CN116478150A

CN116478150A - Compounds having RIPK1 inhibiting activity, preparation method and use thereof

Info

Publication number: CN116478150A
Application number: CN202211688025.6A
Authority: CN
Inventors: 段文虎; 耿美玉; 张贺峰; 艾菁; 兰垚瀚; 戴阳; 金泽宸; 彭霞; 方晨; 季寅淳; 冯大智
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2022-01-21
Filing date: 2022-12-27
Publication date: 2023-07-25
Also published as: WO2023138317A1

Abstract

The invention discloses a compound with RIPK1 inhibitory activity, a preparation method and application thereof, wherein the structure of the compound is shown in a general formula I, and the definition of each substituent is shown in the specification and the claims. The compounds of the present invention can be used for the treatment of inflammatory diseases, ischemic diseases, neurodegenerative diseases, tumors and other conditions and diseases associated with receptor-interacting protein kinase 1.

Description

Compounds having RIPK1 inhibiting activity, preparation method and use thereof

Technical Field

The invention relates to a compound with receptor interaction protein kinase 1 inhibitory activity, a preparation method and application thereof, in particular to a series of compounds or a pharmaceutical composition containing the series of compounds and application of a therapeutic agent in treating inflammatory diseases, ischemic diseases, neurodegenerative diseases, tumors and other diseases related to the receptor interaction protein kinase 1.

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 (RIPK 1) and RIPK3 are two classes of serine/threonine kinases that are homologous and 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, better physicochemical properties, more potent drug effects, 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

It is an object of the present invention to provide RIPK1 kinase inhibitors.

In a first aspect of the present invention there is provided 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-labelled compound thereof,

Wherein Cy ¹ Selected from the group consisting of:

R ⁵ independently at each occurrence selected from: H. d, halogen, CD ₃ C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, cyano, amino, C1-C8 alkyl substituted amino, hydroxy, mercapto, C1-C8 alkylthio;

Cy ² selected from the group consisting of 0-5R ⁸ The substituted following groups: C3-C14 cycloalkyl, C6-C14 aryl, 6-14 heteroaryl, or 3-14 heterocyclyl;

R ⁴ independently at each occurrence selected from: H. d, CH ₃ 、CD ₃ ；

Each dotted line independently represents a single bond or a double bond;

Z ¹ selected from: o, S, N, CR ^z1 、C＝O、SO、SO ₂ 、NH；

Z ² Selected from C (R) ^z2 ) ₂ 、N、CR ^z2 The method comprises the steps of carrying out a first treatment on the surface of the Each R is ^z2 Independently H, halogen, hydroxy, optionally substituted C1-C8 alkyl, or two R ^z2 Together with the carbon atoms to which they are attached form an optionally substituted C3-C6 carbocyclic ring or a 3-6 membered heterocyclic ring,

or R is ^z2 、R ^z1 Together with the carbon atoms to which they are attached, form an optionally substituted C3-C6 carbocyclic ring or a 3-6 membered heterocyclic ring;

Z ³ 、Z ⁴ selected from C, CH, N;

ring A is a C6-C14 membered aromatic ring, a 5 membered heteroaromatic ring, a 6-14 membered heteroaromatic ring, a C3-C14 carbocyclic ring or a 3-14 membered heterocyclic ring;

m is selected from 1, 2, 3, 4;

R ¹ independently at each occurrence selected from H, D, "R ⁷ -C≡C-”、R ^1a The method comprises the steps of carrying out a first treatment on the surface of the Preferably at least one R on ring A ¹ Is "R ⁷ -a substituent of c≡c-;

R ^1a 、R ⁷ independently at each occurrence from 0 to 5R ^1a2 R substituted ^1a1 ；

R ^1a1 、R ^1a2 Optionally by 0-5R ^1a3 Substitution;

R ^1a3 is "-Linker2-R ^1a4 "; linker2 is absent, or Linker2 is selected from: bond, O, NH, NR ^1a4 、-C(＝O)O-、-C(＝O)NH-、-C(＝O)NR ^1a4 -3-14 membered cycloalkyl, 3-14 membered heterocyclyl, C6-C14 aryl, 5-14 membered heteroaryl;

R ² absent, or R ² At Z ⁴ Ortho to R ³ And the atoms to which they are attached together form an optionally substituted or unsubstituted 5-6 membered heterocyclic ring;

