Compounds with RIPK1 inhibitory activity, preparation methods and uses thereof

Abstract

The present invention discloses a compound with RIPK1 inhibitory activity, a preparation method, and uses thereof. The compound structure is shown in Formula I, and the definitions of the substituents are as described in the specification and claims. The compound of the present invention can be used to treat inflammatory diseases, ischemic diseases, neurodegenerative diseases, tumors, and other conditions and diseases associated with receptor-interacting protein kinase 1.

Description

Technical Field

[0001] The present invention relates to compounds having receptor interacting protein kinase 1 inhibitory activity, preparation methods and uses thereof, in particular to uses of the series of compounds or pharmaceutical compositions and therapeutic agents containing the series of compounds for treating inflammatory diseases, ischemic diseases, neurodegenerative diseases, tumors and other conditions and diseases associated with receptor interacting protein kinase 1. Background Art

[0002] Protein kinases are proteins (enzymes) that regulate various cellular functions by phosphorylating specific amino acids on proteins. Proteins regulate their activity and ability to bind to their chemical components through conformational changes. Protein kinase activity refers to the rate at which the kinase incorporates a phosphate group onto its substrate, which can be measured by measuring the amount of substrate converted to product over a given period of time. Substrate phosphorylation occurs at the activation site of the protein kinase. Protein kinases can be divided into five categories based on the type of amino acid residue phosphorylated on their substrate proteins: serine / threonine protein kinases, tyrosine protein kinases, histidine protein kinases, tryptophan protein kinases, and aspartyl / glutamyl protein kinases. Serine / threonine protein kinases are enzymes that catalyze the phosphorylation of serine / threonine residues on a variety of substrate proteins; tyrosine kinases are protein enzymes that catalyze the transfer of adenosine triphosphate to tyrosine residues on proteins. Pathological conditions associated with protein kinases include inflammatory diseases, immune disorders, cardiovascular diseases, and tumors.

[0003] Cell death mainly includes apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death processes related to autophagy and non-programmed necrosis. Necroptosis, also known as programmed cell death or programmed necrosis, is a new type of cell death discovered in recent studies. Programmed necrosis is a highly inflammatory form of cell death that leads to the release of danger-associated molecular patterns from cells and is considered to be an important pathological factor in a variety of degenerative and inflammatory diseases. The above diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and many other related diseases. Receptor interacting protein kinase 1 (RIPK1) and RIPK3 are two homologous serine / threonine kinases that are key elements in mediating cell necroptosis.

[0004] RIPK1 kinase is recognized as a potential therapeutic target for diseases associated with programmed cell death (necroptosis). Necrostatin-1 (Nec-1), a first-in-class RIPK1 inhibitor, and its analogs have demonstrated clear efficacy in preclinical studies against a variety of degenerative diseases, inflammatory conditions, and cancers. For example, it has a relieving effect on Alzheimer's disease, Parkinson's disease, Huntington's disease, and age-related macular degeneration; it has a protective effect on psoriasis, retinitis pigmentosa, inflammatory bowel disease, autoimmune diseases, bombesin-induced acute pancreatitis, and sepsis / systemic inflammatory response syndrome; it can effectively alleviate ischemic brain injury, ischemic myocardial injury, retinal ischemia / reperfusion injury, retinal detachment-induced photoreceptor cell necrosis, glaucoma, renal ischemia-reperfusion injury, cisplatin-induced renal injury, and traumatic brain injury; and it can at least partially alleviate other diseases associated with RIPK1-dependent apoptosis, necrosis, or cytokine production, including hematological and solid organ malignancies, bacterial and viral infections (including tuberculosis and influenza), and lysosomal storage diseases (especially Gaucher disease). Another RIPK1 inhibitor, GSK2982772, is also in clinical trials for the treatment of multiple autoimmune diseases.

[0005] There is a demand for kinase inhibitors used as pharmaceuticals, especially RIPK1 kinase inhibitors. However, existing inhibitors targeting programmed necrosis-related kinases all have defects to varying degrees, such as poor selectivity, less than ideal in vivo inhibitory activity, poor pharmacokinetic properties, low oral bioavailability, and some are unable to cross the blood-brain barrier and enter the central nervous system. These shortcomings have limited their further research and clinical application. There is still a need in this field for more novel kinase inhibitors with more novel chemical structures, better physicochemical properties, and more prominent pharmacokinetic properties as candidate drugs for the detection, prevention and treatment of diseases involving necroptosis-related kinases (such as RIPK1). Summary of the Invention

[0006] The object of the present invention is to provide a RIPK1 kinase inhibitor.

[0007] In a first aspect, the present invention provides a compound represented by 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, or an isotope-labeled compound thereof.

[0008]

[0009] Among them, Cy 1 Select from the following groups:

[0010]

[0011] R 5 is independently selected at each occurrence from the group consisting of: H, D, halogen, CD3, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, cyano, amino, C1-C8 alkyl-substituted amino, hydroxy, mercapto, C1-C8 alkylthio;

[0012] Cy 2 Selected from 0-5 R 8 Substituted C3-C14 cycloalkyl, C6-C14 membered aryl, 6-14 membered heteroaryl, or 3-14 membered heterocyclyl;

[0013] R 4 is independently selected at each occurrence from: H, D, CH3, CD3;

[0014] Each dashed line independently represents a single bond or a double bond;

[0015] Z 1 Selected from: O, S, N, CR z1 , C=O, SO, SO2, NH;

[0016] Z 2 Selected from C(R z2 )2、N、CR z2 ; Each R z2 are independently H, halogen, hydroxy, optionally substituted C1-C8 alkyl, or two R z2 Together with the carbon atoms to which they are attached, they form an optionally substituted C3-C6 carbocyclic ring or a 3-6 membered heterocyclic ring,

[0017] or R z2 、R z1 Together with the carbon atoms to which they are attached, they form an optionally substituted C3-C6 carbocyclic ring or a 3-6 membered heterocyclic ring;

[0018] Z 3 、Z 4 Selected from C, CH, N;

[0019] 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;

[0020] m is selected from 1, 2, 3, and 4;

[0021] R 1 independently selected at each occurrence from H, D, "R 7 -C≡C-", R 1a ; Preferably, there is at least one R on ring A 1 For "R 7 -C≡C-"substituent;

[0022] R 1a 、R 7 Each occurrence is independently divided into 0-5 R 1a2 Replaced R 1a1 ;

[0023] R 1a1 、R 1a2 Optional 0-5 R 1a3 replace;

[0024] R 1a3 For "-Linker2-R 1a4 "; Linker2 does not exist, 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;

[0025] R 2 Does not exist, or R 2 In Z 4 Ortho position, and with R 3 and the atoms to which they are attached together form an optionally substituted or unsubstituted 5-6 membered heterocyclic ring;

[0026] R 3 Selected from: H, D, CH3, CD3;

[0027] Y is O, S, or NR y , where R y and R 3 Together with the atoms to which they are attached, they form an optionally substituted 5-6 membered heterocyclic ring or a 5-6 membered heteroaryl ring;

[0028] R 6 Selected from: CD3, C1-C8 alkyl, halogenated C1-C8 alkyl, C6-C14 aryl;

[0029] R 8 is independently selected at each occurrence from: H, D, halogen, CD3, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, cyano, amino, C1-C8 alkyl-substituted amino, hydroxy, thiol, C1-C8 alkylthio, halo-C1-C8 alkylthio, -C(=O)NH2, -C(=O)NH(C1-C8 alkyl), -C(=O)-(C1-C8 alkyl), oxo, thioxo;

[0030] R 1a1 、R 1a2are independently selected at each occurrence from the group consisting of H, D, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C2-C8 alkenyl, halo-C2-C8 alkenyl, C2-C8 alkenyloxy, halo-C2-C8 alkenyloxy, C2-C8 alkynyl, halo-C2-C8 alkynyl, C2-C8 alkynyloxy, halo-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 C (=O)-, (C3-C14 cycloalkyl)-(C1-C8 alkyl)-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 cycloalkyl)-(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)O-(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)-OC(=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)-, NH2C(=O)-(C3-C14 cycloalkyl)-, (C1-C8 alkyl)NHC(=O)-(C3-C14 cycloalkyl)-, NH2C(=O)-(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 (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) (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 (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)-OC(=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)-, NH2C(=O)-(3-14 membered heterocyclyl)-, (C1-C8 alkyl)NHC(=O)-(3-14 membered heterocyclyl)-, NH2C(=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)NH-(C1-C8 alkyl)-, (C6-C14 aryl)-NHC(=O)-, (C6-C14 aryl)-(C1 -C8 alkyl)-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)-(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)-OC(=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)-, NH2C(=O)-(C6-C14 aryl)-, (C1-C8 alkyl)NHC(=O)-(C6-C14 aryl)-, NH2C(=O)-(C1-C8 alkyl)-(C6-C14 aryl)-, (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)-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)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)-OC(=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)-, NH2C(=O)-(5-14 membered heteroaryl)-, (C1-C8 alkyl)NHC(=O)-(5-14 membered heteroaryl)-, NH2C(=O)-(C1-C8 alkyl)-(5-14 membered heteroaryl)-, (C1-C8 alkyl)-(5-14 membered heteroaryl)-(C1-C8 alkyl)-, hydroxy, hydroxy-substituted C1-C8 alkyl, mercapto, mercapto-substituted C1-C8 alkyl, amino C1-C8 alkyl), -NH(C1-C8 alkyl), -N(C1-C8 alkyl)(C1-C8 alkyl), cyano, C1-C8 alkyl substituted with cyano, -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), NH2C(=O)-, NH2C(O)- substituted by one or two C1-C8 alkyl groups, NH2C(O)- substituted by one or two C1-C8 cycloalkyl groups, NH2C(O)- substituted by one or two C6-C14 aryl groups, NH2C(O)- substituted by one or two 5-14 membered heteroaryl groups, NH2C(O)- substituted by one or two 4-10 membered heterocyclyl groups, NH 2C(═O)-(C1-C8 alkyl)-, NH2C(O)-(C1-C8 alkyl)-substituted by one or two C1-C8 alkyl groups, NH2C(O)-(C1-C8 alkyl)-substituted by one or two C1-C8 cycloalkyl groups, NH2C(O)-(C1-C8 alkyl)-substituted by one or two C6-C14 aryl groups, NH2C(O)-(C1-C8 alkyl)-substituted by one or two 5-14 membered heteroaryl groups, NH2C(O)-(C1-C8 alkyl)-substituted by one or two 4-10 membered heterocyclyl groups, oxo (═O), thioxo (═S);

[0031] R 1a4and independently selected at each occurrence 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 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)-, (C1-C15 alkyl)-C(=O)O-. , (C6-C14 aryl)-C(=O)O-, (4-12 membered heterocyclyl)-C(=O)O-, (5-14 membered heteroaryl)-C(=O)O-, (halogenated C1-C15 alkyl)-OC(=O)-, (halogenated C6-C14 aryl)-OC(=O)-, (halogenated 4-12 membered heterocyclyl)-OC(=O)-, (halogenated 5-14 membered heteroaryl)-OC(=O)-, (halogenated C1-C15 alkyl)-C(=O)-, (halogenated C6-C14 aryl)-C(=O)-, (halogenated 4-12 membered heterocyclyl)-C(=O)-, (halogenated 5-14 membered heteroaryl)-C(=O)-, (halogenated C1-C15 alkyl)-C(=O)O-, ( C1-C8 alkyl-substituted (C6-C14 aryl)-OC(=O)-, (halogenated 4-12 membered heterocyclyl)-C(=O)O-, (halogenated 5-14 membered heteroaryl)-C(=O)O-, (C1-C8 alkyl-substituted (C1-C15 alkyl)-OC(=O)-, (C6-C14 aryl)-OC(=O)-, (4-12 membered heterocyclyl)-OC(=O)-, (5-14 membered heteroaryl)-OC(=O)-, (C1-C8 alkyl-substituted (C1-C15 alkyl)-C(=O)-, (C1-C8 alkyl-substituted (C6-C14 aryl)-C(=O)-, (C1-C8 alkyl-substituted (C1-C15 alkyl)-C(=O)-, (C1-C8 alkyl-substituted (C6-C14 aryl)-C(=O)-, (4-12 membered heterocyclyl)-C(=O)-, (5-14 membered heteroaryl)-C(=O)-substituted by C1-C8 alkyl, (C1-C15 alkyl)-C(=O)O-substituted by C1-C8 alkyl, (C6-C14 aryl)-C(=O)O-substituted by C1-C8 alkyl, (4-12 membered heterocyclyl)-C(=O)O-substituted by C1-C8 alkyl, (5-14 membered heteroaryl)-C(=O)O-substituted by C1-C8 alkyl, (C1-C8 alkyl)3-Si-(C1-C8 alkyl)-O-(C1-C8 alkylene)-, (C1-C8 alkyl)-OC(=O)-(C1-C8 alkyl)C(=O)O-substituted by halogen,(C1-C8 alkyl)-OC(=O)-(C3-C14 cycloalkyl)C(=O)O-, saccharide, -OP(=O)(O-halogenated or unhalogenated C6-C14 aryl)(NH-(C1-C8 alkyl)C(=O)O(C1-C8 alkyl)), -OP(=O)(O-halogenated or unhalogenated C6-C14 aryl)(O-(C1-C8 alkyl)C(=O)O(C1-C8 alkyl)), -OP(=O)(O-halogenated or unhalogenated C6-C14 aryl)(NH-(C1-C8 alkyl)OC(=O)(C1-C8 alkyl)), -OP(=O)(O-halogenated or unhalogenated C6-C14 aryl)(O-(C1-C8 alkyl)OC(=O)(C1-C8 alkyl)), -OP(=O)(O-halogenated or unhalogenated C6-C14 aryl)(NH-(C1-C8 alkyl)-SC(=O)(C1-C8 alkyl)), -OP(=O)(O-halogenated or unhalogenated C6-C14 aryl)(O-(C1-C8 alkyl)-SC(=O)(C1-C8 alkyl)), -OP(=O)(ONa)2, -OP(=O)(OK)2, -OP(=O)(OLi)2, -O-(halogenated or unhalogenated 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. 、

