CN116265452A

CN116265452A - Nitrogen-containing heterocyclic compound, preparation method and application thereof

Info

Publication number: CN116265452A
Application number: CN202211615954.4A
Authority: CN
Inventors: 段文虎; 耿美玉; 张贺峰; 艾菁; 兰垚瀚; 彭霞; 方晨; 季寅淳; 金泽宸; 冯大智; 丁健
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2021-12-17
Filing date: 2022-12-15
Publication date: 2023-06-20
Also published as: WO2023109918A1

Abstract

The invention relates to a nitrogen-containing heterocyclic compound, a preparation method and application thereof, wherein the structure of the nitrogen-containing heterocyclic compound is shown in a general formula I, and each substituent group is defined in the specification and the claims. The nitrogen-containing heterocyclic compound of the present invention is useful as a therapeutic agent for treating inflammatory diseases, ischemic diseases, degenerative diseases, tumors and other related disorders and diseases.

Description

Nitrogen-containing heterocyclic compound, preparation method and application thereof

Technical Field

The present invention relates to nitrogen-containing heterocyclic compounds, processes for their preparation, pharmaceutical compositions containing the series of compounds and their use as therapeutic agents, in particular for the treatment of inflammatory diseases, degenerative diseases, ischemic diseases, tumors and the like and related conditions and diseases.

Background

Protein kinases are proteins (enzymes) that regulate various cellular functions by phosphorylating specific amino acids on proteins. Proteins regulate activity through conformational changes and their ability to bind to chemical components. Protein kinase activity refers to the rate at which a kinase binds a phosphate group to a substrate, which can be measured by detecting the amount of substrate converted to product over time. Phosphorylation of the substrate occurs at the activation site of the protein kinase. Protein kinases can be classified into five classes, depending on the kind of amino acid residues of the protein kinase substrate protein that is phosphorylated: serine/threonine protein kinases, tyrosine protein kinases, histidine protein kinases, tryptophan protein kinases and aspartyl/glutamyl protein kinases. Among them, serine/threonine protein kinases are a class of enzymes capable of catalyzing the phosphorylation of serine/threonine residues on a variety of substrate proteins; tyrosine kinase is a protease that catalyzes the transfer of adenosine triphosphate to protein tyrosine residues. Pathological conditions associated with protein kinases include inflammatory diseases, immune diseases, cardiovascular diseases, and tumors, among others.

Cell death mainly includes apoptosis, necrotic apoptosis, pyro-apoptosis, iron death, and cell death processes associated with autophagy and non-programmed necrosis. Necrotic apoptosis, also known as programmed cell death or programmed necrosis, is a novel means of cell death that has been discovered in recent years. Programmed necrosis, which is a highly inflammatory form of cell death, results in the release of dangerously related molecular patterns from cells, is considered an important pathological factor in a variety of degenerative and inflammatory diseases. Such diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and various other related diseases. Receptor interacting protein kinase 1, abbreviated RIPK1, is a homologous class of two serine/threonine kinases to RIPK3, which are key elements mediating necrotic apoptosis.

RIPK1 kinase is recognized as a potential therapeutic target for diseases associated with apoptosis. The first RIPK1 inhibitor Necrostatin-1 (Nec-1) and analogues thereof have shown definite curative effects on various degenerative diseases, inflammations, cancers and other diseases in preclinical researches. For example, has an alleviating effect on Alzheimer's disease, parkinson's disease, huntington's disease, senile macular degeneration, etc.; has protective effect on psoriasis, retinitis pigmentosa, inflammatory bowel disease, autoimmune disease, bombesin-induced acute pancreatitis and septicemia/systemic inflammatory response syndrome; can effectively relieve ischemic brain injury, ischemic myocardial injury, retinal ischemia/reperfusion injury, photoreceptor cell necrosis induced by retinal detachment, glaucoma, renal ischemia reperfusion injury, cisplatin-induced renal injury and traumatic brain injury: other diseases associated with RIPK 1-dependent apoptosis, necrosis or cytokine production, including hematological and solid organ malignancies, bacterial and viral infections (including tuberculosis, influenza, etc.), and lysosomal storage disorders (especially gaucher disease) are at least partially alleviated. Another class of RIPK1 inhibitors, GSK2982772, is also in clinical trials for the treatment of various autoimmune diseases.

There is a need for kinase inhibitors, particularly RIPK1 kinase inhibitors, for use as a medicament. However, the existing inhibitors targeting the kinase related to the programmed necrosis have defects of different degrees, such as poor selectivity, unsatisfactory in-vivo inhibition activity, poor drug substitution property, low oral bioavailability and the like, and some of the inhibitors cannot penetrate through the blood brain barrier to enter the central nervous system, and the defects limit further research and clinical application of the inhibitors. There remains a need in the art for more novel kinase inhibitors with more novel chemical structures and more prominent pharmacokinetic properties as candidates for detection, prevention and treatment of diseases involving necrotic apoptosis-related kinases (e.g., RIPK 1).

Disclosure of Invention

The invention provides a compound shown in a general formula (I), which can be used as a kinase inhibitor for detecting, preventing and treating diseases or symptoms related to kinase, in particular RIPK1 kinase; the invention also provides a preparation method of the compound shown in the general formula (I).

In a first aspect the present invention provides a compound of formula (I) or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, an isotopically labelled compound thereof,

Wherein ring A is a 6 membered heteroaromatic ring; ring E is a benzene ring or a 6 membered heteroaromatic ring; ring G is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring;

z is selected from CH ₂ CH substituted by one or two halogens ₂ 、CDH、CD ₂ 、O、S、NH、N(CH ₃ )、N(CD ₃ )；

Y1 is N or C-R ^1a The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^1a Selected from H, D, halogen, NR ¹ R ² ；R ¹ 、R ² Independently selected from: H. d, C1C 1-C8 alkyl, C1-C15 alkyl C (=O) -, C1-C15 alkyl OC (=O) -, C1-C15 alkyl-O- (C1-C8 alkylene) -, C1-C15 alkyl (O=) CO-, C2-C8 alkenyl, C2-C8 alkynyl, C6-C14 aryl C (=O) -, amino acid acyl, C1-C8 alkyl-C (=O) -CH=CH-; r is as described above ¹ 、R ² The groups are optionally substituted with 1-5 groups selected from the group consisting of: C6-C14 aryl, (C1-C8 alkyl) ₃ Amino groups of Si-, amino-, hydroxy-, halogen-, one or two C1-C8 alkyl substituentsOxo (=o), C1-C8 alkyl;

y2 is N or C-R ^2a The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^2a Selected from the group consisting of: H. d, halogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl; r is as described above ^2a The groups are optionally substituted with 1-5 (1, 2, 3, 4 or 5) groups selected from the group consisting of: D. halogen, hydroxy, amino of one or two C1-C8 alkyl substituents, cyano, NH ₂ C (=o) -, C1-C8 alkyl;

Y3 is N or C-R ^3a The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^3a Selected from the group consisting of: H. d, halogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, 5-14 membered heteroaryl, C3-C14 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclyl, NH ₂ CO-, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, hydroxy-substituted C1-C8 alkyl, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano cyano-substituted C1-C8 alkyl, -COOH, - (C1-C8 alkyl) -COOH, -C (=o) O- (C1-C8 alkyl), -C1-C8 alkyl) -C (=o) O- (C1-C8 alkyl), -OC (=o) H, - (C1-C8 alkyl) -OC (=o) - (C1-C8 alkyl), -C (=o) H, - (C1-C8 alkyl) -C (=o) H, -C (=o) - (C1-C8 alkyl), -C (=c-C8 alkyl), -C1-C8 alkyl) -C (=o) - (C1-C8 alkyl), NH (NH) ₂ C (=o) (C1-C8 alkyl) -, (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) N-C (=o) -, (C1-C8 alkyl) -NHC (=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) N-C (=o) - (C1-C8 alkyl) -, HC (=o) NH-, HC (=o) N (C1-C8 alkyl) -, (C1-C8 alkyl) -C (=o) NH-, (C1-C8 alkyl) -C (=o) N (C1-C8 alkyl) -, (5-14 membered heteroaryl) -NHC (=o) -; wherein R is ^3a Optionally by 0-5 (0, 1, 2, 3, 4 or 5) R ^3a1 Substitution;

each R is ^3a1 Independently at each occurrence selected from: C1-C8 alkyl, oxo (=O), C2-C8 alkenyl, C2-C8 alkynyl, C1-C8Alkoxy, 3-14 membered heterocyclyl-C (=o) -, C3-C14 cycloalkyl, 5-14 membered heteroaryl, H, D, halogen, halo C1-C8 alkyl, halo C1-C8 alkoxy, halo C2-C8 alkenyl, C2-C8 alkenyloxy, halo C2-C8 alkynyl, C2-C8 alkynyloxy, halo C2-C8 alkynyloxy, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) oxy, (C3-C14 cycloalkyl) - (C1-C8 alkyl) oxy, (C3-C14 cycloalkyl) oxy (C1-C8 alkyl) -, (C3-C14 cycloalkyl) thio, (C3-C14 cycloalkyl) - (C1-C8 alkyl) thio, (C3-C14 cycloalkyl) thio (C1-C8 alkyl) -, (C3-C14 cycloalkyl) - (C1-C14 cycloalkyl) -, (NH) -, (C3-C14 cycloalkyl) - (C1-C14 cycloalkyl) -, (C1-C8 alkyl) -, or (C1-C8 alkyl) - (C3-C14 cycloalkyl) C (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) O-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) O-, (C3-C14 cycloalkyl) -C (=o) O- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -OC (=o) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -OC (=o) -, (C3-C14 cycloalkyl) -OC (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) NH-, (C3-C14 cycloalkyl) - (C (=o) NH-, (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -NHC (=o) -, (C3-C14 cycloalkyl) - (C (=c) -, (C1-C8 alkyl) -NHC (=o) -, (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -NHC (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, hydroxy (C3-C14 cycloalkyl) -, (C1-C8 alkoxy) - (C3-C14 cycloalkyl) -, hydroxy (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, mercapto (C3-C14 cycloalkyl) -, (C1-C8 alkylthio) - (C3-C14 cycloalkyl) -, mercapto (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, amino (C3-C14 cycloalkyl), (C1-C8 alkyl) NH- (C3-C14 cycloalkyl) -, amino (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) - (C3-C14 cycloalkyl) -, HC (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) O- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) - (C3-C14 cycloalkyl) -, HC (=c 1-C14 cycloalkyl) -, HC (=o) - (C1-C14 cycloalkyl) - HOC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -O-C (=o) - (C3-C14 cycloalkyl) -, HO-C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) NH- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) C (=o) NH- (C3-C14 cycloalkyl) -, HC (=o) NH- (C1-C8 alkyl) - (C3-C14 ring) Alkyl) -, NH ₂ C (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) NHC (=o) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) oxy, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -oxy, (3-14 membered heterocyclyl) oxy- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) thio, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -thio, (3-14 membered heterocyclyl) thio- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (3-14 membered heterocyclyl) (C1-C8 alkyl) NH-, (3-14 membered heterocyclyl) -NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) -, (3-14 membered heterocyclyl) -C (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (=o) -, C1-14 membered heterocyclyl) (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) O-, (3-14 membered heterocyclyl) -C (=o) O- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -OC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -OC (=o) -, (3-14 membered heterocyclyl) -OC (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) NH-, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) NH-, (3-14 membered heterocyclyl) -C (=o) NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -NHC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -NHC (=o) -, (3-14 membered heterocyclyl) -NHC (=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclyl), hydroxy (3-14 membered heterocyclyl), (C1-C8 alkoxy) - (3-14 membered heterocyclyl) -, hydroxy (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (3-14 membered heterocyclyl) -, mercapto (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, amino (3-14 membered heterocyclyl), (C1-C8 alkyl) NH- (3-14 membered heterocyclyl) -, amino (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) - (3-14 membered heterocyclyl) -, HC (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) O- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) O- (3-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl) - (C1-C8 alkyl) -O-C (=o) - (3-14 membered heterocyclyl) -, HO-C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) NH- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) C (=o) NH- (3-14 membered heterocyclyl) -, HC (=o) NH- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, NH ₂ C (=O) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl)) NHC (=o) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (C6-C14 aryl) -oxy, (C6-C14 aryl) - (C1-C8 alkyl) oxy, (C6-C14 aryl) oxy (C1-C8 alkyl) -, (C6-C14 aryl) thio, (C6-C14 aryl) - (C1-C8 alkyl) thio, (C6-C14 aryl) thio (C1-C8 alkyl) -, (C6-C14 aryl) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -NH-, (C6-C14 aryl) -NH- (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -, (C (=o) -, (C6-C14 aryl) -, (C1-C8 alkyl) - (-C1-C8 alkyl) -) (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) O-, (C6-C14 aryl) -C (=o) O- (C1-C8 alkyl) -, (C6-C14 aryl) -OC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -OC (=o) -, (C6-C14 aryl) -OC (=o) - (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) NH-, (C6-C14 aryl) -C (=o) NH- (C1-C8 alkyl) -, (C6-C14 aryl) -NHC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (C (=c 6-C14 aryl) -, (C1-C8 alkoxy) -, (C1-C8 aryl) - Hydroxy (C1-C8 alkyl) - (C6-C14 aryl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C6-C14 aryl) -, mercapto (C1-C8 alkyl) - (C6-C14 aryl) -, amino (C6-C14 aryl) -, (C1-C8 alkyl) NH- (C6-C14 aryl) -, amino (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) - (C6-C14 aryl) -, (C1-C8 alkyl) -C (=O) - (C6-C14 aryl) -, HC (=O) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) O- (C6-C14 aryl) -, (C1-C8 alkyl) -C (=O) O- (C6-C14 aryl) -, HC (=O) O- (C1-C8 alkyl) - (C6-C14 aryl) -, HOC (=O) - (C6-C14 aryl) -, HC (=C 1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) - (C6-C14 aryl) - HO-C (=O) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) NH- (C6-C14 aryl) -, (C1-C8 alkyl) C (=O) NH- (C6-C14 aryl) -, HC (=O) NH- (C1-C8 alkyl) - (C6-C14 aryl) -, NH ₂ C (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) NHC (=o) - (C6-C14 aryl) -, NH ₂ C (=o) - (C1-C8 alkyl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (C6-C14 aryl) -, (C1-C8 alkyl) - (C6-C14 aryl) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (5-14)A membered heteroaryl) oxy, (5-14 membered heteroaryl) - (C1-C8 alkyl) oxy, (5-14 membered heteroaryl) oxy (C1-C8 alkyl) -, (5-14 membered heteroaryl) thio, (5-14 membered heteroaryl) - (C1-C8 alkyl) thio, (5-14 membered heteroaryl) thio (C1-C8 alkyl) -, (5-14 membered heteroaryl) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NH-, (5-14 membered heteroaryl) -NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) -, (5-14 membered heteroaryl) C (=o) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) O-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) O-, (5-14 membered heteroaryl) -C (=o) O- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -OC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -OC (=o) -, (5-14 membered heteroaryl) -OC (=o) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) NH-, (5-14 membered heteroaryl) -C (=o) NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -NHC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) -, hydroxy (5-14 membered heteroaryl) -, (C1-C8 alkoxy) - (5-14 membered heteroaryl) -, hydroxy (C1-C8 alkyl) - (5-14 membered heteroaryl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C5-14 membered heteroaryl) - Mercapto (C1-C8 alkyl) - (5-14 membered heteroaryl) -, amino (5-14 membered heteroaryl), (C1-C8 alkyl) NH- (5-14 membered heteroaryl) -, amino (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) - (5-14 membered heteroaryl) -, HC (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) O- (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) O- (5-14 membered heteroaryl) -, HC (=o) O- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HOC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -O-C (=o) - (5-14 membered heteroaryl) -, HC (=o) NH- (5-14 membered heteroaryl) -, and the like, (C1-C8 alkyl) C (=O) NH- (5-14 membered heteroaryl) -, HC (=O) NH- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, NH ₂ C (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) NHC (=o) - (5-14 membered heteroaryl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) - (C1-C8 alkyl) -, hydroxy-substituted C1-C8 alkyl, mercapto-substituted C1-C8 alkyl, ammoniaA group, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano-substituted C1-C8 alkyl, -COOH, - (C1-C8 alkyl) -COOH, -C (=o) O- (C1-C8 alkyl), -OC (=o) H, - (C1-C8 alkyl) -OC (=o) H, -OC (=o) - (C1-C8 alkyl), -C1-C8 alkyl) -OC (=o) - (C1-C8 alkyl), -C (O) H, - (C1-C8 alkyl) -C (=o) H, -C (=o) - (C1-C8 alkyl), NH ₂ C (=o) -, (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) N-C (=o) -, (C1-C8 alkyl) -NHC (=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) N-C (=o) - (C1-C8 alkyl) -, HC (=o) NH-, HC (=o) N (C1-C8 alkyl) -, (C1-C8 alkyl) -C (=o) NH-, (C1-C8 alkyl) -C (=o) N (C1-C8 alkyl) -, thio (=s); wherein R is ^3a1 Optionally by 0-5 (0, 1, 2, 3, 4 or 5) R ^3a2 Substitution (provided that when R ^3a Selected from the group consisting of 1-5R ^3a1 Substituted 5-14 membered heteroaryl, C3-C14 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclyl);

each R is ^3a2 Independently at each occurrence selected from: -CN, (C6-C14 aryl) - (C1-C8 alkyl) oxy, amino, hydroxy, halo C1-C8 alkyl, C1-C8 alkoxy, -N (C1-C8 alkyl), C1-C8 alkyl, oxo (=o), -NH (C1-C8 alkyl), NH ₂ CO-, C1-C8 alkoxy-substituted C1-C8 alkoxy, C1-C14 alkyl OC (=O) -, C1-C14 alkyl C (=O) -, C3-C14 cycloalkyloxy, C1-C8 alkyl-substituted 3-14 heterocyclyl, H, D, halogen, halogenated C1-C8 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) oxy, (C3-C14 cycloalkyl) oxy (C1-C8 alkyl) -, (C3-C14 cycloalkyl) thio, (C3-C14 cycloalkyl) - (C1-C8 cycloalkyl) thio, (C1-C8 cycloalkyl) - (C1-C8 cycloalkyl) thio, (C3-C14 cycloalkyl) - (C1-C14 cycloalkyl) -, (C3-C14 cycloalkyl) -, C1-C14 cycloalkyl- (C1-C14 cycloalkyl) oxy (C1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=O) -, (C3-C14 cycloalkyl) C (=O) - (C1-C8 Alkyl) -, (C3-C14 cycloalkyl) -C (=o) O-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) O-, (C3-C14 cycloalkyl) -C (=o) O- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -OC (=o) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -OC (=o) -, (C3-C14 cycloalkyl) -OC (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) NH-; (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) NH-, (C3-C14 cycloalkyl) -C (=o) NH- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -NHC (=o) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, and, hydroxy (C3-C14 cycloalkyl) -, (C1-C8 alkoxy) - (C3-C14 cycloalkyl) -, hydroxy (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C3-C14 cycloalkyl) -, mercapto (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, amino (C3-C14 cycloalkyl), (C1-C8 alkyl) NH- (C3-C14 cycloalkyl) -, amino (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) - (C3-C14 cycloalkyl) -, HC (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) O- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) O- (C3-C14 cycloalkyl) -, HC (=o) O- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=c 1-C14 cycloalkyl) -, HC (=o) - (C3-C14 cycloalkyl) -, HC (=c 3-C14 cycloalkyl) - (C1-C8 alkyl) -O-C (=o) - (C3-C14 cycloalkyl) -, HO-C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) NH- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) C (=o) NH- (C3-C14 cycloalkyl) -, HC (=o) NH- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) NHC (=o) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, 3-14 membered heterocyclyl, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) oxy, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -oxy, (3-14 membered heterocyclyl) oxy- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) thio, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -thio, (3-14 membered heterocyclyl) thio- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (3-14 membered heterocyclyl) (C1-C8 alkyl) NH-, (3-14 membered heterocyclyl) -NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (C1-C8 alkyl) - (3-14 membered heterocyclyl) -C (=o) O-, (3-14 membered heterologyA cyclic group) - (C1-C8 alkyl) -C (=o) O-, a (3-14 membered heterocyclic group) -C (=o) O- (C1-C8 alkyl) -, (3-14 membered heterocyclic group) -OC (=o) -, (3-14 membered heterocyclic group) - (C1-C8 alkyl) -OC (=o) -, (3-14 membered heterocyclic group) -OC (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclic group) -C (=o) NH-, a (3-14 membered heterocyclic group) - (C1-C8 alkyl) -C (=o) NH-, a (3-14 membered heterocyclic group) -C (=o) NH- (C1-C8 alkyl) -, (3-14 membered heterocyclic group) -NHC (=o) -, (3-14 membered heterocyclic group) - (C1-C8 alkyl) -NHC (=o) -, (3-14 membered heterocyclic group) - (C (=o) - (C1-C8 alkyl) -, a hydroxyl group (3-14 membered heterocyclic group) -, (C1-C8 alkoxy) - (3-14 membered heterocyclic group), hydroxy (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (3-14 membered heterocyclyl) -, mercapto (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, amino (3-14 membered heterocyclyl), (C1-C8 alkyl) NH- (3-14 membered heterocyclyl) -, amino (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) - (3-14 membered heterocyclyl) -, HC (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) O- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) O- (3-14 membered heterocyclyl) -, HC (=o) O- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HOC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -O) - (3-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl) -, and the like, HO-C (=O) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=O) NH- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) C (=O) NH- (3-14 membered heterocyclyl) -, HC (=O) NH- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) NHC (=o) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, C6-C14 aryl, (C6-C14 aryl) - (C1-C8 alkyl) -, (C6-C14 aryl) oxy (C1-C8 alkyl) -, (C6-C14 aryl) thio, (C6-C14 aryl) - (C1-C8 alkyl) thio, (C6-C14 aryl) thio (C1-C8 alkyl) -, (C6-C14 aryl) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -NH-, (C6-C14 aryl) -NH- (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) -, (C6-C14 aryl) - (C (=c 1-C8 alkyl) -, (C6-C14 aryl) -, (C1-C14 aryl) -, (C (=c 1-C8 alkyl) -) (C6-C14 aryl) -C (=o) O- (C1-C8 alkyl) -, (C6-C14 aryl) -OC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -OC (=o) -, (C6-C14 aryl)) -OC (=o) - (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) NH-, (C6-C14 aryl) -C (=o) NH- (C1-C8 alkyl) -, (C6-C14 aryl) -NHC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (C6-C14 aryl) -, hydroxy (C6-C14 aryl) -, (C1-C8 alkoxy) - (C6-C14 aryl) -, hydroxy (C1-C8 alkyl) - (C6-C14 aryl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C6-C14 aryl) -, mercapto (C1-C8 alkyl) - (C14 aryl) -, amino (C6-C14 aryl) -, (C1-C14 aryl) -, hydroxy (C1-C8 aryl) -, hydroxy (C1-C14 aryl) -, mercapto) Amino (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) -C (=o) - (C6-C14 aryl) -, HC (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) O- (C6-C14 aryl) -, (C1-C8 alkyl) -C (=o) O- (C6-C14 aryl) -, HC (=o) O- (C1-C8 alkyl) - (C6-C14 aryl) -, HOC (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) -O-C (=o) - (C6-C14 aryl) -, HO-C (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) NH- (C6-C14 aryl) -, (C1-C8 alkyl) C (=o) NH- (C6-C14 aryl) -, HC (=o) NH- (C1-C8 alkyl) - (C14 aryl) -, NH ₂ C (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) NHC (=o) - (C6-C14 aryl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, (C1-C8 alkyl) - (C6-C14 aryl) - (C1-C8 alkyl) -, 5-14 membered heteroaryl, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) oxy, (5-14 membered heteroaryl) - (C1-C8 alkyl) oxy, (5-14 membered heteroaryl) oxy (C1-C8 alkyl) -, (5-14 membered heteroaryl) thio, (5-14 membered heteroaryl) - (C1-C8 alkyl) thio, (5-14 membered heteroaryl) thio (C1-C8 alkyl) -, (5-14 membered heteroaryl) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NH-, (5-14 membered heteroaryl) -NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) -C (=o) O-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) O-, (5-14 membered heteroaryl) -C (=o) O- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -OC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -OC (=o) -, (5-14 membered heteroaryl) -OC (=o) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) NH-, (5-14 membered heteroaryl) -C (=o) NH- (C1-C8)Alkyl) -, (5-14 membered heteroaryl) -NHC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) -, hydroxy (5-14 membered heteroaryl) -, (C1-C8 alkoxy) - (5-14 membered heteroaryl) -, hydroxy (C1-C8 alkyl) - (5-14 membered heteroaryl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (5-14 membered heteroaryl) -, mercapto (C1-C8 alkyl) - (5-14 membered heteroaryl) -, amino (5-14 membered heteroaryl), (C1-C8 alkyl) NH- (5-14 membered heteroaryl) -, amino (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) -, mercapto (C1-C8 alkyl) - (5-14 membered heteroaryl), HC (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) O- (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) O- (5-14 membered heteroaryl) -, HC (=o) O- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HOC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -O-C (=o) - (5-14 membered heteroaryl) -, HO-C (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) NH- (5-14 membered heteroaryl) -, (C1-C8 alkyl) C (=o) NH- (5-14 membered heteroaryl) -, HC (=o) NH- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, NH ₂ C (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) NHC (=o) - (5-14 membered heteroaryl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) - (C1-C8 alkyl) -, hydroxy-substituted C1-C8 alkyl, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, cyano-substituted C1-C8 alkyl, -COOH, - (C1-C8 alkyl) -C (=O) O- (C1-C8 alkyl), -OC (=O) H, - (C1-C8 alkyl) -OC (=O) H, -OC (=O) - (C1-C8 alkyl), -C (O) H, - (C1-C8 alkyl) -C (=O) - (C1-C8 alkyl), -C (O) H, -C (=O) - (C1-C8 alkyl), -C1-C8 alkyl) - (C (=O) - (C1-C8 alkyl), one or two C1-C8 alkyl-substituted NH ₂ C (O) -, one or two C1-C8 cycloalkyl-substituted NH ₂ C (O) -, NH substituted with one or two C6-C14 aryl groups ₂ C (O) -, one or two 5-14 membered heteroaryl substituted NH ₂ C (O) -, NH substituted with one or two 4-10 membered heterocyclic groups ₂ C(O)-、NH ₂ C (=O) - (C1-C8 alkyl) -, one or two C1-C8 alkyl substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two C1-C8 cycloalkyl-substituted NH ₂ C(O) - (C1-C8 alkyl) -, NH substituted by one or two C6-C14 aryl groups ₂ C (O) - (C1-C8 alkyl) -, one or two 5-14 membered heteroaryl substituted NH ₂ C (O) - (C1-C8 alkyl) -, NH substituted with one or two 4-10 membered heterocyclic groups ₂ C (O) - (C1-C8 alkyl) -, thio (=s); r is as described above ^3a1 、R ^3a2 Optionally 0 to 5 (0, 1, 2, 3, 4 or 5) R ^3a3 Substitution;