R ³ selected from: H. d, CH ₃ 、CD ₃ ；

Y is O, S, NR ^y Wherein R is ^y And R is ³ Together with the atoms to which they are attached, form an optionally substituted 5-6 membered heterocyclic ring or 5-6 membered heteroaryl ring;

R ⁶ selected from: CD (compact disc) ₃ C1-C8 alkyl, halogenated C1-C8 alkyl, C6-C14 aryl;

R ⁸ independently at each occurrence selected from: H. d, halogen, CD ₃ C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, cyano, amino, C1-C8 alkyl substituted amino, hydroxy, mercapto, C1-C8 alkylthio, halogenated C1-C8 alkylthio, -C (=O) NH2, -C (=O) NH (C1-C8 alkyl), -C (=O) - (C1-C8 alkyl), oxo, thio;

R ^1a1 、R ^1a2 independently at each occurrence selected from the group consisting of: 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 (=c (=o) -, (C3-C14 cycloalkyl) -, (C1-C8 alkyl) -, C (=o) -, C (=c 1-C8 alkyl) - (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) -, 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-C14 cycloalkyl) -, HC, (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) 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) -, and a pharmaceutically acceptable salt thereofHeterocyclyl) 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) -C (=o) -, (3-14 membered heterocyclyl) -C (=o) - (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) -, (3-14 membered heterocyclyl) - (C (=o) - (C1-C8 alkyl) -NH-, (3-14 membered heterocyclyl) - (C (=o) -, C1-C8 alkyl-) (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) -, (C1-C14 membered heterocyclyl) -, mercapto) - (C1-14 membered heterocyclyl) -, mercapto (C1-C8 alkyl) -, 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) -, 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, (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) -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) - (C1-C8 alkyl) -C (=o) NH-, (C6-C14 aryl) -C (=o) -, C (=c 1-C8 alkyl) -, C (=c 6-C14 alkyl) - (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) - (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) - (C14 aryl) -, HC (=o) - (C1-C14 aryl) -, HC (=c 1-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) - (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) 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) -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) -, HC (=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, -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) -, one orTwo C1-C8 alkyl substituted NH s 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);

R ^1a4 independently at each occurrence selected from the group consisting of: H. d, halogen, hydroxy, 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) -, (C1-C15 alkyl) -C (=o) -, (C6-C14 aryl) -C (=o) -, (C (=o) O) -, (4-12 membered heterocyclyl) -C (=o) -, (5-14 membered heteroaryl) -C (=o) -, (halo C1-C15 alkyl) -OC (=o) -, (4-12 membered heterocyclyl) -OC (=o) -, and (C1-C14 membered heteroaryl) -OC (=o) -, and (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) -, C 1-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.

In another preferred embodiment, at least one R ¹ Is R ⁷ -c≡c- ". I.e. m is 1, R ¹ Is R ⁷ -c≡c- "; m is 2, 3 or 4, one R ¹ Is R ⁷ -C≡C- ", other R ¹ Independently selected from H, D, "R ⁷ -C≡C-”、R ^1a 。

In another preferred embodiment, the compound of formula (I) has the structure:

in another preferred example, the compound of formula (I) has a structure of formula (II):

in another preferred embodiment, the compound is selected from the group consisting of formulas (IV-1), (IV-2), (IV-4), (IV-5), (IV-6), (IV-7), (IV-9):

wherein Cy ³ Selected from formulas (III-1) to (III-14):

Z ⁵ selected from C-R ¹ Or N; r is R ¹ 、m、Z ¹ 、R ³ Is as defined above; preferably, Z ⁵ Selected from CH or N; when m is 1, R ¹ Is R ⁷ -C≡C-；R ⁷ Is as defined above.

In another preferred embodiment, the compound is selected from the group consisting of formulas (V-1), (V-2), (V-3), (V-4):

wherein Z is ⁵ Selected from C-R ¹ Or N; r is R ^1a1 、R ¹ 、R ³ 、Z ¹ 、Cy ¹ 、Cy ² 、R ⁵ Is as defined above.

In another preferred embodiment, the compound is selected from:

wherein Z is ⁵ Selected from CH or N; r is R ¹ Is C1-C8 alkyl; r is R ^1a1 、R ³ 、Z ¹ 、Cy ² 、R ⁵ Is as defined above.

In another preferred embodiment, R ¹ At each occurrenceIndependently selected from the group consisting of: H. d, methyl group,

In another preferred embodiment, the compound is a compound as set forth in claim 5.

