Heterocyclic compound having GLP-1 receptor agonist effect and use thereof

Abstract

The present invention relates to the field of pharmaceuticals, and particularly relates to a GLP-1R agonist capable of increasing insulin secretion and reducing blood glucose levels in a glucose-dependent manner. The GLP-1R agonist is a compound having a structure represented by formula (I), or a stereoisomer thereof, a tautomer thereof, a diastereomer thereof, a racemate thereof, a cis-trans isomer thereof, an isotopically labeled compound (preferably a deuterated compound) thereof, an N-oxide thereof, a metabolite thereof, an ester thereof, a prodrug thereof, a crystal form thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

Description

Heterocyclic compounds with GLP-1 receptor agonist effects and their applications

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese Patent Application No. 202510111633.8 filed on January 23, 2025, Chinese Patent Application No. 202510255394.3 filed on March 5, 2025, Chinese Patent Application No. 202510816704.4 filed on June 18, 2025, and Chinese Patent Application No. 202511054870.1 filed on July 30, 2025, the contents of which are incorporated herein by reference in their entirety and for all purposes. Technical Field

[0003] This invention relates to the pharmaceutical field, specifically to a GLP-1R agonist that can enhance insulin secretion and lower blood glucose levels in a glucose-dependent manner. Background Technology

[0004] In recent years, with the improvement of people's living standards and changes in dietary habits, obesity has gradually become a global health problem, and its prevalence continues to increase worldwide. Obesity is a key risk factor for metabolic complications such as non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), cardiovascular disease, hypercholesterolemia, and hypertension.

[0005] Type 2 diabetes accounts for 90-95% of all diabetes cases, and its prevalence is increasing worldwide. According to the International Diabetes Federation (IDF), 382.5 million people were affected by T2DM in 2015, and this number is projected to exceed 578 million within 20 years.

[0006] Glucagon-like peptide-1 (GLP-1) is an incretin, a 30-amino acid polypeptide secreted by L cells in the small intestine. GLP-1 participates in the regulation of glucose homeostasis through signal transduction via its interaction with the GLP-1 receptor (GLP-1R). The insulinotropic effect of GLP-1 is glucose-dependent; once plasma glucose levels drop to normal, it will not further stimulate insulin secretion, thus reducing the risk of hypoglycemia. Furthermore, GLP-1 primarily regulates glucose homeostasis by promoting insulin gene transcription, stimulating pancreatic β-cell proliferation and regeneration, inhibiting β-cell apoptosis, and blocking glucagon release. It can also delay gastric emptying and promote satiety, thereby aiding in weight loss. In the intestine, GLP-1 can stimulate 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 related to certain foods. GLP-1R is also expressed in the cardiovascular system, which can increase heart rate and cardiac output, and has a cardioprotective function.

[0007] Therefore, GLP-1 receptor agonists can be used to treat obesity and metabolic syndrome with significant clinical manifestations, and have been widely used in the treatment of type 2 diabetes. They also possess properties such as weight loss, protection of pancreatic β-cells, promotion of pancreatic β-cell proliferation, and minimal side effects. Furthermore, GLP-1 receptor agonists exhibit various biological effects, including reducing neuroinflammation, promoting nerve growth, improving cardiac function, suppressing appetite, delaying gastric emptying, regulating lipid metabolism, and reducing fat deposition. Moreover, GLP-1 receptor agonists have neuroprotective, anti-infective, cardiovascular protective, and metabolic regulatory effects, demonstrating promising application prospects. The relationship between GLP-1 receptor agonists and tumor occurrence, development, and prognosis in patients with type 2 diabetes mellitus is also receiving increasing attention.

[0008] GLP-1 receptor agonists (GLP-1RAs) can bind to GLP-1Rs and exert the same effects as GLP-1. All currently approved GLP-1 receptor agonists are synthetic analogs of the endogenous agonist GLP-1 or its paralogous homolog exendin-4, primarily optimized for pharmacokinetic properties through various modification methods to improve protein hydrolysis stability and / or avoid renal clearance. These FDA-approved peptide drugs are mainly used to treat type 2 diabetes mellitus (T2DM) or obesity; however, these peptide GLP-1 receptor agonist drugs usually require subcutaneous injection, leading to poor patient compliance. Currently, no small molecule GLP-1 receptor agonist drugs are approved for the treatment of T2DM or obesity; therefore, this invention aims to develop orally administered small molecule GLP-1 receptor agonists to meet this need.

[0009] Novo Nordisk's oral semaglutide Rybelsus is the first and only marketed oral GLP-1 receptor agonist, but its administration requirements are strict and cumbersome. Non-peptide oral small molecule GLP-1 receptor agonists have advantages such as oral administration, high stability, easy storage, and low cost, and represent the future trend in research and development.

[0010] Patent CN109790161B discloses a pyrazolopyridine derivative with GLP-1 receptor agonist activity, specifically compound 67. This compound is Orforglipron (LY3502970), an oral small-molecule GLP-1R agonist drug being developed by Eli Lilly. Phase II clinical trials reported that at 26 weeks, subjects experienced a weight loss of 8.6%-12.6%, and type 2 diabetic subjects experienced an average HbA1c reduction of 2.1%; at 36 weeks, subjects experienced a weight loss of 9.4%-14.7%. Due to the low oral bioavailability of this drug, a relatively high dosage is required.

[0011] There are currently no commercially available small molecule GLP-1R agonist drugs, and there is an urgent need to develop new GLP-1R agonist drugs. Summary of the Invention

[0012] In view of the above-mentioned technical status, the present invention aims to provide a GLP-1R agonist, which is a compound with the structure shown in formula (Ⅰ).

[0013] Or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts.

[0014] in:

[0015] X1, X2, X4, X5, X6, X7, and X8 are each independently selected from C or N;

[0016] X3 is selected from C, N, O, or S;

[0017] Ring M1 is selected from a benzene ring or a 6-membered heteroaromatic ring;

[0018] Ring M2 is selected from 5-membered heteroaryl rings;

[0019] R 6a and R 6b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-10 alkenyl, C 2-10alkynyl group, or R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-10 Cyclic hydrocarbon group or 3-12 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 The cyclic hydrocarbon group and the 3-12 membered heterocyclic group are optionally each independently selected by one or more (e.g., 1 to 5) selected from R h The substituents are replaced;

[0020] R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced;

[0021] R 10 Selected from C 1-10 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-10 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced;

[0022] Or, R8 and R 9 R 9 and R 10 Or R 10 and R 11 They form C together with the atoms they are attached to. 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl, wherein C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced;

[0023] L is selected from 3-12-membered heterocyclic groups or 5-14-membered heteroaryl groups, wherein the 3-12-membered heterocyclic group and the 5-14-membered heteroaryl group are optionally selected from R by one or more (e.g., 1 to 5). h The substituents are replaced;

[0024] R 2 Selected from C 3-20 Cyclic hydrocarbon groups, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl, wherein C 3-20 Cyclic hydrocarbon groups, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced;

[0025] R 1 Selected from C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl, wherein C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl groups are optionally each selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced;

[0026] Ring Q1 is selected from 8-18 membered heterocyclic groups; the 8-18 membered heterocyclic group is optionally selected from one or more (e.g., 1 to 5) of R. h The substituents are replaced;

[0027] Cyclomeric Q2 is selected from 3-12-membered heterocyclic groups and 5-10-membered heteroaryl groups; wherein the 3-12-membered heterocyclic group and 5-10-membered heteroaryl group are optionally selected from R by one or more (e.g., 1 to 3) groups. h The substituents are replaced;

[0028] Each R hEach group is independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, nitro, SF5, and C. 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CR x R y ) t -C(O)R A 、-(CR x R y ) t -C(O)NR B R C 、-(CR x R y ) t -NR D C(O)R E 、-(CR x R y ) t -NR D C(O)NR E R F 、-(CR x R y ) t -C(O)OR A 、-(CR x R y ) t -S(O) n R A 、-(CR x R y ) t -S(O) n NR B R C , The C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CR x R y ) t -C(O)R A 、-(CRx R y ) t -C(O)NR B R C 、-(CR x R y ) t -NR D C(O)R E 、-(CR x R y ) t -NR D C(O)NR E R F 、-(CR x R y ) t -C(O)OR A 、-(CR x R y ) t -S(O) n R A 、-(CR x R y ) t -S(O) n NR B R C , Optionally and independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, nitro, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Substituents of aryl and 5-10 heteroaryl groups;

[0029] R x R y Each is independently selected from H or C 1-6 alkyl;

[0030] t is selected from 0, 1, 2, 3, or 4;

[0031] n is selected from 1 or 2;

[0032] R A R B R C R D R E R F R G RH R I Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated deuterated alkyl, hydroxy C 1-6 Alkyl-, C 1-6 Alkoxy C 1-6 Alkyl-, cyano-C 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 aryl, 5-12 heteroaryl, or, R B and R C Together with the atoms they are attached to, they form 3-12 membered heterocyclic groups, or, R D and R E or R D and R F Together with the atoms they are attached to, they form 3-12 membered heterocyclic groups.

[0033] In this invention, as one embodiment, the compound has the structure shown in formula (II):

[0034] in:

[0035] Y1, Y3, Y4, and Y5 are each independently selected from C or N;

[0036] Y2 is selected from CR e O, S, NR e Or N;

[0037] Y6 is selected from CH or N;

[0038] Ring M3 is selected from 5-membered heterocyclic aromatic rings;

[0039] R 4 R 5 R e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 Alkyl; more preferably, R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; more preferably, R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl (e.g., C10) 1-3 Alkyl groups, such as methyl groups;

[0040] R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, the C 3-10 Cyclic hydrocarbon groups and 3-12 membered heterocyclic groups are optionally and independently each composed of 1 to 5 groups selected from R h The substituents are replaced;

[0041] X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined above.

[0042] In this invention, as one embodiment, the compound has the structure shown in formula (II'):

[0043] in:

[0044] O ring is selected from C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, wherein C 3-10 Cycloalkyl groups and 3-12-membered heterocycloalkyl groups are optionally each independently composed of 1 to 5 groups selected from R h The substituents are replaced;

[0045] X1, X2, X3, X4, X5, X6, X7, X8, Y1, Y2, Y3, Y4, Y5, Y6, L, R1 R 2 R 4 R 5 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined above.

[0046] In this invention, as one embodiment, the ring O is selected from C. 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl; the C 3-7 Cycloalkyl groups and 3-7-membered heterocycloalkyl groups are optionally each independently composed of 1 to 5 groups selected from R h The substituents are replaced;

[0047] Preferably, the ring O is selected from C. 3-6 Cycloalkyl, 4-7 membered heterocyclic alkyl; preferably, the ring O is selected from C. 3-6 cycloalkyl;

[0048] Preferably, the ring O is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxacyclobutyl; preferably, the ring O is selected from cyclopropyl, cyclobutyl, and cyclopentyl; preferably, the ring O is selected from cyclopropyl.

[0049] More preferably, Selected from Preferred Preferred

[0050] In this invention, as one embodiment, Y4 and Y5 are selected from C;

[0051] Y1 and Y3 are each independently selected from C or N; preferably, one of Y1 and Y3 is C and the other is N; preferably, Y1 is N and Y3 is C;

[0052] Y2 is selected from CH or N, preferably Y2 is selected from N;

[0053] Y6 is selected from CH or N, preferably Y6 is selected from CH; and / or

[0054] Structural unit Selected from in, Representing single or double bonds, and adjacent to each other. Not both are double bonds;

[0055] Preferably, structural unit Selected from Preferred

[0056] More preferably, structural unit Selected from Preferred and / or structural units Selected from Preferred Preferred selection (Preferred) ), (Preferred) Preferred (Preferred) Preferred selection (Preferred) ), (Preferred) Preferred (Preferred) Preferred selection (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) Preferred selection (Preferred) ), (Preferred) ), (Preferred) Preferred (Preferred) ); where the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0057] In this invention, as one embodiment, the compound has the structure shown in formula (II-1) or (II-2):

[0058] Preferably, formula (II-1) or (II-2) has the structure shown in formula (II-1') or formula (II-2'):

[0059] More preferably, formula (II-1') or (II-2') is the structure shown in formula (II-1'-A) or formula (II-2'-A):

[0060] Among them, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 4 R 5 R 6a R 6b R 7 R 8 R 9 R 10 R 11 The ring O is defined as described in any of the above terms.

[0061] In this invention, as one embodiment, the compound has the structure shown in formula (III):

[0062] in:

[0063] Y1, Y3, Y4, and Y5 are each independently selected from C or N;

[0064] Y2 is selected from CR e O, S, NR e Or N;

[0065] Ring M3 is selected from 5-membered heterocyclic aromatic rings;

[0066] R 3 R 4 R 5 R e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituents are replaced;

[0067] R 3’Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino; more preferably, R 3’ Selected from hydrogen;

[0068] Or, R 3 and R 3’ Together with the carbon atoms they are attached to, they form C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, the C 3-10 Cyclic hydrocarbon groups and 3-12 membered heterocyclic groups are optionally and independently each composed of 1 to 5 groups selected from R h The substituents are replaced;

[0069] Preferably, R 3 R 3’ R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; or, R 3 and R 3’ Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl or 4-7 membered heterocyclic alkyl;

[0070] More preferably, R 3 R 3’ R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; or, R 3 and R 3’ Together with the carbon atoms they are attached to, they form cyclopropyl groups;

[0071] More preferably, R 3 R 3’ R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups);

[0072] X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined above.

[0073] In this invention, as one embodiment, Y4 and Y5 are selected from C;

[0074] Y1 and Y3 are each independently selected from C or N;

[0075] Y2 is selected from CH or N, preferably Y2 is selected from N; and / or

[0076] Structural unit Selected from in, Representing single or double bonds, and adjacent to each other. Not both are double bonds;

[0077] Preferably, structural unit Selected from

[0078] More preferably, structural unit Selected from and / or

[0079] Structural unit Selected from Preferred More The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0080] In this invention, as one embodiment, the compound has the structure shown in formula (III-1):

[0081] Among them, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 3 R 3’ R 4 R 5 R 6a R 6b R 7 R 8 R 9 R 10 R 11 As defined in any of the above items.

[0082] In this invention, as one embodiment, the compound has the structure shown in formula (IV):

[0083] in:

[0084] Y1, Y3, Y4, and Y5 are each independently selected from C or N;

[0085] Y2 is selected from CR e O, S, NR e Or N;

[0086] Y6 is selected from CH or N;

[0087] Ring M3 is selected from 5-membered heterocyclic aromatic rings;

[0088] R 4 R 5 R e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1- 6-alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; more preferably, R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; more preferably, R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups);

[0089] R 3c and R 3d Each is independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably R 3c and R 3d Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl; preferably, R 3c and R 3dOne of them is selected from hydrogen, and the other is selected from halogens (such as F) or C. 1-6 Alkyl (e.g., methyl); or, more preferably R 3c and R 3d It is also selected from halogens (e.g., F);

[0090] X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined above.

[0091] In this invention, as one of the embodiments, R 3c and R 3d Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl; preferably, R 3c and R 3d One of them is selected from hydrogen, and the other is selected from halogens (such as F) or C. 1-6 Alkyl (e.g., methyl), or, R 3c and R 3d Simultaneously selected from halogens (e.g., F), or R 3c and R 3d Simultaneously selected from C 1-6 Alkyl (e.g., methyl), or, R 3c and R 3d One of them is selected from halogens (e.g., F), and the other is selected from C. 1-6 Alkyl (e.g., methyl).

[0092] In this invention, as one of the embodiments, R 3c and R 3d One of them is selected from hydrogen, and the other is selected from halogens (e.g., F); preferably, R 3c Selected from F, R 3d Selected from H; preferably, R 3c Selected from H, R 3d Selected from F.

[0093] In this invention, as one of the embodiments, R 3c and R 3d One of them is selected from hydrogen, and the other is selected from C. 1-3 Alkyl (e.g., methyl); preferably, R 3c Selected from C 1-3 Alkyl (e.g., methyl), R 3d Selected from H; preferably, R3c Selected from H, R 3d Selected from C 1-3 Alkyl (e.g., methyl).

[0094] In this invention, as one of the embodiments, R 3c and R 3d Simultaneously selected from C 1-3 Alkyl (e.g., methyl).

[0095] In this invention, as one of the embodiments, R 3c and R 3d One of them is selected from halogens (e.g., F), and the other is selected from C. 1-3 Alkyl (e.g., methyl); preferably, R 3c Selected from C 1-3 Alkyl (e.g., methyl), R 3d Selected from F; preferably, R 3c Selected from F, R 3d Selected from C 1-3 Alkyl (e.g., methyl).

[0096] In this invention, as one embodiment, Y4 and Y5 are selected from C;

[0097] Y1 and Y3 are each independently selected from C or N; preferably, Y1 is selected from N and Y3 is selected from C;

[0098] Y2 is selected from CH or N, preferably Y2 is selected from N;

[0099] Y6 is selected from CH or N, preferably Y6 is selected from CH; and / or

[0100] Structural unit Selected from in, Representing single or double bonds, and adjacent to each other. Not both are double bonds;

[0101] Preferably, structural unit Selected from Preferred

[0102] More preferably, structural unit Selected from Preferred and / or

[0103] Structural unit Selected from Preferred selection (Preferred) Preferred selection (Preferred) (Preferred) (Preferred) ); where the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0104] In this invention, as one of the embodiments, the structural unit

[0105] Selected from (Preferred) (Preferred) (Preferred) The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0106] In this invention, as one of the embodiments, the structural unit Selected from (Preferred) The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0107] In this invention, as one of the embodiments, the structural unit Selected from (Preferred) The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0108] In this invention, as one of the embodiments, the structural unit Selected from The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0109] In this invention, as one of the embodiments, the structural unit Selected from The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0110] In this invention, as one of the embodiments, the structural unit Selected from The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0111] In this invention, as one of the embodiments, the structural unit Selected from The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0112] In this invention, as one of the embodiments, the structural unit Selected from The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0113] In this invention, as one embodiment, the compound has the structure shown in formula (IV-1):

[0114] Preferably, formula (IV-1) has the structure shown in formula (IV-1'):

[0115] Among them, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 3c R 3d R 4 R 5 R 6a R 6b R 7 R 8 R 9 R 10 R 11 As defined in any of the above items.

[0116] In this invention, as one embodiment, the compound has the structure shown in formula (V):

[0117] in:

[0118] Y6 is selected from CH or N;

[0119] Y7, Y8, Y9, Y 10 Y 11 Each is independently selected from C or N;

[0120] Ring M4 is selected from 5-membered heterocyclic aromatic rings or 5-membered heterocyclic rings; preferably, ring M4 is selected from 5-membered heterocyclic aromatic rings.

[0121] Ring W is selected from C 4-10 Cyclic hydrocarbon group, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl; the C 4-10 Cyclic hydrocarbon group, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally and independently each selected from 1 to 3 R groups. h The substituents are replaced;

[0122] R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; more preferably, R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; more preferably, R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups);

[0123] X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined above.

[0124] In this invention, as one embodiment, the compound has the structure shown in formula (V-1):

[0125] in:

[0126] W1, W2, and W3 are each independently selected from CH or N; preferably, W1, W2, and W3 are selected from CH.

[0127] Ring W is selected from a benzene ring or a 6-membered heteroaromatic ring; preferably, ring W is selected from a benzene ring.

[0128] R g Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently bounded by 1 to 5 groups selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The substituents of the alkylamino group are replaced; preferably, R g Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl; more preferably, R g Selected from hydrogen, halogens, C 1-6 alkyl;

[0129] g is selected from 0, 1, 2 or 3; preferably, g is selected from 0 or 1; preferably, g is selected from 0;

[0130] X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R7 R 8 R 9 R 10 R 11 Y6, Y7, Y8, Y9, Y 10 Y 11 R 4 R 5 As defined above.

[0131] In this invention, as one embodiment, Y6 is selected from CH or N, preferably, Y6 is selected from CH;

[0132] Y7, Y8, Y9, Y 10 Selected from C;

[0133] Y 11 Selected from N;

[0134] W1, W2, and W3 are each independently selected from CH or N; preferably, W1, W2, and W3 are selected from CH; and / or

[0135] Structural unit Selected from (or ), (or ), Preferred (or Preferred (or Preferred (or Preferred (or Preferred (or Preferred (or (Preferred) ); where the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0136] In this invention, as one embodiment, the compound has the structure shown in formula (V-2):

[0137] Preferably, formula (V-2) has the structure shown in formula (V-2-A):

[0138] Among them, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R6a R 6b R 7 R 8 R 9 R 10 R 11 R h R 4 R 5 W1, W2, W3, R g g is as defined in any of the above terms.

[0139] In this invention, as one embodiment, the compound has the structure shown in formula (VI):

[0140] in:

[0141] Y6 is selected from CH or N;

[0142] W4 and W5 are each independently selected from CR W Or N; preferably, one of W4 and W5 is selected from N;

[0143] R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; more preferably, R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; more preferably, R 4 Selected from hydrogen, R 5 Selected from C1-6 Alkyl groups (e.g., methyl groups);

[0144] R W Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 2-10 alkenyl, C 2-1 0-alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino groups are optionally each independently composed of 1 to 5 groups selected from R h The substituent is replaced by; preferably, R W Selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, SF5, C1-6 alkyl; more preferably, R W Selected from hydrogen;

[0145] X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined above.

[0146] In this invention, as one embodiment, Y6 is selected from CH or N; preferably, Y6 is selected from CH.

[0147] One of W4 and W5 is selected from N; and / or

[0148] Structural unit Selected from (Preferred) Preferred (Preferred) ); More preferably (Preferred) ); where the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

[0149] In this invention, as one embodiment, the compound has the structure shown in formula (VI-1):

[0150] Preferably, formula (VI-1) has the structure shown in formula (VI-2):

[0151] Among them, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R 4 R 5 W4 and W5 are as defined in any of the above items.

[0152] In this invention, as one embodiment, the compound has the structure shown in formula (VII):

[0153] Among them, Y1, Y3, Y4, and Y5 are each independently selected from C or N;

[0154] Y2 is selected from CR e O, S, NR e Or N;

[0155] R 3 R 4 R 5 R e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 3 R 4 R 5Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; more preferably, R 3 R 4 R 5 Each is independently selected from hydrogen or C1-6 alkyl; more preferably, R 3 R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups);

[0156] R 8 and R 9 Together with the atoms they are attached to, they form C3-18 cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, and C 6-18 Aryl or 5-18 heteroaryl, wherein C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituents are replaced;

[0157] X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 10 R 11 R h As defined above;

[0158] Preferably, formula (VII) has the structure shown in formula (VII-1):

[0159] In this invention, as one embodiment, the compound described in (I) of this invention, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotope-labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the ring Q1 is an 8-18 membered bicyclic heterocyclic group or an 8-18 membered tricyclic heterocyclic group;

[0160] Preferably, when ring Q1 is an 8-18 quintile tricyclic heterocyclic group, it is further preferred that ring Q1 is... The substituents are as defined in formulas (II') and (V);

[0161] Further preferably, when the ring Q1 is an 8-18 quintic bicyclic heterocyclic group, the ring Q1 is... The substituents are as defined in formulas (III), (IV), (VI-1), and (VI-2); the condition being that Q1 is selected from... At that time, R 8 and R 9 They form rings with the atoms they are connected to.

[0162] In this invention, as one embodiment, the R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl or C 2-6 alkynyl group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl or C 2-6 The alkynyl group is optionally and independently surrounded by one, two, or three groups selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Substituted with cycloalkyl or 4-7 membered heterocycloalkyl groups;

[0163] Or, R 8 and R 9 Together with the atoms they are attached to, they form 5-14 membered heteroaryl groups or 5-12 membered heterocyclic groups; the 5-14 membered heteroaryl groups and 5-12 membered heterocyclic groups are optionally each independently bound by 1, 2 or 3 atoms selected from halogen, hydroxyl, amino, mercapto, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Substituents of the alkylamine group;

[0164] Preferably, R 7 and R 11 Each is independently selected from non-existent, hydrogen, or halogen, R8 Selected from: non-existent, hydrogen, halogen, cyano, SF5, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2-6 alkenyl or C 2-6 alkynyl group, the C 2-6 alkenyl and C 2-6 The alkynyl group is optionally and independently surrounded by one, two, or three groups selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl or 4-7 membered heterocyclic alkyl groups, R 9 Selected from: non-existent, hydrogen, halogen, cyano, SF5, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2-6 alkenyl or C 2-6 Alkyne group; or, R 8 and R 9 Together with the atoms they are attached to, they form 5-6 heteroaryl groups, which are optionally surrounded by 1, 2, or 3 atoms selected from halogens, C, and D. 1-6 Alkyl or C 1-6 The 5-6-membered heteroaryl group is substituted by a haloalkyl substituent and has 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from oxygen or sulfur.

[0165] Preferably, R 8 and R 9 Together with the atoms they are attached to, they form a 5-membered heteroaryl group, which is optionally surrounded by 1, 2, or 3 atoms selected from halogens, C, and D. 1-6 Alkyl or C 1-6 The 5-membered heteroaryl group is substituted by a haloalkyl substituent and has 0, 1, or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from oxygen or sulfur; preferably, the 5-membered heteroaryl group has 2 nitrogen heteroatoms.

[0166] More preferably, R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, or halogen;

[0167] More preferably, R 7 R 8 R 9 and R 11 All are hydrogen;

[0168] R 10 Selected from hydroxyl C 1-6 Alkyl-, 5-8 membered heterocyclic groups; the hydroxyl group C 1-6 Alkyl- or 5-8-membered heterocyclic groups are optionally each independently surrounded by 1, 2, or 3 groups selected from halogens, C1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0169] Or, R 9 and R 10 Together with the carbon atoms attached to them, they form 5-12 membered heterocyclic groups, wherein the heteroatoms of the 5-12 membered heterocyclic groups are selected from N, S, or O, or two or more combinations thereof, and are optionally surrounded by one, two, or three atoms selected from halogens, oxo groups, thio groups, hydroxyl groups, mercapto groups, cyano groups, amino groups, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Haloalkanes, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl or -S(O)2C 1-6 Substituents of haloalkyl groups;

[0170] Preferably, R 7 R 8 R 11 Both are hydrogen, R 9 and R 10 The atoms bonded to them together form a 9-11 membered spirobicyclic heterocyclic group, wherein the heteroatom of the 9-11 membered spirobicyclic heterocyclic group is selected from nitrogen or oxygen (preferably oxygen), and the number of heteroatoms is 1 or 2 (preferably 2); the 9-11 membered spirobicyclic heterocyclic group is optionally surrounded by 1 or 2 groups selected from halogen, oxo, or C. 1-6 The alkyl substituent is replaced; preferably, the 9-11 membered spirobicyclic heterocyclic group is replaced by one oxo group.

[0171] In this invention, as one embodiment, the...

[0172] Structural unit Selected from

[0173] Among them, G1, G2, G3, G4, G5, G6, G7, and G8 are each independently selected from CH2, NH, O, or S; Z1, Z2, and Z3 are each independently selected from CH, NH, N, O, or S; ring Z is a 5-membered heteroaromatic ring;

[0174] Preferably,

[0175] G1 is selected from O, CH2, S, or NH; more preferably O or CH2;

[0176] G2 is selected from CH2, O, or NH; more preferably CH2 or O.

[0177] G3 is selected from O, CH2, or NH;

[0178] G4 is selected from CH2, O, or NH;

[0179] G5 is selected from CH2 or O;

[0180] G6 is selected from O or CH2;

[0181] G7 is selected from CH2, O, or NH;

[0182] G8 is selected from CH2, NH, or O;

[0183] Z1 is selected from CH;

[0184] Z2 is selected from N or NH;

[0185] Z3 is selected from N or NH;

[0186] R g1 R g2 R g3 R g4 R g5 R g6 Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Haloalkanes, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl or -S(O)2C 1-6 Haloalkyl, or R g1 and R g2 R g3 and R g4 R g5 and R g6 Together they form an oxygen group; or, R g1 and R g2 R g3 and R g4 R g5 and R g6 Together with the carbon atoms they are attached to, they form C 3-7 cycloalkyl or 4-7 membered heterocyclic groups, wherein the C3-7 The cycloalkyl group and the 4-7 membered heterocyclic group are optionally surrounded by 1, 2 or 3 groups selected from halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Haloalkanes, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl or -S(O)2C 1-6 Substituents of haloalkyl groups;

[0187] r1, r2, r3, and r4 are each independently selected from 0, 1, or 2;

[0188] R r1 R r2 R r3 Each is independently selected from halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Haloalkanes, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl or -S(O)2C 1-6 Halogenated alkyl groups;

[0189] R r4 Selected from halogen, hydroxyl, amino, mercapto, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Halogenated alkylamine; preferably halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0190] Preferably, structural unit Selected from Preferred

[0191] Wherein, f1 and f2 are selected from 1, 2, or 3; preferably, f1 and f2 are selected from 2;

[0192] G9 is selected from O, CH2, S or NH; preferably, G9 is selected from O.

[0193] In this invention, as one embodiment, the R 10 Selected from hydroxyl C 1-6 Alkyl or 5-8 membered heterocyclic group, wherein the 5-8 membered heterocyclic group is optionally surrounded by 1, 2 or 3 elements selected from halogen, C 1-6 Alkyl or C 1-6 Substituents of haloalkyl groups;

[0194] Preferably, R 10 Selected from 6-8 membered heterocyclic groups, wherein the 6-8 membered heterocyclic group is optionally surrounded by 1, 2 or 3 elements selected from halogens, C 1-6 Alkyl or C 1-6 Substituents of haloalkyl groups;

[0195] Preferably, the heterocyclic group is selected from saturated monocyclic, partially unsaturated monocyclic, saturated bridged bicyclic, saturated fused bicyclic, and saturated spirobicyclic; saturated monocyclic is preferred.

[0196] Preferably, the heteroatom of the heterocyclic group is selected from O or N, and the number of heteroatoms is selected from 1 or 2; more preferably, the heteroatom of the heterocyclic group is selected from O, and the number of heteroatoms is selected from 1.

[0197] Preferably, R 10 Selected from More

[0198] In this invention, as one of the embodiments, R 10 Selected from tetrahydropyranyl, wherein the tetrahydropyranyl group is optionally surrounded by one or two C atoms. 1-6 Alkyl substitution.

[0199] In this invention, as one of the embodiments, R 10 Selected from (Preferred) ); R 10a R 10b Each is independently selected from hydrogen or C. 1-6 Alkyl; preferably, R 10a R 10b Each is independently selected from hydrogen or C. 1-4 Alkyl; preferably, R 10a R10b Each is independently selected from hydrogen or methyl; preferably, R 10a R 10b All are hydrogen; preferably, R 10a R 10b Each is independently selected from C 1-4 Alkyl; preferably, R 10a R 10b All are methyl groups.

[0200] In this invention, as one of the embodiments, R 10 Selected from (Preferred) ), (Preferred) Preferred (Preferred) )or More preferably

[0201] In this invention, as one embodiment, the...

[0202] Structural unit Selected from

[0203] Wherein, ring M1 is selected from a benzene ring or a 6-membered heteroaromatic ring; preferably, ring M1 is selected from a benzene ring or a 6-membered nitrogen-containing heteroaromatic ring; preferably, ring M1 is selected from a benzene ring;

[0204] Ring M2 is selected from a 5-membered heteroaromatic ring; preferably, ring M2 is selected from a 5-membered nitrogen-containing heteroaromatic ring, a 5-membered sulfur-containing heteroaromatic ring, or a 5-membered oxygen-containing heteroaromatic ring; preferably, ring M2 is selected from a 5-membered nitrogen-containing heteroaromatic ring.

[0205] X1, X2, X4, X5, X6, X7, and X8 are each independently selected from C or N;

[0206] X3 is selected from C, N, O or S; preferably, X3 is selected from C;

[0207] Preferably, structural unit Selected from (For example

[0208] Preferably, structural unit Selected from

[0209] Preferred Preferred Preferred More

[0210] In this invention, as one embodiment, the structural unit Selected from Preferred Preferred

[0211] In this invention, as one embodiment, the...

[0212] Structural unit Selected from Preferred Preferred Preferred Among them, "#R" 10 The key of the identifier is connected to R. 10 The key identified by "#C(O)" is connected to -C(O)-.

[0213] In this invention, as one embodiment, the following is described:

[0214] R 6a and R 6b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; the C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)NHC 1-6 Alkyl, -C 1-3 Alkyl-C(O)NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl, -C 1-3 Alkyl-NHC(O)C 1-6 The alkyl substituents are substituted; the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)NHC 1-6 Alkyl, -C 1-3 Alkyl-C(O)NHC 1-6 Alkyl group, -NHC(O)C1-6 Alkyl, -C 1-3 Alkyl-NHC(O)C 1-6 Alkyl groups may be substituted, each independently, with substituents selected from deuterium, halogen, hydroxyl, or cyano;

[0215] Preferably, R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; the C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, or 3 atoms selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups;

[0216] Preferably, R 6a and R 6b Together with the carbon atoms they are attached to, they form a cyclopropyl group, which is optionally composed of one, two, or three atoms selected from C1, C2, or C3. 1-6 Alkyl substituents;

[0217] Preferably, Selected from (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) Preferred (Preferred) ), More preferably, Selected from The key marked with "$" is connected to ring Q2 or

[0218] In this invention, as one embodiment, the following is described:

[0219] L is selected from 5-10 membered heterocyclic groups, wherein the 5-10 membered heterocyclic group is optionally surrounded by 1, 2, 3, 4 or 5 groups selected from halogen, hydroxyl, mercapto, amino, cyano, SF5, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Substituents of alkylamino groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6Alkylamino groups may be substituted independently by substituents selected from deuterium and halogens;

[0220] Preferably, L is selected from in Indicates a single or double bond, and they are adjacent. Not both are double bonds; X is selected from O or S, X0 is selected from C or N, and the ring CL is selected from C. 3-6 Cycloalkyl, 5-7-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl, optionally with 1, 2, or 3 rings selected from halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 The alkylamino group is substituted; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 The alkylamino groups are optionally and independently substituted by substituents selected from deuterium and halogens; marked with "#R 2 The key of the identifier is connected to R. 2 ;

[0221] Preferably, L is selected from More With "#R 2 The key of the identifier is connected to R. 2 .

[0222] In this invention, as one embodiment, the R 1 Selected from C 5-14 Cyclic hydrocarbon groups, 5-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl; the C 5-14 Cyclic hydrocarbon groups, 5-14 membered heterocyclic groups, C 6-14 The aryl group and the 5-14 heteroaryl group are optionally and independently each surrounded by 1, 2, 3, 4 or 5 groups selected from deuterium, halogen, SF5, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 4-12 membered heterocyclic group, C 6-10 Substituted with aryl or 5-10 heteroaryl groups; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 4-12 membered heterocyclic group, C 6-10 The aryl or 5-10 heteroaryl groups are optionally and independently replaced by substituents selected from deuterium and halogens;

[0223] Preferably, R 1 Selected from C 6-12 Cyclic hydrocarbon groups, 5-14 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; the C 6-12 Cyclic hydrocarbon groups, 5-14 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently bounded by 1, 2, 3 or 4 groups selected from halogen, SF5, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 The C group is substituted with substituents of cycloalkyl, 4-7 membered monocyclic heterocyclic groups, 7-11 membered spirobicyclic heterocyclic groups, 7-11 membered bridged bicyclic heterocyclic groups, and 8-10 membered fused bicyclic heterocyclic groups; 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered monocyclic heterocyclic, 7-11 membered spirobicyclic heterocyclic, 7-11 membered bridged bicyclic heterocyclic, and 8-10 membered fused bicyclic heterocyclic are optionally and independently substituted by substituents selected from deuterium and halogens;

[0224] Preferably, R 1 Selected from phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, 9-10 membered bicyclic heteroaryl, benzo[C] 5-7 Monocyclic cycloalkyl, benzo[C] 7-10 Bridged bicyclic cycloalkyl, benzo[C] 6-10 Fused bicyclic cycloalkyl, benzo[C] 7-10 Spirobicyclic cycloalkyl, benzo5-7 membered monocyclic heterocyclic group, benzo7-10 membered bridged bicyclic heterocyclic group, benzo6-10 membered fused bicyclic heterocyclic group, benzo7-10 membered spirobicyclic heterocyclic group; the above groups are optionally and independently surrounded by 1, 2, 3 or 4 groups selected from halogen, SF5, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Alkylamino, C 3-6 The C group is substituted by substituents of cycloalkyl, 4-7 membered monocyclic heterocyclic alkyl, 7-9 membered spirobicyclic heterocyclic alkyl, 7-9 membered bridged bicyclic heterocyclic alkyl, and 8-10 membered fused bicyclic heterocyclic groups; 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 member monocyclic heterocyclic alkyl, 7-9 member spirobicyclic heterocyclic alkyl, 7-9 member bridged bicyclic heterocyclic alkyl, and 8-10 member fused bicyclic heterocyclic alkyl are optionally and independently substituted by substituents selected from deuterium and halogens;

[0225] Preferably, R 1 Selected from phenyl, naphthyl, indole, indanyl, tetrahydronaphthyl, The above groups are optionally each independently surrounded by 1, 2, 3 or 4 groups selected from halogen, SF5, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 The C group is substituted by substituents of cycloalkyl, 4-7 membered monocyclic heterocyclic alkyl, 7-9 membered spirobicyclic heterocyclic alkyl, 7-9 membered bridged bicyclic heterocyclic alkyl, and 8-10 membered fused bicyclic heterocyclic groups; 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered monocyclic heterocyclic alkyl, 7-9 membered spirobicyclic heterocyclic alkyl, 7-9 membered bridged bicyclic heterocyclic alkyl, and 8-10 membered fused bicyclic heterocyclic alkyl are optionally and independently substituted by substituents selected from halogens;

[0226] Preferably, R 1 Selected from phenyl, naphthyl, indole, indanyl, tetrahydronaphthyl, The aforementioned groups are optionally and independently surrounded by 1, 2, 3, or 4 groups selected from F, Cl, methyl, cyclopropyl, ethynyl, CF3, SF5, SCF3, The substituents are replaced;

[0227] Preferably, R1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 elements selected from deuterium, halogen, SF5, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups;

[0228] Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 elements selected from deuterium, halogen, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups;

[0229] Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 elements selected from halogens, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Substituents of cycloalkyl groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group is optionally substituted with one or more (e.g., 2, 3, 4 or 5) halogens;

[0230] Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 elements selected from halogens, SF5, C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0231] Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 ions selected from halogens (preferably F, Cl), SF5, C 1-6 Substituents of alkyl groups;

[0232] Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 atoms selected from halogens (preferably F, Cl, C). 1-6 Substituents of alkyl groups;

[0233] Preferably, R 1 Selected from

[0234] Preferred Preferred

[0235] Preferably, R 1 Selected from Preferred Preferred Preferred Preferred Preferred

[0236] In this invention, as one of the embodiments, R 1 Selected from phenyl, said phenyl is given by 2 or 3 ions selected from halogens (e.g., F, Cl), SF5, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups.

[0237] In this invention, as one of the embodiments, R 1 Selected from phenyl, said phenyl is given by 2 or 3 ions selected from halogens (e.g., F, Cl), SF5, C 1-6 Alkyl groups are substituted.

[0238] In this invention, as one of the embodiments, R 1 Selected from phenyl, said phenyl is oxidized by 2 or 3 ions selected from halogens (e.g., F, Cl), C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups.

[0239] In this invention, as one of the embodiments, R 1 Selected from phenyl, said phenyl is oxidized by 2 or 3 ions selected from halogens (e.g., F, Cl), C 1-6 Alkyl groups are substituted.

[0240] In this invention, as one of the embodiments, R 1 Selected from R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group is optionally substituted with one or more (e.g., 2, 3, 4, or 5) halogens, and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), SF5, C 1-6 Alkyl (e.g., methyl), C 3-6Cycloalkyl (e.g., cyclopropyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), and C. 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), SF5, C 1-6 Alkyl (e.g., methyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), and C. 1-6 Alkyl (e.g., methyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from SF5, C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from SF5 or C 1-6 Alkyl (e.g., methyl); preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R 1a Selected from C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from C 1-6Alkyl (e.g., methyl).

[0241] In this invention, as one of the embodiments, R 2 Selected from C 12-20 Cyclic hydrocarbon groups, 12-20 membered heterocyclic groups, C 12-20 Aryl or 12-20 heteroaryl, wherein C 12-20 Cyclic hydrocarbon groups, 12-20 membered heterocyclic groups, C 12-20 Aryl or 12-20 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced;

[0242] Preferably, the R 2 Selected from C 12-18 Cyclic hydrocarbon groups, 12-18 membered heterocyclic groups, C 12-18 Aryl or 12-18 heteroaryl, wherein C 12-18 Cyclic hydrocarbon groups, 12-18 membered heterocyclic groups, C 12-18 The aryl or 12-18 membered heteroaryl group is tricyclic or tetracyclic; the heteroatom of the 12-18 membered heterocyclic group or 12-18 membered heteroaryl group is selected from nitrogen, oxygen, or sulfur; the C 12-18 Cyclic hydrocarbon groups, 12-18 membered heterocyclic groups, C 12-18 Aryl and 12-18 heteroaryl groups are optionally and independently bounded by 1 to 5 groups selected from deuterium, halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl or The substituents are replaced by the C; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -C(O)C 1-6 Alkyl groups and -S(O)2C 1-6 Alkyl groups are optionally and independently selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Substituents of alkylamino groups;

[0243] R G R HEach is independently selected from hydrogen or halogen;

[0244] Preferably, R 2 The heterocyclic group is selected from 13-18 membered heterocyclic groups, wherein the 13-18 membered heterocyclic group is tricyclic or tetracyclic, and the heteroatom of the 13-18 membered heterocyclic group is selected from nitrogen, oxygen, or sulfur, and the number of heteroatoms is selected from 1, 2, 3, or 4; the 13-18 membered heterocyclic group is optionally surrounded by 1 to 5 heteroatoms selected from halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl or The substituents are replaced by the C; 1-6 Alkyl, C1 -6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -C(O)C 1-6 Alkyl groups and -S(O)2C 1-6 Alkyl groups are optionally and independently selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Substituents of alkylamino groups;

[0245] R G R H Each is independently selected from hydrogen or halogen.

[0246] In this invention, as one embodiment, the R 2 Selected from group (1) or group (2), with group (1) preferred:

[0247] (1)

[0248] Wherein, ring A is selected from phenyl or 6-membered nitrogen-containing aryl group; preferably phenyl;

[0249] Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic hydrocarbon group; preferably 5-6 member monocyclic heterocyclic group; more preferably 5 member monocyclic heterocyclic group having 1 nitrogen heteroatom or oxygen heteroatom, 5 member monocyclic heterocyclic group having 2 oxygen heteroatom, 6 member monocyclic heterocyclic group having 1 or 2 nitrogen heteroatom and 0 or 1 oxygen heteroatom; even more preferably 5 member monocyclic heterocyclic group having 1 nitrogen heteroatom;

[0250] Cycle C is selected from 4-7 member monocyclic heterocyclic groups, 7-10 member bridged bicyclic heterocyclic groups, 7-10 member spirobicyclic heterocyclic groups, 7-10 member fused bicyclic heterocyclic groups, and C. 4-7 Monocyclic cyclic hydrocarbon group, C 7-10 Bridged bicyclic cyclic hydrocarbon group, C 7-10 Spirobicyclic cyclic hydrocarbon group, C 7-10 Fused bicyclic alkyl group; preferably a 4-6 membered monocyclic heterocyclic alkyl group having one nitrogen heteroatom, oxygen heteroatom, or sulfur heteroatom; a 7-9 membered bridged bicyclic heterocyclic alkyl group having one oxygen heteroatom; a 7-9 membered spirobicyclic heterocyclic alkyl group having one oxygen heteroatom; C 4-6 Monocyclic cycloalkyl, C 5-6 Monocyclic cycloalkenyl, C 7-10 Spirobicycloalkyl, C 7-10 Fused bicyclic cycloalkyl, benzo[C] 5-6 Monocyclic cycloalkyl group, benzo5-6 membered oxamonocyclic heterocyclic group; preferably a 6-membered heterocyclic alkyl group having one oxatom;

[0251] a, b, and c are each independently selected from 0, 1, 2, 3, or 4;

[0252] Preferably, a is selected from 0 or 1; b is selected from 0, 1, 2, 3 or 4; c is selected from 0, 1 or 2;

[0253] R a Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; preferably, R a Selected from deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; R a Halogens (e.g., F) are preferred;

[0254] R b Selected from hydrogen, deuterium, halogen, oxo group, thio group, cyano group, hydroxyl group, mercapto group, amino group, SF5, C1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, hydroxyl groups, and C. 1-6 The alkoxy group is substituted; or two R groups attached to the same carbon atom are substituted. b Formation C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; preferably, R b Selected from deuterium, halogen, oxo group, thio group, cyano group, hydroxyl group, mercapto group, amino group, SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, hydroxyl groups, and C. 1-6 The alkoxy group is substituted; or two R groups attached to the same carbon atom are substituted. b Formation C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; R b Preferred halogens, oxo groups, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; or two R groups attached to the same carbon atom are substituted. b Formation C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; R b More preferably, F, oxo group, methyl, cyclopropyl, -(CH2)2OCH3, -CH2CF3, Or two R atoms attached to the same carbon atom b Formation of cyclopropyl; further preferably, at least one R is present. b Selected from oxo groups;

[0255] R c Selected from hydrogen, deuterium, halogen, oxo group, hydroxyl group, mercapto group, amino group, cyano group, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl, The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C(O)C 1-6 Alkyl groups and -S(O)2C 1-6Alkyl groups are optionally and independently substituted with substituents selected from deuterium, halogen, cyano, and hydroxyl; R G R H Each is independently selected from hydrogen or halogen; preferably, R c Selected from deuterium, halogen, oxo group, hydroxyl group, mercapto group, amino group, cyano group, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl, The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C(O)C 1-6 Alkyl groups and -S(O)2C 1-6 Alkyl groups are optionally and independently substituted with substituents selected from deuterium, halogen, cyano, and hydroxyl; R G R H Each is independently selected from hydrogen or halogen; R is preferred. c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 alkyl, The C 1-6 Alkyl, -C(O)C 1-6 Alkyl groups are optionally and independently substituted with substituents selected from deuterium, halogen, cyano, and hydroxyl; R G R H Each is independently selected from hydrogen or halogen; more preferably R c Preferred radicals include F, oxoyl, methyl, ethyl, methoxy, -CH2CF3, -CH2CN, -(CH2)2CN, -C(O)CH3, -C(O)CF3, and -C(O)CH(OH)CH3.

[0256] (2)

[0257] Wherein, cyclo-A phenyl or a 6-membered nitrogen-containing aryl group; preferably phenyl;

[0258] Ring B is selected from phenyl, 5-6 membered heteroaryl, and 5-6 membered monocyclic heterocyclic group; preferably 5-membered nitrogen heteroaryl; more preferably pyrrole;

[0259] The ring C is selected from phenyl, 5-6 membered heteroaryl, 5-7 membered monocyclic heterocyclic group, C 5-7 Monocyclic cyclic hydrocarbon groups, 8-11 membered spirobicyclic heterocyclic groups;

[0260] a, b, and c are each independently selected from 0, 1, or 2; preferably, a is selected from 0 or 1, b is selected from 0 or 1, and c is selected from 0, 1, or 2.

[0261] R a Selected from deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; preferably, R a Selected from halogens (e.g., F);

[0262] R b Selected from deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; preferably R b Selected from halogens, C 1-6 Alkyl groups (e.g., methyl groups);

[0263] R c Selected from deuterium, oxo group, halogen, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl or -S(O)2C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl or -S(O)2C 1-6 Alkyl groups are optionally and independently substituted with substituents selected from deuterium, halogen, cyano, and hydroxyl; preferably R c Selected from oxo groups, C 1-6 Alkyl (e.g., methyl).

[0264] In this invention, as one embodiment, the... Choose any one of the following groups:

[0265] in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; single bonds are preferred.

[0266] A1, A2, A3, C2, C3, C4, C5, C9, C 10 C 11 C 12 Each is independently selected from CH or N; preferably A1, A2, A3, C2, C3, C4, C5, C9, C 10 C 11 C 12 Selected from CH;

[0267] Preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH; preferably, A1 is N, and A2 and A3 are both CH; preferably, C9, C 10 C 11 C 12 All are CH;

[0268] B1 and B2 are each independently selected from CH2, NH or O, and at least one of B1 and B2 is selected from CH2; preferably one of B1 and B2 is selected from NH or O, and the other is selected from CH2.

[0269] C1 is selected from O, NH, S, CH2, or CH; preferably O;

[0270] Each C6 atom is independently selected from CH2, NH, O, or S, and no two adjacent C6 atoms are heteroatoms at the same time; preferably, C6 is selected from CH2 or O.

[0271] C7 and C8 are each independently selected from CH2, NH, O or S, preferably C7 and C8 are each independently selected from CH2 or O; more preferably C7 and C8 are both CH2 or both C7 and C8 are both O; preferably C7 and C8 are both O.

[0272] C 13 C 14 Each is independently selected from CH2, NH, O, or S, with C being preferred. 13 C 14 Both are O;

[0273] C 15 Selected from CH2, NH, O or S, with CH2 being preferred;

[0274] p1, p2, p3, p4, p5, p7, and p8 are each independently selected from 1, 2, or 3; preferably, p1, p2, p3, p4, p5, p7, and p8 are each independently selected from 1 or 2; more preferably, p1 and p2 are selected from 2, p3 is selected from 1, p4 is selected from 2, p5 is selected from 1, p7 is selected from 1 or 2, and p8 is selected from 2.

[0275] p6 is selected from 1, 2, 3, 4 or 5; preferably, p6 is selected from 1, 2, 3 or 4; more preferably, p6 is selected from 1 or 2;

[0276] R a R b R c a, b, and c are as defined above;

[0277] Preferably, R a Selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl group; preferably halogen, more preferably F;

[0278] Preferably, R b Selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably C. 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably C. 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably C 1-6 Alkyl (e.g., methyl); more preferably C 1-3 Alkyl groups (e.g., methyl groups);

[0279] Preferably, R c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1- 6-alkyl, R G R HEach is independently selected from hydrogen or halogen (e.g., F); preferably, R c Selected from -S(O)2C 1-4 Alkyl, cyano C 1-4 alkyl-;

[0280] Preferably, 'a' is selected from 0 or 1;

[0281] Preferably, b is selected from 0 or 1;

[0282] Preferably, c is selected from 0, 1, or 2;

[0283] Preferably, the Selected from Preferred Preferred Preferred More Among them, p01 and p02 are each independently selected from 1, 2, or 3; A1, A2, A3, R a a, R b R c p1, p2, C9, C 10 C 11 C 12 As defined above;

[0284] Preferably, p1, p2, p01, and p02 are each independently selected from 1 or 2; preferably, p1, p2, p01, and p02 are all 1; preferably, R a Selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; preferably, R a For halogen, more preferably, R a For F; preferably, a is selected from 0 or 1; more preferably, a is 0; preferably, R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6 Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl (e.g., methyl); preferably, R cSelected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; more preferably, R c Selected from -S(O)2C 1-4 Alkyl, cyano C 1-4 Alkyl group; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH; preferably, A1 is N, and A2 and A3 are both CH; preferably, C9, C 10 C 11 C 12 All are CH; preferably, C9, C 10 C 11 C 12 One or two of them are N;

[0285] Preferably, the Selected from Preferred More Among them, A1, A2, A3, R a a, R b R c C9, C 10 C 11 C 12 As defined above;

[0286] Preferably, the Selected from Among them, A1, A2, A3, R a a, R b R c c is as defined above.

[0287] In this invention, as one embodiment, the... Selected from Preferred Preferred Preferred Preferred Preferred Preferred More Among them, p01 and p02 are each independently selected from 1, 2, or 3; A1, A2, A3, R a a, R b R c p1, p2, C9, C 10 C 11 C 12 As defined above;

[0288] Preferably, p1, p2, p01, and p02 are each independently selected from 1 or 2; preferably, p1, p2, p01, and p02 are all 1; preferably, each R a Independently selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; preferably, each R a Independently selected from halogens (e.g., F), C 1-6 Alkyl; preferably, each R a Independently selected from halogens, more preferably, R a For F; preferably, a is selected from 0 or 1; more preferably, a is 0; preferably, R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6 Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl (e.g., methyl); R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C1-6 Alkyl; preferably, R c Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; more preferably, R c Selected from -S(O)2C 1-4 Alkyl, cyano C 1-4 Alkyl-; preferably, R c Selected from hydrogen, C 1-4 Alkyl group, -S(O)2C 1-4 Alkyl, cyano C 1-4 Alkyl-; preferably, R c Selected from hydrogen, C 1-4 Alkyl, cyano C 1-4 Alkyl-; more preferably, R c Selected from hydrogen; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH; preferably, A1 is N, and A2 and A3 are both CH; preferably, C9, C 10 C 11 C 12 All are CH; preferably, C9, C 10 C 11 C 12 One or two of them are N; preferably, R a Substitutable hydrogen atoms on the ring atoms involved in replacing A2 or A3.

[0289] In this invention, as one of the implementation schemes,

[0290] The Choose any one of the following groups:

[0291] in:

[0292] A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the rest are CH.

[0293] B3 is selected from CH2, CF2, O, NH, and NR. b Preferred components: CH2, CF2, NH, NR b CH2 and NR are preferred. b CH2 and NCH3 are preferred; CH2 is preferred.

[0294] C 16 Selected from CH2, NH, O or S, with O being preferred;

[0295] C 17 Selected from CH2, NH, O or S, preferably O or CH2; more preferably O;

[0296] p9, p10, p11, and p12 are each independently selected from 1, 2, or 3; preferably, p9, p10, p11, and p12 are each independently selected from 1 or 2; preferably, p11 and p12 are both 1, or p11 and p12 are both 2; more preferably, p11 and p12 are both 2; preferably, p9 and p10 are both 1, or p9 and p10 are both 2; preferably, p9 and p10 are both 2.

[0297] R a R b R c a and c are as defined above;

[0298] Preferably, R a Selected from halogens, cyano groups, hydroxyl groups, mercapto groups, amino groups, SF5, and C1-6 alkyl groups; more preferably halogens; even more preferably halogens (e.g., F); preferably, each R a Independently selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; preferably, each R a Independently selected from halogens (e.g., F), C 1-6 Alkyl; more preferably, each R a Independently selected from halogens (e.g., F);

[0299] R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl groups (e.g., methyl groups);

[0300] Preferably, R c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 alkyl, R G R H Each is independently selected from hydrogen or halogen (e.g., F); more preferably halogen (e.g., F);

[0301] Preferably, 'a' is selected from 0 or 1; more preferably, 0.

[0302] Preferably, c is selected from 0, 1, or 2; more preferably, c is selected from 0.

[0303] Preferably, the Selected from Among them, A1, A2, A3, B3, R a a, R b Pages 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 are as defined above;

[0304] Preferably, the Selected from Among them, A1, A2, A3, B3, R a a, R b p11 and p12 are defined as above.

[0305] In this invention, as one embodiment, the... Selected from Preferred More Among them, A1, A2, A3, R a a, R b p9, p10, p11, and p12 are as defined in any embodiment of the present invention.

[0306] In this invention, as one of the embodiments, R a Substitutable hydrogen atoms on the ring atoms involved in replacing A2 or A3.

[0307] In this invention, as one of the embodiments, R aThe substituted hydrogen atoms on the ring atoms involved in replacing A2.

[0308] In this invention, as one of the embodiments, R a The substituted hydrogen atoms on the ring atoms involved in replacing A3.

[0309] In this invention, as one of the implementation schemes,

[0310] The Selected from

[0311] in, It is a single or double bond, and they are adjacent. Not both are double bonds;

[0312] A1, A2, and A3 are each independently selected from CH or N; CH is preferred.

[0313] B4 is selected from NH and NR. b , O, S, CH, CR b CH2, C(R) b )2; Preferably, B4 is selected from NH, CH, NR b or CR b ; More preferably CR b Or CH; further preferred CH;

[0314] B5 is selected from C or N; N is preferred.

[0315] Ring B is selected from a 5-membered heterocyclic aromatic ring or a 5-membered heterocyclic ring; preferably, ring B is selected from a 5-membered heterocyclic aromatic ring.

[0316] The ring C is selected from phenyl, 6-membered heteroaryl, C6 monocyclic cyclic hydrocarbon, 6-membered monocyclic heterocyclic group, and 9-11-membered spirobicyclic heterocyclic group;

[0317] R a R b R c a and c are as defined above;

[0318] Preferably, R a Selected from halogen or C 1-6 alkyl;

[0319] Preferably, R b Selected from halogens, C 1-6 alkyl;

[0320] Preferably, R c Selected from oxo groups, halogens, C 1-6 alkyl;

[0321] Preferably, 'a' is selected from 0 or 1;

[0322] Preferably, c is selected from 1 or 2.

[0323] In this invention, as one of the implementation schemes,

[0324] The Selected from

[0325] in:

[0326] C 18 Selected from CH2, CHF, CF2, NH, O, or S; preferably C. 18 Selected from O;

[0327] p13 and p14 are each independently selected from 1, 2 or 3; preferably p13 and p14 are each independently selected from 1 or 2; more preferably p13 and p14 are selected from 2;

[0328] A1, A2, A3, B4, B5, R a R c As defined above;

[0329] Preferably, R c Selected from halogen or C 1-6 alkyl.

[0330] In this invention, as one of the implementation schemes,

[0331] The R 2 Selected from Preferred R 2 Selected from Preferred Preferred Preferred More

[0332] In this invention, as one of the implementation schemes,

[0333] The R 2 Selected from

[0334] In this invention, as one of the implementation schemes,

[0335] The R2 Selected from

[0336] In this invention, as one of the implementation schemes,

[0337] The R 2 Selected from

[0338] In this invention, as one of the implementation schemes,

[0339] The R 2 Selected from Preferred More In this invention, as one embodiment, the R 2 Selected from Preferred Preferred Preferred More

[0340] In this invention, as one embodiment, the R 2 Selected from Preferred Preferred Preferred

[0341] In this invention, as one embodiment, the R 2 Selected Preferred Preferred

[0342] In this invention, as one embodiment, the compound of this invention is shown in any one of formulas (X-1) to (X-7):

[0343] Among them, R 1 R 2 R 10 f1, f2, and G9 are as defined in any embodiment of the present invention.

[0344] In this invention, as one embodiment, the compound described herein is as shown in formula (X-1-1):

[0345] Among them, R 10a R 10b R 1a R 1b R 1c and R 2 As defined in any embodiment of the present invention.

[0346] In this invention, as one embodiment, the following is provided:

[0347] R 10a R 10b Each is independently selected from hydrogen or C. 1-4 Alkyl; preferably, R 10a R 10b Each is independently selected from hydrogen or methyl; preferably, R 10a R 10b All are hydrogen; preferably, R 10a R 10b Each is independently selected from C 1-4 Alkyl; preferably, R 10a R 10b All are methyl;

[0348] R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group is optionally substituted with one or more (e.g., 2, 3, 4, or 5) halogens, and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), SF5, C 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), and C. 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), SF5, C 1-6 Alkyl (e.g., methyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), and C. 1-6 Alkyl (e.g., methyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from SF5, C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from SF5 or C 1-6 Alkyl (e.g., methyl); preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R1a Selected from C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from C 1-6 Alkyl groups (e.g., methyl groups);

[0349] R 2 Selected from groups (1) and (2):

[0350] (1) Wherein, p1, p2, p01, and p02 are each independently selected from 1 or 2; preferably, p1, p2, p01, and p02 are all 1; A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH (for example, A1 is N, and A2 and A3 are both CH); C9, C 10 C 11 C 12 Each is independently selected from CH or N; preferably, C9, C 10 C 11 C 12 All are CH; preferably, C9, C 10 C 11 C 12 One or two of them are N, and the rest are CH; each R a Independently selected from halogens (e.g., F), C 1-6 Alkyl; preferably, each R a Independently selected from halogens (e.g., F); R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6 Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl (e.g., methyl); preferably, R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; preferably, R c Selected from hydrogen, C 1-4 Alkyl group, -S(O)2C 1-4 Alkyl, cyano C 1-4 Alkyl-; preferably, R c Selected from hydrogen, C 1-4 Alkyl, cyano C 1-4 Alkyl-; more preferably, R c Selected from hydrogen; a is selected from 0 or 1; preferably, a is 0; preferably, R a The substituted hydrogen atoms on the ring atoms involved in replacing A2 or A3; preferably Preferred Preferred Preferred Preferred Preferred More

[0351] (2) Wherein, A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; B3 is selected from CH2, CF2, NH, and NR. b Or O; preferably, B3 is selected from CH2, CF2, NH, NR b Preferably, B3 is selected from CH2 and NR. b Preferably, B3 is selected from CH2 or NCH3; preferably, B3 is selected from CH2; p11 and p12 are each independently selected from 1 or 2; preferably, p11 and p12 are both 1, or p11 and p12 are both 2; preferably, p11 and p12 are both 2; p9 and p10 are each independently selected from 1 or 2; preferably, p9 and p10 are both 1, or p9 and p10 are both 2; preferably, p9 and p10 are both 2; each R a Independently selected from halogens (e.g., F), C 1-6 Alkyl; preferably, each R a Independently selected from halogens (e.g., F); R b Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6 Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl (e.g., methyl); a is selected from 0 or 1; preferably, a is 0; preferably, R a The substituted hydrogen atoms on the ring atoms involved in replacing A2 or A3; preferably Preferred More

[0352] Preferably, R 2 Selected from group (1).

[0353] In this invention, as one embodiment, the compound is as shown in formula (IV-1'-1):

[0354] Among them, R 1 R 2 R 3c R 3d R 4 R 5 R 6a R 6b R 10 As defined in any embodiment of the present invention.

[0355] In this invention, as one embodiment, the compound is as shown in formula (IV-1'-1A):

[0356] Among them, R 10a R 10b R 1a R 1b R 1c and R 2 As defined in any embodiment of the present invention.

[0357] In this invention, as one embodiment, the R 2 Selected from 9-10-membered bicyclic heteroaryl groups and 11-15-membered tricyclic heterocyclic groups; wherein the 9-10-membered bicyclic heteroaryl group and the 11-15-membered tricyclic heterocyclic group are optionally each independently selected from R... h The substituents are replaced;

[0358] Preferably, R 2 Selected from 9-10-membered bicyclic heteroaryl groups and 11-15-membered tricyclic heterocyclic groups; wherein each of the 9-10-membered bicyclic heteroaryl groups is optionally and independently selected from one or more (e.g., 1, 2, or 3) groups selected from halogen, hydroxyl, mercapto, cyano, amino, SF5, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-7-membered heterocyclic alkyl groups are optionally and independently selected from halogens, hydroxyl groups, mercapto groups, amino groups, cyano groups, SF5, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 The 11-15 membered tricyclic heterocyclic groups are optionally and independently each replaced by one or more (e.g., 1, 2, or 3) groups selected from halogen, hydroxyl, mercapto, cyano, amino, SF5, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-7-membered heterocyclic alkyl groups are optionally and independently selected from halogens, hydroxyl groups, mercapto groups, amino groups, cyano groups, SF5, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 The alkylamino group is substituted; the heteroatom of the 9-10 membered bicyclic heteroaryl group is selected from nitrogen, oxygen, and sulfur, preferably nitrogen; the number of heteroatoms of the 9-10 membered bicyclic heteroaryl group is selected from 1, 2, and 3, preferably 2; the heteroatom of the 11-15 membered tricyclic heterocyclic group is selected from nitrogen, oxygen, and sulfur, preferably nitrogen and oxygen, preferably nitrogen; the number of heteroatoms of the 11-15 membered tricyclic heterocyclic group is selected from 1, 2, and 3, preferably 1 and 2;

[0359] Preferably, R 2Selected from 9-10-membered bicyclic heteroaryl groups and 11-15-membered tricyclic heterocyclic groups; wherein each of the 9-10-membered bicyclic heteroaryl groups is optionally and independently selected by one or more (e.g., 1, 2 or 3) halogens (e.g., F, C). 1-6 Alkyl, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; the 11-15 membered tricyclic heterocyclic group is optionally and independently each replaced by one or more (e.g., 1, 2 or 3) selected from halogens (e.g., F), oxo groups, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; the heteroatom of the 9-10 membered bicyclic heteroaryl group is selected from nitrogen, oxygen, and sulfur, preferably nitrogen; the number of heteroatoms of the 9-10 membered bicyclic heteroaryl group is selected from 1, 2, and 3, preferably 2; at least one heteroatom of the 11-15 membered tricyclic heterocyclic group is selected from nitrogen, and if an additional heteroatom is present, the additional heteroatom is selected from nitrogen, oxygen, and sulfur (preferably the additional heteroatom is selected from nitrogen and oxygen, more preferably the additional heteroatom is selected from oxygen); the number of heteroatoms of the 11-15 membered tricyclic heterocyclic group is selected from 1, 2, and 3, preferably 1 and 2;

[0360] Preferably, R 2 Selected from

[0361] Wherein, A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH.

[0362] B7 and B8 are each independently selected from CH or N; preferably, one of B7 and B8 is selected from CH and the other is selected from N; preferably, B8 is selected from CH and B7 is selected from N;

[0363] B6 is selected from NH, O, or S; preferably, B6 is selected from NH.

[0364] C 19 Selected from NR c O or S; preferably, C 19 Selected from O;

[0365] R a Selected from hydrogen, halogens (e.g., F), cyano, SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl; preferably, R aSelected from hydrogen, halogens (e.g., F); preferably, R a Selected from halogens (e.g., F);

[0366] R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl, C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., C10) 1-3 Alkyl groups, such as methyl groups;

[0367] R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; preferably, R c Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano C 1-4 alkyl-;

[0368] a is selected from 0 or 1; preferably, a is selected from 0; preferably, a is selected from 1;

[0369] b is selected from 0 or 1; preferably, b is selected from 1;

[0370] p15 is selected from 1, 2, 3 or 4; preferably, p15 is selected from 1, 2 or 3; preferably, p15 is selected from 1 or 2; preferably, p15 is selected from 1.

[0371] p16 and p17 are each independently selected from 1 or 2; preferably, p16 and p17 are both selected from 2.

[0372] Preferably, R a The substituted hydrogen atom on the ring atom involved in replacing A2 or A3; more preferably, R a Substitutable hydrogen atoms on the ring atoms involved in replacing A3;

[0373] Preferably, R2 Selected from More preferably, R 2 Selected from

[0374] In this invention, as one embodiment, the compound is as shown in formula (V-2-1):

[0375] Among them, R 1 R 2 R g R 4 R 5 R 6a R 6b R 10 g is as defined in any embodiment of the present invention.

[0376] In this invention, as one embodiment, the compound formula (V-2-1A) is shown:

[0377] Among them, R g , g, R 4 R 5 R 10a R 10b R 1a R 1b R 1c and R 2 As defined in any embodiment of the present invention.

[0378] In this invention, as one embodiment, the R 2 Selected from 11-15 quinary tricyclic heterocyclic groups; wherein each of the 11-15 quinary tricyclic heterocyclic groups is optionally selected independently from one or more (e.g., 1, 2 or 3) of R h The substituents are replaced;

[0379] Preferably, R 2 Selected from 11-15 membered tricyclic heterocyclic groups; wherein each of the 11-15 membered tricyclic heterocyclic groups is optionally and independently selected from one or more (e.g., 1, 2 or 3) groups selected from halogen, hydroxyl, mercapto, cyano, amino, SF5, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-7-membered heterocyclic alkyl groups are optionally and independently selected from halogens, hydroxyl groups, mercapto groups, amino groups, cyano groups, SF5, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 The alkylamino group is substituted; the heteroatom of the 11-15 membered tricyclic heterocyclic group is selected from nitrogen, oxygen and sulfur, preferably nitrogen and oxygen, and more preferably nitrogen; the number of heteroatoms of the 11-15 membered tricyclic heterocyclic group is selected from 1, 2 and 3, preferably 1 and 2;

[0380] Preferably, R 2 Selected from 11-15 membered tricyclic heterocyclic groups; wherein each of the 11-15 membered tricyclic heterocyclic groups is optionally and independently selected by one or more (e.g., 1, 2 or 3) groups selected from halogens (e.g., F), oxo groups, C. 1-6 Alkyl, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; at least one heteroatom of the 11-15 membered tricyclic heterocyclic group is selected from nitrogen, and if there is an additional heteroatom, the additional heteroatom is selected from nitrogen, oxygen and sulfur (preferably the additional heteroatom is selected from nitrogen and oxygen, more preferably the additional heteroatom is selected from oxygen); the number of heteroatoms of the 11-15 membered tricyclic heterocyclic group is selected from 1, 2 and 3, preferably 1 and 2;

[0381] Preferably, R 2 Selected from Preferred

[0382] Wherein, A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH.

[0383] C 19 Selected from NR c O or S; preferably, C 19 Selected from O;

[0384] R a Selected from hydrogen, halogens (e.g., F), cyano, SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl; preferably, R a Selected from hydrogen, halogens (e.g., F); preferably, R a Selected from halogens (e.g., F);

[0385] R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl, C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., C10) 1-3 Alkyl groups, such as methyl groups;

[0386] R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; preferably, R c Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano C 1-4 alkyl-;

[0387] a is selected from 0 or 1; preferably, a is selected from 0;

[0388] p15 is selected from 1, 2, 3 or 4; preferably, p15 is selected from 1, 2 or 3; preferably, p15 is selected from 1 or 2; preferably, p15 is selected from 1.

[0389] p16 and p17 are each independently selected from 1 or 2; preferably, p16 and p17 are both selected from 2.

[0390] Preferably, R a The substituted hydrogen atom on the ring atom involved in replacing A2 or A3; more preferably, R a The substituted hydrogen atoms on the ring atoms involved in replacing A3.

[0391] In this invention, as one embodiment, when ring Q1 is selected from... At that time, the R 2 Selected from The ring C contains at least one heteroatom; the heteroatom is selected from nitrogen, oxygen and sulfur, preferably nitrogen and oxygen, and more preferably oxygen.

[0392] In this invention, as one embodiment, when ring Q1 is selected from... At that time, the R 2 Selected from 11-15 quinary tricyclic heterocyclic groups, wherein each of the 11-15 quinary tricyclic heterocyclic groups is optionally independently selected from R1, 1-2, or 3. h The substituents are replaced by the substituents.

[0393] In this invention, as one embodiment, the compound is selected from Table 1A:

[0394] Table 1A

[0395] In this invention, as one embodiment, the compound is selected from Table 1B:

[0396] Table 1B

[0397] In this invention, as one embodiment, the compound is selected from Table 1C:

[0398] Table 1C

[0399] In this invention, as one embodiment, the compound is selected from Table 1D:

[0400] Table 1D

[0401] In this invention, as one embodiment, the compound is selected from Table 1E:

[0402] Table 1E

[0403] In this invention, as one embodiment, the compound is selected from Table 1F:

[0404] Table 1F

[0405] In this invention, as one embodiment, the compound is selected from Table 1G:

[0406] Table 1G

[0407] In this invention, as one embodiment, the compound described in this invention is not...

[0408] In this invention, as one embodiment, the compound described in this invention is not...

[0409] The various embodiments of the present invention can be combined in any way.

[0410] In a first aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0411] In a second aspect, the present invention provides pharmaceutical compositions comprising the aforementioned compounds, or stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and optionally pharmaceutically acceptable excipients.

[0412] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-described compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and another therapeutically active agent.

[0413] In a fourth aspect, the present invention provides the use of the aforementioned compounds, or stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of GLP-1 receptor-mediated diseases or disorders or GLP-1-related diseases, conditions, or symptoms, or for the modulation of GLP-1 receptors.

[0414] In a fifth aspect, the present invention provides a method for regulating insulin levels in a patient requiring such regulation, the method comprising: administering to the individual a therapeutically effective amount of the aforementioned compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical composition; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical combination.

[0415] In a sixth aspect, the invention provides a method for regulating insulin levels in a patient who requires such regulation, wherein the regulation causes an increase in insulin levels.

[0416] In a seventh aspect, the present invention provides a method for regulating glucose levels in a patient requiring such regulation, the method comprising: administering to the individual a therapeutically effective amount of the aforementioned compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical composition; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical combination.

[0417] In an eighth aspect, the present invention provides a method for regulating glucose levels in a patient who requires such regulation, wherein the regulation causes a decrease in glucose levels.

[0418] In a ninth aspect, the present invention provides a method for preventing and / or treating GLP-1 receptor-mediated diseases or disorders or GLP-1-related diseases, symptoms, or conditions, the method comprising: administering to the individual a therapeutically effective amount of the aforementioned compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical composition; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical combination.

[0419] In a tenth aspect of the invention, the GLP-1 receptor-mediated diseases or disorders or GLP-1-related diseases, conditions or symptoms include metabolic diseases, cardiovascular diseases, liver diseases, kidney diseases, and neurodegenerative diseases.

[0420] Preferably,

[0421] The metabolic diseases mentioned include diabetes, diabetic complications, and obesity;

[0422] The cardiovascular diseases mentioned include hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, and cerebral infarction;

[0423] The liver diseases mentioned include non-alcoholic steatohepatitis;

[0424] The kidney disease mentioned includes type 2 diabetes mellitus complicated with chronic kidney disease;

[0425] The neurodegenerative diseases mentioned include Parkinson's disease or dementia.

[0426] Terminology Explanation

[0427] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0428] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps (i.e., these terms also cover the terms “consistently made up of” and “comprises of”).

[0429] As used herein, the term "alkyl" refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon, which can be considered as a group obtained by losing one hydrogen atom from an alkane. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight-chain or branched group with 1 to 6 carbon atoms, including "C". 2-6 Alkyl", C 2-5 "alkyl" and "C" 1-4 Alkyl group. "C" 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. The term "C" 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0430] As used herein, the term "alkenyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms ("C"). 2-10 "alkenyl", "C" 2-6 "Alkenyl", for example "C 2-4 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side) form, pure Z (iso-side) form, or any mixture thereof.

[0431] As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms ("C"). 2-10 "Alkyne", "C" 2-6 "Alkyne group", for example "C 2-4 The alkynyl group is, for example, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2-C≡C-CH3, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-2-butynyl, and 2-methyl-3-pentynyl.

[0432] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group is as defined above.

[0433] As used herein, the term "alkylthio" refers to -S-alkyl, wherein the alkyl group is as defined above.

[0434] As used herein, the term "alkylamino" refers to -NH-alkyl or -N-(alkyl)2, wherein the alkyl group is as defined above, for example, C 1-6 Alkylamino groups include -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2.

[0435] As used herein, the term "cycloalkyl group" refers to a saturated (i.e., "cycloalkyl") or partially unsaturated (i.e., having one or more (preferably one) double (i.e., "cycloalkenyl") and / or triple bonds within the ring, having, for example, 3 to 20 (suitably 12 to 20, 13 to 18, 3 to 10, 3 to 8, 3 to 8, 3 to 8, 3 to 8, 3 to 6) ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, etc. The cycloalkyl group includes spiro, bridged, or fused forms and combinations thereof. In some embodiments, the cycloalkyl group includes aryl-fused cycloalkyl groups, provided that the entire ring system is non-aromatic, for example... In some implementations, when the monocyclic hydrocarbon group is partially unsaturated, there is one and only one intracyclic double bond, for example...

[0436] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems and combinations thereof (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.). The cycloalkyl group has 3-20 carbon atoms, suitably 12-20, 13-18, 3-12, 3-10, 3-8, 3-7, 3-6, 4-6 or 5-6 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring with 3 to 6 cyclic carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0437] As used herein, the term "heterocyclic group" or "heterocycle" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) cyclic structure that is saturated (i.e., "heterocyclic alkyl") or partially unsaturated (e.g., having one or more (preferably one) double bonds (i.e., "heterocyclic alkenyl") within the ring, having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms and one or more (e.g., one, two, three, or four) heteroatoms selected from nitrogen, oxygen, and sulfur (preferably nitrogen and oxygen). The heterocycle may be attached to the remainder of the molecule by any of the carbon atoms or a nitrogen atom (if present). Specifically, a 3-20 membered heterocycle is a group having 3-20 (e.g., 12-20, 13-18, 3-10, 3-8, 3-7, 3-6, 4-11, 4-9, 4-7, 4-6, 5-12, 5-6, 6-10, 6-9, 6-8, 7-11 or 8-12) carbon atoms and heteroatoms in the ring. Examples that can be listed include, but are not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazine, trithianyl, azetidinyl, dihydropyrrolyl, dihydroimidazolyl, and azetidinyl octenyl. The heterocyclic group includes spiro, bridged, or fused forms and combinations thereof. The heterocyclic group includes heteroaryl fused heterocyclic groups or cyclic hydrocarbon groups, as well as aryl fused heterocyclic groups, provided that the entire ring system is non-aromatic, for example... In some embodiments, when the monocyclic heterocyclic group is partially unsaturated, it has one and only one intracyclic double bond, for example...

[0438] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6-10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0439] As used herein, the term "heteroaryl" or "heteroary ring" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 20 ring atoms, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups can be benzofused. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thiophene, oxazolyl, furanyl, pyrroloyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazole, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzoisothiazolyl, imidazole-pyridyl, quinolinyl, indolyl, pyrrolopyridazinyl, and benzofuran. The following are listed: benzothiophene, indazole, benzoxazolyl, benzoisoxazolyl, quinazolinyl, pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridyl, triazolopyridyl, isoquinolinyl, benzimidazolyl, cyclolinyl, indoleyl, phthalazinyl, isoindolyl, pteridinyl, purineyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthidyl, or furanolopyridyl.

[0440] If a group is described as “optionally substituted” or “optionally substituted”, then the group may be: (1) unsubstituted or (2) substituted. If the carbon of the group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0441] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0442] As used herein, the term “one or more” means one or more under reasonable conditions, such as two, three, four, five, six or ten.

[0443] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0444] When a substituent is bonded as a traversing bond connecting two atoms in a ring (“floating bond”), such a substituent may be bonded to any cyclic atom in the substituted ring, unless otherwise stated. In cases where a substituted hydrogen atom is present in a ring member, when the floating bond is bonded to that ring member, the substituted hydrogen atom is substantially substituted (i.e., not present). Specifically, in the presence of a polycyclic system, the group referred to by the floating bond may only substitute for any substituted site in the ring system through which the floating bond passes, for example… This indicates that R can only substitute any substituted site in the Cy1 ring, while This means that R can replace any substituted site in the rings Cy1 and Cy2.

[0445] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and hindered isomers, etc.

[0446] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0447] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0448] The terms “racemate,” “racemic mixture,” or “racemic mixture” refer to an equimolar mixture of two enantiomers that lack optical activity.

[0449] As used herein, the terms "cis-trans isomers" or "geometric isomers" arise from the fact that double bonds (including double bonds in alkenes, C=N double bonds, and N=N double bonds) or single bonds of cyclic carbon atoms cannot rotate freely. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers, and their corresponding mixtures.

[0450] As used herein, the term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms of the same number but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in compounds of the present invention include, but are not limited to, hydrogen isotopes such as... 2 H, 3 H; carbon isotopes, for example 11 C, 13 C and 14 C; Chlorine isotopes, for example 36 Cl; fluorine isotopes, for example 18 F; Iodine isotopes, for example 123 I and 125 I; nitrogen isotopes, for example 13 N and 15 N; oxygen isotopes, for example 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0451] The term "nitrogen oxide" or "N-oxide" refers to the oxidation of one or more nitrogen atoms to form N-oxides when a compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th ed., Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0452] The term "metabolite" or "metabolite" refers to the product obtained in vivo through the metabolic processes of a specific compound or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0453] The term "ester" refers to esters that can undergo hydrolysis in vivo, including those that readily decompose within the human body and separate from the parent compound. The hydroxyl-containing compounds of the present invention can form esters with organic or inorganic acids, or the carboxyl-containing compounds of the present invention can form esters with alcohols such as methanol, ethanol, or propanol.

[0454] The term "prodrug" as used in this invention refers to the conversion of a compound into a compound represented by Formula I in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C14) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent hydroxyl group. A complete discussion of prodrugs can be found in the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270; and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0455] The term "crystal form" refers to the different crystal structures formed when a compound undergoes crystallization due to various factors that alter the intramolecular or intermolecular bonding patterns, resulting in different arrangements of molecules or atoms in the crystal lattice. The phenomenon where the same substance exhibits two or more spatial arrangements and unit cell parameters, forming multiple crystal forms, is called polymorphism.

[0456] The term "hydrate" refers to an associative compound formed by one or more water molecules with the compound of the present invention.

[0457] The term "solvent" or "solvent compound" refers to a compound formed by one or more solvent molecules with the compound of the present invention.

[0458] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: salts formed by addition to inorganic or organic acids, salts containing acidic protons present on the parent compound but surrounded by metal ions, or salts forming coordination compounds with organic bases.

[0459] As used in this invention, carbon atoms marked with an asterisk (*) in a compound structural formula represent chiral centers and indicate that the compound is a specific stereoisomer. In stereochemical reaction formulas, two identically drawn compounds containing chiral centers marked with an asterisk (*) essentially represent two different stereoisomers of that structure. For example... Although compounds GS-14A and GS-14 are structurally identical, they are actually different stereoisomers of the structure shown in GS-13.

[0460] Solid lines may be used in this article. solid wedge virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.). Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the stereoisomers shown. Attached Figure Description

[0461] Figure 1: Blood glucose concentrations in mice before and after drug administration and area under the glucose tolerance curve from 0 to 120 min in the drug administration group. Detailed Implementation

[0462] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the invention in any way.

[0463] The control compound 1 is LY3502970, which was prepared according to patent CN109790161B; the structure of control compound 1 (LY3502970) is as follows:

[0464] The structure of the control compound 2 is as follows:

[0465] Synthesis route:

[0466] Step 1: Synthesis of compound X-2

[0467] Compound K (471 mg, 1.07 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (126 mg, 0.89 mmol), potassium carbonate (307 mg, 2.23 mmol), and cuprous iodide (85 mg, 0.045 mmol) were added to 10 mL of NMP solution (250 mg, 0.89 mmol) of compound X-1. The mixture was heated to 130 °C and stirred for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound X-2. MS m / z (ESI): 643.3 [M+H] + .

[0468] Step 2: Synthesis of compound X-3

[0469] Sodium hydride (25 mg, 0.62 mmol) was added to a DMF (5 mL) solution of compound X-2 (200 mg, 0.31 mmol) under ice bath conditions. The mixture was stirred at room temperature for 30 min, followed by the addition of iodomethane (88 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound X-3. MS m / z (ESI): 657.4 [M+H] + .

[0470] Step 3: Synthesis of compound X-4

[0471] A solution of dioxane (4.0 M, 0.5 mL) was added to a dichloromethane (5 mL) solution of compound X-3 (150 mg, 0.23 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was washed three times with dichloromethane and dried to give compound X-4. MS m / z (ESI): 557.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.65(d,J=8.0Hz,1H),7.37(d,J=3.2Hz,1H),7.34–7.27(m,2H),7 .14(d,J=6.2Hz,2H),6.94(d,J=3.3Hz,1H),4.58(d,J=7.2Hz,1H),4.05(dt,J=11.6,5.6H z,2H),3.83(dt,J=11.2,5.1Hz,2H),3.62(d,J=11.2Hz,1H),3.11(s,3H),3.08–2.95(m,2 H), 2.21 (d, J = 2.2Hz, 6H), 1.73 (t, J = 5.4Hz, 3H), 1.38 (d, J = 6.4Hz, 3H), 1.31–1.20 (m, 2H).

[0472] Step 4: Synthesis of control compound 2

[0473] To a 0.6 mL solution of compound GS (30.00 mg, 0.07 mmol) in N,N-dimethylformamide, N,N-diisopropylethylamine (75 mg, 0.56 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (83 mg, 0.21 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then compound X-4 (61 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 11.57 min) to obtain control compound 2. MS m / z (ESI): 950.4 [M+H] + . 1HNMR(400MHz,CD3OD)δ7.62–7.37(m,3H),7.31–7.24(m,2H),7.14(dd,J=11.6,4 .8Hz,2H),7.07(s,1H),6.99–6.54(m,3H),5.57(m,1H),4.50–3.57(m,8H),3.23– 2.94(m,6H),2.27–2.22(m,6H),1.80(d,J=28.8Hz,8H),1.66–1.57(m,3H),1.52( d,J=6.8Hz,3H),1.36–1.24(m,6H),1.20(d,J=5.2Hz,2H),1.06(d,J=5.6Hz,1H).

[0474] The structure of the control compound 3 is as follows:

[0475] The control compound 3 was synthesized by a similar method to that used for compound 1 in Example 4.

[0476] Control compound 3: MS m / z (ESI): 909.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.12–7.39(m,4H),7.32–7.18(m,2H),7.14(m,1H),7.08(d,J=6.0Hz,1H),6.88(d,J=7.2Hz,1H),6.78–6.53(m,2H),5 .65(m,1H),4.23–3.70(m,7H),3.06(m,1H),2.31–2.22(m,6H),1.86– 1.44(m,12H),1.29(d,J=42.0Hz,6H),1.21(m,1H),1.15–0.72(m,4H).

[0477] Example 1: Preparation of compound GS

[0478] Synthesis route:

[0479] Step 1: Preparation of compounds GS-2 and GS-2A

[0480] Under nitrogen protection and at -78°C, lithium bis(trimethylsilyl)amino (1.0 M, 937 mL, 937 mmol) was added dropwise to a tetrahydrofuran (1000 mL) solution of compound GS-1 (100 g, 780 mmol). After the addition was complete, the mixture was stirred at -78°C for 1 hour. Then, N-phenylbis(trifluoromethanesulfonyl)imide (306 g, 858 mmol) was added to the above reaction solution, and the temperature was raised to 25°C and the reaction was carried out for 18 hours. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (1000 mL), and extracted with ethyl acetate (1000 mL × 2). The organic phase was washed with saturated brine (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give a mixture of compounds GS-2 and GS-2A. 1 H NMR (400MHz, CDCl3) δ5.79–5.62(m,1H), 4.24–3.80(m,2H), 2.36–2.22(m,2H), 1.26–1.22(m,6H).

[0481] Step 2: Synthesis of compounds GS-3 and GS-3A

[0482] Under nitrogen protection, a mixture of compounds GS-2 and GS-2A (60.0 g, 231 mmol), potassium acetate (45.4 g, 461 mmol), and pinacol diboron ester (64.5 g, 254 mmol) in 1,4-dioxane (100 mL) was added to palladium dichloride [1,1'-bis(diphenylphosphine)ferrocene] (16.9 g, 23.1 mmol). After purging with nitrogen three times, the reaction mixture was heated to 90°C and stirred for 10 hours. The reaction mixture was diluted in water (1000 mL) and extracted with ethyl acetate (1000 mL × 2). The organic phase was washed with saturated brine (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give a mixture of compounds GS-3 and GS-3A. 1 H NMR (400MHz, CDCl3) δ6.47–6.31(m,1H),4.14–4.12(m,1H),3.68(t,J=5.4Hz,1H),2.08–2.01(m,2H),1.20(s,12H),1.18(s,3H),1.13(s,3H).

[0483] Step 3: Synthesis of compounds GS-5 and GS-5A:

[0484] Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (12.9 g, 17.5 mmol) was added to a mixed solvent of a mixture of compounds GS-3 and GS-3A (50.0 g, 210 mmol), potassium carbonate (48.4 g, 350 mmol), and 1,4-dioxane (500 mL) and water (100 mL). After purging with nitrogen three times, the reaction solution was heated to 100°C and stirred for 10 hours. The reaction solution was diluted in water (1000 mL) and extracted with ethyl acetate (1000 mL x 2). The organic phase was washed with saturated brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give a mixture of compounds GS-5 and GS-5A. MS m / z(ESI): 300.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.83(s,1H),7.62–7.54(m,1H),7.37–7.29(m,2H),7.13(d,J=2.0Hz,1H),6.05–5.89(m ,1H),4.37–4.28(m,3H),3.90(t,J=5.2Hz,1H),2.45–2.37(m,2H),1.35(t,J=7.2Hz,3H),1.26–1.29(m,6H).

[0485] Step 4: Synthesis of compound GS-6

[0486] A mixture of compounds GS-5 and GS-5A (40.0 g, 133.6 mmol) was added to a solution of methanol (150 mL) and N,N-dimethylformamide (150 mL), followed by the addition of 10% palladium on carbon (4.0 g). Hydrogen gas was then purged three times, and the reaction mixture was stirred at 25°C for 10 hours. After diatomaceous earth filtration, the filter cake was washed three times with ethyl acetate, diluted with water (500 mL), and extracted with ethyl acetate (500 mL × 2). The organic phase was washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound GS-6. MS m / z (ESI): 302.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.75(s,1H),7.47(s,1H),7.38(d,J=8.4Hz,1H),7.18(dd,J=8.4,1.6Hz,1H),7.08(dd,J=2.4,0.8Hz,1H),4.33(q,J=7. 2Hz,2H),3.70(dd,J=8.8,2.0Hz,2H),2.99–2.94(m,1H),1.72–1.64(m, 2H), 1.60–1.46 (m, 2H), 1.34 (t, J = 7.2Hz, 3H), 1.26 (s, 3H), 1.18 (s, 3H).

[0487] Step 5: Synthesis of compound GS-7

[0488] Sodium hydroxide (13.5 g, 338.4 mmol) was added to a methanol (250 mL) and water (50 mL) solution of compound GS-6 (34.0 g, 112.8 mmol) at 25°C. The reaction solution was stirred at 25°C for 1 hour. The reaction solution was then heated to 50°C and reacted for 2 hours. The pH of the reaction solution was adjusted to approximately 3 with 2M dilute hydrochloric acid. A solid precipitated, was filtered, and the filter cake was washed three times with water and concentrated under reduced pressure to obtain compound GS-7. MS m / z (ESI): 274.2 [M+H] + .

[0489] Step 6: Synthesis of compound GS-8

[0490] To a solution of compound GS-7 (26.0 g, 95.1 mmol) and N-methylaniline (12.2 g, 114 mmol) in N,N-dimethylacetamide (200 mL), N-methylimidazole (15.6 g, 190 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (32.0 g, 114 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, a solid precipitated, which was filtered. The filter cake was washed three times with water and concentrated under reduced pressure to obtain compound GS-8. MS m / z (ESI): 363.2 [M+H] + .

[0491] Step 7: Synthesis of compound F

[0492] Bromoacetonitrile (6.6 g, 55.2 mmol) was added to a solution of compound GS-8 (10.0 g, 27.6 mmol) and potassium tert-butoxide (9.3 g, 82.8 mmol) in N,N-dimethylacetamide (150 mL). The mixture was purged with nitrogen three times under nitrogen protection, and stirred at 90 °C for 10 hours. After cooling to room temperature, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 2). The organic phase was washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound F. MS m / z (ESI): 402.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.56 (d, J = 8.4Hz, 1H), 7.37–7.33 (m, 4H), 7.28–7.20 (m, 3H), 5.95 (s, 1H), 5.62 (s, 2H), 3. 69–3.63(m,2H),3.43(s,3H),2.98–2.90(m,1H),1.65–1.57(m,2H),1.56–1.40(m,2H),1.22(s,3H),1.14(s,3H).

[0493] Step 8: Synthesis of compound GS-11

[0494] Under nitrogen protection and at -10°C, lithium bis(trimethylsilyl)amino (1.0 M, 109 mL, 109 mmol) was added dropwise to a solution of compound F (7.3 g, 18.2 mmol) and compound GS-10 (7.53 g, 55.5 mmol) in N,N-dimethylpropenylurea (120 mL). After the addition was complete, the mixture was stirred at -10°C for 1 hour, then heated to 25°C and stirred for 18 hours. The reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (500 mL), and extracted with ethyl acetate (500 mL × 2). The organic phase was washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound GS-11. MS m / z (ESI): 442.2 [M + H] + .

[0495] Step 9: Synthesis of compound GS-12

[0496] Sodium bicarbonate (4.7 g, 56.5 mmol) was added to a dimethyl sulfoxide (DMSO) solution of compound GS-11 (5.0 g, 11.3 mmol) and hydroxylamine hydrochloride (1.6 g, 22.6 mmol) in 50 mL of dimethyl sulfoxide. The mixture was purged with nitrogen three times under nitrogen protection, and stirred at 60 °C for 10 hours. After cooling to room temperature, the mixture was diluted with 100 mL of water and extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound GS-12, which was used directly in the next reaction. MS m / z (ESI): 475.2 [M+H] + .

[0497] Step 10: Synthesis of compound GS-13

[0498] At 25°C, N,N'-carbonyldiimidazole (2.6 g, 15.8 mmol) was added to a solution of compound GS-12 (5.0 g, 10.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.8 g, 31.6 mmol) in dimethyl sulfoxide (50 mL). The mixture was purged with nitrogen three times under nitrogen protection, and stirred at 25°C for 3 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound GS-13. MS m / z (ESI): 501.2 [M+H] + .

[0499] Step 11: Synthesis of compound GS-14

[0500] Compound GS-13 (2.7 g, 5.39 mmol) was separated by SFC (Separation column: ChiralPakAD 250×30 mm ID, 5 μm; Mobile phase: A for CO2 and B for Methanol (0.1% DEA); Flow rate: 100 mL / min; Column temperature: 35 °C; ABPR: 100 psi). The first peak was compound GS-14A (retention time: 2.458 min), and the second peak was compound GS-14 (retention time: 2.724 min). Compound GS-14: 1HNMR(400MHz,DMSO-d6)δ12.21–11.69(m,1H),7.47–7.10(m,8H),6.00–5.89(m,1H),3.67–3.65(m,1H) ,3.45–3.38(m,1H),2.96–2.89(m,1H),2.04–2.00(s,1H),1.82–1.25(m,9H),1.22(s,3H),1.14(s,3H).

[0501] Chiral HPLC analysis revealed that compound GS-14 has the same retention time as compound 31j synthesized from compound 31c using the same synthetic method as in patent CN109790161A. Therefore, it can be determined that compound GS-14 has the same configuration as compound 31j in patent CN109790161A, i.e., the carbon atom marked with "*" in GS-14 has the S configuration.

[0502] Step 12: Synthesis of compound GS

[0503] Potassium hydroxide (1.35 g, 24.0 mmol) was added to a 12 mL solution of compound GS-14 (1.2 g, 2.4 mmol) in ethylene glycol monomethyl ether. The reaction mixture was stirred at 120 °C for 12 hours. After cooling to room temperature, the mixture was diluted with ice water, and the pH was adjusted to approximately 3 by adding 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was slurried with methyl tert-butyl ether, filtered, and the filter cake was concentrated and dried to obtain compound GS. MS m / z (ESI): 412.2 [M + H] + .

[0504] Example 2: Preparation of compound K

[0505] The structural formula of compound K is as follows:

[0506] Synthesis route:

[0507] Step 1: Synthesis of compound D-2

[0508] Under nitrogen protection at -78°C, n-butyllithium (197 mL, 492.5 mmol, 2.5 M) was slowly added dropwise to a tetrahydrofuran (1000 mL) solution of compound D-1 (100 g, 492.5 mmol). The reaction mixture was stirred at -78°C for 1 hour, followed by the addition of di-tert-butyl azide dicarboxylate (113.5 g, 492.5 mmol). The mixture was then heated to room temperature and stirred for 18 hours. The reaction solution was quenched with saturated ammonium chloride (300 mL) and extracted with ethyl acetate (1000 mL × 2). The organic phase was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound D-2. MS m / z (ESI): 377.0 [M + Na] + . 1 H NMR (400MHz, DMSO-d6) δ9.60 (s, 1H), 7.00 (t, J = 6.8Hz, 2H), 2.19 (d, J = 2.4Hz, 6H), 1.42 (d, J = 6.0Hz, 18H).

[0509] Step 2: Synthesis of compound D-4

[0510] Trifluoroacetic acid (250 mL) was added to a solution of compound D-2 (50.0 g, 141.24 mmol) in dichloromethane (500 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and evaporated to dryness. An ethanol solution (500 mL) containing pyridine hydrochloride (1.65 g, 14.12 mmol) and compound D-3 (33.6 g, 141.24 mmol) was added. The reaction mixture was heated to 85°C and stirred for 2 hours. The reaction solution was quenched with water (200 mL) and extracted with ethyl acetate (500 mL × 2). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound D-4. MS m / z (ESI): 375.2 [M+H] + .

[0511] Step 3: Synthesis of compound D-5

[0512] N,N-diisopropylethylamine (5.92 g, 45.80 mmol) and p-nitrophenyl chloroformate (16.0 g, 79.38 mmol) were added to a solution of aminoacetaldehyde dimethyl acetal (12.0 g, 114 mmol) in tetrahydrofuran (160 mL). The reaction mixture was stirred at 40 °C for 6 hours under nitrogen protection. The reaction solution was concentrated to dryness under reduced pressure, and a solution of compound D-4 (5.0 g, 13.35 mmol) in pyridine (50 mL) was added. The reaction solution was stirred at 40 °C for 48 hours. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (200 mL × 2). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound D-5. MS m / z (ESI): 506.2 [M+H] + .

[0513] Step 4: Synthesis of compound K

[0514] Methylsulfonic acid (761 mg, 7.92 mmol) was added to a tetrahydrofuran (50 mL) solution of compound D-5 (5.0 g, 9.90 mmol), and the reaction mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, a saturated potassium phosphate solution was added to adjust the pH of the reaction mixture to approximately 9. Then, di-tert-butyl dicarbonate (864 mg, 3.96 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound K. MS m / z (ESI): 442.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(d,J=2.4Hz,1H),7.07(d,J=6.4Hz,2H),6.57(dt,J=16.4,2.8Hz,2H),5.05( s,1H),3.30(d,J=2.8Hz,2H),2.75–2.56(m,2H),2.20(d,J=2.0Hz,6H),1.43(s,9H),1.13(d,J=6.4Hz,3H).

[0515] Example 3: Preparation of compound L

[0516] The structural formula of compound L is as follows:

[0517] Synthesis route:

[0518] Step 1: Synthesis of compound L-2

[0519] Under nitrogen protection at 0°C, sodium acetate (1.37 g, 16.67 mmol) and sodium triacetoxyborohydride (5.30 g, 25.01 mmol) were added sequentially to a solution of compound L-1 (2.00 g, 16.67 mmol) and methyl 1-formylcyclopropanecarboxylate (2.13 g, 16.67 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound L-2. MS m / z (ESI): 197.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ3.66 (s, 3H), 3.07–2.97 (m, 1H), 2.80 (d, J = 12.0Hz, 1H), 2.65 (d, J = 12.0Hz, 1H), 2. 43(d,J=5.6Hz,2H),1.71(s,1H),1.27(dd,J=5.6,3.6Hz,2H),1.23(d,J=6.4Hz,3H),0.87–0.78(m,2H).

[0520] Step 2: Synthesis of compound L-3

[0521] Di-tert-butyl dicarbonate (5.14 g, 23.60 mmol) was added to a 20 mL ethanol solution of compound L-2 (1.85 g, 9.44 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound L-3. MS m / z (ESI): 197.1 [M-Boc+H] + . 1 H NMR (400MHz, CDCl3) δ4.05(dd,J=14.4,7.2Hz,1H),3.60(s,3H),3.58(d,J=2.0Hz,2H),2.88(d,J=78.0Hz,1H) ,2.52(dd,J=16.8,6.8Hz,1H),1.40(s,9H),1.29(d,J=6.8Hz,3H),1.22(dd,J=17.2,6.4Hz,2H),1.01(s,2H).

[0522] Step 3: Synthesis of compound L-4

[0523] Potassium tert-butoxide (0.95 g, 8.45 mmol) was added to a tetrahydrofuran (40 mL) solution of compound L-3 (2.50 g, 8.45 mmol) under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to 5 with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound L-4. MS m / z (ESI): 209.1 [M-56+H] + . 1 H NMR (400MHz, CDCl3) δ4.11–3.84(m,1H),3.79(d,J=14.4Hz,1H),3.57–3.42(m,2H),1.49(s,9H),1.47–1.42(m,5H),1.06–0.90(m,2H).

[0524] Step 4: Synthesis of compound L-5

[0525] Trifluoroacetic acid (8 mL) was added to a dichloromethane (20 mL) solution of compound D-2 (3.42 g, 9.66 mmol). The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. A solution of compound L-4 (1.70 g, 6.44 mmol) and pyridine hydrochloride (0.15 g, 1.29 mmol) in ethanol (20 mL) was added to the residue. The reaction mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the pH of the reaction mixture was adjusted to 8 with 10% sodium hydroxide solution. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound L-5. MS m / z (ESI): 401.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.03(d,J=6.0Hz,2H),5.25(d,J=14.4Hz,1H),3.50(s,2H),2.21(d ,J=2.0Hz,6H),1.42(s,9H),1.31(d,J=6.8Hz,3H),1.27–1.21(m,2H),0.83–0.77(m,2H).

[0526] Step 5: Synthesis of compound L-6

[0527] To a tetrahydrofuran solution (20 mL) of aminoacetaldehyde dimethyl acetal (1.89 g, 18.00 mmol), phenyl p-nitrochloroformate (2.71 g, 13.50 mmol) was added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. A pyridine solution (10 mL) containing compound L-5 (900 mg, 2.25 mmol) was added to the residue. The reaction mixture was stirred at 80°C for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The extract was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound L-6. MS m / z (ESI): 532.3 [M+H] + .

[0528] Step 4: Synthesis of compound L

[0529] Methylsulfonic acid (107 mg, 1.11 mmol) was added to a tetrahydrofuran solution (10 mL) of compound L-6 (740 mg, 1.39 mmol). The reaction mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, the mixture was diluted with water (3 mL) and extracted with ethyl acetate (10 mL × 3). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound L. MS m / z (ESI): 468.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.59 (s, 1H), 7.00 (d, J = 6.4Hz, 2H), 6.33 (s, 1H), 6.16 (s, 1H), 5.34 (s, 1H), 3.51(s,2H),2.20(d,J=2.0Hz,6H),1.48(s,9H),1.30(s,3H),1.24(s,2H),0.88(t,J=6.8Hz,2H).

[0530] Example 4: Preparation of Compound 1

[0531] Synthesis route:

[0532] Step 1: Synthesis of Compounds 1-2

[0533] Compound 1-1 (65.0 g, 288 mmol) was dissolved in N,N-dimethylacetamide (1500 mL). Sodium hydride (28.75 g, 719 mmol, 60%) was slowly added under ice bath conditions. After stirring for 30 minutes, 2,2'-dibromodiethyl ether (80.0 g, 345 mmol) was slowly added. Stirring continued under ice bath conditions for 2.5 hours. The reaction mixture was poured into ice water (1000 mL) and extracted with ethyl acetate (1000 mL × 3). The combined organic phases were washed with saturated brine (6000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 1-2. MS m / z (ESI): 296.0, 298.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.51(d,J=8.0Hz,1H),7.29(d,J=1.6Hz,1H),7.23(dd,J=8.0,1.6Hz,1H), 4.06(ddd,J=11.6,6.8,4.8Hz,2H), 3.81(dt,J=11.6,4.8Hz,2H), 3.14(s,3H),1.80–1.65(m,4H).

[0534] Step 2: Synthesis of compounds 1-3

[0535] Compound L (507 mg, 1.71 mmol), potassium carbonate (709 mg, 5.13 mmol), cuprous iodide (65 mg, 0.34 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (122 mg, 0.86 mmol) were added to a solution of compounds 1-2 (506 mg, 1.71 mmol) in N-methylpyrrolidone (10 mL). The mixture was stirred at 130 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compounds 1-3. MS m / z (ESI): 683.4 [M+H] + .

[0536] Step 3: Synthesis of compounds 1-4

[0537] To compounds 1-3 (850 mg, 1.24 mmol), 1 mL of 4 M dioxane hydrochloride solution was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude compounds 1-4. The crude product was used directly in the next step. MS m / z (ESI): 583.2 [M+H] + .

[0538] Step 4: Synthesis of Compound 1

[0539] To an N,N-dimethylformamide solution (8 mL) of compound GS (600 mg, 1.46 mmol), N,N-diisopropylethylamine (283 mg, 2.19 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (665 mg, 1.75 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then compounds 1-4 (37 mg, 0.08 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7μm-30*150mm A:0.1% TFA / H2O B:ACN 20% A-80% B:Ret 1.554 min) and then lyophilized to obtain compound 1. MS m / z (ESI): 976.4 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.55–7.49(m,2H),7.40–7.24(m,3H),7.17–7.14(m,1H),7.09–7.06(m,2H),6. 98–6.95(m,1H),6.88–6.80(m,1H),6.60–6.54(m,1H),5.55–5.46(m,1H),4.25–4.16(m,3H),3.99–3. 77(m,6H),3.26–3.23(m,1H),3.11–3.02(m,3H),2.28–2.23(m,6H),1.89–1.84(m,2H),1.81–1.76(m ,5H),1.72–1.68(m,3H),1.66–1.56(m,4H),1.40–1.34(m,4H),1.29–1.24(m,4H),1.18–1.06(m,4H).

[0540] Example 5: Preparation of Compound 2

[0541] Synthesis route:

[0542] Step 1: Synthesis of Compound 2-2

[0543] At -78°C, a tetrahydrofuran solution (6 mL) of lithium diisopropylamino in tetrahydrofuran (2.7 mL, 2.7 mmol, 1.0 M) was added to a tetrahydrofuran solution of methyl tetrahydropyran-4-carboxylate (300 mg, 2.08 mmol). The reaction mixture was stirred at -78°C for 0.5 hours. Then, a tetrahydrofuran solution (2 mL) of compound 2-1 (821 mg, 2.50 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound 2-2. MS m / z (ESI): 393.0 [M + H] + .

[0544] Step 2: Synthesis of compounds 2-3

[0545] Sodium hydroxide (61 mg, 1.53 mmol) was added to a mixed solution of compound 2-2 (200 mg, 0.51 mmol) in methanol (2 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 3 with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 2-3. The crude product was used directly in the next step. MS m / z (ESI): 376.9 [MH] - .

[0546] Step 3: Synthesis of compounds 2-4

[0547] To a solution of compound 2-3 (190 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (195 mg, 1.51 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (287 mg, 0.75 mmol), and ammonium chloride (134 mg, 2.51 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound 2-4. MS m / z (ESI): 378.0 [M+H] + .

[0548] Step 4: Synthesis of compounds 2-5

[0549] To a solution of compounds 2-4 (74 mg, 0.20 mmol) in dimethyl sulfoxide (2 mL), cuprous iodide (3.7 mg, 0.02 mmol), cesium carbonate (64 mg, 0.20 mmol), and 1,10-phenanthroline (7.0 mg, 0.04 mmol) were added. The reaction mixture was stirred in a nitrogen atmosphere at 110 °C for 1 hour under microwave heating. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to give compounds 2-5. MS m / z (ESI): 296.0, 298.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.14–7.09(m,2H),7.01(d,J=1.6Hz,1H),3.85–3.80(m ,2H),3.76–3.70(m,2H),2.92(s,2H),1.95–1.89(m,2H),1.46–1.39(m,2H).

[0550] Step 5: Synthesis of compounds 2-6

[0551] Sodium hydride (7.0 mg, 0.17 mmol) was added to a solution of compound 2-5 (43 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) under ice bath conditions. The reaction mixture was stirred in an ice bath under nitrogen protection for 10 minutes. Then, iodomethane (31 mg, 0.22 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-6. MS m / z (ESI): 310.0, 312.0 [M+H] + .

[0552] Step 6: Synthesis of compounds 2-7

[0553] Compound L (126 mg, 0.41 mmol), potassium carbonate (168 mg, 1.22 mmol), cuprous iodide (15.5 mg, 0.8 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (29 mg, 0.20 mmol) were added to a solution of N-methylpyrrolidone (2 mL) containing compounds 2-6 (127 mg, 0.41 mmol). The mixture was stirred at 130 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compounds 2-7. MS m / z (ESI): 697.4 [M+H] + .

[0554] Step 7: Synthesis of compounds 2-8

[0555] To compounds 2-7 (160 mg, 0.23 mmol), 2 mL of 4 M dioxane hydrochloride solution was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude compounds 2-8. The crude product was used directly in the next step. MS m / z (ESI): 597.3 [M+H] + .

[0556] Step 4: Synthesis of Compound 2

[0557] To a 1 mL solution of compound GS (65 mg, 0.16 mmol) in N,N-dimethylformamide, N,N-diisopropylethylamine (30 mg, 0.24 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (73 mg, 0.19 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then compound 2-8 (95 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated.

[0558] The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7μm-30*150mm A:0.1% TFA / H2O B:ACN 20% A-80% B:Ret 1.362 min) to obtain compound 2. MS m / z (ESI): 990.4 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.56–7.49(m,2H),7.40–7.28(m,2H),7.24–7.09(m,3H),7.08–7.05(m,1H),6.98–6.96(m,0.5H),6 .91–6.80(m,2H),6.56–6.54(m,0.5H),5.57–5.46(m,1H),4.27–4.11(m,1H),3.97–3.87(m,2H),3.86–3.76(m,4H),3.75– 3.69(m,2H),3.44–3.39(m,1H),3.17–3.11(m,1H),3.09(s,2H),2.93(s,1H),2.29–2.21(m,7H),1.94–1.85(m,2H),1.82– 1.76(m,4H),1.70–1.67(m,2H),1.66–1.55(m,4H),1.48–1.42(m,2H),1.39(s,6H),1.30–1.26(m,4H),1.14–1.12(m,2H).

[0559] Example 6: Preparation of Compound 3

[0560] Synthesis route:

[0561] Step 1: Synthesis of compound 3-2

[0562] Under ice bath conditions, concentrated sulfuric acid (1 mL, 18.66 mmol) was added dropwise to a 70 mL ethanol solution of compound 3-1 (7.00 g, 25.18 mmol). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was quenched dropwise in ice water (10 mL), the pH was adjusted to neutral with sodium carbonate aqueous solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give compound 3-2. MS m / z (ESI): 306.0, 308.0 [M+H] + .

[0563] Step 2: Synthesis of compound 3-3

[0564] Under ice bath conditions, 4,4'-bipyridine (30.6 mg, 0.20 mmol) was added to a solution of compound 3-2 (600.0 mg, 1.96 mmol) in N,N-dimethylformamide (10 mL). After stirring the mixture for 2 minutes, tetrahydroxydiboron (527.2 mg, 5.88 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give crude compound 3-3. The crude product was used directly in the next step. MS m / z (ESI): 276.0, 278.0 [M+H] + .

[0565] Step 3: Synthesis of compounds 3-4

[0566] Compound 3-3 (5.00 g, 18.1 mmol) was dissolved in glacial acetic acid (25 mL) and stirred at 100 °C for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 3-4. MS m / z (ESI): 229.9, 231.9 [M+H] + .

[0567] Step 4: Synthesis of compounds 3-5

[0568] Under ice bath conditions, sodium hydroxide (290.0 mg, 7.17 mmol) was added to a solution of compounds 3-4 (400.0 mg, 1.74 mmol) in tetrahydrofuran (5 mL) and water (5 mL). After stirring at room temperature for 30 minutes, dimethyl sulfate (218.0 mg, 1.74 mmol) was added dropwise. The reaction mixture was heated to 60°C and stirred for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compounds 3-5. MS m / z (ESI): 244.0, 246.0 [M+H] + .

[0569] Step 5: Synthesis of compounds 3-6

[0570] Under ice bath conditions, cesium carbonate (1.07 g, 3.28 mmol) was added to a solution of compounds 3-5 (200.0 mg, 0.82 mmol) in N,N-dimethylacetamide (2 mL). After stirring for 10 minutes, a solution of 1-iodo-2-(2-iodoethoxy)ethane (320.5 mg, 0.98 mmol) in N,N-dimethylacetamide (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compounds 3-6. MS m / z (ESI): 314.0, 316.0 [M+H] + .

[0571] Step 6: Synthesis of compounds 3-7

[0572] Compounds 3-6 (80.0 mg, 0.25 mmol), potassium carbonate (70.4 mg, 0.51 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (18.1 mg, 0.13 mmol), and cuprous iodide (9.7 mg, 0.05 mmol) were added to a solution of compound L (112.4 mg, 0.25 mmol) in N-methylpyrrolidone (2 mL). The reaction mixture was stirred at 130 °C for 3 hours. Water (4 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compounds 3-7. MS m / z (ESI): 701.4 [M+H] + .

[0573] Step 7: Synthesis of compounds 3-8

[0574] To a solution of compounds 3-7 (150.0 mg, 0.22 mmol) in dichloromethane (3 mL), 1 mL of 4 M dioxane hydrochloride solution was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude compounds 3-8. The crude product was used directly in the next step. MS m / z (ESI): 601.3 [M+H] + .

[0575] Step 8: Synthesis of Compound 3

[0576] To a 0.5 mL solution of compound GS (21.5 mg, 0.05 mmol) in N,N-dimethylformamide, N,N-diisopropylethylamine (13.5 mg, 0.10 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (23.8 mg, 0.05 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then compound 3-8 (30.0 mg, 0.05 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative HPLC (Gilson_GX281; Cloumn: YMC-Triart-C18-10um-30*250mm; Mobile phase: A: 0.1% TFA / H2O, B: ACN; Gradient: 90%-100% in 12.9 min; Flow rate: 30 ml / min; UV wavelength: 220 nm) to obtain compound 3. MS m / z (ESI): 994.4 [M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.17–11.66(m,1H),7.60–7.23(m,6H),7.13–7.01(m,3H),6.88–6.72(m,1H),4.13–4.05(m,2H),3.80–3.63(m,9H),3. 15(s,2H),3.06–2.77(m,3H),2.23–2.14(m,6H),2.13–1.95(m,3H),1.7 3–1.58(m,6H),1.56–1.34(m,6H),1.28–1.24(m,3H),1.20–1.07(m,6H).

[0577] Example 7: Preparation of Compound 4

[0578] Synthesis route:

[0579] Step 1: Synthesis of Compound 4-1

[0580] Under nitrogen protection at 0°C, sodium hydride (26.5 mg, 1.11 mmol) was added to a solution of compound 1-1 (100.0 mg, 0.44 mmol) in N,N-dimethylformamide (1 mL). After completion, stirring was continued for 1 hour, followed by the addition of a solution of N,N-bis(2-chloroethyl)carbamate tert-butyl (128.5 mg, 0.53 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 60°C for 2 hours. The reaction solution was cooled to 0°C, quenched with saturated ammonium chloride (10 mL), diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with water (10 mL), washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 25%) to give compound 4-1. MS m / z (ESI): 339.0, 341.0 [M+H-56] + . 1 H NMR (400MHz, CDCl3) δ7.13(dd,J=8.0,1.6Hz,1H),7.06(d,J=8.0Hz,1H),6.93(d,J=1.6Hz ,1H),3.82–3.63(m,4H),3.11(s,3H),1.77–1.72(m,2H),1.68–1.63(m,2H),1.40(s,9H).

[0581] Step 2: Synthesis of compound 4-2

[0582] At room temperature, a solution of dioxane hydrochloride (0.25 mL, 1.00 mmol) was added to a solution of compound 4-1 (80 mg, 0.20 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction solution was directly concentrated to give crude compound 4-2, which was used directly in the next step. MS m / z (ESI): 295.0, 297.0 [M+H] + .

[0583] Step 3: Synthesis of compound 4-3

[0584] To a solution of compound 4-2 (200 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL), triethylamine (0.48 mL, 3.39 mmol) and methanesulfonyl chloride (116 mg, 1.02 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 4-3. MS m / z (ESI): 373.0, 375.0 [M+H]+ .

[0585] Step 4: Synthesis of compound 4-4

[0586] Potassium carbonate (69 mg, 0.50 mmol), cuprous iodide (24 mg, 0.125 mmol), and trans-(1S,2S)-N,N-dimethylcyclohexanediamine (7 mg, 0.05 mmol) were added to a solution of compound L (117 mg, 0.25 mmol) and compound 4-3 (100 mg, 0.27 mmol) in N-methylpyrrolidone (3 mL). The reaction mixture was stirred at 130 °C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 4-4. MS m / z (ESI): 760.4 [M+H] + .

[0587] Step 5: Synthesis of compounds 4-5

[0588] A solution of compound 4-4 (30 mg, 0.04 mmol) in dioxane (3 mL, 4 M, 12 mmol) of hydrogen chloride was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude compound 4-5, which was used directly in the next step. MS m / z (ESI): 660.4 [M+H] + .

[0589] Step 6: Synthesis of Compound 4

[0590] At room temperature, triethylamine (20 mg, 0.20 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (23 mg, 0.06 mmol) were added to a solution of compounds 4-5 (25 mg, 0.04 mmol) and compound GS (20 mg, 0.048 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (YMC-Triart-C18-10 μm-30*250 mm; Mobile: phase A: 0.1% TFA / H2O; B: ACN; Gradient; 95% to 100%) to give compound 4. MS m / z (ESI): 1053.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.17–11.66(m,1H),7.73–7.51(m,2H),7.19(m,8H),6 .76–6.54(m,1H),4.23(t,J=6.4Hz,1H),3.71(m,2H),3.59–3.40(m,4H),3.19– 3.04(m,3H),2.99(s,3H),2.21(s,6H),1.95–1.82(m,4H),1.69–1.60(m,4H),1 .42–1.33(m,6H),1.26(d,J=14.0Hz,6H),1.20–1.09(m,6H),0.97–0.84(m,4H).

[0591] Example 8: Preparation of Compound 5

[0592] Synthesis route:

[0593] Step 1: Synthesis of Compound 5-2

[0594] At room temperature, potassium carbonate (1.26 g, 9.10 mmol) and compound 5-1 (1.0 g, 4.55 mmol) were added to a solution of 3-aminooxetane-3-carboxylic acid (0.64 g, 5.45 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, iodomethane (0.77 g, 5.45 mmol) was added under nitrogen protection, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and washed with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 5-2. MS m / z (ESI): 330.9, 332.9 [M+H] + .

[0595] Step 2: Synthesis of Compound 5-3

[0596] To a mixed solution of compound 5-2 (120 mg, 0.36 mmol) in methanol (2 mL), water (2 mL), and tetrahydrofuran (2 mL), ammonium chloride (194 mg, 3.62 mmol) and reduced iron powder (101 mg, 1.81 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 5-3. MS m / z (ESI): 268.9, 270.9 [M+H] + .

[0597] Step 3: Synthesis of Compounds 5-4

[0598] Under ice bath conditions, sodium hydride (42 mg, 60%, 1.06 mmol) was added to a solution of compound 5-3 (95 mg, 0.35 mmol) in N,N-dimethylformamide (3 mL), and the reaction mixture was stirred under ice bath conditions for 30 minutes. Iodomethane (250 mg, 1.77 mmol) was then added dropwise to the above solution under ice bath conditions, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 5-4. MS m / z (ESI): 297.0, 299.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.18–7.15(m,2H),6.83(d,J=9.2Hz,1H),5.05(d,J=7.2Hz,2H),4.86(d,J=7.2Hz,2H),3.83(s,3H),3.22(s,3H).

[0599] Step 4: Synthesis of compound 5-5

[0600] Cesium carbonate (230 mg, 0.71 mmol), cuprous iodide (9.0 mg, 0.05 mmol), and trans-(1S,2S)-N,N-dimethylcyclohexanediamine (13.4 mg, 0.09 mmol) were added to a solution of compound 5-4 (70 mg, 0.24 mmol) and compound L (110 mg, 0.24 mmol) in N-methylpyrrolidone (2 mL). The reaction mixture was stirred at 130 °C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 5-5. MS m / z (ESI): 684.4 [M+H] + .

[0601] Step 5: Synthesis of compounds 5-6

[0602] To a solution of compound 5-5 (92 mg, 0.13 mmol) in dichloromethane (2 mL), 0.2 mL of trifluoroacetic acid was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude compound 5-6, which was used directly in the next step. MS m / z (ESI): 584.2 [M+H] + .

[0603] Step 6: Synthesis of Compound 5

[0604] At room temperature, N,N-diisopropylethylamine (63 mg, 0.49 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (55 mg, 0.15 mmol) were added to a solution of compounds 5-6 (70 mg, 0.12 mmol) and compound GS (50 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H2O, B:CH3CN, Gradient: 50% B-70% B, Ret 12.58 min) to obtain compound 5. MS m / z (ESI): 977.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.34–11.58(m,1H),8.34–6.56(m,11H),5.64–5.33(m,1H),4.99–4.02(m,4H),3.77– 3.59(m,4H),3.22–3.11(m,5H),2.22–2.18(m,5H),1.77–1.48(m,8H),1.45–1.26(m,8H),1.25–0.77(m,10H).

[0605] Example 9: Preparation of Compound 6

[0606] Synthesis route:

[0607] Step 1: Synthesis of Compound 6-1

[0608] Under ice bath conditions, N-chlorosuccinimide (443 mg, 3.32 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (606 mg, 3.98 mmol) were added to a tetrahydrofuran (6 mL) solution of compound 1-1 (300 mg, 1.33 mmol). The reaction mixture was stirred under ice bath conditions for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude compound 6-1. The crude product was used directly in the next step. MS m / z (ESI): 312.9 [M + NH4] + .

[0609] Step 2: Synthesis of Compound 6-2

[0610] At room temperature, potassium carbonate (547 mg, 3.96 mmol) was added to an acetonitrile (8 mL) solution of compound 6-1 (390 mg, 1.32 mmol) and catechol (145 mg, 1.32 mmol). The reaction mixture was stirred at 80 °C for 3 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 6-2. MS m / z (ESI): 331.9, 333.9 [M+H] + .

[0611] Step 3: Synthesis of Compound 6-3

[0612] Potassium carbonate (25.0 mg, 0.18 mmol), cuprous iodide (3.4 mg, 0.2 mmol), and trans-(1S,2S)-N,N-dimethylcyclohexanediamine (6.4 mg, 0.05 mmol) were added to a solution of compound 6-2 (30 mg, 0.09 mmol) and compound L (42.3 mg, 0.09 mmol) in N-methylpyrrolidone (1 mL). The reaction mixture was stirred at 130 °C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 6-3. MS m / z (ESI): 719.4 [M+H] + .

[0613] Step 4: Synthesis of compound 6-4

[0614] A 3 mL solution of 4 M dioxane hydrochloride in compound 6-3 (30 mg, 0.04 mmol) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give crude compound 6-4. The crude product was used directly in the next step. MS m / z (ESI): 619.2 [M+H] + .

[0615] Step 5: Synthesis of Compound 6

[0616] At room temperature, N,N-diisopropylethylamine (10.5 mg, 0.08 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (23.1 mg, 0.06 mmol) were added to a solution of compound 6-4 (25 mg, 0.04 mmol) and compound GS (16.6 mg, 0.04 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Gilson_GX281; Cell: YMC-Triart-C18-10 μm-30*250 mm; Mobile phase: A: 0.1% TFA / H2O, B: ACN; Gradient: 90%-100% in 12.9 min; Flow rate: 30 mL / min; UV wavelength: 220 nm) to obtain compound 6. MS m / z (ESI): 1012.4 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.55–7.45(m,3H),7.30–7.14(m,4H),7.10–7.08(m,2H),6.97–6.96(m,3 H),6.93–6.87(m,1H),6.84–6.80(m,1H),6.67–6.57(m,1H),5.52–5.33(m,1H),4.25–4.12(m,1 H),3.98–3.72(m,1H),3.27–3.23(m,1H),3.02(s,3H),2.30–2.20(m,4H),2.08–2.02(m,1H),1 .79–1.75(m,3H),1.64–1.61(m,6H),1.42–1.23(m,13H),1.14–1.12(m,2H),0.91–0.80(m,2H).

[0617] Example 10: Preparation of Compound 7

[0618] Synthesis route:

[0619] Step 1: Synthesis of Compound 7-2

[0620] Potassium carbonate (80 mg, 0.58 mmol), cuprous iodide (41 mg, 0.22 mmol), and trans-(1S,2S)-N,N-dimethylcyclohexanediamine (12 mg, 0.086 mmol) were added to a solution of compound L (200 mg, 0.43 mmol) and compound 7-1 (81 mg, 0.29 mmol) in N-methylpyrrolidone (5 mL). The reaction mixture was stirred at 130 °C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 7-2. MS m / z (ESI): 669.2 [M+H] + .

[0621] Step 2: Synthesis of Compound 7-3

[0622] A solution of compound 7-2 (150 mg, 0.22 mmol) and cyclopropylboronic acid (56 mg, 0.66 mmol) in 1,2-dichloroethane (3 mL) was reacted with potassium carbonate (61 mg, 0.44 mmol), copper acetate (80 mg, 0.44 mmol), and pyridine (104 mg, 1.32 mmol). The mixture was purged three times with oxygen, and stirred at 50 °C for 18 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 7-3. MS m / z (ESI): 709.4 [M+H] + .

[0623] Step 3: Synthesis of Compound 7-4

[0624] A solution of 50 mg (0.07 mmol) of compound 7-3 in dichloromethane (1 mL) was added to a solution of dioxane (1 mL, 4 M) containing hydrogen chloride, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give crude compound 7-4. The crude compound was used directly in the next step. MS m / z (ESI): 609.4 [M+H] + .

[0625] Step 4: Synthesis of Compound 7

[0626] At room temperature, triethylamine (40 mg, 0.40 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (50 mg, 0.13 mmol) were added to a solution of compound 7-4 (40 mg, 0.066 mmol) and compound GS (35 mg, 0.08 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (YMC-Triart-C18-10 μm-30*250 mm; Mobile: phase A: 0.1% TFA / H2O; B: ACN; Gradient; 95% to 100%) to obtain compound 7. MS m / z (ESI): 1002.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.25–11.67(m,1H),7.64–7.05(m,10H),6.87–6. 70(m,1H),5.65–5.22(m,1H),4.05–4.01(m,2H),3.85–3.70(m,8H),3.64–3 .52(m,2H),3.11–2.98(m,1H),2.77–2.63(m,1H),2.23–2.19(m,6H),1.73– 1.57(m,6H),1.54–1.35(m,6H),1.27(d,J=14.8Hz,6H),1.20–0.83(m,9H).

[0627] Example 11: Preparation of Compound 8

[0628] Compound 8 was synthesized by a similar method to that used for compound 4 in Example 7 (using GS as a raw material).

[0629] Compound 8: MS m / z (ESI): 1014.6 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.64–7.56(m,1H),7.54(s,2H),7.40–7.31(m,3H),7.16(s,1H),7. 08–7.06(m,1H),6.99–6.94(m,1H),6.88–6.56(m,2H),5.58–5.29(m,1H),4.26–4.22(m, 1H),4.02–3.80(m,4H),3.27(s,2H),3.09–2.84(m,6H),2.26(d,J=12.8Hz,6H),2.10–1. 94(m,4H),1.86–1.68(m,6H),1.62–1.57(m,2H),1.48–1.24(m,12H),1.14–0.82(m,4H).

[0630] Example 12: Preparation of Compound 9

[0631] Compound 9 was synthesized by a method similar to steps 5 to 8 of Compound 2 in Example 5 (using GS as a raw material).

[0632] Compound 9: MS m / z (ESI): 977.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.83–9.55(m,1H),8.89–8.28(m,1H),7.80–6.98( m,7H),6.66–6.51(m,1H),5.82–5.36(m,1H),4.12–3.90(m,4H),3.74–3.6 4(m,2H),3.21–2.96(m,4H),2.23–1.98(m,8H),1.89–1.63(m,7H),1.58–1 .35(m,7H),1.25(d,J=13.6Hz,6H),1.19–1.09(m,5H),0.93–0.80(m,2H).

[0633] Example 13: Preparation of Compound 10

[0634] Compound 10 was synthesized by a similar method to that used for compound 7 in Example 10 (using GS as a raw material).

[0635] Compound 10: MS m / z (ESI): 1020.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.74–7.36(m,4H),7.27–7.20(m,2H),7.14–7.04(m,3H), 6.88–6.73(m,1H),5.96–5.14(m,1H),4.12–4.03(m,3H),3.76–3.69(m,4H),3.07 –2.98(m,1H),2.21(s,6H),2.08–1.99(m,3H),1.72–1.65(m,5H),1.58–1.47(m,5 H),1.36–1.31(m,4H),1.28(s,3H),1.24(s,3H),1.19(s,3H),0.99–0.80(m,7H).

[0636] Example 14: Preparation of Compound 11

[0637] Compound 11 was synthesized by a similar method to that used for Compound 1 in Example 4 (using GS as a raw material).

[0638] Compound 11: MS m / z (ESI): 960.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.43–11.62(m,1H),7.64–7.46(m,1H),7.41–7.01(m,8H),6.94–6.67(m,2H),5.92–5.28(m,1H),4.15–3.95 (m,1H),3.77–3.68(m,3H),3.23–2.97(m,4H),2.21(s,6H),1.97(s,6H),1.82–1.47(m,10H),1.36–1.08(m,13H),0.95–0.85(m,2H).

[0639] Example 15: Preparation of compound H

[0640] Compound H was synthesized using a method similar to that used for compound GS in Example 1.

[0641] Compound H: MS m / z (ESI): 384.2 [M+H] + .

[0642] Example 16: Preparation of Compound 12

[0643] Compound 12 was synthesized by a similar method to that used for compound 1 in Example 4 (using H as a starting material).

[0644] Compound 12: MS m / z (ESI): 948.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.30–11.65(m,1H),7.71–7.59(m,1H),7.55–6.99(m,9H),6.92–6.64(m,1H),5.95–5.21(m,1H),4.11–3.82(m,7 H),3.70–3.46(m,11H),3.19–3.01(m,3H),2.91–2.79(m,1H),2.27–2.16(m,6H),1.75–1.70(m,6H),1.47–1.32(m,5H),1.18–1.08(m,2H).

[0645] Example 17: Preparation of Compound 13

[0646] Synthesis route:

[0647] Step 1: Synthesis of Compound 13-2

[0648] Sodium bicarbonate (24.4 g, 291 mmol) was added to a solution of compound 13-1 (25.0 g, 145 mmol) and ethyl 3-bromopyruvate (42.5 g, 272 mmol) in acetonitrile (200 mL). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound 13-2. MS m / z (ESI): 267.9, 269.9 [M+H] + .

[0649] Step 2: Synthesis of Compound 13-3

[0650] To a mixed solution of compound 13-2 (2.0 g, 7.46 mmol) and 2-(3,6-dihydro-2,2-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.13 g, 8.95 mmol) in dioxane (30 mL) and water (3 mL), potassium carbonate (2.06 g, 14.92 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (0.55 g, 0.75 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 13-3. MS m / z(ESI): 300.1 [M+H] + .

[0651] Step 3: Synthesis of Compound 13-4

[0652] Palladium on carbon (10%) (750 mg) was added to a methanol (30 mL) solution of compound 13-3 (1.43 g, 4.78 mmol). The reaction mixture was stirred for 16 hours under hydrogen balloon protection at room temperature. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 13-4. MS m / z (ESI): 302.1 [M+H] + .

[0653] Step 4: Synthesis of Compounds 13-5

[0654] Under ice bath conditions, ferrous sulfate heptahydrate (0.99 g, 3.57 mmol), sodium iodide (1.07 g, 7.13 mmol), and hydrogen peroxide (5.35 g, 47.22 mmol) were added to a dimethyl sulfoxide (45 mL) solution of compound 13-4 (2.15 g, 7.13 mmol) and bromoacetonitrile (0.94 g, 7.85 mmol). The reaction mixture was stirred under nitrogen atmosphere in an ice bath for 20 minutes. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 13-5. MS m / z (ESI): 341.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.75-7.73(m,1H),7.15-7.14(m,1H),6.74(d,J=0.8Hz,1H),6.60-6.58(m,1H),4.47(s,2H),4.33-4.28(m ,2H),3.83-3.70(m,2H),2.85-2.77(m,1H),1.73-1.67(m,2H),1.52-1.49(m,2H),1.26(s,3H),1.22(s,3H),1.22-1.17(m,3H).

[0655] Step 5: Synthesis of Compounds 13-6

[0656] Under ice bath conditions, bis(trimethylsilylaminolithium) (3.54 g, 21.15 mmol) was added to a solution of compound 13-5 (800 mg, 2.35 mmol) and vinyl sulfate (875 mg, 7.05 mmol) in N,N-dimethylpropenylurea (16 mL). The reaction mixture was stirred for 1 hour under a nitrogen atmosphere in an ice bath. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 13-6. MS m / z (ESI): 367.2 [M+H] + .

[0657] Step 6: Synthesis of compounds 13-7

[0658] Sodium hydroxide (170 mg, 4.22 mmol) was added to a mixed solution of compound 13-6 (309 mg, 0.84 mmol) in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction mixture was acidified to pH 5 with dilute hydrochloric acid (2 M), diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to give compound 13-7. MS m / z (ESI): 337.1 [MH] - .

[0659] Step 7: Synthesis of compounds 13-8

[0660] Compounds 1-4 (172.2 mg, 0.30 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (168.5 mg, 0.44 mmol), and N,N-diisopropylethylamine (89.7 mg, 0.89 mmol) were added to a solution of compound 13-7 (100 mg, 0.30 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 13-8. MS m / z (ESI): 903.4 [M+H] + .

[0661] Step 8: Synthesis of compounds 13-9

[0662] To a solution of compound 13-8 (80 mg, 0.09 mmol) in ethanol (3 mL), hydroxylamine hydrochloride (12.3 mg, 0.18 mmol) and N,N-diisopropylethylamine (22.9 mg, 0.18 mmol) were added. The reaction mixture was stirred at 60 °C for 3 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give crude compound 13-9. The crude product was used directly in the next step. MS m / z (ESI): 936.4 [M+H] + .

[0663] Step 9: Synthesis of Compound 13

[0664] To a solution of compound 13-9 (60 mg, 0.06 mmol) in dimethyl sulfoxide (3 mL), N,N'-carbonyldiimidazole (15.6 mg, 0.10 mmol) and 1,8-diazabicycloundec-7-ene (29.3 mg, 0.19 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC (YMC-Triart-C18-10 μm-30*250 mm, A: 0.1% TFA / H2O, B: ACN, Ret 12.9 min) to obtain compound 13. MS m / z (ESI): 962.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.03–11.95(m,1H),8.18–8.14(m,1H),7.76–7.53(m,1H), 7.39–7.33(m,3H),7.19–7.04(m,4H),6.73(d,J=7.2Hz,1H),6.43–6.36(m,1H),5.81 –5.04(m,1H),4.36–3.80(m,6H),3.43–3.38(m,1H),3.18–3.11(m,3H),2.95–2.93( m,1H),2.23–2.17(m,6H),1.79–1.67(m,8H),1.55–1.03(m,15H),0.91–0.80(m,3H).

[0665] Example 18: Preparation of Compound 14

[0666] Synthesis route:

[0667] Step 1: Synthesis of Compound 14-2

[0668] Under nitrogen protection and at 0°C, (triphenylphosphine)acetonitrile (160 g, 532 mmol) was added to a solution of compound 14-1 (90.0 g, 484 mmol) in dichloromethane (1000 mL). After the addition was complete, the mixture was stirred at 0°C for 1 hour, and then at 25°C for 17 hours. The reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (1000 mL), and extracted with dichloromethane (1000 mL × 2). The combined organic phases were washed with saturated brine (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 14-2. MS m / z (ESI): 209.0, 211.0 [M+H] + .

[0669] Step 2: Synthesis of Compound 14-3

[0670] Sodium borohydride (7.3 g, 191.3 mmol) was added to a methanol (200 mL) mixture of compound 14-2 (20.0 g, 95.7 mmol) at room temperature. After the addition was complete, nickel chloride hexahydrate (2.28 g, 9.61 mmol) was added in portions, and the reaction was stirred at 0°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (400 mL), and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give compound 14-3. MS m / z (ESI): 211.0, 213.0 [M+H] + .

[0671] Step 3: Synthesis of compound 14-4

[0672] Sodium bicarbonate (7.9 g, 94.7 mmol) was added to a solution of compound 14-3 (5.0 g, 23.7 mmol) in 1,2-dichloroethane (10 mL) at 0°C. After the addition was complete, ethyl 3-bromopyruvate (6.9 mL, 54.5 mmol) was added dropwise. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give compound 14-4. MS m / z (ESI): 307.0, 309.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.66(dd,J=1.6,0.8Hz,1H),8.12(s,1H),7.17(d,J=9.2Hz,1H) ,6.99(dd,J=9.6,1.6Hz,1H),4.31(q,J=7.2Hz,2H),4.26(s,2H),1.34(t,J=7.2Hz,3H).

[0673] Step 4: Synthesis of Compounds 14-5

[0674] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (430 mg, 0.6 mmol) was added to a mixed solvent of compound 14-4 (1.4 g, 4.6 mmol), potassium carbonate (1.62 g, 11.7 mmol), 2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (1.7 g, 7.1 mmol), 1,4-dioxane (20 mL), and water (4 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and stirred for 10 hours. The reaction solution was diluted in water (100 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give compound 14-5. MS m / z (ESI): 339.2 [M + H] + .

[0675] Step 5: Synthesis of Compounds 14-6

[0676] To a solution of compound 14-5 (1.3 g, 3.84 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL), 10% palladium on carbon (0.2 g, 1.88 mmol) was added, purging with hydrogen three times. The reaction mixture was stirred at 25°C for 18 hours. After diatomaceous earth filtration, the filtrate was washed three times with ethyl acetate, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 14-6. MS m / z (ESI): 341.2 [M + H] + .

[0677] Step 6: Synthesis of compounds 14-7

[0678] Under nitrogen protection and at 0°C, lithium bis(trimethylsilyl)amino (28 mL, 28.0 mmol, 1.0 M) was added dropwise to a solution of compound 14-6 (1.2 g, 3.5 mmol) and vinyl sulfate (1.5 g, 12.3 mmol) in N,N-dimethylpropenylurea (20 mL). After the addition was complete, the mixture was stirred at 0°C for 1 hour, then heated to 25°C and stirred for 18 hours. The reaction solution was quenched with saturated ammonium chloride (50 mL), diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 14-7. MS m / z (ESI): 367.2 [M+H] + .

[0679] Step 7: Synthesis of compounds 14-8

[0680] Sodium hydroxide (164 mg, 4.1 mmol) was added to a methanol (4 mL) and water (1 mL) solution of compound 14-7 (0.5 g, 1.36 mmol) at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then heated to 50°C and stirred for 2 hours. The pH of the reaction mixture was adjusted to approximately 3 with 2 M dilute hydrochloric acid. The mixture was filtered, and the filter cake was washed three times with water and concentrated under reduced pressure to obtain compound 14-8. MS m / z (ESI): 339.2 [M+H] + .

[0681] Step 8: Synthesis of compounds 14-9a and 14-9b

[0682] Compound 14-8 (0.45 g, 1.23 mmol) was separated by SFC (ChiralPakAD 250 × 30 mm ID, 5 μm; mobile phase: A for CO2 and B for methanol (0.1% DEA); flow rate: 3 mL / min; column temperature: 35 °C; ABPR: 2000 psi), yielding the first peak (retention time 4.070 min) belonging to compound 14-9a. MS m / z (ESI): 339.2 [M+H] + The second peak (retention time 4.749 min) was obtained as compound 14-9b. MS m / z (ESI): 339.2 [M+H] + .

[0683] Step 9: Synthesis of compound 14-10a

[0684] Compound 1-4 (34 mg, 0.06 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (27 mg, 0.07 mmol), and N,N-diisopropylethylamine (23 mg, 0.2 mmol) were added to a solution of compound 14-9a (20.0 mg, 0.06 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 14-10a. MS m / z (ESI): 903.4 [M+H] + .

[0685] Step 10: Synthesis of compounds 14-11a

[0686] To a solution of compound 14-10a (40.0 mg, 0.04 mmol) in ethanol (1 mL), hydroxylamine hydrochloride (4.6 mg, 0.07 mmol) and N,N-diisopropylethylamine (17 mg, 0.13 mmol) were added. The reaction mixture was stirred at 60 °C for 3 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give crude compound 14-11a. The crude product was used directly in the next step. MS m / z (ESI): 936.4 [M+H] + .

[0687] Step 11: Synthesis of Compound 14

[0688] To a solution of compound 14-11a (30.0 mg, 0.03 mmol) in dimethyl sulfoxide (1 mL), N,N'-carbonyldiimidazole (13 mg, 0.08 mmol) and 1,8-diazabicycloundec-7-ene (19 mg, 0.13 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (waters-xbridge-C18-10 μm-19*250 mm, Mobilephase: 0.1% TFA / H2O, B:CH3CN, Gradient: 70% B-90% B, Ret 8.35 min) to give compound 14. MS m / z (ESI): 962.4 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.07–8.03(m,1H),7.67–7.48(m,3H),7.34(s,1H),7 .17–7.15(m,3H),6.94–6.66(m,3H),6.08–5.22(m,1H),4.34–4.22(m,2H) ,3.95–3.69(m,6H),3.28–3.16(m,4H),2.97(s,1H),2.26–2.24(m,6H),1. 85–1.79(m,5H),1.61–1.45(m,6H),1.39–1.24(m,10H),0.99–0.80(m,3H).

[0689] Example 19: Preparation of compound M

[0690] Compound M was synthesized by a similar method to that used for compound L in Example 3.

[0691] Compound M: MS m / z (ESI): 482.2 [M+H] + .

[0692] Example 20: Preparation of compound N

[0693] Compound N was synthesized by a similar method to that used for compound L in Example 3.

[0694] Compound N: MS m / z (ESI): 496.2 [M+H] + .

[0695] Example 21: Preparation of Compound 15

[0696] Compound 15 was synthesized by a similar method to that used for Compound 1 in Example 4 (using GS as a raw material).

[0697] Compound 12: MS m / z (ESI): 990.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.35–11.68(m,1H),7.73–6.57(m,11H),5.73–5.28(m,1H),5.04–4.51(m,1H),4.15– 3.96(m,2H),3.83–3.48(m,5H),3.19–2.66(m,5H),2.23–2.03(m,9H),1.87–1.55(m,11H),1.44–0.75(m,14H).

[0698] Example 22: Preparation of Compound 16

[0699] Compound 16 was synthesized by a similar method to that used for Compound 1 in Example 4 (using GS as a raw material).

[0700] Compound 12: MS m / z (ESI): 1004.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.82–7.58(m,1H),7.57–7.28(m,4H),7.27–6.97(m,4H),6. 96–6.54(m,2H),6.08–5.22(m,1H),4.22–4.20(m,2H),4.01–3.72(m,4H),3.27–3 .06(m,4H),2.48–2.40(m,1H),2.28(s,6H),2.17–1.96(m,3H),1.89–1.58(m,12H ),1.51–1.42(m,3H),1.38(d,J=5.6Hz,3H),1.35–1.25(m,8H),1.12–0.84(m,3H).

[0701] Example 23: Preparation of compound J

[0702] Synthesis route:

[0703] Step 1: Synthesis of compound J-2

[0704] Under dry ice bath conditions, 122 mL of butyllithium (305 mmol, 2.5 M) was added to a tetrahydrofuran (8.0 L) solution of compound J-1 (100 g, 305 mmol). The reaction mixture was stirred at -78°C for 0.5 hours under nitrogen protection. Then, tetrahydropyranone (31 g, 305 mmol) was slowly added. The mixture was stirred at room temperature for 16 hours, diluted with saturated ammonium chloride solution (2.0 L), and extracted with ethyl acetate (5.0 L × 3). The combined organic phases were washed with saturated brine (3.0 L × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound J-2. MS m / z (ESI): 302.0, 304.0 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.39(d,J=2.4Hz,1H),8.28(dd,J=8.8,2.4Hz,1H),8.11(d, J=8.8Hz,1H),5.61(s,1H),3.85–3.75(m,4H),2.72–2.66(m,2H),1.62–1.45(m,2H).

[0705] Step 2: Synthesis of compound J-3

[0706] Iron powder (10.35 g, 185 mmol) and ammonium chloride (11.90 g, 222 mmol) were added to a mixed solution of compound J-2 (11.2 g, 37 mmol) in ethanol (150 mL) and water (50 mL). The reaction mixture was stirred at 90 °C for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The filtrate was then slurried at 0 °C with dichloromethane / methanol = 10 / 1, and the filter cake was concentrated under reduced pressure to give compound J-3. MS m / z (ESI): 272.0, 274.0 [M+H] + .

[0707] Step 3: Synthesis of compound J-4

[0708] To a mixed solution of compound J-3 (8.4 g, 30.87 mmol) in N,N-dimethylformamide (100 mL) and methanol (100 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.26 g, 3.09 mmol) and triethylamine (6.25 g, 61.73 mmol) were added. The reaction mixture was stirred at 100 °C for 18 hours under carbon monoxide balloon protection. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound J-4. MS m / z (ESI): 220.0 [M+H] + .

[0709] Step 4: Synthesis of compound J-5

[0710] Sodium nitrite (1.56 g, 22.58 mmol) was slowly added to a mixed solution of compound J-4 (4.5 g, 20.53 mmol) in concentrated hydrochloric acid (40 mL) and water (40 mL) under ice bath conditions. After stirring at 0°C for 1 hour, stannous chloride dihydrate (15.57 g, 82.10 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound J-5. The crude product was used directly in the next step. MS m / z (ESI): 235.1 [M+H] + .

[0711] Step 5: Synthesis of compound J-6

[0712] Ethyl pyruvate (2.18 g, 18.78 mmol) was slowly added to a 50 mL ethanol solution of compound J-5 (4.0 g, 16.98 mmol) at room temperature, and the reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound J-6. MS m / z (ESI): 333.1 [M+H] + .

[0713] Step 6: Synthesis of compound J-7

[0714] Eaton reagent (5.25 g, 22.03 mmol) was added to a toluene (35 mL) solution of compound J-6 (3.5 g, 10.53 mmol) at room temperature, and the mixture was stirred at 90 °C for 2 hours. The reaction solution was poured into ice water (40 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC (ASA-AZZOTA—C18-7 μm-30*150 mm A: 10 mM NH4HCO3 / H2O B: ACN 69% A-31% B: Ret 1.64 min) to obtain compound J-7. MS m / z (ESI): 316.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),7.97(s,1H),7.88(s,1H),7.29(d,J=2.4Hz,1H),4.41(dd,J=8.0Hz,2 H), 4.00–3.94 (m, 2H), 3.79–3.70 (m, 2H), 2.35–2.26 (m, 2H), 1.64 (d, J = 16.0Hz, 2H), 1.38 (t, J = 8.0Hz, 3H).

[0715] Step 7: Synthesis of compound J-8

[0716] Under ice bath conditions, potassium tert-butoxide (374 mg, 3.33 mmol) was added to a solution of compound J-7 (350 mg, 1.11 mmol) in N,N-dimethylacetamide (20 mL). The reaction mixture was stirred at room temperature for 0.5 hours under nitrogen protection, followed by slow addition of bromoacetonitrile (399 mg, 3.33 mmol) and stirring at 90°C for 18 hours. The mixture was diluted with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound J-8. MS m / z (ESI): 355.2 [M+H] + .

[0717] Step 8: Synthesis of Compound J

[0718] Compound GS-10 (351 mg, 2.54 mmol) was added to a tetrahydrofuran (3 mL) solution of compound J-8 (300 mg, 0.85 mmol) under ice bath conditions. The reaction mixture was stirred at -10°C for 10 minutes under nitrogen protection. Then, sodium bis(trimethylsilylamino)sodium (3.0 mL, 5.93 mmol, 2 M) was slowly added. After stirring the mixture at room temperature for 1 hour, quenching was performed with saturated ammonium chloride solution (2 mL). The mixture was dried under nitrogen, and the residue was purified by preparative HPLC (Agela-Durashell-C18-10 μm-25*250 mm 10 mM NH4HCO3 / H2O B:ACN 2% A-2% B:Ret 1.60 min) to obtain compound J. MS m / z (ESI): 367.1 [M+H] + .

[0719] Example 24: Preparation of Compound 17

[0720] Compound 17 was synthesized by a method similar to steps 7 to 9 of compound 13 in Example 17 (using J as the starting material).

[0721] Compound 17: MS m / z (ESI): 990.4 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.14–6.53(m,10H),5.95–5.33(m,1H),4.40–3.60(m,9H),3.27–3 .07(m,4H),2.71–2.20(m,8H),1.90–1.63(m,9H),1.60–1.09(m,9H),1.05–0.86(m,1H).

[0722] Example 27: Preparation of Compound 20

[0723] Compound 20 was synthesized by a similar method to that used for Compound 1 in Example 4 (using GS as a raw material).

[0724] Compound 20: MS m / z (ESI): 962.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.58–7.03(m,8H),7.01–6.44(m,3H),4.36–3.78(m,8H),3.30–3.08(m,4H),2.53–2.40(m,1H),2.2 6(d,J=11.6Hz,6H),2.18–2.00(m,1H),1.91–1.43(m,13H),1.38(d,J=4.4Hz,3H),1.33–1.20(m,5H),1.16–0.94(m,3H).

[0725] Example 28: Preparation of Compound 21

[0726] Compound 21 was synthesized by a similar method to that used for Compound 1 in Example 4 (using GS as a raw material).

[0727] Compound 21: MS m / z (ESI): 988.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.42–11.39(m,1H),7.65–7.33(m,5H),7.29–7.02(m,5H),6.89–6.65(m,1H),5.86–5.62(m,1H),4.84– 4.62(m,4H),4.15–3.72(m,4H),3.13–2.99(m,4H),2.66–2.59(m,3H),2.21–2.06(m,6H),1.69–1.47(m,8H),1.40–0.79(m,16H).

[0728] Example 29: Preparation of Compound 22

[0729] Compound 22 was synthesized by a similar method to that used for Compound 1 in Example 4 (using GS as a raw material).

[0730] Compound 22: MS m / z (ESI): 946.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.35–11.70(m,1H),7.76–7.60(m,1H),7.58–7.44(m,1H),7.43–7 .34(m,2H),7.32–7.22(m,2H),7.21–6.62(m,5H),5.96–5.26(m,1H),4.25–3.92(m,1H),3. 82–3.64(m,3H),3.39(s,3H),3.10–2.92(m,2H),2.49–2.41(m,2H),2.39–2.26(m,3H),2.2 3–2.16(m,6H),1.76–1.49(m,8H),1.45–1.23(m,8H),1.23–1.12(m,5H),1.03–0.74(m,2H).

[0731] Example 30: Preparation of compound P

[0732] Synthesis route:

[0733] Step 1: Synthesis of compound P-2

[0734] Nitric acid (5 mL) was added to a sulfuric acid (5 mL) solution of compound P-1 (1.00 g, 4.5 mmol), and the mixture was stirred at 25 °C for 10 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound P-2. 1 HNMR (400MHz, CDCl3) δ8.71 (dd, J=5.6, 2.8Hz, 1H), 8.45 (dt, J=9.2, 3.2Hz, 1H), 7.44 (t, J=9.6Hz, 1H).

[0735] Step 2: Synthesis of compound P-3

[0736] To a methanol (1 mL) solution of compound P-2 (20 mg, 0.07 mmol), 10% wet palladium on carbon (5 mg) was added. The mixture was purged three times with hydrogen gas, and stirred at 25°C for 3 hours under hydrogen balloon protection. The reaction mixture was filtered, and the filter cake was washed with methanol (3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound P-3. MS m / z (ESI): 238.0 [M+H] + .

[0737] Step 3: Synthesis of compound P-4

[0738] Under ice bath conditions, sodium nitrite (5012 mg, 72.65 mmol) was added to a hydrochloric acid (10 mL) solution of compound P-3 (800 mg, 3.37 mmol). After stirring the reaction solution in an ice bath for 1 hour, a hydrochloric acid (40 mL) and water (40 mL) solution of stannous chloride dihydrate (2.76 g, 14.53 mmol) was added. The reaction solution was stirred under ice bath conditions for 2 hours. After quenching with water (100 mL), the pH was adjusted to 8 with 50% NaOH aqueous solution. The mixture was filtered, and the filtrate was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure, and purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, Mobile phase: 0.1% FA / H2O, B:CH3CN, Gradient: 50% B-70% B, Ret 11.51 min) to obtain compound P-4. MS m / z (ESI): 253.2 [M+H] + .

[0739] Step 4: Synthesis of compound P-5

[0740] Compound D-3 (286 mg, 1.20 mmol) and pyridine hydrochloride (13.9 mg, 0.12 mmol) were added to a 2 mL ethanol solution of compound P-4 (150 mg, 0.59 mmol). The reaction mixture was refluxed at 90 °C and stirred for 2 hours. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound P-5. MS m / z (ESI): 473.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.07(dd,J=6.2,2.4Hz,1H),7.97(ddd,J=9.2,4.0,2.4Hz,1H),7.67(dd,J=11.6,9.2Hz,1 H),5.44(s,2H),5.21–5.01(m,1H),4.27–4.07(m,1H),3.13–2.96(m,2H),2.36–2.27(m,1H),1.46–1.37(m,12H).

[0741] Step 5: Synthesis of compound P-6

[0742] Under ice bath conditions, N,N-diisopropylethylamine (150 mg, 1.16 mmol) and phenyl p-nitrochloroformate (195 mg, 0.97 mmol) were added to a tetrahydrofuran solution (3 mL) of aminoacetaldehyde dimethyl acetal (143 mg, 1.36 mmol). After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. A pyridine solution (2 mL) containing compound P-5 (150 mg, 0.32 mmol) was added to the residue. The reaction solution was stirred at 40°C for 48 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound P-6. MS m / z (ESI): 604.2 [M+H] + .

[0743] Step 6: Synthesis of compound P

[0744] Methylsulfonic acid (20 mg, 0.21 mmol) was added to a tetrahydrofuran (1 mL) solution of compound P-6 (100 mg, 0.17 mmol). The reaction mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, triethylamine (586 mg, 5.80 mmol) and di-tert-butyl dicarbonate (158 mg, 0.73 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (15 mL), extracted with ethyl acetate (15 mL × 3), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound P. MS m / z (ESI): 540.4 [M + H] + .

[0745] Example 31A: Preparation of Compound 23

[0746] Compound 23 was synthesized by a similar method to that used for compound 1 in Example 4 (using GS as a raw material).

[0747] Compound 23: MS m / z (ESI): 1074.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.22–11.69(m,1H),8.16(s,1H),7.92–7.85(m,2H),7.77–7.68(m,2H),7.46–7.38(m,3H) ,7.35–7.28(m,2H),7.21–7.15(m,2H),5.96–5.26(m,1H),4.13–3.97(m,4H),3.92–3.77(m,4H),3.76–3.61(m,4H) ,3.17(s,3H),3.12–3.09(m,1H),3.08–2.95(m,2H),1.74(d,J=17.20Hz,6H),1.61–1.57(m,2H),1.43–1.39(m,1H) ,1.38–1.34(m,2H),1.30–1.28(m,3H),1.26–1.25(m,1H),1.21–1.19(m,4H),1.13–1.10(m,1H),0.90–0.84(m,1H).

[0748] Example 31B: Preparation of compound Q

[0749] Synthesis route:

[0750] Step 1: Synthesis of compound Q-2

[0751] Sodium hydride (400 mg, 10.00 mmol) was added to a DMF (16 mL) solution of tetrahydropyran-4-carboxylic acid ethyl ester (1.58 g, 10.00 mmol) under ice bath conditions. The reaction mixture was stirred at room temperature for 30 minutes, followed by the addition of a DMF (20 mL) solution of compound Q-1 (2.00 g, 9.09 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give compound Q-2. MS m / z (ESI): 357.9, 359.9 [M+H] + .

[0752] Step 2: Synthesis of compound Q-3

[0753] To a solution of compound Q-2 (5.00 g, 13.96 mmol) and potassium N-aminomethyltrifluoroborate (4.96 g, 20.92 mmol) in dioxane (50 mL) and water (10 mL), 1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride (0.91 g, 1.41 mmol) and potassium carbonate (5.80 g, 41.84 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours under nitrogen protection. After cooling to room temperature, the mixture was quenched in water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound Q-3. MS m / z (ESI): 431.2 [M + Na] + . 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),8.16(dd,J=8.8,2.4Hz,1H),7.64(d,J=8.8Hz,1H),4.43(d,J=6.0Hz,2H),4.2 3(q,J=7.2Hz,2H),3.94–3.85(m,4H),2.50–2.44(m,2H),2.19–2.09(m,2H),1.51(s,9H),1.24(t,J=7.2Hz,3H).

[0754] Step 3: Synthesis of compound Q-4

[0755] A solution of compound Q-3 (1.58 g, 3.9 mmol) in dichloromethane (10 mL) was added to a solution of dioxane hydrochloride (5 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (10 mL) and water (2 mL). Sodium hydroxide (1.66 g, 41.50 mmol) was added at 0°C, and the reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound Q-4. MS m / z (ESI): 263.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.34(s,1H),8.27(d,J=2.4Hz,1H),8.18(dd,J=8.8,2.4Hz,1H),7.78(d,J=8.8H z,1H),4.55(d,J=3.2Hz,2H),3.96–3.90(m,2H),3.80–3.74(m,2H),2.10–2.02(m,2H),1.93–1.85(m,2H).

[0756] Step 4: Synthesis of compound Q-5

[0757] Sodium hydride (260 mg, 6.50 mmol) was added to a DMF (20 mL) solution of compound Q-4 (1.40 g, 5.34 mmol) at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. Iodomethane (1.14 g, 8.0 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched in water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound Q-5. MS m / z (ESI): 277.2 [M+H] + .

[0758] Step 5: Synthesis of compound Q-6

[0759] To a tetrahydrofuran (10 mL) solution of compound Q-5 (1.40 g, 5.1 mmol), 10% wet palladium on carbon (600 mg, 5.62 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours under hydrogen balloon protection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, Mobile phase: 0.1% FA / H2O, B:CH3CN, Gradient: 55% B-70% B, Ret 8.63 min) to obtain compound Q-6. MS m / z (ESI): 247.2 [M+H] + .

[0760] Step 6: Synthesis of compound Q

[0761] At 0°C, tert-butyl nitrite (38 mg, 0.37 mmol) was added dropwise to a solution of compound Q-6 (60 mg, 0.24 mmol) and copper bromide (35 mg, 0.16 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 18 hours under nitrogen protection. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound Q. MS m / z (ESI): 310.0, 312.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.56–7.50(m,2H),7.43(d,J=8.4Hz,1H),4.58(s,2H),3.93 –3.86(m,2H),3.76–3.72(m,2H),2.98(s,3H),1.98–1.94(m,2H),1.87–1.80(m,2H).

[0762] Example 32: Preparation of Compound 24

[0763] Compound 24 was synthesized by a similar method to that used for compound 1 in Example 4 (using GS as a raw material).

[0764] Compound 24: MS m / z (ESI): 990.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.41–11.74(m,1H),7.72–6.43(m,11H),5.83–5.25(m,1H),4.64–4.50(m,2H),4.16– 4.06(m,2H),3.93–3.72(m,4H),3.14–3.01(m,4H),2.24–2.17(m,6H),2.05–1.51(m,11H),1.49–0.85(m,18H).

[0765] Example 33: Preparation of Compound 25

[0766] Compound 25 was synthesized by a similar method to that used for compound 13 in Example 17 (using 13-7 as raw materials).

[0767] Compound 25: MS m / z (ESI): 976.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.03–11.97(m,1H),8.19–8.15(m,2H),7.70–7.56(m,2H) ,7.53–7.22(m,2H),7.16–7.01(m,3H),6.74–6.71(m,1H),6.43–6.36(m,1H),5.86– 5.03(m,1H),4.63–4.56(m,2H),3.98–3.82(m,4H),3.71–3.40(m,3H),3.01–2.99(m ,4H),2.25–2.10(m,6H),2.05–1.63(m,8H),1.60–1.06(m,16H),0.88–0.70(m,2H).

[0768] Example 34: Preparation of Compound 26

[0769] Synthesis route:

[0770] Step 1: Synthesis of Compound 26-1

[0771] Under nitrogen protection, a selective fluorine reagent (2.51 g, 7.09 mmol) was added to a DMF (30 mL) solution of compound 1-2 (1.4 g, 4.73 mmol), and the reaction mixture was stirred at 60 °C for 24 hours. The reaction mixture was quenched with ice water (90 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with water (20 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 26-1. MS m / z (ESI): 314.0, 316.0 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.69(d,J=8.4Hz,1H),7.38(d,J=5.6Hz,1H),4.00–4.0 6(m,2H),3.76–3.82(m,2H),3.12(s,3H),1.74–1.80(m,2H),1.66–1.72(m,2H).

[0772] Step 2: Synthesis of compound 26-2

[0773] Compound 26-1 (170 mg, 0.54 mmol), potassium carbonate (188 mg, 1.35 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (32 mg, 0.23 mmol), and cuprous iodide (17 mg, 0.09 mmol) were added to a solution of compound L (153 mg, 0.33 mmol) in N-methylpyrrolidone (3 mL). The reaction mixture was stirred at 130 °C for 16 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 26-2. MS m / z (ESI): 701.4 [M+H] + .

[0774] Step 3: Synthesis of compound 26-3

[0775] To a solution of compound 26-2 (200 mg, 0.29 mmol) in dichloromethane (3 mL), 1 mL of 4 M dioxane hydrochloride solution was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude compound 26-3. The crude product was used directly in the next step. MS m / z (ESI): 601.2 [M+H] + .

[0776] Step 4: Synthesis of Compound 26

[0777] To a 2 mL solution of compound GS (82 mg, 0.20 mmol) in N,N-dimethylformamide, N,N-diisopropylethylamine (52 mg, 0.40 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (91 mg, 0.24 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then compound 26-3 (120 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative HPLC (Column Nouryon-Kromasil-C18, 10 μm, 25 x 250 mm; Mobile: Phase A: 10 mM TFA / H2O; Phase B: ACN; Gradient; 70% to 95%) to give compound 26. MS m / z (ESI): 994.4 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ12.28–11.72(m,1H),7.81–7.78(m,1H),7.63–7.34(m,2H),7.30–6.86(m,6H),6.81–6.61(m,1H),5.88–5.30(m,1 H),4.18–4.02(m,2H),3.91–3.68(m,5H),3.16–3.07(m,4H),2.28–2. 15(m,6H),1.88–1.46(m,12H),1.46–1.06(m,14H),1.00–0.76(m,2H).

[0778] Example 35: Preparation of Compound 27

[0779] Compound 27 was synthesized by a similar method to that of Compound 2 in Example 5 (using cyclopropyl trifluoromethanesulfonate and GS as raw materials).

[0780] Compound 27: MS m / z (ESI): 1016.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.19–11.72(m,1H),7.64–7.52(m,1H),7.50–6.88(m,9H),6.83–6.62(m,1 H),5.88–5.31(m,1H),4.14–3.54(m,9H),3.09–2.72(m,4H),2.21–2.18(m,6H),1.83–0.83(m,30H).

[0781] Example 36: Preparation of Compound 28

[0782] Compound 28 was produced by a similar method to that used for compound 26 in Example 34 (using the isomer from step 1). It was synthesized using GS as raw material.

[0783] Compound 28: MS m / z (ESI): 994.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.19–11.73(m,1H),7.62–7.34(m,3H),7.28–7.24(m,1H),7.19–6.87(m,5H),6.94–6.69(m,1H),5.65–5 .30(m,1H),4.14–3.96(m,2H),3.91–3.65(m,5H),2.30–2.18(m,6H),1.88–1.48(m,13H),1.37–1.11(m,16H),0.99–0.75(m,3H).

[0784] Example 37: Preparation of Compound 29

[0785] Compound 29 was synthesized by a similar method to that used for compound 1 in Example 4 (using 1,5-dibromopentane and GS as raw materials).

[0786] Compound 29: MS m / z (ESI): 974.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.32–11.82(m,1H),7.79–6.54(m,11H),6.04–5.28(m,1H),4.19–3.64(m,4H),3.2 2–3.08(m,4H),2.21(s,6H),1.90–1.74(m,3H),1.59–1.40(m,15H),1.38–1.09(m,13H),1.00–0.75(m,2H).

[0787] Example 38: Preparation of Compound 30

[0788] Compound 30 was synthesized by a similar method to that used for compound 7 in Example 10 (step 2 and using GS as a raw material are omitted).

[0789] Compound 30: MS m / z (ESI): 962.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.17–11.72(m,1H),10.55–10.45(m,1H),7.66–7.23(m,6H),7.15–6.90(m,4H),6.81–6.61(m,1H),5. 92–5.31(m,2H),4.11–3.94(m,3H),3.86–3.64(m,5H),3.09–2.96(m,1H),2.20(s,6H),1.79–1.23(m,20H),1.20–0.93(m,6H).

[0790] Example 39: Preparation of compound R

[0791] Compound R was synthesized by a similar method to that used for compound L in Example 3.

[0792] Compound R: MS m / z (ESI): 502.1 [M+H] + .

[0793] Example 40: Preparation of Compound 31

[0794] Synthesis route:

[0795] Step 1: Synthesis of compound 31-1

[0796] Compound R (213 mg, 0.43 mmol), cesium carbonate (346 mg, 1.46 mmol), cuprous iodide (81 mg, 0.43 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (121 mg, 0.85 mmol) were added to a solution of compound 4-1 (187 mg, 0.43 mmol) in N-methylpyrrolidone (4 mL). The reaction mixture was stirred at 130 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 31-1. MS m / z (ESI): 760.4 [M-56+H] + .

[0797] Step 2: Synthesis of compound 31-2

[0798] Palladium on carbon (32 mg, 20% wt) was added to a methanol (5 mL) solution of compound 31-1 (165 mg, 0.18 mmol), and the reaction mixture was stirred at 25°C under a hydrogen atmosphere at atmospheric pressure for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 31-2. MS m / z (ESI): 682.4 [M+H] + .

[0799] Step 3: Synthesis of compound 31-3

[0800] To compound 31-2 (60 mg, 0.08 mmol) and compound GS (65.2 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (60 mg, 0.16 mmol) and N,N-diisopropylethylamine (51 mg, 0.40 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 31-3. MS m / z (ESI): 975.2 [M-Boc+H] + .

[0801] Step 4: Synthesis of Compound 31

[0802] Compound 31-3 (0.12 mmol) was treated with 2.0 mL of 4 M dioxane hydrochloride, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Pre-HPLC: Gilson_GX281, Column: Waters-SunFire-C18-10μm-30*230mm, Flow rate: 35, Mobile phase: A: 0.1% FA / H2O, B: ACN, UV wavelength: 220, Gradient: Gradient_time=12.0 is in time_range=[8,15]40%~50%) to obtain compound 31. MS m / z (ESI): 975.4 [M+H) + . 1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.70–6.32(m,11H),5.90–4.67(m,1H),3.77–3.67(m,2H),3.57–3 .45(m,4H),3.22–2.97(m,5H),2.24(s,6H),2.05–1.45(m,12H),1.23–1.20(m,13H),1.08–0.45(m,3H).

[0803] Example 41: Preparation of compound 32

[0804] Compound 32 was synthesized by a similar method to that used for compound 4 in Example 7 (using iodomethane and GS as raw materials).

[0805] Compound 32: MS m / z (ESI): 962.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.59–6.49(m,11H),5.99–4.94(m,1H),4.30–3.80(m,3H),3.71–3.44(m,2H),3.28 –2.94(m,8H),2.78–2.64(m,3H),2.25(s,6H),2.13–1.94(m,4H),1.86–1.50(m,9H),1.46–0.76(m,13H).

[0806] Example 42: Preparation of compound S

[0807] Synthesis route:

[0808] Step 1: Synthesis of compound S-1

[0809] Ethyl 2,3-epoxypropionate (594.37 mmol) was added to a methanol (500 mL) solution of compound L-1 (594.37 mmol), and the reaction mixture was stirred at 85 °C for 18 hours. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound S-1. MS m / z (ESI): 201.1 [M+H] + .

[0810] Step 2: Synthesis of compound S-2

[0811] Imidazole (25.96 g, 381.29 mmol) and tert-butyldimethylchlorosilane (57.47 g, 381.29 mmol) were added to a dichloromethane (70 mL) solution of compound S-1 (381.29 mmol). The reaction mixture was stirred at 25 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to give crude compound S-2, which was used directly in the next reaction. MS m / z (ESI): 315.2 [M+H] + .

[0812] Step 3: Synthesis of compound S-3

[0813] A solution of compound S-2 (332.81 mmol) in dichloromethane (100 mL) was mixed with triethylamine (50.52 g, 499.21 mmol) and di-tert-butyl dicarbonate (87.16 g, 399.37 mmol). The reaction mixture was stirred at 25 °C for 18 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound S-3. MS m / z (ESI): 315.2 [M-Boc+H] + .

[0814] Step 4: Synthesis of compound S-4

[0815] Potassium tert-butoxide (15.69 g, 139.79 mmol) was added to a tetrahydrofuran (200 mL) solution of compound S-3 (28 g, 69.90 mmol). The reaction mixture was stirred at 25 °C for 2 hours under nitrogen protection. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with saturated brine (1 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10 / 1) to give compound S-4. MS m / z (ESI): 369.2 [M+H] + .

[0816] Step 5: Synthesis of compound S-5

[0817] Compound D-2 (17.93 mmol) and pyridine hydrochloride (2.06 g, 17.94 mmol) were added to a 60 mL ethanol solution of compound S-4 (6.6 g, 17.93 mmol). The reaction mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10 / 1) to give compound S-5. MS m / z (ESI): 505.4 [M+H] + .

[0818] Step 6: Synthesis of compound S-6

[0819] To a tetrahydrofuran solution (20 mL) of aminoacetaldehyde dimethyl acetal (1.89 g, 18.00 mmol), phenyl p-nitrochloroformate (2.71 g, 13.50 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure. A pyridine solution (50 mL) of compound S-5 (2.4 g, 4.76 mmol) was added to the mixture, and the reaction mixture was stirred at 70°C for 18 hours under nitrogen protection. The reaction mixture was concentrated. The residue was diluted with ethyl acetate (100 mL), washed with 0.5 M dilute hydrochloric acid (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound S-6. MS m / z (ESI): 636.4 [M+H] + .

[0820] Step 7: Synthesis of compound S-7

[0821] Methylsulfonic acid (180 mg, 1.89 mmol) was added to a tetrahydrofuran (20 mL) solution of compound S-6 (1.2 g, 1.89 mmol), and the reaction mixture was stirred at 25 °C for 2 hours under nitrogen protection. The reaction solution was concentrated. The residue was purified by reverse-phase column chromatography (1‰ aqueous trifluoroacetic acid / acetonitrile = 30%–45%) to give compound S-7. MS m / z (ESI): 358.2 [M+H] + .

[0822] Step 8: Synthesis of compound S

[0823] To a solution of compound S-7 (600 mg, 1.68 mmol) and triethylamine (680 mg, 6.72 mmol) in dichloromethane (10 mL), di-tert-butyl dicarbonate (400 mg, 1.85 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours under nitrogen protection. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 5 / 1) to give compound S. MS m / z (ESI): 458.2 [M+H] + .

[0824] Example 43: Preparation of compound 33

[0825] Synthesis route:

[0826] Step 1: Synthesis of compound 33-1

[0827] Compounds 1-2 (388 mg, 1.31 mmol), cesium carbonate (1.3 g, 3.93 mmol), cuprous iodide (50 mg, 0.26 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (75 mg, 0.52 mmol) were added to a solution of compound S (600 mg, 1.31 mmol) in N-methylpyrrolidone (10 mL). The reaction mixture was stirred at 130 °C for 2 hours under nitrogen protection. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 33-1. MS m / z (ESI): 673.4 [M+H] + .

[0828] Step 2: Synthesis of compound 33-2

[0829] A solution of compound 33-1 (600 mg, 0.89 mmol) in 10 mL of dichloromethane was added to a solution of Dys-Martin oxidant (756 mg, 1.78 mmol), and the reaction mixture was stirred at 25 °C for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 5 / 1) to give compound 33-2. MS m / z (ESI): 671.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.70–7.53(m,1H),7.40–6.80(m,6H),5.45–5.10(m,1H),4.62–4.25(m,1H),4.12–4.03(m,2H ),3.89–3.80(m,2H),3.19–3.09(m,3H),2.34–2.05(m,6H),1.81–1.61(m,5H),1.54–1.39(m,10H),1.30–1.21(m,2H).

[0830] Step 3: Synthesis of compounds 33-3-P1 and 33-3-P2

[0831] At -78°C, a 1M solution of bis(trimethylsilylamine)lithium tetrahydrofuran (1.2 mL, 1.20 mmol) was added dropwise to a solution of (fluoromethyl)triphenylphosphonium tetrafluoroborate (427 mg, 0.89 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at -78°C for 1 hour under a nitrogen atmosphere. A solution of compound 33-2 (300 mg, 0.45 mmol) in tetrahydrofuran (3 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (30 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (Pre-HPLC: Gilson_GX281; Cell: ASA-AZZOTA—C18-7μm-30*150mm; Mobile phase: A: 0.1% FA / H2O, B: ACN; Gradient: 73%-83% in 12 min; Flow rate: 35 mL / min; UV wavelength: 220 nm) to obtain compound 33-3-P1 (retention time: 7.03 min) and compound 33-3-P2 (retention time: 7.27 min). MS m / z (ESI): 687.1 [M+H] + .

[0832] Step 4: Synthesis of compound 33-4

[0833] To compound 33-3-P2 (80 mg, 0.12 mmol), dioxane hydrochloride (2.0 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain compound 33-4. The crude product was used directly in the next reaction step. MS m / z (ESI): 587.2 [M+H] + .

[0834] Step 5: Synthesis of Compound 33

[0835] Compound 33-4 (65 mg, 0.11 mmol) and compound GS (46 mg, 0.11 mmol) were added to N,N-dimethylformamide (2 mL) with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (51 mg, 0.13 mmol) and N,N-diisopropylethylamine (29 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7 μm-30*150 mm A: 0.1% TFA / H2O B: ACN 75% A-95% B: Ret 7.554 min) to obtain compound 33. MS m / z (ESI): 980.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.21–11.70(m,1H),7.93–7.61(m,2H),7.55–7.51(m,1H),7.43–7.19(m,6H),7.15–6.63(m,3H),5.4 1(s,1H),4.27–4.03(m,3H),3.90–3.64(m,5H),3.17–2.99(m,4H),2.24–2.21(m,6H),1.79–1.33(m,14H),1.36–0.95(m,9H).

[0836] Example 44: Preparation of compound 34

[0837] Compound 34 was synthesized by a similar method to that used for compound 33 in Example 43 (using 33-3-P1 as a starting material).

[0838] Compound 34: MS m / z (ESI): 980.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.25–11.71(m,1H),7.71–7.50(m,2H),7.41–7.20(m,7H),7.14–6.73(m,3H),5.63–4.84(m,1 H),4.34–4.04(m,3H),3.91–3.65(m,5H),3.17–3.00(m,4H),2.25–2.22(m,6H),1.77–1.33(m,15H),1.29–1.16(m,8H).

[0839] Example 45: Preparation of compound T

[0840] Synthesis route:

[0841] Step 1: Synthesis of compound T

[0842] At 0°C, sodium hydride (221 mg, 5.53 mmol, 60% w / w) was added to a solution of compound 1-1 (500 mg, 2.21 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred under a nitrogen atmosphere for 30 minutes, and then compound 1,2-dibromoethane (623 mg, 3.32 mmol) was added dropwise. The mixture was then stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (20 mL) was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound T. MS m / z (ESI): 252.0, 254.0 [M+H] + .

[0843] Example 46: Preparation of compound U

[0844] Synthesis route:

[0845] Step 1: Synthesis of compound U-2

[0846] Compound U-1 (1.00 g, 4.72 mmol) was dissolved in tetrahydrofuran (15 mL), and 2 M diisopropylaminolithium tetrahydrofuran solution (7.07 mL, 14.15 mmol) was added at -40 °C, followed by stirring at -40 °C for 0.5 h. Then, 1,2-dibromoethane (1.22 mL, 14.15 mmol) was added to the mixture, and the mixture was stirred at 25 °C for 18 h. The reaction solution was diluted with ice water (20 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound U-2. MS m / z (ESI): 238.0, 240.0 [M+H] + .

[0847] Step 2: Synthesis of compound U

[0848] To a toluene (8 mL) solution of compound U-2 (0.20 g, 0.76 mmol), cyclopropylboronic acid (0.10 g, 1.13 mmol), 4-dimethylaminopyridine (0.37 g, 3.02 mmol), copper acetate (0.21 g, 1.13 mmol), and sodium diisopropylamino (0.76 mL, 0.76 mmol) were added, and the mixture was stirred at 95 °C for 18 hours under an oxygen atmosphere. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound U. MS m / z (ESI): 278.0, 280.0 [M+H] + .

[0849] Example 47: Preparation of Compound V

[0850] Compound V was synthesized by a similar method to that used for compound T in Example 45 (using 6-bromo-7-fluoro-1-methylindoline-2-one as a starting material).

[0851] Compound V: MS m / z (ESI): 270.0, 272.0 [M+H] + .

[0852] Example 48: Preparation of compound W

[0853] Compound W was synthesized by a similar method to that used for compound T in Example 45 (using 6-bromo-5-fluoro-1-methylindoline-2-one as a starting material).

[0854] Compound W: MS m / z (ESI): 270.0, 272.0 [M+H] + .

[0855] Example 52: Preparation of compound 35

[0856] Compound 35 was synthesized by a similar method to that used for compound 34 in Example 44 (using compounds T and GS as raw materials).

[0857] Compound 35: MS m / z (ESI): 936.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.22–11.70(m,1H),7.65–6.58(m,12H),5.63–4.84(m,1H),4.30–3.9 8(m,1H),3.72(s,2H),3.30–2.90(m,4H),2.25(s,6H),1.85–1.42(m,13H),1.35–1.15(m,11H).

[0858] Example 53: Preparation of Compound 36

[0859] Compound 36 was synthesized by a similar method to that used for compound 33 in Example 43 (using compounds T and GS as raw materials).

[0860] Compound 36: MS m / z (ESI): 936.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.22–11.70(m,1H),7.88–6.64(m,12H),5.69–5.37(m,1H),4.26–4.07(m ,1H),3.74–3.65(m,2H),3.33–2.90(m,4H),2.24(s,6H),1.75–1.39(m,13H),1.38–0.80(m,11H).

[0861] Example 54: Preparation of Compound 37

[0862] Compound 37 was synthesized by a similar method to that of compound 33 in Example 43 (using 5-bromo-4-fluoro-1-methyl-1H-indazole and GS as raw materials).

[0863] Compound 37: MS m / z (ESI): 913.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.44–11.56(m,1H),8.23–8.15(m,1H),7.92–6.63(m,11H),5.87–5.25(m,2H),4.33–3.98(m,4H),3. 73–3.56(m,2H),3.14–2.94(m,1H),2.28(s,6H),2.09–1.82(m,1H),1.76–1.47(m,8H),1.45–1.32(m,2H),1.31–1.13(m,8H).

[0864] Example 55: Preparation of Compound 38

[0865] Compound 38 was synthesized by a similar method to that used for compound 34 in Example 44 (using 5-bromo-4-fluoro-1-methyl-1H-indazole and GS as raw materials).

[0866] Compound 38: MS m / z (ESI): 913.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.49–11.42(m,1H),8.41–8.15(m,1H),7.70–6.63(m,11H),5.67–5.08(m,1H),4.88–4.30(m,1H), 4.13(s,3H),3.74–3.69(m,2H),3.34–3.00(m,2H),2.29(s,6H),2.03–1.85(m,1H),1.74–1.51(m,8H),1.40–1.18(m,10H).

[0867] Example 56: Preparation of compound 39

[0868] Compound 39 was synthesized by a similar method to that used for compound 33 in Example 43 (using compounds U and GS as raw materials).

[0869] Compound 39: MS m / z (ESI): 962.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.28–11.74(m,1H),7.87–6.61(m,12H),5.79–5.25(m,2H),4.24–4.01(m,1H),3.82–3.61(m,2H),3.14– 2.90(m,1H),2.84–2.70(m,1H),2.29–2.18(m,6H),2.07–1.82(m,1H),1.72–1.44(m,12H),1.38–1.14(m,10H),1.03–0.81(m,4H).

[0870] Example 57: Preparation of Compound 40

[0871] Compound 40 was synthesized by a similar method to that used for compound 34 in Example 44 (using compounds U and GS as raw materials).

[0872] Compound 40: MS m / z (ESI): 962.4 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ12.32–11.70(m,1H),7.70–6.70(m,12H),5.79–4.76(m,2H),4.38–4.02(m,1H),3.81–3.64(m,2H),3.1 4–2.93(m,1H),2.84–2.68(m,1H),2.24(s,6H),2.06–1.79(m,1H),1.71–1.43(m,12H),1.35–1.10(m,10H),1.03–0.82(m,4H).

[0873] Example 58: Preparation of Compound 41

[0874] Compound 41 was synthesized by a similar method to that used for compound 33 in Example 43 (using 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole and GS as raw materials).

[0875] Compound 41: MS m / z (ESI): 939.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.41–11.69(m,1H),8.29–8.13(m,1H),7.91–6.63(m,11H), 5.75–5.30(m,2H),4.27–3.67(m,4H),3.05(s,1H),2.28(s,6H),1.98–0.96(m,23H).

[0876] Example 59: Preparation of Compound 42

[0877] Compound 42 was synthesized by a similar method to that used for compound 34 in Example 44 (using 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole and GS as raw materials).

[0878] Compound 42: MS m / z (ESI): 939.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.22–11.71(m,1H),8.29–8.13(m,1H),7.71–6.73(m,11H),5.64–5.3 0(m,1H),5.12–4.83(m,1H),4.29–3.69(m,4H),3.05(s,1H),2.29(s,6H),1.92–0.88(m,23H).

[0879] Example 60: Preparation of Compound 43

[0880] Compound 43 was synthesized by a similar method to that used for compound 33 in Example 43 (using compound W and GS as raw materials).

[0881] Compound 43: MS m / z (ESI): 954.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.36–11.55(m,1H),7.94–6.62(m,11H),5.79–5.57(m,1H),5.51–5.20(m,1H),4.33–3.94(m,1H),3.80– 3.64(m,2H),3.29–3.20(m,2H),3.19–2.91(m,2H),2.32–2.19(m,6H),2.09–1.83(m,1H),170-1.48(m,12H),1.43–1.10(m,10H).

[0882] Example 61: Preparation of Compound 44

[0883] Compound 44 was synthesized by a similar method to that used for compound 34 in Example 44 (using compound W and GS as raw materials).

[0884] Compound 44: MS m / z (ESI): 954.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.34–11.66(m,1H),7.68–6.71(m,11H),5.90–5.33(m,1H),5.29–4.74(m,1H),4.38–3.92(m,1H),3.76– 3.69(m,2H),3.27–3.22(m,2H),3.20–2.92(m,2H),2.32–2.20(m,6H),2.05–1.80(m,1H),1.78–1.48(m,12H),1.40–1.15(m,10H).

[0885] Example 62: Preparation of Compound 45

[0886] Compound 45 was synthesized by a similar method to that used for compound 33 in Example 43 (using compound V and GS as raw materials).

[0887] Compound 45: MS m / z (ESI): 954.6 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ12.41–11.45(m,1H),7.96–6.57(m,11H),5.79–5.57(m,1H),5.53–5.20(m,1H),4.35–3.95(m,1H),3.78–3.68(m,2 H),3.43–3.35(m,3H),3.15–2.98(m,1H),2.30–2.20(m,6H),2.05–1.85(m,1H),1.79–1.47(m,12H),1.42–1.36(m,1H),1.32–1.14(m,9H).

[0888] Example 63: Preparation of Compound 46

[0889] Compound 46 was synthesized by a similar method to that used for compound 34 in Example 44 (using compound V and GS as raw materials).

[0890] Compound 46: MS m / z (ESI): 954.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.36–11.65(m,1H),7.64–6.72(m,11H),5.93–5.29(m,1H),5.27–4.79(m,1H),4.40–3.93(m,1H),3.81– 3.60(m,2H),3.39–3.28(m,3H),3.14–2.97(m,1H),2.30–2.20(m,6H),2.05–1.85(m,1H),1.78–1.43(m,13H),1.31–1.16(m,9H).

[0891] Example 64: Preparation of Compound B

[0892] Compound B was synthesized by a similar method to that used for compound S in Example 42 (using 1,2-diBoc-1-(3-cyclopropyl-4-fluorophenyl)hydrazine as a starting material).

[0893] Compound B: MS m / z (ESI): 470.4 [M+H] + .

[0894] Example 65: Preparation of Compound 47

[0895] Compound 47 was synthesized by a similar method to that used for compound 36 in Example 53 (using compound B and GS as raw materials).

[0896] Compound 47: MS m / z (ESI): 948.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.23–11.60(m,1H),7.97–7.48(m,1H),7.42–7.25(m, 7H),7.17–6.95(m,3H),6.89–6.62(m,2H),5.70–5.53(m,1H),5.44–5.28(m,1H ),4.31–4.15(m,1H),3.31–3.19(m,3H),3.13–2.96(m,2H),2.11–1.89(m,2H), 1.71–1.48(m,13H),1.30–1.13(m,10H),1.02–0.97(m,2H),0.66–0.55(m,2H).

[0897] Example 66: Preparation of Compound 48

[0898] Compound 48 was synthesized by a similar method to that used for compound 41 in Example 58 (using compound B and GS as raw materials).

[0899] Compound 48: MS m / z (ESI): 951.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.23–11.69(m,1H),8.31–8.13(m,1H),7.94–7.62(m, 2H),7.58–7.27(m,6H),7.14–6.91(m,3H),6.74–6.58(m,1H),5.73–5.62(m,1H ),5.45–5.27(m,1H),3.91–3.60(m,4H),3.13–2.98(m,1H),2.14–1.89(m,2H), 1.76–1.37(m,10H),1.31–1.11(m,12H),1.06–0.95(m,2H),0.73–0.58(m,2H).

[0900] Example 67: Preparation of Compound 49

[0901] Compound 49 was synthesized by a similar method to that used for compound 42 in Example 59 (using compound B and GS as raw materials).

[0902] Compound 49: MS m / z (ESI): 951.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.80–11.65(m,1H),8.26–8.14(m,1H),7.69–7.48(m ,3H),7.41–7.09(m,6H),7.05–6.72(m,3H),5.67–5.43(m,1H),5.06–4.80(m,1 H),4.32–4.19(m,1H),3.90–3.65(m,4H),3.09–2.98(m,1H),2.13–1.86(m,2H) ,1.72–1.46(m,8H),1.35–1.13(m,13H),1.03–0.95(m,2H),0.69–0.59(m,2H).

[0903] Example 68: Preparation of Compound 50

[0904] Compound 50 was synthesized by a similar method to that used for compound 35 in Example 52 (using triphenylethylphosphine iodide and GS as raw materials).

[0905] Compound 50: MS m / z (ESI): 932.4 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.45(s,1H),7.52–7.44(m,2H),7.34–7.18(m,3H),7.12–7.03 (m,2H),6.97–6.45(m,4H),5.85–5.68(m,1H),5.48–5.22(m,1H),4.15–3.78(m,3H) ,3.31(s,3H),3.15–3.02(m,1H),2.30–2.17(m,6H),2.05–1.81(m,5H),1.68–1.62( m,5H),1.59–1.55(m,3H),1.44–1.27(m,7H),1.26–1.24(m,4H),0.94–0.89(m,2H).

[0906] Example 69: Preparation of Compound 51

[0907] Compound 51 was synthesized by a similar method to that used for compound 36 in Example 53 (using isopropyltriphenylphosphonium iodide and GS as raw materials).

[0908] Compound 51: MS m / z (ESI): 946.4 [M+H] + . 1 H NMR(400MHz,CD3OD)δ7.57–7.47(m,2H),7.39–7.22(m,3H),7.17–6.99(m ,3H),6.92–6.80(m,2H),6.65–6.60(m,1H),5.82–5.62(m,1H),5.36–5.1 6(m,1H),4.13–3.82(m,3H),3.25–3.16(m,3H),2.43–2.25(m,3H),2.31– 2.17(m,8H),1.85–1.64(m,4H),1.72–1.58(m,10H),1.47–1.29(m,11H).

[0909] Example 70: Preparation of Compound 52

[0910] Compound 52 was synthesized by a similar method to that of compound 36 in Example 53 (using 2-((1-fluoroethyl)sulfonyl)benzothiazole as a starting material).

[0911] Compound 52: MS m / z (ESI): 950.4 [M+H] + . 1 H NMR(400MHz,CD3OD)δ7.57–7.47(m,2H),7.39–7.22(m,3H),7.17–6.99(m ,3H),6.92–6.80(m,2H),6.65–6.60(m,1H),5.82–5.62(m,1H),5.36–5.1 6(m,1H),4.13–3.82(m,3H),3.25–3.16(m,1H),2.43–2.25(m,2H),2.31– 2.17(m,8H),1.85–1.64(m,4H),1.72–1.58(m,10H),1.47–1.29(m,11H).

[0912] Example 71: Preparation of Compound 53

[0913] Synthesis route:

[0914] Step 1: Synthesis of Compound 53-2

[0915] At 0°C, aluminum trichloride (189 g, 1.42 mol) was added in portions to a solution of compound 53-1 (100 g, 675 mmol) in dichloromethane (2.0 L), followed by the slow dropwise addition of acetyl chloride (57 mL, 794 mmol). The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with ice water (800 mL), resulting in the precipitation of a solid. The mixture was filtered, and the filter cake was washed with water (800 mL). The filter cake was dissolved in dichloromethane (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 53-2. MS m / z (ESI): 188.0 [M+H] + .

[0916] Step 2: Synthesis of compound 53-3

[0917] To a 200 mL solution of compound 53-2 (20.0 g, 102 mmol) in 1,2-dichloroethane, 4-methoxybenzylamine (15.32 g, 112 mmol) and acetic acid (1.89 g, 10.15 mmol) were added. The mixture was stirred at room temperature for 30 minutes, purged three times with nitrogen, and sodium borohydride acetate (64.53 g, 304 mmol) was added in an ice bath. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL × 2). The organic phase was washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give compound 53-3. MS m / z (ESI): 293.2 [M+H] + .

[0918] Step 3: Synthesis of compound 53-4

[0919] To a methanol (100 mL) solution of compound 53-3 (8.0 g, 27.36 mmol), palladium on carbon (2.0 g, 10% w / w) and di-tert-butyl dicarbonate (4.02 g, 18.44 mmol) were added. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 4 / 1) to give compound 53-4. MS m / z (ESI): 217.0 [M-56+H] + .

[0920] Step 4: Synthesis of compound 53-5

[0921] Sodium hydride (850 mg, 21.15 mmol) was added to a solution of compound 53-4 (4.5 g, 17.21 mmol) in N,N-dimethylformamide (100 mL) under ice bath conditions. The mixture was stirred for 30 minutes, followed by the addition of p-toluenesulfonyl chloride (5.0 g, 26.44 mmol). The mixture was stirred under ice bath conditions for 2 hours. Water (300 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (300 mL × 2). The organic phase was washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 53-5. MS m / z (ESI): 326.9 [M-Boc+H] + .

[0922] Step 5: Synthesis of Compound 53-6

[0923] At -78°C, a solution of diisopropylaminolithium tetrahydrofuran (8.8 mL, 17.58 mmol, 2 M) was slowly added dropwise to a tetrahydrofuran (50 mL) solution of compound 53-5 (5.0 g, 11.72 mmol). Under nitrogen protection, the reaction mixture was stirred at -78°C for 1 hour, then purged with carbon dioxide and stirred for another hour. The reaction was quenched dropwise with 0.2 M dilute hydrochloric acid (50 mL), extracted with ethyl acetate (30 mL × 2), washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (1‰ trifluoroacetic acid aqueous solution: acetonitrile = 85%-90%) to give compound 53-6. MS m / z (ESI): 415.0 [M-56+H] + .

[0924] Step 6: Synthesis of Compounds 53-7

[0925] To a solution of compound 53-6 (2.0 g, 4.25 mmol) and triethylamine (1.3 g, 12.75 mmol) in anhydrous toluene (100 mL), diphenyl azidophosphate (2.3 g, 8.50 mmol) was added. The mixture was stirred at 80 °C for 1 hour. A toluene solution of aminoacetaldehyde dimethyl acetal (4.4 g, 42.50 mmol) in toluene (5 mL) was added dropwise. The reaction mixture was then heated and stirred at 80 °C for another 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 4 / 1) to give compound 53-7. MS m / z (ESI): 595.2 [M+Na] + .

[0926] Step 7: Synthesis of Compounds 53-8

[0927] Methylsulfonic acid (40 mg, 0.42 mmol) was added to a tetrahydrofuran (2 mL) solution of compound 53-7. The reaction mixture was stirred at 25°C for 3 hours under nitrogen protection. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 1) to give compound 53-8. MS m / z (ESI): 453.2 [M-56+H] + .

[0928] Step 8: Synthesis of Compounds 53-9

[0929] Compounds 1-2 (58 mg, 0.20 mmol), cesium carbonate (192 mg, 0.59 mmol), cuprous iodide (8 mg, 0.04 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.08 mmol) were added to a solution of N-methylpyrrolidone (2 mL). The mixture was stirred at 130 °C for 2 hours under nitrogen protection. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was diluted with methanol (2 mL), and cesium carbonate (192 mg, 0.59 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 5 / 1) to give compound 53-9. MS m / z (ESI): 514.2 [M-56+H] + .

[0930] Step 9: Synthesis of Compounds 53-10

[0931] A solution of compound 53-9 (75 mg, 0.13 mmol) in acetonitrile (2 mL) was reacted with 3,5-dimethyl-4-fluorophenylboronic acid (33 mg, 0.20 mmol), cesium carbonate (0.71 g, 5.12 mmol), copper acetate (24 mg, 0.26 mmol), and pyridine (21 mg, 0.26 mmol). The mixture was purged three times with oxygen, and stirred at 80°C for 1 hour. After concentration under reduced pressure, the residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 4 / 1) to give compound 53-10. MS m / z (ESI): 636.2 [M-56+H] + .

[0932] Step 10: Synthesis of Compounds 53-11

[0933] To compound 53-10 (22 mg, 0.03 mmol), dioxane hydrochloride (1.0 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain compound 53-11, which was used directly in the next reaction. MS m / z (ESI): 592.2 [M+H] + .

[0934] Step 11: Synthesis of Compound 53

[0935] Compound 53-11 (18 mg, 0.03 mmol) and compound GS (13 mg, 0.03 mmol) were reacted with N,N-dimethylformamide (1 mL) containing O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (14 mg, 0.04 mmol) and N,N-diisopropylethylamine (8 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7 μm-30*150 mm A: 0.1% TFA / H2O B: ACN 75% A-95% B: Ret 7.554 min) to obtain compound 53. MS m / z (ESI): 985.6 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.65–7.43(m,2H),7.39–6.91(m,8H),6.91–6.73(m,2H),6.55–6.45(m,1H),6.02–5.85(m,1H),5.55–5.36(m,1H), 5.19–4.71(m,1H),4.25–4.20(m,2H),4.01–3.77(m,4H),3.27–3.06(m,3H),2.36–2.10(m,6H),1.91–1.57(m,11H),1.41–1.25(m,14H).

[0936] Example 73: Preparation of Compound 55

[0937] Compound 55 was synthesized by a similar method to that used for compound 53 in Example 71 (using compounds U and GS as raw materials).

[0938] Compound 55: MS m / z (ESI): 967.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.55–11.75(m,1H),7.60–6.63(m,14H),6.52–5.26(m,2H),5.13–4.50(m,1H),3.82–3.50(m,2H),3. 13–2.84(m,1H),2.78–2.61(m,1H),2.24(s,6H),2.13–1.85(m,1H),1.73–1.45(m,12H),1.36–1.14(m,9H),1.07–0.72(m,5H).

[0939] Example 76: Preparation of Compound 59

[0940] Compound 59 was synthesized by a similar method to that used for compound 53 in Example 71 (using compounds T and GS as raw materials).

[0941] Compound 59: MS m / z (ESI): 941.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.35–11.48(m,1H),7.56–7.10(m,11H),6.94–6.03(m,2H),5.95–5.38(m,1H),5.15–4.71(m,1H),3.81– 3.57(m,2H),3.32–2.78(m,5H),2.66–2.54(m,1H),2.16–2.30(m,6H),2.11–1.86(m,1H),1.76–1.47(m,12H),1.40–1.06(m,10H).

[0942] Example 78: Preparation of Compound 61

[0943] Compound 61 was synthesized by a similar method to that of compound 59 in Example 76 (using 2-(3-cyclopropyl-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane and GS as raw materials).

[0944] Compound 61: MS m / z (ESI): 953.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.20–11.66(m,1H),7.42–7.12(m,10H),7.04–6.70(m,4H),6.44–5.38(m,3H),5.10–4.58(m,1H),3.2 6(s,3H),3.13–2.83(m,2H),2.12–1.90(m,2H),1.74–1.45(m,13H),1.37–1.09(m,10H),1.01–0.90(m,2H),0.73–0.53(m,2H).

[0945] Example 79: Preparation of Compound 62

[0946] Compound 62 was synthesized by a similar method to that used for compound 35 in Example 52 (using compound B and GS as raw materials).

[0947] Compound 62: MS m / z (ESI): 948.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.23–11.67(m,1H),7.65–7.48(m,1H),7.42–7.22(m, 7H),7.16–6.95(m,3H),6.92–6.73(m,2H),5.65–5.38(m,1H),5.09–4.84(m,1H ),4.34–4.21(m,1H),3.31–3.19(m,3H),3.12–2.98(m,2H),2.12–1.95(m,2H), 1.75–1.43(m,13H),1.35–1.17(m,10H),1.02–0.95(m,2H),0.64–0.54(m,2H).

[0948] Example 80: Preparation of Compound 63

[0949] Compound 63 was synthesized by a similar method to that of compound 35 in Example 52 (using 2-((1-fluoroethyl)sulfonyl)benzothiazole as a starting material).

[0950] Compound 63: MS m / z (ESI): 950.6 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.62–7.45(m,3H),7.40–7.21(m,3H),7.19–7.05(m,2H),7.04–6.55(m,3H),5.90–5.30(m,1H), 5.05–4.90(m,1H),4.05–3.65(m,3H),3.20–3.05(m,4H),2.45–1.85(m,9H),1.80–1.65(m,13H),1.40–1.30(m,10H).

[0951] Example 82: Preparation of Compound 66

[0952] Compound 66 was synthesized by a similar method to that used for compound 36 in Example 53 (using triphenylethylphosphine iodide as a starting material).

[0953] Compound 66: MS m / z (ESI): 932.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.65–6.50(m,11H),6.10–5.70(m,1H),5.50–5.30(m,1H),3.95–3.85(m,3H),3.40–3.30(m,3H) ,3.20–3.00(m,2H),2.40–2.20(m,6H),2.10–2.00(m,3H),1.90–1.60(m,10H),1.45–1.40(m,11H),0.95–0.91(m,2H).

[0954] Example 83: Preparation of compounds 67 and 68

[0955] Compounds 67 and 68 were obtained by separating compound 59 using an SFC (Waters_SFC150, Column: ChiralPak OD, 250×30mm ID, 5μm, Mobile phase: Methanol [0.1% NH3 (7M in MeOH)], Flow rate: 100.0, Gradient: 40, Wavelength: 215). The first peak was compound 67 (retention time: 2.179 min), and the second peak was compound 68 (retention time: 2.946 min).

[0956] Compound 67: MS m / z (ESI): 941.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.17–11.75(m,1H),7.54–7.07(m,12H),7.02–6.72(m,2H),6.45–6.10(m,1H),5.80–5.55(m,1H),4.96– 4.58(m,2H),3.77–3.64(m,2H),3.28–3.21(m,2H),3.12–2.95(m,2H),2.31–2.10(m,6H),1.95–1.46(m,13H),1.38–1.11(m,9H).

[0957] Compound 68: MS m / z (ESI): 941.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.13–11.64(m,1H),7.53–6.58(m,14H),6.38–5.40(m,3H),5.02–4.58(m,1H),3.78– 3.58(m,2H),3.28–2.87(m,4H),2.32–2.09(m,6H),2.02–1.85(m,1H),1.76–1.43(m,12H),1.41–1.08(m,9H).

[0958] Example 84: Preparation of Compound 69

[0959] Compound 69 was synthesized by a similar method to that used for compound 48 in Example 66 (using 5-bromo-4-fluoro-1-methyl-1H-indazole and GS as raw materials).

[0960] Compound 69: MS m / z (ESI): 925.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.27–11.59(m,1H),8.33–8.17(m,1H),7.93–7. 22(m,8H),7.13–6.92(m,3H),6.75–6.61(m,1H),5.72–5.33(m,2H),4.28– 4.03(m,4H),3.77–3.68(m,2H),3.11–3.00(m,1H),2.15–1.89(m,2H),1.7 4–1.49(m,8H),1.37–1.14(m,10H),1.06–0.97(m,2H),0.75–0.57(m,2H).

[0961] Example 85: Preparation of Compound 70

[0962] Compound 70 was synthesized by a similar method to that used for compound 49 in Example 67 (using 5-bromo-4-fluoro-1-methyl-1H-indazole and GS as raw materials).

[0963] Compound 70: MS m / z (ESI): 925.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.21–11.59(m,1H),8.35–8.14(m,1H),7.68–7.18(m ,8H),7.13–6.93(m,3H),6.77–6.57(m,1H),5.63–5.35(m,1H),5.14–4.85(m,1 H),4.32–4.00(m,4H),3.79–3.66(m,2H),3.13–3.07(m,1H),2.15–1.96(m,2H) ,1.79–1.47(m,8H),1.31–1.18(m,10H),1.08–0.97(m,2H),0.86–0.62(m,2H).

[0964] Example 86: Preparation of Compound C

[0965] Synthesis route:

[0966] Step 1: Synthesis of compound C-2

[0967] At -78°C, a tetrahydrofuran solution (50 mL, 50 mmol, 1 M) of potassium bis(trimethylsilyl)amino in 40 mL of oxetane-3-carboxylic acid methyl ester (3.00 g, 25.84 mmol) was slowly added dropwise. Under nitrogen protection, the reaction mixture was stirred at -78°C for 1 hour, followed by the addition of a tetrahydrofuran solution (10 mL) of compound C-1 (5.14 g, 25.84 mmol). The reaction mixture was stirred at -78°C for 1 hour, allowed to rise naturally to room temperature, and stirred for another 18 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound C-2. MS m / z(ESI): 296.0 [M+H] + .

[0968] Step 2: Synthesis of compound C-3

[0969] Iron powder (1.36 g, 24.4 mmol) and ammonium chloride (2.61 g, 48.8 mmol) were added to a solution of compound C-2 (4.88 mmol) in ethanol (50 mL) and water (5 mL). The reaction mixture was stirred at 60 °C for 18 hours. After filtration, the filtrate was concentrated and then diluted with water (50 mL). Extraction was performed with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound C-3. MS m / z (ESI): 234.2 [M+H] + .

[0970] Step 3: Synthesis of compound C-4

[0971] To a solution of compound C-3 (650 mg, 2.79 mmol) in N,N-dimethylformamide (5 mL), iodomethane (782 mg, 5.57 mmol) and cesium carbonate (2.27 g, 6.97 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound C-4. MS m / z (ESI): 248.2 [M+H] + .

[0972] Step 4: Synthesis of compound C-5

[0973] To a methanol (2.0 mL) solution of compound C-4 (520 mg, 2.10 mmol), tetrahydrofuran (2.0 mL) and water (2.0 mL) were added sequentially. The reaction mixture was stirred at room temperature for 5 minutes. Then, lithium hydroxide monohydrate (265 mg, 6.31 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and diluted with water (10 mL). The pH was then adjusted to approximately 4 with 1 M dilute hydrochloric acid. A solid precipitated out. The mixture was filtered, and the filter cake was dried to obtain compound C-5. MS m / z (ESI): 234.0 [M+H] + .

[0974] Step 5: Synthesis of compound C-6

[0975] To a solution of compound C-5 (420 mg, 1.80 mmol) in tetrahydrofuran (10 mL), diphenyl azidophosphate (594.72 mg, 2.16 mmol) and triethylamine (0.7 mL, 5.40 mmol) were added, and the reaction mixture was stirred at 50 °C for 1 hour. Then, tert-butanol (10 mL) was added, and the reaction mixture was stirred at 75 °C for 18 hours. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound C-6. MS m / z (ESI): 305.3 [M+H] + .

[0976] Step 6: Synthesis of compound C-7

[0977] Trifluoroacetic acid (1 mL) was added to a dichloromethane (5 mL) solution of compound C-6 (270 mg, 1.38 mmol). The reaction mixture was stirred at room temperature for 5 hours. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound C-7. MS m / z (ESI): 205.2 [M + H] + .

[0978] Step 7: Synthesis of Compound C

[0979] To a solution of compound C-7 (220 mg, 1.08 mmol) in acetonitrile (5 mL), trifluoroacetic acid (0.12 mL, 1.62 mmol) and tert-butyl nitrite (222 mg, 2.15 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Cuprous bromide (309 mg, 2.15 mmol) was then added, and the reaction mixture was stirred at 60 °C for another 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound C. MS m / z (ESI): 268.0, 270.0 [M+H] + .

[0980] Example 87: Preparation of Compound 71

[0981] Compound 71 was synthesized by a similar method to that used for compound 7 in Example 10 (using compound C and GS as raw materials).

[0982] Compound 71: MS m / z (ESI): 948.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.41–11.66(m,1H),7.91–6.62(m,11H),6.03–5.18(m,1H),4.95 –4.60(m,4H),4.29–3.44(m,4H),3.24–2.90(m,4H),2.35–2.15(m,6H),1.8–0.77(m,23H).

[0983] Reference compound 4 and control compound 5 Synthesized with reference to patent WO2025140533.

[0984] Other compounds of the present invention can be prepared by methods similar to those described in the above embodiments (with appropriate modifications if necessary).

[0985] Experimental Example 1: Determination of the ability of compounds to stimulate cAMP production in human GLP1 receptor-stabilized cell lines

[0986] The purpose of this test case was to evaluate the ability of the compound to activate the human GLP-1 receptor on the cell surface. The EC50 of cAMP production following activation characterized the compound's activation ability on the human GLP-1 receptor.

[0987] Cell culture: A cell line stably expressing human GLP1R (H_GLP1R CHO-K1 Cell Line, purchased from Jimon Biotechnology, GM-C35369) was used in the experiment. Cells were maintained in F12K medium (ATCC-30-2004), supplemented with 10% fetal bovine serum (Corning-35-081-CV) and 4 μg / mL puromycin (Gibco-A1113803).

[0988] cAMP assay: When the cell density approaches 80%, remove the culture medium and gently rinse the culture flask with PBS. Add non-enzymatic cell lysis buffer (Sigma-C5914) and incubate at 37°C and 5% CO2 for 5–10 minutes until cells detach. Centrifuge the cell suspension at 1000 rpm for 5 minutes to remove the supernatant. Resuspend the cell pellet in assay buffer (F12K medium containing 0.1% BSA and 0.5 mM IBMX (MCE-HY-12318)) and adjust the cell density to 750 cells / 10 μL / well in white Proxiplate-384 plates (PerkinElmer-6007290) containing serial dilution buffer (maximum concentration 25 μM, 5-fold serial dilution, 12 spots). Centrifuge at 1000 rpm for 1 minute, vortex to mix, and incubate at 37°C and 5% CO2 for 30 minutes. The assay was performed using the Cisbio cAMP-Gs Dynamic Kit (Revvity-62AM4PEB). cAMP-d2 (5 μL, 1x) and Anti-cAMP-Cryptate (5 μL, 1x) were added, and the mixture was incubated at room temperature for 1 hour. HTRF signals were read using an Envision microplate reader with excitation at 320 nm and emission at 620 nm and 665 nm.

[0989] The signal ratio (665nm / 620nm*10,000) was calculated, and the signal ratio was nonlinearly fitted to the sample concentration using a four-parameter equation in GraphPad Prism to obtain the EC. 50 value.

[0990] Experimental results show that the compounds of this invention can significantly increase the accumulation of cAMP in hGLP-1R CHO-K1 cells. The test results of some compounds are shown in Table 1.

[0991] Table 1. EC50 of some compounds in the in vitro cAMP signal activation assay 50

[0992] Experimental Example 2: Human Liver Microsomal Stability Test

[0993] Preheat empty "Incubation" plates T60 and NCF60 for 10 minutes. Dilute human liver microsomes to 0.56 mg / mL in 100 mM phosphate buffer. Transfer 445 μL of the microsome working solution (0.56 mg / mL) to the preheated "Incubation" plates T60 and NCF60, and then incubate the plates at 37°C with shaking for 10 minutes. Transfer 54 μL of liver microsomes to a blank plate, then add 6 μL of NADPH cofactor, followed by 180 μL of quenching solution. Add 5 μL of the compound working solution (100 μM) to the "Incubation" plates (T60 and NCF60) containing microsomes and mix thoroughly three times. For the NCF60 plate, add 50 μL of buffer and mix thoroughly three times. Start timing; the plates will incubate at 37°C for 60 minutes with shaking. In the quenching plate T0, add 180 μL of quenching solution and 6 μL of NADPH cofactor. Ensure the plate is cooled to prevent evaporation. For the T60 plate, mix thoroughly three times, and immediately remove 54 μL of the mixture to the quenching plate at time 0 min. Then add 44 μL of NADPH cofactor to the culture plate (T60). Start timing; the plate will incubate at 37 °C for 60 min with shaking. At 5, 15, 30, 45, and 60 min, add 180 μL of quenching solution to the quenching plate, mix once, and continuously transfer 60 μL of sample from the T60 plate to the quenching plate at each time point. For NCF60: mix once, and at time 60 min, transfer 60 μL of sample from the NCF60 incubator to the quenching plate containing the quenching solution. Shake all sampled plates for 10 min, then centrifuge at 4000 rpm for 20 min at 4 °C. Transfer 80 μL of supernatant to 240 μL of HPLC water and shake for 10 minutes. Seal each bioanalytical plate and shake for 10 minutes, then perform LC-MS / MS analysis.

[0994] Experimental results show that some compounds of the present invention have excellent metabolic stability in human liver microsomes, and some test results are shown in Table 2.

[0995] Table 2. Metabolic stability of human liver microsomes

[0996] Experimental Example 3: Pharmacokinetic Test in Mice

[0997] This study used male CD1 mice (6-8 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.) as test animals. The plasma drug concentrations of the test compounds at different time points after intravenous or oral administration were quantitatively determined using LC-MS / MS to evaluate the pharmacokinetic characteristics of the compounds in mice. Clarified solutions of the test compounds were injected into mice via the tail vein (no fasting, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH, pH 9) and orally (no fasting, food was given 4 hours after administration, with free access to water, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH, pH 10). For intravenous administration, blood samples were collected from the jugular vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. The samples were placed in anticoagulant tubes containing EDTA-K2, mixed thoroughly, and centrifuged at 4000×g for 5 minutes at 4°C to obtain plasma. For oral administration, blood samples were collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. The samples were placed in anticoagulant tubes containing EDTA-K2, mixed thoroughly, and centrifuged at 4000×g for 5 minutes at 4°C to obtain plasma. Plasma concentrations were determined using LC-MS / MS with Phoenix WinNonlin. TM Version 7.0 (Pharsight, USA) pharmacokinetic software calculates relevant pharmacokinetic parameters using the linear logarithmic trapezoidal method with a non-compartmental model.

[0998] Experimental results show that some compounds of the present invention have excellent pharmacokinetic properties. Some test results are shown in Table 3. Among them, compound 1 has a significantly increased exposure level compared with control compounds 1 and 2.

[0999] Table 3. Relevant pharmacokinetic parameters of some compounds in mouse pharmacokinetic tests.

[1000] Experiment Example 4: Rat Pharmacokinetic Test

[1001] In this study, male SD rats (6-9 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.) were used as test animals. The plasma drug concentrations of the test compounds at different time points after intravenous or oral administration were quantitatively determined using LC-MS / MS to evaluate the pharmacokinetic characteristics of the compounds in rats. Clarified solutions of the test compounds were injected into SD rats via the tail vein (no fasting, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH, pH 9) and orally (no fasting, food was given 4 hours after administration, with free access to water, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH, pH 10). For intravenous administration, blood samples were collected from the jugular vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. The samples were placed in anticoagulant tubes containing EDTA-K2, mixed thoroughly, and centrifuged at 6800×g for 6 minutes at 2-8°C to obtain plasma. For oral administration, blood samples were collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. The samples were placed in anticoagulant tubes containing EDTA-K2, mixed thoroughly, and centrifuged at 6800×g for 6 minutes at 2-8°C to obtain plasma. Plasma concentrations were determined using LC-MS / MS with Phoenix WinNonlin. TM Version 7.0 (Pharsight, USA) pharmacokinetic software calculates relevant pharmacokinetic parameters using the linear logarithmic trapezoidal method with a non-compartmental model.

[1002] Experimental results show that some compounds of the present invention have excellent pharmacokinetic properties. Some test results are shown in Table 4. Among them, compound 1 has a significantly increased exposure level compared with control compounds 1 and 2.

[1003] Table 4. Relevant pharmacokinetic parameters of some compounds in rat pharmacokinetic tests

[1004] Experimental Example 5: CYP 2C8 & 2C9 Inhibition Test

[1005] The test compound was prepared as a 10 mM stock solution and then diluted to 0.005, 0.015, 0.05, 0.15, 0.5, 1.5 and 5 mM. The final test concentrations of the test compound were 0.05, 0.15, 0.5, 1.5, 5.0, 15 and 50 μM. The inhibitor substrate was prepared as a 10 mM stock solution with DMSO and then diluted to 20 and 100 μM. The final test concentrations of the inhibitor substrate (the substrates for CYP 2C8 & 2C9 were amodiaquine and diclofenac, respectively) were 2 and 10 μM. The incubation time was 10 min. 100 mM NADPH (MCE, Cat. No. HYF003 / CS-4998) was diluted to 10 mM with phosphate buffer. The final test concentration was 1 mM. Add 2 μL of each concentration of compound and inhibitor solution to a 96-well plate, followed by 20 μL of diluted substrate solution and 158 μL of liver microsome solution. Mix at 1000 rpm for 10 s, pre-incubate at 37°C for 10 min, then add 20 μL of 10 mM NADPH solution and continue incubation for 10 min. Terminate the reaction with 400 μL of ice-cold acetonitrile containing internal standards (500 nM tolbutamide, 10 nM terfenadine). Shake at 1000 rpm for 1 min, then centrifuge at 4000 rpm for 20 min. Take 200 μL of the supernatant, add it to 100 μL of pure water, mix for 10 min, and then inject for LC-MS / MS analysis.

[1006] Experimental results show that some compounds of the present invention have low inhibitory activity against CYP 2C8 and CYP 2C9, which is significantly improved compared with control compounds 1 and 3. Some test results are shown in Table 5.

[1007] Table 5. CYP enzyme inhibition data

[1008] Experiment Example 6: Glucose Tolerance Test in GLP-1R Humanized Mice

[1009] This experiment used male GLP-1R humanized mice, 8 weeks old, provided by Biocytogen Jiangsu Gene Biotechnology Co., Ltd. After arriving at the animal facility, the experimental animals underwent an acclimatization period of at least 3 days before the experiment began. One week before drug administration, animals underwent oral solvent acclimatization training, and their body weight, food intake, and random blood glucose levels were monitored. One week after solvent acclimatization, animals were randomly assigned to groups based on their body weight, fasting blood glucose, and food intake: blank solvent control group, control compound (0.1 mg / kg), and test compound (0.1 mg / kg). All compounds were administered at a dose of 0.1 mg / kg. The blank solvent control group received a single oral administration of the solvent (10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH pH 10), while other groups received a single oral administration of the corresponding compound and the same solvent. Five hours after administration of the compound, a single intraperitoneal injection of glucose (2 g / kg, 10 mL / kg) was administered. Blood glucose levels were collected from the tail vein of the animals for blood glucose testing. Blood glucose values ​​were recorded at the following time points: -5 h, 0 h, 15 min, 30 min, 60 min, and 120 min (the glucose injection time was defined as 0 h). Data were processed, blood glucose-time curves were plotted, and statistical analysis was performed.

[1010] Data for some compounds are shown in Figure 1. The experimental results show that some compounds of this invention can effectively reduce blood glucose in GLP-1R humanized mice during glucose tolerance tests, and the results are statistically significant. Among them, compound 1 significantly reduced blood glucose at a dose of 0.1 mg / kg compared with the control group, and the results were statistically significant (***p<0.001).

[1011] Experimental Example 7: High-fat diet-induced GLP-1R humanized obese mouse model

[1012] Male GLP-1R humanized mice, 6-8 weeks old, were provided by Shanghai Southern Model Biotechnology Co., Ltd. After arriving at the animal facility, the experimental animals underwent an acclimatization period of at least 3 days before the experiment began. The animals were first fed a high-fat diet for 20 weeks, and then randomly divided into groups (N=8) based on their body weight and fasting blood glucose: blank solvent control group, control compound 1 (1, 3, 10 mg / kg), and test compound 1 (1, 3, 10 mg / kg). The corresponding compound or blank solvent (10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH pH 10) was administered orally once daily for 28 days at a volume of 5 mL / kg. Animal body weight and food intake were recorded at least twice a week. Curves were plotted based on animal body weight and food intake for statistical analysis. Random blood glucose was not restricted to fasting, while fasting blood glucose was restricted to fasting for 5 hours. The test results are shown in Table 6.

[1013] Table 6. Data from a high-fat diet-induced GLP-1R humanized obese mouse model.

[1014] Experimental Results: Some compounds of this invention significantly reduced body weight, food intake, and random blood glucose in high-fat diet-induced GLP-1R humanized obese mice. After administration of compound 1 of this invention, mouse body weight decreased significantly, with a clear dose-dependent reduction; the high-dose group showed a body weight reduction of up to 28.3% on day 13 and up to 32.7% on day 28; random blood glucose levels also decreased significantly, showing a dose-dependent effect, with the high-dose group showing lower random blood glucose levels on day 7 compared to the control compound 1. At the same doses of 1 mg / kg, 3 mg / kg, and 10 mg / kg, compound 1 of this invention resulted in a greater reduction in mouse body weight compared to the control compound 1.

[1015] Experimental Example 8: High-fat diet-induced GLP-1R humanized obese mouse model

[1016] Male GLP-1R humanized mice, 6-8 weeks old, were provided by Shanghai Southern Model Biotechnology Co., Ltd. After arriving at the animal facility, the experimental animals underwent an acclimatization period of at least 3 days before the experiment began. The animals were first fed a high-fat diet for 20 weeks, and then randomly divided into three groups (N=8) based on their body weight and fasting blood glucose: a blank solvent control group, control compound 2 (3, 10 mg / kg), and test compound 1 (3, 10 mg / kg). The corresponding compound or blank solvent (10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH pH 10) was administered orally once daily for 13 days at a volume of 5 mL / kg. Animal body weight and food intake were recorded at least twice a week. Curves were plotted based on animal body weight and food intake for statistical analysis. Random blood glucose was not restricted to fasting, while fasting blood glucose was restricted to fasting for 5 hours. The test results are shown in Table 7.

[1017] Table 7 Data from the high-fat diet-induced GLP-1R humanized obese mouse model

[1018] Experimental Results: Some compounds of this invention significantly reduced body weight, food intake, and random blood glucose in high-fat diet-induced GLP-1R humanized obese mice. After administration of compound 1, mouse body weight decreased significantly, with a clear dose-dependent reduction; by day 13, the high-dose group showed a body weight reduction of up to 28.3%. Random blood glucose levels also decreased significantly, showing a dose-dependent effect; the high-dose group had lower random blood glucose levels on day 7 compared to the control compound 2. At the same doses of 3 mg / kg and 10 mg / kg, compound 1 of this invention resulted in a greater reduction in mouse body weight compared to the control compound 2.

[1019] Experimental Example 9: High-fat diet-induced GLP-1R humanized obese mouse model

[1020] This experiment used 6-week-old male GLP-1R humanized mice provided by Shanghai Southern Model Biotechnology Co., Ltd. During the modeling period, the animals were fed a high-fat diet for 16 weeks. After arriving at the animal facility, the experimental animals were individually acclimatized for one week. Then, during the drug adaptation period of one week, all animals were administered solvent 2 (V2) once daily via PO, and simultaneously, all animals were administered solvent 1 (V1) once every 3 days via SC for one week. Finally, the animals were randomly divided into 7 groups according to their body weight and food intake: G1 was the blank solvent V1+V2 control group; G2 was Semaglutide+V2; G3 was Mazdutide+V2; G4 was Tirzepatide+V2; G5 was Tirzepatide+V2; G6 was compound 1+V1; and G7 was compound 1+V1. Solutol 1 (V1) was 0.01 mol / L PBS, and solvent 2 (V2) was 10% Solutol. In groups G2 and G5, the dosage was 30 nmol / kg on Day 1 and Day 4, increasing to 100 nmol / kg from Day 7 onwards. The dosing cycle was 27 days, with a dosage volume of 5 mL / kg. Animal body weight and food intake were recorded daily, and curves were plotted based on animal body weight and food intake for statistical analysis. Some test results are shown in Table 8.

[1021] Table 8 Data from a high-fat diet-induced GLP-1R humanized obese mouse model

[1022] Experimental Results: Some compounds of this invention can significantly reduce the body weight and food intake of GLP-1R humanized obese mice induced by a high-fat diet. After administration of compound 1 of this invention, the mice experienced a significant decrease in body weight, reaching a weight loss plateau at a dose of 10 mg / kg. The weight loss effect was superior to that of Semaglutide and comparable to that of existing Mazdutide and Tirzepatide.

[1023] Experimental Example 10: Pharmacokinetic Test in Monkeys

[1024] In this study, male cynomolgus monkeys (over 2 years old, from Hainan Jingang Biotechnology Co., Ltd.) were used as test animals. The plasma drug concentrations of the test compounds at different time points after intravenous or oral administration were quantitatively determined using LC-MS / MS to evaluate the pharmacokinetic characteristics of the compounds in the monkeys (n=3). Clarified solutions of the test compounds were injected into the monkeys via peripheral vein (no fasting, solvent: 10% PEG400 + 10% PG + 80% Glycine buffer (100mM glycine, 64mM NaOH, pH 10)) and orally (no fasting, food was given 4 hours after administration, with free access to water, solvent: 10% PEG400 + 10% PG + 80% Glycine buffer (100mM glycine, 64mM NaOH, pH 10)). For intravenous administration, blood samples were collected from peripheral veins at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. The samples were placed in anticoagulant tubes containing EDTA-K2, mixed thoroughly, and centrifuged at 3200×g for 10 minutes at 2-8°C to obtain plasma. For oral administration, blood samples were collected from peripheral veins at 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. The samples were placed in anticoagulant tubes containing EDTA-K2, mixed thoroughly, and centrifuged at 3200×g for 10 minutes at 2-8°C to obtain plasma. Plasma concentrations were determined using LC-MS / MS with Phoenix WinNonlin. TM Version 7.0 (Pharsight, USA) pharmacokinetic software calculates relevant pharmacokinetic parameters using the linear logarithmic trapezoidal method with a non-compartmental model.

[1025] Experimental results show that some compounds of the present invention have excellent pharmacokinetic properties in monkeys. Some test results are shown in Table 9, in which compound 1 showed a significantly increased exposure level compared with control compound 1.

[1026] Table 9. Relevant pharmacokinetic parameters of some compounds in monkey pharmacokinetic tests.

[1027] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. A GLP-1R agonist, which is a compound with the structure shown in formula (Ⅰ): Or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts. in: X1, X2, X4, X5, X6, X7, and X8 are each independently selected from C or N; X3 is selected from C, N, O, or S; Ring M1 is selected from a benzene ring or a 6-membered heteroaromatic ring; Ring M2 is selected from 5-membered heterocyclic aromatic rings; R 6a and R 6b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl group, or R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-10 Cyclic hydrocarbon group or 3-12 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 The cyclic hydrocarbon group and the 3-12 membered heterocyclic group are optionally each independently selected by one or more (e.g., 1 to 5) selected from R h The substituents are replaced; R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C1-6 alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced; R 10 Selected from C 1-10 Alkyl, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-10 Alkyl, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced; Or, R 8 and R 9 R 9 and R 10 or R 10 and R 11 They form C together with the atoms they are attached to. 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl, wherein C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced; L is selected from 3-12-membered heterocyclic groups or 5-14-membered heteroaryl groups, wherein the 3-12-membered heterocyclic group and the 5-14-membered heteroaryl group are optionally selected from R by one or more (e.g., 1 to 5). h The substituents are replaced; R 2 Selected from C 3-20 Cyclic hydrocarbon groups, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl, wherein C 3-20 Cyclic hydrocarbon groups, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced; R 1 Selected from C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl, wherein C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl groups are optionally each selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced; Cycle Q1 is selected from 8-18 membered heterocyclic groups; the 8-18 membered heterocyclic group is optionally selected from one or more (e.g., 1 to 5) of R h The substituents are replaced; Cyclomeric Q2 is selected from 3-12-membered heterocyclic groups and 5-10-membered heteroaryl groups; wherein the 3-12-membered heterocyclic group and 5-10-membered heteroaryl group are optionally selected from R by one or more (e.g., 1 to 3) groups. h The substituents are replaced; Each R h Each group is independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, nitro, SF5, and C. 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, -(CR x R y ) t -C(O)R A 、-(CR x R y ) t -C(O)NR B R C 、-(CR x R y ) t -NR D C(O)R E 、-(CR x R y ) t -NR D C(O)NR E R F 、-(CR x R y ) t -C(O)OR A 、-(CR x R y ) t -S(O) n R A 、-(CR x R y ) t -S(O) n NR B R C , The C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, -(CR x R y ) t -C(O)R A 、-(CR x R y ) t -C(O)NR B R C 、-(CR x R y ) t -NR D C(O)R E 、-(CR x R y ) t -NR D C(O)NR E R F 、-(CR x R y ) t -C(O)OR A 、-(CR x R y ) t -S(O) n R A 、-(CR x R y ) t -S(O) n NR B R C , Optionally and independently selected from deuterium, halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, nitro, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Substituents of aryl and 5-10 heteroaryl groups; R x R y Each is independently selected from H or C 1-6 alkyl; t is selected from 0, 1, 2, 3, or 4; n is selected from 1 or 2; R A R B R C R D R E R F R G R H R I Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated deuterated alkyl, hydroxy C 1-6 Alkyl-, C 1-6 Alkoxy C 1-6 Alkyl-, cyano-C 1-6 Alkyl, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 aryl, 5-12 heteroaryl, or, R B and R C Together with the atoms they are attached to, they form 3-12 membered heterocyclic groups, or, R D and R E or R D and R F Together with the atoms they are attached to, they form 3-12 membered heterocyclic groups.

2. The compound according to claim 1, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (II): in: Y1, Y3, Y4, and Y5 are each independently selected from C or N; Y2 is selected from CR e O, S, NR e Or N; Y6 is selected from CH or N; Ring M3 is selected from 5-membered heterocyclic aromatic rings; R 4 R 5 R e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituents are replaced; Preferably, R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 Alkyl; more preferably, R 4 R 5 Each is independently selected from hydrogen or C1-6 alkyl; more preferably, R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl (e.g., C10) 1-3 Alkyl groups, such as methyl groups; R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, the C 3-10 Cyclic hydrocarbon groups and 3-12 membered heterocyclic groups are optionally and independently each composed of 1 to 5 groups selected from R h The substituents are replaced; X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined in claim 1.

3. The compound according to claim 2, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (II'): in: O ring is selected from C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, wherein C 3-10 Cycloalkyl groups and 3-12-membered heterocycloalkyl groups are optionally each independently composed of 1 to 5 groups selected from R h The substituents are replaced; X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined in claim 1; Y1, Y2, Y3, Y4, Y5, Y6, R 4 R 5 As defined in claim 2.

4. The compound according to claim 3, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: O ring is selected from C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl; the C 3-7 Cycloalkyl groups and 3-7-membered heterocycloalkyl groups are optionally each independently composed of 1 to 5 groups selected from R h The substituents are replaced; Preferably, the ring O is selected from C. 3-6 Cycloalkyl, 4-7 membered heterocyclic alkyl; preferably, the ring O is selected from C. 3-6 cycloalkyl; More preferably, the ring O is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and oxacyclobutyl; preferably, the ring O is selected from cyclopropyl, cyclobutyl, and cyclopentyl; more preferably, the ring O is selected from cyclopropyl. More preferably, Selected from Preferred More 5. The compound according to any one of claims 2-4, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: Y4 and Y5 are selected from C; Y1 and Y3 are each independently selected from C or N; preferably, one of Y1 and Y3 is C and the other is N; preferably, Y1 is N and Y3 is C; Y2 is selected from CH or N, preferably Y2 is selected from N; Y6 is selected from CH or N, preferably Y6 is selected from CH; and / or Structural unit Selected from in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; Preferably, structural unit Selected from Preferred More preferably, structural unit Selected from Preferred and / or Structural unit Selected from Preferred Preferred selection (Preferred) )、 (Preferred) Preferred (Preferred) Preferred selection (Preferred) )、 (Preferred) Preferred (Preferred) Preferred selection (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) Preferred selection (Preferred) )、 (Preferred) )、 (Preferred) Preferred (Preferred) ); where the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

6. The compound according to any one of claims 2-5, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (II-1) or (II-2): Preferably, formula (II-1) or (II-2) has the structure shown in formula (II-1') or formula (II-2'): More preferably, formula (II-1') or (II-2') is the structure shown in formula (II-1'-A) or formula (II-2'-A): in, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 As defined in claim 1; R 4 R 5 As defined in claim 2; ring O as defined in any one of claims 3-5.

7. The compound according to claim 1, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (III): in: Y1, Y3, Y4, and Y5 are each independently selected from C or N; Y2 is selected from CR e O, S, NR e Or N; Ring M3 is selected from 5-membered heterocyclic aromatic rings; R 3 R 4 R 5 R e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituents are replaced; R 3’ Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino; more preferably, R 3’ Selected from hydrogen; Or, R 3 and R 3’ Together with the carbon atoms they are attached to, they form C 3-10 Cyclic hydrocarbon groups, 3-12 membered heterocyclic groups, the C 3-10 Cyclic hydrocarbon groups and 3-12 membered heterocyclic groups are optionally and independently each composed of 1 to 5 groups selected from R h The substituents are replaced; Preferably, R 3 R 3’ R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; or, R 3 and R 3’ Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl or 4-7 membered heterocyclic alkyl; More preferably, R 3 R 3’ R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; or, R 3 and R 3’ Together with the carbon atoms they are attached to, they form cyclopropyl groups; More preferably, R 3 R 3’ R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups); X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined in claim 1.

8. The compound according to claim 7, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: Y4 and Y5 are selected from C; Y1 and Y3 are each independently selected from C or N; Y2 is selected from CH or N, preferably Y2 is selected from N; and / or Structural unit Selected from in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; Preferably, structural unit Selected from More preferably, structural unit Selected from and / or Structural unit Selected from Preferred Preferred The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

9. The compound according to claim 7 or 8, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (III-1): in, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 As claimed in claim 1; R 3 R 3’ R 4 R 5 As defined in any one of claims 7 or 8.

10. The compound according to claim 1, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (IV): in: Y1, Y3, Y4, and Y5 are each independently selected from C or N; Y2 is selected from CR e O, S, NR e Or N; Y6 is selected from CH or N; Ring M3 is selected from 5-membered heterocyclic aromatic rings; R 4 R 5 R e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; more preferably, R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; more preferably, R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups); R 3c and R 3d Each is independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably, R 3c and R 3d Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl; preferably, R 3c and R 3d One of them is selected from hydrogen, and the other is selected from halogens (such as F) or C. 1-6 Alkyl (e.g., methyl), or, R 3c and R 3d Simultaneously selected from halogens (e.g., F), or, R 3c and R 3d Simultaneously selected from C 1-6 Alkyl (e.g., methyl), or, R 3c and R 3d One of them is selected from halogens (e.g., F), and the other is selected from C. 1-6 Alkyl (e.g., methyl); preferably, R 3c and R 3d Each is independently selected from hydrogen or halogen; preferably, R 3c and R 3d Simultaneously selected from halogens (e.g., F), or R 3c and R 3d One of them is selected from hydrogen, and the other is selected from halogens (e.g., F); preferably, R 3c and R 3d One of them is selected from hydrogen, and the other is selected from halogens (e.g., F); preferably, R 3c Selected from F, R 3d Selected from H; preferably, R 3c Selected from H, R 3d Selected from F; preferably, R 3c and R 3d One of them is selected from hydrogen, and the other is selected from C. 1-3 Alkyl (e.g., methyl); preferably, R 3c Selected from C 1-3 Alkyl (e.g., methyl), R 3d Selected from H; preferably, R 3c Selected from H, R 3d Selected from C 1-3 Alkyl (e.g., methyl); preferably, R 3c and R 3d Simultaneously selected from C 1-3 Alkyl (e.g., methyl); preferably, R 3c and R 3d One of them is selected from halogens (e.g., F), and the other is selected from C. 1-3 Alkyl (e.g., methyl); preferably, R 3c Selected from C 1-3 Alkyl (e.g., methyl), R 3d Selected from F; preferably, R 3c Selected from F, R 3d Selected from C 1-3 Alkyl groups (e.g., methyl groups); X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined in claim 1.

11. The compound according to claim 10, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: Y4 and Y5 are selected from C; Y1 and Y3 are each independently selected from C or N; preferably, Y1 is selected from N and Y3 is selected from C; Y2 is selected from CH or N, preferably Y2 is selected from N; Y6 is selected from CH or N, preferably Y6 is selected from CH; and / or Structural unit Selected from in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; Preferably, structural unit Selected from Preferred More preferably, structural unit Selected from Preferred and / or Structural unit Selected from Preferred selection (Preferred) Preferred selection (Preferred) )、 (Preferred) )、 (Preferred) )、 Preferred selection (Preferred) )、 (Preferred) )、 (Preferred) Preferred selection (Preferred) Preferred selection (Preferred) Preferred selection Preferred selection Preferred selection Preferred selection Preferred selection The key marked with "#L" is connected to L, and the key marked with "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

12. The compound according to any one of claims 10-11, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (IV-1): Preferably, formula (IV-1) has the structure shown in formula (IV-1'): in, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 As defined in claim 1; R 3c R 3d R 4 R 5 As defined in any one of claims 10 or 11.

13. The compound according to claim 1, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (V): in: Y6 is selected from CH or N; Y7, Y8, Y9, Y 10 Y 11 Each is independently selected from C or N; Ring M4 is selected from 5-membered heterocyclic aromatic rings or 5-membered heterocyclic rings; preferably, ring M4 is selected from 5-membered heterocyclic aromatic rings. Ring W is selected from C 4-10 Cyclic hydrocarbon group, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl; the C 4-10 Cyclic hydrocarbon group, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups are optionally and independently each selected from 1 to 3 R groups. h The substituents are replaced; R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; more preferably, R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; more preferably, R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups); X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined in claim 1.

14. The compound according to claim 13, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (V-1): in: W1, W2, and W3 are each independently selected from CH or N; preferably, W1, W2, and W3 are selected from CH. Ring W is selected from a benzene ring or a 6-membered heteroaromatic ring; preferably, ring W is selected from a benzene ring. R g Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently bounded by 1 to 5 groups selected from deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The substituents of the alkylamino group are replaced; preferably, R g Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl; more preferably, R g Selected from hydrogen, halogens, C 1-6 alkyl; g is selected from 0, 1, 2 or 3; preferably, g is selected from 0 or 1; preferably, g is selected from 0; X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 As defined in claim 1; Y6, Y7, Y8, Y9, Y 10 Y 11 R 4 R 5 As defined in claim 13.

15. The compound according to claim 13 or 14, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: Y6 is selected from CH or N, preferably Y6 is selected from CH; Y7, Y8, Y9, Y 10 Selected from C; Y 11 Selected from N; W1, W2, and W3 are each independently selected from CH or N; preferably, W1, W2, and W3 are selected from CH; and / or Structural unit Selected from Preferred Preferred Preferred Preferred Preferred Preferred (Preferred) ); where the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

16. The compound according to any one of claims 13-15, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (V-2): Preferably, formula (V-2) has the structure shown in formula (V-2-A): in, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R 4 R 5 As defined in any one of claims 13-15; W1, W2, W3, R g g is as defined in claim 14 or 15.

17. The compound according to claim 1, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (VI): in: Y6 is selected from CH or N; W4 and W5 are each independently selected from CR W Or N; preferably, one of W4 and W5 is selected from N; R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; more preferably, R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; more preferably, R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups); R W Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino groups are optionally each independently composed of 1 to 5 groups selected from R h The substituent is replaced by; preferably, R W Selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl; more preferably, R W Selected from hydrogen; X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 R h As defined in claim 1.

18. The compound according to claim 17, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: Y6 is selected from CH or N; preferably, Y6 is selected from CH. One of W4 and W5 is selected from N; and / or Structural unit Selected from (Preferred) Preferred (Preferred) ); More preferably (Preferred) ); where the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 1 The key of the identifier is connected to R. 1 .

19. The compound according to claim 17 or 18, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (VI-1): Preferably, formula (VI-1) has the structure shown in formula (VI-2): in, X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 8 R 9 R 10 R 11 As defined in claim 1, R 4 R 5 W4 and W5 are as defined in claim 17 or 18.

20. The compound according to claim 1, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (VII): in, Y1, Y3, Y4, and Y5 are each independently selected from C or N; Y2 is selected from CR e O, S, NR e Or N; R 3 R 4 R 5 R e Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituent is replaced by; preferably, R 3 R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; more preferably, R 3 R 4 R 5 Each is independently selected from hydrogen or C. 1-6 Alkyl; more preferably, R 3 R 4 Selected from hydrogen, R 5 Selected from C 1-6 Alkyl groups (e.g., methyl groups); R 8 and R 9 Together with the atoms they are attached to, they form C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl, wherein C 3-18 Cyclic hydrocarbon groups, 3-18 membered heterocyclic groups, C 6-18 Aryl or 5-18 heteroaryl groups are optionally and independently composed of 1 to 5 groups selected from R h The substituents are replaced; X1, X2, X3, X4, X5, X6, X7, X8, L, R 1 R 2 R 6a R 6b R 7 R 10 R 11 R h As defined in claim 1; Preferably, formula (VII) has the structure shown in formula (VII-1):

21. The compound according to claim 1, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein ring Q1 is an 8-18 membered bicyclic heterocyclic group or an 8-18 membered tricyclic heterocyclic group; Preferably, when ring Q1 is an 8-18 quintile tricyclic heterocyclic group, it is further preferred that ring Q1 is... The substituents thereon are as defined in claims 3 and 13; Further preferably, when the ring Q1 is an 8-18 quintic bicyclic heterocyclic group, the ring Q1 is... The substituent is as defined in claims 7, 10, 19, and 20; The condition is that Q1 is selected from At that time, R 8 and R 9 They form rings with the atoms they are connected to.

22. The compound according to any one of claims 1-21, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl or C 2-6 alkynyl group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl or C 2-6 The alkynyl group is optionally and independently surrounded by one, two, or three groups selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Substituted with cycloalkyl or 4-7 membered heterocycloalkyl groups; Or, R 8 and R 9 Together with the atoms they are attached to, they form 5-14 membered heteroaryl groups or 5-12 membered heterocyclic groups; the 5-14 membered heteroaryl groups and 5-12 membered heterocyclic groups are optionally each independently bound by 1, 2 or 3 atoms selected from halogen, hydroxyl, amino, mercapto, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Substituents of the alkylamine group; Preferably, R 7 and R 11 Each is independently selected from non-existent, hydrogen, or halogen, R 8 Selected from: non-existent, hydrogen, halogen, cyano, SF5, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2-6 alkenyl or C 2-6 alkynyl group, the C 2-6 alkenyl and C 2-6 The alkynyl group is optionally and independently surrounded by one, two, or three groups selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl or 4-7 membered heterocyclic alkyl groups, R 9 Selected from: non-existent, hydrogen, halogen, cyano, SF5, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2-6 alkenyl or C 2-6 alkynyl group; or, R 8 and R 9 Together with the atoms they are attached to, they form 5-6 heteroaryl groups, which are optionally surrounded by 1, 2, or 3 atoms selected from halogens, C, and D. 1-6 Alkyl or C 1-6 The 5-6-membered heteroaryl group is substituted by a haloalkyl substituent and has 0, 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from oxygen or sulfur. Preferably, R 8 and R 9 Together with the atoms they are attached to, they form a 5-membered heteroaryl group, which is optionally surrounded by 1, 2, or 3 atoms selected from halogens, C, and D. 1-6 Alkyl or C 1-6 The 5-membered heteroaryl group is substituted by a haloalkyl substituent and has 0, 1, or 2 nitrogen heteroatoms and 0 or 1 heteroatom selected from oxygen or sulfur; preferably, the 5-membered heteroaryl group has 2 nitrogen heteroatoms. More preferably, R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, or halogen; More preferably, R 7 R 8 R 9 and R 11 All are hydrogen; R 10 Selected from hydroxyl C 1-6 Alkyl-, 5-8 membered heterocyclic groups; the hydroxyl group C 1-6 Alkyl- or 5-8-membered heterocyclic groups are optionally each independently surrounded by 1, 2, or 3 groups selected from halogens, C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups; Or, R 9 and R 10 Together with the carbon atoms attached to them, they form 5-12 membered heterocyclic groups, wherein the heteroatoms of the 5-12 membered heterocyclic groups are selected from N, S, or O, or two or more combinations thereof, and are optionally surrounded by one, two, or three atoms selected from halogens, oxo groups, thio groups, hydroxyl groups, mercapto groups, cyano groups, amino groups, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Haloalkanesamine, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl or -S(O)2C 1-6 Substituents of haloalkyl groups; Preferably, R 7 R 8 R 11 Both are hydrogen, R 9 and R 10 The atoms bonded to them together form a 9-11 membered spirobicyclic heterocyclic group, wherein the heteroatom of the 9-11 membered spirobicyclic heterocyclic group is selected from nitrogen or oxygen (preferably oxygen), and the number of heteroatoms is 1 or 2 (preferably 2); the 9-11 membered spirobicyclic heterocyclic group is optionally surrounded by 1 or 2 groups selected from halogen, oxo, or C. 1-6 The alkyl substituent is replaced; preferably, the 9-11 membered spirobicyclic heterocyclic group is replaced by one oxo group.

23. The compound according to claim 22, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: Structural unit Selected from Among them, G1, G2, G3, G4, G5, G6, G7, and G8 are each independently selected from CH2, NH, O, or S; Z1, Z2, and Z3 are each independently selected from CH, NH, N, O, or S; ring Z is a 5-membered heteroaromatic ring; Preferably, G1 is selected from O, CH2, S, or NH; more preferably O or CH2; G2 is selected from CH2, O, or NH; more preferably CH2 or O. G3 is selected from O, CH2, or NH; G4 is selected from CH2, O, or NH; G5 is selected from CH2 or O; G6 is selected from O or CH2; G7 is selected from CH2, O, or NH; G8 is selected from CH2, NH, or O; Z1 is selected from CH; Z2 is selected from N or NH; Z3 is selected from N or NH; R g1 R g2 R g3 R g4 R g5 R g6 Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Haloalkanesamine, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl or -S(O)2C 1-6 Haloalkyl, or R g1 and R g2 R g3 and R g4 R g5 and R g6 Together they form an oxygen group; or, R g1 and R g2 R g3 and R g4 R g5 and R g6 Together with the carbon atoms they are attached to, they form C 3-7 cycloalkyl or 4-7 membered heterocyclic groups, wherein the C 3-7 The cycloalkyl group and the 4-7 membered heterocyclic group are optionally surrounded by 1, 2 or 3 groups selected from halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Haloalkanesamine, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl or -S(O)2C 1-6 Substituents of haloalkyl groups; r1, r2, r3, and r4 are each independently selected from 0, 1, or 2; R r1 R r2 R r3 Each is independently selected from halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Haloalkanesamine, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl or -S(O)2C 1-6 Halogenated alkyl groups; R r4 Selected from halogen, hydroxyl, amino, mercapto, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 1-6 Halogenated alkylamine; preferably halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Preferably, structural unit Selected from Preferred Wherein, f1 and f2 are selected from 1, 2, or 3; preferably, f1 and f2 are selected from 2; G9 is selected from O, CH2, S or NH; preferably, G9 is selected from O.

24. The compound according to any one of claims 1-23, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: R 10 Selected from hydroxyl C 1-6 Alkyl or 5-8 membered heterocyclic group, wherein the 5-8 membered heterocyclic group is optionally surrounded by 1, 2 or 3 elements selected from halogen, C 1-6 Alkyl or C 1-6 Substituents of haloalkyl groups; Preferably, R 10 Selected from 6-8 membered heterocyclic groups, wherein the 6-8 membered heterocyclic group is optionally surrounded by 1, 2 or 3 elements selected from halogens, C 1-6 Alkyl or C 1-6 Substituents of haloalkyl groups; Preferably, the heterocyclic group is selected from saturated monocyclic, partially unsaturated monocyclic, saturated bridged bicyclic, saturated fused bicyclic, and saturated spirobicyclic; saturated monocyclic is preferred. Preferably, the heteroatom of the heterocyclic group is selected from O or N, and the number of heteroatoms is selected from 1 or 2; more preferably, the heteroatom of the heterocyclic group is selected from O, and the number of heteroatoms is selected from 1. Preferably, R 10 Selected from tetrahydropyranyl, wherein the tetrahydropyranyl group is optionally surrounded by one or two C atoms. 1-6 Alkyl substitution; Preferably, R 10 Selected from (Preferred) ); R 10a R 10b Each is independently selected from hydrogen or C. 1-6 Alkyl; preferably, R 10a R 10b Each is independently selected from hydrogen or C. 1-4 Alkyl; preferably, R 10a R 10b Each is independently selected from hydrogen or methyl; preferably, R 10a R 10b All are hydrogen; preferably, R 10a R 10b Each is independently selected from C 1-4 Alkyl; preferably, R 10a R 10b All are methyl groups; Preferably, R 10 Selected from (Preferred) )、 (Preferred) Preferred (Preferred) )or More 25. The compound according to any one of claims 1-24, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: Structural unit Selected from Wherein, ring M1 is selected from benzene ring or 6-membered heteroaromatic ring; preferably, ring M1 is selected from benzene ring or 6-membered nitrogen-containing heteroaromatic ring; preferably, ring M1 is selected from benzene ring; Ring M2 is selected from a 5-membered heteroaromatic ring; preferably, ring M2 is selected from a 5-membered nitrogen-containing heteroaromatic ring, a 5-membered sulfur-containing heteroaromatic ring, or a 5-membered oxygen-containing heteroaromatic ring; preferably, ring M2 is selected from a 5-membered nitrogen-containing heteroaromatic ring. X1, X2, X4, X5, X6, X7, and X8 are each independently selected from C or N; X3 is selected from C, N, O or S; preferably, X3 is selected from C; Preferably, structural unit Selected from (Preferred) )； Preferably, structural unit Selected from Preferred Preferred More Preferred Preferred Preferred 26. The compound according to any one of claims 1-25, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: Structural unit Selected from Preferred Preferred Preferred Among them, "#R" 10 The key of the identifier is connected to R. 10 The key identified by "#C(O)" is connected to -C(O)-.

27. The compound according to any one of claims 1-26, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: R 6a and R 6b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; the C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, hydroxyl, mercapto, oxo, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)NHC 1-6 Alkyl, -C 1-3 Alkyl-C(O)NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl, -C 1-3 Alkyl-NHC(O)C 1-6 The alkyl substituents are substituted; the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)NHC 1-6 Alkyl, -C 1-3 Alkyl-C(O)NHC 1-6 Alkyl group, -NHC(O)C 1-6 Alkyl, -C 1-3 Alkyl-NHC(O)C 1-6 Alkyl groups may be substituted, each independently, with substituents selected from deuterium, halogen, hydroxyl, or cyano; Preferably, R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; the C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, or 3 atoms selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups; Preferably, R 6a and R 6b Together with the carbon atoms they are attached to, they form a cyclopropyl group, which is optionally composed of one, two, or three atoms selected from C14 and C24. 1-6 Alkyl substituents; Preferably, Selected from (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) Preferred (Preferred) )、 More preferably, Selected from The key marked with "$" is connected to ring Q2 or 28. The compound according to any one of claims 1-27, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: L is selected from 5-10 membered heterocyclic groups, wherein the 5-10 membered heterocyclic group is optionally surrounded by 1, 2, 3, 4 or 5 groups selected from halogen, hydroxyl, mercapto, amino, cyano, SF5, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Substituents of alkylamino groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino groups may be substituted independently by substituents selected from deuterium and halogens; Preferably, L is selected from in Indicates a single or double bond, and they are adjacent. Not both are double bonds; X is selected from O or S, X0 is selected from C or N, and the ring CL is selected from C. 3-6 Cycloalkyl, 5-7-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl, optionally with 1, 2, or 3 rings selected from halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 The alkylamino group is substituted; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 The alkylamino groups are optionally and independently substituted by substituents selected from deuterium and halogens; [#R] 2 The key of the identifier is connected to R. 2 ; Preferably, L is selected from More With "#R 2 The key of the identifier is connected to R. 2 .

29. The compound according to any one of claims 1-28, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: R 1 Selected from C 5-14 Cyclic hydrocarbon groups, 5-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl; the C 5-14 Cyclic hydrocarbon groups, 5-14 membered heterocyclic groups, C 6-14 The aryl group and the 5-14 heteroaryl group are optionally and independently each surrounded by 1, 2, 3, 4 or 5 groups selected from deuterium, halogen, SF5, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 4-12 membered heterocyclic group, C 6-10 Substituted with aryl or 5-10 heteroaryl groups; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-10 Cyclic hydrocarbon group, 4-12 membered heterocyclic group, C 6-10 The aryl or 5-10 heteroaryl groups are optionally and independently replaced by substituents selected from deuterium and halogens; Preferably, R 1 Selected from C 6-12 Cyclic hydrocarbon groups, 5-14 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; the C 6-12 Cyclic hydrocarbon groups, 5-14 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally and independently bound by 1, 2, 3 or 4 groups selected from halogen, SF5, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 The C group is substituted with substituents of cycloalkyl, 4-7 membered monocyclic heterocyclic groups, 7-11 membered spirobicyclic heterocyclic groups, 7-11 membered bridged bicyclic heterocyclic groups, and 8-10 membered fused bicyclic heterocyclic groups; 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered monocyclic heterocyclic, 7-11 membered spirobicyclic heterocyclic, 7-11 membered bridged bicyclic heterocyclic, and 8-10 membered fused bicyclic heterocyclic are optionally and independently substituted by substituents selected from deuterium and halogens; Preferably, R 1 Selected from phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, 9-10 membered bicyclic heteroaryl, benzo[C] 5-7 Monocyclic cycloalkyl, benzo[C] 7-10 Bridged bicyclic cycloalkyl, benzo[C] 6-10 Fused bicyclic cycloalkyl, benzo[C] 7-10 Spirobicyclic cycloalkyl, benzo5-7 membered monocyclic heterocyclic group, benzo7-10 membered bridged bicyclic heterocyclic group, benzo6-10 membered fused bicyclic heterocyclic group, benzo7-10 membered spirobicyclic heterocyclic group; the above groups are optionally and independently surrounded by 1, 2, 3 or 4 groups selected from halogen, SF5, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 The C group is substituted by substituents of cycloalkyl, 4-7 membered monocyclic heterocyclic alkyl, 7-9 membered spirobicyclic heterocyclic alkyl, 7-9 membered bridged bicyclic heterocyclic alkyl, and 8-10 membered fused bicyclic heterocyclic groups; 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, C1-6 alkoxy group, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 member monocyclic heterocyclic alkyl, 7-9 member spirobicyclic heterocyclic alkyl, 7-9 member bridged bicyclic heterocyclic alkyl, and 8-10 member fused bicyclic heterocyclic alkyl are optionally and independently substituted by substituents selected from deuterium and halogens; Preferably, R 1 Selected from phenyl, naphthyl, indole, indanyl, tetrahydronaphthyl, The above groups are optionally each independently surrounded by 1, 2, 3 or 4 groups selected from halogen, SF5, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 The C group is substituted by substituents of cycloalkyl, 4-7 membered monocyclic heterocyclic alkyl, 7-9 membered spirobicyclic heterocyclic alkyl, 7-9 membered bridged bicyclic heterocyclic alkyl, and 8-10 membered fused bicyclic heterocyclic groups; 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered monocyclic heterocyclic alkyl, 7-9 membered spirobicyclic heterocyclic alkyl, 7-9 membered bridged bicyclic heterocyclic alkyl, and 8-10 membered fused bicyclic heterocyclic alkyl are optionally and independently substituted by substituents selected from halogens; Preferably, R 1 Selected from phenyl, naphthyl, indole, indanyl, tetrahydronaphthyl, The aforementioned groups are optionally and independently surrounded by 1, 2, 3, or 4 groups selected from F, Cl, methyl, cyclopropyl, ethynyl, CF3, SF5, SCF3, The substituents are replaced; Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 elements selected from deuterium, halogen, SF5, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups; Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 elements selected from halogens, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Substituents of cycloalkyl groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group is optionally substituted with one or more (e.g., 2, 3, 4 or 5) halogens; Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 elements selected from halogens, SF5, C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups; Preferably, R 1 Selected from phenyl, wherein the phenyl group is optionally surrounded by 1, 2 or 3 ions selected from halogens (preferably F, Cl), SF5, C 1-6 Substituents of alkyl groups; Preferably, R 1 Selected from phenyl, said phenyl is given by 2 or 3 ions selected from halogens (e.g., F, Cl), SF5, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups; Preferably, R 1 Selected from phenyl, said phenyl is given by 2 or 3 ions selected from halogens (e.g., F, Cl), SF5, C 1-6 Substituents of alkyl groups; Preferably, R 1 Selected from phenyl, said phenyl is oxidized by 2 or 3 ions selected from halogens (e.g., F, Cl), C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups; Preferably, R 1 Selected from phenyl, said phenyl is oxidized by 2 or 3 ions selected from halogens (e.g., F, Cl), C 1-6 Substituents of alkyl groups; Preferably, R 1 Selected from R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group is optionally substituted with one or more (e.g., 2, 3, 4, or 5) halogens, and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), SF5, C 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), and C. 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), SF5, C 1-6 Alkyl (e.g., methyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), and C. 1-6 Alkyl (e.g., methyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from SF5, C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from SF5 or C 1-6 Alkyl (e.g., methyl); preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R 1a Selected from C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from C 1-6 Alkyl groups (e.g., methyl groups); Preferably, R 1 Selected from Preferred Preferred Preferred Preferred Preferred 30. The compound according to any one of claims 1-29, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: R 2 Selected from C 12-20 Cyclic hydrocarbon groups, 12-20 membered heterocyclic groups, C 12-20 Aryl or 12-20 heteroaryl, wherein C 12-20 Cyclic hydrocarbon groups, 12-20 membered heterocyclic groups, C 12-20 Aryl or 12-20 heteroaryl groups are optionally and independently selected from R by one or more (e.g., 1 to 5) groups. h The substituents are replaced; Preferably, R 2 Selected from C 12-18 Cyclic hydrocarbon groups, 12-18 membered heterocyclic groups, C 12-18 Aryl or 12-18 heteroaryl, wherein C 12-18 Cyclic hydrocarbon groups, 12-18 membered heterocyclic groups, C 12-18 The aryl group or 12-18-membered heteroaryl group is tricyclic or tetracyclic; the heteroatom of the 12-18-membered heterocyclic group or 12-18-membered heteroaryl group is selected from nitrogen, oxygen, or sulfur; the C 12-18 Cyclic hydrocarbon groups, 12-18 membered heterocyclic groups, C 12-18 Aryl and 12-18 heteroaryl groups are optionally and independently bounded by 1 to 5 groups selected from deuterium, halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl or The substituents are replaced by the C; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -C(O)C 1-6 Alkyl groups and -S(O)2C 1-6 Alkyl groups are optionally and independently selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Substituents of alkylamino groups; R G R H Each is independently selected from hydrogen or halogen; Preferably, R 2 The heterocyclic group is selected from 13-18 membered heterocyclic groups, wherein the 13-18 membered heterocyclic group is tricyclic or tetracyclic, and the heteroatom of the 13-18 membered heterocyclic group is selected from nitrogen, oxygen, or sulfur, and the number of heteroatoms is selected from 1, 2, 3, or 4; the 13-18 membered heterocyclic group is optionally surrounded by 1 to 5 heteroatoms selected from halogen, hydroxyl, mercapto, oxo, thio, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl or The substituents are replaced by the C; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -C(O)C 1-6 Alkyl groups and -S(O)2C 1-6 Alkyl groups are optionally and independently selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Substituents of alkylamino groups; R G R H Each is independently selected from hydrogen or halogen.

31. The compound according to claim 30, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: R 2 Selected from group (1) or group (2), with group (1) preferred: (1) Wherein, ring A is selected from phenyl or 6-membered nitrogen-containing aryl group; preferably phenyl; Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic hydrocarbon group; preferably 5-6 member monocyclic heterocyclic group; more preferably 5 member monocyclic heterocyclic group having 1 nitrogen heteroatom or oxygen heteroatom, 5 member monocyclic heterocyclic group having 2 oxygen heteroatom, 6 member monocyclic heterocyclic group having 1 or 2 nitrogen heteroatom and 0 or 1 oxygen heteroatom; even more preferably 5 member monocyclic heterocyclic group having 1 nitrogen heteroatom; Cycle C is selected from 4-7 member monocyclic heterocyclic groups, 7-10 member bridged bicyclic heterocyclic groups, 7-10 member spirobicyclic heterocyclic groups, 7-10 member fused bicyclic heterocyclic groups, and C. 4-7 Monocyclic cyclic hydrocarbon group, C 7-10 Bridged bicyclic cyclic hydrocarbon group, C 7-10 Spirobicyclic cycloalkyl group, C7-10 fused bicyclic cycloalkyl group; preferably a 4-6 membered monocyclic heterocyclic alkyl group having one nitrogen heteroatom, oxygen heteroatom, or sulfur heteroatom; a 7-9 membered bridged bicyclic heterocyclic alkyl group having one oxygen heteroatom; a 7-9 membered spirobicyclic heterocyclic alkyl group having one oxygen heteroatom; C 4-6 Monocyclic cycloalkyl, C 5-6 Monocyclic cycloalkenyl, C 7-10 Spirobicycloalkyl, C 7-10 Fused bicyclic cycloalkyl, benzo[C] 5-6 Monocyclic cycloalkyl group, benzo5-6 membered oxamonocyclic heterocyclic group; preferably a 6-membered heterocyclic alkyl group having one oxatom; a, b, and c are each independently selected from 0, 1, 2, 3, or 4; Preferably, a is selected from 0 or 1; b is selected from 0, 1, 2, 3 or 4; c is selected from 0, 1 or 2; R a Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; preferably, R a Selected from deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; R a Halogens (e.g., F) are preferred; R b Selected from hydrogen, deuterium, halogen, oxo group, thio group, cyano group, hydroxyl group, mercapto group, amino group, SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, hydroxyl groups, and C. 1-6 The alkoxy group is substituted; or two R groups attached to the same carbon atom are substituted. b Forming C3-6 cycloalkyl or 4-6 membered heterocycloalkyl; preferably, R b Selected from deuterium, halogen, oxo group, thio group, cyano group, hydroxyl group, mercapto group, amino group, SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, hydroxyl groups, and C. 1-6 The alkoxy group is substituted; or two R groups attached to the same carbon atom are substituted. b Formation C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; R b Preferred halogens, oxo groups, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; or two R groups attached to the same carbon atom are substituted. b Formation C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; R b More preferably, F, oxo group, methyl, cyclopropyl, -(CH2)2OCH3, -CH2CF3, Or two R atoms attached to the same carbon atom b Formation of cyclopropyl; further preferably, at least one R is present. b Selected from oxo groups; R c Selected from hydrogen, deuterium, halogen, oxo group, hydroxyl group, mercapto group, amino group, cyano group, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl, The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C(O)C 1-6 Alkyl groups and -S(O)2C 1-6 Alkyl groups are optionally and independently substituted with substituents selected from deuterium, halogen, cyano, and hydroxyl; R G R H Each is independently selected from hydrogen or halogen; preferably, R c Selected from deuterium, halogen, oxo group, hydroxyl group, mercapto group, amino group, cyano group, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl, The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C(O)C 1-6 Alkyl groups and -S(O)2C1-6 alkyl groups are optionally and independently substituted with substituents selected from deuterium, halogen, cyano, and hydroxyl groups; R G R H Each is independently selected from hydrogen or halogen; R is preferred. c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 alkyl, The C 1-6 Alkyl, -C(O)C 1-6 Alkyl groups are optionally and independently substituted with substituents selected from deuterium, halogen, cyano, and hydroxyl; R G R H Each is independently selected from hydrogen or halogen; more preferably R c Preferred radicals include F, oxoyl, methyl, ethyl, methoxy, -CH2CF3, -CH2CN, -(CH2)2CN, -C(O)CH3, -C(O)CF3, and -C(O)CH(OH)CH3. (2) Wherein, cyclo-A phenyl or a 6-membered nitrogen-containing aryl group; preferably phenyl; Ring B is selected from phenyl, 5-6 membered heteroaryl, and 5-6 membered monocyclic heterocyclic group; preferably 5-membered nitrogen heteroaryl; more preferably pyrrole; The ring C is selected from phenyl, 5-6 membered heteroaryl, 5-7 membered monocyclic heterocyclic group, C 5-7 Monocyclic cyclic hydrocarbon groups, 8-11 membered spirobicyclic heterocyclic groups; a, b, and c are each independently selected from 0, 1, or 2; preferably, a is selected from 0 or 1, b is selected from 0 or 1, and c is selected from 0, 1, or 2. R a Selected from deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; preferably, R a Selected from halogens (e.g., F); R b Selected from deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; preferably R b Selected from halogens, C 1-6 Alkyl groups (e.g., methyl groups); R c Selected from deuterium, oxo group, halogen, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl or -S(O)2C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl or -S(O)2C 1-6 Alkyl groups are optionally and independently substituted with substituents selected from deuterium, halogen, cyano, and hydroxyl; preferably R c Selected from oxo groups, C 1-6 Alkyl (e.g., methyl).

32. The compound according to claim 31, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: The Choose any one of the following groups: in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; single bonds are preferred. A1, A2, A3, C2, C3, C4, C5, C9, C 10 C 11 C 12 Each is independently selected from CH or N; preferably A1, A2, A3, C2, C3, C4, C5, C9, C 10 C 11 C 12 Selected from CH; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH; preferably, A1 is N, and A2 and A3 are both CH; preferably, C9, C 10 C 11 C 12 All are CH; B1 and B2 are each independently selected from CH2, NH or O, and at least one of B1 and B2 is selected from CH2; preferably one of B1 and B2 is selected from NH or O, and the other is selected from CH2. C1 is selected from O, NH, S, CH2, or CH; preferably O; Each C6 atom is independently selected from CH2, NH, O, or S, and no two adjacent C6 atoms are heteroatoms at the same time; preferably, C6 is selected from CH2 or O. C7 and C8 are each independently selected from CH2, NH, O or S, preferably C7 and C8 are each independently selected from CH2 or O; more preferably C7 and C8 are both CH2 or both C7 and C8 are both O; preferably C7 and C8 are both O. C 13 C 14 Each is independently selected from CH2, NH, O, or S, with C being preferred. 13 C 14 Both are O; C 15 Selected from CH2, NH, O or S, with CH2 being preferred; p1, p2, p3, p4, p5, p7, and p8 are each independently selected from 1, 2, or 3; preferably, p1, p2, p3, p4, p5, p7, and p8 are each independently selected from 1 or 2; more preferably, p1 and p2 are selected from 2, p3 is selected from 1, p4 is selected from 2, p5 is selected from 1, p7 is selected from 1 or 2, and p8 is selected from 2. p6 is selected from 1, 2, 3, 4 or 5; preferably, p6 is selected from 1, 2, 3 or 4; more preferably, p6 is selected from 1 or 2; R a R b R c a, b, and c are as defined in claim 30; Preferably, R a Selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl group; preferably halogen, more preferably F; Preferably, R b Selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 Alkyl groups are substituted; preferably C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 Alkyl groups are substituted; preferably C 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably C 1-6 Alkyl (e.g., methyl); more preferably C 1-3 Alkyl groups (e.g., methyl groups); Preferably, R c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 alkyl, R G R H Each is independently selected from hydrogen or halogen (e.g., F); preferably, R c Selected from -S(O)2C 1-4 Alkyl, cyano C 1-4 alkyl-; Preferably, 'a' is selected from 0 or 1; Preferably, b is selected from 0 or 1; Preferably, c is selected from 0, 1, or 2; Preferably, the Selected from Preferred Preferred Preferred Preferred Preferred Preferred Preferred Preferred Preferred Preferred More Among them, p01 and p02 are each independently selected from 1, 2, or 3; A1, A2, A3, R a a, R b R c p1, p2, C9, C 10 C 11 C 12 As defined above; Preferably, p1, p2, p01, and p02 are each independently selected from 1 or 2; preferably, p1, p2, p01, and p02 are all 1; preferably, each R a Independently selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; preferably, each R a Independently selected from halogens (e.g., F), C 1-6 Alkyl; preferably, each R a Independently selected from halogens, more preferably, R a For F; preferably, a is selected from 0 or 1; more preferably, a is 0; preferably, R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6 Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl (e.g., methyl); R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; preferably, R c Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; more preferably, R c Selected from -S(O)2C 1-4 Alkyl, cyano C 1-4 Alkyl-; preferably, R c Selected from hydrogen, C 1-4 Alkyl group, -S(O)2C 1-4 Alkyl, cyano C 1-4 Alkyl-; preferably, R c Selected from hydrogen, C 1-4 Alkyl, cyano C 1-4 Alkyl-; more preferably, R c Selected from hydrogen; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH; preferably, A1 is N, and A2 and A3 are both CH; preferably, C9, C 10 C 11 C 12 All are CH; preferably, C9, C 10 C 11 C 12 One or two of them are N; preferably, R a Substitutable hydrogen atoms on the ring atoms involved in replacing A2 or A3; Preferably, the Selected from Among them, A1, A2, A3, R a a, R b R c c is as defined above.

33. The compound according to claim 32, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: The Choose any one of the following groups: in: A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the rest are CH. B3 is selected from CH2, CF2, O, NH, and NR. b Preferred components: CH2, CF2, NH, NR b CH2 and NR are preferred. b CH2 and NCH3 are preferred; CH2 is preferred. C 16 Selected from CH2, NH, O or S, with O preferred; C 17 Selected from CH2, NH, O or S, preferably O or CH2; more preferably O; p9, p10, p11, and p12 are each independently selected from 1, 2, or 3; preferably, p9, p10, p11, and p12 are each independently selected from 1 or 2; preferably, p11 and p12 are both 1, or p11 and p12 are both 2; more preferably, p11 and p12 are both 2; preferably, p9 and p10 are both 1, or p9 and p10 are both 2; preferably, p9 and p10 are both 2. R a R b R c a, c are as defined in claim 30; Preferably, each R a Independently selected from halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; preferably, each R a Independently selected from halogens (e.g., F), C 1-6 Alkyl; more preferably halogen (e.g., F); R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6 Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl groups (e.g., methyl groups); Preferably, R c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 alkyl, R G R H Each is independently selected from hydrogen or halogen (e.g., F); more preferably halogen (e.g., F); Preferably, 'a' is selected from 0 or 1; more preferably, 0. Preferably, c is selected from 0, 1, or 2; more preferably, c is selected from 0. Preferably, R a Substitutable hydrogen atoms on the ring atoms involved in replacing A2 or A3; Preferably, the Selected from Preferred Preferred More Among them, A1, A2, A3, B3, R a a, R b p9, p10, p11, and p12 are defined as above.

34. The compound according to claim 33, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: The Selected from in, It is a single or double bond, and they are adjacent. Not both are double bonds; A1, A2, and A3 are each independently selected from CH or N; CH is preferred. B4 is selected from NH and NR. b , O, S, CH, CR b CH2, C(R) b )2; Preferably, B4 is selected from NH, CH, NR b or CR b ; More preferably CR b Or CH; further preferred CH; B5 is selected from C or N; N is preferred. Ring B is selected from a 5-membered heterocyclic aromatic ring or a 5-membered heterocyclic ring; preferably, ring B is selected from a 5-membered heterocyclic aromatic ring. The ring C is selected from phenyl, 6-membered heteroaryl, C6 monocyclic cyclic hydrocarbon, 6-membered monocyclic heterocyclic group, and 9-11-membered spirobicyclic heterocyclic group; R a R b R c a, c are as defined in claim 30; Preferably, R a Selected from halogen or C 1-6 alkyl; Preferably, R b Selected from halogens, C 1-6 alkyl; Preferably, R c Selected from oxo groups, halogens, C 1-6 alkyl; Preferably, 'a' is selected from 0 or 1; Preferably, c is selected from 1 or 2.

35. The compound according to claim 34, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: The Selected from in: C 18 Selected from CH2, CHF, CF2, NH, O, or S; preferably C. 18 Selected from O; p13 and p14 are each independently selected from 1, 2 or 3; preferably p13 and p14 are each independently selected from 1 or 2; more preferably p13 and p14 are selected from 2; A1, A2, A3, B4, B5, R a R c As defined in claim 30 or 33; Preferably, R c Selected from halogen or C 1-6 alkyl.

36. The compound according to any one of claims 1-35, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein: The R 2 Selected from Preferred R 2 Selected from Preferred Preferred Preferred More Preferred Preferred Preferred Preferred Preferred Preferred Preferred Preferred Preferred Preferred Preferred Preferred 37. The compound according to any one of claims 1-36, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is shown in any of the structures of formulas (X-1) to (X-7): Among them, R 1 R 2 R 10 f1, f2, and G9 are as defined in any one of claims 1-36.

38. The compound according to claim 37, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is shown in formula (X-1-1): Among them, R 10a R 10b R 1a R 1b R 1c and R 2 As defined in any one of claims 1-37.

39. The compound according to claim 38, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, R 10a R 10b Each is independently selected from hydrogen or C. 1-4 Alkyl; preferably, R 10a R 10b Each is independently selected from hydrogen or methyl; preferably, R 10a R 10b All are hydrogen; preferably, R 10a R 10b Each is independently selected from C 1-4 Alkyl; preferably, R 10a R 10b All are methyl groups; R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group is optionally substituted with one or more (e.g., 2, 3, 4, or 5) halogens, and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), SF5, C 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), and C. 1-6 Alkyl (e.g., methyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), SF5, C 1-6 Alkyl (e.g., methyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a R 1b and R 1c Each is independently selected from hydrogen, halogens (e.g., F, Cl), and C. 1-6 Alkyl (e.g., methyl), and R 1a R 1b and R 1c Not simultaneously selected from hydrogen; preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from SF5, C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from SF5 or C 1-6 Alkyl (e.g., methyl); preferably, R 1a Selected from hydrogen or C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R 1a Selected from C 1-6 Alkyl (e.g., methyl), R 1b Selected from halogens (e.g., F), R 1c Selected from C 1-6 Alkyl groups (e.g., methyl groups); R 2 Selected from groups (1) and (2): (1) Wherein, p1, p2, p01, and p02 are each independently selected from 1 or 2; preferably, p1, p2, p01, and p02 are all 1; A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH (for example, A1 is N, and A2 and A3 are both CH); C9, C 10 C 11 C 12 Each is independently selected from CH or N; preferably, C9, C 10 C 11 C 12 All are CH; preferably, C9, C 10 C 11 C 12 One or two of them are N, and the rest are CH; each R a Independently selected from halogens (e.g., F), C 1-6 Alkyl; preferably, each R a Independently selected from halogens (e.g., F); R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6 Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl (e.g., methyl); preferably, R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; preferably, R c Selected from hydrogen, C 1-4 Alkyl group, -S(O)2C 1-4 Alkyl, cyano C 1-4 Alkyl-; preferably, R c Selected from hydrogen, C 1-4 Alkyl, cyano C 1-4 Alkyl-; more preferably, R c Selected from hydrogen; a is selected from 0 or 1; preferably, a is 0; preferably, R a The substituted hydrogen atoms on the ring atoms involved in replacing A2 or A3; preferably Preferred Preferred Preferred Preferred Preferred More (2) Wherein, A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; B3 is selected from CH2, CF2, NH, and NR. b Or O; preferably, B3 is selected from CH2, CF2, NH, NR b Preferably, B3 is selected from CH2 and NR. b Preferably, B3 is selected from CH2 or NCH3; preferably, B3 is selected from CH2; p11 and p12 are each independently selected from 1 or 2; preferably, p11 and p12 are both 1, or p11 and p12 are both 2; preferably, p11 and p12 are both 2; p9 and p10 are each independently selected from 1 or 2; preferably, p9 and p10 are both 1, or p9 and p10 are both 2; preferably, p9 and p10 are both 2; each R a Independently selected from halogens (e.g., F), C 1-6 Alkyl; preferably, each R a Independently selected from halogens (e.g., F); R b Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, R b Selected from C 1-6 Alkyl (e.g., methyl); more preferably, R b Selected from C 1-3 Alkyl (e.g., methyl); a is selected from 0 or 1; preferably, a is 0; preferably, R a The substituted hydrogen atoms on the ring atoms involved in replacing A2 or A3; preferably Preferred More Preferably, R 2 Selected from group (1).

40. The compound according to any one of claims 1-36, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is shown in formula (IV-1'-1): Among them, R 1 R 2 R 3c R 3d R 4 R 5 R 6a R 6b R 10 As defined in any one of claims 1-36; Preferably, formula (IV-1'-1) is as shown in formula (IV-1'-1A): Among them, R 10a R 10b R 1a R 1b R 1c and R 2 As defined in any one of claims 1-36.

41. The compound according to claim 40, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, R 2 Selected from 9-10-membered bicyclic heteroaryl groups and 11-15-membered tricyclic heterocyclic groups; wherein the 9-10-membered bicyclic heteroaryl group and the 11-15-membered tricyclic heterocyclic group are optionally each independently selected from R... h The substituents are replaced; Preferably, R 2 Selected from 9-10-membered bicyclic heteroaryl groups and 11-15-membered tricyclic heterocyclic groups; wherein each of the 9-10-membered bicyclic heteroaryl groups is optionally and independently selected from one or more (e.g., 1, 2, or 3) groups selected from halogen, hydroxyl, mercapto, cyano, amino, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-7-membered heterocyclic alkyl groups are optionally and independently selected from halogens, hydroxyl groups, mercapto groups, amino groups, cyano groups, SF5, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 The 11-15 membered tricyclic heterocyclic groups are optionally and independently each replaced by one or more (e.g., 1, 2, or 3) groups selected from halogen, hydroxyl, mercapto, cyano, amino, SF5, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-7-membered heterocyclic alkyl groups are optionally and independently selected from halogens, hydroxyl groups, mercapto groups, amino groups, cyano groups, SF5, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 The alkylamino group is substituted; the heteroatom of the 9-10 membered bicyclic heteroaryl group is selected from nitrogen, oxygen, and sulfur, preferably nitrogen; the number of heteroatoms of the 9-10 membered bicyclic heteroaryl group is selected from 1, 2, and 3, preferably 2; the heteroatom of the 11-15 membered tricyclic heterocyclic group is selected from nitrogen, oxygen, and sulfur, preferably nitrogen and oxygen, preferably nitrogen; the number of heteroatoms of the 11-15 membered tricyclic heterocyclic group is selected from 1, 2, and 3, preferably 1 and 2; Preferably, R 2 Selected from 9-10-membered bicyclic heteroaryl groups and 11-15-membered tricyclic heterocyclic groups; wherein each of the 9-10-membered bicyclic heteroaryl groups is optionally and independently selected by one or more (e.g., 1, 2 or 3) halogens (e.g., F, C). 1-6 Alkyl, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; the 11-15 membered tricyclic heterocyclic group is optionally and independently each replaced by one or more (e.g., 1, 2 or 3) selected from halogens (e.g., F), oxo groups, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; the heteroatom of the 9-10 membered bicyclic heteroaryl group is selected from nitrogen, oxygen, and sulfur, preferably nitrogen; the number of heteroatoms of the 9-10 membered bicyclic heteroaryl group is selected from 1, 2, and 3, preferably 2; at least one heteroatom of the 11-15 membered tricyclic heterocyclic group is selected from nitrogen, and if an additional heteroatom is present, the additional heteroatom is selected from nitrogen, oxygen, and sulfur (preferably the additional heteroatom is selected from nitrogen and oxygen, more preferably the additional heteroatom is selected from oxygen); the number of heteroatoms of the 11-15 membered tricyclic heterocyclic group is selected from 1, 2, and 3, preferably 1 and 2; Preferably, R 2 Selected from Wherein, A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH. B7 and B8 are each independently selected from CH or N; preferably, one of B7 and B8 is selected from CH and the other is selected from N; preferably, B8 is selected from CH and B7 is selected from N; B6 is selected from NH, O, or S; preferably, B6 is selected from NH. C 19 Selected from NR c O or S; preferably, C 19 Selected from O; R a Selected from hydrogen, halogens (e.g., F), cyano, SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl; preferably, R a Selected from hydrogen, halogens (e.g., F); preferably, R a Selected from halogens (e.g., F); R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl, C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., C10) 1-3 Alkyl groups, such as methyl groups; R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; preferably, R c Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano C 1-4 alkyl-; a is selected from 0 or 1; preferably, a is selected from 0; preferably, a is selected from 1; b is selected from 0 or 1; preferably, b is selected from 1; p15 is selected from 1, 2, 3 or 4; preferably, p15 is selected from 1, 2 or 3; preferably, p15 is selected from 1 or 2; preferably, p15 is selected from 1. p16 and p17 are each independently selected from 1 or 2; preferably, p16 and p17 are both selected from 2. Preferably, R a The substituted hydrogen atom on the ring atom involved in replacing A2 or A3; more preferably, R a Substitutable hydrogen atoms on the ring atoms involved in replacing A3; Preferably, R 2 Selected from More preferably, R 2 Selected from 42. The compound according to any one of claims 1-36, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is shown in formula (V-2-1): Among them, R 1 R 2 R g R 4 R 5 R 6a R 6b R 10 g is as defined in any one of claims 1-36; Preferably, the formula (V-2-1) is as shown in formula (V-2-1A): Among them, R g , g, R 4 R 5 R 10a R 10b R 1a R 1b R 1c and R 2 As defined in any one of claims 1-36.

43. The compound according to claim 42, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, R 2 Selected from 11-15 quinary tricyclic heterocyclic groups; wherein each of the 11-15 quinary tricyclic heterocyclic groups is optionally selected independently from one or more (e.g., 1, 2 or 3) of R h The substituents are replaced; Preferably, R 2 Selected from 11-15 membered tricyclic heterocyclic groups; wherein each of the 11-15 membered tricyclic heterocyclic groups is optionally and independently selected from one or more (e.g., 1, 2 or 3) groups selected from halogen, hydroxyl, mercapto, cyano, amino, SF5, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups and 4-7-membered heterocyclic alkyl groups are optionally and independently selected from halogens, hydroxyl groups, mercapto groups, amino groups, cyano groups, SF5, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 The alkylamino group is substituted; the heteroatom of the 11-15 membered tricyclic heterocyclic group is selected from nitrogen, oxygen and sulfur, preferably nitrogen and oxygen, and more preferably nitrogen; the number of heteroatoms of the 11-15 membered tricyclic heterocyclic group is selected from 1, 2 and 3, preferably 1 and 2; Preferably, R 2 Selected from 11-15 membered tricyclic heterocyclic groups; wherein each of the 11-15 membered tricyclic heterocyclic groups is optionally and independently selected by one or more (e.g., 1, 2 or 3) groups selected from halogens (e.g., F), oxo groups, C. 1-6 Alkyl, C 3-6 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; at least one heteroatom of the 11-15 membered tricyclic heterocyclic group is selected from nitrogen, and if an additional heteroatom is present, the additional heteroatom is selected from nitrogen, oxygen and sulfur (preferably the additional heteroatom is selected from nitrogen and oxygen, more preferably the additional heteroatom is selected from oxygen); the number of heteroatoms of the 11-15 membered tricyclic heterocyclic group is selected from 1, 2 and 3, preferably 1 and 2; Preferably, R 2 Selected from Preferred Wherein, A1, A2, and A3 are each independently selected from CH or N; preferably, A1, A2, and A3 are all CH; preferably, one of A1, A2, and A3 is N, and the other two are CH. C 19 Selected from NR c O or S; preferably, C 19 Selected from O; R a Selected from hydrogen, halogens (e.g., F), cyano, SF5, C 1-6 Alkyl, C 1-6 Halogenated alkyl; preferably, R a Selected from hydrogen, halogens (e.g., F); preferably, R a Selected from halogens (e.g., F); R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from halogens, cyano groups, and C6 groups. 1-4 The alkoxy group is substituted; preferably, R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl, C 3-6 cycloalkyl; preferably, R b Selected from C 1-6 Alkyl (e.g., C10) 1-3 Alkyl groups, such as methyl groups; R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkyl-, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Haloalkyl, -C(O)C 1-6 Hydroxyalkyl, -S(O)2C 1-6 Alkyl; preferably, R c Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano C 1-4 alkyl-; a is selected from 0 or 1; preferably, a is selected from 0; p15 is selected from 1, 2, 3 or 4; preferably, p15 is selected from 1, 2 or 3; preferably, p15 is selected from 1 or 2; preferably, p15 is selected from 1. p16 and p17 are each independently selected from 1 or 2; preferably, p16 and p17 are both selected from 2. Preferably, R a The substituted hydrogen atom on the ring atom involved in replacing A2 or A3; more preferably, R a The substituted hydrogen atoms on the ring atoms involved in replacing A3.

44. The compound according to any one of claims 1-43, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is selected from:

45. The compound according to any one of claims 1-44, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is not 46. ​​The compound according to any one of claims 1-44, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is not 47. A pharmaceutical composition comprising the compound of any one of claims 1-46, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, diluents, or excipients.

48. A pharmaceutical combination comprising the compound of any one of claims 1-46, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and another therapeutically active agent.

49. The compound according to any one of claims 1-46, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or the use of the individual in administering a therapeutically effective amount of the pharmaceutical composition according to claim 47; or the use of the individual in administering a therapeutically effective amount of the pharmaceutical composition according to claim 48 in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or disorders or GLP-1-related diseases, conditions, or symptoms, or for modulating GLP-1 receptors.

50. A method for preventing and / or treating GLP-1 receptor-mediated diseases or disorders or GLP-1-related diseases, conditions, or symptoms, said method comprising: The individual is given a therapeutically effective amount of the compound according to any one of claims 1-46, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or the individual is given a therapeutically effective amount of the pharmaceutical composition according to claim 47; or the individual is given a therapeutically effective amount of the pharmaceutical combination according to claim 48.

51. The application according to claim 49 or the method according to claim 50, characterized in that, The GLP-1 receptor-mediated diseases or disorders, or GLP-1-related diseases, conditions, or symptoms include metabolic diseases, cardiovascular diseases, liver diseases, kidney diseases, and neurodegenerative diseases. Preferably, The metabolic diseases mentioned include diabetes, diabetic complications, and obesity; The cardiovascular diseases mentioned include hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, and cerebral infarction; The liver diseases mentioned include non-alcoholic steatohepatitis; The kidney disease mentioned includes type 2 diabetes mellitus complicated with chronic kidney disease; The neurodegenerative diseases mentioned include Parkinson's disease or dementia.

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