R ^3a3 is "-Linker-R ^3a4 "; the Linker is selected from: bond, O, NH, NR ^3a4 、-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-、-C(＝O)NR ^3a4 -3-14 membered cycloalkyl, 3-14 membered heterocyclyl, C6-C14 aryl, 5-14 membered heteroaryl;

R ^3a4 selected from: H. d, halogen, C1-C8 alkyl, hydroxy substituted C1-C8 alkyl, halo C1-C8 alkyl, C2-C8 alkenyl, halo C2-C8 alkenyl, C2-C8 alkynyl, halo C2-C8 alkynyl, (C1-C15 alkyl) -OC (=o) -, (C6-C14 aryl) -OC (=o) -, (4-12 membered heterocyclyl) -OC (=o) -, (5-14 membered heteroaryl) -OC (=o) -, (C1-C15 alkyl) -C (=o) -, (C6-C14 aryl) -C (=o) -, (4-12 membered heterocyclyl) -C (=o) -, (5-14 membered heteroaryl) -C (=o) -, (halo) C (=c (=o) -, (4-12 membered heteroaryl) -OC (=o) -, and (C (=o) -, C1-C15 alkyl) -OC (=o) -, C (=o) -, and (C1-C14 membered heteroaryl) -OC (=o) -, C (=o) - (halo 5-14 membered heteroaryl) -OC (=o) -, (halo C1-C15 alkyl) -C (=o) -, (halo C6-C14 aryl) -C (=o) -, (halo 4-12 membered heterocyclyl) -C (=o) -, (halo 5-14 membered heteroaryl) -C (=o) -, (C1-C8 alkyl) -OC (=o) -, C1-C15 alkyl) -OC (=o) -, C1-C8 alkyl-substituted (C6-C14 aryl) -OC (=o) -, C1-C8 alkyl-substituted (4-12 membered heterocyclyl) -OC (=o) -, C1-C8 alkyl-substituted (5-14 membered heteroaryl) -OC (=o) -, C1-C8 alkyl-C (=c 1-C8 alkyl) -C (=c 1-C15 alkyl) -OC (=o) -, C1-C8 alkyl-substituted (C (=c 1-C8 alkyl) - C1-C8 alkyl-substituted (4-12 membered heterocyclyl) -C (=O) -, C1-C8 alkyl-substituted (5-14 membered heteroaryl) -C (=O) -, C1-C8 alkyl-substituted (C1-C15 alkyl) -C (=O) O-), C1-C8 alkyl-substituted (C6-C14 aryl) -C (=O) O-, C1-C8 alkyl-substituted (4-12 membered heterocyclyl) -C (=O) O-, C1-C8 alkyl-substituted (5-14 membered heteroaryl) -C (=O) O-, (C1-C8 alkyl) ₃ -Si- (C1-C8 alkyl) -O- (C1-C8 alkylene) -, halogen-substituted or unsubstituted (C1-C8 alkyl) -OC (=o) - (C1-C8 alkyl) C (=o) - (C3-C14 cycloalkyl) C (=o) -glycosyl, -O-P (=o) (O-halo or non-halo C6-C14 aryl) (NH- (C1-C8 alkyl) C (=o) O (C1-C8 alkyl)), -O-P (=o) (O-halo or non-halo C6-C14 aryl) (O- (C1-C8 alkyl) C (=o) O (C1-C8 alkyl)), -O-P (=o) (O-halo or non-halo C6-C14 aryl) (NH- (C1-C8 alkyl)), -OC (=o) (O) halo or non-halo C6-C14 aryl) (NH- (C1-C8 alkyl)), -O (=o) (O) halo or non-halo (C1-C8 alkyl) -O-P (=o) (O-halogenated or non-halogenated C6-C14 aryl) (NH- (C1-C8 alkyl) -S-C (=o) (C1-C8 alkyl)), -O-P (=o) (O-halogenated or non-halogenated C6-C14 aryl) (O- (C1-C8 alkyl) -S-C (=o) (C1-C8 alkyl)), -O-P (=o) (ONa) ₂ 、-O-P(＝O)(OK) ₂ 、-O-P(＝O)(OLi) ₂ -O- (halogenated or non-halogenated C1-C8 alkyl) -P (=o) (O-C1-C8 alkyl) ₂ (C1-C8 alkyl) -C (=o) -ch=ch-, amino acid acyl, C1-C16 alkyl, halogenated C1-C16 alkyl, C6-C14 aryl, halogenated C6-C14 aryl;

Wherein optionally two R' s ^3a1 May form, together with the atoms to which they are each attached, a 4-15 or 3-18 membered ring structure;

wherein optionally two R' s ^3a2 May form, together with the atoms to which they are each attached, a 4-15 or 3-18 membered ring structure;

y4 is N or C-R ^4a ；R ^4a Selected from H, D, C-C6 alkyl, amino, halogen, -C (R) ^4b )＝C(R ^4c )-R ^4d 、-C(R ^4b )＝N-R ^4d 、-N＝C(R ^4c )-R ^4d 、-N＝N-R ^4d 、-C(R ^4e )(R ^4f )-R ^4d 、-C(＝O)-R ^4d 、-C(＝S)-R ^4d 、NR ^4e R ^4f 、NR ^4b C(＝O)R ^4d The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^4a Optionally by 0-5 (0, 1, 2, 3, 4 or 5) R ^4a1 Instead of the above-mentioned,each R is ^4a1 Independently at each occurrence selected from: halogen, C3-C6 cycloalkyl, C1-C6 alkyl C (=o) -;

alternatively, R ^2a 、R ^3a Together with the carbons to which they are each attached form from 0 to 5 (0, 1, 2, 3, 4 or 5) R ^b1 A substituted or unsubstituted 3-18 membered ring structure;

alternatively, R ^4a 、R ^3a Together with the carbons to which they are each attached form from 0 to 5 (0, 1, 2, 3, 4 or 5) R ^b2 A substituted or unsubstituted 3-18 membered ring structure,

each R is ^b1 Each R is ^b2 Independently at each occurrence selected from: H. d, halogen, oxo, thio, C1-C8 alkyl, hydroxyC 1-C8 alkyl, C1-C8 alkoxy, C3-C14 cycloalkyl, halogenated C1-C8 alkyl, halogenated hydroxyC 1-C6 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C14 cycloalkyl, 3-14 membered heterocyclyl, C6-C14 aryl, 5-14 membered heteroaryl, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano-substituted C1-C8 alkyl; alternatively, R ^b1 、R ^b2 Can be substituted with 0-5R ^b3 Substitution; r is R ^b3 Selected from the group consisting of: H. d, halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, hydroxyC 1-C8 alkyl, halogenated hydroxyC 1-C8 alkyl, mercapto, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano-substituted C1-C8 alkyl, oxo, thio, (C1-C6 alkyl) 3-Si- (C1-C6 alkyl) -O- (C1-C6 alkylene) -, C1-C15 alkyl OC (O) -, (C1-C8 alkyl) -OC (O) - (C1-C8 alkyl) COO-, C1-C8 alkyl-C (O) -ch=ch-;

v1, V2, V3 are each independently selected from N, C-R ^c ；R ^c Selected from the group consisting of: H. d, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl;

v4, V5 are each independently C or N;

each bond represented by a dashed line is independently selected from the group consisting of: a single bond, a double bond;

w is absent and V5 is directly linked to X1, or W is C (=O), C (=S), C (R) ^d )(R ^e )、N(R ^d )、C、N、O、S；

X1, X2 are independently selected from C (=o), C (=s), C (R) ^f )、C(R ^f )(R ^g )、N、N(R ^f )；

L is selected from 1 to 5R ^h Substituted or unsubstituted groups of the following groups: C1-C12 straight-chain or branched alkylene, - (CH 2) _m -NH-(CH2) _n -、-(CH2) _m -O-(CH2) _n -、-(CH2) _m -S-(CH2) _n -、-(CH2) _m -(S＝O)-(CH2) _n -、-(CH2) _m -(S＝O)2-(CH2) _n -; each R is ^h Independently at each occurrence selected from: halogen, C1-C6 alkyl; alternatively, R ^h Forming a 3-6 membered saturated ring with the attached carbon;

m is independently selected from 1, 2, 3, 4 for each occurrence;

n is independently selected from 0, 1, 2, 3 for each occurrence;

u is from 1 to 5R ⁱ Substituted or unsubstituted groups of the following groups: C5-C14 membered aryl, 5-C14 membered heteroaryl, C3-C14 cycloalkyl, 3-C14 membered heterocyclyl; each R is ⁱ Independently at each occurrence selected from: halogenated C1-C8 alkyl, halogen, C6-C14 aryl, benzo 5-C14 membered heteroaryl, halogenated C1-C8 alkoxy, H, D, C-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, 3-C14 membered heterocyclyl, 5-C14 membered heteroaryl, hydroxy-substituted C1-C8 alkyl, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl) (C1-C8 alkyl) Cyano, cyano-substituted C1-C8 alkyl, -COOH, - (C1-C8 alkyl) -COOH, -C (=o) O- (C1-C8 alkyl), -C (=c 1-C8 alkyl) -C (=o) O- (C1-C8 alkyl), -OC (=o) H, - (C1-C8 alkyl) -OC (=o) - (C1-C8 alkyl), -C (=o) H, - (C1-C8 alkyl) -C (=o) H, -C (=o) - (C1-C8 alkyl), -C (=c) alkyl) -C (=o) - (C1-C8 alkyl), NH ₂ C(＝O)-、NH ₂ C (=o) (C1-C8 alkyl) -, (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) N-C (=o) -, (C1-C8 alkyl) -NHC (=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) N-C (=o) - (C1-C8 alkyl) -, HC (=o) NH-, HC (=o) N (C1-C8 alkyl) -, (C1-C8 alkyl) -C (=o) NH-, (C1-C8 alkyl) -C (=o) N (C1-C8 alkyl) -, oxo (=o), thio (=s); wherein R is ⁱ Optionally by 0-5 (0, 1, 2, 3, 4 or 5) R ⁱ¹ Substitution;

each R is ⁱ¹ Independently at each occurrence selected from: H. d, halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) oxy (C3-C14 cycloalkyl) - (C1-C8 alkyl) oxy, (C3-C14 cycloalkyl) oxy (C1-C8 alkyl) -, (C3-C14 cycloalkyl) thio, (C3-C14 cycloalkyl) - (C1-C8 alkyl) thio, (C3-C14 cycloalkyl) thio (C1-C8 alkyl) -, (C3-C14 cycloalkyl) NH-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -NH-, (C3-C14 cycloalkyl) -NH- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=O) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=O) -, (C3-C14 cycloalkyl) C (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) O-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) O-, (C3-C14 cycloalkyl) -C (=o) O- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -OC (=o) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -OC (=o) -, (C3-C14 cycloalkyl) -OC (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) NH-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) NH-, (C3-C14 cycloalkyl) -C (=o) NH- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -NHC (=o) -, (C3-C14 ring) Alkyl) - (C1-C8 alkyl) -NHC (=O) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -NHC (=O) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, hydroxy (C3-C14 cycloalkyl) -, (C1-C8 alkoxy) - (C3-C14 cycloalkyl) -, hydroxy (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C3-C14 cycloalkyl) -, mercapto (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, amino (C3-C14 cycloalkyl) -, (C1-C8 alkyl) NH- (C3-C14 cycloalkyl) -, amino (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=O) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=O) - (C3-C14 cycloalkyl) -, HC (=O) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=O) O- (C3-C14 cycloalkyl) -, and the like, (C1-C8 alkyl) -C (=o) O- (C3-C14 cycloalkyl) -, HC (=o) O- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HOC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -O-C (=o) - (C3-C14 cycloalkyl) -, HO-C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) NH- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) C (=o) NH- (C3-C14 cycloalkyl) -, HC (=o) NH- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) NHC (=o) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, 3-14 membered heterocyclyl, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) oxy, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -oxy, (3-14 membered heterocyclyl) oxy- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) thio, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -thio, (3-14 membered heterocyclyl) thio- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (3-14 membered heterocyclyl) (C1-C8 alkyl) NH-, (3-14 membered heterocyclyl) -NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (C1-C8 alkyl) - (3-14 membered heterocyclyl) -C (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) O-, (3-14 membered heterocyclyl) -C (=o) O- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -OC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -OC (=o) -, (3-14 membered heterocyclyl) -OC (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) NH-, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) NH-, (3-14 membered heterocyclyl) -C (=o) NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -NHC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -NHC (=o) -, (3-14) A membered heterocyclic group) -NHC (=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclic group) -, hydroxy (3-14 membered heterocyclic group) -, (C1-C8 alkoxy) - (3-14 membered heterocyclic group) -, hydroxy (C1-C8 alkyl) - (3-14 membered heterocyclic group) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (3-14 membered heterocyclic group) -, mercapto (C1-C8 alkyl) - (3-14 membered heterocyclic group) -, amino (3-14 membered heterocyclic group), (C1-C8 alkyl) NH- (3-14 membered heterocyclic group) -, amino (C1-C8 alkyl) - (3-14 membered heterocyclic group) -, HC (=o) - (3-14 membered heterocyclic group) -, (C1-C8 alkyl) -C (=o) - (3-14 membered heterocyclic group) -, HC (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclic group) -, HC (=o) - (3-14 membered heterocyclic group) -, (C1-C8 alkyl) -O- (3-14 membered heterocyclic group) -, HC (=o) - (C1-14 membered heterocyclic group) -,) O- (C1-14 membered heterocyclic group) -, amino (C1-C8 alkyl) -O) -, C1-14 membered heterocyclic group) HC (=o) O- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HOC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -O-C (=o) - (3-14 membered heterocyclyl) -, HO-C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) NH- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) C (=o) NH- (3-14 membered heterocyclyl) -, HC (=o) NH- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) NHC (=o) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (C6-C14 aryl) -oxy, (C6-C14 aryl) - (C1-C8 alkyl) oxy, (C6-C14 aryl) oxy (C1-C8 alkyl) -, (C6-C14 aryl) thio, (C6-C14 aryl) - (C1-C8 alkyl) thio, (C6-C14 aryl) thio (C1-C8 alkyl) -, (C6-C14 aryl) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -NH-, (C6-C14 aryl) -NH- (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -, (C (=o) -, (C6-C14 aryl) -, (C1-C8 alkyl) - (-C1-C8 alkyl) -) (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) O-, (C6-C14 aryl) -C (=o) O- (C1-C8 alkyl) -, (C6-C14 aryl) -OC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -OC (=o) -, (C6-C14 aryl) -OC (=o) - (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) NH-, (C6-C14 aryl) -C (=o) NH- (C1-C8 alkyl) -, (C6-C14 aryl) -NHC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (C6-C14 aryl) -, (C1-C8 alkoxy) -, (C6-C14 aryl) - (C1-C8 alkoxy) Aryl) -, hydroxy (C1-C8 alkyl) - (C6-C14 aryl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C6-C14 aryl) -, mercapto (C1-C8 alkyl) - (C6-C14 aryl) -, amino (C6-C14 aryl), (C1-C8 alkyl) NH- (C6-C14 aryl) -, amino (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) -C (=o) - (C6-C14 aryl) -, HC (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) O- (C6-C14 aryl) -, (C1-C8 alkyl) -C (=o) O- (C6-C14 aryl) -, HC (=o) O- (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) - (C6-C14 aryl) -, HC (=c 6-C14 aryl) - HO-C (=O) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) NH- (C6-C14 aryl) -, (C1-C8 alkyl) C (=O) NH- (C6-C14 aryl) -, HC (=O) NH- (C1-C8 alkyl) - (C6-C14 aryl) -, NH ₂ C (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) NHC (=o) - (C6-C14 aryl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, (C1-C8 alkyl) - (C6-C14 aryl) - (C1-C8 alkyl) -, 5-14 membered heteroaryl, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) oxy, (5-14 membered heteroaryl) - (C1-C8 alkyl) oxy, (5-14 membered heteroaryl) oxy (C1-C8 alkyl) -, (5-14 membered heteroaryl) thio, (5-14 membered heteroaryl) - (C1-C8 alkyl) thio, (5-14 membered heteroaryl) thio (C1-C8 alkyl) -, (5-14 membered heteroaryl) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NH-, (5-14 membered heteroaryl) -NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) -C (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) O-, (5-14 membered heteroaryl) -C (=o) O- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -OC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -OC (=o) -, (5-14 membered heteroaryl) -OC (=o) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) NH-, (5-14 membered heteroaryl) -C (=o) NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -NHC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, 5-14 membered heteroaryl) Hydroxy (5-14 membered heteroaryl) -, (C1-C8 alkoxy) - (5-14 membered heteroaryl) -, hydroxy (C1-C8 alkyl) - (5-14 membered heteroaryl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (5-14 membered heteroaryl) Aryl) -, mercapto (C1-C8 alkyl) - (5-14 membered heteroaryl) -, amino (5-14 membered heteroaryl), (C1-C8 alkyl) NH- (5-14 membered heteroaryl) -, amino (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) - (5-14 membered heteroaryl) -, HC (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) O- (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) O- (5-14 membered heteroaryl) -, HC (=o) O- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HOC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -O-C (=o) - (5-14 membered heteroaryl) -, HO-C (=o) - (5-14 membered heteroaryl) -, HC (=o) - (5-14 membered heteroaryl) -, HO (=o) - (5-14 membered heteroaryl), (C1-C8 alkyl) C (=O) NH- (5-14 membered heteroaryl) -, HC (=O) NH- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, NH ₂ C (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) NHC (=o) - (5-14 membered heteroaryl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) - (C1-C8 alkyl) -, -COOH, - (C1-C8 alkyl) -COOH, -C (=o) O- (C1-C8 alkyl), -C (=o) O- (C1-C8 alkyl), -OC (=o) H, - (C1-C8 alkyl) -OC (=o) H, -OC (=o) - (C1-C8 alkyl), -C (O) H, - (C1-C8 alkyl) -C (=o) - (C1-C8 alkyl), -C (=c (=o) - (C1-C8 alkyl), -C (=o) - (C1-C8 alkyl), NH ₂ C (=O) -, one or two C1-C8 alkyl-substituted NH ₂ C (O) -, one or two C1-C8 cycloalkyl-substituted NH ₂ C (O) -, NH substituted with one or two C6-C14 aryl groups ₂ C (O) -, one or two 5-14 membered heteroaryl substituted NH ₂ C (O) -, NH substituted with one or two 4-10 membered heterocyclic groups ₂ C(O)-、NH ₂ C (=O) - (C1-C8 alkyl) -, one or two C1-C8 alkyl substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two C1-C8 cycloalkyl-substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two C6-C14 aryl substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two 5-14 membered heteroaryl substituted NH ₂ C (O) - (C1-C8 alkyl) -, NH substituted with one or two 4-10 membered heterocyclic groups ₂ C (O) - (C1-C8 alkyl) -, oxo (=o), thio (=s), (C1-C6 alkyl) 3-Si- (C1-C6 alkyl) -O- (C1-C6 alkylene) -, C1-C15 alkyl OC (O) -, (C1-C8 alkyl) -OC (O) - (C1-C8 alkyl) COO-, C1-C8 alkyl-C (O) -CH =CH-；

Wherein optionally two R' s ⁱ¹ Can form a 3-18 membered ring structure together with the atoms to which they are each attached;

R ^4b 、R ^4c 、R ^4d 、R ^4e 、R ^4f independently at each occurrence selected from the group consisting of: H. d, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl;

R ^d 、R ^e independently at each occurrence selected from the group consisting of: H. d, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C3-C6 cycloalkyl;

R ^f 、R ^g Independently at each occurrence selected from the group consisting of: H. d, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy.