In a second aspect of the present invention, there is provided a process for preparing a compound of formula (I) according to the first aspect, wherein the synthesis step comprises at least one of the following reaction schemes 1 and 2:

wherein,,

G ² selected from: -OH, halogen, C1-C8 alkoxy, C6-C14 aryloxy, -OC (=o) - (C1-C8 alkoxy), -OS (=o) ₂ - (C1-C8 alkoxy), -OC (=O) - (C6-C14 aryloxy), -OS (=O) ₂ - (C6-C14 aryloxy);

R ⁴ 、R ¹ 、m、R ² 、R ³ 、Y、Z ¹ 、Z ² 、Z ³ 、Z ⁴ dotted line, cy ¹ Is as defined above.

In a third aspect of the invention, there is provided a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and one or more of the compounds of the first aspect or stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labeled compounds thereof.

In a fourth aspect of the invention there is provided an inhibitor of receptor interacting protein kinase 1 (RIPK 1) comprising one or more of a compound according to the first aspect or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, or a pharmaceutical composition according to the third aspect.

In a fifth 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 the pharmaceutical composition according to the third aspect, 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 alternatively

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

In a sixth aspect of the present 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, a prodrug thereof, a hydrate or solvate thereof, an isotopically labelled compound thereof or a pharmaceutical composition according to the third aspect, characterized in that it is for the manufacture of a medicament for the detection and/or prevention and/or treatment of a disease selected from the group consisting of:

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, neocoronavirus infection, 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, tauopathies, alzheimer's disease, parkinson's disease, lewy body dementia, multiple system atrophy, multiple sclerosis, frontotemporal dementia, fabry's disease, redbis's ataxia, 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 muscular atrophy, schizophrenia, demyelinating diseases, chronic inflammatory demyelinating polyneuropathy, niemann pick disease, corticobasal degeneration, lysosomal storage diseases, sandhoff disease, gangliocytopathy, neuronal ceroid lipofuscinosis, post-operative 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 stroke, geographic atrophy, acetaminophen poisoning, acute liver failure, acute kidney injury, acute respiratory distress syndrome, intracranial hemorrhage, cerebral ischemia, ischemia, ischemic injury, hypoxic brain injury, hypoxia, burn shock, ischemia reperfusion injury of a solid organ, cisplatin-induced kidney injury, smoking-induced injury, myocardial infarction, heart failure, toxic epidermonecrobiosis, acute tubular necrosis, heart failure, NF- κB critical regulator gene mutation, leukemia, myeloid leukemia, lymphoblastic 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, carcinoma of the area of the small cell lung, 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, head and/or neck cancer, 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 amaurosis, 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 fundus disease, ocular vascular disease, you Saishi syndrome, type I diabetes mellitus, nonalcoholic fatty liver, vitiligo, sialosidosis, irritable bowel syndrome, danong's disease, cholesterol ester storage disease, vollman disease, hypolipidemia, atherosclerosis, multiple sulfatase deficiency, fabry disease, gaucher disease, myelofibrosis, osteoporosis, cystine storage disease, muscular dystrophy, polyglutamine disease, crabb disease, chronic kidney disease, mentha's disease, cystic fibrosis, pang Pibing Tay-saxotwo'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.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.

Detailed description of the preferred embodiments

The inventors of the present invention have studied intensively for a long time, and have unexpectedly developed a compound represented by general formula (I) and/or general formula (II) which has a novel structure and a remarkable kinase inhibitory effect. 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" means a hydrogen atom which may be substituted in a substituted speciesAtoms or groups of the sub-groups. 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 which are stable or chemically realizable。

"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, 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 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 is meant that the aromatic ring to which the aryl group is attached to the parent structure has from 6 to 14 carbon atoms, but the aryl group may optionally be fused to other ring structures, which refer to ring structures having from 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 atoms selected from N, O or S. Alternatively, the aryl group may be fused to an aryl group, a heterocyclic group, a cycloalkyl group, 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 groupThe heteroaryl ring, which is the group attached to the parent structure, has 5 to 14 ring atoms, but the heteroaryl group may optionally be fused to other ring structures, which are ring structures having 3 to 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 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.

"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 term "amino acid acyl" refers to a substituent of an amino acid that is converted to an acyl group and attached to the substituted object through the acyl group. The exemplary examples are wrapped with but not limited to the following examples: glycine acyl group is a structure of glycine (NH) ₂ -CH ₂ -COOH) to an acyl group to obtain glycine acyl (NH) ₂ -CH ₂ -C (=o) -. 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.

The term "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.

The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula (I). Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula (I). Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, such as tetramethylammonium.

In another preferred embodiment, "pharmaceutically acceptable salt" refers to salts of the compounds of formula (I) with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalacetic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula (I) with an inorganic base; or the methylamine, ethylamine or ethanolamine salt of the compounds of the formula I with organic bases.

Pharmaceutical composition

The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more therapeutically effective amounts of a compound 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 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, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) 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.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions (e.g.those described in Sambrook et al, molecular cloning: A laboratory Manual (New York: cold Spring Harbor LaboratoryPress, 1989)) or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts 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.

Abbreviation definition

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-tert-butyl dicarbonate

DMSO: dimethyl sulfoxide; pd (dppf) Cl ₂ : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

Example 1:

30mg of (IM-1), 35mg of (Acid-1) and 78mg of N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluoro-phosphoric Acid urea (HATU, CAS: 148893-10-1) were dissolved in 3mL of N, N-Dimethylformamide (DMF), 50. Mu.L of Diisopropylethylamine (DIPEA) was added with stirring, followed by stirring at room temperature for 12 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 preparative thin layer chromatography to give I-1, yield: 47mg, yield: 92.1%. ¹ HNMR(400MHz,Chloroform-d)δ11.02(d,J＝7.3Hz,1H),8.80–8.74(m,1H),8.56(dd,J＝4.9,1.7Hz,1H),8.34(s,1H),7.82(dt,J＝7.9,2.0Hz,1H),7.53(dt,J＝5.2,1.9Hz,3H),7.41(d,J＝2.0Hz,1H),7.37(dd,J＝8.2,1.9Hz,1H),7.33–7.28(m,1H),7.27(s,1H),7.25(d,J＝3.3Hz,1H),7.17(d,J＝8.2Hz,1H),6.54(d,J＝0.9Hz,1H),5.14(dt,J＝11.3,7.2Hz,1H),4.68(dd,J＝9.7,7.3Hz,1H),4.40(dd,J＝11.4,9.7Hz,1H),3.45(s,3H),2.05(s,3H).LC-MS:505.3.[M+H] ⁺

Using the same synthesis procedure, starting from different amino and carboxyl compounds, the following compounds were obtained:

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experimental example 2: effect of Compound molecular level on RIPK1 kinase Activity

In 384-well plates, 2. Mu.L of enzyme and 1. Mu.L 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, Incubate at room temperature for 10min. The addition of 2. Mu.L of the mixture of ATP and substrate peptide fragment (substrate final concentration 100. Mu.g/mL, ATP final 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 KinaseDetection 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 +represents IC ₅₀ Less than (less than or equal to) 0.1 mu M

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

Experimental example 3: 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, stimulation with tnfα at 20ng/mL 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 SpectraMax190, 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

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Wherein "+" denotes IC ₅₀ Less than (less than or equal to) 1 mu M; "-" means 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 remarkable restoring effect on tnfα -induced Hepa1-6 cell death, relative to "comparative compound 1".

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,

Wherein Cy ¹ Selected from the group consisting of:

Each dotted line independently represents a single bond or a double bond;

Z ¹ selected from: o, S, N, C =o, SO ₂ 、NH；

Z ² Selected from C (R) ^z2 ) ₂ 、N、CR ^z2 ；

Each R is ^z2 Independently H, halogen, hydroxy, optionally substituted C1-C8 alkyl, or two R ^z2 Together with the carbon atoms to which they are attached, form an optionally substituted C3-C6 carbocyclic ring or a 3-6 membered heterocyclic ring;

Z ³ 、Z ⁴ selected from C, CH, N;

m is selected from 1, 2, 3, 4;

R ^1a1 、R ^1a2 Optionally by 0-5R ^1a3 Substitution;

R ³ selected from: H. d, CH ₃ 、CD ₃ ；

R ^1a1 、R ^1a2 independently at each occurrence selected from the group consisting of: 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) -, (C (=o) -, C1-C8 alkyl) -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) -, 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-C14 cycloalkyl) -, HC, (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) 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) -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) -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) - (C1-14 membered heterocyclyl) -, mercapto (C1-C8 alkyl) - (C1-14 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) -, 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, (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) C (=o) - (C1-C8 alkyl) -, (C6-C14 aryl) -C (=o) O-, (C6-C14 aryl) - (C1-C8 alkyl) -C (=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) - (C (=o) -, (C1-C8 alkyl) -, (C6-C14 aryl) -, (C (=c 1-C8 alkyl) -, C (=o) -, C1-C8 alkyl) -, 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) - (C6-C14 aryl) -, amino (C6-C14 aryl), (C1-C8 alkyl) NH- (C6-C14 aryl) -, amino (C1-C8 alkyl) - (C14 aryl) -, HC (=c 6-C14 aryl) -, (C1-C14 aryl) -, mercapto (C1-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) - (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) -1-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) - (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) -C (=o) - (5-14 membered heteroaryl) -, HC (=o) - (C1-C8 alkyl) - (5-14 membered heteroaryl) -, HC (=o) -, (C1-14 membered heteroaryl) -, (C1-C8 alkyl) -O- (5-14 membered heteroaryl) -, HC (=o) -, and (C1-C8 alkyl) - (C1-14 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, -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), -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), - (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);

R ^1a4 independently at each occurrence selected from the group consisting of: H. d, halogen, hydroxy, 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) -, (C1-C15 alkyl) -C (=o) -, (C6-C14 aryl) -C (=o) -, (C (=o) O) -, (4-12 membered heterocyclyl) -C (=o) -, (5-14 membered heteroaryl) -C (=o) -, (halo C1-C15 alkyl) -OC (=o) -, (4-12 membered heterocyclyl) -OC (=o) -, and (C1-C14 membered heteroaryl) -OC (=o) -, and (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) -, C (=c 1-C8 alkyl) - Group-substituted (C6-C14 aryl) -C (=o) -, 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.

2. The compound according to claim 1, or a stereoisomer, enantiomer, diastereomer, atrop, optical isomer, racemate, polymorph, 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 formula (IV-1), (IV-2), (IV-4), (IV-5), (IV-6), (IV-7), (IV-9):

wherein Cy ³ Selected from formulas (III-1) to (III-14):

Z ⁵ selected from C-R ¹ Or N; r is R ¹ 、m、Z ¹ 、R ³ 、Cy ² 、R ⁵ 、R ⁶ Is as defined in claim 1;

preferably, Z ⁵ Selected from CH or N; when m is 1, R ¹ Is R ⁷ -C≡C-；R ⁷ Is as defined in claim 1.

3. The compound according to claim 1, or a stereoisomer, enantiomer, diastereomer, atrop, optical isomer, racemate, polymorph, 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 formula (V-1), (V-2), (V-3), (V-4):

Wherein Z is ⁵ Selected from C-R ¹ Or N; r is R ^1a1 、R ¹ 、R ³ 、Z ¹ 、Cy ¹ 、Cy ² 、R ⁵ Is as defined in claim 1;

preferably, the compound is selected from:

wherein Z is ⁵ Selected from CH or N; r is R ¹ Is C1-C8 alkyl; r is R ^1a1 、R ³ 、Z ¹ 、Cy ² 、R ⁵ Is as defined in claim 1.

4. The compound according to claim 1, or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, polymorph, tautomer or pharmaceutically acceptable salt thereof, prodrug, hydrate or solvate thereof, isotopically labeled compound thereof, wherein R ¹ Independently at each occurrence selected from the group consisting of: H. d, methyl group,

5. The compound of claim 1, or a stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, polymorph, tautomer or pharmaceutically acceptable salt thereof, prodrug, hydrate or solvate thereof, isotopically labeled compound thereof, wherein the compound is:

or->

6. A process for preparing a compound of formula (I) according to claim 1, wherein the step of synthesizing the compound comprises at least one of the following reaction schemes 1 and 2:

[ reaction type 1]

[ reaction type 2]

Wherein,,

R ⁴ 、R ¹ 、m、R ² 、R ³ 、Y、Z ¹ 、Z ² 、Z ³ 、Z ⁴ dotted line, cy ¹ Is as defined in claim 1.

7. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier and one or more of the compounds of any one of claims 1-5 or stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labeled compounds thereof.

8. A receptor interacting protein kinase 1 (RIPK 1) inhibitor comprising one or more compounds according to any one of claims 1 to 5 or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts thereof, prodrugs, hydrates or solvates thereof, or a pharmaceutical composition according to claim 7.

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 7, for the preparation of a medicament for:

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

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

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

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

10. Use of a compound according to any one of claims 1-5 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 or a pharmaceutical composition according to claim 7 for the preparation of a medicament for the detection and/or prevention and/or treatment of a disease selected from the group consisting of: