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

Abstract

The present invention relates to the field of pharmaceutics and specifically relates to a GLP-1R agonist capable of lowering the blood glucose level by enhancing insulin secretion in a glucose-dependent manner, which is a compound having a structure represented by formula (I) or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated compound), a N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, 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. 202510117448.X, filed with the China National Intellectual Property Administration on January 24, 2025, and Chinese patent application No. 202510255429.3, filed with the China National Intellectual Property Administration on March 5, 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. Currently approved GLP-1 receptor agonists are all 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 heterocyclic aromatic 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 group, 3-12 membered heterocyclic group, 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 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;

[0021] 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,

[0022] 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 The aryl and 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 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 The aryl and 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;

[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 The aryl and 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;

[0026] 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;

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

[0028] Ring Q3 is selected from C3-18 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 The aryl and 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;

[0029] Each R h Each group is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, oxo (=O), thio (=S), cyano, 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 2-10alkenyl, 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, each independently is selected from one or more groups 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;

[0030] R x R y Each is independently selected from H or C 1-6 alkyl;

[0031] t is selected from 0, 1, 2, 3, or 4;

[0032] n is selected from 1 or 2;

[0033] 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, 5-10 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.

[0034] In this invention, as one embodiment, the ring Q2 is selected from 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups; the 5-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally each independently surrounded by 1, 2 or 3 groups selected from deuterium, halogen, hydroxyl, mercapto, amino, oxo, thio, 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 Substituents of alkylamino groups;

[0035] Preferably, ring Q2 is selected from

[0036] In this invention, as one embodiment, ring Q1 is selected from 9-14 membered heterocyclic groups, wherein the 9-14 membered heterocyclic group has 2, 3, or 4 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms (preferably having 2, 3, or 4 nitrogen heteroatoms and 0 oxygen or sulfur heteroatoms); the 9-14 membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, or 5 atoms selected from deuterium, halogen, hydroxyl, mercapto, amino, oxo, thio, 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, The substituents are replaced by 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 groups are optionally and independently 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 Substituents of alkylamino groups; R G R H Each is independently selected from hydrogen or halogen.

[0037] In this invention, as one embodiment, the ring Q1 is selected from...

[0038] in, Indicates a double bond or a single bond, and they are adjacent. Not both are double bonds;

[0039] Keys identified by "#L" are connected to L, and keys identified by "#R" are connected to L. 1 The key of the identifier is connected to R. 1 ;

[0040] Y1, Y3, Y4, and Y5 are each independently selected from C or N;

[0041] Y2 is selected from C (=O), C (=S), CR e O, S, NR e Or N;

[0042] Each Y6 is independently selected from C or N;

[0043] W4 and W5 are each independently selected from CR WOr N; preferably, one of W4 and W5 is selected from N, and the other is selected from CR. W ;

[0044] Ring M3 is selected from 5-membered heterocyclic aromatic rings or 5-membered heterocyclic rings; preferably 5-membered heterocyclic aromatic rings;

[0045] Each R 3a R 3b R 4a R 4b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, and 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, or, R 3a and R 3b R 4a and R 4b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 3a and R 3b R 4a and R 4b Together with the carbon atoms they are attached to, they form Or, R 3a and R 4a Or R 4b R 3b and R 4a Or R 4b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl; 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 3-7 The cycloalkyl group and the 3-7 membered heterocycloalkyl group are optionally and independently 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 Substituents of alkylamino groups; R G R H Each is independently selected from hydrogen or halogen;

[0046] Each R 5aand R 5b Each is independently selected from non-existent, hydrogen, 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, or, R 5a and R 5b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 5a and R 3a Or R 3b Or R 4a Or R 4b R 5b and R 3a Or R 3b Or R 4a Or R 4b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl; 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 3-7 The cycloalkyl group and the 3-7 membered heterocycloalkyl group are optionally and independently 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 The substituents of the alkylamino group are replaced; the condition is that when Y6 is selected from N, R 5a and R 5b There is one and only one that does not exist;

[0047] R e Selected from hydrogen, 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, or, R e and R 3a Or R 3b Together with the atoms they are attached to, they form C 3-7Cyclic hydrocarbon group or 4-7 membered heterocyclic group, or, R e and R 3a and R 3b Together with the atoms they are attached to, they form C 6-10 Aryl or 5-10 heteroaryl; 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 3-7 Cyclic hydrocarbon group, 4-7 membered heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are optionally and independently 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 Substituents of alkylamino groups;

[0048] R W Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, 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, 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 groups are optionally and independently 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 The substituents of the alkylamino group are replaced.

[0049] In this invention, as one embodiment, ring Q1 is selected from... in:

[0050] 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 N and the other is C;

[0052] Y2 is selected from C (=O), CR e Or N, preferably, Y2 is selected from C or N; more preferably, Y2 is selected from N;

[0053] Y6 is selected from C or N;

[0054] R 3a R 3b R 4a R 4b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Haloalkyl, or R 3a and R 3b Together with the carbon atoms they are attached to form Or, R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 3a and R 4a Or R 4b R 3b and R 4a Or R 4b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocyclic alkyl; R G R H Each is independently selected from hydrogen or halogen; R 5a and R 5b Each is independently selected from non-existent, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Haloalkyl, or R 5a and R 5b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 5a and R 3a Or R 3b Or R 4a Or R 4b R 5b and R 3a Or R 3b Or R 4a Or R 4b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl; provided that when Y6 is selected from N, R 5a and R 5b There is one and only one that does not exist; R e Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Haloalkyl, or R eand R 3a and R 3b Together with the atoms they are attached to, they form phenyl or 6-membered heteroaryl groups;

[0055] Preferably, Selected from More Keys identified by "#L" are connected to L, and keys identified by "#R" are connected to L. 1 The key of the identifier is connected to R. 1 .

[0056] In this invention, as one of the implementation schemes, 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 .

[0057] In this invention, as one of the embodiments, Y4 and Y5 are selected from C.

[0058] In this invention, as one embodiment, Y1 and Y3 are each independently selected from C or N; preferably, one of Y1 and Y3 is N and the other is C.

[0059] In this invention, as one of the embodiments, Y1 is selected from N and Y3 is selected from C.

[0060] In this invention, as one embodiment, Y2 is selected from C (=O) and CR. e Or N, preferably, Y2 is selected from N.

[0061] In this invention, as one of the embodiments, Y6 is selected from C or N, preferably C.

[0062] In this invention, as one of the embodiments, R 3a R 3b R 4a R 4b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Haloalkyl, or R 3a and R 3b Together with the carbon atoms they are attached to form Or, R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 3a and R4a Or R 4b R 3b and R 4a Or R 4b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocyclic alkyl; R G R H Each is independently selected from hydrogen or halogen.

[0063] In this invention, as one of the embodiments, R 3a R 3b Each is independently selected from hydrogen, halogens, and C. 1-6 Alkyl, or R 3a and R 3b Together with the carbon atoms they are attached to form R G R H Each is independently selected from hydrogen and halogens (e.g., F); or, R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-6 Cycloalkyl.

[0064] In this invention, as one of the embodiments, R 3a R 3b All are selected from hydrogen.

[0065] In this invention, as one of the embodiments, R 3a and R 3b Together with the carbon atoms they are attached to form R G R H Each is independently selected from hydrogen and halogens (e.g., F), preferably, R G R H One of them is selected from halogens (e.g., F), and the other is selected from hydrogen; preferably, R G Selected from hydrogen, R H Selected from halogens (e.g., F); preferably, R G Selected from halogens (e.g., F), R H Selected from hydrogen; preferably, R G R H All are selected from halogens (e.g., F).

[0066] In this invention, as one of the embodiments, R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-6 Cycloalkyl (e.g., cyclopropyl).

[0067] In this invention, as one of the embodiments, R 4a R 4bEach is independently selected from hydrogen, halogens, and C. 1-6 alkyl.

[0068] In this invention, as one of the embodiments, R 4a R 4b All are selected from hydrogen.

[0069] In this invention, as one of the embodiments, R 5a and R 5b Each is independently selected from non-existent, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Haloalkyl, or R 5a and R 5b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 5a and R 3a Or R 3b Or R 4a Or R 4b R 5b and R 3a Or R 3b Or R 4a Or R 4b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl; provided that when Y6 is selected from N, R 5a and R 5b There is one and only one that does not exist.

[0070] In this invention, as one of the embodiments, R 5b Selected from hydrogen, R 5a Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0071] In this invention, as one of the embodiments, R 5b Selected from hydrogen, R 5a Selected from C 1-6 Alkyl (e.g., methyl, preferably) ).

[0072] In this invention, as one of the implementation schemes, 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 .

[0073] In this invention, as one of the embodiments, R e Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6Haloalkyl, or R e and R 3a and R 3b Together with the atoms they are attached to, they form phenyl or 6-membered heteroaryl groups.

[0074] In this invention, as one embodiment, the ring Q1 is selected from... in:

[0075] The Y6 is selected from C or N;

[0076] R 4a R 4b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0077] R 5a R 5b Each is independently selected from non-existent, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Haloalkyl, provided that when Y6 is selected from N, R 5a and R 5b There is one and only one that does not exist;

[0078] W4 and W5 are each independently selected from CR W Or N;

[0079] R W Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0080] Preferably, Y6 is selected from C;

[0081] R 4a R 4b One of them is selected from hydrogen, and the other is selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0082] R 5a R 5b One of them is selected from hydrogen, and the other is selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0083] W4 is selected from CR W W5 is selected from N, or W4 is selected from N and W5 is selected from CR. W ;

[0084] R W Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0085] Preferably, Selected from More Keys identified by "#L" are connected to L, and keys identified by "#R" are connected to L. 1 The key of the identifier is connected to R. 1 .

[0086] In this invention, as one embodiment, the compound is as shown in formula (I-1), (I-2), (I-3), (I-4), or (I-5):

[0087] Among them, X1, X2, X3, X4, X5, X6, X7, X8, R 6a R 6b R 7 R 8 R 9 R 10 R 11 L, Q3, R 2 R 1 Y6, R 3a R 3b R 4a R 4b R 5a R 5b R e W4 and W5 are as defined in any of the above items.

[0088] In this invention, as one embodiment, the 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 1-6Alkyl, 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;

[0089] 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 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkyne group, -C(O)NHC 1-3 Alkyl, -C 1-3 Alkylene-C(O)NHC 1-3 Alkyl group, -NHC(O)C 1-3 Alkyl, -C 1-3 Alkylene-NHC(O)C 1-3 Alkyl substituents;

[0090] 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 groups selected from cyano, C 1-3 Alkyl, C 2-3 alkynyl group, -C 1-3 Alkylene-C(O)NHC 1-3 Alkyl group, -NHC(O)C 1-3 Alkyl substituents;

[0091] 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;

[0092] Preferably, Selected from Preferred More The key marked with "$" is connected to Q2 or

[0093] In this invention, as one of the implementation schemes, Selected from (For example )and The key marked with "$" is connected to Q2 or

[0094] In this invention, as one embodiment, L is selected from 5-10 membered heterocyclic groups, and the 5-10 membered heterocyclic group is optionally surrounded by 1 to 5 groups selected from deuterium, 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;

[0095] 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 CH, 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 Substituents of alkylthio or C1-6 alkylamino groups; 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 ;

[0096] Preferably, L is selected from More The key identified by "#Q3" is connected to Q3.

[0097] In this invention, as one embodiment, the ring Q3 is selected from C. 3-10 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally and independently each bound 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 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl 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 3-6 Cycloalkyl groups and 4-7-membered heterocycloalkyl groups may be independently substituted with substituents selected from deuterium or halogens;

[0098] Preferably, ring Q3 is selected from phenyl, 5-6 membered heteroaryl (e.g., pyridyl) or C 4-8 Cycloalkyl (e.g., bicyclo[1.1.1]pentyl), the phenyl, 5-6 heteroaryl (e.g., pyridyl) and C 4-8 Cycloalkyl groups (e.g., bicyclo[1.1.1]pentyl) are optionally each independently composed of one, two, or three groups selected from 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 The alkylamino group is substituted; 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 groups may be substituted by halogens, each independently;

[0099] Preferably, ring Q3 is selected from

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

[0101] K1 and K3 are each independently selected from C or N; preferably, K1 and K3 are selected from C;

[0102] K2, K5, and K6 are each independently selected from CH, NH, N, O, or S; preferably, K2 is selected from S or CH, K5 is selected from CH or S, and K6 is selected from CH.

[0103] K7, K8, K9, K 10 Each is independently selected from CH or N; preferably, K7, K8, K9, K 10 Selected from CH;

[0104] q is selected from 0, 1, 2 or 3; preferably, q is selected from 0, 1 or 2; more preferably, q is selected from 0 or 1;

[0105] Each R Q Each is independently 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 The alkylamino group is substituted; 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 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; preferably, R Q Selected from halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl; more preferably, R Q Selected from deuterium or halogens;

[0106] The It is a heterocyclic aromatic ring; the described It is an aromatic ring or a heterocyclic aromatic ring;

[0107] Preferably, ring Q3 is selected from: More The key marked "#L" is connected to L, and "#R" is used to denote the key. 2 The key of the identifier is connected to R. 2 .

[0108] In this invention, as one of the implementation schemes, K7, K8, K9, K 10 One of them is selected from N, and the rest are selected from CH; preferably, K7 is selected from N, and K8, K9, and K 10 Selected from CH; preferably, K8 is selected from N, K7, K9, K10 Selected from CH.

[0109] In this invention, as one embodiment, q is selected from 0; preferably, q is selected from 1.

[0110] In this invention, as one embodiment, ring Q3 is selected from... Preferably, ring Q3 is selected from In this context, the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 2 The key of the identifier is connected to R. 2 .

[0111] In this invention, as one of the embodiments, ring Q3 is selected from: Preferred Preferred More In this context, the key identified by "#L" is connected to L, and the key identified by "#R" is connected to L. 2 The key of the identifier is connected to R. 2 .

[0112] 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 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 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;

[0113] Or, R 8 and R 9Together 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;

[0114] 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 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 deuterium, halogens, C, and N. 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.

[0115] 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 1-6The 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 and 0 heteroatoms selected from oxygen or sulfur.

[0116] More preferably, R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, or halogen;

[0117] R 10 Selected from 5-8 membered heterocyclic groups; each of the 5-8 membered heterocyclic groups is optionally and independently composed of 1, 2, or 3 elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0118] 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 Substitution of alkyl halogens.

[0119] In this invention, as one embodiment, the...

[0120] Structural unit Selected from

[0121] 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;

[0122] Preferably,

[0123] G1 is selected from O, CH2, S, or NH; more preferably O or CH2;

[0124] G2 is selected from CH2, O, or NH; more preferably CH2 or O.

[0125] G3 is selected from O, CH2, or NH;

[0126] G4 is selected from CH2, O, or NH;

[0127] G5 is selected from CH2 or O;

[0128] G6 is selected from O or CH2;

[0129] G7 is selected from CH2, O, or NH;

[0130] G8 is selected from CH2, NH, or O;

[0131] Z1 is selected from CH;

[0132] Z2 is selected from N or NH;

[0133] Z3 is selected from N or NH;

[0134] 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 C3-7 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;

[0135] r1, r2, r3, and r4 are each independently selected from 0, 1, or 2;

[0136] Each 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;

[0137] Each R r4 Each is independently 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;

[0138] Preferably, structural unit Selected from

[0139] Wherein, f1 and f2 are selected from 1, 2, or 3; preferably, f1 and f2 are selected from 2;

[0140] G9 is selected from O, CH2, S or NH; preferably, G9 is selected from O.

[0141] In this invention, as one embodiment, the R 10 Selected from 6-8 membered heterocyclic groups, wherein the 6-8 membered heterocyclic group is optionally selected by 1, 2 or 3 from halogens, C 1-6 Alkyl or C 1-6 Substituents of haloalkyl groups;

[0142] 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.

[0143] 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.

[0144] Preferably, R 10 Selected from: More

[0145] In this invention, as one of the embodiments, R 10 Selected from (For example )or More (For example ).

[0146] In this invention, as one embodiment, the...

[0147] Structural unit Selected from

[0148] 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;

[0149] 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;

[0150] X1, X2, X4, X5, X6, X7, and X8 are each independently selected from C or N;

[0151] X3 is selected from C, N, O or S; preferably, X3 is selected from C;

[0152] Preferably, structural unit Selected from (For example );

[0153] Preferably, structural unit Selected from

[0154] Preferred More

[0155] In this invention, as one embodiment, the...

[0156] Structural unit Selected from Preferred With "#R 10 The key of the identifier is connected to R. 10 The key identified by "#C(O)" is connected to -C(O)-.

[0157] 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 Substituents of cyclic hydrocarbon groups, 4-12 membered heterocyclic groups, C6-10 aryl groups, or 5-10 membered 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 6-10The aryl and 5-10 heteroaryl groups are optionally and independently replaced by substituents selected from deuterium or halogens;

[0158] 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 Monocyclic cycloalkyl, C 5-9 The C group is substituted with substituents of bridged bicyclic 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 Monocyclic cycloalkyl, C 5-9 Bridged bicyclic cycloalkyl groups, 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 may be independently substituted by halogens.

[0159] Preferably, R 1 Selected from

[0160] Among them, T1, T2, T3, T4, T5, T6, T7, T8, T9, T 10 T 11 T 12 T 13 T 14 T 15 Each is independently selected from CH or N; CH is preferred;

[0161] V is selected from CH2, NH, O or S, preferably CH2 or O;

[0162] Each R 01 R 02 R 03R 04 R 05 R 06 R 07 R 08 Each is independently selected from halogen, cyano, SF5, hydroxyl, mercapto, amino, 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 Monocyclic cycloalkyl, C 5-9 The C group is substituted with substituents of bridged bicyclic 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 Monocyclic cycloalkyl, C 5-9 Bridged bicyclic cycloalkyl groups, 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 may be independently substituted by halogens.

[0163] Preferably, each R 01 Each is independently selected from halogens (e.g., F, Cl), SF5, cyano, C. 1-6 Alkyl (e.g., methyl), C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thiols (e.g., -SCH3), C 1-6 Haloalkylthio groups (e.g., -SCF3), C 2-6 alkenyl, C 2-6 Alkyne group (e.g., ethynyl group), C 3-6 Monocyclic cycloalkyl (e.g., cyclopropyl), C 5-9 Bridged bicyclic cycloalkyl (e.g.) ), 4-7 nucleotide monocyclic heterocyclic groups, 7-11 nucleotide bridged bicyclic heterocyclic groups (e.g. ), 7-11 spirobicyclic heterocyclic groups, 8-10 fused bicyclic heterocyclic groups (e.g. );

[0164] Each R 02 R 03 R 04 R05 R 06 R 07 R 08 Each is independently selected from halogens (e.g., F), C 1-6 Alkyl (e.g., methyl), C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thiols (e.g., -SCH3), C 1-6 Haloalkylthio groups (e.g., -SCF3), C 2-6 alkenyl, C 2-6 Alkyne group (e.g., ethynyl group), C 3-6 Cycloalkyl groups (e.g., cyclopropyl);

[0165] q1 is selected from 0, 1, 2, 3 or 4; preferably, q1 is selected from 0, 1, 2 or 3;

[0166] q2 is selected from 0, 1, 2 or 3; preferably, q2 is selected from 0, 1 or 2;

[0167] q3 is selected from 0, 1, 2 or 3; preferably, q3 is selected from 0, 1 or 2;

[0168] q4 is selected from 0, 1, 2 or 3; preferably, q4 is selected from 0, 1 or 2;

[0169] q5 is selected from 0, 1, 2, 3 or 4; preferably, q5 is selected from 0, 1, 2 or 3;

[0170] q6 is selected from 0, 1, 2 or 3; preferably, q6 is selected from 0, 1 or 2;

[0171] q7 is selected from 0, 1, or 2; preferably, q7 is selected from 0 or 1.

[0172] q8 is selected from 0, 1, or 2; preferably, q8 is selected from 0 or 1.

[0173] v1 is selected from 1, 2, or 3; preferably, v1 is selected from 1 or 2;

[0174] v2 is selected from 1, 2 or 3; preferably, v2 is selected from 1 or 2; more preferably, v2 is selected from 1;

[0175] v3 and v4 are each independently selected from 1, 2 or 3, preferably v3 and v4 are each independently selected from 1 or 2;

[0176] v5 is selected from 1, 2 or 3; preferably, v5 is selected from 3.

[0177] In this invention, as one embodiment, the R 1 Selected from

[0178] In this invention, as one of the embodiments, T1, T2, T3, T4, and T5 are all selected from CH; preferably, one of T1, T2, T3, T4, and T5 is selected from N, and the rest are selected from CH.

[0179] In this invention, as one embodiment, each R 01 Each is independently selected from halogens (e.g., F, Cl), SF5, cyano, C. 1-6 Alkyl (e.g., methyl), C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thiols (e.g., -SCH3), C 1-6 Haloalkylthio groups (e.g., -SCF3), C 3-6 Monocyclic cycloalkyl groups (e.g., cyclopropyl) and 4-7 membered monocyclic heterocyclic groups; preferably, each R 01 Each is independently selected from halogens (e.g., F, Cl) and C. 1-6 Alkyl (e.g., methyl).

[0180] In this invention, as one embodiment, q1 is selected from 1, 2 and 3; more preferably, q1 is selected from 2 and 3.

[0181] In this invention, as one embodiment, the R 1 Selected from:

[0182] In this invention, as one embodiment, the R 1 Selected from More

[0183] In this invention, as one embodiment, the 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 The aryl group and the 12-20 membered heteroaryl group are tricyclic or tetracyclic; the C 12-20 Cyclic hydrocarbon groups, 12-20 membered heterocyclic groups, C 12-20 The aryl and 12-20 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituents are replaced;

[0184] Preferably, the 12-20 membered heterocyclic group and the 12-20 membered heteroaryl group have 0, 1, 2 or 3 nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from oxygen or sulfur; more preferably, the 12-20 membered heterocyclic group and the 12-20 membered heteroaryl group have 0, 1, 2 or 3 nitrogen heteroatoms and 0, 1 or 2 oxygen heteroatoms and 0 sulfur heteroatoms; more preferably, the 12-20 membered heterocyclic group and the 12-20 membered heteroaryl group have 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms and 0 sulfur heteroatoms.

[0185] 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 and the 12-18 heteroaryl group are tricyclic or tetracyclic; optionally, each is 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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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;

[0186] R G R H Each is independently selected from hydrogen or halogen;

[0187] Preferably, the 12-18 membered heterocyclic group and the 12-18 membered heteroaryl group have 0, 1 or 2 nitrogen heteroatoms and 0, 1 or 2 oxygen heteroatoms and 0 sulfur heteroatoms; more preferably, they have 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms and 0 sulfur heteroatoms.

[0188] Preferably, R 2 Selected from 12-18 membered heterocyclic groups, wherein the 12-18 membered heterocyclic group is tricyclic or tetracyclic, optionally each independently bound 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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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;

[0189] R G R H Each is independently selected from hydrogen or halogen;

[0190] Preferably, the 12-18 membered heterocyclic group has 0, 1, or 2 nitrogen heteroatoms and 0, 1, or 2 oxygen heteroatoms and 0 sulfur heteroatoms; more preferably, it has 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms and 0 sulfur heteroatoms.

[0191] Preferably, R 2The group is selected from 12-15-membered tricyclic heterocyclic groups or 15-18-membered tetracyclic heterocyclic groups, wherein the 12-15-membered tricyclic heterocyclic group and the 15-18-membered tetracyclic heterocyclic group are optionally each independently surrounded by 1 to 5 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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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;

[0192] R G R H Each is independently selected from hydrogen or halogen;

[0193] Preferably, the 12-15 member tricyclic heterocyclic group and the 15-18 member tetracyclic heterocyclic group have 0, 1 or 2 nitrogen heteroatoms and 0, 1 or 2 oxygen heteroatoms and 0 sulfur heteroatoms; more preferably, they have 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms and 0 sulfur heteroatoms.

[0194] In this invention, as one of the embodiments, R 2The heteroatoms are selected from 9-10-membered bicyclic heteroaryl groups and 11-15-membered tricyclic heterocyclic groups; the heteroatoms of the 9-10-membered bicyclic heteroaryl group are 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 heteroatoms of the 11-15-membered tricyclic heterocyclic group are selected from nitrogen, oxygen, and sulfur, preferably nitrogen and oxygen, 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, more preferably 1; the 9-10-membered bicyclic heteroaryl group and the 11-15-membered tricyclic heterocyclic group are optionally each independently selected by one or more (e.g., 1, 2, or 3) groups selected from halogens, oxo groups, C... 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Substituents include alkylene-, C3-6 cycloalkyl, and 4-7 heterocyclic alkyl groups.

[0195] In this invention, as one of the embodiments, R 2 Selected from group (0), group (1) and group (2), with preferred group (0) and group (1), and more preferably group (1):

[0196] (0)

[0197] Among them, cyclo-A phenyl and 6-membered nitrogen-containing aryl group; preferably phenyl;

[0198] Ring B is selected from phenyl and 5-6-membered heteroaryl; preferably 5-membered heteroaryl; more preferably 5-membered nitrogen heteroaryl;

[0199] Each R a Each is independently 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, C 2-6 alkenyl and 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 and C 2-6 The alkynyl groups are optionally and independently substituted by substituents selected from deuterium or halogens; preferably, each R a Each is independently selected from hydrogen and halogens (e.g., F);

[0200] Each R b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkylene-, C3-6 Cycloalkyl and 4-7 membered heterocyclic alkyl; preferably, each R b Each is independently selected from C 1-6 Alkyl and C 3-6 cycloalkyl; preferably, each R b Each is independently selected from C 1-6 alkyl;

[0201] a is selected from 0 and 1; preferably, a is selected from 1;

[0202] b is selected from 0, 1, and 2; preferably, b is selected from 1;

[0203] (1)

[0204] Wherein, ring A is selected from phenyl or 6-membered nitrogen-containing aryl group; preferably phenyl;

[0205] Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic cyclic hydrocarbon group; preferably 5-6 membered monocyclic heterocyclic group; preferably 5 membered monocyclic heterocyclic group having 1 nitrogen heteroatom or oxygen heteroatom, 5 membered monocyclic heterocyclic group having 2 oxygen heteroatoms, 6 membered monocyclic heterocyclic group having 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms; preferably 5 membered monocyclic heterocyclic group having 1 nitrogen heteroatom; more preferably 5 membered monocyclic heterocyclic group, wherein the heteroatom of the 5 membered monocyclic heterocyclic group is selected from nitrogen, and the number of heteroatoms is selected from 1;

[0206] Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 3-7 Monocyclic cyclic hydrocarbon group, 7-10 membered bridged bicyclic heterocyclic group, 7-10 membered spirobicyclic heterocyclic group, 7-10 membered fused bicyclic heterocyclic group, C 7-10 Bridged bicyclic cyclic hydrocarbon group, C 7-10 Spirobicyclic cyclic hydrocarbon group, C 7-10 Fused bicyclic cyclic hydrocarbon group; preferably 4-7 membered monocyclic heterocyclic group, C 4-7 Monocyclic cyclic hydrocarbon group, 7-10 membered bridged bicyclic heterocyclic group, 7-10 membered spirobicyclic heterocyclic group, 7-10 membered fused bicyclic heterocyclic group, C 7-10 Bridged bicyclic cyclic hydrocarbon group, C 7-10 Spirobicyclic cyclic hydrocarbon group, C 7-10 Fused bicyclic hydrocarbon group; preferably a 4-6 membered monocyclic heterocyclic alkyl group having one nitrogen heteroatom, oxygen heteroatom, or sulfur heteroatom, C 4-6 Monocyclic cycloalkyl, C 5-6 Monocyclic cycloalkenyl, C 7-10 Fused bicyclic cycloalkyl, C 7-10 Spirobicyclic cycloalkyl, 7-9 membered spirobicyclic heterocyclic alkyl with one oxygen atom, 7-9 membered bridged bicyclic heterocyclic alkyl with one oxygen atom, benzo[C] 5-6Monocyclic cycloalkyl groups, benzo5-6 membered oxamonocyclic heterocyclic groups; preferably 6-membered heterocyclic alkyl groups having one oxygen atom; preferably 4-6 membered monocyclic heterocyclic alkyl groups, C 3-6 Monocyclic cycloalkyl, wherein the heteroatoms of the 4-6 membered monocyclic heterocyclic alkyl are selected from nitrogen, oxygen and sulfur, preferably nitrogen and oxygen, more preferably oxygen, and the number of heteroatoms is selected from 1 and 2, preferably 1;

[0207] a, b, and c are each independently selected from 0, 1, 2, 3, or 4;

[0208] 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;

[0209] Preferably, 'a' is selected from 0 and 1, and more preferably 0;

[0210] Preferably, b is selected from 1 and 2, with 2 being the most preferred;

[0211] Preferably, c is selected from 0, 1, and 2, more preferably 0 and 1, and even more preferably 0;

[0212] Each R a Each is independently 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, 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 and C 2-6 The alkynyl group is optionally and independently substituted by a substituent selected from deuterium or halogen; R a Halogens (e.g., F) are preferred;

[0213] Each R b Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, cyano group, hydroxyl group, mercapto group, amino group, 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 Cycloalkyl or 4-6 heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C2-6 alkynyl group, C 3-6 The cycloalkyl and 4-6 heterocycloalkyl groups are optionally each independently selected from deuterium, halogen, cyano, hydroxyl, or 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, methyl, isopropyl, cyclopropyl, -(CH2)2OCH3, -CH2CF3, Or two R atoms attached to the same carbon atom b Formation of cyclopropyl; preferably, at least one R is present. b Selected from oxo groups; preferably, 1 R b Selected from oxo groups, the rest are R b Each is independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from halogens and C. 1-6 Substituents of alkoxy groups;

[0214] Each R c Each is independently 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; R is preferred.c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl or The C 1-6 Alkyl, -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; more preferably R c Preferred radicals include F, oxoyl, methyl, ethyl, methoxy, -CH2CF3, -CH2CN, -(CH2)2CN, -C(O)CH3, -C(O)CF3, -C(O)CH(OH)CH3, and -S(O)2CH3.

[0215] (2)

[0216] Wherein, cyclo-A phenyl or a 6-membered nitrogen-containing aryl group; preferably phenyl;

[0217] 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;

[0218] The ring C is selected from phenyl, 5-6 membered heteroaryl, 5-7 membered monocyclic heterocyclic group, C5-7 monocyclic cyclic hydrocarbon group, and 8-11 membered spirobicyclic heterocyclic group;

[0219] 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.

[0220] Each R a Each is independently 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, 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 and C 2-6 The alkynyl group is optionally and independently substituted by a substituent selected from deuterium or halogen; R a Halogens (e.g., F) are preferred;

[0221] Each R b Each is independently 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 b Selected from halogens, C 1-6 Alkyl groups (e.g., methyl groups);

[0222] Each R c Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and 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 groups and -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).

[0223] In this invention, as one embodiment, the R 2 Selected from group (1) or group (2), with group (1) preferred:

[0224] (1)

[0225] Wherein, ring A is selected from phenyl or 6-membered nitrogen-containing aryl group; preferably phenyl;

[0226] 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;

[0227] Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7Monocyclic cyclic hydrocarbon group, 7-10 membered bridged bicyclic heterocyclic group, 7-10 membered spirobicyclic heterocyclic group, 7-10 membered fused bicyclic heterocyclic group, C 7-10 Bridged bicyclic cyclic hydrocarbon group, C 7-10 Spirobicyclic cyclic hydrocarbon group, C 7-10 Fused bicyclic hydrocarbon group; preferably a 4-6 membered monocyclic heterocyclic alkyl group having one nitrogen heteroatom, oxygen heteroatom, or sulfur heteroatom, C 4-6 Monocyclic cycloalkyl, C 5-6 Monocyclic cycloalkenyl, C 7-10 Fused bicyclic cycloalkyl, C 7-10 Spirobicyclic cycloalkyl, 7-9 membered spirobicyclic heterocyclic alkyl with one oxygen atom, 7-9 membered bridged bicyclic heterocyclic alkyl with one oxygen atom, benzo[C] 5-6 Monocyclic cycloalkyl group, benzo5-6 membered oxamonocyclic heterocyclic group; more preferably, 6 membered heterocyclic alkyl group having 1 oxamonoatom;

[0228] a, b, and c are each independently selected from 0, 1, 2, 3, or 4;

[0229] 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;

[0230] Each R a Each is independently 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, 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 and C 2-6 The alkynyl group is optionally and independently substituted by a substituent selected from deuterium or halogen; R a Halogens (e.g., F) are preferred;

[0231] Each R b Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, cyano group, hydroxyl group, mercapto group, amino group, 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 Cycloalkyl or 4-6 heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl and 4-6 heterocycloalkyl groups are optionally each independently selected from deuterium, halogen, cyano, hydroxyl, or 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, methyl, isopropyl, 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;

[0232] Each R c Each is independently 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; R is preferred. c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl group, -S(O)2C1-6 alkyl or The C 1-6 Alkyl, -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; more preferably R c Preferred radicals include F, oxoyl, methyl, ethyl, methoxy, -CH2CF3, -CH2CN, -(CH2)2CN, -C(O)CH3, -C(O)CF3, -C(O)CH(OH)CH3, and -S(O)2CH3.

[0233] (2)

[0234] Wherein, cyclo-A phenyl or a 6-membered nitrogen-containing aryl group; preferably phenyl;

[0235] 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;

[0236] 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;

[0237] 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.

[0238] Each R a Each is independently 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, 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 and C 2-6 The alkynyl group is optionally and independently substituted by a substituent selected from deuterium or halogen; R a Halogens (e.g., F) are preferred;

[0239] Each R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, SF5, cyano, C1-6 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);

[0240] Each R c Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and 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 groups and -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).

[0241] In this invention, as one of the implementation schemes,

[0242] The Choose any one of the following groups: Preferred

[0243] Among them, A1, A2, A3, B1, B2, B4, B5, B6, and B7 are each independently selected from CH and N; B3 is selected from NH, O, and S;

[0244] Preferably, A1, A2, and A3 are all selected from CH; preferably, one of A1, A2, and A3 is selected from N, and the rest are selected from CH.

[0245] Preferably, both B1 and B2 are selected from CH; preferably, one of B1 and B2 is selected from N and the other is selected from CH; preferably, B1 is selected from CH and B2 is selected from N.

[0246] Preferably, B3 is selected from NH;

[0247] Preferably, B4, B5, B6, and B7 are all selected from CH; preferably, one of B4, B5, B6, and B7 is selected from N, and the rest are selected from CH.

[0248] R a R b a, b are as defined in any embodiment of the present invention;

[0249] Preferably, each R a Each is independently selected from hydrogen and halogens (e.g., F); more preferably, each R a Each is independently selected from halogens (e.g., F);

[0250] Preferably, each R b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-4 Alkylene-, C 3-6 Cycloalkyl and 4-7 membered heterocyclic alkyl; more preferably, each R b Each is independently selected from C 1-6 Alkyl (e.g., methyl) and C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, each R b Each is independently selected from C 1-6 Alkyl (e.g., C10) 1-4 Alkyl groups, such as C 1-3 Alkyl groups, especially methyl groups, etc.

[0251] Preferably, 'a' is selected from 1;

[0252] Preferably, b is selected from 1.

[0253] In this invention, as one of the implementation schemes,

[0254] The Selected from Among them, A1, A2, A3, B1, B2, R a R b a is as defined in any embodiment of the present invention.

[0255] In this invention, as one of the implementation schemes,

[0256] The Choose any one of the following groups:

[0257] in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; single bonds are preferred.

[0258] A1, A2, A3, C2, C3, C4, C5, C9, C 10 C 11 C 12Each 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;

[0259] 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.

[0260] C1 is selected from O, NH, S, CH2, or CH; preferably O;

[0261] 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.

[0262] 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 C7 and C8 are both O.

[0263] C 13 C 14 Each is independently selected from CH2, NH, O, or S, with C being preferred. 13 C 14 Both are O;

[0264] C 15 Selected from CH2, NH, O or S, with CH2 being preferred;

[0265] p0 is selected from 1, 2, 3, 4 and 5, preferably 1, 2, 3 and 4, and more preferably 1;

[0266] 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.

[0267] 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;

[0268] R a R b R c a, b, and c are as defined in any embodiment of the present invention;

[0269] Preferably, each R a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6Alkyl; more preferably hydrogen or halogen;

[0270] Preferably, each R b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 Substituents of alkoxy groups; more 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 Substituents of alkoxy groups;

[0271] Preferably, each R c Each is independently selected from hydrogen, halogen, oxo group, 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 halogens (e.g., F);

[0272] Preferably, a is selected from 0 or 1; preferably, a is selected from 0.

[0273] Preferably, b is selected from 0 or 1;

[0274] Preferably, c is selected from 0, 1, or 2; more preferably, c is selected from 0 and 1; more preferably, c is selected from 0.

[0275] In this invention, as one of the implementation schemes,

[0276] The Choose any one of the following groups:

[0277] in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; single bonds are preferred.

[0278] A1, A2, A3, C2, C3, C4, C5, C9, C 10 C 11 C12 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;

[0279] 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.

[0280] C1 is selected from O, NH, S, CH2, or CH; preferably O;

[0281] 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.

[0282] 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 C7 and C8 are both O.

[0283] C 13 C 14 Each is independently selected from CH2, NH, O, or S, with C being preferred. 13 C 14 Both are O;

[0284] C 15 Selected from CH2, NH, O or S, with CH2 being preferred;

[0285] 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.

[0286] 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;

[0287] R a R b R c a, b, and c are as defined above;

[0288] Preferably, each R a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; more preferably hydrogen or halogen;

[0289] Preferably, each Rb Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 Substituents of alkoxy groups; more 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 Substituents of alkoxy groups;

[0290] Preferably, each R c Each is independently selected from hydrogen, halogen, oxo group, 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 halogens (e.g., F);

[0291] Preferably, 'a' is selected from 0 or 1;

[0292] Preferably, b is selected from 0 or 1;

[0293] Preferably, c is selected from 0, 1, or 2.

[0294] In this invention, as one of the implementation schemes,

[0295] The Selected from Preferably, the Selected from Among them, A1, A2, A3, C1, p0, p1, p2, R a R b a is as defined in any embodiment of the present invention; preferably, A1, A2, and A3 are all selected from CH; preferably, one of A1, A2, and A3 is selected from N, and the rest are selected from CH;

[0296] Preferably, p0 is selected from 1, 2, 3, and 4; preferably, p0 is selected from 1 and 4; preferably, p0 is selected from 1; preferably, p0 is selected from 4.

[0297] Preferably, p1 and p2 are each independently selected from 1 and 2; preferably, one of p1 and p2 is selected from 1 and the other is selected from 2; preferably, p1 and p2 are both selected from 1; preferably, p1 and p2 are both selected from 2.

[0298] Preferably, C1 is selected from NH, O and S; more preferably, C1 is selected from NH and O; more preferably, C1 is selected from O.

[0299] Preferably, each R a Each is independently selected from hydrogen and halogens (e.g., F); more preferably, each R a Each is independently selected from halogens (e.g., F);

[0300] Preferably, a is selected from 0 and 1; preferably, a is selected from 0;

[0301] Preferably, R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from halogens and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from C 1-6 Alkyl and C 3-6 cycloalkyl; more preferably, R b Selected from C 1-6 Alkyl (e.g., C10) 1-4 Alkyl groups, such as C 1-3 Alkyl groups, especially methyl groups (e.g., alkyl groups).

[0302] In this invention, as one embodiment, the... Selected from

[0303] R a R b R c a and c are as defined above;

[0304] A1, A2, and A3 are as defined above.

[0305] In this invention, as one embodiment, the... Choose any one of the following groups:

[0306] in:

[0307] A1, A2, and A3 are each independently selected from CH or N; CH is preferred.

[0308] B3 is selected from CH2, CF2, O, and NR. b;

[0309] C 16 Selected from CH2, NH, O or S, with O preferred;

[0310] C 17 Selected from CH2, NH, O or S, preferably O or CH2;

[0311] 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.

[0312] R a R b R c a and c are as defined above;

[0313] Preferably, each R a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; more preferably hydrogen or halogen;

[0314] Preferably, each R b Each is independently selected from hydrogen and 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 Substituents of alkoxy groups; more preferably hydrogen or C. 1-6 alkyl;

[0315] Preferably, each R c Each is independently selected from hydrogen, halogen, oxo group, 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, deuterium, and halogens (e.g., F); more preferably hydrogen or halogens (e.g., F);

[0316] Preferably, 'a' is selected from 0 or 1; more preferably, 0.

[0317] Preferably, c is selected from 0, 1, or 2; more preferably, c is selected from 0.

[0318] In this invention, as one embodiment, the... Selected from

[0319] in, It is a single or double bond, and they are adjacent. Not both are double bonds;

[0320] A1, A2, and A3 are each independently selected from CH or N; CH is preferred.

[0321] B4 is selected from N and NR. b O, S, CR b or C(R) b )2; Preferred B4 is selected from NR b or CR b ; More preferably CR b ;

[0322] B5 is selected from C or N; N is preferred.

[0323] 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.

[0324] 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;

[0325] R a R b R c a and c are as defined above;

[0326] Preferably, each R a Each is independently selected from hydrogen, halogen, or C. 1-6 alkyl;

[0327] Preferably, each R b Each is independently selected from hydrogen, halogen, and C. 1-6 alkyl;

[0328] Preferably, each R c Each is independently selected from hydrogen, oxo group, halogen, C 1-6 alkyl;

[0329] Preferably, 'a' is selected from 0 or 1;

[0330] Preferably, c is selected from 1 or 2.

[0331] In this invention, as one embodiment, the... Selected from

[0332] in:

[0333] C 18 Selected from CH2, CHF, CF2, NH, O, or S; preferably C.18 Selected from O;

[0334] 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;

[0335] A1, A2, A3, B4, B5, R a R c As defined above;

[0336] Preferably, R c Selected from halogen or C 1-6 Alkyl, more preferably C 1-6 alkyl.

[0337] In this invention, as one embodiment, the R 2 Selected from:

[0338] In this invention, as one embodiment, the R 2 Selected from:

[0339] In this invention, as one embodiment, the R 2 Selected from:

[0340] In this invention, as one embodiment, the compound is as shown in formula (IA):

[0341] Among them, R 5a R 6a R 6b R 1 R 2 R 10 Q3 is as defined in any embodiment of the present invention.

[0342] In this invention, as one embodiment, the compound is as shown in formula (IB):

[0343] Among them, R 5a R 6a R 6b R 1 R 2 R 10 R G R H Q3 is as defined in any embodiment of the present invention.

[0344] In this invention, as one embodiment, the compound is as shown in formula (IC):

[0345] Among them, R 5a R 6a R 6b R 1 R 2 R 10 Q3 is as defined in any embodiment of the present invention.

[0346] In this invention, as one embodiment, the compound is selected from:

[0347] The various embodiments of the present invention can be combined in any way.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] In a fourth aspect, the present invention provides the use of the aforementioned compound, 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 pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of GLP-1 receptor-mediated diseases or disorders, or for the modulation of GLP-1 receptors.

[0352] In five aspects, 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] In a ninth aspect, the present invention provides a method for preventing and / or treating 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.

[0357] In a tenth aspect of the invention, the GLP-1 related diseases, conditions or symptoms include, but are not limited to, GLP-1 receptor-mediated diseases or disorders, or GLP-1 related diseases, conditions or symptoms including metabolic diseases, cardiovascular diseases, liver diseases, kidney diseases, and neurodegenerative diseases.

[0358] Preferably,

[0359] The metabolic diseases mentioned include diabetes, diabetic complications, and obesity;

[0360] The cardiovascular diseases mentioned include hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, and cerebral infarction;

[0361] The liver diseases mentioned include non-alcoholic steatohepatitis;

[0362] The kidney disease mentioned includes type 2 diabetes mellitus complicated with chronic kidney disease;

[0363] The neurodegenerative diseases mentioned include Parkinson's disease or dementia.

[0364] Terminology Explanation

[0365] 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.

[0366] 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”).

[0367] 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).

[0368] 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.

[0369] 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.

[0370] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group is as defined above.

[0371] As used herein, the term "alkylthio" refers to -S-alkyl, wherein the alkyl group is as defined above.

[0372] 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.

[0373] 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...

[0374] 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).

[0375] 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 ring 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) ring atoms, said ring atoms including carbon atoms and heteroatom groups. 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...

[0376] 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.

[0377] 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.

[0378] 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.

[0379] 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.

[0380] As used herein, the term “one or more” means one or more under reasonable conditions, such as two, three, four, five, six or ten.

[0381] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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.

[0386] The terms “racemate,” “racemic mixture,” or “racemic mixture” refer to an equimolar mixture of two enantiomers that lack optical activity.

[0387] 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.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] The term "hydrate" refers to an associative compound formed by one or more water molecules with the compound of the present invention.

[0395] The term "solvent" or "solvent compound" refers to a compound formed by one or more solvent molecules with the compound of the present invention.

[0396] 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.

[0397] As used in this invention, "*" indicates a chiral center.

[0398] 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.

[0399] In chemical structure, crossed double bonds The purpose is to represent a double bond between two atoms. When a crossed double bond is used in the structural formula of a compound, it indicates that the compound is a mixture of cis and trans isomers with a double bond configuration. Detailed Implementation

[0400] The control compound LY3502970 was prepared according to patent CN109790161B; the structure of the control compound LY3502970 is as follows:

[0401] Example 1: Preparation of compound GS

[0402] Synthesis route:

[0403] Step 1: Preparation of compounds GS-2 and GS-2A

[0404] 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.

[0405] 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).

[0406] Step 2: Synthesis of compounds GS-3 and GS-3A

[0407] 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.

[0408] 1H 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).

[0409] Step 3: Synthesis of compounds GS-5 and GS-5A:

[0410] 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 × 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 / 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).

[0411] Step 4: Synthesis of compound GS-6

[0412] 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] + . 1 H 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).

[0413] Step 5: Synthesis of compound GS-7

[0414] 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] + .

[0415] Step 6: Synthesis of compound GS-8

[0416] 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] + .

[0417] Step 7: Synthesis of compound F

[0418] 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).

[0419] Step 8: Synthesis of compound GS-11

[0420] 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] + .

[0421] Step 9: Synthesis of compound GS-12

[0422] 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] + .

[0423] Step 10: Synthesis of compound GS-13

[0424] 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] + .

[0425] Step 11: Synthesis of compound GS-14

[0426] Compound GS-13 (2.7 g, 5.39 mmol) was separated by SFC (Separation column: ChiralPak AD 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: 1 H NMR (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).

[0427] 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.

[0428] Step 12: Synthesis of compound GS

[0429] 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] + .

[0430] Example 2: Preparation of compound K

[0431] The structural formula of compound K is as follows:

[0432] Synthesis route:

[0433] Step 1: Synthesis of compound D-2

[0434] 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).

[0435] Step 2: Synthesis of compound D-4

[0436] 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 mixture was concentrated and evaporated to dryness. An ethanol solution (500 mL) containing pyridine hydrochloride (1.65 g, 14.12 mmol) and (2S)-3-cyano-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (33.6 g, 141.24 mmol) was added. The reaction mixture was heated to 85°C and stirred for 2 hours. The reaction mixture 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] + .

[0437] Step 3: Synthesis of compound D-5

[0438] 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] + .

[0439] Step 4: Synthesis of compound K

[0440] 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).

[0441] Example 3: Preparation of Compound 1

[0442] Synthesis route:

[0443] Step 1: Synthesis of Compounds 1-2

[0444] 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] + .

[0445] Step 2: Synthesis of compounds 1-3

[0446] To a solution of compounds 1-2 (2.0 g, 6.80 mmol) in 1,4-dioxane (50 mL) and water (5 mL), 4-bromo-3-fluorophenylboronic acid (1.6 g, 7.45 mmol), potassium carbonate (2.8 g, 20.26 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (494 mg, 0.71 mmol) were added. The reaction mixture was stirred at 100 °C for 3 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 under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compounds 1-3. MS m / z (ESI): 390.0 [M+H] + .

[0447] Step 3: Synthesis of compounds 1-4

[0448] Compound K (567 mg, 1.28 mmol), potassium carbonate (531 mg, 3.84 mmol), cuprous iodide (49 mg, 0.26 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (91 mg, 0.64 mmol) were added to a solution of compounds 1-3 (500 mg, 1.28 mmol) in 20 mL of N-methylpyrrolidone. 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 (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 under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compounds 1-4. MS m / z (ESI): 751.4 [M+H] + .

[0449] Step 4: Synthesis of compounds 1-5

[0450] 10 mL of 4 M dioxane hydrochloride solution was added to compounds 1-4 (770 mg, 1.28 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude compounds 1-5. The crude product was used directly in the next step. MS m / z (ESI): 651.3 [M+H] + .

[0451] Step 5: Synthesis of Compound 1

[0452] To a 15 mL solution of compound GS (452 ​​mg, 1.10 mmol) in N,N-dimethylformamide, N,N-diisopropylethylamine (387 mg, 3.00 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (570 mg, 1.50 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then compound 1-5 (650 mg, 1.00 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-SunFire-C18-5μm-19*250mm, A: 0.1% TFA / H2O, B: CAN 2.009 min) to obtain compound 1. MS m / z (ESI): 1044.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.75(s,1H),7.96–7.79(m,2H),7.71(t,J=9.2Hz,2H),7.64–7.49(m,2H),7.4 0(d,J=8.4Hz,1H),7.26(d,J=8.4Hz,1H),7.20–7.08(m,4H),7.05–6.88(m,2H),5.62–5.16(m,1H),4.39 (d,J=12.8Hz,1H),4.15–4.05(m,2H),3.93–3.82(m,2H),3.71(d,J=8.0Hz,2H),3.17(s,3H),3.08–2.8 7(m,2H),2.26(s,6H),1.98–1.88(m,2H),1.79–1.57(m,8H),1.43(d,J=6.4Hz,3H),1.33–1.05(m,12H).

[0453] Example 4: Preparation of Compound 2

[0454] Compound 2 was synthesized by a similar method to that of Compound 1 in Example 3 (using 2-chloroethylchloromethyl ether and 6-bromo-1-methylindoline-2-one as raw materials).

[0455] Compound 2: MS m / z (ESI): 1030.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.29–11.77(m,1H),7.88(d,J=11.6Hz,1H),7.78–6.94(m,13H),5.60–5.13(m,1H),4.79–4.04(m ,3H),3.90–3.86(m,2H),3.74–3.66(m,3H),3.27–3.24(m,4H),3.05–2.91(m,2H),2.41–2.10(m,8H),1.88–1.09(m,19H).

[0456] Example 5: Preparation of Compound 3

[0457] Compound 3 was synthesized by a similar method to that used for compound 1 in Example 3 (using 1,5-dibromopentane as a starting material).

[0458] Compound 3: MS m / z (ESI): 1042.6 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.29–11.75(m,1H),7.82–6.95(m,14H),5.74–5.53(m,1H),4.39(d,J=8.8Hz,1H),3.73–3.61(m,3H),3 .16(s,4H),3.09–2.87(m,2H),2.28–2.22(m,7H),1.98–1.91(m,2H),1.71–1.52(m,15H),1.46–1.42(m,2H),1.29–1.15(m,9H).

[0459] Example 6: Preparation of Compound 4

[0460] Compound 4 was synthesized by a similar method to that used for compound 1 in Example 3 (using 5-bromopyridine-2-boronic acid and 1,5-dibromopentane as raw materials).

[0461] Compound 4: MS m / z (ESI): 513.4 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.30–11.76(m,1H),9.00–8.72(m,1H),8.28–8. 03(m,3H),8.02–6.69(m,10H),5.62–5.15(m,1H),4.55–4.39(m,1H),3.7 4–3.62(m,5H),3.19(s,3H),3.10–2.77(m,3H),2.24–2.20(m,5H),1.97– 1.95(m,2H),1.83–1.49(m,13H),1.43–1.42(m,2H),1.29–0.85(m,11H).

[0462] Example 7: Preparation of Compound 5

[0463] Synthesis route:

[0464] Step 1: Synthesis of Compound 5-2

[0465] In a glove box, a solution of compound 5-1 (15.19 mmol) and 1-methyl bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (3.00 g, 10.13 mmol) in dimethyl sulfoxide (50 mL) was added to di[2-(2,4-difluorophenyl)-5-methylpyridine][2,2'-bi(tetra-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (0.21 g, 0.20 mmol), nickel(II) ethylene glycol dimethyl ether complex (0.11 g, 0.51 mmol), and 4-methoxypyridine amide hydrochloride (0.10 g, 0.51 mmol). The mixture was stirred, and then 2-tert-butyl-1,1,3,3-tetramethylguanidine (2.60 g, 15.19 mmol) was added. The reaction mixture was stirred for 72 hours under 450 nm blue LED illumination. The reaction mixture was diluted with water (150 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 (petroleum ether / ethyl acetate = 3 / 1) to give compound 5-2. MS m / z (ESI): 342.1 [M+H] + .

[0466] Step 2: Synthesis of Compound 5-3

[0467] Lithium hydroxide (0.70 g, 29.29 mmol) was added to a solution of compound 5-2 (2.5 g, 7.32 mmol) in methanol (30 mL) and water (10 mL). The reaction mixture was stirred at 50 °C for 1 hour. The pH of the reaction mixture was adjusted to 6 with 1 M dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The mixed organic layer was washed with saturated brine (50 mL) and dried over sodium sulfate. After filtration through filter paper, the organic layer was concentrated under reduced pressure to give compound 5-3. MS m / z (ESI): 328.0 [M + H] + .

[0468] Step 3: Synthesis of Compounds 5-4

[0469] To a solution of compound 5-3 (600 mg, 1.83 mmol) in tert-butanol (8 mL), diphenyl azidophosphate (0.79 mL, 3.67 mmol) and triethylamine (0.76 mL, 5.5 mmol) were added. The reaction mixture was stirred at 80 °C for 18 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 (10 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 5-4. MS m / z (ESI): 399.2 [M+H]+ .

[0470] Step 4: Synthesis of compound 5-5

[0471] Compound 5-4 (200 mg, 0.5 mmol) was dissolved in 4 M hydrochloric acid / dioxane (4 mL) solution, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give crude compound 5-5. The crude product was used directly in the next step. MS m / z (ESI): 299.2 [M+H] + .

[0472] Step 5: Synthesis of compounds 5-6

[0473] Triphosgene (79.3 mg, 0.82 mmol) was added to a 2 mL solution of dichloromethane containing compound D-4 (90 mg, 0.24 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol). The mixture was stirred at 0°C for 30 minutes, and then a 1 mL solution of dichloromethane containing compound 5-5 (72 mg, 0.24 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. The mixture was diluted with 10 mL of water and extracted with 20 mL of dichloromethane (3 times). The extract was washed with 20 mL of saturated brine, 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 compound 5-6. MS m / z (ESI): 699.4 [M+H] + .

[0474] Step 6: Synthesis of compounds 5-7

[0475] To a solution of compounds 5-6 (0.07 mmol) and cesium carbonate (91 mg, 0.28 mmol) in N,N-dimethylacetamide (2 mL), 1,2-dichloroethoxyethane (20 mg, 0.14 mmol) was added, and the reaction mixture was stirred at 40 °C for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was 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 under reduced pressure to give compounds 5-7. The crude product was used directly in the next step. MS m / z (ESI): 741.4 [M+H] + .

[0476] Step 7: Synthesis of compounds 5-8

[0477] Methylsulfonic acid (3 mg, 0.03 mmol) was added to a tetrahydrofuran (5 mL) solution of compounds 5-7 (0.03 mmol), and the reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, Mobile phase: 0.1% NH4HCO3 / H2O, B:CH3CN, Gradient: 35% B-55% B, Ret 8.35 min) to obtain compounds 5-8. MS m / z (ESI): 623.4 [M+H] + .

[0478] Step 8: Synthesis of Compound 5

[0479] To a 1 mL solution of compound GS (4 mg, 0.01 mmol) in N,N-dimethylformamide, N,N-diisopropylethylamine (5 mg, 0.04 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (4.5 mg, 0.01 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then compound 5-8 (6 mg, 0.01 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 under reduced pressure. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Gradient: 75% B-95% B, Ret 8.15 min) to obtain compound 5. MS m / z (ESI): 1016.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.13–11.77(m,1H),7.56–7.09(m,6H),7.06–6.77(m,3H),6.67–6.54(m,2H),5.35–5.32(m,1H),4.08–4.05(m,1H ),3.83–3.72(m,2H),3.15–3.01(m,3H),2.28–2.22(m,4H),2.04–1.97(m,4H),1.76–1.37(m,10H),1.32–1.23(m,22H),1.21–1.17(m,3H).

[0480] Example 8: Preparation of compound L

[0481] The structural formula of compound L is as follows:

[0482] Synthesis route:

[0483] Step 1: Synthesis of compound L-2

[0484] 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 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 = 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).

[0485] Step 2: Synthesis of compound L-3

[0486] 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] + . 1H 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).

[0487] Step 3: Synthesis of compound L-4

[0488] 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).

[0489] Step 4: Synthesis of compound L-5

[0490] 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] + . 1H 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).

[0491] Step 5: Synthesis of compound L-6

[0492] 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] + .

[0493] Step 4: Synthesis of compound L

[0494] 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).

[0495] Example 9: Preparation of Compound 6

[0496] Compound 6 was synthesized by a similar method to that used for compound 1 in Example 3 (using 6-bromo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one and compound L as starting materials).

[0497] Compound 6: MS m / z (ESI): 1070.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.35–11.51(m,1H),7.90–7.66(m,3H),7.61–7.55(m,1H),7 .46–7.26(m,5H),7.18–7.02(m,3H),6.91–6.57(m,2H),5.89–5.23(m,1H),4.20–4.0 1(m,3H),3.93–3.65(m,5H),3.24(s,3H),3.08–3.00(m,1H),2.26(s,6H),1.80–1.76 (m,3H),1.74–1.50(m,7H),1.49–1.33(m,5H),1.31–1.16(m,8H),1.13–0.84(m,4H).

[0498] Example 10: Preparation of Compound 7

[0499] Compound 7 was synthesized by a similar method to that used for compound 3 in Example 5 (using compound L as a starting material).

[0500] Compound 7: MS m / z (ESI): 1068.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.30–11.61(m,1H),77.93–7.43(m,6H),7.40–7.2 3(m,2H),7.18–6.75(m,6H),6.00–5.23(m,1H),4.17–3.83(m,1H),3.78–3.5 7(m,3H),3.16(s,3H),3.06–2.96(m,1H),2.24(s,6H),1.96–1.92(m,2H),1. 73–1.61(m,11H),1.54–1.34(m,6H),1.29–1.06(m,12H),1.00–0.80(m,2H).

[0501] Example 11: Preparation of Compound 8

[0502] Compound 8 was synthesized by a similar method to that used for compound 6 in Example 9 (using 4-bromophenylboronic acid and 5-bromo-4-fluoro-1-methyl-1H-indazole as raw materials).

[0503] Compound 8: MS m / z (ESI): 985.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.41–11.53(m,1H),8.24(s,1H),7.84–7.73(m,3H),7.63–7.59(m,2H),7.53–7.21(m,5H),7.18–6.53(m,4 H),6.00–5.18(m,1H),4.18–3.84(m,4H),3.62–3.49(m,3H),3.11–2.95(m,1H),2.22(s,6H),1.80–1.41(m,9H),1.40–0.87(m,14H).

[0504] Example 12: Preparation of compound T

[0505] Synthesis route:

[0506] Step 1: Synthesis of compound T

[0507] At 0°C, sodium hydride (221 mg, 5.53 mmol, 60% w / w) was added to a solution of compound T-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] + .

[0508] Example 13: Preparation of compound U

[0509] Synthesis route:

[0510] Step 1: Synthesis of compound U-2

[0511] 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] + .

[0512] Step 2: Synthesis of compound U

[0513] To a toluene (8 mL) solution of compound U-2 (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] + .

[0514] Example 14: Preparation of Compound 9

[0515] Compound 9 was synthesized by a similar method to that used for compound 6 in Example 9 (using compound T as a starting material).

[0516] Compound 9: MS m / z (ESI): 1026.8 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.43–11.67(m,1H),7.90–7.64(m,3H),7.56–7.35(m,4H),7.30–7.06(m,5H),7.02–6.74(m ,2H),5.80–5.32(m,1H),3.87–3.60(m,4H),3.15–2.95(m,1H),2.25(s,6H),2.02–2.00(m,1H),1.75–0.93(m,29H).

[0517] Example 15: Preparation of Compound 10

[0518] Compound 10 was synthesized by a similar method to that used for compound 8 in Example 11 (using 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole as a starting material).

[0519] Compound 10: MS m / z (ESI): 506.3 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.30–11.73(m,1H),8.21(s,1H),7.93–7.56(m,5H),7.40(m,5H),6.94(m,4H),6.1 3–5.23(m,1H),4.39–3.42(m,5H),3.12–2.88(m,1H),2.23(s,6H),1.82–1.24(m,15H),1.20–0.81(m,12H).

[0520] Example 16: Preparation of Compound 11

[0521] Compound 11 was synthesized by a similar method to that used for compound 6 in Example 9 (using compound U as a starting material).

[0522] Compound 11: MS m / z (ESI): 1052.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.27–11.65(m,1H),7.83–6.51(m,14H),6.03–5.15(m,1H),4.41–4.17(m,1H),3 .87–3.59(m,3H),3.06–3.01(m,1H),2.82(brs,1H),2.25(s,6H),1.80–1.07(m,28H),0.95–0.82(m,3H).

[0523] Example 17: Preparation of compound S

[0524] Synthesis route:

[0525] Step 1: Synthesis of compound S-1

[0526] Ethyl 2,3-epoxypropionate (61 g, 594.37 mmol) was added to a methanol (500 mL) solution of compound L-1 (50 g, 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] + .

[0527] Step 2: Synthesis of compound S-2

[0528] 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 (71 g, 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] + .

[0529] Step 3: Synthesis of compound S-3

[0530] Triethylamine (50.52 g, 499.21 mmol) and di-tert-butyl dicarbonate (87.16 g, 399.37 mmol) were added to a solution of compound S-2 (100 g, 332.81 mmol) in 100 mL of dichloromethane. 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] + .

[0531] Step 4: Synthesis of compound S-4

[0532] 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] + .

[0533] Step 5: Synthesis of compound S-5

[0534] Compound D-2 (34.08 g, 179.35 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, 179.35 mmol). The reaction mixture was stirred at 80 °C for 2 hours, and then concentrated under reduced pressure after cooling to room temperature. 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] + .

[0535] Step 6: Synthesis of compound S-6

[0536] 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] + .

[0537] Step 7: Synthesis of compound S-7

[0538] 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] + .

[0539] Step 8: Synthesis of compound S

[0540] 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] + .

[0541] Example 18: Preparation of compounds 12 and 13

[0542] Synthesis route:

[0543] Step 1: Synthesis of Compound 12-1

[0544] To a solution of compound U (2.0 g, 7.19 mmol) in 1,4-dioxane (50 mL) and water (5 mL), 4-bromo-3-fluorophenylboronic acid (1.6 g, 7.45 mmol), potassium carbonate (2.8 g, 20.26 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (494 mg, 0.71 mmol) were added. The reaction mixture was stirred at 100 °C for 3 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 under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 12-1. MS m / z (ESI): 372.1, 374.1 [M+H] + .

[0545] Step 2: Synthesis of Compound 12-2

[0546] Compound S (615 mg, 1.34 mmol), potassium carbonate (531 mg, 3.84 mmol), cuprous iodide (49 mg, 0.26 mmol), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (91 mg, 0.64 mmol) were added to a solution of compound 12-1 (500 mg, 1.34 mmol) in 20 mL of N-methylpyrrolidone. 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 (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 under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 12-2. MS m / z (ESI): 749.4 [M+H] + .

[0547] Step 3: Synthesis of Compound 12-3

[0548] A solution of compound 12-2 (600 mg, 0.80 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. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 5 / 1) to give compound 12-3. MS m / z (ESI): 747.4 [M+H] + .

[0549] Step 4: Synthesis of Compound 12-4

[0550] At -78°C, a 1M solution of bis(trimethylsilylaminolithium)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 12-3 (300 mg, 0.40 mmol) in tetrahydrofuran (3 mL) was added dropwise to the reaction mixture, and the 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 silica gel column chromatography (dichloromethane / ethyl acetate = 5 / 1) to give compound 12-4. MS m / z (ESI): 763.4 [M+H] + .

[0551] Step 5: Synthesis of Compound 12-5

[0552] To compound 12-4 (80 mg, 0.10 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 12-5, which was used directly in the next reaction. MS m / z (ESI): 663.4 [M+H] + .

[0553] Step 6: Synthesis of compounds 12 and 13

[0554] To the N,N-dimethylformamide (2 mL) of compound 12-5 (65 mg, 0.10 mmol) and compound GS (46 mg, 0.11 mmol), 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) were added, and 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. The crude product was purified by preparative HPLC (Waters-2545-QDA / 2998, Column: Waters-Xbridge-C18-10μm-19*250mm, Flow rate: 20, Mobile phase: A: 0.1% FA / H2O, B: ACN, UV wavelength: 254, Gradient: 10%–65%). The first peak (retention time: 7.805 min) was identified as compound 12, and the second peak (retention time: 8.022 min) was identified as compound 13.

[0555] Compound 12: MS m / z (ESI): 1056.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.81–7.52(m,5H),7.45–6.62(m,10H),6.03–5.81(m,1H),5.60–5.42(m,1H),4.30–3.98(m,1H),3.95– 3.57(m,2H),3.13–3.00(m,1H),2.98–2.79(m,1H),2.32(s,6H),1.94–1.77(m,2H),1.72–1.62(m,10H),1.42–0.92(m,15H).

[0556] Compound 13: MS m / z (ESI): 1056.6 [M+H] + .1 H NMR (400MHz, CD3OD) δ7.80–7.50(m,5H),7.45–6.60(m,10H),5.98–5.83(m,1H),5.58–5.44(m,1H),4.25–4.05(m,1H),3.99– 3.61(m,2H),3.17–2.98(m,1H),2.95–2.78(m,1H),2.31(s,6H),1.96–1.75(m,2H),1.73–1.61(m,10H),1.48–0.92(m,15H).

[0557] Experimental Example 1: Determination of the ability of compounds to stimulate cAMP production in human GLP1 receptor-stabilized cell lines

[0558] 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.

[0559] 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).

[0560] 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.

[0561] 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 GraphPadPrism to obtain the EC. 50 The test results for some compounds are shown in Table 1.

[0562] Table 1. EC50 values ​​of some compounds in the in vitro cAMP signal activation experiment.

[0563] Experimental results show that the compound of this invention can significantly increase the accumulation of cAMP in hGLP-1R-CHO-K1 cells.

[0564] Experimental Example 2: Pharmacokinetic Test in Mice

[0565] 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 (fed after 4 hours of fasting, 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, and centrifuged at 4000g 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, and centrifuged at 4000g 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 was used to calculate relevant pharmacokinetic parameters using a non-compartmental model linear logarithmic trapezoidal method. Test results for some compounds are shown in Table 2.

[0566] Table 2 Pharmacokinetic parameters in mice

[0567] Experimental results show that some of the compounds in this invention have excellent pharmacokinetic properties in mice.

[0568] Experimental Example 3: Rat Pharmacokinetic Test

[0569] 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) orally (after 4 hours of fasting, followed by free access to water, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH, pH 10 or 27% Peceol, 48% Cremophor RH40, 25% Sesame Oil). 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 6800g 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 6800g 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.

[0570] Experimental results show that some compounds of this invention have excellent pharmacokinetic properties in rats.

[0571] Experiment Example 4: Human Liver Microsomal Stability Test

[0572] 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 working microsome 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 working solution of the test compound (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 transfer 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.

[0573] Experimental results show that some compounds of this invention have excellent metabolic stability in human liver microsomes.

[0574] Experimental Example 5: CYP 2C8 & 2C9 Inhibition Test

[0575] 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.

[0576] Experimental results show that some compounds of this invention have low inhibitory activity against CYP 2C8 and CYP 2C9.

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 Meta-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, 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 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 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; 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 The aryl and 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 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 The aryl and 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; 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 The aryl and 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; 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; Cyclomeric Q2 is selected from 3-12-membered heterocyclic groups and 5-10-membered heteroaryl groups; the 3-12-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally each independently selected by one or more (e.g., 1 to 5) groups selected from R. h The substituents are replaced; Ring Q3 is 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 The aryl and 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; Each R h Each group is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, oxo (=O), thio (=S), cyano, 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 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, each independently is selected from one or more groups 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; 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 groups, 3-12 membered heterocyclic groups, C 6-10 aryl, 5-10 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: Cycle Q2 is selected from 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups; the 5-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally each independently surrounded by 1, 2 or 3 groups selected from deuterium, halogen, hydroxyl, mercapto, amino, oxo, thio, 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 Substituents of alkylamino groups; Preferably, ring Q2 is selected from 3. 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: Ring Q1 is selected from 9-14 membered heterocyclic groups, wherein the 9-14 membered heterocyclic group has 2, 3, or 4 nitrogen heteroatoms and 0 or 1 oxygen or sulfur heteroatoms (preferably having 2, 3, or 4 nitrogen heteroatoms and 0 oxygen or sulfur heteroatoms); the 9-14 membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, or 5 atoms selected from deuterium, halogen, hydroxyl, mercapto, amino, oxo, thio, 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, The substituents are replaced by 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 groups are optionally and independently 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 Substituents of alkylamino groups; R G R H Each is independently selected from hydrogen or halogen.

4. The compound according to any one of claims 1-3, 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: Ring Q1 is selected from in, Indicates a double bond or a single bond, and they are adjacent. Not both are double bonds; Keys identified by "#L" are connected to L, and keys identified by "#R" are connected to L. 1 The key of the identifier is connected to R. 1 ; Y1, Y3, Y4, and Y5 are each independently selected from C or N; Y2 is selected from C (=O), C (=S), CR e O, S, NR e Or N; Each Y6 is independently selected from C or N; W4 and W5 are each independently selected from CR W Or N; preferably, one of W4 and W5 is selected from N, and the other is selected from CR. W ; Ring M3 is selected from 5-membered heterocyclic aromatic rings or 5-membered heterocyclic rings; preferably 5-membered heterocyclic aromatic rings; Each R 3a R 3b R 4a R 4b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, SF5, and 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, or, R 3a and R 3b R 4a and R 4b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 3a and R 3b R 4a and R 4b Together with the carbon atoms they are attached to, they form Or, R 3a and R 4a Or R 4b R 3b and R 4a Or R 4b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl; 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 3-7 The cycloalkyl group and the 3-7 membered heterocycloalkyl group are optionally and independently 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 Substituents of alkylamino groups; R G R H Each is independently selected from hydrogen or halogen; Each R 5a and R 5b Each is independently selected from non-existent, hydrogen, 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, or, R 5a and R 5b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 5a and R 3a Or R 3b Or R 4a Or R 4b R 5b and R 3a Or R 3b Or R 4a Or R 4b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl; 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 3-7 The cycloalkyl group and the 3-7 membered heterocycloalkyl group are optionally and independently 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 The substituents of the alkylamino group are replaced; the condition is that when Y6 is selected from N, R 5a and R 5b There is one and only one that does not exist; R e Selected from hydrogen, 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, or, R e and R 3a Or R 3b Together with the atoms they are attached to, they form C 3-7 Cyclic hydrocarbon group or 4-7 membered heterocyclic group, or, R e and R 3a and R 3b Together with the atoms they are attached to, they form C 6-10 Aryl or 5-10 heteroaryl; 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 3-7 Cyclic hydrocarbon group, 4-7 membered heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are optionally and independently 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 Substituents of alkylamino groups; R W Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, 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, 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 groups are optionally and independently 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 The substituents of the alkylamino group are replaced.

5. The compound according to claim 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: Ring Q1 is selected from in: 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 N and the other is C; preferably, Y1 is selected from N and Y3 is selected from C; Y2 is selected from C (=O), CR e Or N, preferably, Y2 is selected from C or N; more preferably, Y2 is selected from N; Y6 is selected from C or N; preferably, Y6 is selected from C; R 3a R 3b R 4a R 4b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Haloalkyl, or R 3a and R 3b Together with the carbon atoms they are attached to form Or, R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 3a and R 4a or R 4b R 3b and R 4a or R 4b Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocyclic alkyl; R G R H Each is independently selected from hydrogen or halogen; Preferably, R 3a R 3b Each is independently selected from hydrogen, halogens, and C. 1-6 Alkyl, or R 3a and R 3b Together with the carbon atoms they are attached to form R G R H Each is independently selected from hydrogen and halogens (e.g., F); or, R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; Preferably, R 3a R 3b All are selected from hydrogen; Preferably, R 3a and R 3b Together with the carbon atoms they are attached to form R G R H Each is independently selected from hydrogen and halogens (e.g., F), preferably, R G R H One of them is selected from halogens (e.g., F), and the other is selected from hydrogen; preferably, R G Selected from hydrogen, R H Selected from halogens (e.g., F); preferably, R G Selected from halogens (e.g., F), R H Selected from hydrogen; preferably, R G R H All are selected from halogens (e.g., F); Preferably, R 3a and R 3b Together with the carbon atoms they are attached to, they form C 3-6 Cycloalkyl groups (e.g., cyclopropyl); Preferably, R 4a R 4b Each is independently selected from hydrogen, halogens, and C. 1-6 alkyl; Preferably, R 4a R 4b All are selected from hydrogen; R 5a and R 5b Each is independently selected from non-existent, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Haloalkyl, or R 5a and R 5b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, or, R 5a and R 3a or R 3b or R 4a or R 4b R 5b and R 3a or R 3b or R 4a or R 4b Together with the atoms they are attached to, they form C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl; provided that when Y6 is selected from N, R 5a and R 5b There is one and only one that does not exist; Preferably, R 5b Selected from hydrogen, R 5a Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Preferably, R 5b Selected from hydrogen, R 5a Selected from C 1-6 Alkyl groups (e.g., methyl, preferably) )； R e Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Haloalkyl, or R e and R 3a and R 3b Together with the atoms they are attached to, they form phenyl or 6-membered heteroaryl groups; Preferably, Selected from More 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 .

6. The compound according to claim 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: The ring Q1 is selected from in: Y6 is selected from C or N; R 4a R 4b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5a R 5b Each is independently selected from non-existent, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Haloalkyl, provided that when Y6 is selected from N, R 5a and R 5b There is one and only one that does not exist; W4 and W5 are each independently selected from CR W Or N; R W Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Preferably, Y6 is selected from C; R 4a R 4b One of them is selected from hydrogen, and the other is selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5a R 5b One of them is selected from hydrogen, and the other is selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; W4 is selected from CR W W5 is selected from N, or W4 is selected from N and W5 is selected from CR. W ; R W Selected from hydrogen, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Preferably, Selected from More Keys identified by "#L" are connected to L, and keys identified by "#R" are connected to L. 1 The key of the identifier is connected to R. 1 .

7. The compound according to any one of claims 1-6, 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 represented by formula (I-1), (I-2), (I-3), (I-4), or (I-5): in, X1, X2, X3, X4, X5, X6, X7, X8, R 6a R 6b R 7 R 8 R 9 R 10 R 11 L, Q3, R 2 R 1 Y6, R 3a R 3b R 4a R 4b R 5a R 5b R e W4 and W5 are as defined in any one of claims 1-6.

8. The compound according to any one of claims 1-7, 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: 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)C 1-6 Alkyl, -C 1-3 The alkyl-NHC(O)C1-6 alkyl groups are optionally and independently substituted 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 groups selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkyne group, -C(O)NHC 1-3 Alkyl, -C 1-3 Alkylene-C(O)NHC 1-3 Alkyl group, -NHC(O)C 1-3 Alkyl, -C 1-3 Alkylene-NHC(O)C 1-3 Alkyl substituents; 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 groups selected from cyano, C 1-3 Alkyl, C 2-3 alkynyl group, -C 1-3 Alkylene-C(O)NHC 1-3 Alkyl group, -NHC(O)C 1-3 Alkyl substituents; 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 (For example )and More Keys marked with "$" are connected to Q2 or 9. The compound according to any one of claims 1-8, 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: L is selected from a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group is optionally surrounded by 1 to 5 groups selected from deuterium, 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 CH, 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 The key identified by "#Q3" is connected to Q3.

10. The compound according to any one of claims 1-9, 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: Ring Q3 is selected from C 3-10 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally and independently each bound 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 Substituents of cycloalkyl and 4-7 membered heterocyclic alkyl 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 3-6 Cycloalkyl groups and 4-7-membered heterocycloalkyl groups may be independently substituted with substituents selected from deuterium or halogens; Preferably, ring Q3 is selected from phenyl, 5-6 membered heteroaryl (e.g., pyridyl) or C 4-8 Cycloalkyl (e.g., bicyclo[1.1.1]pentyl), the phenyl, 5-6 heteroaryl (e.g., pyridyl) and C 4-8 Cycloalkyl groups (e.g., bicyclo[1.1.1]pentyl) are optionally each independently composed of one, two, or three groups selected from 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 The alkylamino group is substituted; 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 groups may be substituted by halogens, each independently; Preferably, ring Q3 is selected from in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; K1 and K3 are each independently selected from C or N; preferably, K1 and K3 are selected from C; K2, K5, and K6 are each independently selected from CH, NH, N, O, or S; preferably, K2 is selected from S or CH, K5 is selected from CH or S, and K6 is selected from CH. K7, K8, K9, K 10 Each is independently selected from CH or N; preferably, K7, K8, K9, K 10 Selected from CH; preferably, K7, K8, K9, K 10 One of them is selected from N, and the rest are selected from CH; preferably, K7 is selected from N, and K8, K9, and K 10 Selected from CH; preferably, K8 is selected from N, K7, K9, K 10 Selected from CH; q is selected from 0, 1, 2 or 3; preferably, q is selected from 0, 1 or 2; preferably, q is selected from 0 or 1; preferably, q is selected from 0; preferably, q is selected from 1; Each R Q Each is independently 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 The alkylamino group is substituted; 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 The alkylamino group is optionally and independently substituted with a substituent selected from deuterium or halogen; preferably, R Q Selected from halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl; more preferably, R Q Selected from halogens; The It is a heterocyclic aromatic ring; the described It is an aromatic ring or a heterocyclic aromatic ring; Preferably, ring Q3 is selected from Preferably, ring Q3 is selected from Preferably, ring Q3 is selected from: Preferred Preferred More The key identified by "#L" is connected to L, and "#R" is used to denote the key. 2 The key of the identifier is connected to R. 2 .

11. The compound according to any one of claims 1-10, 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: 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 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 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 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 and 0 heteroatoms selected from oxygen or sulfur. More preferably, R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, or halogen; R 10 Selected from 5-8 membered heterocyclic groups; each of the 5-8 membered heterocyclic groups is optionally and independently composed of 1, 2, or 3 elements 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 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 Substitution of alkyl halogens.

12. The compound according to claim 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: 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 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 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 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; r1, r2, r3, and r4 are each independently selected from 0, 1, or 2; Each 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; Each R r4 Each is independently 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 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.

13. The compound according to any one of claims 1-12, 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 6-8 membered heterocyclic groups, wherein the 6-8 membered heterocyclic group is optionally selected by 1, 2 or 3 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: Preferred Preferred (For example )or More (For example )。 14. The compound according to any one of claims 1-13, 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: 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; 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; 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 (For example Preferably, structural unit Selected from Preferred More 15. The compound according to any one of claims 1-14, 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: Structural unit Selected from Preferred With "#R 10 The key of the identifier is connected to R. 10 The key identified by "#C(O)" is connected to -C(O)-.

16. The compound according to any one of claims 1-15, 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: 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 and 5-10 heteroaryl groups are optionally and independently replaced by substituents selected from deuterium or 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 Monocyclic cycloalkyl, C 5-9 The C group is substituted with substituents of bridged bicyclic 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 Monocyclic cycloalkyl, C 5-9 Bridged bicyclic cycloalkyl groups, 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 may be independently substituted by halogens. Preferably, R 1 Selected from Preferably, R 1 Selected from Among them, T1, T2, T3, T4, T5, T6, T7, T8, T9, T 10 T 11 T 12 T 13 T 14 T 15 Each of them is independently selected from CH or N; preferably CH; preferably, T1, T2, T3, T4, and T5 are all selected from CH; preferably, one of T1, T2, T3, T4, and T5 is selected from N, and the rest are selected from CH. V is selected from CH2, NH, O or S, preferably CH2 or O; Each R 01 R 02 R 03 R 04 R 05 R 06 R 07 R 08 Each is independently selected from halogen, cyano, SF5, hydroxyl, mercapto, amino, 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 Monocyclic cycloalkyl, C 5-9 The C group is substituted with substituents of bridged bicyclic 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 Monocyclic cycloalkyl, C 5-9 Bridged bicyclic cycloalkyl groups, 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 may be independently substituted by halogens. Preferably, each R 01 Each is independently selected from halogens (e.g., F, Cl), SF5, cyano, C. 1-6 Alkyl (e.g., methyl), C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thiols (e.g., -SCH3), C 1-6 Haloalkylthio groups (e.g., -SCF3), C 2-6 alkenyl, C 2-6 Alkyne group (e.g., ethynyl group), C 3-6 Monocyclic cycloalkyl (e.g., cyclopropyl), C 5-9 Bridged bicyclic cycloalkyl (e.g.) ), 4-7 nucleotide monocyclic heterocyclic groups, 7-11 nucleotide bridged bicyclic heterocyclic groups (e.g. ), 7-11 spirobicyclic heterocyclic groups, 8-10 fused bicyclic heterocyclic groups (e.g. Preferably, each R 01 Each is independently selected from halogens (e.g., F, Cl), SF5, cyano, C. 1-6 Alkyl (e.g., methyl), C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thiols (e.g., -SCH3), C 1-6 Haloalkylthio groups (e.g., -SCF3), C 3-6 Monocyclic cycloalkyl groups (e.g., cyclopropyl) and 4-7 membered monocyclic heterocyclic groups; preferably, each R 01 Each is independently selected from halogens (e.g., F, Cl) and C. 1-6 Alkyl groups (e.g., methyl groups); Each R 02 R 03 R 04 R 05 R 06 R 07 R 08 Each is independently selected from halogens (e.g., F), C 1-6 Alkyl (e.g., methyl), C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thiols (e.g., -SCH3), C 1-6 Haloalkylthio groups (e.g., -SCF3), C 2-6 alkenyl, C 2-6 Alkyne group (e.g., ethynyl group), C 3-6 Cycloalkyl groups (e.g., cyclopropyl); q1 is selected from 0, 1, 2, 3 or 4; preferably, q1 is selected from 0, 1, 2 or 3; more preferably, q1 is selected from 1, 2 and 3; more preferably, q1 is selected from 2 and 3; q2 is selected from 0, 1, 2 or 3; preferably, q2 is selected from 0, 1 or 2; q3 is selected from 0, 1, 2 or 3; preferably, q3 is selected from 0, 1 or 2; q4 is selected from 0, 1, 2 or 3; preferably, q4 is selected from 0, 1 or 2; q5 is selected from 0, 1, 2, 3 or 4; preferably, q5 is selected from 0, 1, 2 or 3; q6 is selected from 0, 1, 2 or 3; preferably, q6 is selected from 0, 1 or 2; q7 is selected from 0, 1, or 2; preferably, q7 is selected from 0 or 1. q8 is selected from 0, 1, or 2; preferably, q8 is selected from 0 or 1. v1 is selected from 1, 2, or 3; preferably, v1 is selected from 1 or 2; v2 is selected from 1, 2 or 3; preferably, v2 is selected from 1 or 2; more preferably, v2 is selected from 1; v3 and v4 are each independently selected from 1, 2 or 3, preferably v3 and v4 are each independently selected from 1 or 2; v5 is selected from 1, 2 or 3; preferably, v5 is selected from 3.

17. The compound according to claim 16, 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: Preferably, R 1 Selected from:

18. The compound according to any one of claims 1-17, 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: 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 The aryl group and the 12-20 membered heteroaryl group are tricyclic or tetracyclic; the C 12-20 Cyclic hydrocarbon groups, 12-20 membered heterocyclic groups, C 12-20 The aryl and 12-20 heteroaryl groups are optionally and independently selected from 1 to 5 groups of R h The substituents are replaced; Preferably, the 12-20 membered heterocyclic group and the 12-20 membered heteroaryl group have 0, 1, 2 or 3 nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from oxygen or sulfur; more preferably, the 12-20 membered heterocyclic group and the 12-20 membered heteroaryl group have 0, 1, 2 or 3 nitrogen heteroatoms and 0, 1 or 2 oxygen heteroatoms and 0 sulfur heteroatoms; more preferably, the 12-20 membered heterocyclic group and the 12-20 membered heteroaryl group have 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms and 0 sulfur heteroatoms. 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 and the 12-18 heteroaryl group are tricyclic or tetracyclic; optionally, each is 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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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, the 12-18 membered heterocyclic group and the 12-18 membered heteroaryl group have 0, 1 or 2 nitrogen heteroatoms and 0, 1 or 2 oxygen heteroatoms and 0 sulfur heteroatoms; more preferably, they have 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms and 0 sulfur heteroatoms. Preferably, R 2 Selected from 12-18 membered heterocyclic groups, wherein the 12-18 membered heterocyclic group is tricyclic or tetracyclic, optionally each independently bound 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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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, the 12-18 membered heterocyclic group has 0, 1, or 2 nitrogen heteroatoms and 0, 1, or 2 oxygen heteroatoms and 0 sulfur heteroatoms; more preferably, it has 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms and 0 sulfur heteroatoms. Preferably, R 2 The group is selected from 12-15-membered tricyclic heterocyclic groups or 15-18-membered tetracyclic heterocyclic groups, wherein the 12-15-membered tricyclic heterocyclic group and the 15-18-membered tetracyclic heterocyclic group are optionally each independently surrounded by 1 to 5 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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -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, the 12-15 membered tricyclic heterocyclic group and the 15-18 membered tetracyclic heterocyclic group have 0, 1 or 2 nitrogen heteroatoms and 0, 1 or 2 oxygen heteroatoms and 0 sulfur heteroatoms; more preferably, they have 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms and 0 sulfur heteroatoms. Preferably, R 2 The heteroatoms are selected from 9-10-membered bicyclic heteroaryl groups and 11-15-membered tricyclic heterocyclic groups; the heteroatoms of the 9-10-membered bicyclic heteroaryl group are 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 heteroatoms of the 11-15-membered tricyclic heterocyclic group are selected from nitrogen, oxygen, and sulfur, preferably nitrogen and oxygen, 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, more preferably 1; the 9-10-membered bicyclic heteroaryl group and the 11-15-membered tricyclic heterocyclic group are optionally each independently selected by one or more (e.g., 1, 2, or 3) groups selected from halogens, oxo groups, C... 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Substituents include alkylene-, C3-6 cycloalkyl, and 4-7 heterocyclic alkyl groups.

19. The compound according to claim 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: R 2 Selected from group (0), group (1) and group (2), with preferred group (0) and group (1), and more preferably group (1): (0) Among them, cyclo-A phenyl and 6-membered nitrogen-containing aryl group; preferably phenyl; Ring B is selected from phenyl and 5-6-membered heteroaryl; preferably 5-membered heteroaryl; more preferably 5-membered nitrogen heteroaryl; Each R a Each is independently 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, C 2-6 alkenyl and 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 and C 2-6 The alkynyl groups are optionally and independently substituted by substituents selected from deuterium or halogens; preferably, each R a Each is independently selected from hydrogen and halogens (e.g., F); Each R b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkylene-, C 3-6 Cycloalkyl and 4-7 membered heterocyclic alkyl; preferably, each R b Each is independently selected from C 1-6 Alkyl and C 3-6 cycloalkyl; preferably, each R b Each is independently selected from C 1-6 alkyl; a is selected from 0 and 1; preferably, a is selected from 1; b is selected from 0, 1, and 2; preferably, b is selected from 1; (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 cyclic hydrocarbon group; preferably 5-6 membered monocyclic heterocyclic group; preferably 5 membered monocyclic heterocyclic group having 1 nitrogen heteroatom or oxygen heteroatom, 5 membered monocyclic heterocyclic group having 2 oxygen heteroatoms, 6 membered monocyclic heterocyclic group having 1 or 2 nitrogen heteroatoms and 0 or 1 oxygen heteroatoms; preferably 5 membered monocyclic heterocyclic group having 1 nitrogen heteroatom; more preferably 5 membered monocyclic heterocyclic group, wherein the heteroatom of the 5 membered monocyclic heterocyclic group is selected from nitrogen, and the number of heteroatoms is selected from 1; Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 3-7 Monocyclic cyclic hydrocarbon group, 7-10 membered bridged bicyclic heterocyclic group, 7-10 membered spirobicyclic heterocyclic group, 7-10 membered fused bicyclic heterocyclic group, C 7-10 Bridged bicyclic cyclic hydrocarbon group, C 7-10 Spirobicyclic cyclic hydrocarbon group, C 7-10 Fused bicyclic cyclic hydrocarbon group; preferably 4-7 membered monocyclic heterocyclic group, C 4-7 Monocyclic cyclic hydrocarbon group, 7-10 membered bridged bicyclic heterocyclic group, 7-10 membered spirobicyclic heterocyclic group, 7-10 membered fused bicyclic heterocyclic group, C 7-10 Bridged bicyclic cyclic hydrocarbon group, C 7-10 Spirobicyclic cyclic hydrocarbon group, C 7-10 Fused bicyclic hydrocarbon group; preferably a 4-6 membered monocyclic heterocyclic alkyl group having one nitrogen heteroatom, oxygen heteroatom, or sulfur heteroatom, C 4-6 Monocyclic cycloalkyl, C 5-6 Monocyclic cycloalkenyl, C 7-10 Fused bicyclic cycloalkyl, C 7-10 Spirobicyclic cycloalkyl, 7-9 membered spirobicyclic heterocyclic alkyl with one oxygen atom, 7-9 membered bridged bicyclic heterocyclic alkyl with one oxygen atom, benzo[C] 5-6 Monocyclic cycloalkyl groups, benzo5-6 membered oxamonocyclic heterocyclic groups; preferably 6-membered heterocyclic alkyl groups having one oxygen atom; preferably 4-6 membered monocyclic heterocyclic alkyl groups, C 3-6 Monocyclic cycloalkyl, wherein the heteroatoms of the 4-6 membered monocyclic heterocyclic alkyl are selected from nitrogen, oxygen and sulfur, preferably nitrogen and oxygen, more preferably oxygen, and the number of heteroatoms is selected from 1 and 2, preferably 1; 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; Preferably, 'a' is selected from 0 and 1, and more preferably 0; Preferably, b is selected from 1 and 2, with 2 being the most preferred; Preferably, c is selected from 0, 1, and 2, more preferably 0 and 1, and even more preferably 0; Each R a Each is independently 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, 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 and C 2-6 The alkynyl group is optionally and independently substituted by a substituent selected from deuterium or halogen; R a Halogens (e.g., F) are preferred; Each R b Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, cyano group, hydroxyl group, mercapto group, amino group, 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 Cycloalkyl or 4-6 heterocycloalkyl, wherein 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 The cycloalkyl and 4-6 heterocycloalkyl groups are optionally each independently selected from deuterium, halogen, cyano, hydroxyl, or 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, methyl, isopropyl, cyclopropyl, -(CH2)2OCH3, -CH2CF3, Or two R atoms attached to the same carbon atom b Formation of cyclopropyl; preferably, at least one R is present. b Selected from oxo groups; preferably, 1 R b Selected from oxo groups, the rest are R b Each is independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from halogens and C. 1-6 Substituents of alkoxy groups; Each R c Each is independently 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; R is preferred. c Selected from halogens, oxo groups, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl group, -S(O)2C 1-6 alkyl or The C 1-6 Alkyl, -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; more preferably R c Preferred radicals include F, oxoyl, methyl, ethyl, methoxy, -CH2CF3, -CH2CN, -(CH2)2CN, -C(O)CH3, -C(O)CF3, -C(O)CH(OH)CH3, and -S(O)2CH3. (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. Each R a Each is independently 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, 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 and C 2-6 The alkynyl group is optionally and independently substituted by a substituent selected from deuterium or halogen; R a Halogens (e.g., F) are preferred; Each R b Each is independently 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 b Selected from halogens, C 1-6 Alkyl groups (e.g., methyl groups); Each R c Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and 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 groups and -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).

20. The compound according to claim 19, 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: Preferred Among them, A1, A2, A3, B1, B2, B4, B5, B6, and B7 are each independently selected from CH and N; B3 is selected from NH, O, and S; Preferably, A1, A2, and A3 are all selected from CH; preferably, one of A1, A2, and A3 is selected from N, and the rest are selected from CH. Preferably, both B1 and B2 are selected from CH; preferably, one of B1 and B2 is selected from N and the other is selected from CH; preferably, B1 is selected from CH and B2 is selected from N. Preferably, B3 is selected from NH; Preferably, B4, B5, B6, and B7 are all selected from CH; preferably, one of B4, B5, B6, and B7 is selected from N, and the rest are selected from CH. R a R b a, b, as defined in claim 19; Preferably, each R a Each is independently selected from hydrogen and halogens (e.g., F); more preferably, each R a Each is independently selected from halogens (e.g., F); Preferably, each R b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-4 Alkylene-, C 3-6 Cycloalkyl and 4-7 membered heterocyclic alkyl; more preferably, each R b Each is independently selected from C 1-6 Alkyl (e.g., methyl) and C 3-6 Cycloalkyl (e.g., cyclopropyl); preferably, each R b Each is independently selected from C 1-6 Alkyl (e.g., C10) 1-4 Alkyl groups, such as C 1-3 Alkyl groups, especially methyl groups, etc. Preferably, 'a' is selected from 1; Preferably, b is selected from 1; Preferably, the Selected from Among them, A1, A2, A3, B1, B2, R a R b a is as defined above.

21. The compound according to claim 19, 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; 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 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; p0 is selected from 1, 2, 3, 4 and 5, preferably 1, 2, 3 and 4, and more preferably 1; 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 19; Preferably, each R a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; more preferably hydrogen or halogen; Preferably, each R b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 heterocycloalkyl, wherein C 1-6 Alkyl groups are optionally selected from deuterium, halogens, and C. 1-6 Substituents of alkoxy groups; more 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 Substituents of alkoxy groups; Preferably, each R c Each is independently selected from hydrogen, halogen, oxo group, 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 halogens (e.g., F); Preferably, a is selected from 0 or 1; preferably, a is selected from 0. Preferably, b is selected from 0 or 1; Preferably, c is selected from 0, 1, or 2; more preferably, c is selected from 0 and 1; more preferably, c is selected from 0.

22. The compound according to claim 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: Preferably, the Selected from Preferably, the Selected from Among them, A1, A2, A3, C1, p0, p1, p2, R a R b a) as defined in claim 19 or 21; Preferably, A1, A2, and A3 are all selected from CH; preferably, one of A1, A2, and A3 is selected from N, and the rest are selected from CH. Preferably, p0 is selected from 1, 2, 3, and 4; preferably, p0 is selected from 1 and 4; preferably, p0 is selected from 1; preferably, p0 is selected from 4. Preferably, p1 and p2 are each independently selected from 1 and 2; preferably, one of p1 and p2 is selected from 1 and the other is selected from 2; preferably, p1 and p2 are both selected from 1; preferably, p1 and p2 are both selected from 2. Preferably, C1 is selected from NH, O and S; more preferably, C1 is selected from NH and O; more preferably, C1 is selected from O. Preferably, each R a Each is independently selected from hydrogen and halogens (e.g., F); more preferably, each R a Each is independently selected from halogens (e.g., F); Preferably, a is selected from 0 and 1; preferably, a is selected from 0; Preferably, R b Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 heterocycloalkyl, the C 1-6 Alkyl groups are optionally selected from halogens and C. 1-6 The alkoxy group is substituted; preferably, R b Selected from C 1-6 Alkyl and C 3-6 cycloalkyl; more preferably, R b Selected from C 1-6 Alkyl (e.g., C10) 1-4 Alkyl groups, such as C 1-3 Alkyl groups, especially methyl groups (e.g., alkyl groups).

23. The compound according to claim 19, 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; CH is preferred. B3 is selected from CH2, CF2, O, and NR. b ; C 16 Selected from CH2, NH, O or S, with O being preferred; C 17 Selected from CH2, NH, O or S, preferably O or CH2; 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. R a R b R c a, c are as defined in claim 19; Preferably, each R a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, SF5, C 1-6 Alkyl; more preferably hydrogen or halogen; Preferably, each R b Each is independently selected from hydrogen and 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 Substituents of alkoxy groups; more preferably hydrogen or C. 1-6 alkyl; Preferably, each R c Each is independently selected from hydrogen, halogen, oxo group, 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, deuterium, and halogens (e.g., F); more preferably hydrogen or halogens (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.

24. The compound according to claim 19, 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 N and NR. b O, S, CR b or C(R) b )2; Preferred B4 is selected from NR b or CR b ; More preferably CR b ; 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 19; Preferably, each R a Each is independently selected from hydrogen, halogen, or C. 1-6 alkyl; Preferably, each R b Each is independently selected from hydrogen, halogen, and C. 1-6 alkyl; Preferably, each R c Each is independently selected from hydrogen, oxo group, halogen, C 1-6 alkyl; Preferably, 'a' is selected from 0 or 1; Preferably, c is selected from 1 or 2.

25. The compound according to claim 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: 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 3 or 7; Preferably, R c Selected from halogen or C 1-6 Alkyl, more preferably C 1-6 alkyl.

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, R 2 Selected from: Preferably, R 2 Selected from 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 the compound is represented by formula (IA), (IB), or (IC): in, R 5a R 6a R 6b R 1 R 2 R 10 R G R H Q3 is as defined in any one of claims 1-26.

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 the compound is selected from:

29. A pharmaceutical composition comprising the compound of 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, and pharmaceutically acceptable carriers, diluents, or excipients.

30. A pharmaceutical combination comprising the compound of 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, and another therapeutically active agent.

31. The use of a compound according to any one of claims 1-28, 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; or administration to said individual of a therapeutically effective amount of the pharmaceutical composition according to claim 29; or administration to said individual of a therapeutically effective amount of the pharmaceutical composition according to claim 30 in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or disorders or for modulating GLP-1 receptors.

32. A method for preventing and / or treating GLP-1-related diseases, conditions, or symptoms, the method comprising: The individual is given a therapeutically effective amount of 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 derivatives), 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 29; or the individual is given a therapeutically effective amount of the pharmaceutical combination according to claim 30.

33. The application according to claim 31 or 32, 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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