In another preferred embodiment, the compound is selected from the group consisting of compounds of formula (II), formula (III), and formula (IV):

wherein R is ¹ 、R ² 、R ^2a 、R ^3a 、R ^4a Y2, Y3, Y4, V1, V2, V3, L, U, the dotted lines are as defined above.

In another preferred embodiment, the compound is selected from the group consisting of compounds of formula (V) and (VI):

wherein Y2, Y3, V1, V2, V3, L, U, R ^4a The definition of the dashed line is as described above;

R ^1b 、R ^1c independently at each occurrence selected from: H. d, halogen, -NH (CH) ₃ ) C1-C6 alkyl CONH-, C1-C6 alkyl OC (O) NH-, -NH ₂ (C1-C8 alkyl) ₃ Si- (C1-C8 alkyl) O (C1-C8 alkyl) NH-, C6-C14 aryl (C1-C8 alkyl) OC (O) NH-, C6-C14 aryl C (O) NH-, -NH (C2-C8 alkenyl), said groups being optionally substituted with 1-5 groups selected from the group consisting of: amino, hydroxy, C1-C8 alkyl, oxo;

ring Q is a five-membered ring; q1, Q2, Q3 are independently selected from: c (=o), C (=s), C (R) ^4e )、C(R ^4e )(R ^4f )、N、N(R ^4e )；

R ^4e 、R ^4f Is defined as before.

In another preferred embodiment, Z is O; w is absent and ring G is a five membered heterocycle or five membered heteroaryl; l is "- (CH) ₂ ) - "or- (CH) ₂ CH ₂ ) -; u is selected from the group consisting of 1-5R ⁱ Substituted or unsubstituted phenyl, 5-6 membered heteroaryl ring, C3-C8 cycloalkyl; r is R ⁱ Is defined as before.

In another preferred embodiment, U is defined by 1, 2 or 3R ⁱ Substituted or unsubstituted groups of the following groups: phenyl, 5-10 membered heteroaryl, C3-C8 cycloalkyl; each R is ⁱ Independently at each occurrence is: halogenated C1-C4 alkyl, halogen, phenyl, benzo 5-6 membered heteroaryl or halogenated C1-C4 alkoxy; r is R ⁱ Optionally by 1-2R ⁱ¹ Substituted, each R ⁱ¹ Independently at each occurrence selected from: halogen, C1-C4 alkyl. In another preferred embodiment, each R ⁱ Independently at each occurrence is: trifluoromethyl, trifluoromethoxy, methyl, isopropyl, fluoro, benzo 5-6 membered heteroaryl or phenyl; r is R ⁱ Optionally by 1-2R ⁱ¹ Substituted, each R ⁱ¹ Independently at each occurrence selected from: halogen, C1-C4 alkyl.

In another preferred embodiment L is 1, 2 or 3R ^h Substituted or unsubstituted C1-C4 straight or branched alkylene, each R ^h Independently at each occurrence selected from: halogen, C1-C4 alkyl; or R is ^h Forming a 3-6 membered saturated ring with the attached carbon. In another preferred embodiment, L is-CH ₂ -、-CH ₂ CH ₂ -、-CH(CH ₃ ) -, or-CF ₂ -。

In another preferred embodiment, W is absent, V5 is linked to X1 by a single bond, the bond between X1 and X2 being single A bond or double bond, each independently of the other being-CH ₂ -CH-. In another preferred embodiment, V4 and V5 are C. In another preferred embodiment, V1, V2, V3 are each independently selected from N, C-R ^c ；R ^c Selected from the group consisting of: H. d, halogen, C1-C4 alkyl. In another preferred embodiment, V1 is C-R ^c The method comprises the steps of carrying out a first treatment on the surface of the V2 is C-R ^c The method comprises the steps of carrying out a first treatment on the surface of the V3 is N or C-R ^c ，R ^c Selected from the group consisting of: H. d, halogen, C1-C4 alkyl. In another preferred embodiment, V1 is C-R ^c The method comprises the steps of carrying out a first treatment on the surface of the V2 is CH; v3 is N or CH, R ^c Selected from the group consisting of: H. d, halogen, C1-C4 alkyl.

In another preferred embodiment, ring E is a benzene ring or a pyridine ring, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of; halogen, C1-C4 alkyl.

In a further preferred embodiment of the present invention,

is->

In another preferred embodiment, Z is selected from CH ₂ 、O、S、NH。

In another preferred embodiment, ring a is a pyridine ring or a pyridazine ring; optionally by R ^1a 、R ^1b 、R ^1c 、R ^1d And (3) substitution.

In a further preferred embodiment of the present invention,

is->

Y4 is N or CR ^4a 。

In another preferred embodiment, R ^1a Selected from H, D, halogen, NR ¹ R ² ；R ¹ 、R ² Independently selected from: H. d, C1C 1-C4 alkyl, C1-C4 alkylC (=O) -, C1-C4 alkylOC (=O) -, C1-C4 alkyl-O- (C1-C4 alkylene) -, C1-C4 alkyl (O) CO-, C2-C6 alkenyl, C2-C4 alkynyl, phenylC (O) -; r is as described above ¹ 、R ² The groups are optionally substituted with 1, 2 or 3 groups selected from the group consisting of: phenyl, (C1-C4 alkyl) ₃ Si-, amino-, hydroxy-, halogen-, oxo (=o), C1-C4 alkyl;

in another preferred embodiment, R ^2a H, D, halogen or C1-C4 alkyl.

In another preferred embodiment, R ^3a Is H, 5-6 membered heteroaryl, C3-C6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, (5-6 membered heteroaryl) -NHC (=O) -; wherein R is ^3a Optionally by 1, 2 or 3R ^3a1 Substitution; each R is ^3a1 Independently at each occurrence selected from: C1-C8 alkyl, oxo (=O), C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, 3-14 membered heterocyclyl-C (=O) -, C3-C14 cycloalkyl, NH ₂ C (=o) - (C1-C8 alkyl) -; r is R ^3a1 Optionally by 1-5R ^3a2 Substitution; each R is ^3a2 Independently at each occurrence selected from: CN, amino, hydroxy, halo C1-C8 alkyl, C1-C8 alkoxy, -N (C1-C8 alkyl), C1-C8 alkyl, oxo (=O), -NH (C1-C8 alkyl), NH ₂ CO-, C1-C8 alkoxy-substituted C1-C8 alkoxy, C1-C14 alkyl OC (=O) -, C1-C14 alkyl C (=O) O-, C3-C14 cycloalkyloxy, 3-14 membered heterocyclyl, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) oxy, (C6-C14 aryl) - (C1-C8 alkyl) -O-, (C6-C14 aryl) -C (=O) O-, R as described above ^3a1 、R ^3a2 Optionally by 1-5R ^3a3 Substitution; r is R ^3a3 Is "-Linker-R ^3a4 "; the Linker is selected from: bond, O, -C (=o) O-, -OC (=o) -; r is R ^3a4 Selected from: H. d, halogen, C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl, glycosyl, -O-P (=O) (O-halogenated or unhalogenated C6-C14 aryl) (NH- (C1-C8 alkyl) C (=O) O (C1-C8 alkyl)), -O-P (=O) (O-halogenated or unhalogenated C6-C14 aryl) (O- (C1-C8 alkyl) -S-C (=O) (C1-C8 alkyl)), -O-P (=O) (ONa) ₂ 、-O-P(＝O)(OK) ₂ 、-O-P(＝O)(OLi) ₂ -O- (halogenated or non-halogenated C1-C8 alkyl) -P (=o) (O-C1-C8 alkyl) ₂ 。

In another preferred embodiment Y4 is N or C-R ^4a ；R ^4a Selected from H, D, C1-C6 alkyl, amino, halogen, NR ^4b C(＝O)R ^4d The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^4a Optionally by 1-5R ^4a1 Substituted, each R ^4a1 Independently at each occurrence selected from: halogen, C3-C6 cycloalkyl, C1-C6 alkyl C (=o) -.

In another preferred embodiment, R ^2a 、R ^3a Together with the carbons to which they are each attached form a 3-6 membered ring structure.

In another preferred embodiment, R ^4a 、R ^3a Together with the carbons to which they are each attached form a 3-6 membered ring structure.

In another preferred embodiment, the compound has the formula:

the definition of each substituent is as described above, cy ³ Selected from C5-C14 membered aryl, 5-14 membered heteroaryl.

In another preferred embodiment, in the present invention, Y1, Y2, Y3, Y4, R ^1a 、R ^2a 、R ^3a 、R ^4a And the like are specific groups corresponding to specific compounds.

In another preferred embodiment, the compound is selected from the compounds of claim 5.

In a second aspect of the present invention, there is provided a method for preparing a compound represented by formula (I) according to the first aspect, comprising at least one of formula 1, formula 2 or formula 3:

in the reaction formulae 1, 2 and 3,

R ^6a selected from the group consisting of

-O-R ⁶ⁱ Halogen, C1-C12 alkyl, -SO ₃ H，-SO ₃ Na，-OB(OH) ₂ ，-B(OH) ₂ ；R ^6b Selected from-OH, halogen, -OC (=O) -R ⁶ⁱ ，-OS(＝O)-R ⁶ⁱ ，-OS(＝O)2-R ⁶ⁱ ；R ^6c Selected from the group consisting of-L-U, -L-X, -L-Mg-X, -L-OH, -L-O-R ⁶ⁱ ，-L-R ⁶ⁱ ；R ^6d Selected from-CN, halogen, -NO ₂ ，-CONR ⁶ⁱ R ^6j ，-COOR ⁶ⁱ ；

R ^6e ，R ^6f Independently at each occurrence selected from H, -C (=O) -L-U, -C (=O) -L-X, -C (=O) -L-Mg-X, -C (=O) -L-OH, -C (=O) -L-O-R ⁶ⁱ ，-C(＝O)-L-R ⁶ⁱ ；R ^6g 、R ^6h Selected from halogen, -Mg-X, -Li, -Na, -K, -B (OH) ₂ 4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl or other boron-containing substituents; r is R ⁶ⁱ 、R ^6j At each occurrence independently H, D, C C8 alkyl, C1C 8 alkoxy, C6C 14 aryl, C6C 14 aryloxy;

x is independently selected from the following group at each occurrence: F. cl, br, I;

Y1、Y2、Y3、Y4、V1、V2、V3、V4、V5、W、X1、X2、Z、R ^3a the definition of the dashed line is as described above.

In a third aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) according to the first aspect, selected from the following schemes one to six:

scheme one:

carrying out aromatic nucleophilic substitution reaction or coupling reaction on RX-1a and RX-1b to obtain RX-1c;

Hydrogenating and reducing RX-1c to obtain RX-1d;

condensing RX-1d with carboxylic acid RX-1e to obtain a compound shown as RX-1;

scheme II:

condensing RX-2a with RX-1e to obtain RX-2b;

carrying out aromatic nucleophilic substitution reaction on RX-2b and RX-2c to obtain RX-2d;

hydrolyzing the cyano group of RX-2d to obtain RX-2e;

carrying out Hoffman degradation reaction on RX-2e to obtain RX-2f;

RX-2f and R ^3a Carrying out coupling reaction on boric acid or pinacol borate to obtain RX-2;

scheme III:

carrying out aromatic nucleophilic substitution reaction on RX-1a and RX-2c to obtain RX-3b, and further hydrolyzing to obtain RX-3d;

or RX-1a was combined with di-tert-butyl dicarbonate (Boc ₂ O) reacting to obtain RX-3a, then carrying out substitution reaction with RX-2c to obtain RX-3c, and then hydrolyzing RX-3c into RX-3d in the presence of sodium hydroxide;

RX-3d is subjected to Curtius rearrangement reaction to obtain RX-3e;

carrying out reduction reaction on RX-3e to obtain RX-3f;

amide condensing RX-3f with the corresponding carboxylic acid to give RX-3g;

RX-3g was combined with R ^3a Carrying out coupling reaction on boric acid or pinacol borate to obtain RX-3;

scheme IV:

introducing an amino group of RX-2d into a substituent to obtain RX-4a;

RX-4a is combined with R ^3a Carrying out coupling reaction on boric acid or pinacol borate to obtain RX-4;

Wherein R is C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkyl-O- (C1-C8 alkylene) -, C1-C15 alkyl-O-or C6-C14 aryl;

scheme five:

carrying out substitution reaction on RX-5a and RX-3c to obtain RX-5b;

removing protecting groups from RX-5b to obtain RX-5c;

reducing RX-5c to obtain RX-5d;

amide condensing RX-5d with the corresponding carboxylic acid to obtain RX-5;

scheme six:

performing substitution reaction on RX-6a and RX-3c to obtain RX-6b;

hydrolyzing the cyano group of RX-6b to obtain RX-6c;

RX-6d is obtained by the Curtius rearrangement reaction of RX-6c;

reducing RX-6d to obtain RX-6e;

amide condensation of RX-6e with the corresponding carboxylic acid to give RX-6;

Y1、Y2、Y3、Y4、V1、V2、V3、V4、V5、W、X1、X2、L、U、R ^3a the definition of the dotted line is as described above; x is independently selected from the following group at each occurrence: F. cl, br, I.

In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and

one or more therapeutically effective amounts of a compound according to the first aspect of the invention or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, prodrug thereof, hydrate or solvate thereof, isotopically labeled compound thereof.

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 50-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween

) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.

The pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

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

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

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antineoplastic agents).

The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.

When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 5 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

In a fifth aspect of the invention there is provided a kinase inhibitor comprising an inhibitory effective amount of one or more compounds of the first aspect of the invention or stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labelled compounds thereof or a pharmaceutical composition of the fourth aspect.

In another preferred embodiment, the kinase inhibitor is an inhibitor of Receptor Interacting Protein Kinase (RIPK).

In another preferred embodiment, the kinase inhibitor is an inhibitor of receptor interacting protein kinase 1 (RIPK 1).

In a sixth aspect of the invention there is provided the use of a compound according to the first aspect of the invention or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, an isotopically labelled compound thereof, for the manufacture of a medicament for: 1) Detecting and/or preventing and/or treating a kinase-associated disease; 2) Detecting and/or preventing and/or treating immune, inflammatory and/or infection-related diseases; 3) Detecting and/or preventing and/or treating ischemia and/or reperfusion injury related diseases; 4) Detecting and/or preventing and/or treating a degenerative disease; 5) Detecting and/or preventing and/or treating a tumor-associated disease; 6) Detecting and/or preventing and/or treating a disease associated with cell necrosis; 7) Detecting and/or preventing and/or treating a metabolic-related disorder; 8) Detecting and/or preventing and/or treating ocular diseases.

In another preferred embodiment, the kinase is preferably selected from the group consisting of: RIPK1, RIPK3.

In another preferred embodiment, the immune, inflammatory and/or infectious disease is preferably selected from the group consisting of: colitis, crohn's disease, ulcerative enteritis, rheumatoid arthritis, sepsis, hepatitis B, hepatitis C, systemic lupus erythematosus, and asthma.

In another preferred embodiment, the degenerative disease is preferably selected from the group consisting of: alzheimer's disease, parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis.

In another preferred embodiment, the tumor-associated disease is preferably selected from the group consisting of: leukemia, non-small cell lung cancer, cervical cancer, uterine cancer, ovarian cancer, thyroid cancer, parathyroid cancer, glioblastoma, squamous cell carcinoma, renal or ureter cancer, head and/or neck cancer, gastric cancer, prostate cancer, pancreatic cancer, rectal cancer, glioma.

In another preferred embodiment, the metabolic-related disorder is preferably selected from the group consisting of: type I diabetes, non-alcoholic fatty liver, gout, chronic kidney disease, and the like.

In another preferred embodiment, the cell necrosis-related disorder is preferably selected from the group consisting of: ischemic injury, hypoxic brain injury, and burn shock.

In another preferred embodiment, the ocular disease is preferably selected from the group consisting of: maculopathy, glaucoma, ischemic optic neuropathy, ischemic retinal disease, diabetic retinopathy, retinal detachment, retinal vascular disease.

In a seventh aspect of the invention there is provided the use of a compound according to the first aspect or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, prodrug thereof, hydrate or solvate thereof, isotopically labelled compound thereof, or a pharmaceutical composition according to the fourth aspect, for: 1) Detecting and/or preventing and/or treating a kinase-associated disease; 2) Detecting and/or preventing and/or treating inflammation and/or infection related disorders; 3) Detecting and/or preventing and/or treating ischemia and/or reperfusion injury related diseases; 4) Detecting and/or preventing and/or treating a degenerative disease; 5) Detecting and/or preventing and/or treating a tumor-associated disease; 6) Detecting and/or preventing and/or treating a disease associated with cell necrosis; 7) Detecting and/or preventing and/or treating metabolic diseases; 8) Detecting and/or preventing and/or treating ocular diseases.

In another preferred embodiment, the use of a compound according to the first aspect or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, prodrug, hydrate or solvate thereof, isotopically labeled compound thereof, or a pharmaceutical composition according to the fourth aspect, for the preparation of a medicament for the treatment of diseases including but not limited to:

systemic juvenile idiopathic arthritis, behcet's disease, interleukin-1 converting enzyme-related fever syndrome, sepsis, alopecia areata, allergic diseases, hepatitis B, hepatitis C, multiple sclerosis, pulmonary sarcoidosis, pulmonary fibrosis, pneumonia, mycobacterial infection, celiac disease, sjogren's syndrome, osteoarthritis, suppurative sweat gland inflammation, necrotizing enterocolitis, acute pancreatitis, spondyloarthritis, colitis, crohn's disease, antiphospholipid syndrome, crohn's disease, ulcerative enteritis, rheumatoid arthritis, bacterial infection, influenza, chronic obstructive pulmonary disease, viral infection, sepsis, dermatitis, staphylococcal infection, autoimmune diseases, systemic lupus erythematosus, systemic inflammatory response syndrome, systemic scleroderma, prion diseases, adrenocortical degeneration, nephritis, history-about syndrome, surgical infection, atopic dermatitis, wegener granulomatosis, systemic lupus erythematosus, asthma, vasculitis, periodontitis, inflammatory bowel disease, pancreatitis, graft rejection, psoriasis, primary sclerosing cholangitis, tumor necrosis factor receptor-associated periodic fever syndrome, interleukin-1 converting enzyme-associated fever syndrome, autoimmune idiopathic thrombocytopenic purpura, fahr's disease, GM1 gangliosidosis, GM2 gangliosidosis, AIDS-associated dementia syndrome, tau's proteinopathy, alzheimer's disease, parkinson's disease, lewy body dementia, multiple sclerosis, frontotemporal dementia, fabry disease, friedel-crafts disease, guillain Barre syndrome, huntington's disease, primary lateral sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, pseudobulbar paralysis, progressive bulbar paralysis, tuberous sclerosis, progressive supranuclear paralysis, progressive muscle atrophy, schizophrenia, demyelinating diseases, chronic inflammatory demyelinating polyneuropathy, niemann pick disease, corticobasal degeneration, lysosomal storage diseases, morderhoff disease, gangliocytopathy, neuronal ceroid lipofuscinosis, postoperative cognitive disorders, bipolar disorders, diabetic neuropathy, pain (neuropathic pain), delirium, depression, peripheral neuropathy, autism, trauma, traumatic brain injury, ischemia, traumatic retinal injury, cerebrovascular accident, cerebral apoplexy, geographic atrophy, acetaminophen poisoning, acute liver failure, acute kidney injury, acute respiratory distress syndrome, intracranial hemorrhage, cerebral ischemia, ischemic injury, hypoxic brain injury, hypoxia, burns, burn shock, ischemia reperfusion injury to solid organs, cisplatin-induced kidney injury, smoke-induced injury, myocardial infarction, heart failure, toxic epidermonecrobiosis, acute tubular necrosis, heart failure, NF- κB key regulator gene mutation, leukemia, myelogenous leukemia, lymphocytic leukemia, T-cell leukemia, lymphoma, T-cell lymphoma, nasopharyngeal carcinoma, epidermoid carcinoma, pituitary adenoma, biliary tract carcinoma sarcoma, cholangiocarcinoma, multiple myeloma, childhood solid tumor, hodgkin's disease, non-hodgkin's lymphoma, non-small cell lung cancer, anal region cancer, testicular cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, bone cancer, osteosarcoma, melanoma, environmentally induced cancer, spinal tumor, thyroid cancer, parathyroid cancer, glioblastoma, colorectal cancer, kaposi's sarcoma, squamous cell carcinoma, brain glioma, cancer of the endocrine system, cancer of the urinary tract, bladder cancer, skin cancer, cutaneous or intraocular malignant melanoma, prostate cancer, triple negative breast cancer, glioma, renal or ureteral cancer, renal pelvis cancer, adrenal cancer, solid organ malignancy, esophageal cancer, fallopian tube cancer, cancer of the head and/or neck, vulval cancer, gastric cancer, gastrointestinal stromal tumor, small intestine cancer, hematological malignancy, pancreatic cancer, hereditary large aneurysm, vaginal cancer, penile cancer, rectal cancer, tumor angiogenesis, maculopathy, macular hole, macular telangiectasia, dry eye, progressive retinal atrophy, leber's congenital melanoma, cystic macular edema, age-related macular degeneration, glaucoma, retinal neurodegeneration, ischemic optic neuropathy, ischemic retinal disease, diabetic retinopathy, retinitis pigmentosa, retinal photoreceptor disease, retinal degenerative disease, optic nerve disease, retinal detachment, iatrogenic retinal injury, retinal vascular disease, cone rod dystrophy, choroidal free disease, ocular vascular disease, you Saishi syndrome, type I diabetes, nonalcoholic fatty liver, vitiligo, sialidosis, irritable bowel syndrome, danong's disease, cholesterol ester storage disease, volman disease, hypolipidemia, atherosclerosis, multiple sulfatase deficiency, fabry disease, gaucher disease, myelofibrosis, osteoporosis, cystine storage disease, muscular dystrophy, polyglutamine disease, crabbe disease, chronic kidney disease, mentha's disease, cystic disease, pang Pibing, taii-Sak's disease, lysosomal acid lipase deficiency, aspartyl-glucosaminuria, gout, wilson's disease, mitochondrial disorders, fucosidosis, metachromatic leukodystrophy, bathyme acid lipase deficiency, mucopolysaccharide accumulation disease, mucolipid accumulation, compact osteogenesis imperfecta, hemochromatosis, niemann-Pick disease, heme-oxidized IRP2 ubiquitin ligase-1 deficiency, osteonecrosis, chain ubiquitin chain assembly complex deficiency syndrome, fibromatosis, and the like.

Detailed description of the preferred embodiments

The inventor of the present invention has studied intensively for a long time and unexpectedly developed a compound of general formula (I) with novel structure and remarkable kinase inhibition. The kinase inhibitor has excellent RIPK1 inhibiting activity, and thus, can be used for preparing a pharmaceutical composition for detecting and/or preventing and/or treating diseases related to cell death and/or related diseases. On this basis, the inventors completed the present invention.

Terminology

Unless explicitly indicated otherwise, the terms used according to the invention and herein have the following meanings:

the term "C ₁ -C ₆ "means having 1, 2, 3, 4, 5 or 6 carbon atoms," C ₁ -C ₈ "means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "5-8 membered" means having 5-8 ring atoms, and so on.

"substituent" refers to an atom or group that may replace a hydrogen atom in a substituted species. Examples are as follows (but are not limited to the following): deuterated, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, isocyanato, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, thio, -C (=o) R ⁿ 、-C(＝O)OR ⁿ 、-C(＝O)NR ⁿ R ^o 、-NR ⁿ R ^o 、-NR ⁿ C(＝O)R ^o 、-NR ⁿ C(＝O)OR ^o 、NR ⁿ C(＝O)NR ^o R ^p 、-NR ⁿ S(＝O)R ^o 、NR ⁿ S(＝O)NR ^o R ^p 、-NR ⁿ S(＝O) ₂ R ^o 、NR ⁿ S(＝O) ₂ NR ^o R ^p 、-OR ⁿ 、-SR ⁿ 、-OC(＝O)R ⁿ 、-OC(＝O)NR ⁿ R ^o 、-OC(＝O)OR ⁿ 、-S(＝O)NR ⁿ R ^o 、-S(＝O) ₂ NR ⁿ R ^o 、-BR ⁿ R ^o 、B(OR ⁿ )(OR ^o )、-SiR ⁿ R ^o R ^p 、-OP(＝O)R ⁿ R ^o 、-P(＝O)R ⁿ R ^o 、-OP(＝O) ₂ R ⁿ 、-P(＝O) ₂ R ⁿ 、-NP(＝O)R ⁿ R ^o 、-NP(＝O)R ⁿ R ^o 、-NP(＝O) ₂ R ⁿ 、-NP(＝O) ₂ R ⁿ Etc., wherein R is ⁿ 、R ^o 、R ^p Independently at each occurrence selected from the group consisting of: H. d, C1C 1-C12 alkyl, halogenated C1-C12 alkyl, C1-C12 heteroalkyl, halogenated C1-C12 heteroalkyl, C3-C12 cycloalkyl, halogenated C3-C12 cycloalkyl, C3-C12 aryl, halogenated C3-C12 aryl, C3-C12 heteroaryl, halogenated C3-C12 heteroaryl; alternatively, R ⁿ 、R ^o And the atoms to which they are attached, together may form a ring structure. It will be appreciated by those skilled in the art that combinations of substituents and substituents contemplated by the present invention are those that are stable or chemically achievable.

"substituted" means that one or more hydrogen atoms on a particular group is replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such as (but not limited to): alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkyl Thio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, thio, -C (=o) R ⁿ 、-C(＝O)OR ⁿ 、-C(＝O)NR ⁿ R ^o 、-NR ⁿ R ^o 、-NR ⁿ C(＝O)R ^o 、-NR ⁿ C(＝O)OR ^o 、NR ⁿ C(＝O)NR ^o R ^p 、-NR ⁿ S(＝O)R ^o 、NR ⁿ S(＝O)NR ^o R ^p 、-NR ⁿ S(＝O) ₂ R ^o 、NR ⁿ S(＝O) ₂ NR ^o R ^p 、-OR ⁿ 、-SR ⁿ 、-OC(＝O)R ⁿ 、-OC(＝O)NR ⁿ R ^o 、-OC(＝O)OR ⁿ 、-S(＝O)NR ⁿ R ^o 、-S(＝O) ₂ NR ⁿ R ^o 、-BR ⁿ R ^o 、B(OR ⁿ )(OR ^o )、-SiR ⁿ R ^o R ^p 、-OP(＝O)R ⁿ R ^o 、-P(＝O)R ⁿ R ^o 、-OP(＝O) ₂ R ⁿ 、-P(＝O) ₂ R ⁿ 、-NP(＝O)R ⁿ R ^o 、-NP(＝O)R ⁿ R ^o 、-NP(＝O) ₂ R ⁿ 、-NP(＝O) ₂ R ⁿ Etc., wherein R is ⁿ 、R ^o 、R ^p Is as defined above.

"alkyl" refers to a saturated aliphatic hydrocarbon group, which may be straight or branched. The alkyl groups may be independently substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 3-methylpentyl. The alkyl group may be optionally substituted or unsubstituted.

"alkenyl" straight or branched chain hydrocarbyl wherein at least one C-C is sp ² Double bonds, wherein the alkenyl groups may be independently optionally substituted with one or more substituents as described herein, specific examples of which include, but are not limited to, vinyl, allyl,

etc. Alkenyl groups may be optionally substituted or unsubstituted.

"alkynyl" refers to a straight or branched hydrocarbon radical wherein at least one C-C is an sp triple bond, wherein the alkynyl group may be independently optionally substituted with one or more substituents described herein, specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be optionally substituted or unsubstituted.

"Ring structure" refers to a monocyclic or polycyclic structure. Typically, two or more segments attached to one atom of a cyclic structure are linked to form a closed structure, including but not limited to cycloalkanes, heterocycloalkanes, cyclic lactams, arenes, heteroarenes, parallel rings, bridged rings, spiro rings, and the like, examples of which are as follows (but not limited to the following examples): cyclopropane, cyclobutane, oxetane, cyclopentane, cyclohexane, adamantane, cyclohexene, cyclooctyne, pyrazole, benzene, pyridine, 3, 4-dihydro-1, 4-benzoxazepin-5 (2H) -one, naphthalene, anthracene, phenanthrene, quinoline, pyrrolopyridine, pyrazolopyridine, indole, indoline, steroidal ring, porphyrin ring, and the like. The ring structure may be optionally substituted or unsubstituted. When present as substituents, it means that one or more hydrogen atoms on a single ring or multiple rings are removed and can be a substituent for the substituted article.

"halogen" means F, cl, br or I. "halo" refers to substitution with one or more halogens.

"aryl" refers to a carbocyclic aromatic system containing one or more rings that do not contain heteroatoms. Alternatively, the aryl group may be fused to a heteroaryl, heterocyclyl or other ring structure. Examples are as follows (but are not limited to the following): phenyl, naphthyl, tetrahydronaphthyl,

Etc. The aryl group may be optionally substituted or unsubstituted. When the aryl group is described as a "C6-C14 aryl group", it means thatThe aromatic ring in which the aryl group is attached to the parent structure has 6 to 14 carbon atoms, but the aryl group may optionally be fused to other ring structures, which refer to ring structures having 3 to 18 ring atoms, which may be optionally substituted or unsubstituted.

"heteroaryl" refers to an aromatic ring structure containing one or more rings, which may contain one or more (e.g., 1, 2, 3, or 4) atoms selected from N, O or S atoms. Alternatively, the heteroaryl group may be fused to an aryl, heterocyclyl, cycloalkyl, or other ring structure. Examples are as follows (but are not limited to the following): furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl,

Etc. The heteroaryl group may be optionally substituted or unsubstituted. When the heteroaryl group is described as a "5-14 membered heteroaryl," it is meant that the heteroaryl ring that the heteroaryl group is attached to the parent structure has 5-14 ring atoms, but the heteroaryl group may optionally be fused to other ring structures, which are ring structures having 3-18 ring atoms, which may be optionally substituted or unsubstituted.

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The first ring structure to which the cycloalkyl is directly attached to the substituted is non-aromatic. Examples of monocyclic cycloalkyl groups (but are not limited to the following examples): cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctynyl and the like; examples of polycyclic cycloalkyl groups (but not limited to the following): spiro, fused and bridged cycloalkyl groups. Alternatively, the cycloalkyl group may be fused with an aryl, heterocyclyl, cycloalkyl, or other ring structure or form a spiro ring. Examples of condensed or spiro rings with other ring structures (but are not limited to the following examples):

the cycloalkyl group may be optionally substituted or unsubstituted. When the cycloalkyl group is described as "C3-C14 cycloalkyl", it is meant that the cycloalkyl ring to which the parent structure is attached has 3-14 carbon atoms, but the cycloalkyl group is optionally fused or forms a spiro ring with other ring structures, meaning ring structures having 3-18 ring atoms, which may be optionally substituted or unsubstituted.

"heterocyclyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic ring structure in which at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom (e.g., O, N, S atom, etc.). Examples are as follows (but are not limited to the following): tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothienyl, piperidinyl, piperazinyl, azetidinyl, azepanyl, morpholinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and the like. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl. The heterocyclic group may be optionally substituted or unsubstituted. When the heteroalkyl group is described as a "3-14 membered heterocyclyl," it is meant that the heterocyclyl ring that the heterocyclyl is attached to the parent structure has 3-14 ring atoms, but that the heterocyclyl is optionally fused or formed into a spiro ring with other ring structures, which are ring structures having 3-18 ring atoms, which may be optionally substituted or unsubstituted.

"amino acid acyl" refers to a substituent of an amino acid that is converted to an acyl group and attached to the substituted article through the acyl group. The exemplary examples are wrapped with but not limited to the following examples: the structure of glycine acyl is that carboxyl of glycine (NH 2-CH 2-COOH) is converted into acyl to obtain glycine acyl (NH 2-CH 2-CO-). The amino acids include, but are not limited to, alpha-amino acids, beta-amino acids, gamma-amino acids, omega-amino acids. The amino acids include, but are not limited to, the following examples: glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, pyrrolysine, beta-alanine and the like.

"glycosyl" refers to a substituent of a monosaccharide or oligosaccharide formed by providing a hemiacetal hydroxyl group. The monosaccharides include aldoses and ketoses. The monosaccharide comprises triose, tetrose, pentose, hexose and heptose. The oligosaccharide is also called as oligosaccharide, and refers to a compound which contains 2-11 monosaccharides and is formed by polymerizing each monosaccharide through glycosidic bonds. Examples of the monosaccharides or polysaccharides are as follows (but are not limited to the following examples): erythrose, su Litang, arabinose, ribose, xylose, lyxose, glucose, mannose, fructose, galactose, lactose, sucrose, maltose, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin.

"tautomers" means that structural isomers having different energies can exceed the low energy barrier and thus interconvert. For example, proton tautomers (i.e., proton transfer) include interconversions by proton transfer, such as 1H-indazole with 2H-indazole, 1H-benzo [ d ] imidazole with 3H-benzo [ d ] imidazole, valence tautomers include interconversions by recombination of some bonding electrons.

"stereoisomers" refer to molecules having atoms of the same linkage but different spatial arrangement. For example, two compounds having one chiral center and the same two-dimensional linkage, such as R-glyceraldehyde and S-glyceraldehyde, R-serine and S-serine.

"enantiomers" means stereoisomers that are in physical and mirror image relationship with each other and that are non-superimposable. Such as R-serine and S-serine.

"diastereoisomers" means stereoisomers in which the molecule has two or more chiral centers and the molecules are in a non-mirror relationship. Such as tartaric acid.

"atropisomers" means a group of conformational isomers that result from the blocking of a molecule by rotation about a single bond. Such as the individual stereoisomers of 6,6 '-dinitro-2, 2' -biphenyldicarboxylic acid.

"optical isomer" means a compound in which two or more molecules have the same two-dimensional linkage but exhibit different optical properties due to differences in configuration. Such as levamlodipine and dexamlodipine.

"racemates" means compounds having the same two-dimensional attachment pattern but being optical isomers with each other, which are mixed together to finally exhibit optically inactive properties. And the specific is racemic amlodipine.

The present application will be described in detail below with reference to certain embodiments thereof, which illustrate structures and formulas by way of example. While the present application is described in conjunction with the enumerated embodiments, it will be understood that it is not intended to limit the present application to those embodiments described. On the contrary, the intent is to cover all alternatives, modifications and equivalents as included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize other methods and materials similar or equivalent to those described herein that may be used in the practice of the present application, and the present application is not limited in any way to the methods and materials described.

It is also to be understood that certain features that are described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be provided separately or in any suitable subcombination.

Examples

The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

HATU: n, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate urea

DMF: n, N-dimethylformamide; TEA: triethylamine; DIPEA: diisopropylethylamine

DMAC: n, N-dimethylacetamide; pd (dppf) Cl ₂ : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

NBS: n-bromosuccinimide; NMP: n-methylpyrrolidone; pd (PPh) ₃ ) ₄ : tetratriphenylphosphine palladium

DPPA: diphenyl azide phosphate; 4-DMAP: 4-dimethylaminopyridine; naBH ₃ CN: sodium cyanoborohydride

PTSA: p-toluenesulfonic acid; meOH: methanol; etOH: ethanol

Boc ₂ O: di-t-butyl dicarbonate; DMSO: dimethyl sulfoxide

Example 1:

step 1:

898mg of potassium t-butoxide, 532mg of 5-hydroxyindole (I-1 a) were dissolved in 2mL of dimethyl sulfoxide (DMSO), 904mg of 2-trifluoromethyl-5-bromopyridine (I-1 b) was added, and then reacted at 100℃for 2 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography to give I-1c, yield: 390mg, yield: 35%. ¹ H NMR(400MHz,CDCl ₃ )δ8.47(d,J＝2.8Hz,1H),8.30(s,1H),7.56(d,J＝8.7Hz,1H),7.48–7.40(m,1H),7.36(d,J＝2.3Hz,1H),7.31(t,J＝2.8Hz,1H),7.29–7.22(m,1H),6.95(dd,J＝8.7,2.3Hz,1H),6.58–6.55(m,1H).

Step 2:

278mg of I-1c was dissolved in 5mL of glacial acetic acid, and 190mg of sodium cyanoborohydride (NaBH) was added under ice bath ₃ CN), and then stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected toPurifying by column chromatography to obtain I-1d. Yield 209mg, 75%. ¹ H NMR(400MHz,CDCl ₃ )δ8.42(d,J＝2.8Hz,1H),7.56(d,J＝8.8Hz,1H),7.28–7.22(m,2H),6.85(dd,J＝2.3,1.1Hz,1H),6.80–6.72(m,1H),6.63(d,J＝8.3Hz,1H),3.62(t,J＝8.4Hz,2H),3.04(t,J＝8.5Hz,2H).

Step 3:

40mg of I-1d,44mg of m-trifluoromethylphenylacetic Acid (Acid-1) and 109mg of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 3mL of N, N-Dimethylformamide (DMF), 75. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-1-1, yield: 52mg, yield: 78%. LC-MS 467.3 ([ M+H) ] ⁺ ).

The replacement of I-1b in step 1 of example 1 with a different kind of halogenated heterocycle, the remaining required starting materials, reagents and preparation method are the same as in example 1, the following compounds:

example 2:

step 1: 600mg of 5-hydroxyindole (I-1 a) was dissolved in 5mL of acetic acid and 340mg of sodium cyanoborohydride (NaBH) was added in three portions under argon protection ₃ CN), then stirred at room temperature for 24 hours, and 340mg of NaBH was added ₃ CN, stirring was continued at room temperature for 24 hours. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to give I-2a. Yield 199mg, 33%. ¹ H NMR(400MHz,CDCl ₃ )δ6.70–6.43(m,3H),3.53(t,J＝8.3Hz,2H),2.98(t,J＝8.2Hz,2H).

Step 2: 150mg of I-2a, 227mg of m-trifluoromethylphenylacetic Acid (Acid-1) and 506mg of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 8mL of N, N-Dimethylformamide (DMF), triethylamine (TEA) was added with stirring, and then stirred at room temperature for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-2b, yield: 217mg, yield: 61%. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.17(s,1H),7.83(d,J＝8.6Hz,1H),7.70–7.53(m,4H),6.64(d,J＝2.4Hz,1H),6.50(dd,J＝8.6,2.5Hz,1H),4.15(t,J＝8.4Hz,2H),3.93(s,2H),3.10(t,J＝8.4Hz,2H).

Step 3: 200mg of I-2b was dissolved in 2mL of DMF, 28mg of sodium hydrogen (NaH, 60%) was added at 0℃under argon, stirred for 10 minutes, 153mg of 5-bromo-2-cyano-3-nitropyridine (I-2 c) was added, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-2d, yield: 150mg, yield: 48%. ¹ H NMR(400MHz,CDCl ₃ )δ8.41(d,J＝1.8Hz,1H),8.32(d,J＝8.4Hz,1H),7.62–7.44(m,4H),7.29(d,J＝1.8Hz,1H),6.99–6.88(m,2H),4.21(t,J＝8.5Hz,2H),3.27(t,J＝8.4Hz,2H).

Step 4: 25mg of I-2d was dissolved in 0.4mL of concentrated sulfuric acid and stirred under argon for 6 hours. The reaction mixture was poured into ice water, pH was adjusted to 3 with 1N aqueous sodium hydroxide solution, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated water and once with saturated sodium chloride, finally the organic phase was dried over anhydrous sodium sulfate and concentrated to give I-2e, yield: 26mg, yield: 100%. ¹ H NMR(400MHz,CDCl ₃ )δ8.37(d,J＝1.8Hz,1H),8.27(d,J＝8.7Hz,1H),7.61–7.45(m,5H),7.35(d,J＝1.8Hz,1H),6.94(d,J＝2.4Hz,1H),6.89(dd,J＝8.7,2.6Hz,1H),5.69(s,1H),4.18(t,J＝8.5Hz,2H),3.87(s,2H),3.24(t,J＝8.4Hz,2H).

Step 5: 30mg of I-2e was dissolved in 2mL of methanol (MeOH), 13mg of N-bromosuccinimide (NBS) was added, and the mixture was stirred at room temperature for 5 minutes, followed by slowly dropping a solution of 17mg of sodium hydroxide in 0.3mL of water at 0℃to react at room temperature for 1 hour and then heating to 75℃to react for 4 hours. The reaction mixture was poured into ammonium chloride (NH ₄ Cl), ethyl acetate extraction three times, combining ethyl acetate layers, washing once with saturated sodium chloride, finally drying the organic phase over anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-2f, yield: 2.7mg, yield: 11%. ¹ H NMR(400MHz,CDCl ₃ )δ8.35–8.25(m,1H),7.63–7.43(m,5H),7.11–6.87(m,3H),4.21(t,J＝8.2Hz,2H),3.90(s,2H),3.84(s,2H),3.26(q,J＝8.1Hz,2H).

Step 6: 30mg of I-2f, 15mg of 1-methylpyrazole-4-boronic acid pinacol ester, 25mg of potassium carbonate (K) ₂ CO ₃ ) To a mixed solution of 1mL of 1, 4-dioxane and 0.1mL of water was added 5mg of Pd (dppf) Cl ₂ (CAS: 72287-26-4), and finally reacted at 100℃for 8 hours under an argon atmosphere. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-2, yield: 13mg, yield: 43%. ¹ H NMR(400MHz,CD ₃ OD)δ8.11(d,J＝8.8Hz,1H),7.91(d,J＝2.0Hz,1H),7.76(s,1H),7.68–7.50(m,5H),7.15(d,J＝2.0Hz,1H),6.94(d,J＝2.6Hz,1H),6.86(dd,J＝8.8,2.6Hz,1H),4.22(t,J＝8.4Hz,2H),3.97(s,2H),3.85(s,3H),3.20(t,J＝8.4Hz,2H).LC MS:494.3([M+H] ⁺ ).

Example 3:

step 1: 5g of 5-hydroxyindole (I-1 a) were dissolved in 150mL of acetonitrile, and 460mg of 4-dimethylaminopyridine (4-DMAP) and 21.5mL of di-tert-butyldicarbonate (Boc) were added sequentially under the protection of argon ₂ O) and then reacted at room temperature for 3h. Then acetonitrile was removed by concentration under reduced pressure, and the residue was then taken upRedissolved in 120mL of methanol, and added with 15.6g of potassium carbonate (K) ₂ CO ₃ ) The reaction was stirred at room temperature for 6h. After the TLC monitoring reaction is finished, directly filtering diatomite, spin-drying filtrate, adding a proper amount of water for dilution, regulating pH to be neutral by acetic acid, extracting by ethyl acetate for three times, combining ethyl acetate layers, washing by saturated sodium chloride once, finally drying an organic phase by anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-3a, and obtaining the yield: 8.71g, yield: 99.5%. ¹ H NMR(400MHz,CDCl ₃ )δ7.98(d,J＝8.2Hz,1H),7.56(d,J＝3.7Hz,1H),6.98(d,J＝2.5Hz,1H),6.84(dd,J＝8.8,2.5Hz,1H),6.46(d,J＝3.7Hz,1H),4.94(s,1H),1.66(s,9H).

Step 2: 2g of I-3a was dissolved in 30mL of DMF, 150mg of sodium hydrogen (NaH, 60%) was added at 0℃under argon protection, the mixture was stirred at 0℃for 10 minutes and then allowed to react at room temperature for 0.5h, 2.35g of 5-bromo-2-cyano-3-nitropyridine was dissolved in 8mL of DMF, the mixture was added dropwise to the reaction mixture at 0℃and then allowed to stand at room temperature again and stirred overnight. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed twice with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-3b, yield: 3.116g, yield: 88%. ¹ H NMR(400MHz,CDCl ₃ )δ8.39(d,J＝1.8Hz,1H),8.25(d,J＝9.0Hz,1H),7.70(d,J＝3.7Hz,1H),7.31(d,J＝2.4Hz,1H),7.26(s,1H),7.06(dd,J＝8.9,2.5Hz,1H),6.59(d,J＝3.7Hz,1H),1.69(s,9H).

Step 3: 2.5g of I-3b was dispersed in 30mL of ethanol (EtOH), and then 30mL of 6N sodium hydroxide solution was added thereto, and after constructing a reflux apparatus, argon was sufficiently replaced, and the reaction was carried out at 80℃for 3 hours. After the reaction is finished, ethanol is removed by spinning, the pH value is regulated to 1-2 by concentrated hydrochloric acid at 0 ℃, the solution is directly filtered, filter cakes are fully leached by water and dried by spinning to obtain I-3c, and the yield is: 2.1g, yield: 100%, and the crude product is directly fed to the next step.

Step 4: 1.9g of I-3c was dispersed in 25mL of toluene, 1.6mL of Triethylamine (TEA), 600. Mu.L of water, and 2.5mL of diphenyl azide phosphate (DPPA) were sequentially added, a reflux apparatus was set up, and then argon was sufficiently replaced, and the reaction was carried out at 90℃for 3 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate The ethyl acetate layers were combined, washed twice with saturated sodium chloride and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-3d, yield: 911mg, yield: 52.6%. ¹ HNMR(400MHz,CDCl ₃ )δ8.37(s,1H),7.80(d,J＝1.9Hz,1H),7.41(d,J＝8.7Hz,1H),7.33–7.27(m,2H),6.93(dd,J＝8.7,2.3Hz,1H),6.91(d,J＝2.0Hz,1H),6.55(t,J＝2.6Hz,1H),4.85(s,2H).

Step 5: 1.05g of I-3d are dissolved in 15mL of acetic acid and 650mg of sodium cyanoborohydride (NaBH) are added in three portions under argon ₃ CN), and then stirred at room temperature overnight. After the TLC tracking detection reaction is finished, directly spinning acetic acid, concentrating, and purifying by column chromatography to obtain I-3e. Yield 854mg, 80.9%. ¹ H NMR(400MHz,CDCl ₃ )δ7.76(d,J＝2.1Hz,1H),6.89(d,J＝2.1Hz,1H),6.82(d,J＝2.4Hz,1H),6.72(dd,J＝8.3,2.4Hz,1H),6.63(d,J＝8.3Hz,1H),4.93(s,2H),3.62(t,J＝8.4Hz,2H),3.05(t,J＝8.4Hz,2H).

Step 6: 100mg of I-3e, 60mg of phenylacetic Acid (Acid-2) and 186mg of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 7mL of N, N-Dimethylformamide (DMF), 165. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-3f, yield: 138mg, yield: 100%. ¹ H NMR(400MHz,CDCl ₃ )δ8.28(d,J＝8.7Hz,1H),7.43–7.21(m,6H),6.94(s,1H),6.89–6.79(m,2H),4.96(s,2H),4.12(t,J＝8.5Hz,2H),3.82(s,2H),3.17(t,J＝8.4Hz,2H).

Step 7: 130mg of I-3f, 83mg of 1-methylpyrazole-4-boronic acid pinacol ester, 100mg of sodium carbonate (Na ₂ CO ₃ ) To a mixed solution of 7mL of 1, 4-dioxane and 0.8mL of water was added 106mg of Pd (PPh) ₃ ) ₄ Finally, the reaction was carried out overnight at 90℃under argon. After the reaction was completed, the reaction mixture was poured into water, extracted three times with ethyl acetate, and the ethyl acetate layers were combined, followed byWashing with saturated sodium chloride once, drying the organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-3, and yield: 117.6mg, yield: 90.5%. ¹ H NMR(400MHz,CDCl ₃ )δ8.26(d,J＝8.8Hz,1H),7.96(d,J＝2.0Hz,1H),7.57(d,J＝0.9Hz,1H),7.44(d,J＝0.8Hz,1H),7.36(dt,J＝6.8,1.2Hz,1H),7.34–7.27(m,4H),7.00(d,J＝2.0Hz,1H),6.89(dd,J＝8.8,2.6Hz,1H),6.83(d,J＝2.5Hz,1H),4.69(s,2H),4.11(t,J＝8.5Hz,2H),3.89(s,3H),3.82(s,2H),3.15(t,J＝8.4Hz,2H).

The phenylacetic acid in step 6 of example 3 was replaced with a different carboxylic acid, and the other required raw materials, reagents and preparation methods were the same as in example 3, the following compounds were obtained:

the following compounds were obtained by substituting 4-fluoro-5-oxindole for 5-oxindole (I-1 a) in step 1 of example 3 and by following the same procedure as in example 3: />

Example 4:

step 1: 500mg of 5-bromo-2-cyano-3-nitropyridine, 15mL of 1, 4-dioxane and 350mg of 1H-pyrrolo [2,3-B are added sequentially to the tube]Pyridin-5-ol (I-10 a), 700mg Potassium phosphate (K) ₃ PO ₄ ) After argon was sufficiently replaced, the reaction was carried out at 90℃for 4 hours. Taking out after the reaction is finished, cooling to room temperature, extracting with ethyl acetate for three times, combining ethyl acetate layers, washing with saturated sodium chloride once, finally drying an organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-10b, and obtaining the yield: 680 mg, yield: 100%. ¹ H NMR(400MHz,CDCl ₃ )δ9.15(s,1H),8.44(d,J＝1.8Hz,1H),8.20(d,J＝2.6Hz,1H),7.73(dd,J＝2.6,0.8Hz,1H),7.47(dd,J＝3.6,2.5Hz,1H),7.28(d,J＝1.8Hz,1H),6.58(dd,J＝3.5,2.0Hz,1H).

Step 2: 770mg of I-10b was dispersed in 15mL of ethanol (EtOH), 15mL of 6N sodium hydroxide solution was added thereto, and after constructing a reflux apparatus, argon was sufficiently replaced, and the mixture was then heated to 80℃to react for 3 hours. After the reaction is finished, ethanol is removed by spinning, the pH value is adjusted to 4-5 by concentrated hydrochloric acid at 0 ℃, the solution is directly filtered, filter cakes are fully leached by water and dried by spinning to obtain I-10c, and the yield is: 470mg, yield: 57.2%, and the crude product is directly fed to the next step.

Step 3: 470mg of I-10c was dispersed in 20mL of toluene, 400. Mu.L of Triethylamine (TEA), 150. Mu.L of water, and 610. Mu.L of diphenyl azide phosphate (DPPA) were sequentially added to the mixture, and after constructing a reflux apparatus, argon was sufficiently replaced, and the mixture was reacted at 90℃for 3 hours. After the reaction, taking out and cooling to room temperature, pouring the reaction mixture into water, extracting with ethyl acetate three times, combining ethyl acetate layers, washing with saturated sodium chloride twice, finally drying an organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-10d, and obtaining the yield: 191mg, yield: 44.4%. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.78(s,1H),8.10(d,J＝2.7Hz,1H),7.75(d,J＝2.1Hz,1H),7.71(dd,J＝2.6,0.6Hz,1H),7.58–7.50(m,1H),6.90(d,J＝2.1Hz,1H),6.45(dd,J＝3.4,1.9Hz,1H),6.35(s,2H).

Step 4: 190mg of I-10d are dissolved in 10mL of acetic acid, and 120mg of sodium cyanoborohydride (NaBH) is added under argon protection ₃ CN) and then reacted at 80 c overnight. Directly spin-removing acetic acid after the post-treatment, purifying and recovering 135mg of raw material by column chromatography, purifying to obtain a target product I-10e, and obtaining the yield: 46mg, yield: 81.8 percent, directly put into the next step.

Step 5: 46mg of I-10e, 46mg of m-trifluoromethylphenylacetic Acid (Acid-1) and 114mg of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 6mL of N, N-Dimethylformamide (DMF), 74. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, ethyl acetateExtracting the ester three times, combining ethyl acetate layers, washing with saturated sodium chloride five times, finally drying an organic phase by using anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-10f, and obtaining the yield: 32mg, yield: 43.2%. ¹ H NMR(400MHz,CDCl ₃ )δ7.97(d,J＝2.6Hz,1H),7.50(d,J＝2.4Hz,2H),7.43(dd,J＝14.1,7.1Hz,3H),7.21(dt,J＝2.8,1.3Hz,1H),6.97(d,J＝1.8Hz,1H),4.58(s,2H),4.27–4.16(t,J＝8.5Hz,2H),3.10(t,J＝8.5Hz,2H).

Step 6: 32mg of I-10f, 21mg of 1-methylpyrazole-4-boronic acid pinacol ester, 21mg of sodium carbonate (Na ₂ CO ₃ ) To a mixed solution of 5mL of 1, 4-dioxane and 0.6mL of water was added 23mg of Pd (PPh) ₃ ) ₄ Finally, the reaction was carried out overnight at 90℃under argon. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography to give I-10, yield: 10mg, yield: 31.3%. ¹ H NMR(400MHz,CDCl ₃ )δ8.00(d,J＝2.6Hz,2H),7.66(s,1H),7.58(d,J＝6.9Hz,2H),7.52–7.46(m,2H),7.42(t,J＝7.7Hz,1H),7.22(dt,J＝2.6,1.3Hz,1H),7.05(d,J＝1.7Hz,1H),5.20(s,2H),4.58(s,2H),4.19(t,J＝8.5Hz,2H),3.91(s,3H),3.09(t,J＝8.5Hz,2H).

Example 5:

Step 1: 1g of 5-hydroxyindole (I-1 a) was dispersed in 10mL of absolute ethanol, followed by adding 1.7mL of a 33% aqueous dimethylamino solution and 700. Mu.L of a 37% aqueous formaldehyde solution, and stirring the mixture at room temperature for 8 hours. After TLC detection of the reaction of the raw materials is finished, the solvent is removed by rotation, toluene is added for twice, and the crude product of I-11a is obtained by full pumping. Yield: 1.37g, yield: 96.5% and the crude product is directly fed to the next step.

Step 2: dispersing 1.37g of I-11a in 30mL of absolute ethanol, fully replacing argon, stirring at 0 ℃ for 20min, and adding 1.43g of sodium borohydride (NaBH) ₄ ) After the addition, the reaction is carried outThe temperature is raised to 80 ℃ to react for 12 hours. After the reaction was completed, the mixture was taken out and cooled to room temperature, stirred again for 20 minutes in an ice bath, 570mg of sodium borohydride was added thereto, and the mixture was refluxed again for 1 hour. After the reaction was completed, the mixture was stirred under ice bath for 20 minutes, and 50mL of water was added dropwise to quench the reaction. Extracting with ethyl acetate three times after quenching, combining ethyl acetate layers, washing with saturated sodium chloride once, drying the organic phase over anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-11b, yield: 795mg, yield: 72.3%. ¹ H NMR(400MHz,CDCl ₃ )δ8.06(s,1H),7.18(t,J＝2.9Hz,1H),7.11(d,J＝8.5Hz,1H),6.77(d,J＝8.6Hz,1H),6.55–6.46(m,1H),4.57(s,1H),2.45(s,3H).

Step 3: into the tube was successively added 2.3g of 5-bromo-2-cyano-3-nitropyridine, 30mL of acetonitrile, 750mg of I-11b, 1.76g of potassium phosphate (K ₃ PO ₄ ) After argon was sufficiently replaced, the reaction was carried out at 80℃for 12 hours. Taking out after the reaction is finished, cooling to room temperature, extracting with ethyl acetate for three times, combining ethyl acetate layers, washing with saturated sodium chloride once, finally drying an organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-11c, and obtaining the yield: 777.7mg, yield: 46.8%. ¹ H NMR(400MHz,CDCl ₃ )δ8.43(s,1H),8.36(d,J＝1.8Hz,1H),7.36–7.30(m,2H),7.12(d,J＝1.8Hz,1H),6.87(d,J＝8.7Hz,1H),6.63(ddd,J＝3.2,2.1,0.9Hz,1H),2.37(s,3H).

Step 4: 770mg of I-11c was dispersed in 10mL of ethanol (EtOH), and then 8mL of a 6N sodium hydroxide solution was added thereto, and after constructing a reflux apparatus, argon was sufficiently replaced, and the mixture was then allowed to react at 80℃for 3 hours. After the reaction is finished, ethanol is removed by spinning, the pH value is regulated to 1-2 by concentrated hydrochloric acid at 0 ℃, the solution is directly filtered, filter cakes are fully leached by water and dried by spinning to obtain I-11d, and the yield is: 660mg, yield: 80.2% of crude product is directly fed into next step.

Step 5: 470mg of I-11d was dispersed in 20mL of toluene, 480. Mu.L of Triethylamine (TEA), 600. Mu.L of water, and 740. Mu.L of diphenyl azide phosphate (DPPA) were sequentially added to the mixture, and after constructing a reflux apparatus, argon was sufficiently replaced, and the reaction was carried out at 90℃overnight. After the reaction was completed, the mixture was cooled to room temperature, poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed twice with saturated sodium chloride, and the mostThe latter organic phase is dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to give I-11e, yield: 180.2mg, yield: 33.4%. ¹ H NMR(400MHz,CDCl ₃ )δ8.39(s,1H),7.75(d,J＝2.0Hz,1H),7.32–7.28(m,1H),7.26(d,J＝1.7Hz,1H),6.88(d,J＝8.7Hz,1H),6.70–6.58(m,2H),4.95(s,2H),2.36(s,3H).

Step 6: 180mg of I-11e was dissolved in 10mL of acetic acid, and 107mg of sodium cyanoborohydride (NaBH) was added under argon shield ₃ CN), and then reacted at room temperature overnight. The post-treatment directly removes acetic acid, and the target product I-11f is obtained by column chromatography purification. Yield: 128.4mg, yield 70.9%. ¹ H NMR(400MHz,CDCl3)δ7.73(dd,J＝2.0,1.0Hz,1H),6.86–6.62(m,2H),6.49(d,J＝8.2Hz,1H),4.89(s,2H),3.64(t,J＝8.4Hz,2H),3.00(t,J＝8.4Hz,2H),2.01(s,3H).

Step 7: 120mg of I-11f, 115mg of m-trifluoromethylphenylacetic Acid (Acid-1) and 286mg of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 10mL of N, N-Dimethylformamide (DMF), 186. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-11g, yield: 190mg, yield: 100%. ¹ H NMR(400MHz,CDCl ₃ )δ8.11(d,J＝8.7Hz,1H),7.76(t,J＝1.8Hz,1H),7.53(dq,J＝25.3,7.8Hz,5H),6.85(d,J＝8.7Hz,1H),4.96(s,2H),4.24–4.16(m,2H),3.87(s,2H),3.17(t,J＝8.4Hz,2H),2.06(s,3H).

Step 8: 180mg of I-11g, 111mg of 1-methylpyrazole-4-boronic acid pinacol ester, 114mg of sodium carbonate (Na ₂ CO ₃ ) To a mixed solution of 10mL of 1, 4-dioxane and 1mL of water was added 111mg of Pd (PPh) ₃ ) ₄ Finally, the reaction was carried out overnight at 90℃under argon. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography Purifying to obtain I-11, yield: 71.6mg, yield: 39.7%. ¹ H NMR(400MHz,CDCl ₃ )δ8.09(d,J＝8.7Hz,1H),7.90(d,J＝1.9Hz,1H),7.60–7.47(m,5H),7.42–7.35(m,1H),6.85(d,J＝8.7Hz,1H),6.74(d,J＝1.9Hz,1H),4.79(s,2H),4.20(t,J＝8.4Hz,2H),3.88(d,J＝2.1Hz,5H),3.17(t,J＝8.4Hz,2H),2.10(s,3H).

Example 6:

step 1: 150mg of I-2f was taken in 6mL of anhydrous dichloromethane, argon was fully replaced, and 151. Mu.L of Diisopropylethylamine (DIPEA) was added thereto, followed by stirring under ice-bath conditions for 20 minutes. 49. Mu.L of pivaloyl chloride was added dropwise thereto, and the mixture was allowed to react at 0℃for 30 minutes, and then allowed to warm to room temperature overnight. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography to give I-12a, yield: 143.1mg, yield: 81.7%. ¹ H NMR(400MHz,CDCl ₃ )δ8.26(dd,J＝9.9,8.6Hz,1H),7.58–7.44(m,4H),7.16(s,1H),7.03–6.77(m,3H),4.82(s,1H),4.17(t,J＝8.4,3.9Hz,2H),3.87(s,J＝2.3Hz,2H),3.22(t,J＝8.5,3.1Hz,2H),1.26(s,9H).

Step 2: 100mg of I-12a, 55mg of 1-methylpyrazole-4-boronic acid pinacol ester, 55mg of sodium carbonate (Na ₂ CO ₃ ) To a mixed solution of 8mL of 1, 4-dioxane and 1mL of water was added 60mg of Pd (PPh) ₃ ) ₄ Finally, the reaction was carried out overnight at 90℃under argon. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography to give I-12, yield: 69mg, yield: 69%. ¹ H NMR(400MHz,CDCl ₃ )δ8.33(d,J＝2.0Hz,1H),8.25(d,J＝8.7Hz,1H),7.91(s,1H),7.62(s,1H),7.58–7.47(m,5H),7.17(d,J＝2.0Hz,1H),6.95–6.81(m,2H),4.16(t,J＝8.4Hz,2H),3.92(s,3H),3.87(s,2H),3.21(t,J＝8.4Hz,2H),1.27(s,9H).

Example 7:

step 1: 88mg of I-2f was taken in 3mL of anhydrous tetrahydrofuran, and the mixture was stirred for 20 minutes under ice bath conditions while fully replacing argon. 8mg of sodium hydride (60% NaH) was added thereto, and the mixture was kept in an ice bath for 30 minutes, and then warmed to room temperature and reacted for 1 hour. After that, 12. Mu.L of methyl iodide (MeI) was added dropwise, and the reaction was carried out overnight after completion of the dropwise addition. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by a preparative thin layer to give I-13a, yield: 23mg, yield: 25.5%. ¹ H NMR(400MHz,CDCl ₃ )δ8.32(d,J＝8.8Hz,1H),7.81(s,1H),7.65–7.50(m,3H),7.47(t,J＝7.7Hz,1H),6.94(d,J＝1.9Hz,1H),6.89(dd,J＝8.7,2.6Hz,1H),6.82(d,J＝2.5Hz,1H),4.94(s,1H),4.20(td,J＝10.3,6.5Hz,1H),3.95(q,J＝6.9Hz,1H),3.84(td,J＝10.3,6.4Hz,1H),3.17(ddd,J＝16.8,10.4,6.5Hz,1H),3.06(ddd,J＝16.6,10.5,6.5Hz,1H),1.56(d,J＝6.8Hz,3H).

Step 2: 23mg of I-13a, 15mg of 1-methylpyrazole-4-boronic acid pinacol ester, 55mg of sodium carbonate (Na ₂ CO ₃ ) To a mixed solution of 5mL of 1, 4-dioxane and 0.5mL of water was added 16mg of Pd (PPh) ₃ ) ₄ Finally, the reaction is carried out for 6 hours at 90 ℃ under the protection of argon. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography to give I-13, yield: 11.5mg, yield: 50%. ¹ H NMR(400MHz,CDCl ₃ )δ8.31(d,J＝8.8Hz,1H),7.94(d,J＝1.8Hz,1H),7.62–7.52(m,4H),7.50–7.41(m,2H),7.01(d,J＝1.9Hz,1H),6.91(dd,J＝8.7,2.5Hz,1H),6.82(d,J＝2.6Hz,1H),4.88(s,1H),4.19(td,J＝10.3,6.6Hz,1H),3.95(q,J＝6.7Hz,1H),3.89(s,3H),3.83(dt,J＝10.2,5.1Hz,1H),3.16(ddd,J＝16.7,10.5,6.7Hz,1H),3.05(ddd,J＝16.6,10.4,6.5Hz,1H),1.56(d,J＝6.8Hz,3H).

Example 8:

76mg of I-2f, 42mg of 3, 4-dimethoxyphenylboronic acid, 50mg of sodium carbonate (Na ₂ CO ₃ ) To a mixed solution of 8mL of 1, 4-dioxane and 1mL of water was added 42mg of Pd (PPh) ₃ ) ₄ Finally, the reaction is carried out for 6 hours at 90 ℃ under the protection of argon. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography to give I-14, yield: 37mg, yield: 44%. ¹ H NMR(400MHz,CDCl ₃ )δ8.23(d,J＝8.8Hz,1H),8.04(d,J＝2.1Hz,1H),7.68–7.63(m,2H),7.55–7.53(m,2H),7.48–7.44(m,3H),7.16(d,J＝2.0Hz,1H),6.93(d,J＝1.7Hz,2H),4.81(s,2H),4.14(t,J＝8.4Hz,2H),3.89(d,J＝6.0Hz,6H),3.86(s,2H),3.19(t,J＝8.4Hz,2H).

The 3, 4-dimethoxy phenylboronic acid in the example 8 is replaced by boric acid or boric acid ester with other aromatic rings and heterocyclic rings, and the other required raw materials, reagents and preparation methods are unchanged, so that the following compounds are obtained:

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example 9:

step 1: 300mg of 4-pyrazoloboronic acid pinacol ester (I-15 a), 7mL of N, N-Dimethylformamide (DMF) and 600mg of cesium carbonate are sequentially added into a tube, the reaction is stirred at room temperature for 20min, 280 mu L of 2- (2-bromoethoxy) tetrahydro-2H-pyran is added dropwise, argon is fully replaced, and the reaction is carried out at 70 ℃ for 18H. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography to give I-15b, yield: 237.6mg, yield: 47.6%. Directly put into the next step.

Step 2: the procedure for substituting 3, 4-dimethoxyphenylboronic acid with I-15b was the same as in example 7, except for the remaining raw materials, reagents and preparation method to give product I-15c, yield: 62mg, yield: 43%. Directly put into the next step.

Step 3: 40mg of I-15c was dissolved in 7mL of anhydrous methanol, and 3mg of p-toluene sulfonic acid (PTSA) was added after sufficient argon substitution, and the reaction was kept at room temperature overnight. After TLC detection reaction is finished, directly concentrating, preparing, separating and purifying by a thin layer to obtain I-15, and the yield is: 32mg, yield: 92.7%. ¹ H NMR(400MHz,CDCl ₃ )δ8.24(d,J＝8.7Hz,1H),7.92(s,1H),7.61(s,1H),7.52(td,J＝15.8,15.2,7.1Hz,6H),7.01(d,J＝1.9Hz,1H),6.94–6.88(m,1H),6.87(s,1H),5.02(s,2H),4.25–4.21(m,2H),4.17(t,J＝8.4Hz,2H),4.01(dd,J＝5.5,4.1Hz,2H),3.87(s,2H),3.22(t,J＝8.4Hz,2H).

Example 10:

step 1: 300mg of 2-amino-3, 5-dibromopyrazine (I-16 a) and 15mL of N-methylpyrrolidone (NMP) were added to the tube, followed by 331mg of I-3a and 330mg of potassium carbonate (K) ₂ CO ₃ ) After argon was sufficiently replaced, the reaction was carried out at 100℃for 6 hours. Taking out the mixture after the reaction is finished, cooling the mixture to room temperature,pouring the reaction solution into water, extracting with ethyl acetate for three times, combining ethyl acetate layers, washing with saturated sodium chloride for three times, finally drying an organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-16b, and obtaining the yield: 310mg, yield: 64.5%. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.25(s,1H),7.68(s,1H),7.45–7.38(m,2H),7.34(d,J＝2.3Hz,1H),6.91(dd,J＝8.7,2.3Hz,1H),6.88–6.70(s,2H),6.44(t,J＝2.6Hz,1H).

Step 2: 300mg of I-16b are dissolved in 15mL of acetic acid and 190mg of sodium cyanoborohydride (NaBH) are added in three portions under the protection of argon ₃ CN), and then stirred at room temperature overnight. After the TLC detection reaction is finished, directly spinning acetic acid, concentrating, and purifying by column chromatography to obtain I-16c. Yield: 130mg, 43.3% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.66(d,J＝1.4Hz,1H),6.95–6.88(m,1H),6.78(dt,J＝8.3,2.0Hz,1H),6.62(dd,J＝8.4,1.4Hz,1H),5.23(s,2H),3.58(t,J＝8.4Hz,2H),3.04(t,J＝8.4Hz,2H),2.69(d,J＝1.4Hz,1H).

Step 3: 110mg of I-16c, 81mg of m-trifluoromethylphenylacetic Acid (Acid-1) and 205mg of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 10mL of N, N-Dimethylformamide (DMF), 180. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-16d, yield: 123mg, yield: 70%. ¹ H NMR(400MHz,CDCl ₃ )δ8.26(dd,J＝8.8,2.5Hz,1H),7.75(d,J＝2.4Hz,1H),7.64–7.42(m,4H),7.09–6.86(m,2H),4.95(s,2H),4.16(td,J＝8.5,2.5Hz,2H),3.86(d,J＝2.6Hz,2H),3.24(t,J＝8.5Hz,2H).

Step 4: 120mg of I-16d, 76mg of 1-methylpyrazole-4-boronic acid pinacol ester, 78mg of sodium carbonate (Na ₂ CO ₃ ) To a mixed solution of 10mL of 1, 4-dioxane and 1mL of water was added 85mg of Pd (PPh) ₃ ) ₄ Finally, the reaction is carried out for 12 hours at 90 ℃ under the protection of argon. After the reaction, the reaction mixture was reactedPouring into water, extracting with ethyl acetate three times, combining ethyl acetate layers, washing with saturated sodium chloride once, finally drying the organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-16, yield: 92.7mg, yield: 77%. ¹ H NMR(400MHz,CDCl ₃ )δ8.30–8.24(m,1H),7.87(s,1H),7.70–7.66(m,1H),7.60–7.52(m,3H),7.50(d,J＝6.5Hz,2H),7.08–7.02(m,2H),4.89(s,2H),4.18(t,J＝8.4Hz,2H),3.87(d,J＝8.6Hz,5H),3.24(t,J＝8.4Hz,2H).

Example 11:

step 1: 200mg of 2-nitro-3-fluoropyridine (I-17 a) and 15mL of acetonitrile (MeCN) were sequentially added to the tube, followed by 400mg of I-3a and 290mg of potassium carbonate (K) ₂ CO ₃ ) After argon was sufficiently replaced, the reaction was carried out at 80℃for 16 hours. Taking out after the reaction is finished, cooling to room temperature, pouring the reaction solution into water, extracting with ethyl acetate for three times, combining ethyl acetate layers, washing with saturated sodium chloride for three times, finally drying an organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-17b, and obtaining the yield: 501mg, yield: 100%. ¹ H NMR(400MHz,CDCl ₃ )δ8.24–8.07(m,2H),7.65(d,J＝4.1Hz,1H),7.42(ddt,J＝8.8,4.5,2.2Hz,1H),7.33(dt,J＝8.5,2.0Hz,1H),7.04(dt,J＝9.0,2.3Hz,1H),6.98–6.76(m,1H),6.53(dt,J＝4.3,2.3Hz,1H),1.66(s,9H).

Step 2: 800mg of I-17b was dispersed in 20mL of ethanol, and 10mL of a saturated ammonium chloride solution was added thereto, followed by sufficient argon substitution, and then reaction was carried out at 80℃overnight. Taking out after the reaction is finished, cooling to room temperature, removing ethanol by rotation, extracting with ethyl acetate for three times, combining ethyl acetate layers, washing with saturated sodium chloride for three times, finally drying an organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-17c, and obtaining the yield: 380mg, yield: 76%. ¹ H NMR(400MHz,CDCl ₃ )δ8.35(s,1H),7.78(dd,J＝5.0,1.5Hz,1H),7.38(dt,J＝8.7,0.7Hz,1H),7.27(t,J＝2.3Hz,2H),6.94(dd,J＝8.7,2.3Hz,1H),6.89(dd,J＝7.8,1.5Hz,1H),6.55(dd,J＝7.8,5.0Hz,1H),6.51(ddd,J＝3.1,2.1,1.0Hz,1H),4.79(s,2H).

Step 3: 200mg of I-17c are dissolved in 8mL of acetic acid and 116mg of sodium cyanoborohydride (NaBH) are added in three portions under argon protection ₃ CN), and then stirred at room temperature overnight. After the TLC detection reaction is finished, directly spinning acetic acid, concentrating, and purifying by column chromatography to obtain I-17d. Yield: 213mg, 100% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.58(dd,J＝5.5,1.4Hz,1H),6.89(dd,J＝7.9,1.4Hz,1H),6.82(dt,J＝2.5,1.2Hz,1H),6.71(dd,J＝8.3,2.4Hz,1H),6.62(d,J＝8.3Hz,1H),6.53(dd,J＝7.8,5.5Hz,1H),5.34(s,2H),3.60(t,J＝8.4Hz,2H),3.03(t,J＝8.4Hz,2H).

Step 4: 115mg of I-17d, 115mg of m-trifluoromethylphenylacetic Acid (Acid-1) and 285mg of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 8mL of N, N-Dimethylformamide (DMF), 245. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-17, yield: 70mg, yield: 34%. ¹ H NMR(400MHz,CDCl ₃ )δ8.20(d,J＝8.7Hz,1H),7.81(dd,J＝5.0,1.5Hz,1H),7.57–7.43(m,4H),6.95(dd,J＝7.8,1.5Hz,1H),6.87–6.80(m,2H),6.58(dd,J＝7.8,5.0Hz,1H),4.82(s,2H),4.13(t,J＝8.4Hz,2H),3.85(s,2H),3.18(t,J＝8.4Hz,2H).

Example 12:

step 1: 3g of 2-bromo-3-fluoro-4-methylpyridine (I-18 a), 1.85g of zinc cyanide and 3.6g of tetrakis (triphenylphosphine) palladium were dispersed in 30mL of N, N-dimethylformamide, and reacted at 90℃for 18 hours after sufficient substitution of argon. Taking out after the reaction is finished, cooling to room temperature, pouring the reaction mixture into water, extracting with ethyl acetate three times, combining ethyl acetate layers, washing with saturated sodium chloride five times, drying the organic phase with anhydrous sodium sulfate, concentrating, and passing through column layerSeparating and purifying to obtain I-18b, and yield: 1.056g, yield: 49.3%. ¹ H NMR(400MHz,CDCl ₃ )δ8.36(d,J＝4.8Hz,1H),7.42(t,J＝5.4Hz,1H),2.39(s,3H).

Step 2: into the tube was successively added 900mg of I-18b, 6mL of N, N-dimethylformamide, 2g of I-3a and 4.3g of cesium carbonate (Cs) ₂ CO ₃ ) After argon was sufficiently replaced, the reaction was carried out at 80℃for 3 hours. Taking out after the reaction is finished, cooling to room temperature, pouring the reaction solution into water, extracting with ethyl acetate for three times, combining ethyl acetate layers, washing with saturated sodium chloride for three times, finally drying an organic phase with anhydrous sodium sulfate, concentrating, purifying by column chromatography to obtain I-18c, and obtaining the yield: 1.89g, yield: 74.3%. ¹ H NMR(400MHz,CDCl ₃ )δ8.45(d,J＝4.7Hz,1H),8.09(d,J＝8.9Hz,1H),7.61(d,J＝3.7Hz,1H),7.50–7.39(m,1H),6.92(dd,J＝9.0,2.6Hz,1H),6.88(d,J＝2.6Hz,1H),6.46(d,J＝3.7Hz,1H),2.22(s,3H),1.66(s,9H).

Step 3: 1.89g of I-18c was dispersed in 20mL of ethanol (EtOH), 18mL of 6N sodium hydroxide solution was added thereto, and after constructing a reflux apparatus, argon was sufficiently replaced, and the reaction was carried out at 80℃for 3 hours. After the reaction is finished, ethanol is removed by spinning, the pH value is regulated to 1-2 by concentrated hydrochloric acid at 0 ℃, the solution is directly filtered, filter cakes are fully leached by water and dried by spinning to obtain I-18d, and the yield is: 877mg, yield: 60.4 percent, and the crude product is directly put into the next step.

Step 4: 777mg of I-18d was dispersed in 20mL of toluene, and 0.8mL of Triethylamine (TEA), 500. Mu.L of water, and 1.3mL of diphenyl azide phosphate (DPPA) were sequentially added to the mixture, and after constructing a reflux apparatus, argon was sufficiently replaced, and the reaction was carried out at 90℃overnight. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed twice with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-18e, yield: 211mg, yield: 30.4%. Directly put into the next step.

Step 5: 211mg of I-18e are dissolved in 10mL of acetic acid and 190mg of sodium cyanoborohydride (NaBH) are added in three portions under argon protection ₃ CN), and then stirred at room temperature overnight. After the TLC detection reaction is finished, directly spinning acetic acid, concentrating, and purifying by column chromatography to obtain I-18f. Yield: 227mg, yieldThe rate was 100%. Directly put into the next step.

Step 6: 80mg of I-18f, 68mg of m-trifluoromethylphenylacetic Acid (Acid-1) and 164mg of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 8mL of N, N-Dimethylformamide (DMF), 170. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to give I-18, yield: 60mg, yield: 42.8%. ¹ H NMR(400MHz,CDCl ₃ )δ8.15(d,J＝8.8Hz,1H),7.82(d,J＝5.1Hz,1H),7.57–7.43(m,4H),6.70(dd,J＝8.8,2.7Hz,1H),6.66–6.61(m,1H),6.56(d,J＝5.2Hz,1H),4.57(s,2H),4.10(t,J＝8.4Hz,2H),3.84(s,2H),3.15(t,J＝8.4Hz,2H),2.07(s,3H).

Example 13:

the 3, 5-dimethylpyrazole-4-boronic acid pinacol ester was used in place of the I-15a, and the other required raw materials, reagents and preparation method were the same as the procedure in example 9, to obtain the product I-19. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.11(d,J＝8.8Hz,1H),7.64(s,1H),7.54(dd,J＝14.4,7.3Hz,6H),6.99(s,1H),4.23(q,J＝7.9,7.4Hz,3H),4.10(t,J＝5.4Hz,2H),3.98(s,2H),3.83(t,J＝5.4Hz,2H),3.31(s,7H),3.22(t,J＝8.5Hz,2H),2.20(s,3H),2.10(s,3H).

Example 14:

step 1: 60mg of I-3e, 80mg of Acid-3 and 164mg of N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate urea were dissolved in 8mL of N, N-Dimethylformamide (DMF), 210. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and spun dry to give the crude product which was directly put into the next step.

Step 2: 163mg of I-20a, 100mg of I-19b, 110mg of sodium carbonate were added to a mixed solution of 5mL of 1, 4-dioxane and 0.5mL of water, and 40mg of Pd (PPh) ₃ ) ₄ Finally, the reaction is carried out for 12 hours at 90 ℃ under the protection of argon. After the reaction, the reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed once with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography to give I-20, yield: 98mg, yield: 66.7%.1H NMR (400 MHz, chloro-d) delta 8.19 (d, J=8.5 Hz, 1H), 7.73-7.62 (m, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.45-7.35 (m, 2H), 6.91-6.78 (m, 3H), 4.89 (s, 2H), 4.49 (t, J=3.4 Hz, 1H), 4.18 (t, J=5.6 Hz, 2H), 4.12 (t, J=8.4 Hz, 2H), 4.04-3.93 (m, 3H), 3.78-3.52 (m, 3H), 3.49-3.37 (m, 4H), 3.18 (t, J=8.4 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H), 1.75-1.34 (m, 9H).

Step 3: 50mg of I-20b was dissolved in 7mL of anhydrous methanol, and after sufficient argon substitution, 5mg of p-toluene sulfonic acid (PTSA) was added thereto, and the reaction was kept at room temperature overnight. After TLC detection reaction is finished, directly concentrating, preparing, separating and purifying by a thin layer to obtain I-20, and the yield is: 40mg, yield: 93%.1H NMR (400 MHz, chloroform-d) δ8.16 (d, J=8.6 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.68-7.62 (m, 2H), 7.59 (d, J=7.7 Hz, 1H), 6.90-6.83 (m, 2H), 6.81 (d, J=1.9 Hz, 1H), 4.91 (s, 2H), 4.32 (t, J=8.4 Hz, 2H), 4.06 (d, J=6.0 Hz, 4H), 3.97 (dd, J=5.6, 3.9Hz, 2H), 3.19 (t, J=8.3 Hz, 2H), 2.13 (d, J=14.7 Hz, 6H).

The Acid-3 in example 14 was replaced with a different kind of carboxylic Acid, and the remaining required starting materials, reagents and preparation methods were unchanged, the following compounds:

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example 15: effect of Compound molecular level on RIPK1 kinase Activity

In 384 well plates, 2 μl of enzyme and 1 μl of different concentrations of compound were added, while a 0% kinase activity control well without kinase and compound and a 100% kinase activity control well without compound were set and incubated at room temperature for 10min. The addition of 2. Mu.L of the mixture of ATP and substrate (final substrate concentration 100. Mu.g/mL, final ATP concentration 10. Mu.M) was continued and incubated at 37℃for 1h. mu.L of ADP-Glo was added to each well ^TM Reagent, incubated at room temperature for 40 minutes, and unreacted ATP was removed. 10 mu L Kinase Detection Reagent was added to each well and incubated at room temperature for 30-60 minutes to convert ADP produced in the reaction to ATP. Fluorescent signals (luminescence: integration time 0.5 s) were detected. Inhibition per well, IC, was calculated by mean RLU values representing 0% kinase activity (no enzyme and compound) and 100% kinase activity (no compound) ₅₀ The values were calculated using GraphPad Prism software.

Table 1: compounds having RIPK1 enzyme inhibitory activity

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Wherein A represents IC ₅₀ Less than (less than or equal to) 0.1 mu M; b represents IC ₅₀ Less than (less than) 1 mu M and greater than (greater than) 0.1 mu M

C represents IC ₅₀ Greater than (>) 1. Mu.M

As can be seen from Table 1, the compounds of the present invention have a remarkable inhibitory effect on RIPK1 enzyme.

Example 16: compound return to I2.1 cell apoptosis necrosis

Testing I2.1 cell line (FADD mutant of human acute T cell leukemia Jurkat cell, FADD protein in cell is deleted, and TNF alpha alone can induce programmed necrosis of cell). Detection was performed with the CCK-8 cell counting kit (Dojindo).

I2.1 cells in log phase were seeded at the appropriate density into 96-well plates, after overnight incubation, compounds at different concentrations were added first, tnfα stimulation at different concentrations was added after one hour, and no compound plus stimulator control wells (positive control) and no compound plus stimulator control wells (negative control) were set. After the compound acts on cells for 24 hours, the influence of the compound on cell proliferation is detected by using a CCK-8 cell counting kit (Dojindo), 10 mu L of CCK-8 reagent is added into each hole, the mixture is placed in a 37 ℃ incubator for 2 to 4 hours, and then the mixture is read by a full-wave microplate reader SpectraMax 190, and the measurement wavelength is 450nm. The recovery (%) of the compound against cell programmed necrosis was calculated using the following formula:

Recovery (%) = (OD dosing well-OD negative control well)/(OD positive control well-OD negative control well) ×100%

IC ₅₀ The values were calculated using GraphPad Prism software.

Table 2: reversion of Compounds to I2.1 cell death

Compounds of formula (I)	IC ₅₀	Compounds of formula (I)	IC ₅₀
				I-2	A	I-20	A
I-5	A	I-20-2	B
				I-6	B	I-20-3	B
I-7	B	I-20-4	B
				I-11	B	I-20-5	A
I-14	A	I-20-6	A
				I-15	A	I-20-8	A
I-17	B	I-20-9	A
				I-18	B	I-20-10	B
I-14-12	A	I-20-15	A
				I-14-15	B	I-20-16	A
I-14-17	B	I-20-17	A
				I-19	A	I-20-18	A

Wherein A represents IC ₅₀ Less than (less than or equal to) 0.1 mu M; b represents IC ₅₀ Less than (less than) 1 mu M and greater than (>) 0.1 mu M; c represents IC ₅₀ Greater than (>) 1. Mu.M

From the above test results, it can be seen that the compounds of the present invention have a significant restoring effect on tnfα -induced I2.1 cell death.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

1. A compound represented by the general formula (I) or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, an isotopically labeled compound thereof,

Y1 is N or C-R ^1a The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^1a Selected from H, D, halogen, NR ¹ R ² ；R ¹ 、R ² Independently selected from: H. d, C1C 1-C8 alkyl, C1-C15 alkyl C (=O) -, C1-C15 alkyl OC (=O) -, C1-C15 alkyl-O- (C1-C8 alkylene) -, C1-C15 alkyl (O=) CO-, C2-C8 alkenyl, C2-C8 alkynyl, C6-C14 aryl C (=O) -, amino acid acyl, C1-C8 alkyl-C (=O) -CH=CH-; r is as described above ¹ 、R ² The groups are optionally substituted with 1-5 groups selected from the group consisting of: C6-C14 aryl, (C1-C8 alkyl) ₃ Amino, hydroxy, halogen, amino of one or two C1-C8 alkyl substituents, oxo (=o), C1-C8 alkyl;

y2 is N or C-R ^2a The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^2a Selected from the group consisting of: H. d, halogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl; r is as described above ^2a The groups are optionally substituted with 1-5 groups selected from the group consisting of: D. halogen, hydroxy, amino of one or two C1-C8 alkyl substituents, cyano, NH ₂ C (=O) -, C1-C8 alkyl ；

Y3 is N or C-R ^3a The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^3a Selected from the group consisting of: H. d, halogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, 5-14 membered heteroaryl, C3-C14 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclyl, NH ₂ CO-, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, hydroxy-substituted C1-C8 alkyl, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano cyano-substituted C1-C8 alkyl, -COOH, - (C1-C8 alkyl) -COOH, -C (=o) O- (C1-C8 alkyl), -C1-C8 alkyl) -C (=o) O- (C1-C8 alkyl), -OC (=o) H, - (C1-C8 alkyl) -OC (=o) - (C1-C8 alkyl), -C (=o) H, - (C1-C8 alkyl) -C (=o) H, -C (=o) - (C1-C8 alkyl), -C (=c-C8 alkyl), -C1-C8 alkyl) -C (=o) - (C1-C8 alkyl), NH (NH) ₂ C (=o) (C1-C8 alkyl) -, (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) N-C (=o) -, (C1-C8 alkyl) -NHC (=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) N-C (=o) - (C1-C8 alkyl) -, HC (=o) NH-, HC (=o) N (C1-C8 alkyl) -, (C1-C8 alkyl) -C (=o) NH-, (C1-C8 alkyl) -C (=o) N (C1-C8 alkyl) -, (5-14 membered heteroaryl) -NHC (=o) -; wherein R is ^3a Optionally by 0-5R ^3a1 Substitution;

each R is ^3a1 Independently at each occurrence selected from: C1-C8 alkyl, oxo (=O), C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, 3-14 membered heterocyclyl-C (=O) -, C3-C14 cycloalkyl, 5-14 membered heteroaryl, H, D, halogen, haloC 1-C8 alkyl, haloC 1-C8 alkoxy, haloC 2-C8 alkenyl, C2-C8 alkenyloxy, haloC 2-C8 alkynyl, C2-C8 alkynyloxy, haloC 2-C8 alkynyloxy, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) oxy, (C3-C14 cycloalkyl) - (C1-C8 alkyl) oxy, (C3-C14 cycloalkyl) oxy (C1-C8 alkyl) -, (C3-C14 cycloalkyl) thio, (C3-C14 cycloalkyl) - (C1-C8 alkyl) thio, (C1-C8 cycloalkyl) thio, (C1-C8 cycloalkyl) thio-, (C3-C14 cycloalkyl) NH-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -NH-, (C3-C14 cycloalkyl) -NH- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) -, (C3-C14 cycloalkyl) C (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) O-, (C3-C14 cycloalkyl) -C (=o) O- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -OC (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) -, (C1-C14 cycloalkyl) -NH-, (C1-C8 cycloalkyl) - (C3-C14 cycloalkyl) -C (=o) NH- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -NHC (=o) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, hydroxy (C3-C14 cycloalkyl) -, (C1-C8 alkoxy) - (C3-C14 cycloalkyl) -, hydroxy (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C3-C14 cycloalkyl) -, mercapto (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, amino (C3-C14 cycloalkyl), (C1-C8 alkyl) NH- (C3-C14 cycloalkyl) -, amino (C1-C8 alkyl) - (C14 cycloalkyl) -, HC (=o) - (C3-C14 cycloalkyl) -, (C1-C14 cycloalkyl) -, mercapto) C1-C14 cycloalkyl) - HC (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) O- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) O- (C3-C14 cycloalkyl) -, HC (=o) O- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HOC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -O-C (=o) - (C3-C14 cycloalkyl) -, HO-C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) NH- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) C (=o) NH- (C3-C14 cycloalkyl) -, HC (=o) NH- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) NHC (=o) - (C3-C14 cycloalkyl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) oxy, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -oxy, (3-14 membered heterocyclyl) oxy- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) thio, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -thio, (3-14 membered heterocyclyl) thio- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (3-14 membered heterocyclyl) (C1-C8 alkyl) NH-, (3-14 membered heterocycylCyclic group) -NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) -, (3-14 membered heterocyclyl) -C (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) O-, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) O-, (3-14 membered heterocyclyl) -C (=o) O- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -OC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -OC (=o) -, (3-14 membered heterocyclyl) -OC (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) NH-, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) NH-, (3-14 membered heterocyclyl) -C (=o) NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -OC (=o) -, nhj (3-14 membered heterocyclyl) - (C1-C8 alkyl) -NHC (=o) -, (3-14 membered heterocyclyl) -NHC (=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, (C1-C8 alkoxy) - (3-14 membered heterocyclyl) -, hydroxy (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (3-14 membered heterocyclyl) -, mercapto (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, amino (3-14 membered heterocyclyl), (C1-C8 alkyl) NH- (3-14 membered heterocyclyl) -, amino (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) - (3-14 membered heterocyclyl), HC (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) - (C1-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl) -, HC (=c 1-14 membered alkyl) -, HC) -, 3-14 membered heterocyclyl), (C1-C8 alkyl) -C (=o) O- (3-14 membered heterocyclyl) -, HC (=o) O- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HOC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -O-C (=o) - (3-14 membered heterocyclyl) -, HO-C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) NH- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) C (=o) NH- (3-14 membered heterocyclyl) -, HC (=o) NH- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) NHC (=o) - (3-14 membered heterocyclyl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (C6-C14 aryl) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -NH-, (C6-C14 aryl) -NH- (C1-C8 alkyl) -, (C6-C14 aryl) oxy (C1-C8 alkyl) -, (C6-C14 aryl) thio, (C6-C14 aryl) - (C1-C8 alkyl) thio, (C6-C14 aryl) thio (C1-C8 alkyl) -, (C6-C14 aryl) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -NH-, (C6-C14 aryl) -NH- (C1-C8 alkyl) -, (C6-C14 aryl) -C (=O) -, (C6-C14 aryl) - (C1-C8 alkyl) --, (C6-C14 aryl) C (=o) - (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) O-, (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) O-, (C6-C14 aryl) -C (=o) O- (C1-C8 alkyl) -, (C6-C14 aryl) -OC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -OC (=o) -, (C6-C14 aryl) -OC (=o) - (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) NH-, (C6-C14 aryl) - (C (=o) NH-, (C6-C14 aryl) -C (=o) NH- (C1-C8 alkyl) -, (C6-C14 aryl) -NHC (=o) -, (C6-C14 aryl) - (C (=c 8 alkyl) -NHC) -, (C6-C14 aryl) -NHC (=o) -, and (C6-C14 aryl) -NHC (=c 8 alkyl) - (C1-C8 alkyl) - (C6-C14 aryl) -, hydroxy (C6-C14 aryl) -, (C1-C8 alkoxy) - (C6-C14 aryl) -, hydroxy (C1-C8 alkyl) - (C6-C14 aryl) -, mercapto (C3-C14 cycloalkyl) -, (C1-C8 alkylthio) - (C6-C14 aryl) -, mercapto (C1-C8 alkyl) - (C6-C14 aryl) -, amino (C6-C14 aryl) -, (C1-C8 alkyl) NH- (C6-C14 aryl) -, amino (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) -C (=o) - (C6-C14 aryl) -, HC (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) O- (C6-C14 aryl) -, (C1-C8 alkyl) -C (=o) - (C6-C14 aryl) -, HC (=c 6-C14 aryl) -, HC (=o) - (C6-C14 aryl) -, HC (=c 1-C14 aryl) -, HC (=c 6-C14 aryl) -, HC) - (C1-C8 alkyl) -O-C (=o) - (C6-C14 aryl) -, HO-C (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) NH- (C6-C14 aryl) -, (C1-C8 alkyl) C (=o) NH- (C6-C14 aryl) -, HC (=o) NH- (C1-C8 alkyl) - (C6-C14 aryl) -, NH ₂ C (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) NHC (=o) - (C6-C14 aryl) -, NH ₂ C (=o) - (C1-C8 alkyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, (C1-C8 alkyl) - (C6-C14 aryl) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -oxy, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) oxy (C1-C8 alkyl) -, (5-14 membered heteroaryl) thio, (5-14 membered heteroaryl) - (C1-C8 alkyl) thio, (5-14 membered heteroaryl) thio (C1-C8 alkyl) -, (5-14 membered heteroaryl) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NH-, (5-14 membered heteroaryl) -NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) -, (5-14 membered heteroaryl) - (C (=o) -, (C1-C8 alkyl) - (-O) -) (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) O-, (5-14 membered heteroaryl) -C (=o)O- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -OC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -OC (=o) -, (5-14 membered heteroaryl) -OC (=o) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) NH-, (5-14 membered heteroaryl) -C (=o) NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -NHC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) -, hydroxy (5-14 membered heteroaryl) -, (C1-C8 alkoxy) - (5-14 membered heteroaryl), hydroxy (C1-C8 alkyl) - (5-14 membered heteroaryl), mercapto (C3-cycloalkyl), (C1-C8 alkylthio) - (5-14 membered heteroaryl) -, mercapto (C1-C8 alkyl) - (5-14 membered heteroaryl) -, amino (5-14 membered heteroaryl) -, (C1-C8 alkyl) NH- (5-14 membered heteroaryl) -, amino (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) - (5-14 membered heteroaryl) -, HC (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) O- (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) O- (5-14 membered heteroaryl) -, HC (=o) O- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HOC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -O-C (=o) - (5-14 membered heteroaryl) -, HO-C (=o) - (C1-8 alkyl) - (5-14 membered heteroaryl) - HC (=o) NH- (5-14 membered heteroaryl) -, (C1-C8 alkyl) C (=o) NH- (5-14 membered heteroaryl) -, HC (=o) NH- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, NH ₂ C (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) NHC (=o) - (5-14 membered heteroaryl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) - (C1-C8 alkyl) -, hydroxy-substituted C1-C8 alkyl, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano-substituted C1-C8 alkyl, -COOH- (C1-C8 alkyl) -COOH, -C (=o) O- (C1-C8 alkyl), - (C1-C8 alkyl) -C (=o) O- (C1-C8 alkyl), -OC (=o) H, - (C1-C8 alkyl) -OC (=o) H, -OC (=o) - (C1-C8 alkyl), - (C1-C8 alkyl) -OC (=o) - (C1-C8 alkyl), -C (O) H, - (C1-C8 alkyl) -C (=o) H, -C (=o) - (C1-C8 alkyl), - (C1-C8 alkyl) -C (=o) - (C1-C8 alkyl), NH (NH) ₂ C (=o) -, (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) N-C (=o) -, (C1-C8 alkyl) -NHC(=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) N-C (=o) - (C1-C8 alkyl) -, HC (=o) NH-, HC (=o) N (C1-C8 alkyl) -, (C1-C8 alkyl) -C (=o) NH-, (C1-C8 alkyl) -C (=o) N (C1-C8 alkyl) -, thio (=s); wherein R is ^3a1 Optionally by 0-5R ^3a2 Substitution;

each R is ^3a2 Independently at each occurrence selected from: -CN, (C6-C14 aryl) - (C1-C8 alkyl) oxy, amino, hydroxy, halo C1-C8 alkyl, C1-C8 alkoxy, -N (C1-C8 alkyl), C1-C8 alkyl, oxo (=o), -NH (C1-C8 alkyl), NH ₂ CO-, C1-C8 alkoxy-substituted C1-C8 alkoxy, C1-C14 alkyl OC (=O) -, C1-C14 alkyl C (=O) -, C3-C14 cycloalkyloxy, C1-C8 alkyl-substituted 3-14 heterocyclyl, H, D, halogen, halogenated C1-C8 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) oxy, (C3-C14 cycloalkyl) oxy (C1-C8 alkyl) -, (C3-C14 cycloalkyl) thio, (C3-C14 cycloalkyl) - (C1-C8 cycloalkyl) thio, (C1-C8 cycloalkyl) - (C1-C8 cycloalkyl) thio, (C3-C14 cycloalkyl) - (C1-C14 cycloalkyl) -, (C3-C14 cycloalkyl) -, C1-C14 cycloalkyl- (C1-C14 cycloalkyl) oxy (C1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) -, (C3-C14 cycloalkyl) -C (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) O-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) O-, (C3-C14 cycloalkyl) -C (=o) O- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -OC (=o) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -OC (=o) -, (C3-C14 cycloalkyl) -OC (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) NH-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) NH-, (C3-C14 cycloalkyl) -C (=o) NH- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -NHC (=o) -, (C3-C14 cycloalkyl) - (C (=c 1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -NHC (=O) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, hydroxy (C3-C14 cycloalkyl) -, (C1-C8 alkoxy) - (C3-C14 cycloalkyl) -, hydroxy (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C3-C14 cycloalkyl) -, mercapto (C1- C8 alkyl) - (C3-C14 cycloalkyl) -, amino (C3-C14 cycloalkyl), (C1-C8 alkyl) NH- (C3-C14 cycloalkyl) -, amino (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) - (C3-C14 cycloalkyl) -, HC (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) O- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) O- (C3-C14 cycloalkyl) -, HC (=o) O- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HOC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -O-C (=o) - (C3-C14 cycloalkyl) -, HO-C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) O- (C3-C14 cycloalkyl) -, HC (=o) NH- (C3-C14 cycloalkyl) - (C1-C8 alkyl) C (=O) NH- (C3-C14 cycloalkyl) -, HC (=O) NH- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) NHC (=o) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, 3-14 membered heterocyclyl, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) oxy, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -oxy, (3-14 membered heterocyclyl) oxy- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) thio, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -thio, (3-14 membered heterocyclyl) thio- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (3-14 membered heterocyclyl) (C1-C8 alkyl) NH-, (3-14 membered heterocyclyl) -NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (C1-C8 alkyl) - (3-14 membered heterocyclyl) -C (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) O-, (3-14 membered heterocyclyl) -C (=o) O- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -OC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -OC (=o) -, (3-14 membered heterocyclyl) -OC (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) NH-, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) NH-, (3-14 membered heterocyclyl) -C (=o) NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -NHC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -NHC (=o) -, (3-14 membered heterocyclyl) -NHC (=o) - (C1-C8 alkyl) -, hydroxy (3-14 membered heterocyclyl), (C1-C8 alkoxy) - (3-14 membered heterocyclyl) -, hydroxy (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (3-14 membered heterocyclyl) -, mercapto (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, amino (3-14 membered heterocyclyl), (C1-C8 alkyl) ) NH- (3-14 membered heterocyclyl) -, amino (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) - (3-14 membered heterocyclyl) -, HC (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) O- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) O- (3-14 membered heterocyclyl) -, HC (=o) O- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HOC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -O-C (=o) - (3-14 membered heterocyclyl) -, HO-C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) NH- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) C (=o) NH- (3-14 membered heterocyclyl) -, and the like, HC (=O) NH- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) NHC (=o) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, C6-C14 aryl, (C6-C14 aryl) - (C1-C8 alkyl) -, (C6-C14 aryl) oxy (C1-C8 alkyl) -, (C6-C14 aryl) thio, (C6-C14 aryl) - (C1-C8 alkyl) thio, (C6-C14 aryl) thio (C1-C8 alkyl) -, (C6-C14 aryl) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -NH-, (C6-C14 aryl) -NH- (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) -, (C6-C14 aryl) - (C (=c 1-C8 alkyl) -, (C6-C14 aryl) -, (C1-C14 aryl) -, (C (=c 1-C8 alkyl) -) (C6-C14 aryl) -C (=o) O- (C1-C8 alkyl) -, (C6-C14 aryl) -OC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -OC (=o) -, (C6-C14 aryl) -OC (=o) - (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) NH-, (C6-C14 aryl) -C (=o) NH- (C1-C8 alkyl) -, (C6-C14 aryl) -NHC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -, (C1-C8 alkyl) - (C6-C14 aryl) -, hydroxy (C6-C14 aryl) -, (C1-C8 alkoxy) - (C6-C14 aryl) - (C1-C8 alkyl) -, hydroxy (C6-C14 cycloalkyl) -, 3-C6-C14 cycloalkyl) (C1-C8 alkylthio) - (C6-C14 aryl) -, mercapto (C1-C8 alkyl) - (C6-C14 aryl) -, amino (C6-C14 aryl), (C1-C8 alkyl) NH- (C6-C14 aryl) -, amino (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) - (C6-C14 aryl) -, (C1-C8 alkyl) -C (=O) - (C6-C14 aryl) -, HC (=O) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) O- (C6-C14 aryl) - Group) -, (C1-C8 alkyl) -C (=o) O- (C6-C14 aryl) -, HC (=o) O- (C1-C8 alkyl) - (C6-C14 aryl) -, HOC (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) -O-C (=o) - (C6-C14 aryl) -, HO-C (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=o) NH- (C6-C14 aryl) -, (C1-C8 alkyl) C (=o) NH- (C6-C14 aryl) -, HC (=o) NH- (C1-C8 alkyl) - (C14 aryl) -, NH ₂ C (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) NHC (=o) - (C6-C14 aryl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C6-C14 aryl) -, (C1-C8 alkyl) - (C6-C14 aryl) - (C1-C8 alkyl) -, 5-14 membered heteroaryl, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) oxy, (5-14 membered heteroaryl) - (C1-C8 alkyl) oxy, (5-14 membered heteroaryl) oxy (C1-C8 alkyl) -, (5-14 membered heteroaryl) thio, (5-14 membered heteroaryl) - (C1-C8 alkyl) thio, (5-14 membered heteroaryl) thio (C1-C8 alkyl) -, (5-14 membered heteroaryl) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NH-, (5-14 membered heteroaryl) -NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) -C (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) O-, (5-14 membered heteroaryl) -C (=o) O- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -OC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -OC (=o) -, (5-14 membered heteroaryl) -OC (=o) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) NH-, (5-14 membered heteroaryl) -C (=o) NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -NHC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, 5-14 membered heteroaryl) Hydroxy (5-14 membered heteroaryl) -, (C1-C8 alkoxy) - (5-14 membered heteroaryl) -, hydroxy (C1-C8 alkyl) - (5-14 membered heteroaryl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (5-14 membered heteroaryl) -, mercapto (C1-C8 alkyl) - (5-14 membered heteroaryl) -, amino (5-14 membered heteroaryl), (C1-C8 alkyl) NH- (5-14 membered heteroaryl) -, amino (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) - (5-14 membered heteroaryl) -, HC (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) O- (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) O- (5-14 membered heteroaryl) -, HC (=o) O- (C1-14 membered heteroaryl) - 1-C8 alkyl) - (5-14 membered heteroaryl) -, HOC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -O-C (=o) - (5-14 membered heteroaryl) -, HO-C (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) NH- (5-14 membered heteroaryl) -, (C1-C8 alkyl) C (=o) NH- (5-14 membered heteroaryl) -, HC (=o) NH- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, NH ₂ C (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) NHC (=o) - (5-14 membered heteroaryl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) - (C1-C8 alkyl) -, hydroxy-substituted C1-C8 alkyl, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, cyano-substituted C1-C8 alkyl, -COOH, - (C1-C8 alkyl) -C (=O) O- (C1-C8 alkyl), -OC (=O) H, - (C1-C8 alkyl) -OC (=O) H, -OC (=O) - (C1-C8 alkyl), -C (O) H, - (C1-C8 alkyl) -C (=O) - (C1-C8 alkyl), -C (O) H, -C (=O) - (C1-C8 alkyl), -C1-C8 alkyl) - (C (=O) - (C1-C8 alkyl), one or two C1-C8 alkyl-substituted NH ₂ C (O) -, one or two C1-C8 cycloalkyl-substituted NH ₂ C (O) -, NH substituted with one or two C6-C14 aryl groups ₂ C (O) -, one or two 5-14 membered heteroaryl substituted NH ₂ C (O) -, NH substituted with one or two 4-10 membered heterocyclic groups ₂ C(O)-、NH ₂ C (=O) - (C1-C8 alkyl) -, one or two C1-C8 alkyl substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two C1-C8 cycloalkyl-substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two C6-C14 aryl substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two 5-14 membered heteroaryl substituted NH ₂ C (O) - (C1-C8 alkyl) -, NH substituted with one or two 4-10 membered heterocyclic groups ₂ C (O) - (C1-C8 alkyl) -, thio (=s); r is as described above ^3a1 、R ^3a2 Optionally by 0-5R ^3a3 Substitution;

R ^3a4 selected from: H. d, halogen, C1-C8 alkyl,Hydroxy, hydroxy-substituted C1-C8 alkyl, halo-C1-C8 alkyl, C2-C8 alkenyl, halo-C2-C8 alkenyl, C2-C8 alkynyl, halo-C2-C8 alkynyl, (C1-C15 alkyl) -OC (=o) -, (C6-C14 aryl) -OC (=o) -, (4-12 membered heteroaryl) -OC (=o) -, (5-14 membered heteroaryl) -OC (=o) -, (C1-C15 alkyl) -C (=o) -, (C6-C14 aryl) -C (=o) -, (4-12 membered heterocyclyl) -C (=o) -, (5-14 membered heteroaryl) -C (=o) -, (halo-C (=c 1-15 alkyl) -OC (=o) -, (4-12 membered heterocyclyl) -OC (=o) -, and (C (=o) -, respectively) (halo 5-14 membered heteroaryl) -OC (=o) -, (halo C1-C15 alkyl) -C (=o) -, (halo C6-C14 aryl) -C (=o) -, (halo 4-12 membered heterocyclyl) -C (=o) -, (halo 5-14 membered heteroaryl) -C (=o) -, (C1-C8 alkyl) -OC (=o) -, C1-C15 alkyl) -OC (=o) -, C1-C8 alkyl-substituted (C6-C14 aryl) -OC (=o) -, C1-C8 alkyl-substituted (4-12 membered heterocyclyl) -OC (=o) -, C1-C8 alkyl-substituted (5-14 membered heteroaryl) -OC (=o) -, C1-C8 alkyl-C (=c 1-C8 alkyl) -C (=c 1-C15 alkyl) -OC (=o) -, C1-C8 alkyl-substituted (C (=c 1-C8 alkyl) - C1-C8 alkyl-substituted (4-12 membered heterocyclyl) -C (=O) -, C1-C8 alkyl-substituted (5-14 membered heteroaryl) -C (=O) -, C1-C8 alkyl-substituted (C1-C15 alkyl) -C (=O) O-, C1-C8 alkyl-substituted (C6-C14 aryl) -C (=O) O-, C1-C8 alkyl-substituted (4-12 membered heterocyclyl) -C (=O) O-, C1-C8 alkyl-substituted (5-14 membered heteroaryl) -C (=O) O-, C1-C8 alkyl- ₃ -Si- (C1-C8 alkyl) -O- (C1-C8 alkylene) -, halogen-substituted or unsubstituted (C1-C8 alkyl) -OC (=o) - (C1-C8 alkyl) C (=o) - (C3-C14 cycloalkyl) C (=o) -glycosyl, -O-P (=o) (O-halo or non-halo C6-C14 aryl) (NH- (C1-C8 alkyl) C (=o) O (C1-C8 alkyl)), -O-P (=o) (O-halo or non-halo C6-C14 aryl) (O- (C1-C8 alkyl) C (=o) O (C1-C8 alkyl)), -O-P (=o) (O-halo or non-halo C6-C14 aryl) (NH- (C1-C8 alkyl)), -O (=o) (O) halo or non-halo C6-C14 aryl) (NH- (C1-C8 alkyl)), -O (=o) (O) halo or non-halo (C1-C8 alkyl)), -O- (C1-C8 alkyl) O) - (C1-C8 alkyl)) -O-P (=o) (O-halogenated or non-halogenated C6-C14 aryl) (NH- (C1-C8 alkyl) -S-C (=o) (C1-C8 alkyl)), -O-P (=o) (O-halogenated or non-halogenated C6-C14 aryl) (O- (C1-C8 alkyl) -S-C (=o) (C1-C8 alkyl)), -O-P (=o) (ONa) ₂ 、-O-P(＝O)(OK) ₂ 、-O-P(＝O)(OLi) ₂ -O- (halogenated or non-halogenated C1-C8 alkyl) -P (=o) (O-C1-C8 alkyl) ₂ (C1-C8 alkyl) -C (=o) -ch=ch-, amino acid acyl, C1-C16 alkyl, halogenated C1-C16 alkyl, C6-C14 aryl, halogenated C6-C14 aryl;

wherein optionally two R' s ^3a1 Can form a 3-18 membered ring structure together with the atoms to which they are each attached;

Wherein optionally two R' s ^3a2 Can form a 3-18 membered ring structure together with the atoms to which they are each attached;

y4 is N or C-R ^4a ；R ^4a Selected from H, D, C-C6 alkyl, amino, halogen, -C (R) ^4b )＝C(R ^4c )-R ^4d 、-C(R ^4b )＝N-R ^4d 、-N＝C(R ^4c )-R ^4d 、-N＝N-R ^4d 、-C(R ^4e )(R ^4f )-R ^4d 、-C(＝O)-R ^4d 、-C(＝S)-R ^4d 、NR ^4e R ^4f 、NR ^4b C(＝O)R ^4d The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^4a Optionally by 0-5R ^4a1 Substituted, each R ^4a1 Independently at each occurrence selected from: halogen, C3-C6 cycloalkyl, C1-C6 alkyl C (=o) -;

alternatively, R ^2a 、R ^3a Together with the carbons to which they are each attached form from 0 to 5R ^b1 A substituted or unsubstituted 3-18 membered ring structure;

alternatively, R ^4a 、R ^3a Together with the carbons to which they are each attached form from 0 to 5R ^b2 A substituted or unsubstituted 3-18 membered ring structure,

each R is ^b1 Each R is ^b2 Independently at each occurrence selected from: H. d, halogen, oxo, thio, C1-C8 alkyl, hydroxyC 1-C8 alkyl, C1-C8 alkoxy, C3-C14 cycloalkyl, halogenated C1-C8 alkyl, halogenated hydroxyC 1-C6 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C14 cycloalkyl3-14 membered heterocyclyl, C6-C14 aryl, 5-14 membered heteroaryl, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy halogenated C2-C8 alkynyloxy, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano-substituted C1-C8 alkyl; alternatively, R ^b1 、R ^b2 Can be substituted with 0-5R ^b3 Substitution; r is R ^b3 Selected from the group consisting of: H. d, halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, hydroxyC 1-C8 alkyl, halogenated hydroxyC 1-C8 alkyl, mercapto, mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano-substituted C1-C8 alkyl, oxo, thio, (C1-C6 alkyl) 3-Si- (C1-C6 alkyl) -O- (C1-C6 alkylene) -, C1-C15 alkyl OC (O) -, (C1-C8 alkyl) -OC (O) - (C1-C8 alkyl) COO-, C1-C8 alkyl-C (O) -ch=ch-;

v4, V5 are each independently C or N;

m is independently selected from 1, 2, 3, 4 for each occurrence;

n is independently selected from 0, 1, 2, 3 for each occurrence;

u is from 1 to 5R ⁱ Substituted or unsubstituted groups of the following groups: C5-C14 membered aryl, 5-C14 membered heteroaryl, C3-C14 cycloalkyl, 3-C14 membered heterocyclyl; each R is ⁱ Independently at each occurrence selected from: halogenated C1-C8 alkyl, halogen, C6-C14 aryl, benzo 5-14 membered heteroaryl, halogenated C1-C8 alkoxy, H, D, C-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, hydroxy-substituted C1-C8 alkyl, mercapto mercapto-substituted C1-C8 alkyl, amino-substituted C1-C8 alkyl, -NH (C1-C8 alkyl), -N (C1-C8 alkyl), cyano-substituted C1-C8 alkyl, -COOH, - (C1-C8 alkyl) -COOH, -C (=o) O- (C1-C8 alkyl), -C1-C8 alkyl) -C (=o) O- (C1-C8 alkyl), -OC (=o) H, - (C1-C8 alkyl) -OC (=o) H, -OC (=o) - (C1-C8 alkyl), -OC (=o) - (C1-C8 alkyl), -C (=o) H, - (C1-C8 alkyl) -C (=O) H, -C (=O) - (C1-C8 alkyl), - (C1-C8 alkyl) -C (=O) - (C1-C8 alkyl), NH ₂ C(＝O)-、NH ₂ C (=o) (C1-C8 alkyl) -, (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) N-C (=o) -, (C1-C8 alkyl) -NHC (=o) - (C1-C8 alkyl) -, (C1-C8 alkyl) N-C (=o) - (C1-C8 alkyl) -, HC (=o) NH-, HC (=o) N (C1-C8 alkyl) -, (C1-C8 alkyl) -C (=o) NH-, (C1-C8 alkyl) -C (=o) N (C1-C8 alkyl) -, oxo (=o), thio (=s); wherein R is ⁱ Optionally by 0-5R ⁱ¹ Substitution;

each R is ⁱ¹ Independent at each occurrenceIs selected from: H. d, halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) oxy (C3-C14 cycloalkyl) - (C1-C8 alkyl) oxy, (C3-C14 cycloalkyl) oxy (C1-C8 alkyl) -, (C3-C14 cycloalkyl) thio, (C3-C14 cycloalkyl) - (C1-C8 alkyl) thio, (C3-C14 cycloalkyl) thio (C1-C8 alkyl) -, (C3-C14 cycloalkyl) NH-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -NH-, (C3-C14 cycloalkyl) -NH- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=O) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=O) -, (C3-C14 cycloalkyl) C (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) O-, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -C (=o) O-, (C3-C14 cycloalkyl) -C (=o) O- (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -OC (=o) -, (C3-C14 cycloalkyl) - (C1-C8 alkyl) -OC (=o) -, (C3-C14 cycloalkyl) -OC (=o) - (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -C (=o) NH-, (C3-C14 cycloalkyl) - (C (=o) NH-, (C1-C8 alkyl) -, (C3-C14 cycloalkyl) -NHC (=o) -, (C3-C14 cycloalkyl) - (C (=c) -, (C1-C8 alkyl) -NHC (=o) -, (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -NHC (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, hydroxy (C3-C14 cycloalkyl) -, (C1-C8 alkoxy) - (C3-C14 cycloalkyl) -, hydroxy (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, mercapto (C3-C14 cycloalkyl) -, (C1-C8 alkylthio) - (C3-C14 cycloalkyl) -, mercapto (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, amino (C3-C14 cycloalkyl), (C1-C8 alkyl) NH- (C3-C14 cycloalkyl) -, amino (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) - (C3-C14 cycloalkyl) -, HC (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) O- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -C (=o) - (C3-C14 cycloalkyl) -, HC (=c 1-C14 cycloalkyl) -, HC (=o) - (C1-C14 cycloalkyl) - HOC (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -O-C (=o) - (C3-C14 cycloalkyl) -, HO-C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, HC (=o) NH- (C3-C14 cycloalkyl) -, (C1-C8 alkyl) C (=o) NH- (C3-C14 cycloalkyl) -, H C (=O) NH- (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) NHC (=o) - (C3-C14 cycloalkyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (C3-C14 cycloalkyl) -, (C1-C8 alkyl) - (C3-C14 cycloalkyl) - (C1-C8 alkyl) -, 3-14 membered heterocyclyl, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) oxy, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -oxy, (3-14 membered heterocyclyl) oxy- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) thio, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -thio, (3-14 membered heterocyclyl) thio- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (3-14 membered heterocyclyl) (C1-C8 alkyl) NH-, (3-14 membered heterocyclyl) -NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) NH-, (C1-C8 alkyl) - (3-14 membered heterocyclyl) -C (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) O-, (3-14 membered heterocyclyl) -C (=o) O- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -OC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -OC (=o) -, (3-14 membered heterocyclyl) -OC (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -C (=o) NH-, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -C (=o) NH-, (3-14 membered heterocyclyl) -C (=o) NH- (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -NHC (=o) -, (3-14 membered heterocyclyl) - (C1-C8 alkyl) -NHC (=o) -, (3-14 membered heterocyclyl) -NHC (=o) - (C1-C8 alkyl) -, (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -, 3-14 membered heterocyclyl) Hydroxy (3-14 membered heterocyclyl) -, (C1-C8 alkoxy) - (3-14 membered heterocyclyl) -, hydroxy (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (3-14 membered heterocyclyl) -, mercapto (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, amino (3-14 membered heterocyclyl), (C1-C8 alkyl) NH- (3-14 membered heterocyclyl) -, amino (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) - (3-14 membered heterocyclyl) -, HC (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) O- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) -C (=o) O- (3-14 membered heterocyclyl) -, HC (=o) O- (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=o) - (3-14 membered heterocyclyl), (C1-C8 alkyl) -O-C (=O) - (3-14 membered heterocyclyl) -, HO-C (=O) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, HC (=O) NH- (3-14 membered heterocyclyl) -, (C1-C8 alkyl) C (=O) NH- (3-14 membered heterocyclyl) -, HC (=O) NH- (C1-C8 alkyl) Group) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) NHC (=o) - (3-14 membered heterocyclyl) -, NH ₂ C (=o) - (C1-C8 alkyl) - (3-14 membered heterocyclyl) -, (C1-C8 alkyl) - (3-14 membered heterocyclyl) - (C1-C8 alkyl) -, (C6-C14 aryl) -oxy, (C6-C14 aryl) - (C1-C8 alkyl) oxy, (C6-C14 aryl) oxy (C1-C8 alkyl) -, (C6-C14 aryl) thio, (C6-C14 aryl) - (C1-C8 alkyl) thio, (C6-C14 aryl) thio (C1-C8 alkyl) -, (C6-C14 aryl) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -NH-, (C6-C14 aryl) -NH- (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -, (C (=o) -, (C6-C14 aryl) -, (C1-C8 alkyl) - (-C1-C8 alkyl) -) (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) O-, (C6-C14 aryl) -C (=o) O- (C1-C8 alkyl) -, (C6-C14 aryl) -OC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -OC (=o) -, (C6-C14 aryl) -OC (=o) - (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) NH-, (C6-C14 aryl) - (C1-C8 alkyl) -C (=o) NH-, (C6-C14 aryl) -C (=o) NH- (C1-C8 alkyl) -, (C6-C14 aryl) -NHC (=o) -, (C6-C14 aryl) - (C1-C8 alkyl) -NHC (=o) -, (C1-C8 alkyl) - (C (=c 6-C14 aryl) -, (C1-C8 alkoxy) -, (C1-C8 aryl) - Hydroxy (C1-C8 alkyl) - (C6-C14 aryl) -, mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (C6-C14 aryl) -, mercapto (C1-C8 alkyl) - (C6-C14 aryl) -, amino (C6-C14 aryl) -, (C1-C8 alkyl) NH- (C6-C14 aryl) -, amino (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) - (C6-C14 aryl) -, (C1-C8 alkyl) -C (=O) - (C6-C14 aryl) -, HC (=O) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) O- (C6-C14 aryl) -, (C1-C8 alkyl) -C (=O) O- (C6-C14 aryl) -, HC (=O) O- (C1-C8 alkyl) - (C6-C14 aryl) -, HOC (=O) - (C6-C14 aryl) -, HC (=C 1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) - (C6-C14 aryl) - HO-C (=O) - (C1-C8 alkyl) - (C6-C14 aryl) -, HC (=O) NH- (C6-C14 aryl) -, (C1-C8 alkyl) C (=O) NH- (C6-C14 aryl) -, HC (=O) NH- (C1-C8 alkyl) - (C6-C14 aryl) -, NH ₂ C (=o) - (C6-C14 aryl) -, (C1-C8 alkyl) NHC (=o) - (C6-C14 aryl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (C6-C14 aryl) -, (C1-C8 alkyl) - (C6-C14 aryl) - (C1-C8 alkyl) -)5-14 membered heteroaryl, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) oxy, (5-14 membered heteroaryl) - (C1-C8 alkyl) oxy, (5-14 membered heteroaryl) oxy (C1-C8 alkyl) -, (5-14 membered heteroaryl) thio, (5-14 membered heteroaryl) - (C1-C8 alkyl) thio, (5-14 membered heteroaryl) thio (C1-C8 alkyl) -, (5-14 membered heteroaryl) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -NH-, (5-14 membered heteroaryl) -NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) -, (5-14 membered heteroaryl) - (C (=o) -, (5-14 membered heteroaryl) C (=o) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) -, (5-14) heteroaryl) -C (=o) -, C1-C8 alkyl) -, C (=o) -, C (=c 1-8) heteroaryl) -, C (=o) -, C (=c 1-8) alkyl) -, C (=c (=o) -, C (=c 1-8) and C (=c 8) (5-14 membered heteroaryl) -C (=o) O- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -OC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -OC (=o) -, (5-14 membered heteroaryl) -OC (=o) - (C1-C8 alkyl) -, (5-14 membered heteroaryl) -C (=o) NH-, (5-14 membered heteroaryl) - (C1-C8 alkyl) -C (=o) NH-, (5-14 membered heteroaryl) -C (=o) NH- (C1-C8 alkyl) -, (5-14 membered heteroaryl) -NHC (=o) -, (5-14 membered heteroaryl) - (C1-C8 alkyl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl), hydroxy (5-14 membered heteroaryl) -, (C1-C8 alkoxy) - (5-14 membered heteroaryl) - (C1-C8 alkyl) -, hydroxy (C1-C8 alkyl) - Mercapto (C3-C14 cycloalkyl), (C1-C8 alkylthio) - (5-14 membered heteroaryl) -, mercapto (C1-C8 alkyl) - (5-14 membered heteroaryl) -, amino (5-14 membered heteroaryl), (C1-C8 alkyl) NH- (5-14 membered heteroaryl) -, amino (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) - (5-14 membered heteroaryl) -, HC (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) O- (5-14 membered heteroaryl) -, (C1-C8 alkyl) -C (=o) O- (5-14 membered heteroaryl) -, HC (=o) O- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HOC (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) -O (=o) - (5-14 membered heteroaryl) -, HC (=o) - (5-14 membered heteroaryl) - HO-C (=O) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=O) NH- (5-14 membered heteroaryl) -, (C1-C8 alkyl) C (=O) NH- (5-14 membered heteroaryl) -, HC (=O) NH- (C1-C8 alkyl) - (5-14 membered heteroaryl) -, NH ₂ C (=o) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) NHC (=o) - (5-14 membered heteroaryl) -, NH ₂ C (=O) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, (C1-C8 alkyl) - (5-14 membered heteroaryl) - (C1-C8 alkyl) -, -COOH, - (C1-C8 alkyl) -COOH, -C (=o) O- (C1-C8 alkyl), - (C1-C8 alkyl) -C (=o) O- (C1-C8 alkyl), -OC (=o) H, - (C1-C8 alkyl) -OC (=o) H, -OC (=o) - (C1-C8 alkyl), - (C1-C8 alkyl) -OC (=o) - (C1-C8 alkyl), -C (O) H, - (C1-C8 alkyl) -C (=o) H, -C (=o) - (C1-C8 alkyl), - (C1-C8 alkyl) -C (=o) - (C1-C8 alkyl), NH ₂ C (=O) -, one or two C1-C8 alkyl-substituted NH ₂ C (O) -, one or two C1-C8 cycloalkyl-substituted NH ₂ C (O) -, NH substituted with one or two C6-C14 aryl groups ₂ C (O) -, one or two 5-14 membered heteroaryl substituted NH ₂ C (O) -, NH substituted with one or two 4-10 membered heterocyclic groups ₂ C(O)-、NH ₂ C (=O) - (C1-C8 alkyl) -, one or two C1-C8 alkyl substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two C1-C8 cycloalkyl-substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two C6-C14 aryl substituted NH ₂ C (O) - (C1-C8 alkyl) -, one or two 5-14 membered heteroaryl substituted NH ₂ C (O) - (C1-C8 alkyl) -, NH substituted with one or two 4-10 membered heterocyclic groups ₂ C (O) - (C1-C8 alkyl) -, oxo (=o), thio (=s), (C1-C6 alkyl) 3-Si- (C1-C6 alkyl) -O- (C1-C6 alkylene) -, C1-C15 alkyl OC (O) -, (C1-C8 alkyl) -OC (O) - (C1-C8 alkyl) COO-, C1-C8 alkyl-C (O) -ch=ch-;

R ^f 、R ^g independently at each occurrence selected from the group consisting of: H. d, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy。

2. The compound according to claim 1, or a stereoisomer, enantiomer, diastereomer, atrop, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, prodrug thereof, hydrate or solvate thereof, isotopically labeled compound thereof, wherein the compound is selected from the group consisting of compounds represented by formula (II), formula (III) and formula (IV):

Wherein R is ¹ 、R ² 、R ^2a 、R ^3a 、R ^4a The definitions of Y2, Y3, Y4, V1, V2, V3, L, U and the dotted lines are as defined in claim 1.

3. The compound according to claim 1, or a stereoisomer, enantiomer, diastereomer, atrop, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, prodrug thereof, hydrate or solvate thereof, isotopically labeled compound thereof, wherein the compound is selected from the group consisting of compounds represented by formula (V) and formula (VI):

wherein Y2, Y3, V1, V2, V3, L, U, R ^4a The definition of the dotted line is as defined in claim 1;

R ^1b 、R ^1c independently at each occurrence selected from: H. d, halogen, -NH (CH) ₃ ) C1-C6 alkyl CONH-, C1-C6 alkyl OC (O) NH-, -NH ₂ (C1-C8 alkyl) ₃ Si- (C1-C8 alkyl) O (C1-C8 alkyl) NH-, C6-C14 aryl (C1-C8 alkyl) OC (O) NH-, C6-C14 aryl C (O) NH-, -NH (C2-C8 alkenyl), said groups optionally being substituted with 1-5 groups selected from the group consisting of: amino, hydroxy, C1-C8 alkyl, oxygenSubstitution;

R ^4e 、R ^4f Is defined as in claim 1.

4. A compound of formula (I) or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, prodrug thereof, hydrate or solvate thereof, isotopically-labeled compound thereof according to any one of claims 1 to 3, wherein: z is O; w is absent and ring G is a five membered heterocycle or five membered heteroaryl; l is "- (CH) ₂ ) - "or- (CH) ₂ CH ₂ ) -; u is selected from the group consisting of 1-5R ⁱ Substituted or unsubstituted phenyl, 5-6 membered heteroaryl ring, C3-C8 cycloalkyl; r is R ⁱ Is defined as in claim 1.

5. A compound according to any one of claims 1-4, or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, prodrug thereof, hydrate or solvate thereof, isotopically labeled compound thereof, wherein the compound is selected from the group consisting of:

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6. a process for preparing the compound of claim 1, comprising at least one of formula 1, formula 2, or formula 3:

[ reaction type 1]

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[ reaction type 3]

In the reaction formulae 1, 2 and 3,

R ^6a selected from the group consisting of

-O-R ⁶ⁱ Halogen, C1-C12 alkyl, -SO ₃ H，-SO ₃ Na，-OB(OH) ₂ ，-B(OH) ₂ ；

R ^6b Selected from-OH, halogen, -OC (=O) -R ⁶ⁱ ，-OS(＝O)-R ⁶ⁱ ，-OS(＝O)2-R ⁶ⁱ ；

R ^6c Selected from the group consisting of-L-U, -L-X, -L-Mg-X, -L-OH, -L-O-R ⁶ⁱ ，-L-R ⁶ⁱ ；

R ^6d Selected from-CN, halogen, -NO ₂ ，-CONR ⁶ⁱ R ^6j ，-COOR ⁶ⁱ ；

R ^6e ，R ^6f Independently at each occurrence selected from H, -C (=O) -L-U, -C (=O) -L-X, -C (=O) -L-Mg-X, -C (=O) -L-OH, -C (=O) -L-O-R ⁶ⁱ ，-C(＝O)-L-R ⁶ⁱ ；

R ^6g 、R ^6h Selected from halogen, -Mg-X, -Li, -Na, -K, -B (OH) ₂ 4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl or other boron-containing substituents;

R ⁶ⁱ 、R ^6j At each occurrence independently H, D, C C8 alkyl, C1C 8 alkoxy, C6C 14 aryl, C6C 14 aryloxy;

Y1、Y2、Y3、Y4、V1、V2、V3、V4、V5、W、X1、X2、Z、R ^3a the definition of the dashed line is as defined in claim 1.

7. The method for producing a compound according to claim 1, wherein the production method is selected from the following schemes one to six:

scheme one:

hydrogenating and reducing RX-1c to obtain RX-1d;

condensing RX-1d with carboxylic acid RX-1e to obtain a compound shown as RX-1;

scheme II:

condensing RX-2a with RX-1e to obtain RX-2b;

hydrolyzing the cyano group of RX-2d to obtain RX-2e;

carrying out Hoffman degradation reaction on RX-2e to obtain RX-2f;

scheme III:

RX-3d is subjected to Curtius rearrangement reaction to obtain RX-3e;

carrying out reduction reaction on RX-3e to obtain RX-3f;

amide condensing RX-3f with the corresponding carboxylic acid to give RX-3g;

scheme IV:

introducing an amino group of RX-2d into a substituent to obtain RX-4a;

scheme five:

carrying out substitution reaction on RX-5a and RX-3c to obtain RX-5b;

removing protecting groups from RX-5b to obtain RX-5c;

reducing RX-5c to obtain RX-5d;

amide condensing RX-5d with the corresponding carboxylic acid to obtain RX-5;

scheme six:

performing substitution reaction on RX-6a and RX-3c to obtain RX-6b;

hydrolyzing the cyano group of RX-6b to obtain RX-6c;

RX-6d is obtained by the Curtius rearrangement reaction of RX-6c;

reducing RX-6d to obtain RX-6e;

Y1、Y2、Y3、Y4、V1、V2、V3、V4、V5、W、X1、X2、L、U、R ^3a the definition of the dotted line is as defined in claim 1;

x is independently selected from the following group at each occurrence: F. cl, br, I.

8. A pharmaceutical composition comprising:

A pharmaceutically acceptable carrier; and

one or more compounds according to any one of claims 1 to 5 or stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labeled compounds thereof.

9. Use of a compound according to any one of claims 1-5, or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, an isotopically labeled compound thereof or a pharmaceutical composition according to claim 8, for the preparation of a medicament for:

1) Detecting and/or preventing and/or treating a kinase-associated disease;

2) Detecting and/or preventing and/or treating immune, inflammatory and/or infection-related diseases;

3) Detecting and/or preventing and/or treating ischemia and/or reperfusion injury related diseases;

4) Detecting and/or preventing and/or treating a degenerative disease;

5) Detecting and/or preventing and/or treating a tumor-associated disease;

6) Detecting and/or preventing and/or treating a disease associated with cell necrosis;

7) Detecting and/or preventing and/or treating a metabolic-related disorder; or (b)

8) Detecting and/or preventing and/or treating ocular diseases.

10. Use of a compound according to any one of claims 1 to 5, or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, prodrug thereof, hydrate or solvate thereof, isotopically labeled compound thereof, or a pharmaceutical composition according to claim 8, for:

1) Detecting and/or preventing and/or treating a kinase-associated disease;

2) Detecting and/or preventing and/or treating inflammation and/or infection related disorders;

4) Detecting and/or preventing and/or treating a degenerative disease;

5) Detecting and/or preventing and/or treating a tumor-associated disease;

7) Detecting and/or preventing and/or treating metabolic diseases;

8) Detecting and/or preventing and/or treating an ocular disease;

Such diseases include, but are not limited to, the following: