7, -NR9C(=NH)NR7R8, -OC(=O)NR7R8, -C(=O)R7, -NR7C(=O)R8, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -SO2R7, -SO2NR7R8, -S(=O)(NR7)NR8R9, -NR7SO2NR8R9, -P(=O)R7R8, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, or S, and 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S; the C 1-3 Alkyl, 4-6 membered heterocyclic, and 5-6 membered heteroaryl groups are optionally substituted by 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-3 alkyl;

[0080] In one or more embodiments, R1 is not H;

[0081] In one or more embodiments, R1 is selected from CN, -CF3, -C(=O)R7, -C(O)NR7R8, -SO2NR7R8, -P(=O)R7R8, or any of the following groups:

[0082] Among them, R 111 R 112 Each is independently selected from H, deuterium, or C. 1-3 alkyl;

[0083] R7 and R8 are each independently selected from H and C. 1-3 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic group, C 5-6Aryl or halogenated C 1-3 alkyl.

[0084] In one or more embodiments, R1 is selected from CN, -CF3, -CONH2, -P(O)(CH3)2, R 111 R 112 Each is independently selected from H, deuterium, or C. 1-3 alkyl;

[0085] In one or more embodiments, R1 is selected from: -CONHCH3, -CON(CH3)2, -COCH3 or -SO2NH2.

[0086] In one or more embodiments, R7 and R8 are each independently selected from H and C. 1-3 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic group, C 5-6 Aryl or halogenated C 1-3 alkyl.

[0087] In one or more embodiments, R1 is selected from -CN.

[0088] In one or more embodiments, R1 is selected from H, deuterium, and -NR7R8.

[0089] In one or more embodiments, R2 is selected from phenyl, C 4-8 Cycloalkyl, 5-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, or S, or 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S; wherein the phenyl, 4-8 membered cycloalkyl, 5-6 membered heterocyclic group, or 5-6 membered heteroaryl group may contain 1-6 R groups. 21 Replace; R 21 Selected from H, deuterium, halogens, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-3 Alkyl, C 3-6 cycloalkyl or halogenated C 3-6 Cycloalkyl.

[0090] In one or more embodiments, R 21 Selected from cyclopropyl. In one or more embodiments, R2 is phenyl, C 5-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, and 5-6 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms selected from N, O or S; wherein C 5-6 Cycloalkyl, 5-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are optionally surrounded by 1 to 6 R groups. 21 replace;

[0091] In one or more embodiments, R2 is a phenyl group; the phenyl group may optionally contain 1 to 5 R groups. 21 replace;

[0092] In one or more embodiments, R 21 Selected from H, deuterium, halogens, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, C 3-6 cycloalkyl or halogenated C 3-6 cycloalkyl;

[0093] In one or more embodiments, R2 is R 211 R 212 and R 213 Each is independently selected from H, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyclopropyl, halogenated C 1-3 Alkyl or halocyclopropyl; in one or more embodiments, R 212 For F or -CF3, R 211 and R 213 Each is independently selected from H, deuterium, or C. 1-3 alkyl.

[0094] In one or more embodiments, R 212 For F or -CF3, R 211 and R 213 Each is independently selected from H or cyclopropyl.

[0095] In one or more embodiments, R2 is a 4, 5, 6, 7, or 8-membered cycloalkyl group; the cycloalkyl group may optionally have 1, 2, 3, 4, or 5 R groups. 21 Replace, R 21 Selected from H, deuterium, halogens, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 cycloalkyl or halogenated C 3-6 Cycloalkyl.

[0096] In one or more embodiments, R2 is a 5-6 membered heterocyclic group (e.g., tetrahydropyranyl, piperidinyl); the 5-6 membered heterocyclic group may optionally have 1, 2, 3, 4 or 5 R groups. 21 Replace, R 21 Selected from H, deuterium, halogens, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 cycloalkyl or halogenated C 3-6 Cycloalkyl.

[0097] In one or more embodiments, R2 is a 5-6 membered heteroaryl group (e.g., pyridyl); the 5-6 membered heteroaryl group may optionally have 1, 2, 3, 4, or 5 R groups. 21 Replace, R 21 Selected from H, deuterium, halogens, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 cycloalkyl or halogenated C 3-6 Cycloalkyl.

[0098] In one or more embodiments, R3 is selected from substituted or unsubstituted 3-14 membered heterocyclic groups, C 6-14 Aryl groups and 5-14 heteroaryl groups containing 1-4 heteroatoms selected from N, O and S.

[0099] In one or more embodiments, R3 is selected from substituted or unsubstituted phenyl, 5-6 membered cycloalkyl, 5-8 membered monocyclic heterocyclic, 5-6 membered monocyclic heteroaryl, phenyl-5-6 membered cycloalkyl, phenyl-5-8 membered heterocyclic, phenyl-5-6 membered heteroaryl, 5-6 membered heteroaryl-5-6 membered cycloalkyl, 5-8 membered heteroaryl-5-6 membered cycloalkyl, 5-6 membered heteroaryl-5-8 membered heterocyclic, phenyl-5-6 membered heterocyclic-5-8 membered heterocyclic. , phenyl 5-6-membered cycloalkyl 5-8-membered heterocyclic group, phenyl 5-6-membered heterocyclic group 5-6-membered cycloalkyl group, phenyl 5-6-membered heteroaryl 5-8-membered heterocyclic group, phenyl 5-6-membered heterocyclic group 5-6-membered heteroaryl group, phenyl 5-8-membered heterocyclic group 5-6-membered cycloalkyl group, phenyl 5-6-membered cycloalkyl 5-6-membered heterocyclic group, phenyl 5-8-membered heterocyclic group 5-6-membered heteroaryl group, phenyl 5-6-membered heteroaryl group 5-6-membered heterocyclic group.

[0100] In one or more embodiments, R3 is selected from any of the following groups:

[0101] in, Indicates a single bond or a double bond;

[0102] W1, W2, W3, W4, W5, W6, Z1, Z2, Z3, Z4, Z5, Z6, Z7, K1, K2, K3, K4, and V are each independently selected from -CR 31 -CR 31 R 31 -NR 31 -N-, O or S;

[0103] R 31 As defined above.

[0104] In one or more embodiments, R3 is selected from any of the following groups:

[0105] u0 is 0, 1, 2, 3, 4, or 5; u1 is 0, 1, 2, 3, or 4; u2 is 0, 1, 2, or 3; u3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; u4 is 0, 1, 2, 3, 4, 5, or 6; u5 is 0, 1, 2, 3, 4, 5, or 6; u6 is 0, 1, 2, 3, 4, 5, or 6; u7 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; u8 is 0, 1, 2, 3, or 4; u9 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; u10 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u11 is 0, 1, 2, 3, 4, 5, or 6; u12 The values ​​are 0, 1, 2, 3, or 4; u13 is 0, 1, 2, 3, or 4; u14 is 0, 1, 2, 3, 4, 5, or 6; u15 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; u16 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u17 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; u18 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; u19 is 0, 1, 2, or 3; u20 is 0, 1, or 2; u21 is 0, 1, 2, 3, or 4; u22 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;

[0106] R 31 As defined above.

[0107] In one or more embodiments, R3 is selected from... In one or more embodiments, R3 is selected from...

[0108] In one or more embodiments, R3 is selected from...

[0109] In one or more embodiments, R3 is selected from...

[0110] In one or more embodiments, R3 is selected from...

[0111] In one or more embodiments, R3 is selected from...

[0112] In one or more embodiments, R3 is selected from...

[0113] In one or more embodiments, R3 is selected from...

[0114] In one or more embodiments, R 310 Each is independently selected from H, deuterium, and C. 1-3 Alkyl or C 3-6 Cycloalkyl, p is 0, 1, 2, or 3.

[0115] In one or more embodiments, R3 is selected from...

[0116] In one or more embodiments, R3 is selected from...

[0117] In one or more embodiments, R3 is selected from...

[0118] In one or more embodiments, R3 is selected from...

[0119] In one or more embodiments, R3 is selected from...

[0120] In one or more embodiments, R3 is selected from

[0121] In one or more embodiments, R3 is selected from...

[0122] In one or more embodiments, R3 is selected from...

[0123] In one or more embodiments, R3 is selected from...

[0124] In one or more embodiments, R3 is selected from...

[0125] In one or more embodiments, R 31 Selected from: H, deuterium, halogen, -OH, -CN, oxo (=O), -NR7R8, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR7R8, -NR7C(O)R8, -SO2R7, -S(O)(NR7)R8, -NR7SO2R8, -SO2NR7R8, -S(O)(NR7)NR8R9, -NR7SO2NR8R9, -P(O)R7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6Cycloalkyl, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -CN, -NR7R8, C. 1-3 Alkyl or C 1-3 Alkyl group.

[0126] In one or more embodiments, R 31 Selected from -C(=O)NR9(NR7R8); in one or more embodiments, R 31 Selected from -C(=O)NCH3N(CH3)2.

[0127] In one or more embodiments, R7, R8, and R9 are each independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl; the C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally substituted with 1 to 6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH.

[0128] In one or more embodiments, R 31 Selected from H, deuterium, and C 1-3 alkyl.

[0129] In one or more embodiments, the C 1-3 Alkyl groups may be optionally replaced by deuterium or halogens.

[0130] One or more embodiments of this application provide a compound of formula V, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug thereof, wherein said compound has a structure selected from the group consisting of:

[0131] in

[0132] X1, X2, X3, X4, X5, X6, X7, R2, R3, R5, R6, L2 are defined as in Equation I;

[0133] Ring A is selected from the following group: C 5-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 5-10Cycloalkyl, 5-10-membered heterocyclic, phenyl, and 5-10-membered heteroaryl groups are optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -CN, -NO2, oxo (=O), -NR7R8, =NR7, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 Alkyl group.

[0134] R4 is selected from the following groups: H, deuterium, halogens, -CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1- 6-alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl group.

[0135] One or more embodiments of this application provide a compound of formula VI, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug thereof, wherein said compound has a structure selected from the group consisting of:

[0136] Where: X1, X2, X3, X4, X5, X6, X7, R1, R2, R3, R4, R5, R6 are as defined in Equation I;

[0137] R L2 Each is independently selected from deuterium, halogens, =O, -CN, -OH, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl;

[0138] Or, two R atoms on the same atom L2Formation C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, -CH2O(C 3-6 cycloalkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkyl group.

[0139] In one or more embodiments, Y1 and Y2 are each independently selected from the key.

[0140] In one or more embodiments, Y3 is selected from -C(O)-.

[0141] In one or more embodiments, X1 is selected from C, CH and N.

[0142] In one or more embodiments, X2 is selected from CR and C(R)2.

[0143] In one or more embodiments, X3 is selected from C and CH.

[0144] In one or more embodiments, X7 is selected from C, CH, and N.

[0145] In one or more embodiments, X4, X5, and X6 are each independently selected from N and C. 1-6 Alkyl, CR and C(R)2.

[0146] In one or more embodiments, L1 is selected from

[0147] In one or more embodiments, L2 is selected from -CH2-, -CH2-CH2-,

[0148] In one or more embodiments, R is selected from H and C. 1-6 alkyl.

[0149] In one or more embodiments, R1 is selected from H, deuterium, halogen,

[0150] In one or more embodiments, R2 is selected from...

[0151] In one or more embodiments, R 21 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl;

[0152] In one or more embodiments, R3 is selected from 3-14 membered heterocyclic groups, C 6-14 Aryl groups and 5-14 heteroaryl groups containing 1-4 heteroatoms selected from N, O and S.

[0153] In one or more embodiments, R3 is selected from...

[0154] In one or more embodiments, R4 is selected from oxo (=O) and C. 1-6 alkyl.

[0155] In one or more embodiments, R4 and R1 together with the atoms they are attached to form C. 5-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, or phenyl.

[0156] In one or more embodiments, R5 is selected from...

[0157] In one or more embodiments, R6 is selected from -LC. 2-6 alkynyl, -LC 3-12 Cycloalkyl, -L-containing 1-4 3-12 membered heterocyclic groups selected from N, O and S heteroatoms, -LC 6-12 The aryl group and -L-containing 1-4 5-12-membered heteroaryl groups selected from N, O, and S heteroatoms; preferably, R6 is selected from...

[0158] In one or more embodiments, R 61 Selected from C 1-6 Alkyl and Halogenated C 1-6 alkyl.

[0159] In one or more embodiments, L is a key.

[0160] In one or more embodiments, the compound is:

[0161] In one or more embodiments, any of the above general formulas of this application or the compounds of this application do not include compounds with the following structures:

[0162] One or more embodiments of this application provide pharmaceutical compositions comprising the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, and a pharmaceutically acceptable carrier or excipient.

[0163] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, or pharmaceutical composition of this application in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases.

[0164] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, or pharmaceutical composition of this application in the preparation of a medicament for regulating GLP-1.

[0165] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug or pharmaceutical composition of this application in the preparation of a GLP-1R agonist.

[0166] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, which are used as pharmaceuticals.

[0167] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, or pharmaceutical composition of this application for the treatment and / or prevention of GLP-1 receptor-mediated diseases.

[0168] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug or pharmaceutical composition of this application, which are used as a drug for regulating GLP-1.

[0169] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug or pharmaceutical composition of this application, which are used as GLP-1R agonists.

[0170] One or more embodiments of this application provide methods for treating and / or preventing GLP-1 receptor-mediated diseases, comprising administering to a subject in need of such treatment a compound of this application or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, or a pharmaceutical composition of this application.

[0171] One or more embodiments of this application provide a method for modulating GLP-1, comprising administering to a subject in which such subject a compound of this application or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug or pharmaceutical composition of this application.

[0172] One or more embodiments of this application provide a method for activating GLP-1R, comprising administering to a subject in which such subject a compound of this application or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug or pharmaceutical composition of this application.

[0173] In one or more embodiments, the disease is non-insulin-dependent diabetes mellitus, obesity, hypertension, hyperlipidemia, arteriosclerosis, hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus, diabetic complications, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia. Detailed Implementation

[0174] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0175] the term

[0176] Unless otherwise specified, the following terms used in this invention (including the specification and claims) have the definitions given below.

[0177] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0178] As used in this article, the group is... The "-", "*", or "---" indicates the position where the group is attached to other parts of the compound or molecule.

[0179] As used in this article, Indicates a single bond or a double bond;

[0180] As used in this article, This indicates that any optional site on the ring can be used as a connection site, for example: Any optional site on the five-membered ring, six-membered ring, and seven-membered ring can be used as a connection site.

[0181] As used in this article, for example, the Markush element in the general formula and its subscript "R" x , with the subscript " x "Used to distinguish Markush elements R; in the general formula, "(R x ) y "or" y (R x )”, in which “ y "R" represents the Markush element. x The quantity of “”.

[0182] "alkyl", alone or as part of other groups, refers to a monovalent straight-chain or branched saturated hydrocarbon group (i.e., C12) consisting only of carbon and hydrogen atoms and containing 1 to 12 carbon atoms. 1-12 Alkyl group). For example, an alkyl group is C10. 1-6 Alkyl (i.e., alkyl groups containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, etc. Unless otherwise stated, in this invention, alkyl is also intended to include substituted alkyl, i.e., one or more positions of the alkyl group are substituted, particularly 1-4 substituents, which may be substituted at any position. Unless otherwise stated, in this invention, "substituted alkyl" includes haloalkyl. As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted by the same or different halogens as defined herein. Haloalkyl is, for example, a C14 group. 1- 6-Hydroalkyl, more specifically C6-Hydroalkyl 1-6 Haloalkyl groups. Examples of haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), etc.

[0183] "Alkoxy group," alone or as part of other groups, refers to an alkyl group having an oxygen-containing group attached thereto, possessing an alkyl O- structure, wherein the alkyl group has the definition described above. For example, an alkoxy group is C10 ... 1-6 Alkoxy (i.e. -OC) 1-6 Alkyl groups. Alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, etc. "Haloalkoxy" refers to a group of formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0184] "Thioalkyl" refers to an alkyl group in which the carbon atom is replaced by S, S(O) or S(O)2.

[0185] "Alkenyl," alone or as part of other groups, refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms (i.e., C64-C ... 2-20 Alkenyl). For example, the alkenyl group is C. 2-6 Alkenyl (i.e., alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms). Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. Unless otherwise defined, in this invention, alkenyl groups also include substituted alkenyl groups.

[0186] "Alkyne group," alone or as part of other groups, refers to a straight-chain or branched hydrocarbon chain containing two or more carbon atoms and characterized by having one or more triple bonds, typically having 2 to 20 carbon atoms (i.e., C64-C ... 2-20(Alynyl group). For example, the alkynyl group is C. 2-6 The alkynyl group (i.e., an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms). The alkynyl group includes, but is not limited to, ethynyl, propynyl, and 3-hexynyl. One of the carbon atoms in the triple bond may optionally be the linking point for the alkynyl substituent. In this invention, unless otherwise defined, the alkynyl group also includes substituted alkynyl groups.

[0187] "Cycloalkyl" refers to a monovalent saturated carbocyclic group composed of a single or bicyclic ring, for example, having 3-14 (i.e., C14-C24) carbon atoms. 3-14 Cycloalkyl groups (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms). Unless otherwise defined, cycloalkyl groups may optionally be substituted by one or more substituents. For example, the substituents of a cycloalkyl group may be independently deuterium, hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0188] "Aliphatic groups" refer to straight-chain, branched, or cyclic hydrocarbon groups, including saturated and unsaturated groups such as alkyl, alkenyl, and alkynyl groups.

[0189] "Aromatic ring system" or "aromatic ring" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which at least one ring is aromatic. For example, an "aromatic ring system" or "aromatic ring" has 6-14 ring atoms, i.e., carbon atoms. 6-14 Aromatic rings, examples of which include benzene rings, naphthalene rings, anthracene rings, etc.

[0190] "Aryl," alone or as part of other groups, refers to a monovalent group in an aromatic ring system (aromatic ring). Representative aryl groups include phalloaromatic systems such as phenyl, naphthyl, and anthracene; and ring systems in which an aromatic carbon ring is fused with one or more non-aromatic carbon rings, such as indanyl, phthalimide, naphthylimide, or tetrahydronaphthyl. For example, an aryl group is C 5-14 Aryl groups (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms). In this invention, unless otherwise defined, aryl groups also include substituted aryl groups.

[0191] "Arylalkyl" or "arylalkyl group" refers to an alkyl moiety in which one or more hydrogen atoms of the alkyl group are replaced by aryl groups. Arylalkyl groups include groups in which one or more hydrogen atoms of the alkyl group are replaced by aryl groups, as defined above. Examples of "arylalkyl" or "arylalkyl group" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl.

[0192] "Aryloxy group" refers to -O-(aryl), where the aryl part is defined as above.

[0193] "Heteroalkyl" refers to an alkyl group in which the carbon atom has been replaced, having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, selenium, phosphorus, or combinations thereof. Numerical ranges can be given, for example, C... 1-6 Heteroalkyl refers to the number of carbon atoms in a chain, ranging from 1 to 6. For example, the -CH2OCH2CH3 group is called a "C3" heteroalkyl. Connection to the rest of the molecule can be via heteroatoms or carbons in the heteroalkyl chain.

[0194] A "carbocyclic system" or "carbocyclic ring" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more unsaturated units, but none of the rings are aromatic. For example, a "carbocyclic system" or "carbocyclic ring" has 6-14 ring atoms, i.e., carbon atoms. 6-14 Carbocyclic group. A "carbocyclic group" refers to a carbocyclic system or a monovalent group of a carbocyclic ring as defined above. For example, a carbocyclic group has 6-14 ring atoms, i.e., C atoms. 6-14 Carbocyclic groups. Examples of carbocyclic groups include cycloalkyl groups (such as cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl groups (such as cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).

[0195] "Cycloalkoxy" refers to a group of the formula -OR, where R is a cycloalkyl group as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

[0196] A "heteroaromatic ring system" or "heteroaromatic ring" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (5, 6, 7, 8, 9, 10-membered), or polycyclic (10-, 11-, 12-, 13-, or 14-membered) aromatic ring system, wherein at least one ring is an aromatic ring containing at least one heteroatom (e.g., N, O, or S) as a ring atom and the remaining ring atoms are all carbon. In some cases, the aromatic ring containing at least one heteroatom may contain 1, 2, 3, or 4 heterocyclic atoms. Apart from aromatic rings containing at least one heteroatom as a ring atom, the remaining rings in a "heteroaromatic ring system" or "heteroaromatic ring" may be saturated, partially unsaturated, or fully unsaturated rings.

[0197] "Heteroaryl," alone or as part of other groups, refers to a monovalent group of a "heteroary ring system" or "heteroary ring" as defined above. The junction of the heteroaryl group should be located on the aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzopyranyl, indole, isindole, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazole, and azazolyl. basalt, diazoxide Acridinyl, acridineyl, etc. A heteroaryl group refers to a heteroaryl group as defined above that has two linking sites. Unless otherwise defined, heteroaryl groups include substituted or unsubstituted forms. Non-limitingly, this includes:

[0198] A "heterocyclic system" or "heterocycle" refers to a monocyclic, bicyclic, or polycyclic system in which at least one ring is saturated or partially unsaturated (but not aromatic) and contains at least one heteroatom as a ring atom. Heterocyclic systems or heterocycles can be attached to side groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can optionally be substituted.

[0199] "Heterocyclic group" refers to a heterocyclic system or a monovalent group of a heterocycle as defined above, usually referring to stable monocyclic, bicyclic, or tricyclic (e.g., 3-14 ternary, i.e., 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered), including fused rings, spirocyclic and / or bridged ring structures, which are saturated or unsaturated and non-aromatic, and contain a carbon atom and one, two, three or four heteroatoms independently selected from N, O and S as ring atoms. Spirocyclic hydrocarbon groups, 5-14 membered bridged ring hydrocarbon groups containing 1-4 heteroatoms chosen from N, O, or S, 3-14 membered monocyclic hydrocarbon groups containing 1-4 heteroatoms chosen from N, O, or S, and 4-14 membered fused ring hydrocarbon groups containing 1-4 heteroatoms chosen from N, O, or S, i.e., two adjacent atoms on the ring form an unsaturated structure in the form of a double bond, but the ring is a non-aromatic structure, and includes, without limitation:

[0200] In this invention, "ester group" refers to having a -C(O)-OR or RC(O)-O- structure, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, as defined above.

[0201] In this invention, the term "amide group" refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0202] In this invention, the term "sulfonamide group" refers to a group having the structure -SO2NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in the dialkylamine segment.

[0203] "Ketocarbonyl" refers to RC (=O)-, where R is an alkyl, cycloalkyl, etc., as mentioned above.

[0204] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0205] In this invention, each of the groups in the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cyclohexaalkyl, alkenyl, alkyne, heterocycle, heterocyclic, etc., may be substituted or unsubstituted.

[0206] In this invention, the term "substitution" refers to the substitution of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8) hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8) of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b Rc NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R a It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, ynyl, heterocyclic, or aromatic rings, R b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic, or aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic ring, can be optionally substituted. Such substituents include (but are not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C... 10 Acyl group, C2-C 10 Ester group, amino group, C1-C6 alkoxy group, C1-C 10 Sulfonyl groups and C1-C6 urea groups, etc.

[0207] "Cyano" refers to -CN.

[0208] "Nitro" refers to -NO2.

[0209] "Hydroxy group" refers to -OH.

[0210] "Amino" refers to -NH2 or RNH- or -N(R)2, where R is an alkyl group (such as C). 1-6 alkyl), ketone carbonyl, sulfonyl, sulfonamide, R a -C(=O)-、R a R b NC(=O)- etc., where R a and R b It can be alkyl, cycloalkyl, aryl, or heteroaryl, etc.

[0211] "Halogen (halogenated)" refers to any halogen group, such as -F, -Cl, -Br or -I.

[0212] "Deuterated compounds" refer to compounds in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0213] In this invention, the term "multiple" independently refers to more than one, such as 2, 3, 4, or 5.

[0214] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent of each other; they can be the same or different. That is, the terms "selected from" and "independently selected from" have the same meaning.

[0215] In this invention, the term "1-6" refers to 1, 2, 3, 4, 5, or 6. Other similar terms have similar meanings.

[0216] In this invention, the term "one or more" refers to 1, 2, 3, 4, 5, or 6. Other similar terms have similar meanings.

[0217] The compounds of this invention also include prodrugs of compounds represented by formula (I). The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, when taken by an appropriate method, are metabolized or chemically reacted in the human body to form compounds of formula (I), or salts or solutions of compounds of formula (I). The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0218] The term "solvent" refers to a complex formed by the coordination of the compound of the present invention with a solvent molecule in a specific ratio. It should be understood that the specific method for preparing the compound of formula (I) of the present invention does not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0219] Typically, the compounds of the present invention can be prepared by the process flow shown in the examples, wherein the raw materials and reagents used are commercially available unless otherwise specified.

[0220] Pharmaceutical Compositions and Administration

[0221] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the said compounds and a pharmaceutically acceptable carrier.

[0222] Because the compounds of the present invention have excellent antitumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0223] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0224] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and be mixed with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0225] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0226] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0227] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0228] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0229] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0230] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0231] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0232] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0233] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0234] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0235] The treatment method of this invention can be used alone or in combination with other treatments or medications. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is applied to the mammal (such as a human) requiring treatment. The dosage is the pharmaceutically considered effective dose, and for a person weighing 60 kg, the daily dose is typically 1–2000 mg, for example, 50–1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0236] Compared with the prior art, the present invention has the following main advantages:

[0237] (1) The compound has excellent GLP-1R agonist activity.

[0238] (2) The compound has excellent pharmacokinetic properties.

[0239] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0240] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0241] This invention provides a series of compounds with GLP-1R agonist activity and their synthetic methods, which have broad application prospects.

[0242] Example Synthesis Route

[0243] Unless otherwise stated, the absolute stereochemical definitions of all chiral atoms are as follows: The symbol “or1” indicates that the compound is a monomorphic compound, but the absolute configuration is unknown; the symbol “or2” indicates that the compound is a monomorphic compound, an enantiomer of the “or1” structure, but the absolute configuration is unknown; the symbol “abs” indicates that the absolute configuration of the compound is the structure shown; the symbol “rac” indicates that the compound is a racemic compound; the symbols “S” or “R” indicate that the chirality of the carbon at that position is the known configuration indicated.

[0244] Synthesis of intermediates

[0245] Synthesis of int1

[0246] Synthesis of int1-2:

[0247] At room temperature, 24 g (1.0 eq) of 4-chloro-2-pyridinecarboxaldehyde and 55 mL (3.0 eq) of ethyl acrylate were dissolved in 1,4-dioxane / water (360 mL / 360 mL), followed by the addition of triethylenediamine (19 g, 1.0 eq). The mixture was stirred at room temperature for 5 hours. After the reaction was complete, water was added to the reaction solution, followed by extraction with ethyl acetate (300 mL × 2). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 40.2 g of product.

[0248] Synthesis of int1-3:

[0249] INT1-2 (40.2 g, 1.0 eq) was dissolved in acetic anhydride (200 mL), and the mixture was heated to 100 °C and stirred for 3 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure, and then a saturated sodium bicarbonate aqueous solution was slowly added at room temperature to adjust the pH to greater than 7. Methyl tert-ethyl ether (300 mL × 2) was added for extraction. The methyl tert-ethyl ether phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product.

[0250] Synthesis of int1-4:

[0251] Dissolve int1-3 in xylene (200 mL) and heat to 140 °C for 12 hours. The reaction is complete. Dilute the reaction solution with methyl ether (200 mL), then wash the organic phase with saturated sodium carbonate aqueous solution and sodium chloride aqueous solution, respectively. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure. Purify by column chromatography to obtain 26.8 g of product.

[0252] Synthesis of int1-5:

[0253] Int1-4 (2.0 g, 1.0 eq), pinacol diboronate (6.8 g, 3.0 eq), Pd2(dba)3 (164 mg, 0.02 eq), Xphos (170 mg, 0.04 eq), potassium acetate (2.6 g, 3.0 eq), and 1,4-dioxane (20 mL) were placed in a 50 mL single-necked flask. Under nitrogen protection, the mixture was heated to 110 °C and reacted for 16 hours. The reaction was complete. Water was added to the reaction solution at room temperature, followed by extraction with ethyl acetate (20 mL × 2). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, which was used directly in the next step.

[0254] Synthesis of int1-6:

[0255] Int1-5 (1.4 g, 1.0 eq), int1-0 (1.13 g, 1.1 eq), Pd(dppf)Cl2 (320 mg, 0.1 eq), potassium carbonate (1.2 g, 2.0 eq), and 1,4-dioxane / water (15 mL / 3 mL) were placed in a 50 mL single-necked flask. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 3 hours. The reaction was complete. Water was added to the reaction solution at room temperature, followed by extraction with ethyl acetate (15 mL × 2). The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.4 g of the product.

[0256] Synthesis of int1-7:

[0257] INT1-6 (1.4 g, 1.0 eq) was dissolved in methanol (15 mL), and Pd / C (140 mg) was added. The mixture was then reacted at room temperature for 1 hour under a hydrogen atmosphere. The reaction was completed. The solution was filtered and concentrated under reduced pressure to give 1.4 g of product.

[0258] Synthesis of int1-8:

[0259] At room temperature, INT1-7 (600 mg, 1.0 eq), bromoacetonitrile (290 mg, 1.1 eq), ferrous sulfate heptahydrate (305 mg, 0.5 eq), sodium iodide (329 mg, 1.0 eq), and dimethyl sulfoxide (8 mL) were placed in a three-necked flask under nitrogen protection. Hydrogen peroxide (0.5 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at 0 °C for 20 minutes. The reaction was then complete. Water was added to the reaction solution, followed by extraction with methyl ether (10 mL × 2). The methyl ether phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain 200 mg of the product. (PE:EA = 5:1)

[0260] Synthesis of int1-9:

[0261] At room temperature, INT1-8 (200 mg, 1.0 eq) and vinyl sulfate (238 mg, 3.0 eq) were dissolved in tetrahydrofuran (5 mL) under nitrogen protection. KHMDS (1 M, 2.45 mL, 4.0 eq) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at 0 °C for 2 h. The reaction was then complete. Formic acid (8 eq) was added dropwise to the reaction solution, followed by water. Ethyl acetate (10 mL × 2) was added for extraction. The ethyl acetate phase was washed twice each with saturated sodium bicarbonate and sodium chloride aqueous solutions. The ethyl acetate phase was dried over anhydrous sodium sulfate and subjected to column chromatography to obtain 176 mg of the product.

[0262] Synthesis of int1-10:

[0263] Int1-9 (176 mg, 1.0 eq) was dissolved in dimethyl sulfoxide (3 mL), and then 50% hydroxylamine aqueous solution (0.3 mL, 10 eq) was added. The mixture was stirred at room temperature for 16 h until the reaction was complete. Water was added to the reaction solution, and ethyl acetate (10 mL × 2) was added for extraction. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was dissolved in dimethyl sulfoxide (3 mL), and CDI (168.5 mg, 2.0 eq) and DBU (197.8 mg, 2.5 eq) were added at room temperature. The mixture was stirred at room temperature for 0.5 h. The reaction was monitored by liquid chromatography until complete. Formic acid was added to the reaction solution, followed by water, and then ethyl acetate (10 mL × 2) was added for extraction. The ethyl acetate phase was dried over anhydrous sodium sulfate and column chromatography was performed to obtain 137 mg of the product. Synthesis of int1:

[0264] INT1-10 (137 mg, 1.0 eq) was dissolved in methanol (2 mL), and then 2 M NaOH aqueous solution (2 mL) was added. The reaction was carried out at 65 °C for 2 h. The reaction was completed. The reaction solution was concentrated under reduced pressure, and 5 M HCl was slowly added while stirring. A solid gradually precipitated out. The mixture was filtered, the filter cake was washed twice with water, and the filter cake was collected and dried to obtain 110 mg of product.

[0265] Synthesis of int2

[0266] 1. Composition of int2-1:

[0267] INT1-5 (14 g, 1.0 eq), INT2-0 (11.3 g, 1.1 eq), Pd(dppf)Cl2 (3.2 g, 0.1 eq), potassium carbonate (12 g, 2.0 eq), and 1,4-dioxane / water (150 mL / 30 mL) were placed in a 500 mL single-necked flask. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 3 hours. The reaction was complete. Water was added to the reaction solution at room temperature, followed by extraction with ethyl acetate (150 mL × 2). The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 14 g of product. MS [M+H] + :300.2.

[0268] 2. Composition of int2-3:

[0269] 14 g (1.0 eq) of int2-1 was dissolved in methanol (150 mL), and Pd / C (1.4 g) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 1 hour. The reaction was complete. The solution was filtered and concentrated under reduced pressure to obtain 14 g of crude int2-2. The crude int2-2 was chirally resolved to give 4.9 g of int2-3 (elution time: 10.1 min). MS [M+H] + 302.2,

[0270] The separation conditions are as follows: Instrument: Agilent 1260Ⅱ, Column: Phenomenex 5 μm Cellulose-1 (250 x 30 mm), mobile phase: n-hexane:ethanol = 1:9, flow rate: 25 mL / min, run time: 23 min.

[0271] 3. Composition of int2-4:

[0272] At room temperature, 1.2 g (1.0 eq) of INT2-3, 580 mg (1.1 eq) of bromoacetonitrile, 610 mg (0.5 eq) of ferrous sulfate heptahydrate, 660 mg (1.0 eq) of sodium iodide, and 10 mL of dimethyl sulfoxide were placed in a three-necked flask under nitrogen protection. Hydrogen peroxide (1 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 20 minutes. The reaction was completed. Water was added to the reaction solution, and methyl tert-butyl ether (10 mL × 2) was added for extraction. The methyl tert-butyl ether phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to obtain 600 mg of product. MS [M+H] + :341.2.

[0273] 4. Composition of int2-5:

[0274] At room temperature, INT2-4 (600 mg, 1.0 eq) and vinyl sulfate (720 mg, 3.0 eq) were dissolved in tetrahydrofuran (5 mL). Under nitrogen protection, KHMDS (1 M, 7.35 mL, 4.0 eq) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at 0 °C for 2 h. The reaction was then complete. Formic acid (647 mg, 8 eq) was added dropwise to the reaction solution, followed by extraction with water and ethyl acetate. The ethyl acetate phase was washed twice each with saturated sodium bicarbonate aqueous solution and sodium chloride aqueous solution, respectively. The ethyl acetate phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 380 mg of the product. MS [M+H] + 367.2.

[0275] 5. Composition of int2-6:

[0276] Int2-5 (350 mg, 1.0 eq) was dissolved in dimethyl sulfoxide (3 mL), and then 50% hydroxylamine aqueous solution (0.6 mL, 10 eq) was added. The mixture was stirred at room temperature for 16 h until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate.

[0277] The crude product was dissolved in dimethyl sulfoxide (3 mL), and CDI (337 mg, 2.0 eq) and DBU (396 mg, 2.5 eq) were added at room temperature. The mixture was stirred at room temperature for 0.5 h. After the reaction was complete, formic acid was added to the reaction solution, followed by water, and then extraction with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 271 mg of the product. MS [M+H] + :426.2.

[0278] 6. Composition of int2:

[0279] INT2-6 (260 mg, 1.0 eq) was dissolved in methanol (2 mL), followed by the addition of 2 M NaOH aqueous solution (2 mL). The reaction was carried out at 65 °C for 2 h. The reaction was completed. The reaction solution was concentrated under reduced pressure, and 5 M HCl was slowly added with stirring. A solid gradually precipitated out. The mixture was filtered, the filter cake was washed twice with water, and the cake was collected and dried to obtain 210 mg of the product. MS [M+H] + :398.2.

[0280] Synthesis of int3

[0281] 1. Composition of int3-2

[0282] Int3-1 (35.0 g, 1.0 eq), cyclopropylboronic acid (24.0 g, 1.5 eq), triphenylphosphine (4.83 g, 0.1 eq), palladium acetate (2.06 g, 0.05 eq), and potassium phosphate (117.15 g, 3.0 eq) were dissolved in a mixed solvent of toluene (700 mL) and water (70 mL). The reaction mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere until complete. After cooling to room temperature, the mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The concentrated product was then purified by column chromatography to obtain 25.92 g of the product. MS [M+H] + :152.2.

[0283] 2. Composition of int3

[0284] Int3-2 (25.92 g, 1.0 eq), ethyl bromoacetate (37.27 g, 1.3 eq), and sodium acetate (20.91 g, 1.5 eq) were mixed and dissolved in anhydrous ethanol (280 mL). The reaction mixture was then stirred at 80 °C for 2 h until complete. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, the filtrate was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then slurried with petroleum ether. After filtration, 28.15 g of the product was obtained. MS [M+H] + :238.2.

[0285] Synthesis of int4

[0286] 1. Composition of int4-2

[0287] INT4-1 (25.0 g, 1.0 eq) was dissolved in dioxane (250 mL), followed by the addition of trimethylcycloborane (57.42 g, 1.5 eq), potassium carbonate (37.0 g, 2.0 eq), and Pd(dppf)Cl2 (9.81 g, 0.1 eq). The mixture was then stirred at 100 °C for 2 hours under a nitrogen atmosphere until complete. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give 22.24 g of the product. MS [M+H] + : 167.2.

[0288] 2. Composition of int4-3

[0289] INT4-2 (22.24 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (300 mL). Lithium aluminum hydride (8.19 g, 1.5 eq) was added in portions under a nitrogen atmosphere in an ice-water bath. The mixture was then allowed to rise naturally to room temperature and stirred for 1 h. The reaction was complete. The reaction was quenched in portions by adding sodium sulfate decahydrate under an ice-water bath. After dilution with ethyl acetate, the mixture was filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The concentrated filtrate was then purified by column chromatography to give 18.49 g of the product. MS [M+H] + : 139.2.

[0290] 3. Composition of int4-4

[0291] Cuprous bromide (31.83 g, 1.5 eq), lithium bromide (38.60 g, 3.0 eq), and tert-butyl nitrite (22.85 g, 1.5 eq) were mixed in acetonitrile (500 mL). The mixture was stirred at 60 °C for ten minutes. Then, int4-3 (18.49 g, 1.0 eq) was added in portions to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The reaction was complete. After cooling, the reaction solution was filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate, and ammonia was added to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 22.45 g of crude product. MS[M+H] + :202.2 / 204.2

[0292] 4. Synthesis of C1-5

[0293] INT4-4 (22.45 g, 1.0 eq) was dissolved in dichloromethane (500 mL), and manganese dioxide (77.74 g, 8.0 eq) was added. The reaction mixture was stirred overnight at 30 °C until complete. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, the filtrates were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 19.20 g of product. MS [M+H] + :200.2 / 202.2.

[0294] 5. Composition of int4-6

[0295] INT4-5 (19.20 g, 1.0 eq), INT3 (25.5 g, 1.2 eq), and triethylsilane (42.6 g, 4.0 eq) were dissolved in hexafluoroisopropanol (350 mL), and the reaction mixture was stirred at 30 °C for 6 h. The reaction was complete. After concentrating the reaction mixture at low temperature, it was redissolved in dichloromethane, concentrated under reduced pressure, and purified by column chromatography to obtain 21.06 g of product. MS [M+H] + :421.2 / 423.2.

[0296] 6. Composition of int4-7

[0297] Int4-6 (21.06 g, 1.0 eq), triphenylphosphine (2.63 g, 0.2 eq), palladium acetate (1.24 g, 0.1 eq), and potassium phosphate (31.89 g, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (410 mL). The reaction mixture was stirred at 110 °C for 16 h under a nitrogen atmosphere until complete. The mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 25.33 g of crude product. MS [M+H] + :341.2.

[0298] 7. Composition of int4-8

[0299] INT4-7 (25.33 g, 1.0 eq) was dissolved in dichloromethane (500 mL), and manganese dioxide (97.22 g, 15.0 eq) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was complete. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. After concentration, the product was purified by column chromatography to obtain 20.16 g of product. MS [M+H] + :339.2.

[0300] 8. Composition of int4-9

[0301] INT4-8 (10.68 g, 1.0 eq), p-methoxybenzyl chloride (7.94 g, 1.6 eq), and potassium iodide (10.49 g, 2.0 eq) were dissolved in acetonitrile (220 mL). The reaction mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere until complete. After cooling, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated. After redissolving in methanol, the methanol phase was extracted with petroleum ether, and then concentrated under reduced pressure to obtain 14.50 g of crude product. MS [M+H] + :459.2.

[0302] 9. Composition of int4-10

[0303] INT4-9 (14.50 g, 1.0 eq) was dissolved in methanol (300 mL). Sodium borohydride (3.60 g, 3.0 eq) was added in portions under nitrogen atmosphere and in an ice bath. The reaction mixture was then stirred at room temperature for half an hour until complete. The reaction was quenched with a saturated ammonium chloride solution in an ice bath. The mixture was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 7.17 g of the product. MS [M+H] + :463.2.

[0304] 10. Composition of int4-11

[0305] INT4-10 (570 mg, 1.0 eq) was dissolved in acetonitrile (30 mL). Under a nitrogen atmosphere, an acetonitrile solution of N-succinimide bromide (299 mg, 1.5 eq) was slowly added dropwise with stirring at -15 °C. The reaction mixture was then stirred at this temperature for 1 h. The reaction was complete. The solution was quenched with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 356 mg of the product. MS [M+H] + : 541.2 / 543.2.

[0306] 11. Composition of int4-12

[0307] Int4-11 (466 mg, 1.0 eq), zinc cyanide (202 mg, 2.0 eq), zinc powder (112 mg, 2.0 eq), Brettphos (92 mg, 0.2 eq), and Brettphos Pd G3 (155 mg, 0.2 eq) were mixed in anhydrous N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 375 mg of the product. MS [M+H] + :488.2.

[0308] 12. Composition of int4-13

[0309] Int4-12 (375 mg, 1.0 eq) was dissolved in acetonitrile (30 mL), and potassium trimethylsilanolate (394 mg, 4.0 eq) was added. The reaction mixture was then stirred at 90 °C for 2 h. The reaction was complete. After concentrating the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 500 mg of crude product. MS [M+H] + : 460.2.

[0310] 13. Composition of int4-14

[0311] INT4-13 (500 mg, 1.0 eq), DPPA (424 mg, 2.0 eq), and DIPEA (0.54 mL, 4.0 eq) were dissolved in toluene (20 mL). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Then, aminoacetaldehyde dimethyl acetal (162 mg, 2.0 eq) was added, and the reaction mixture was stirred at 60 °C for another 6 h. The reaction was complete. After extraction with water and ethyl acetate, the product was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 285 mg of the product. MS [M+H] + :562.2.

[0312] 14. Composition of int4-15

[0313] INT4-14 (285 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the addition of methanesulfonic acid (73 mg, 1.5 eq). The reaction mixture was then stirred at 60 °C for 2 h until complete. The solution was cooled to room temperature, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 228 mg of the product. MS [M+H]+ :498.2.

[0314] 15. Composition of int4-16

[0315] Int4-15 (228 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (211 mg, 2.0 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (26 mg, 0.4 eq), cuprous iodide (18 mg, 0.2 eq), and potassium carbonate (190 mg, 3.0 eq) were dissolved in NMP (8 mL). The reaction mixture was stirred at 135 °C for 16 h under a nitrogen atmosphere until complete. The mixture was filtered through diatomaceous earth, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 304 mg of the product. MS [M+H] + :646.2.

[0316] 16. Composition of int4

[0317] INT4-16 (304 mg, 1.0 eq) was dissolved in dichloroethane (8 mL), and 1-chloroethyl chloroformate (270 mg, 4.0 eq) was added. The reaction mixture was then stirred at 85 °C for 16 h. After concentration, the reaction mixture was reconstituted with methanol (8 mL), and then stirred at 60 °C for 0.5 h. The reaction was complete. The reaction mixture was directly concentrated under reduced pressure, and after concentration, it was purified by preparative thin-layer chromatography to obtain 110 mg of product. MS [M+H] + :526.2.

[0318] Synthesis of int5

[0319] 1. Composition of int5-2

[0320] INT5-1 (25.0 g, 1.0 eq) was dissolved in ethanol (250 mL), and ethyl bromoacetate (29.8 g, 1.0 eq) and anhydrous sodium acetate (22.1 g, 1.5 eq) were added with stirring. The mixture was then stirred at 80 °C for 1 hour. The reaction was complete. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give 27.6 g of product. MS [M+H] + :226.1.

[0321] 2. Composition of int5-3

[0322] Int5-2 (27.1 g, 1.2 eq), Int4-5 (20 g, 1.0 eq), and triethylsilane (46.6 g, 4.0 eq) were dissolved in hexafluoroisopropanol (200 mL), and the reaction mixture was stirred at 30 °C for 6 h. The reaction was complete. After concentrating most of the hexafluoroisopropanol at low temperature, it was redissolved in dichloromethane, concentrated, and purified by column chromatography to obtain 32.4 g of product. MS [M+H] + :409.1 / 411.1.

[0323] 3. Composition of int5-4

[0324] Int5-3 (30 g, 1.0 eq), triphenylphosphine (3.85 g, 0.2 eq), palladium acetate (1.64 g, 0.1 eq), and potassium phosphate (46.76 g, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (410 mL). The reaction mixture was stirred at 110 °C for 16 h under a nitrogen atmosphere until complete. The solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated, water was added, and the solution was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 31 g of crude product. MS[M+H] + :329.2.

[0325] 4. Composition of int5-5

[0326] Int5-4 (31 g, 1.0 eq) was dissolved in dichloromethane (500 mL), and manganese dioxide (123.33 g, 15.0 eq) was added. The reaction mixture was stirred at room temperature for 2 h until complete. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, the filtrates were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 22 g of product. MS [M+H] + :327.1.

[0327] 5. Composition of int5-6

[0328] Int5-5 (10 g, 1.0 eq), p-methoxybenzyl chloride (7.70 g, 1.6 eq), and potassium iodide (10.18 g, 2.0 eq) were dissolved in acetonitrile (200 mL). The reaction mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere until complete. After cooling, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated. After redissolving in methanol, the methanol phase was extracted with petroleum ether, and then concentrated under reduced pressure to obtain 13.20 g of crude product. MS [M+H] + :447.2.

[0329] 6. Composition of int5-7

[0330] INT5-6 (13.20 g, 1.0 eq) was dissolved in methanol (150 mL). Sodium borohydride (3.36 g, 3.0 eq) was added in portions under nitrogen atmosphere and in an ice bath. The reaction mixture was then stirred at room temperature for half an hour until complete. The reaction was quenched with a saturated ammonium chloride solution in an ice bath. The mixture was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 8.13 g of product. MS [M+H] + :451.2.

[0331] 7. Composition of int5-8

[0332] Int5-7 (1.5 g, 1.0 eq) was dissolved in acetonitrile (30 mL). Under a nitrogen atmosphere, an acetonitrile solution of N-succinimide bromide (806 mg, 1.5 eq) was slowly added dropwise with stirring at -15 °C. The reaction mixture was then stirred at this temperature for 1 h. The reaction was complete. The solution was quenched with a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 1.2 g of the product. MS [M+H] + : 529.1 / 531.1.

[0333] 8. Composition of int5-9

[0334] Int5-8 (1.2 g, 1.0 eq), zinc cyanide (532 mg, 2.0 eq), zinc powder (295 mg, 2.0 eq), Brettphos (244 mg, 0.2 eq), and Brettphos Pd G3 (412 mg, 0.2 eq) were mixed in anhydrous N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 750 mg of the product. MS [M+H] + :476.2.

[0335] 9. Composition of int5-10

[0336] INT5-9 (750 mg, 1.0 eq) was dissolved in acetonitrile (30 mL), and potassium trimethylsilanolate (788 mg, 4.0 eq) was added. The reaction mixture was then stirred at 90 °C for 2 h. The reaction was complete. After concentrating the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.03 g of crude product. MS [M+H] + : 448.2

[0337] 10. Composition of int5-11

[0338] Int5-10 (1 g, 1.0 eq), DPPA (848 mg, 2.0 eq), and DIPEA (1.08 mL, 4.0 eq) were dissolved in toluene (20 mL). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Then, aminoacetaldehyde dimethyl acetal (324 mg, 2.0 eq) and dry tetrahydrofuran (20 mL) were added, and the reaction mixture was stirred at 60 °C for another 2 h. The reaction was complete. After extraction with water and ethyl acetate, the product was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 600 mg of the product. MS [M+H] + : 550.3.

[0339] 11. Composition of int5-12

[0340] INT5-11 (600 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the addition of methanesulfonic acid (157.3 mg, 1.5 eq). The reaction mixture was then stirred at 60 °C for 1 h until complete. The solution was cooled to room temperature, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 480 mg of the product. MS [M+H] + :486.2.

[0341] 12. Composition of int5-13

[0342] Int5-12 (480 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (453.2 mg, 2.0 eq), N,N'-dimethylethylenediamine (34.8 mg, 0.4 eq), cuprous iodide (37.6 mg, 0.2 eq), and potassium carbonate (409.7 mg, 3.0 eq) were dissolved in NMP (4 mL) and reacted under nitrogen atmosphere at 135 °C for 4 h with stirring. The reaction was complete. The mixture was filtered through diatomaceous earth, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 410 mg of the product. MS [M+H] + :634.3.

[0343] 13. Composition of int5

[0344] Int5-13 (400 mg, 1.0 eq) was dissolved in dichloroethane (10 mL), and 1-chloroethyl chloroformate (360.8 mg, 4.0 eq) was added. The reaction mixture was then stirred at 85 °C for 16 h. The reaction mixture was concentrated, reconstituted with methanol (8 mL), and then stirred at 60 °C for 0.5 h. The reaction was complete. The reaction mixture was directly concentrated under reduced pressure, and then purified by column chromatography to obtain 330 mg of product. MS [M+H] + :514.2.

[0345] Synthesis of int6

[0346] Int6-1 (1.00 g, 1.00 eq), cyclopropylboronic acid (804 mg, 2.00 eq), copper acetate (1.70 g, 2.00 eq), and 2,2-bipyridine (729 mg, 1.00 eq) were dissolved in 25 mL of 1,2-dichloroethane, displacing oxygen. The mixture was stirred overnight at 50 °C under an oxygen atmosphere. The reaction proceeded to completion. The reaction solution was cooled to room temperature and concentrated. Purification by column chromatography yielded 680 mg of product. Ms[M+H] + 255.0, 257.0, 1 H NMR (400MHz, Chloroform-d) δ7.98 (d, J = 0.8Hz, 1H), 7.46 (dd, J = 8.8, 6.4Hz, 1H), 7.31-7.24 (m, 1H), 3.64-3.54 (m, 1H), 1.29-1.13 (m, 4H).

[0347] Synthesis of int7a / int7b

[0348] 1. Composition of int7-2

[0349] Int7-1 (3.00 g, 1.00 eq), ethyl 4-bromobutyrate (6.13 g, 2.00 eq), and potassium carbonate (6.50 g, 3.00 eq) were dissolved in N,N-dimethylformamide (30 mL), and the mixture was heated to 100 °C and reacted for 1 h. The reaction was completed. The reaction solution was cooled to room temperature, water was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. After purification by column chromatography, 5.6 g of the product was obtained.

[0350] 2. Composition of int7-3

[0351] INT7-2 (4.77 g, 1.00 eq) was dissolved in a mixed solvent of tetrahydrofuran / methanol / water (10 mL / 10 mL / 10 mL), and sodium hydroxide (1.88 g, 3.00 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was complete. The pH was adjusted to weakly acidic with 4 M HCl aq, the aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 4.3 g of crude product.

[0352] 3. Composition of int7-4

[0353] Polyphosphoric acid (30 mL) was dissolved in toluene (70 mL), and INT7-3 (3.56 g, 1.00 eq) was added at room temperature. The reaction mixture was reacted at 120 °C for 16 h until complete. The reaction mixture was cooled to room temperature, and the toluene was poured off. Polyphosphoric acid was dissolved in water, and the aqueous phase was extracted with ethyl acetate. The toluene and ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and concentrated. The product was purified by column chromatography to give 425 mg of product. Ms[M+H] + 259.0, 261.0.

[0354] 4. Composition of int7-5

[0355] INT7-4 (425 mg, 1.00 eq) was dissolved in 1,4-dioxane (15 mL), and hydrazine hydrate (1.3 mL, 10.00 eq) was added. The reaction mixture was stirred overnight at 110 °C. The reaction was completed. The reaction mixture was cooled to room temperature and concentrated. After purification by thin-layer chromatography, 370 mg of product was obtained. Ms[M+H] + :253.0,265.0.

[0356] 5. Composition of int7a and int7b

[0357] Int7-5 (370 mg, 1.00 eq) was dissolved in N,N-dimethylformamide (6 mL), and 60% sodium hydride (88 mg, 1.50 eq) was added under ice bath conditions. After stirring under ice bath conditions for 0.5 h, deuterated iodomethane (319 mg, 1.50 eq) was added. The reaction mixture was stirred at room temperature for 0.5 h. The reaction was complete. The reaction was quenched with water under ice bath conditions, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated. The solution was purified by thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the sample with the upper spot (R). f ≈0.5)243mg; lower point (R f ≈0.4)116mg. Ms[M+H] + 270.0, 272.0.

[0358] Int8 Synthesis

[0359] 1. Composition of int8-2

[0360] INT8-1 (10.0 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (150 mL). Isopropyl magnesium chloride (16.6 mL, 2 M in THF, 1.0 eq) was slowly added dropwise under a nitrogen atmosphere at -20 °C. The reaction was then maintained at this temperature with stirring for 1 hour. Next, a tetrahydrofuran solution of diethylphosphonochloride (6.22 g, 1.2 eq) was added dropwise (10 mL). The mixture was allowed to rise naturally to room temperature with stirring for 12 hours. The reaction was complete. Under an ice-water bath, the pH was adjusted to 2 with 1 M dilute hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was then washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to yield 6.14 g.

[0361] 2. Composition of int8-3

[0362] INT8-2 (6.14 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (70 mL). Ethyl magnesium bromide (13.6 mL, 2.0 eq) was slowly added dropwise under a nitrogen atmosphere and in an ice-water bath. The mixture was then allowed to rise naturally to room temperature and stirred for 2 hours. The reaction was complete. The reaction was quenched with a saturated ammonium chloride solution in an ice-water bath. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 3.08 g of the product.

[0363] 3. Composition of int8-4

[0364] INT8-3 (3.08 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (70 mL). Under a nitrogen atmosphere, lithium diisopropylamino (6.8 mL, 1.1 eq) was slowly added dropwise at -70 °C. The reaction was then maintained at this temperature with stirring for 1 hour. Next, a tetrahydrofuran solution of tert-butyl-(2-iodoethoxy)dimethylsilane (4.58 g, 1.3 eq) was added dropwise. The mixture was allowed to rise naturally to room temperature with stirring for 5 hours. The reaction was completed. The reaction was quenched with a saturated ammonium chloride solution under ice-water bath conditions. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to yield 2.62 g.

[0365] 4. Composition of int8

[0366] INT8-4 (1.6 g, 1.0 eq) was dissolved in a methanol solution of methylamine (20 mL), and the reaction was carried out at 80 °C under sealed conditions for 1 hour. The reaction was completed. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain 560 mg of product.

[0367] Synthesis of int9

[0368] 1. Composition of int9-1

[0369] Int8-1 (2 g, 1.0 eq), diethylphosphine oxide (775 mg, 1.1 eq), tris(dibenzylindeneacetone)dipalladium(0) (304 mg, 0.05 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (385 mg, 0.1 eq), and triethylamine (1.34 g, 2.0 eq) were dissolved in 1,4-dioxane (40 mL) and reacted under nitrogen atmosphere at 60 °C for 16 h with stirring. The reactants were completely reacted. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 1.8 g of the product. MS [M+H] + : 279.0, 281.0.

[0370] 2. Composition of int9

[0371] INT9-1 (800 mg, 1.0 eq) was dissolved in a methanol solution of methylamine (18 mL), and the reaction mixture was stirred at 100 °C for 16 h. The starting materials reacted completely. The reaction mixture was concentrated, ethyl acetate was added, and the organic phase was washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain 800 mg of the product. MS [M+H] + :290.0,292.0.

[0372] Int10 synthesis

[0373] 1. Composition of int10-1

[0374] INT5-8 (500 mg, 1.0 eq), methyl fluorosulfonyl difluoroacetate (727 mg, 4.0 eq), cuprous iodide (450 mg, 2.5 eq), and N-methylmorpholine (383 mg, 4 eq) were mixed in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 100 °C for 18 h under a nitrogen atmosphere. The reactants reacted completely. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 310 mg of the product. MS [M+H] + :519.2.

[0375] 2. Synthesis of int10-2

[0376] C10-1 (310 mg, 1.0 eq) was dissolved in acetonitrile (15 mL), and potassium trimethylsilanolate (306 mg, 4.0 eq) was added. The reaction mixture was then stirred at 90 °C for 2 h. The reaction proceeds reacted completely. After concentrating the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 255 mg of crude product. MS [M+H] + :491.2.

[0377] 3. Synthesis of int10-3

[0378] C10-2 (255 mg, 1.0 eq), diphenyl azidophosphate (286 mg, 2.0 eq), and N,N-diisopropylethylamine (0.36 mL, 4.0 eq) were dissolved in toluene (10 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. Then, aminoacetaldehyde dimethyl acetal (162 mg, 2.0 eq) and an equal volume of anhydrous tetrahydrofuran (10 mL) were added, and the reaction mixture was stirred at 60 °C for 6 h. The reaction proceeded completely. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 365 mg of crude product. MS [M+H] + 593.2

[0379] 4. Composition of int10-4

[0380] C10-3 (365 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the addition of methanesulfonic acid (89 mg, 1.5 eq). The reaction mixture was then stirred at 60 °C for 2 h. The reaction proceeded completely. The solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 108 mg of the product. MS [M+H] + : 529.2.

[0381] 5. Composition of int10-5

[0382] C10-4 (108 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (95 mg, 2.0 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (22 mg, 0.4 eq), cuprous iodide (18 mg, 0.2 eq), and potassium carbonate (90 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 135 °C for 3 h under a nitrogen atmosphere. The reactants reacted completely. The solution was filtered through diatomaceous earth, water was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 87 mg of the product. MS [M+H]+ :677.2.

[0383] 6. Composition of int10

[0384] C10-5 (87 mg, 1.0 eq) was dissolved in dichloroethane (8 mL), and 1-chloroethyl chloroformate (125 mg, 4.0 eq) was added. The reaction mixture was then stirred at 85 °C for 16 h. The reaction mixture was concentrated, reconstituted with methanol (8 mL), and then stirred at 60 °C for 0.5 h. The reactants reacted completely. The reaction mixture was directly concentrated under reduced pressure, and after concentration, purified by thin-layer chromatography to obtain 38 mg of product. MS [M+H] + :557.2.

[0385] Int11 Synthesis

[0386] 1. Composition of int11-1

[0387] Int5-8 (0.4 g, 1.0 eq), dimethylphosphine oxide (590 mg, 10.0 eq), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (55 mg, 0.1 eq), and sodium acetate (186 mg, 3.0 eq) were dissolved in 1,4-dioxane / water (5 / 0.5 mL). The reaction mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reactants reacted completely. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 100 mg of the product. MS [M+H] + : 527.3.

[0388] 2. Composition of int11-2

[0389] INT11-1 (100 mg, 1.0 eq) was dissolved in acetonitrile (5 mL), and potassium trimethylsilanolate (97 mg, 4.0 eq) was added. The reaction mixture was then stirred at 90 °C for 2 h. The reaction proceeded to completion. The solution was concentrated under reduced pressure, a small amount of water was added, and the mixture was extracted with a dichloromethane / methanol system. The extract was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 160 mg of crude product. This crude product was not purified and proceeded directly to the next step of the reaction. MS [M+H] + :499.2.

[0390] 3. Composition of int11-3

[0391] Int11-2 (160 mg, 1.0 eq), diphenyl azidophosphate (110 mg, 2.0 eq), and N,N-diisopropylethylamine (100 mg, 4.0 eq) were dissolved in a toluene / tetrahydrofuran mixed solution (5 / 5 mL). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Then, aminoacetaldehyde dimethyl acetal (40 mg, 2.0 eq) and dry tetrahydrofuran (5 mL) were added, and the reaction mixture was stirred at 60 °C for another 2 h. The reaction proceeded completely. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 50 mg of the product. MS [M+H] + :601.2.

[0392] 4. Composition of int11-4

[0393] INT11-3 (50 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (2 mL), followed by the addition of methanesulfonic acid (12 mg, 1.5 eq). The reaction mixture was then stirred at 60 °C for 1 h. The reaction proceeded completely. The solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 30 mg of the product. MS [M+H] + : 537.3.

[0394] 5. Composition of int11-5

[0395] Int11-4 (30 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (26 mg, 2.0 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (3 mg, 0.4 eq), cuprous iodide (2 mg, 0.2 eq), and potassium carbonate (23 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (3 mL). The mixture was stirred at 135 °C for 4 h under a nitrogen atmosphere. The reaction proceeded completely. The solution was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 50 mg of the product. MS [M+H] + : 685.5.

[0396] 6. Composition of int11

[0397] INT11-5 (50 mg, 1.0 eq) was dissolved in dichloroethane (10 mL), and 1-chloroethyl chloroformate (360.8 mg, 4.0 eq) was added. The reaction mixture was then stirred at 85 °C for 6 days. The reaction mixture was concentrated, reconstituted with methanol (8 mL), and then stirred at 60 °C for 0.5 h. The starting materials reacted completely. The reaction mixture was directly concentrated under reduced pressure, and then purified by column chromatography to obtain 30 mg of the product. MS [M+H] + : 565.2.

[0398] Synthesis of int12

[0399] 1. Composition of int12-1

[0400] Int5-8 (400 mg, 1 eq), 2-pyrrolidone (250 mg, 3 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (43 mg, 0.4 eq), cuprous iodide (28 mg, 0.2 eq), and potassium phosphate (480 mg, 3.0 eq) were dissolved in N,N-dimethylformamide (10 mL). The mixture was stirred at 115 °C for 48 h under a nitrogen atmosphere. The reaction proceeded completely. The mixture was filtered, water was added, and the product was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified to give 300 mg of the product. MS [M+H] + :534.2.

[0401] 2. Composition of int12-2

[0402] Int12-1 (300 mg, 1.0 eq) was dissolved in acetonitrile (10 mL), and potassium trimethylsilanolate (450 mg, 5.0 eq) was added. The reaction mixture was then stirred at 90 °C for 5 h. The reaction proceeded completely. After concentration under reduced pressure, 210 mg of the product was obtained. [M+H] + :506.2.

[0403] 3. Composition of int12-3

[0404] Int12-2 (200 mg, 1.0 eq), diphenyl azidophosphate (220 mg, 2.0 eq), and N,N-diisopropylethylamine (200 mg, 4.0 eq) were dissolved in toluene (5 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. Then, aminoacetaldehyde dimethyl acetal (90 mg, 2.0 eq) and dry tetrahydrofuran (5 mL) were added, and the reaction mixture was stirred at 60 °C for 2 h. The reaction proceeded completely. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 130 mg of the product. MS [M+H]+ :608.3.

[0405] 4. Composition of int12-4

[0406] INT12-3 (130 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), followed by the addition of methanesulfonic acid (35 mg, 1.5 eq). The reaction mixture was then stirred at 60 °C for 2 h. The reaction proceeded completely. The solution was cooled to room temperature, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 100 mg of the product. MS [M+H] + :544.3.

[0407] 5. Composition of int12-5

[0408] Int12-4 (100 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (85 mg, 2.0 eq), N,N'-dimethylethylenediamine (7 mg, 0.4 eq), cuprous iodide (7 mg, 0.2 eq), and potassium carbonate (75 mg, 3.0 eq) were dissolved in N-methylpyrrolidone (4 mL). The reaction mixture was stirred at 135 °C for 4 h under a nitrogen atmosphere. The reaction proceeded completely. The mixture was filtered through diatomaceous earth, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 85 mg of the product. MS [M+H] + :692.3.

[0409] 6. Composition of int12

[0410] Int12-5 (85 mg, 1.0 eq) was dissolved in dichloroethane (10 mL), and 1-chloroethyl chloroformate (70 mg, 4.0 eq) was added. The reaction mixture was then stirred at 85 °C for 6 h. The reaction mixture was concentrated, reconstituted with methanol (8 mL), and then stirred at 60 °C for 0.5 h. The starting materials reacted completely. The reaction mixture was directly concentrated under reduced pressure, and then purified by column chromatography to obtain 10 mg of the product. MS [M+H] + :572.3.

[0411] Composition of int13a and int13b

[0412] 5-Bromo-4-fluoroindazole (0.3 g, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (10 mL), followed by the addition of potassium carbonate (380 mg, 2 eq) and bromoethane (330 mg, 1.5 eq). The mixture was stirred at 70 °C for 5 h. After extraction with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain int13a (200 mg, R...). f ≈0.8) and int13b (100mg, R f ≈0.6). MS[M+H] + :243.0.

[0413] Composition of int14a ​​and int14b

[0414] 5-Bromo-4-fluoroindazole (0.5 g, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (10 mL), followed by the addition of cesium carbonate (1.5 g, 2 eq) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (700 mg, 1.3 eq). The mixture was stirred at 70 °C for 5 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain int14a ​​(370 mg, R...). f ≈0.6) and int14b (150mg, R f ≈0.4). MS[M+H] + :297.0.

[0415] Composition of int15a and int15b

[0416] 5-Bromo-4-fluoroindazole (0.5 g, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (10 mL), followed by the addition of cesium carbonate (1.5 g, 2 eq) and bromomethylcyclopropane (410 mg, 1.3 eq). The mixture was stirred at 80 °C for 1.5 h. After extraction with sodium chloride and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain int15a (330 mg, R). f ≈0.8) and int15b (250mg, R f ≈0.6). MS[M+H] + : 269.0.

[0417] Composition of int16a and int16b

[0418] 5-Bromo-4-fluoroindazole (800 mg, 1.0 eq), difluoroiodoethane (857 mg, 1.2 eq), and potassium carbonate (770 mg, 1.5 eq) were dissolved in anhydrous N,N-dimethylformamide (4 mL), and the reaction mixture was stirred at room temperature for 4 h. The reaction proceeds were completely reacted. The mixture was filtered through diatomaceous earth, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain int16a (360 mg, R...). f ≈0.6) and int16b (190mg, R f ≈0.4), MS[M+H] + : 269.0.

[0419] Synthesis of int28

[0420] 1. Synthesis of C28-1

[0421] C15-1 (300 mg, 1.0 eq) was dissolved in ethanol (6 mL), followed by the sequential addition of hydroxylamine (577 mg, 20.0 eq, 50% aqueous solution) and anhydrous magnesium sulfate (91 mg, 50 eq). The mixture was stirred at 80 °C for 16 hours until the reaction was complete. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain 300 mg of the product. MS [M+H] + :647.2.

[0422] 2. Synthesis of C28-2

[0423] C28-1 (100 mg, 1.0 eq) was dissolved in acetic acid (3 mL), and 2,2-dimethoxypropane (9.5 mg, 1.5 eq) was added with stirring. The reaction mixture was stirred at 40 °C for 16 hours until the reactants were completely reacted. The reaction was quenched in an aqueous solution of sodium bicarbonate under ice bath conditions, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 70 mg of the product. MS [M+H] + : 687.3.

[0424] 3. Composition of int28

[0425] A mixture of C17-2 (70 mg, 1.0 eq) was dissolved in dichloromethane (2 mL), cooled to 0 °C, and then trifluoroacetic acid (2 mL) was slowly added. The mixture was then stirred at room temperature for 2 h. The reaction was quenched in an aqueous solution of sodium bicarbonate under ice bath conditions. Extraction with dichloromethane yielded 59 mg of crude product, which was used directly in the next reaction. MS[M+H] + 587.3

[0426] Combining int29 and int30

[0427] 1. Composition of int29-1

[0428] C21-1 (100 mg, 1.0 eq) and triphenylphosphine (241 mg, 6.0 eq) were dissolved in a mixed solution of tetrahydrofuran / methanol (5 mL / 5 mL). Diisopropyl azodicarbonate was added dropwise in an ice bath under a nitrogen atmosphere, and the reaction solution was slowly heated to room temperature for 2 h.

[0429] Thin-layer chromatography was used to monitor the reaction; the reaction proceeded to completion. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 500 mg of a mixture of int 29-1. MS [M+H] + :671.3.

[0430] 2. Combining int29 and int30

[0431] A mixture of int29-1 (500 mg, 1.0 eq) was dissolved in dichloromethane (3 mL). After cooling to 0 °C, a dioxane solution of hydrogen chloride (4 mol / L, 3 mL) was slowly added, followed by stirring at room temperature for 0.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. Water was added, and the aqueous phase was extracted with ethyl acetate to remove triphenylphosphine oxide. The aqueous phase was adjusted to pH 8 with sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 50 mg of crude mixture of int29 and int30. MS [M+H] + :571.2.

[0432] Int31 Synthesis

[0433] 1. Composition of int31-2

[0434] INT31-1 (2.34 g, 1.0 eq) was dissolved in N,N-dimethylformamide (70 mL). 60% sodium hydride (480 mg, 1.2 eq) was added in portions over an ice bath, and the mixture was stirred for 0.5 h. Iodomethane (1.42 g, 1.0 eq) was slowly added dropwise over an ice bath, and the mixture was stirred at room temperature for 16 h until the reactants were fully reacted. The reaction was quenched by slow addition of ice water over an ice bath. The mixture was extracted with ethyl acetate and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 1 g of the product. MS [M+H] + :249.0,251.0.

[0435] 2. Composition of int31-3

[0436] INT31-2 (1 g, 1.0 eq) was dissolved in ethanol / water (20 mL / 20 mL), followed by the addition of ammonium chloride (2.16 g, 10.0 eq). Zinc powder (2.6 g, 10.0 eq) was then added in portions over an ice bath. The reaction mixture was stirred at room temperature for 0.5 h until the reactants were fully reacted. The solution was filtered, and the aqueous phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, concentrated under reduced pressure, and purified by column chromatography to give 680 mg of the product. MS [M+H] + :219.0,221.0.

[0437] 3. Composition of int31-4

[0438] INT31-3 (300 mg, 1.0 eq) was dissolved in sulfuric acid / water (0.3 mL / 15 mL). A solution of sodium nitrite (142 mg, 1.5 eq) in 2.8 mL was added dropwise in an ice bath. The reaction mixture was then stirred in an ice bath for 2 hours until the reactants reacted completely. The pH was adjusted to neutral with sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 110 mg of the product. MS [M+H] + :230.0,232.0.

[0439] 4. Composition of int31-5

[0440] Int5-12 (60 mg, 1.0 eq), Int31-4 (37 mg, 1.3 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (7.1 mg, 0.4 eq), cuprous iodide (4.8 mg, 0.2 eq), and potassium carbonate (51 mg, 3.0 eq) were dissolved in DMF (5 mL). The mixture was stirred at 135 °C for 4 h under a nitrogen atmosphere until the reactants were completely reacted. The mixture was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 71 mg of the product. MS [M+H] + :635.3.

[0441] 5. Composition of int31

[0442] INT31-5 (70 mg, 1.0 eq) was dissolved in dichloroethane (10 mL), and 1-chloroethyl chloroformate (158 mg, 10.0 eq) was added. The reaction mixture was then stirred at 85 °C for 6 h. The reaction mixture was evaporated to dryness, reconstituted with methanol (10 mL), and then stirred at 60 °C for 0.5 h until the reactants were completely reacted. The reaction mixture was then concentrated under reduced pressure and purified by thin-layer chromatography to obtain 34 mg of the product. MS [M+H] + :515.2.

[0443] Int32 Synthesis

[0444] 1. Composition of int32-2

[0445] Int32-1 (1 g, 1.0 eq), iodomethane (872 mg, 1.5 eq), and potassium carbonate (1.13 g, 2.0 eq) were dissolved in N,N-dimethylformamide (15 mL) and reacted at 60 °C with stirring for 2 h until the reactants were completely reacted. An aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 1 g of the product. MS [M+H] + : 257.9, 259.9.

[0446] 2. Composition of int32-3

[0447] INT32-2 (500 mg, 1.0 eq) was dissolved in ethanol (6 mL), and 60% hydrazine hydrate (6 mL) was added. The reaction mixture was then stirred at 130 °C for 7 h until the reactants were completely reacted. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 410 mg of the product. MS [M+H] + :244.0,246.0.

[0448] 3. Composition of int32-4

[0449] Int32-3 (380 mg, 1.0 eq), 2,2'-dibromodiethyl ether (726 mg, 2.0 eq), sodium iodide (469 mg, 2.0 eq), and cesium carbonate (1.02 g, 2.0 eq) were dissolved in N,N-dimethylformamide (15 mL) and reacted at 50 °C for 3 h with stirring until the reactants were completely reacted. The reaction solution was filtered, water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 74 mg of the product. MS [M+H] + : 314.0, 316.0.

[0450] 4. Composition of int32-5

[0451] Int32-12 (80 mg, 1.0 eq), C1-4 (62 mg, 1.2 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (9.4 mg, 0.4 eq), cuprous iodide (6.3 mg, 0.2 eq), and potassium carbonate (68 mg, 3.0 eq) were dissolved in N,N-dimethylformamide (8 mL). The mixture was stirred at 135 °C for 3 h under a nitrogen atmosphere until the reactants were completely reacted. The mixture was filtered through diatomaceous earth, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 100 mg of the product. MS [M+H] + :719.3.

[0452] 5. Composition of int32

[0453] INT32-5 (100 mg, 1.0 eq) was dissolved in dichloroethane (8 mL), and 1-chloroethyl chloroformate (378 mg, 20.0 eq) was added. The reaction mixture was then stirred at 85 °C for 6 h. The reaction mixture was concentrated, reconstituted with methanol (8 mL), and then stirred at 60 °C for 0.5 h until the reactants were completely reacted. The reaction mixture was then concentrated under reduced pressure and purified by thin-layer chromatography to obtain 50 mg of the product. MS [M+H] + : 599.3.

[0454] Synthesis of int36

[0455] 1. Composition of int36-2

[0456] Methaniel hydrochloride (700 mg, 5.3 eq) was dissolved in anhydrous tetrahydrofuran (15 mL). Triethylamine (1.8 mL, 6.3 eq) was added at 0 °C, and stirring was continued for 30 min. 2,3-Difluoro-4-bromonitrobenzene (500 mg, 1.0 eq) was added, and the mixture was stirred at 25 °C for 1.5 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to give 520 mg of the product. MS [M+H] + : 248.9.

[0457] 2. Composition of int36-3

[0458] INT36-2 (500 mg, 1 eq) was dissolved in ethanol (15 mL) and water (15 mL), zinc powder (500 mg, 1 eq) was added, and ammonium chloride (1.1 g, 10.0 eq) was added at 0 °C. The mixture was stirred at room temperature for 30 min. The solution was filtered, washed with dichloromethane, and the filtrate was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified to give 376 mg of the product. MS [M+H] + :219.0.

[0459] 3. Composition of int36-4

[0460] INT36-3 (330 mg, 1.0 eq) was dissolved in acetic acid (12 mL), and sodium nitrite (115 mg, 1.1 eq) was added at 20 °C. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, and the pH was adjusted to 8 by adding saturated sodium bicarbonate at 0 °C. The solution was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to give 88 mg of the product. MS [M+H] + : 229.9.

[0461] 4. Composition of int36-5

[0462] Int5-12 (143 mg, 1.0 eq), Int36-4 (88 mg, 1.3 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (16.9 mg, 0.4 eq), cuprous iodide (11.4 mg, 0.2 eq), and potassium carbonate (121.3 mg, 3.0 eq) were dissolved in N,N-dimethylformamide (12 mL). The mixture was stirred at 135 °C for 4 h under a nitrogen atmosphere until the reactants were completely reacted. The mixture was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to give 161 mg of the product. MS [M+H] + :635.3.

[0463] 5. Composition of int36

[0464] Int36-5 (161 mg, 1.0 eq) was dissolved in dichloroethane (25 mL), and 1-chloroethyl chloroformate (363.4 mg, 10.0 eq) was added. The reaction mixture was then stirred at 85 °C for 6 h. The reaction mixture was evaporated to dryness, reconstituted with methanol (10 mL), and then stirred at 60 °C for 0.5 h until the reactants were completely reacted. The solution was concentrated under reduced pressure and then purified by thin-layer chromatography to obtain 70 mg of the product. MS [M+H] + :515.2.

[0465] Composition of int37a and int37b

[0466] INT37-1 (300 mg, 1.0 eq) was dissolved in acetonitrile (5 mL), followed by the addition of potassium fluoride (161.8 mg, 2.0 eq). Under nitrogen protection, diethyl bromofluorophosphate (593.3 mg, 1.5 eq) was added at room temperature, and the reaction was allowed to proceed for 16 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, followed by extraction twice with ethyl acetate (10 mL). The mixture was separated, and the ethyl acetate phase was dried over anhydrous sodium sulfate. The purified ethyl acetate phase was then purified by column chromatography to obtain INT37a (42 mg, R...). f ≈0.8) and int37b (298mg, R f ≈0.5).

[0467] Synthesis of int 62

[0468] 1. Composition of int62-2

[0469] Ethyl 3-methyl-1H-pyrrole-2-carboxylate (50 g, 1 eq) was dissolved in dichloromethane (200 mL), cooled to 0 °C, and then 4-dimethylaminopyridine (39.8 g, 1.0 eq) and di-tert-butyl dicarbonate (106.8 g, 1.5 eq) were slowly added. The reaction mixture was then naturally heated to room temperature and stirred for 4 h until the reactants reacted completely. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography to obtain 70 g of product. MS [M+Na] + 276.3

[0470] 2. Composition of int62-3

[0471] INT62-2 (70 g, 1.0 eq) was dissolved in tetrahydrofuran (350 mL), and N-bromosuccinimide (51.6 g, 1.05 eq) was added in portions with stirring. The reaction mixture was then stirred at 60 °C for 3 hours until the starting material was completely reacted. The mixture was cooled to room temperature, concentrated under reduced pressure, and then purified by column chromatography to give 79.6 g of the product. MS [M+Na] + : 354.2 / 356.2, 1 H NMR (400MHz, DMSO-d6) δppm 7.54 (s, 1H), 4.25 (q, J = 7.2Hz, 2H), 2.07 (s, 3H), 1.50 (s, 9H), 1.26 (t, J = 7.2Hz, 3H).

[0472] 3. Composition of int62-4

[0473] INT62-3 (70 g, 1.0 eq) and azobisisobutyronitrile (6.92 g, 0.2 eq) were dissolved in carbon tetrachloride (300 mL). N-bromosuccinimide (39.4 g, 1.05 eq) was added in portions with stirring, and the reaction mixture was stirred at 85 °C for 16 hours until the starting material was completely reacted. The mixture was cooled to room temperature, concentrated under reduced pressure, and then purified by column chromatography to obtain 64 g of product. MS [M+Na] + : 432.1 / 434.1 / 436.1, 1 H NMR (400MHz, DMSO-d6) δppm7.68 (s, 1H), 4.52 (s, 2H), 4.37 (q, J = 7.2Hz, 3H), 1.52 (s, 9H), 1.30 (t, J = 7.2Hz, 3H).

[0474] 4. Composition of int62-5

[0475] INT62-4 (64 g, 1.0 eq) was dissolved in acetonitrile (500 mL), cooled to 0 °C, and then N-methylmorpholine oxide (36 g, 1.0 eq) was slowly added. The reaction mixture was then naturally heated to room temperature and stirred for 2 h until the reactants were completely reacted. The solution was concentrated under reduced pressure, then extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 44 g of the product. MS [M+Na] + 368.2 / 370.2 1 H NMR (400MHz, DMSO-d6) δppm 9.84 (s, 1H), 7.68 (s, 1H), 4.35 (q, J = 7.2Hz, 2H), 1.54 (s, 9H), 1.29 (t, J = 7.2Hz, 3H).

[0476] 5. Composition of int62-6

[0477] INT62-5 (44 g, 1.0 eq) was dissolved in dry tetrahydrofuran (300 mL). Tetraethyl titanate (87.2 g, 3 eq) and R-tert-butylsulfinamide (23.2 g, 1.5 eq) were added with stirring. The reaction mixture was stirred at 75 °C for 16 h under a nitrogen atmosphere until the reactants reacted completely. After cooling, water was added to the reaction system, followed by filtration. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. 41 g of the product was then purified by column chromatography. MS [M+Na] + 349.2 / 351.2 1H NMR (400MHz, DMSO-d6) δppm 12.86 (s, 1H), 9.07 (s, 1H), 7.35 (s, 1H), 4.32 (q, J = 7.2Hz, 2H), 1.33 (t, J = 7.2Hz, 3H), 1.17 (d, J = 15.2Hz, 9H).

[0478] 6. Composition of int62-7

[0479] INT62-6 (40 g, 1.0 eq) was dissolved in dry tetrahydrofuran (2000 mL). Under a nitrogen atmosphere and in an ice-water bath, 3 mol / L methylmagnesium bromide (306 mL, 8.0 eq) was slowly added dropwise. The reaction mixture was then stirred at room temperature for 4 h until the reactants were fully reacted. The reaction was quenched with a saturated ammonium chloride solution in an ice-water bath. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 26 g of the product. MS [M+Na] + 365.3 / 367.3 1 H NMR (400MHz, DMSO-d6) δppm 12.10 (s, 1H), 7.09 (d, J = 3.2Hz, 1H), 5.21 (d, J = 7.2Hz, 1H), 4.34 -4.18(m,2H),1.47(d,J=6.8Hz,3H),1.29(t,J=7.2Hz,3H),1.04(s,9H).

[0480] 7. Composition of int62-8

[0481] INT62-7 (26 g, 1.0 eq) was dissolved in dichloromethane (150 mL). A 2 mol / L hydrogen chloride ethanol solution (50 mL) was slowly added dropwise under ice-water bath conditions. The reaction mixture was then naturally heated to room temperature and stirred for 1 h until the reactants reacted completely. The solution was concentrated under reduced pressure to obtain 26 g of crude product, which was used directly in the next reaction without purification. MS[M+Na] + : 244.1 / 246.1

[0482] 8. Composition of int62-9

[0483] INT62-8 (26 g, 1.0 eq) was dissolved in tetrahydrofuran (150 mL), followed by the addition of an aqueous solution of sodium bicarbonate (33.8 g, 3 eq) (75 mL). The mixture was cooled to 0 °C under a nitrogen atmosphere, and then benzyl chloroformate (27.2 g, 1.5 eq) was slowly added dropwise. The mixture was then allowed to warm naturally to room temperature with stirring for 2 h until the reactants were fully reacted. The product was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 25 g of the product. MS [M+Na] + : 417.3 / 419.3

[0484] 9. Composition of int62-10

[0485] INT62-9 (5 g, 1.0 eq) was dissolved in 50 mL of dry dioxane. Then, (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (3.76 g, 1.5 eq), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (0.93 g, 0.05 eq), and potassium carbonate (5.25 g, 3.0 eq) were added. Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 4 h until the reactants were completely reacted. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. It was then extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 3.7 g of the product. MS [M+Na] + 409.2, 1 H NMR (400MHz, DMSO-d6) δppm11.50 (s, 1H), 7.39-7.22 (d, J = 8.2Hz, 1H), 7.39 -7.24(m,5H),6.90(d,J=3.2Hz,1H),6.75(d,J=12.8Hz,1H),5.78(d,J=12.8Hz,1H),5.25- 5.13(m,1H),4.96(s,2H),4.23(q,J=6.8Hz,2H),3.80(q,J=6.8Hz,2H),1.37-1.17(m,9H).

[0486] 10. Composition of int62-11

[0487] INT62-10 (3.7 g, 1.0 eq) was dissolved in dichloromethane (40 mL). A 2 mol / L ethanol solution of hydrogen chloride (20 mL) was slowly added dropwise under ice-water bath conditions. The reaction was continued for 1 h under ice-water bath conditions until the starting material was completely reacted. The solution was concentrated under reduced pressure to obtain 4.15 g of crude product, which was used directly in the next reaction without purification. MS [M+Na] + 341.1

[0488] 11. Composition of int62-12

[0489] INT62-11 (4.15 g, 1.0 eq) was dissolved in dichloromethane (10 mL). Then, under a nitrogen atmosphere, trifluoroacetic acid (11.22 g, 8.0 eq) and triethylsilane (11.32 g, 8.0 eq) were slowly added sequentially. The mixture was stirred at room temperature for 16 h until the reactants were fully reacted. The pH was adjusted to alkaline using sodium carbonate under ice-water bath conditions, followed by extraction with dichloromethane. The organic phase was concentrated under reduced pressure to give 4.9 g of crude product, which was used directly in the next reaction without purification. MS[M+Na] + 365.2

[0490] 12. Composition of int62-13

[0491] INT62-12 (4.9 g, 1.0 eq) was dissolved in methanol (10 mL), and palladium on carbon (0.2 g, 20% wt%) and di-tert-butyl dicarbonate (3.3 g, 1.2 eq) were added. The mixture was then stirred at room temperature under a hydrogen atmosphere for 2 h until the reactants were completely reacted. The mixture was filtered, and the filter cake was washed with dichloromethane / methanol. The filtrate was concentrated under reduced pressure to give 4.8 g of crude product, which was used directly in the next reaction without purification. MS [M+Na] + 331.2

[0492] 13. Composition of int62-14

[0493] Int62-13 (308 mg, 1.0 eq), 4-bromo-2,6-dimethylfluorobenzene (404 mg, 2.0 eq), (S,S)-(+)-N,N′-dimethyl-1,2-cyclohexanediamine (56.8 mg, 0.4 eq), cuprous iodide (38 mg, 0.2 eq), and potassium carbonate (414 mg, 3.0 eq) were dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at 135 °C for 4 h under a nitrogen atmosphere in a sealed system until the reactants were completely reacted. The mixture was filtered through diatomaceous earth, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 320 mg of the product. MS [M+Na] + :453.2.

[0494] 14. Composition of int62

[0495] INT62-14 (0.15 g, 1.0 eq) was dissolved in acetonitrile (30 mL). Under a nitrogen atmosphere, an acetonitrile solution of N-succinimide bromide (81 mg, 1.5 eq) was slowly added dropwise to the reaction solution with stirring at -15°C. The reaction solution was then maintained at this temperature and stirred for 1 h. The reaction was completed. The solution was quenched with a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 0.1 g of the product.

[0496] Synthesis of int 65a

[0497] 1. Synthesis of int65a-2:

[0498] INT65A-1 (1 g, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (280 mg, 1.5 eq) was added at 0°C. After the addition was complete, the reaction was allowed to proceed at 0°C for 0.5 hours. Then, iodoethane (874 mg, 1.2 eq) was slowly added. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with water, extracted twice with ethyl acetate, separated, and the ethyl acetate phase was dried over anhydrous sodium sulfate. The product was purified by column chromatography to obtain 1.07 g of product.

[0499] 2. Synthesis of int65a-3:

[0500] Int65a-2 (1.07 g, 1.0 eq) was dissolved in tert-butanol / water (20 mL / 10 mL). N-bromosuccinimide (2.3 g, 3.0 eq) was added in portions at room temperature. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.5 g of the product.

[0501] 3. Synthesis of int65a-4:

[0502] Int65a-3 (1.5 g, 1.0 eq) was dissolved in acetic acid (30 mL), followed by the addition of iron powder (1 g, 5.0 eq). After the addition was complete, the mixture was reacted at 80 °C for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 865 mg of the product.

[0503] 4. Composition of int65a:

[0504] Int65a-4 (253 mg, 1.0 eq) was dissolved in dichloromethane (7 mL), followed by the addition of zinc trifluoromethanesulfonate (71.4 mg, 0.2 eq), diphenyl(vinyl)sulfonium trifluoromethanesulfonate (356.5 mg, 1.0 eq), and 1,8-diazabicyclo[5.4.0]undec-7-ene (299 mg, 2.0 eq). After the addition was complete, the reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The liquid was separated, and the ethyl acetate phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 197 mg of the product.

[0505] Synthesis of int 72

[0506] 1. Synthesis of int72-2

[0507] INT72-1 (2.0 g, 1.0 eq), (tributyltin)methanol (2.53 g, 2.0 eq), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (619 mg, 0.2 eq) were dissolved in N,N-dimethylformamide (30 mL). The mixture was stirred at 100 °C for 16 h under nitrogen protection until the reactants were completely reacted. The mixture was cooled to room temperature, and 20 mL of potassium fluoride aqueous solution was added. The mixture was stirred at room temperature for 30 min. The mixture was filtered. The filtrate separated into layers. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 1.1 g of the product. MS [M+H] + :461.2.

[0508] 2. Composition of int72-3

[0509] INT72-2 (870 mg, 1.0 eq) was dissolved in dichloromethane (30 mL), cooled in an ice bath, and then Dysmartin reagent (1.6 g, 2.0 eq) was added in portions while in an ice bath. The mixture was stirred at room temperature for 2 h until the reactants were completely reacted. The reaction solution was filtered. Sodium bicarbonate aqueous solution was added to the filtrate, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 480 mg of the product. MS [M+H] + :459.2.

[0510] 3. Composition of int72-4

[0511] Int72-3 (440 mg, 1.0 eq) and 2-methyl-2-butene (1.34 g, 20.0 eq) were dissolved in a mixed solvent of tetrahydrofuran / tert-butanol / water (8 mL / 8 mL / 2 mL). An aqueous solution of sodium dihydrogen phosphate (752 mg, 5.0 eq) was added, and the mixture was cooled in an ice bath. An aqueous solution of sodium chlorite (259 mg, 3.0 eq) was slowly added dropwise while in an ice bath. The reaction mixture was brought to room temperature and stirred for 1 h until the reactants reacted completely. The reaction mixture was separated into two phases, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 480 mg of crude product. MS [M+H] + :475.2.

[0512] 4. Composition of int72-5

[0513] Int72-4 (351 mg, 1.0 eq), morpholine (97 mg, 1.5 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (422 mg, 1.5 eq), and N,N-diisopropylethylamine (284 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 1 h until the reactants were completely reacted. After extraction with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 400 mg of the product. MS [M+H] + :544.3.

[0514] 5. Composition of int72-6

[0515] INT72-5 (400 mg, 1.0 eq) was dissolved in acetonitrile (15 mL), and potassium trimethylsilanolate (377 mg, 4.0 eq) was added. The reaction mixture was then stirred at 90 °C for 2 h until the reactants were completely reacted. After cooling to room temperature and concentrating under reduced pressure, 379 mg of crude product was obtained. MS [M+H] + :516.2.

[0516] 6. Composition of int72-7

[0517] Int72-6 (379 mg, 1.0 eq), diphenyl azidophosphate (405 mg, 2.0 eq), and N,N-diisopropylethylamine (380 mg, 4.0 eq) were dissolved in toluene (20 mL). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Then, aminoacetaldehyde dimethyl acetal (155 mg, 2.0 eq) and dry tetrahydrofuran (20 mL) were added. The reaction mixture was then stirred at 60 °C for 2 h until the reactants were completely reacted. After extraction with water and ethyl acetate, the product was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 492 mg of crude product. MS [M+H]+ :618.3.

[0518] 7. Composition of int72-8

[0519] INT72-7 (492 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the addition of methanesulfonic acid (115 mg, 1.5 eq). The reaction mixture was then stirred at 60 °C for 1 h until the reactants were fully reacted. The solution was cooled to room temperature, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 330 mg of the product. MS [M+H] + :554.3.

[0520] 8. Composition of int72-9

[0521] Int72-8 (150 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (81 mg, 1.3 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.4 eq), cuprous iodide (10 mg, 0.2 eq), and potassium carbonate (112 mg, 3.0 eq) were dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere until the reactants were completely reacted. The solution was filtered, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 160 mg of the product. MS [M+H] + :702.3.

[0522] 9. Composition of int72

[0523] INT72-9 (160 mg, 1.0 eq) was dissolved in dichloromethane (4 mL), and 4 M dioxane hydrochloride solution (2 mL) was added. The reaction mixture was then stirred at room temperature for 30 min until the reactants were completely reacted. The reaction mixture was concentrated under reduced pressure to obtain 137 mg of crude product. MS [M+H] + :602.3.

[0524] Synthesis of int 73

[0525] 1. Synthesis of int73-2

[0526] Int72-1 (200 mg, 1.0 eq), 4-methoxybenzyl mercaptan (68.2 mg, 1.1 eq), tris(dibenzylacetone)dipalladium (80 mg, 0.2 eq), N,N-diisopropylethylamine (160 mg, 3 eq), and xantphos (48 mg, 0.2 eq) were dissolved in anhydrous dioxane (20 mL). The reaction mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 130 mg of the product. MS [M+H] + 583.2

[0527] 2. Synthesis of int73-3

[0528] INT73-2 (130 mg, 1.0 eq) was dissolved in acetonitrile (30 mL), and potassium trimethylsilanolate (115 mg, 4.0 eq) was added. The reaction mixture was then stirred at 90 °C for 2 h until the reactants were completely reacted. The solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.2 g of crude product. MS [M+H] + :555.2.

[0529] 3. Synthesis of int73-4

[0530] Int73-3 (0.2 g, 1.0 eq), DPPA (220 mg, 2.0 eq), and DIPEA (210 mg, 4.0 eq) were dissolved in toluene (20 mL). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Then, aminoacetaldehyde dimethyl acetal (80 mg, 2.0 eq) and dry tetrahydrofuran (20 mL) were added, and the reaction mixture was stirred at 60 °C for another 2 h until the reactants were completely reacted. The mixture was extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.2 g of the product. MS[M+H] + :657.2.

[0531] 4. Synthesis of int73-5

[0532] INT73-4 (0.2 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the addition of methanesulfonic acid (59 mg, 4 eq). The reaction mixture was then stirred at 60 °C for 2 h until the reactants were fully reacted. The solution was cooled to room temperature, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 60 mg of the product. MS [M+H] + : 593.2.

[0533] 5. Synthesis of int73-6

[0534] Int73-5 (60 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (58 mg, 2.0 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.4 eq), cuprous iodide (8 mg, 0.2 eq), and potassium carbonate (39 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (3 mL). The mixture was stirred at 110 °C for 4 h under a nitrogen atmosphere until the reactants were completely reacted. The solution was filtered, extracted with water and ethyl acetate, and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to give 75 mg of the product. MS [M+H] + :741.2.

[0535] 6. Composition of int73-7

[0536] INT73-6 (75 mg, 1.0 eq) was dissolved in acetic acid (4 mL) and water (0.4 mL). N-chlorosuccinimide (49 mg, 2.0 eq) was added under ice-water bath conditions, and the reaction was maintained at this temperature for half an hour. Then, more N-chlorosuccinimide (49 mg, 2.0 eq) was added, and the reaction mixture was stirred at room temperature for 1 hour until the reactants reacted completely. The pH of the reaction mixture was adjusted to greater than 7 with saturated sodium bicarbonate solution, and the organic phase was extracted with ethyl acetate. The organic phase was then concentrated under reduced pressure and purified by thin-layer chromatography to obtain 100 mg of the product. MS [M+H] + :687.2.

[0537] 7. Composition of int73-8

[0538] INT73-7 (100 mg, 1.0 eq) was dissolved in dioxane (4 mL) and ammonia (4 mL). The reaction mixture was then stirred at room temperature for 2 h until the reactants were fully reacted. The reaction mixture was directly concentrated under reduced pressure, and the concentrated product was purified by thin-layer chromatography to obtain 30 mg of product. MS [M+H] + :668.2.

[0539] 8. Synthesis of int73

[0540] INT73-8 (30 mg, 1.0 eq) was dissolved in dichloromethane (4 mL), and 4 M dioxane hydrochloride solution (3 mL) was added under ice bath conditions. The reaction mixture was then stirred at room temperature for 1 h until the starting material reacted completely. The reaction mixture was then concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction step.

[0541] Synthesis of int 75a

[0542] 1. Synthesis of int75a-2:

[0543] INT75A-1 (5.56 g, 1.2 eq) was dissolved in methanol (60 mL), followed by the addition of 3-benzyloxypropionaldehyde (2.44 g, 1.0 eq) and acetic acid (179 mg, 0.2 eq), and then sodium cyanoborohydride (3.7 g, 4.0 eq) was added in portions. The reaction mixture was allowed to react at room temperature for 2 hours after the addition was complete. After the reaction was completed, the reaction solution was quenched with water, extracted twice with ethyl acetate, separated, and the ethyl acetate phase was dried over anhydrous sodium sulfate. The product was purified by column chromatography to obtain 2.59 g of product.

[0544] 2. Synthesis of int75a-3:

[0545] INT75A-2 (2.59 g, 1.0 eq) was dissolved in acetonitrile (15 mL), followed by the addition of 6 M hydrochloric acid (15 mL). After the addition was complete, the reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then cooled to 0 °C, and sodium nitrite (982 mg, 2.0 eq) was added. The reaction mixture was allowed to react for 1 hour. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The liquid was separated, and the ethyl acetate phase was dried over anhydrous sodium sulfate. The product was purified by column chromatography to obtain 2.34 g of product.

[0546] 3. Synthesis of int75a-4:

[0547] INT75A-3 (2.34 g) was dissolved in trifluoroacetic acid (30 mL) and reacted at 90 M for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, then dissolved in methanol (20 mL), followed by the addition of 2 M sodium hydroxide (2 mL), and reacted at room temperature for 10 minutes. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The liquid was separated, and the ethyl acetate phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 1.66 g of the product.

[0548] 4. Synthesis of int75a-5:

[0549] 1.66 g of int75a-4 was dissolved in 30 mL of 2 M boron tribromide dichloromethane solution and reacted at room temperature for 20 hours. After the reaction was completed, methanol was added to quench the reaction solution, the solution was concentrated under reduced pressure, and purified by column chromatography to obtain 1.0 g of product.

[0550] 5. Composition of int75a:

[0551] INT75A-5 (200 mg, 1.0 eq) was dissolved in toluene (5 mL), and then cyanomethylenetri-n-butylphosphine (356.2 mg, 2.0 eq) was slowly added. After the addition was complete, the reaction mixture was reacted at 120 °C for 16 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The liquid was separated, and the ethyl acetate phase was dried over anhydrous sodium sulfate. The product was purified by column chromatography to obtain 85 mg of product. MS [M+H] +:254.1 / 256.1.

[0552] Synthesis of int 82a

[0553] 1. Synthesis of int82a-2

[0554] 2-Nitro-3-fluoro-4-bromoaniline (18.84 g, 1.0 eq), di-tert-butyl dicarbonate (34.80 g, 2.0 eq), triethylamine (24.20 g, 3.0 eq), and 4-dimethylaminopyridine (1.95 g, 0.2 eq) were dissolved in dichloromethane (230 mL). The reaction mixture was then stirred at room temperature for 2 h until the reactants were completely reacted. Water was added, and the mixture was extracted with dichloromethane. The extract was concentrated under reduced pressure and purified by column chromatography to give 24.9 g of the product.

[0555] 2. Synthesis of int82a-3

[0556] 24.9 g (1.0 eq) of int82a-2 was dissolved in methanol (270 mL), and sodium methoxide (31.8 mL, 5.4 min MeOH, 3.0 eq) was added. The reaction mixture was then stirred at room temperature for 4 h until the reactants were completely reacted. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 19.58 g of crude product.

[0557] 3. Synthesis of int82a-4

[0558] Int82a-3 (19.58 g, 1.0 eq) and solid ammonium chloride (15.13 g, 5.0 eq) were dissolved in ethanol (200 mL) and water (200 mL). Zinc powder (18.40 g, 5.0 eq) was added in portions under ice bath conditions. The reaction mixture was then stirred at room temperature for half an hour until the reactants were completely reacted. The mixture was filtered, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography to obtain 16.22 g.

[0559] 4. Synthesis of int82a-5

[0560] Int82a-4 (7.58 g, 1.2 eq), benzyloxyacetaldehyde (3.0 g, 1.0 eq), and acetic acid (240 mg, 0.2 eq) were dissolved in methanol (60 mL). After stirring for ten minutes, sodium cyanoborohydride (5.04 g, 4.0 eq) was added in portions under ice bath conditions. The reaction mixture was then stirred at room temperature for 2 hours until the reactants were completely reacted. After extraction with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 2.94 g of the product.

[0561] 5. Synthesis of int82a-6

[0562] INT82A-5 (2.84 g, 1.0 eq) was dissolved in concentrated sulfuric acid (24 mL) and water (12 mL). An aqueous solution of sodium nitrite (1.31 g, 3.0 eq) (5 mL) was slowly added under ice bath conditions. The reaction mixture was then stirred at room temperature for 2 h until the reactants were completely reacted. After extraction with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 1.12 g of the product.

[0563] 6. Synthesis of int82a-7

[0564] Int82a-6 (1.12 g, 1.0 eq), sodium ethanethiol (1.63 g, 5.0 eq), and dodecyl mercaptan (3.88 g, 5.0 eq) were dissolved in N-methylpyrrolidone (6 mL). The reaction mixture was stirred at 100 °C for 1 h until the reactants were completely reacted. Water was added, and the pH was adjusted to acidic with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate, followed by washing the organic phase with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography to yield 1.07 g.

[0565] 7. Synthesis of int82a

[0566] INT82A-7 (1.07 g, 1.0 eq) was dissolved in toluene (10 mL), followed by the addition of cyanomethylenetri-n-butylphosphine (2.1 g, 2.0 eq). The reaction mixture was then stirred at 120 °C for 6 h until the reactants were completely reacted. The mixture was extracted with water and ethyl acetate, then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 660 mg of the product.

[0567] Synthesis of int83a

[0568] 1. Synthesis of int83a-2

[0569] INT83A-1 (5.3 g, 1.0 eq), hydrazine hydrate (11.4 g, 10.0 eq), and triethylamine (6.9 g, 3.0 eq) were dissolved in dioxane (60 mL). The reaction mixture was then stirred in a sealed container at 113 °C for 48 h until the reactants were completely reacted. The solution was concentrated under reduced pressure and purified by column chromatography to give 2.7 g of the product.

[0570] 2. Synthesis of int83a-3

[0571] INT83A-2 (2.7 g, 1.0 eq) was dissolved in N,N-dimethylformamide (60 mL). Under ice bath conditions, a solution of potassium hydroxide (1.67 g, 2.5 eq) and elemental iodine (4.55 g, 1.5 eq) in N,N-dimethylformamide (10 mL) was added. The reaction mixture was then stirred at room temperature for 3 h until the reactants reacted completely. The reaction mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 4.1 g of the product. 1 HNMR (400MHz, Chloroform-d) δ10.63(s,1H),7.55(d,J=8.9Hz,1H),7.23(d,J=8.9Hz,1H),4.07(s,3H).

[0572] 3. Composition of int83a-4a / int83a-4b

[0573] Dissolve INT83A-3 (1.0 g, 1.0 eq) in anhydrous tetrahydrofuran (20 mL). Add sodium hydride (340 mg, 3.0 eq) under ice bath conditions, and continue stirring under nitrogen atmosphere for half an hour. Then add iodomethane (1.7 g, 4.3 eq), and stir the reaction mixture at room temperature for 1 hour until the reactants are completely reacted. Extract with water and ethyl acetate, then wash the organic phase with saturated brine. Dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain product INT83A-4B (petroleum ether / ethyl acetate = 3 / 1, R). f =0.6)770mg and product int83a-4a (petroleum ether / ethyl acetate = 3 / 1, R f =0.5)220mg.

[0574] 4. Synthesis of int83a-5

[0575] Int83a-4b (770 mg, 1.0 eq) was dissolved in dioxane (25 mL) and water (2.5 mL). Vinylboronic acid pinacol ester (770 mg, 2.2 eq), potassium carbonate (616 mg, 3.0 eq), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (116 mg, 0.1 eq) were added sequentially. The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere until the reactants were completely reacted. After extraction with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 530 mg of the product.

[0576] 5. Synthesis of int83a-6

[0577] INT83A-5 (530 mg, 1.0 eq) was dissolved in dichloromethane (6 mL), and boron tribromide (2.4 mL, 2 M) was added at -78 °C under a nitrogen atmosphere. The reaction mixture was then stirred at 0 °C for 16 h until the reactants were completely reacted. After quenching the reaction with methanol in an ice bath, water was added, followed by extraction with dichloromethane. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 330 mg of the product.

[0578] 6. Synthesis of int83a-7

[0579] Int83a-6 (330 mg, 1.0 eq) was dissolved in acetonitrile (6 mL), followed by the sequential addition of potassium carbonate (450 mg, 3.27 eq) and 3-bromopropene (315 mg, 2.6 eq). The reaction mixture was then stirred at 60 °C for 2 h until the reactants were completely reacted. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. After purification by column chromatography, 280 mg of the product was obtained.

[0580] 7. Synthesis of int83a-8

[0581] INT83A-7 (280 mg, 1.0 eq) was dissolved in dichloroethane (140 mL), and (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxybenzyl)ruthenium (120 mg, 0.2 eq) was added. The reaction mixture was stirred at 70 °C for 4 h under a nitrogen atmosphere until the reactants reacted completely. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to obtain 140 mg of the product.

[0582] 8. Synthesis of int83a

[0583] Int83a-8 (110 mg, 1.0 eq) was dissolved in ethyl acetate (11 mL), and platinum dioxide (11 mg, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 20 min under a hydrogen atmosphere until the reactants were completely reacted. The mixture was filtered, and the filtrate was concentrated under reduced pressure. After purification by thin-layer chromatography, 90 mg of the product was obtained. 1 H NMR (400MHz, Chloroform-d) δ7.47(d,J=8.7Hz,1H),6.81(d,J=8.7Hz,1H),4.59-4.53(m,2H),3.99(s,3H),3.21-3.15(m,2H),2.38-2.30(m,2H).

[0584] Synthesis of int84

[0585] 1. Synthesis of int84-1

[0586] INT72-1 (100 mg, 1.0 eq) was dissolved in dioxane (8 mL) and water (2 mL). Then, 1-methylpyrazole-4-boronic acid pinacol ester (82 mg, 2.0 eq), potassium carbonate (82 mg, 3.0 eq), and tetrakis(triphenylphosphine)palladium (50 mg, 0.4 eq) were added sequentially. Under a nitrogen atmosphere, the reaction mixture was stirred at 90 °C for 16 h until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 100 mg of the product.

[0587] 2. Synthesis of int84-2

[0588] INT84-1 (100 mg, 1.0 eq) was dissolved in acetonitrile (6 mL), followed by the addition of potassium trimethylsilanolate (100 mg, 4.0 eq). The reaction mixture was then stirred at 90 °C for 2 h until the reactants were fully reacted. The reaction mixture was concentrated under reduced pressure to obtain 96 mg of crude product.

[0589] 3. Synthesis of int84-3

[0590] Int84-2 (96 mg, 1.0 eq), diphenyl azidophosphate (110 mg, 2.0 eq), and N,N-diisopropylethylamine (103 mg, 4.0 eq) were dissolved in toluene (8 mL). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Then, aminoacetaldehyde dimethyl acetal (42 mg, 2.0 eq) and dry tetrahydrofuran (8 mL) were added, and the reaction mixture was stirred at 60 °C for another 2 h until the reactants were completely reacted. After extraction with water and ethyl acetate, the product was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 155 mg of crude product.

[0591] 4. Composition of int84-4

[0592] INT84-3 (155 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the addition of methanesulfonic acid (32 mg, 4 eq). The reaction mixture was then stirred at 60 °C for 1 h until the reactants were fully reacted. The mixture was cooled to room temperature, and the pH was adjusted to alkaline with a saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 60 mg of the product.

[0593] 5. Synthesis of int84-5

[0594] Int84-4 (60 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (53 mg, 2.0 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (7 mg, 0.4 eq), cuprous iodide (5 mg, 0.2 eq), and potassium carbonate (48 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (5 mL). The mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere until the reactants were completely reacted. The solution was filtered, extracted with water and ethyl acetate, and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 59 mg of the product.

[0595] 6. Synthesis of int84

[0596] INT84-5 (59 mg, 1.0 eq) was dissolved in dichloromethane (4 mL), and 4 N dioxane hydrochloride solution (4 mL) was added under ice bath conditions. The reaction mixture was then stirred at room temperature for 0.5 h until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, and the crude product was used directly in the next reaction step.

[0597] Synthesis of int85

[0598] 1. Synthesis of int85-1

[0599] INT72-1 (100 mg, 1.0 eq) was dissolved in dioxane (8 mL) and water (2 mL). Then, 5-pyrimidineboronic acid (49 mg, 2.0 eq), potassium carbonate (82 mg, 3.0 eq), and tetraphenylphosphine palladium (91 mg, 0.4 eq) were added sequentially. The reaction mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 83 mg of the product.

[0600] 2. Synthesis of int85-2

[0601] Int85-1 (83 mg, 1.0 eq) was dissolved in acetonitrile (6 mL), and potassium trimethylsilanolate (84 mg, 4.0 eq) was added. The reaction solution was then stirred at 90 °C for 2 h until the reactants were completely reacted. The reaction solution was concentrated under reduced pressure to obtain 78 mg of crude product.

[0602] 3. Synthesis of int85-3

[0603] Int85-2 (78 mg, 1.0 eq), diphenyl azidophosphate (89 mg, 2.0 eq), and N,N-diisopropylethylamine (84 mg, 4.0 eq) were dissolved in toluene (8 mL). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Then, aminoacetaldehyde dimethyl acetal (34 mg, 2.0 eq) and dry tetrahydrofuran (8 mL) were added. The reaction mixture was then stirred at 60 °C for 2 h until the reactants were completely reacted. After extraction with water and ethyl acetate, the product was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 95 mg of crude product.

[0604] 4. Composition of int85-4

[0605] Int85-3 (95 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), followed by the addition of methanesulfonic acid (24 mg, 4 eq). The reaction mixture was then stirred at 60 °C for 1 h until the reactants were fully reacted. The mixture was cooled to room temperature, and the pH was adjusted to alkaline with a saturated sodium bicarbonate solution. The solution was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 44 mg of the product.

[0606] 5. Composition of int85-5

[0607] Int85-4 (44 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (39 mg, 2.0 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.4 eq), cuprous iodide (4 mg, 0.2 eq), and potassium carbonate (35 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (5 mL). The mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere until the reactants were completely reacted. The solution was filtered, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 48 mg of the product.

[0608] 6. Synthesis of int85

[0609] Int85-5 (48 mg, 1.0 eq) was dissolved in dichloromethane (4 mL), and 4 N dioxane hydrochloride solution (4 mL) was added under ice bath conditions. The reaction mixture was then stirred at room temperature for 0.5 h. The reaction mixture was then concentrated under reduced pressure, and the crude product was used directly in the next reaction step.

[0610] Synthesis of int86a

[0611] 1. Synthesis of int86a

[0612] INT72-1 (150 mg, 1.0 eq) was dissolved in ethylene glycol dimethyl ether (6 mL) and water (2 mL). Then, 3-thiopheneboronic acid (150 mg, 3.0 eq), sodium carbonate (160 mg, 5.0 eq), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (98 mg, 0.4 eq) were added sequentially. The reaction mixture was then microwave-stirred at 120 °C for half an hour under a nitrogen atmosphere until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 160 mg of the product.

[0613] Synthesis of int87a

[0614] 1. Synthesis of int87a

[0615] INT72-1 (100 mg, 1.0 eq) was dissolved in dioxane (6 mL) and water (2 mL). Then, 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (80 mg, 2.0 eq), potassium carbonate (80 mg, 3.0 eq), and tetraphenylphosphine palladium (20 mg, 0.4 eq) were added sequentially. Under a nitrogen atmosphere, the reaction mixture was microwave-stirred at 90 °C for 16 h until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 90 mg of the product.

[0616] Synthesis of int88a

[0617] 1. Synthesis of int88a

[0618] INT72-1 (200 mg, 1.0 eq) was dissolved in dioxane (10 mL) and water (3 mL). Then, 2-methylthiazol-5-borate pinacol ester (170 mg, 2.0 eq), potassium carbonate (162 mg, 3.0 eq), and tetraphenylphosphine palladium (44 mg, 0.4 eq) were added sequentially. Under a nitrogen atmosphere, the reaction mixture was microwave-stirred at 90 °C for 16 h until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 90 mg of the product.

[0619] Synthesis of int89a

[0620] 1. Synthesis of int89a

[0621] INT72-1 (150 mg, 1.0 eq) was dissolved in dioxane (6 mL), followed by the sequential addition of 2-(tri-n-butyltinyl)oxazole (318 mg, 3.0 eq), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (86 mg, 0.6 eq), and tris(dibenzylacetone)palladium (81 mg, 0.3 eq). The reaction mixture was stirred in a microwave at 120 °C for half an hour under a nitrogen atmosphere until complete. After stirring with potassium fluoride aqueous solution for one hour, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 120 mg of the product.

[0622] Synthesis of int90a

[0623] 1. Synthesis of int90a

[0624] INT72-1 (150 mg, 1.0 eq) was dissolved in dioxane (6 mL), followed by the sequential addition of tributylthiazol-5-tin (330 mg, 3.0 eq), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (90 mg, 0.6 eq), and tris(dibenzylacetone)palladium (83 mg, 0.3 eq). The reaction mixture was stirred in a microwave at 120 °C for half an hour under a nitrogen atmosphere until complete. After stirring with potassium fluoride aqueous solution for one hour, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 150 mg of the product.

[0625] Synthesis of int100a

[0626] 1. Synthesis of int100a

[0627] INT72-1 (150 mg, 1.0 eq) was dissolved in ethylene glycol dimethyl ether (6 mL) and water (2 mL). Then, 2-thiopheneboronic acid (115 mg, 3.0 eq), sodium carbonate (159 mg, 5.0 eq), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (98 mg, 0.4 eq) were added sequentially. The reaction mixture was then microwave-stirred at 120 °C for half an hour under a nitrogen atmosphere until complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 120 mg of the product.

[0628] General synthesis steps of intermediates:

[0629] Method 1:

[0630] Method 2:

[0631] Method 3:

[0632] Synthesize the following intermediates according to the above reaction.

[0633] Compound Synthesis

[0634] General synthetic route

[0635] Method 1:

[0636] The preparation method for the second step can refer to the splitting method in the examples.

[0637] Method 2:

[0638] Example 1

[0639] The synthesis route and experimental procedure are as follows:

[0640] 1. Synthesis of C1-1

[0641] Int4 (67 mg, 1.0 eq), Int2 (50 mg, 1.0 eq), HATU (53 mg, 1.1 eq), and N,N-diisopropylethylamine (49 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (3 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction was complete. After extraction with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 62 mg of the product. MS [M+H] + : 905.2.

[0642] 2. Synthesis of C1 and C2

[0643] C1-1 was chirally separated as follows, under the following conditions: Instrument: Agilent 1260Ⅱ, Column: Phenomenex 5μm Cellulose-1 (250X 30mm), mobile phase: n-hexane:ethanol (containing 0.1% TFA) = 5:95, flow rate: 20mL / min, run time: 22min, detection wavelength: 254nm, column temperature: 25℃, solvent: ethanol:acetonitrile = 2:1.

[0644] Peak time:

[0645] C1: (14.9min, 13mg) 1H NMR (400MHz, DMSO-d6) δppm 12.04(s,1H),8.26(d,J=26.4Hz,1H),8.09(d,J=7.2Hz,1H),7.76-7.70(m,2H),7.69-7.65(m,2H),7.62(d,J=8.8Hz,1H),7.37(t,J=9.2Hz,1H ),7.24(d,J=29.6Hz,3H),7.08-6.91(m,2H),6.76-6.63(m,2H),6.37(d,J=6.8Hz,1H),5.64(d,J=7.2Hz,1H),4.94(s,1H),4.81(d,J=12.8Hz,1 H),4.23(t,J=6.8Hz,3H),4.09(d,J=14.0Hz,3H),3.72(d,J=8.8Hz,2H),2.94(t,J=12.0Hz,1H),2.09(d,J=7.2Hz,1H),2.00-1.90(m,2H),1.7 4-1.61(m,5H),1.42-1.35(m,4H),1.35-1.29(m,3H),1.29-1.14(m,16H ),1.01(d,J=8.8Hz,1H),0.92(t,J=7.4Hz,5H),0.69(d,J=18.0Hz,2H).

[0646] C2: (17.9min, 12mg) 1H NMR (400MHz, DMSO-d6) δppm 12.02 (s, 1H), 8.26 (d, J = 26.4Hz, 1H), 8.11 (d, J = 7.2Hz, 1H), 7.75-7.70 (m, 1H), 7.70 -7.66(m,1H),7.62(d,J=8.8Hz,1H),7.37(t,J=9.2Hz,1H),7.27(d,J=8.0Hz,2H),7.07-6.91(m,2H),6.77-6.63(m,2H),6 .38(d,J=7.6Hz,1H),5.64(d,J=6.8Hz,1H),5.33(t,J=4.8Hz,1H),4.99-4.76(m,1H),4.23(t,J=6.8Hz,2H),4.09(d,J=13 .6Hz,4H),3.71(t,J=5.6Hz,2H),2.94(dd,J=14.0,10.8Hz,1H),2.71(s,2H),2.15-2.10(m,1H),2.00-1.90(m,2H),1.75- 1.58(m,6H),1.42-1.29(m,6H),1.29-1.16(m,16H),1.01(d,J=9.2Hz,2H),0.92(t,J=7.6Hz,4H),0.68(t,J=11.6Hz,2H).

[0647] Example 2

[0648] The synthesis route and experimental procedure are as follows:

[0649] C3 Synthesis

[0650] C1 (85 mg, 1.0 eq) was dissolved in toluene (8 mL), followed by the addition of acetaldehyde oxime (111 mg, 20.0 eq) and Rh(PPh3)Cl (18 mg, 0.2 eq). The mixture was then stirred at 105 °C for 18 hours under a nitrogen atmosphere until complete. The mixture was cooled to room temperature and concentrated under reduced pressure. After concentration, the product was purified by preparative high-performance liquid chromatography (HPLC) to yield 37 mg of product. MS [M+H]+: 923.2, 1H NMR (400 MHz, DMSO-d6) δppm. 11.97(s,1H),8.28(d,J=4.4Hz,1H),8.15(d,J=7.2Hz,1H),7.61(t,J=8.8Hz,1H),7.38-7.10(m,5H),7.07-6.96(m, 1H),6.85(d,J=17.2Hz,2H),6.73(t,J=8.4Hz,2H),6.39(d,J=4.0Hz,1H),5.59(s,1H),4.17-4.04(m,3H),3.97(d,J =13.2Hz,1H),3.72(d,J=8.4Hz,2H),2.92(q,J=18.8,15.6Hz,2H),2.79-2.63(m,1H),2.10-1.94(m,2H),1.70–1.60 (m,4H),1.59-1.38(m,3H),1.33(d,J=6.4Hz,2H),1.30-1.11(m,10H),0.95(d,J=8.8Hz,2H),0.63(d,J=14.4Hz,2H).

[0651] Example 3

[0652] The synthesis route and experimental procedure are as follows:

[0653] 1. Synthesis of C4

[0654] C2 (50 mg, 1.0 eq) was dissolved in toluene (4 mL), followed by the addition of acetaldehyde oxime (65 mg, 20.0 eq) and Rh(PPh3)Cl (10 mg, 0.2 eq). The mixture was then stirred at 105 °C for 18 hours under a nitrogen atmosphere until complete. The mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. After concentration, 10 mg of the product was obtained by preparative high-performance liquid chromatography (HPLC). MS [M+H]+: 923.2, 1H NMR (400 MHz, DMSO-d6): δppm 11.99(s,1H),8.29(s,1H),8.13(s,1H),7.59(t,J=8.8Hz,1H),7.41-7.07(m,4H),7.03(s,1H), 6.93-6.61(m,4H),6.38(s,1H),5.59(s,1H),4.19-4.04(m,3H),3.97(d,J=13.6Hz,1H),3.72(d, J=8.4Hz,2H),2.92(q,J=20.0,16.3Hz,2H),2.68(s,1H),2.08–1.95(m,3H),1.76-1.58(m,3H),1 .58-1.42(m,3H),1.24(dd,J=16.0,13.2Hz,14H),0.96(d,J=8.4Hz,2H),0.63(d,J=16.4Hz,2H).

[0655] Example 4

[0656] The synthesis route and experimental procedure are as follows:

[0657] 1. Synthesis of C13-1

[0658] Int5-12 (200 mg, 1.0 eq), Int9 (181 mg, 1.5 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (88 mg, 1.5 eq), cuprous iodide (118 mg, 1.5 eq), and potassium carbonate (114 mg, 2.0 eq) were dissolved in N,N-dimethylformamide (6 mL). The mixture was stirred at 135 °C for 5 h under a nitrogen atmosphere. The reaction proceeded completely. The mixture was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 243 mg of the product. MS [M+H] + : 695.3.

[0659] 2. Synthesis of C13-2

[0660] C13-1 (180 mg, 1.0 eq) was dissolved in dichloroethane (8 mL), and 1-chloroethyl chloroformate (775 mg, 20.0 eq) was added. The reaction mixture was then stirred at 85 °C for 16 h. The reaction mixture was dried by rotary evaporation, reconstituted with methanol (8 mL), and then stirred at 60 °C for 0.5 h. The reaction proceeds were completely reacted. The reaction mixture was directly concentrated under reduced pressure, and then purified by thin-layer chromatography to obtain 100 mg of product. MS [M+H] + : 575.3.

[0661] 3. Synthesis of C13-3

[0662] C13-2 (90 mg, 1.0 eq), 5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-1H-indole-2-carboxylic acid (77 mg, 1.2 eq), O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (71 mg, 1.2 eq), and N,N-diisopropylethylamine (61 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at room temperature for 16 h. The starting materials reacted completely. The organic phase was extracted with ethyl acetate after adding water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by thin-layer chromatography to obtain 90 mg of crude product. MS [M+H] + : 968.4.

[0663] 4. Synthesis of C13 and C14

[0664] C13-3 was prepared and separated using the following high-performance preparative chromatography: Instrument: Agilent 1260Ⅱ, Column: Agilent 5 Prep-C18 (100*30mm), Mobile phase: Water (containing 0.1% TFA): Acetonitrile = 30:70.

[0665] C13 (14mg, peak time: 11.7min) 1H NMR(400MHz,DMSO-d6)δppm 11.71(s,1H),7.78-7.66(m,1H),7.64-7.45(m,1H),7.44-7.32(m,1H),7.31-7.03(m,5H),7.02-6.6 5(m,4H),5.80-5.10(m,1H),5.58-5.47(m,1H),4.83-4.53(m,1H),4.42-4.26(m,1H),3.80-3.65(m,2 H),3.64-3.53(m,1H),3.27-3.15(m,1H),3.13-2.81(m,3H),2.80-2.70(m,2H),2.30-2.18(m,5H),2. 00-1.83(m,4H),1.80-1.45(m,7H),1.41-1.22(m,7H),1.21-1.12(m,4H),1.08-0.88(m,6H).MS[M+H] + : 968.4.

[0666] C14 (25mg, peak time: 10.8min) 1 H NMR(400MHz,DMSO-d6)δppm 12.13(s,1H),7.78-7.66(m,1H),7.65-7.32(m,3H),7.31-7.08(m,4H),7.00 -6.65(m,4H),5.71-5.12(m,1H),5.52-5.39(m,1H),4.63-4.44(m,1H),4.35 -4.20(m,1H),3.80-3.65(m,2H),3.59-3.43(m,1H),3.21-2.80(m,4H),2.78-2.69(m, 2H),2.28-2.15(m,5H),2.07-1.79(m,5H),1.78-1.40(m,6H),1.39-1.23(m,7H),1.22 -1.07(m,4H),1.06-0.76(m,6H).MS[M+H] + : 968.4.

[0667] Example 5

[0668] The synthesis route and experimental procedure are as follows:

[0669] 1. Synthesis of C15-1

[0670] Int5 (462 mg, 1.0 eq) was dissolved in methanol (15 mL). Di-tert-butyl dicarbonate (392 mg, 2.0 eq), sodium carbonate (573 mg, 6.0 eq), and water (3 mL) were added in an ice bath. The reaction mixture was stirred at room temperature for 0.5 h. The reactants reacted completely. The reaction mixture was concentrated under reduced pressure, water was added, and the solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 350 mg of the product. MS [M+H] + :614.3.

[0671] 2. Synthesis of C15-2

[0672] C15-1 (300 mg, 1.0 eq) was dissolved in toluene (6 mL), followed by the addition of acetaldehyde oxime (577 mg, 20.0 eq) and Rh(PPh3)Cl (91 mg, 0.2 eq). The mixture was then stirred at 105 °C for 5 hours under a nitrogen atmosphere. The reaction proceeded to completion. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 300 mg of the product. MS [M+H] + :632.3.

[0673] 3. Synthesis of C15-3

[0674] The target compound C15-3 116 mg was prepared by high-performance preparative chromatography (HPLC) of C15-2 (300 mg) as described below, with a peak elution time of 9.4 min. Separation method: Instrument: Agilent 1260Ⅱ, chromatographic column: phenomenex Lux 5μm Cellulose-1 (250×30 mm), mobile phase: n-hexane:ethanol = 75:25.

[0675] 4. Synthesis of C15-4A and C3-4B

[0676] C15-3 (100 mg, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). 60% sodium hydride (9.5 mg, 1.5 eq) was added in an ice bath. The reaction mixture was stirred in an ice bath for 0.5 h, and then iodomethane (11.3 mg, 0.5 eq) was slowly added dropwise. The reaction mixture was slowly brought to room temperature and stirred for 1 h. A small amount of raw material remained. The reaction mixture was quenched with ice water in an ice bath and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 70 mg of the product mixture. MS [M+H] + : 646.3; MS[M+H] + : 660.3.

[0677] 5. Synthesis of C15-5A and C15-5B

[0678] A mixture of C15-4A and C15-4B (70 mg, 1.0 eq) was dissolved in dichloromethane (2 mL). After cooling to 0 °C, a dioxane solution of hydrochloric acid (4 M, 2 mL) was slowly added, followed by stirring at room temperature for 0.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain 59 mg of crude product, which was directly used for the next reaction. MS[M+H] + 546.2; MS[M+H] + : 560.3.

[0679] 6. Synthesis of C15 and C16

[0680] A mixture of C15-5A and C15-5B (59 mg, 1.0 eq), 5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-1H-indole-2-carboxylic acid (53 mg, 1.2 eq), O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (62 mg, 1.5 eq), and N,N-diisopropylethylamine (42 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (3 mL). The reaction mixture was then stirred at room temperature for 16 h. The starting materials reacted completely. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 100 mg of the mixture.

[0681] The mixture was prepared and separated using the following high-performance preparative chromatography method: Instrument: Agilent 1260Ⅱ, Column: Agilent 5 Prep-C18 (100×30mm), Mobile phase: Water (containing 0.1% TFA): Acetonitrile = 35:65.

[0682] C15 (25.9 mg, peak time: 8.5 min) 1H NMR(400MHz,DMSO-d6)δppm 11.77(s,1H),8.33-8.21(m,1H),7.81-7.66(m,1H),7.65 -7.57(m,1H),7.56-7.45(m,1H),7.44-7.32(m,2H),7.31-7.21(m,1H),7.07 -6.90(m,2H),6.88-6.62(m,3H),5.70-5.46(m,1H),5.18-4.55(m,1H),4.34 -4.21(m,1H),4.14-4.02(m,3H),3.80-3.64(m,2H),3.62-3.44(m,1H),3.11 -2.97(m,1H),2.95-2.82(m,1H),2.74-2.59(m,3H),2.28-2.13(m,5H),2.08 -1.94(m,1H),1.86-1.48(m,7H),1.47-1.38(m,2H),1.38-1.22(m,5H),1.22-1.06(m,5H).MS[M+H] + : 939.4.

[0683] C16 (14.3 mg, peak time: 9.7 min) 1 H NMR(400MHz,DMSO-d6)δppm 11.77(s,1H),8.34-8.21(m,1H),7.66-7.59(m,1H),7.58 -7.49(m,1H),7.48-7.33(m,2H),7.31-7.18(m,1H),7.05-6.92(m,2H),6.91 -6.82(m,1H),6.81-6.56(m,2H),5.73-5.47(m,1H),5.16-4.53(m,1H),4.35 -4.23(m,1H),4.16-4.00(m,3H),3.79-3.64(m,2H),3.61-3.47(m,1H),3.18 -2.74(m,7H),2.72-2.66(m,1H),2.26-2.14(m,5H),2.07-1.96(m,1H),1.84 -1.39(m,9H),1.37-1.22(m,5H),1.21-0.95(m,5H).MS[M+H] + : 953.4.

[0684] Example 6

[0685] The synthesis route and experimental procedure are as follows:

[0686] 1. Synthesis of C18-2

[0687] Int5-8 (1.0 g, 1.0 eq), tributyl(1-ethoxyethylene)tin (1.03 g, 1.5 eq), and bis(triphenylphosphine)palladium dichloride (136 mg, 0.1 eq) were dissolved in anhydrous dioxane (20 mL). The reaction mixture was stirred at 85 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, potassium fluoride aqueous solution was added, and the mixture was stirred for one hour. The mixture was then filtered through diatomaceous earth, and the filtrate was directly concentrated. The filtrate was redissolved in ethyl acetate, and then 6 M hydrochloric acid was added, followed by stirring for half an hour. The reaction was complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 760 mg of the product. MS [M+H] + :493.2.

[0688] 2. Synthesis of C18-3

[0689] C18-2 (760 mg, 1.0 eq) was dissolved in acetonitrile (15 mL), and potassium trimethylsilanolate (791 mg, 4.0 eq) was added. The reaction mixture was then stirred at 90 °C for 2 h. The reaction proceeds reacted completely. After concentrating the reaction mixture under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 610 mg of crude product. MS [M+H] + :465.2.

[0690] 3. Synthesis of C18-4

[0691] C18-3 (610 mg, 1.0 eq), diphenyl azidophosphate (723 mg, 2.0 eq), and N,N-diisopropylethylamine (0.91 mL, 4.0 eq) were dissolved in toluene (20 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. Then, aminoacetaldehyde dimethyl acetal (276 mg, 2.0 eq) and an equal volume of anhydrous tetrahydrofuran (10 mL) were added, and the reaction mixture was stirred at 60 °C for another 2 h. The reaction proceeded completely. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 740 mg of the product. MS [M+H]: 567.2.

[0692] 4. Synthesis of C18-5

[0693] C18-4 (740 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (15 mL), followed by the addition of methanesulfonic acid (188 mg, 1.5 eq). The reaction mixture was then stirred at 60 °C for 2 h. The reaction proceeded completely. The solution was cooled to room temperature, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 389 mg of the product. MS [M+H] + :503.2.

[0694] 5. Synthesis of C18-6

[0695] C18-5 (389 mg, 1.0 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (347 mg, 2.0 eq), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (43 mg, 0.4 eq), cuprous iodide (29 mg, 0.2 eq), and potassium carbonate (313 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 135 °C for 3 h under a nitrogen atmosphere. The reaction proceeded completely. The mixture was filtered through diatomaceous earth, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 456 mg of the product. MS [M+H] + :651.2.

[0696] 6. Synthesis of C18-7

[0697] C18-6 (456 mg, 1.0 eq) was dissolved in dichloroethane (10 mL), and 1-chloroethyl chloroformate (402 mg, 4.0 eq) was added. The reaction mixture was then stirred at 85 °C for 6 h. The reaction mixture was concentrated, reconstituted with methanol (8 mL), and then stirred at 60 °C for 0.5 h. The starting materials reacted completely. The reaction mixture was directly concentrated under reduced pressure, and after concentration, purified by thin-layer chromatography to obtain 110 mg of product. MS [M+H] + :531.2.

[0698] 7. Synthesis of C18 and C19

[0699] C18-7 (37 mg, 1.0 eq), 5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-1H-indole-2-carboxylic acid (65 mg, 1.2 eq), O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (46 mg, 1.1 eq), and N,N-diisopropylethylamine (41 mg, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide (3 mL), and the reaction mixture was stirred at room temperature for 2 h. The starting materials reacted completely. After adding water and extracting with ethyl acetate, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 42 mg of crude product. The crude product was then purified by preparative high-performance liquid chromatography (HPLC) under the following conditions: Instrument: Agilent 1260Ⅱ; Column: Agilent 5 Prep-C18 (100×30 mm); Mobile phase: water (containing 0.1% TFA): acetonitrile = 33:67.

[0700] C18 (9mg, peak time: 13.5min) 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.29(s,1H),7.66–7.46(m,2H),7.44–7.09(m,4H),6.96(s,1H),6.84(d,J=11.2 Hz,1H),6.74(d,J=15.5Hz,1H),5.51(s,1H),4.41–4.23(m,1H),4.10(s,2H),3.72(d,J=8.6Hz,2H),3.64–3.45(m,1H), 3.15(d,J=20.2Hz,1H),3.03(d,J=12.2Hz,1H),2.68(t,J=1.9Hz,1H),2.33(t,J=1.9Hz,1H),2.24(d,J=14.0Hz,7H),2. 00(dt,J=13.3,7.0Hz,1H),1.83–1.51(m,6H),1.43(d,J=6.5Hz,2H),1.34–1.21(m,7H),1.18(d,J=5.9Hz,4H).MS[M+H] + : 924.2.

[0701] C19 (13mg, peak time: 11.7min) 1H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.26(d,J=21.6Hz,1H),7.61(s,1H),7.50(s,1H),7.35(d, J=16.9Hz,2H),7.25(d,J=9.1Hz,2H),6.96(s,1H),6.89–6.63(m,3H),5.43(s,1H),4.25(s,1H),4 .11(s,3H),3.72(s,2H),3.15–2.92(m,3H),2.20(d,J=12.7Hz,8H),2.00(dt,J=14.0,7.3Hz,3H) ,1.66(d,J=27.2Hz,4H),1.51(dd,J=35.7,10.4Hz,4H),1.37(s,4H),1.32–1.00(m,13H).MS[M+H] + : 924.2.

[0702] Example 7

[0703] The synthesis route and experimental procedure are as follows:

[0704] 1. Synthesis of C21-1

[0705] C15-1 (100 mg, 1.0 eq) was placed in a sealed glass tube, and tetrabutylammonium fluoride (2 mL) and azide-trimethylsilane (4 mL) were added in an ice bath. The reaction mixture was stirred at 100 °C for 10 days. A small amount of raw material remained. In an ice bath, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 90 mg of product. MS [M+H] + :657.3.

[0706] 2. Synthesis of C21-2

[0707] C21-1 (90 mg, 1.0 eq) was dissolved in dichloromethane (2 mL), cooled to 0 °C, and then a dioxane solution of hydrogen chloride (4 mol / L, 2 mL) was slowly added. The mixture was then stirred at room temperature for 0.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain 59 mg of crude product, which was directly used for the next reaction. MS [M+H] + :557.2.

[0708] 3. Synthesis of C21 and C22

[0709] C21-2 (59 mg, 1.0 eq), 5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-1H-indole-2-carboxylic acid (52 mg, 1.2 eq), O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (52 mg, 1.3 eq), and N,N-diisopropylethylamine (82 mg, 6.0 eq) were dissolved in anhydrous N,N-dimethylformamide (3 mL), and the reaction mixture was stirred at room temperature for 16 h. The reactants reacted completely. Water was added, and the mixture was extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Concentration was performed using the following high-efficiency preparative liquid chromatography (HPLC) separation and purification. The preparative separation conditions were as follows: Instrument: Agilent 1260Ⅱ, Column: Agilent 5 Prep-C18 (100*30mm), Mobile phase: Water (containing 0.1% TFA): Acetonitrile = 38:62.

[0710] C22 (5.5 mg, peak time: 10.2 min) 1 H NMR (400MHz, DMSO-d6) δppm12.17(s,1H),8.33-8.21(m,1H),7.66-7.55(m,1H),7.53 -7.46(m,1H),7.45-7.32(m,2H),7.31-7.16(m,2H),7.11-6.93(m,2H),6.92-6.61(m,3H), 5.86-5.44(m,1H),4.33-4.18(m,1H),4.15-4.09(m,3H),3.76-3.70(m,2H),3.55-3.47(m,2 H),3.14-2.85(m,3H),2.21-2.16(m,5H),2.03-1.93(m,1H),1.74-1.64(m,3H),1.60-1.52( m,2H),1.46-1.40(m,3H),1.38-1.34(m,2H),1.30-1.23(m,6H),1.21-1.17(m,4H).MS[M+H] + : 950.4.

[0711] C21 (8.8 mg, peak time: 11.8 min) 1H NMR(400MHz,DMSO-d6)δppm11.78(s,1H),8.33-8.22(m,1H),7.66-7.59(m,1H),7.57 -7.47(m,1H),7.45-7.32(m,2H),7.31-7.15(m,2H),7.11-6.94(m,2H),6.94-6.5 9(m,3H),5.63-5.54(m,1H),4.37-4.28(m,1H),4.16-4.00(m,3H),3.78-3.67(m,2 H),3.55-3.47(m,2H),3.09-2.85(m,3H),2.23-.13(m,5H),2.05-1.93(m,1H),1. 85-1.40(m,9H),1.38-1.32(m,1H),1.31-1.22(m,5H),1.22-1.04(m,5H).MS[M+H] + : 950.4.

[0712] The following compounds were synthesized using the above method.

[0713] In vitro activity examples

[0714] Measurement of in vitro cAMP signal activation by compounds in human GLP-1R

[0715] The agonistic activity of the compounds of this application against the GLP-1 receptor was evaluated in Flpin-293-human GLP-1R cells (stable expression of human GLP-1R) by culturing cells in DMEM complete medium (containing 10% FBS, 1× penicillin streptomycin, 200ug / mL HB).

[0716] The compound was dissolved in DMSO and then serially diluted 4-fold. The diluted compounds were transferred to 384-well plates using an Echo transducer. Flpin-293-human GLP1R cells were centrifuged to remove the culture medium. Cells were resuspended in experimental buffer (1×HBSS + 20mM HEPES + 0.1% BSA + 500uM IBMX) to prepare a cell suspension. 20uL of the cell suspension was added to each well of the 384-well plate at a cell density of 2000 cells / well. The compound and cells were co-incubated at 37°C for 30 min. Eu-cAMP tracer diluted in lysis buffer was added to each well of the 384-well plate at a volume of 5uL / well, followed by Ulight-anti-cAMP diluted in lysis buffer at a volume of 5uL / well. The plates were incubated at room temperature for 1 hour, and the readings were performed using an Envision 2105 microplate reader at 665nm and 615nm wavelengths. Data processing was as follows: %Activity = (Signal cmpd -Signal Ave_VC ) / (Signal Ave_PC -Signal Ave_VC )×100.

[0717] Where %Activity represents the percentage of activity, Signal cmpd Indicates the numerical value of the compound signal, Signal Ave_VC The mean signal reading of the blank control group. Ave_PC This represents the average signal reading of the positive control.

[0718] The experimental results are shown in the table below.

[0719] Pharmacokinetic evaluation of SD rats

[0720] Experimental animals: SD rats, male, weighing approximately 180-220 grams, 3 rats / compound.

[0721] Formulation solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% glycine buffer

[0722] Animal preparation:

[0723] 1) Patients may drink water freely before and after administration;

[0724] 2) All experiments were conducted using medications based on the animals' actual body weight;

[0725] 3) Administration method: oral gavage (PO), fasting overnight before administration.

[0726] Sample collection:

[0727] Whole blood (0.25 mL) was collected from the rat orbital region and placed in a test tube containing the anticoagulant EDTA-K2 (10% EDTA-K2 solution). The tube was placed on moist ice and centrifuged within 45 minutes (1,500 g, 2–8 °C, 10 min). Plasma was then collected. The plasma was stored in pre-chilled centrifuge tubes, flash-frozen on dry ice, and subsequently stored in an ultra-low temperature freezer at -60 °C or lower. Blood collection time points were 0, 0.5, 1, 2, 4, 6, 8, and 24 hours.

[0728] Positive control drug: Compound A ( Orforglipron)

[0729] Experimental results:

[0730] Compared with compound A, the compound of the present invention has significantly increased exposure in rat plasma and a longer half-life, thus exhibiting better pharmacokinetic properties.

[0731] Pharmacokinetic evaluation of C57BL / 6J mice

[0732] Experimental animals: C57BL / 6J mice, male, weighing approximately 18-25 grams, 6 mice per compound.

[0733] Formulation solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM glycine-NaOH pH 10

[0734] Animal preparation:

[0735] 1) Feeding was resumed 4 hours after administration, and water was allowed freely;

[0736] 2) All experiments were conducted using medications based on the animals' actual body weight;

[0737] 3) Administration method: oral gavage (PO), fasting overnight before administration.

[0738] Sample collection:

[0739] Whole blood (40 μL) was collected from the orbital vein of mice and placed in a test tube containing the anticoagulant EDTA-K2 (15% EDTA-K2 solution). The tube was placed on moist ice and centrifuged within 45 minutes (2,000 g, 2–8 °C, 10 min). Plasma was then collected. The plasma was stored in pre-chilled centrifuge tubes, flash-frozen on dry ice, and subsequently stored in an ultra-low temperature freezer at -60 °C or lower. Blood collection time points: 0, 0.5, 1, 2, 4, 6, 8, and 24 hours.

[0740] Experimental results:

[0741] Compared with compound A, the compounds of the present invention exhibit significantly increased exposure in mouse plasma, thus possessing better pharmacokinetic properties.

[0742] FaSSIF solubility experiment

[0743] 1. Preparation of FaSSIF:

[0744] 0.056% (w / v) lecithin, 0.161% (w / v) sodium taurocholate, 0.39% (w / v) potassium dihydrogen phosphate, 0.77% (w / v) potassium chloride, deionized water, pH 6.5 ± 0.05.

[0745] 2. Steps:

[0746] 1) Add 3.15 μL of the stock solution of the test compound (1% DMSO stock solution) and the control compound to each well of the 96-well plate.

[0747] 2) Add 495 μL of solvent to each well of the 96-well plate. Vortex the dissolved sample for at least 2 minutes. Shake the 96-well plate on a shaker at 800 rpm for 24 hours at room temperature.

[0748] 3) Centrifuge at 4000 rpm for 10 minutes at 25℃.

[0749] 4) Transfer the supernatant to a filter plate, and then collect the filtrate into a new 96-well plate by centrifugation for at least 5 minutes.

[0750] 5) The concentration of the filtrate is quantified using an LC-UV system.

[0751] Experimental results:

[0752]

[0753] The compound of this application has better solubility properties than compound A.

[0754] CYP enzyme inhibition test

[0755] 1. Method

[0756] 1.1) Working solutions were prepared for the test compounds and positive controls.

[0757] 1.2) Remove human liver microparticles from the refrigerator and thaw them on ice.

[0758] 1.3) Transfer the substrate working solution to the corresponding wells, and transfer PB buffer to the blank wells in the incubation plate in a volume of 20 μL.

[0759] 1.4) After that, transfer 158 μL of the solution into all wells of the incubation plate.

[0760] 1.5) Transfer the test compound or positive control working solution to the well. For the inhibitor-free control well, the transfer volume is 2 μL.

[0761] 1.6) Preheat the incubation plate at 37.0℃ for 10 minutes.

[0762] 1.7) After 10 minutes, add 20 μL of NADPH working solution to start the reaction. Incubate the plate in a 37.0°C water bath for 20 minutes for CYP2C19 and CYP2D6, 3 minutes for CYP3A, and 10 minutes for other enzymes.

[0763] 1.8) At the time point, the reaction was terminated by adding 400 μL of a termination solution containing an internal standard.

[0764] 1.9) Shake the mixture for 10 minutes and centrifuge at 3220×g for 20 minutes.

[0765] 1.10) Remove 200 μL of supernatant and mix with 100 μL of ultrapure water.

[0766] 1.11) After shaking the sample for 10 minutes, inject it for LC-MS / MS analysis to determine the metabolites of the substrate.

[0767] 2. Data Analysis

[0768] Use XL fitting or SigmaPlot to plot the relationship between the percentage of the vector control and the concentration of the test compound, and perform nonlinear regression analysis on the data.

[0769] The experimental results are shown in the table below:

[0770] The above experimental results show that the compound of this application has a weak inhibitory effect on CYP2C9 and CYP3A.

[0771] β-arrestin recruitment experiment

[0772] The effect of the test compound on β-arrestin 2 recruitment was detected using GLP1R / n Arrestin / CHO reporter cells. Reporter cell lines were seeded at 20,000 cells per well in complete medium into 96-well cell culture plates. After overnight culture, the complete medium was replaced with Opti-MEM medium, and the test compound (starting working concentration 10 μL, 4-fold dilution, 9 concentration gradients, double replicates) was added and incubated at 37°C and 5% CO2 for 30 minutes, with a total volume of 100 μL. After incubation, 25 μL of Nano-Glo assay reagent was added to each well, and the plates were shaken at 300 rpm for 3 minutes at room temperature. The chemiluminescence value was then read using a multi-mode microplate reader. The effect of the test compound on β-arrestin 2 recruitment was calculated using the following formula: Relative activity (%) = [(chemiluminescence value)] / [(chemiluminescence value)] 受试化合物 —luminescence value 阴性对照 ) / (luminous value) 阳性对照 —luminescence value 阴 性对照 )]×100%.

[0773] The concentration of the test compound that produces 50% recruitment activity is the half-maximal effective concentration (EC). 50 .

[0774] The experimental results are shown in the table below:

[0775] Experimental results show that the compound of this application has no recruitment activity for β-arrestin 2.

[0776] GLP-1R humanized mouse intraperitoneal glucose tolerance test (IPGTT)

[0777] Experimental procedure:

[0778] Male hGLP-1R mice, weighing approximately 30g, were acclimatized for 4 days. During the experiment, the mice's weight, hourly food residue, and supplemental food intake were recorded daily. Then, based on the weight and food intake on the last day, the mice were divided into groups of 6.

[0779] Mice were fasted overnight, with only normal drinking water provided. Thirty minutes before the glucose tolerance test, the mice were weighed, and the medication was administered via gavage according to their weight, with the administration time recorded. Mice were given a 40% glucose injection intraperitoneally at 0 min. Blood glucose levels were measured before glucose administration and at 15, 30, 60, and 120 min after glucose administration, along with the measurement time. The mice's glucose clearance capacity after glucose uptake was evaluated by comparing blood glucose levels at different time points and the area under the glucose curve (AUC), i.e., the glucose tolerance test.

[0780] The above experimental results show that, in the IPGTT experiment, a single oral dose of the compound of this application can significantly increase the hypoglycemic rate in mice.

[0781] GLP-1R humanized mouse acute feeding inhibition experiment

[0782] Experimental Operation

[0783] One week after the IPGTT assay, an acute feeding experiment was conducted. Forty-two mice were transferred to different cages and fasted for 16 hours. After administration of the solvent or the respective compounds, all mice were allowed to rest for 15 minutes before being fed a measured amount of food. Food intake changes were then measured at 2, 4, 6, 8, and 10 hours, and at 24 hours post-administration, along with body weight. The inhibitory effect of the compounds on appetite in mice was evaluated by comparing the food intake of different groups. The time results are shown in the table below.

[0784]

[0785] The above experimental results show that, in the acute feeding inhibition experiment, a single oral dose of 0.01 mg / kg of the compound of this application can significantly inhibit feeding in mice, and the inhibitory effect is superior to that of compound A.

[0786] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

Compounds of formula (I), or their pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, isotopic compounds, deuterated derivatives, metabolites, or prodrugs, in Y1 and Y2 are each independently selected from bonds, CR, CHR, and C(R)2; Y3 is selected from CR and C(R)2; X1 is selected from C, CH, and N; X2 is selected from CR, C(R)2, N, NR, O, and S; X3 and X7 are each independently selected from C, CH, and N; X4, X5, and X6 are each independently selected from CR, C(R)2, N, and NH; L1 is selected from L2 is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with 1 to 6 substituents selected from the group consisting of: deuterium, halogen, =O, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl; Or, two carbon atoms on the same atom 1-6 Alkyl formation C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CH2O(C 3-6 cycloalkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy; R is independently selected from H, deuterium, halogen, -OH, -CN, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2- 6-olefin, C 2-6 The alkynyl group is optionally substituted by 1 to 6 substituents selected from the group consisting of deuterium and halogens; R1 is selected from H, deuterium, halogens, -OH, -CN, -NR7R8, -NO2, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -C(=NH)NR7R8, -OC(=O)NR7R8, -NR9C(=O)NR7R8, -NR9C(=NH)NR7R8, -NR9C(=O)OR7, -NR7C(=O)R8, -SO2R7, -S(=O)(=NR7)R8, -N=S(=O)R7R8, -NR7SO2R8, -SO2NR7R8, -S(=O)(=NR7)NR8R9, -NR7SO2NR8R9, -P(=O)R7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, or S, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S, C 2-6 alkenyl and C 2-6 alkynyl group, in which, The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl, C 2-6 alkenyl, C 2-6 The alkynyl group may optionally be substituted by 1 to 6 substituents selected from the group consisting of: deuterium, halogen, oxo (=O), -OH, -NH2, -CN, -COOH, -C(=O)OC. 1-3 Alkyl group, -C(=O)OC 3- 6-cycloalkyl, -C(=O)NH-C 1-3 Alkyl group, -C(=O)NH-C 3-6 Cycloalkyl, -C(=O)N-(C 1-3 Alkyl)2、-SO2C 1-3 Alkyl, -SO2C 3-6 cycloalkyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-3 alkyl; R2 is selected from C 3-12 Cycloalkyl groups, containing 1-4 3-12 membered heterocyclic groups selected from N, O or S heteroatoms, C 6- 12 Aryl groups and 5-12 heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally surrounded by 1-6 R groups. 21 replace; R 21 Selected from H, deuterium, halogens, -OH, -CN, oxo (=O), -NR7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2- 6-olefin, C 2-6 The alkynyl group is optionally substituted by 1 to 6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl containing 1-4 heteroatoms selected from N, O or S, and halogenated 3-6 membered heterocyclic alkyl containing 1-4 heteroatoms selected from N, O or S; R3 is selected from C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, C 6- 12 Aryl groups and 5-12 heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally surrounded by 1-6 R groups. 31 Replace; or R3 is selected from C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, C 6- 14 Aryl groups and 5-14 heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups are optionally surrounded by 1-6 R groups. 31 replace; R 31 Selected from H, deuterium, halogens, -OH, -CN, -NO2, oxo (=O), -NR7R8, =NR7, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)NR9(NR7R8), -NR7C(=O)R8, -SO2R7, -S(=O)(=NR7)R8, -NR7SO2R8, -SO2NR7R8, -S(=O)(=NR7)NR8R9, -NR7SO2NR8R9, -P(=O)R7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 6-12 aryl, comprising 1-4 5-12 membered heteroaryl groups selected from N, O and S heteroatoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally substituted by 1-6 substituents selected from the following group: deuterium, halogen, -OH, -CN, -NO2, oxo(=O), -NR7R8, =NR7, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -NR7C(=O)R8, -SO2R7, -S(=O)(=NR7)R8, -NR7SO2R8, -SO2NR7R8, -S(=O)(=NR7)NR8R9, -NR7SO2NR8R9, -P(=O)R7R8, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, halogenated 4-6 membered heterocyclic groups, phenyl groups, halophenyl groups, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S, haloated 5-6 membered heteroaryl groups, deuterated C 1-6 Alkyl, deuterated C 1- 6-alkoxy, deuterated C 3-6 Cycloalkyl, deuterated 4-6-membered heterocyclic groups, deuterated phenyl, and deuterated 5-6-membered heteroaryl groups; Or, two Rs 31 Together with the atoms attached to it, they form C 5-10 Cycloalkyl, 4-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, or 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 5-10 Cycloalkyl, 4-10-membered heterocyclic, phenyl, and 5-10-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -CN, -NO2, oxo(=O), -NR7R8, =NR7, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -NR7C(=O)R8, -SO2R7, -S(=O)(=NR7)R8, -NR7SO2R8, -SO2NR7R8, -S(=O)(=NR7)NR8R9, -NR7SO2NR8R9, -P(=O)R7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, oxo (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, and halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino, halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, and deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C 1-6 Alkylamino, deuterated C 3-6 Cycloalkyl groups, containing 1-4 deuterated 4-6 membered heterocyclic groups selected from N, O and S heteroatoms; R4 is selected from H, deuterium, halogens, -CN, oxo (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1- 6-alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy; Alternatively, two R4 atoms attached to the same carbon atom can form an exocyclic double bond (=CR). 41 R 42 C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy; Alternatively, R4 and R1 together with the atoms they are attached to form C. 5-10 Cycloalkyl, 5-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, phenyl, or 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, wherein the C 5-10 Cycloalkyl, 5-10-membered heterocyclic, phenyl, and 5-10-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -CN, -NO2, oxo (=O), -NR7R8, =NR7, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl or deuterated C 1-6 Alkoxy; R 41 R 42 Each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl; R5 is selected from R 51 R 52 Each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl; R6 is selected from -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 3-12 Cycloalkyl, -L-containing 1-4 3-12 membered heterocyclic groups selected from N, O and S heteroatoms, -LC 6-12 aryl and -L-containing 1-4 5-12-membered heteroaryl groups selected from N, O and S heteroatoms, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally surrounded by 1-6 R groups. 61 replace; R 61 Selected from H, deuterium, halogens, -OH, =O, -CN, -NR 6a R 6b C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 Alkyne, phenyl, or 5-10 heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 Alkyne, phenyl, or 5-10 heteroaryl groups are optionally surrounded by 1-6 R groups. 6e replace; Or, two Rs 61 Together with the atoms attached to it, they form an exocyclic double bond (=CR). 6c R 6d C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkoxy; L is the key or can be chosen from -NR L -、-O-、-S-、C 1-6 Alkylene, -NR L -C 1-6 alkylene-, -C 1-6 Alkylene-NR L -、-OC 1-6 alkylene-, -C 1-6 alkylene-O-, wherein the C 1-6 The alkylene group is optionally substituted with 1 to 6 substituents selected from the group consisting of: deuterium, halogen, =O, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C 3-6 Cycloalkyl, or two carbon atoms on the same atom 1-6 Alkyl groups can form C groups optionally substituted with 1-6 halogens. 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms; R 6a R 6b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, containing 1-4 4-6 membered heterocyclic groups selected from N, O, and S heteroatoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl; R 6c R 6d Each is independently selected from the following groups: H, deuterium, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl; R 6e Selected from deuterium, halogens, =O, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, containing 1-4 4-6 membered heterocyclic groups selected from N, O, and S heteroatoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl; R L Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-10-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl; R7, R8, and R9 are each independently selected from H, -CN, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 6-12 aryl, comprising 1-4 5-12 membered heteroaryl groups selected from N, O and S heteroatoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally substituted by 1-6 substituents selected from the following group: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl groups, 4-6 membered heterocycles containing 1-4 heteroatoms selected from N, O, and S, halogenated 4-6 membered heterocycles containing 1-4 heteroatoms selected from N, O, and S, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C 3-6 Cycloalkyl groups, containing 1-4 deuterated 4-6 membered heterocycles selected from N, O and S heteroatoms; Alternatively, R7, R8, or R8, R9 attached to the same nitrogen atom can form a 4-6 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, and S, wherein the 4-6 membered heterocyclic group is optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl groups, 4-6 membered heterocycles containing 1-4 heteroatoms selected from N, O, and S, halogenated 4-6 membered heterocycles containing 1-4 heteroatoms selected from N, O, and S, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, deuterated C 3-6 Cycloalkyl groups, containing 1-4 deuterated 4-6 membered heterocycles selected from N, O and S heteroatoms; n is 0, 1, 2, 3, 4, 5, or 6; It can be a single bond or a double bond. The compound of claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein the compound has a structure selected from the following formula: in: X1, X2, X3, X4, X5, X6, X7, R, R1, R2, R3, R4, R5, R6, Y1, Y2, L1, L2, n as defined in claim 1. The compound of claim 2, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein the compound has a structure selected from the following formula: in: X1, X2, X3, X4, X5, X6, X7, R, R1, R2, R3, R4, R5, R6, L1, L2, n are as defined in claim 1. The compound of claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein... It has a structure selected from the following: in R is independently selected from H, deuterium, halogen, -OH, -CN, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2- 6-olefin, C 2-6 The alkynyl group is optionally substituted by 0-6 substituents selected from the group consisting of deuterium and halogens; m can be 0, 1, 2, 3, 4, 5, or 6. The compound of claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein the compound has a structure selected from the group consisting of: in X1, X2, X3, X4, X5, X6, X7, R1, R2, R3, R5, R6, L2 as defined in claim 1; R4 groups are independently selected from H, deuterium, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 Alkoxy; Alternatively, two R4 atoms attached to the same carbon atom can form an exocyclic double bond (=CR). 41 R 42 C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 Alkoxy; R 41 R 42 Each element is independently selected from the following groups: H, deuterium, halogens, and C. 1-6 Alkyl and halogenated C 1-6 alkyl; n can be 0, 1, 2, 3, 4, 5, or 6. The compound of claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein the compound has the following structure: R L21 Each is independently selected from: H, deuterium, methyl, ethyl, propyl, -CH2-O-cyclopropyl or -CH2CH2-O-cyclopropyl; X1 and X7 are each independently selected from CH and N; R1, R2, and R3 are as defined in claim 1. The compound of claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein the compound has the following structure: X1 and X7 are each independently selected from CH and N; R1, R2, and R3 are as defined in claim 1. The compound as described in any one of claims 1-7, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, R1 represents H, deuterium, -CN, -NO2, and C. 1-3 Alkyl groups, halogens, -NR7R8, -NR7C(=O)R8, -NR9C(=O)NR7R8, -NR9C(=O)OR7, -NR9C(=NH)NR7R8, -OC(=O)NR7R8, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -SO2R7, -SO2NR7R8, -S(=O)(=NR7)NR8R9, -NR7SO2NR8R9, -P(=O)R7R8, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, or S heteroatoms, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S heteroatoms; the C 1-3 Alkyl, 4-6 membered heterocyclic, and 5-6 membered heteroaryl groups are optionally substituted by 1 to 6 substituents selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-3 alkyl; Preferably, R1 is selected from -CN, -CF3, -C(O)NR7R8, -P(O)R7R8, -C(=O)R7, -SO2NR7R8, 5-membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, and 5-6-membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms selected from N, O or S. More preferably: R1 is selected from CN, -CF3, -CONH2, -CONHCH3, -CON(CH3)2, -COCH3, -P(=O)(CH3)2, -SO2NH2 or any of the following groups: in, R 111 R 112 Each is independently selected from H, deuterium, or C. 1-3 alkyl; R7 and R8 are each independently selected from H and C. 1-3 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic group, C 5-6 Aryl or halogenated C 1-3 alkyl. The compound as described in any one of claims 1-7, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, R2 is a phenyl group, C 4-8 Cycloalkyl, 5-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, or S, or 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, or S; wherein the phenyl, 4-8 membered cycloalkyl, 5-6 membered heterocyclic, or 5-6 membered heteroaryl group is optionally surrounded by 1-6 R... 21 Replace; R 21 Selected from H, deuterium, halogens, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-3 Alkyl, C 3-6 cycloalkyl or halogenated C 3-6 cycloalkyl; Preferably, R2 is R 211 R 212 and R 213 Each is independently selected from H, deuterium, halogen, and C. 1-3 Alkyl, cyclopropyl, halogenated C 1-3 Alkyl or halocyclopropyl; more preferably, R 212 For F or -CF3, R 211 and R 213 Each is independently selected from H, deuterium, or C. 1-3 alkyl. The compound as described in any one of claims 1-7, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein R3 is selected from any of the following groups: in, Indicates a single bond or a double bond; W1, W2, W3, W4, W5, W6, Z1, Z2, Z3, Z4, Z5, Z6, Z7, K1, K2, K3, K4, and V are each independently selected from -CR 31 -CR 31 R 31 -NR 31 -N-, O or S; R 31 As defined in claim 1. The compound as described in any one of claims 1-7, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein R3 is selected from any of the following groups: u0 is 0, 1, 2, 3, 4, or 5; u1 is 0, 1, 2, 3, or 4; u2 is 0, 1, 2, or 3; u3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; u4 is 0, 1, 2, 3, 4, 5, or 6; u5 is 0, 1, 2, 3, 4, 5, or 6; u6 is 0, 1, 2, 3, 4, 5, or 6; u7 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; u8 is 0, 1, 2, 3, or 4; u9 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; u10 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u11 is 0, 1, 2, 3... 4, 5, or 6; u12 is 0, 1, 2, 3, or 4; u13 is 0, 1, 2, 3, or 4; u14 is 0, 1, 2, 3, 4, 5, or 6; u15 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; u16 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; u17 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; u18 is 0, 1, 2, 3, 4, 5, or 6; u19 is 0, 1, 2, or 3; u20 is 0, 1, or 2; u21 is 0, 1, 2, 3, or 4; u22 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; R 31 As defined in claim 1. The compound of claim 11, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, R 31 Selected from: H, deuterium, halogen, -OH, -CN, oxo (=O), -NR7R8, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR7R8, -NR7C(O)R8, -SO2R7, -S(O)(NR7)R8, -NR7SO2R8, -SO2NR7R8, -S(O)(NR7)NR8R9, -NR7SO2NR8R9, -P(O)R7R8, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, 5-6 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are optionally substituted by 1-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -CN, -NR7R8, C. 1-3 Alkyl or C 1-3 Alkoxy; R7, R8, and R9 are each independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl; the C 1-6 Alkyl, C 3- The 6-cycloalkyl group is optionally substituted with 1 to 6 substituents selected from the group consisting of: deuterium, halogen, -CN, -OH. The compound of claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein the compound has a structure selected from the group consisting of: in X1, X2, X3, X4, X5, X6, X7, R2, R3, R5, R6, L2 as defined in claim 1; Ring A is selected from the following group: C 5-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, phenyl, 5-10 membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C 5-10 Cycloalkyl, 5-10-membered heterocyclic, phenyl, and 5-10-membered heteroaryl groups are optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, -OH, -CN, -NO2, oxo (=O), -NR7R8, =NR7, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 Alkyl group. R4 is selected from the following groups: H, deuterium, halogens, -CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, C 2-6 alkenyl, C 2-6 alkynyl group, wherein the C 1- 6-alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl group. The compound of claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein the compound has a structure selected from the group consisting of: in: X1, X2, X3, X4, X5, X6, X7, R1, R2, R3, R4, R5, R6 as defined in claim 1; R L2 Each is independently selected from deuterium, halogens, =O, -CN, -OH, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and deuterated C 3-6 cycloalkyl; Or, two R atoms on the same atom L2 Formation C 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O and S heteroatoms, wherein the C 3-6 The cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted by 0-6 substituents selected from the group consisting of: deuterium, halogen, -CH2O(C 3-6 cycloalkyl), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl and deuterated C 1-6 Alkyl group. The compound as claimed in claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, in Y1 and Y2 are each selected independently from the key; Optionally, Y3 is selected from -C(O)-; Optionally, X1 is selected from C, CH, and N; Optionally, X2 is selected from CR and C(R)2; Optionally, X3 is selected from C and CH; Optionally, X7 is selected from C, CH, and N; Optionally, X4, X5, and X6 are each independently selected from N and C. 1-6 Alkyl groups, CR, and C(R)2; Optionally, L1 is selected from Optionally, L2 is selected from -CH2-, -CH2-CH2-, Optionally, R is selected from H and C. 1-6 alkyl; Optionally, R1 is selected from H, deuterium, halogens, Optionally, R2 is selected from Optional, R 21 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; Optionally, R3 is selected from 3-14 membered heterocyclic groups, C 6-14 Aryl groups and 5-14 heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S; preferably, R3 is selected from... Optionally, R4 is selected from oxo (=O) and C. 1-6 alkyl; Optionally, R4 and R1 together with the atoms they are attached to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 heteroatoms selected from N, O and S, or phenyl; Optionally, R5 is selected from Optionally, R6 is selected from -LC 2-6 alkynyl, -LC 3-12 Cycloalkyl, -L-containing 1-4 3-12 membered heterocyclic groups selected from N, O and S heteroatoms, -LC 6-12 The aryl group and -L-containing 1-4 5-12-membered heteroaryl groups selected from N, O, and S heteroatoms; preferably, R6 is selected from... Optional, R 61 Selected from C 1-6 Alkyl and Halogenated C 1-6 alkyl; Optionally, L is the key. The compound of claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite, or prodrug, wherein the compound is selected from the group consisting of: A pharmaceutical composition comprising any one of the compounds of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, and a pharmaceutically acceptable carrier or excipient. Use of any compound of claims 1-16 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, or the pharmaceutical composition of claim 17 in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases. Use of any compound of claims 1-16 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, or the pharmaceutical composition of claim 17 in the preparation of a medicament for modulating GLP-1 receptors. Use of any compound of claims 1-16 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, deuterated product, metabolite or prodrug, or the pharmaceutical composition of claim 17 in the preparation of a GLP-1R agonist. The use as described in claim 18, wherein the disease is non-insulin-dependent diabetes mellitus, obesity, hypertension, hyperlipidemia, arteriosclerosis, hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus, diabetic complications, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia.

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