[0032] In another preferred embodiment, at least one R 1 R 7 -C≡C-". That is, m is 1, R 1 R 7 -C≡C-”; m is 2, 3 or 4, one of which is R 1 R 7 -C≡C-", other R 1 Independently selected from H, D, "R 7 -C≡C-", R 1a .

[0033] In another preferred embodiment, the compound represented by general formula (I) has the structure:

[0034]

[0035] In another preferred embodiment, the compound represented by general formula (I) has the structure represented by formula (II):

[0036]

[0037] In another preferred embodiment, the compound is selected from formula (IV-1), (IV-2), (IV-4), (IV-5), (IV-6), (IV-7), and (IV-9):

[0038]

[0039] Among them, Cy 3 Selected from formula (III-1) to (III-14):

[0040]

[0041] Z 5 Selected from CR 1 or N; R 1 , m, Z 1 、R 3 The definition of is the same as above; preferably, Z 5 is selected from CH or N; when m is 1, R 1 R 7 -C≡C-;R 7 The definition of is the same as above.

[0042] In another preferred embodiment, the compound is selected from formula (V-1), (V-2), (V-3), and (V-4):

[0043]

[0044] Among them, Z 5 Selected from CR 1 or N; R 1a1 、R 1 、R 3 , Z 1 、Cy 1 、Cy 2 、R 5 The definition of is the same as above.

[0045] In another preferred embodiment, the compound is selected from:

[0046]

[0047] Where Z 5 Selected from CH or N; R 1 is a C1-C8 alkyl group; R 1a1 、R 3 , Z 1 、Cy 2 、R 5 The definition of is the same as above.

[0048] In another preferred embodiment, R 1 Each occurrence is independently selected from the group consisting of: H, D, methyl,

[0049] In another preferred embodiment, the compound is the compound listed in claim 5.

[0050] The second aspect of the present invention provides a method for preparing the compound represented by formula (I) according to the first aspect, wherein the synthesis steps include at least one of reaction formulas 1 and 2:

[0051]

[0052] in,

[0053] G 2 Selected from: -OH, halogen, C1-C8 alkoxy, C6-C14 aryloxy, -OC(=O)-(C1-C8 alkoxy), -OS(=O)-(C1-C8 alkoxy), -OS(=O)2-(C1-C8 alkoxy), -OC(=O)-(C6-C14 aryloxy), -OS(=O)-(C6-C14 aryloxy), -OS(=O)2-(C6-C14 aryloxy);

[0054] R 4 、R 1 ,m,R 2 、R 3 , Y, Z 1 , Z 2 , Z 3 , Z 4 , dotted line, Cy 1 The definition of is the same as above.

[0055] The third aspect of the present invention provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and one or more compounds described in the first aspect or their stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, or isotope-labeled compounds thereof.

[0056] The fourth aspect of the present invention provides a receptor interacting protein kinase 1 (RIPK1) inhibitor, comprising one or more compounds described in the first aspect or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, or the pharmaceutical composition described in the third aspect.

[0057] In a fifth aspect, the present invention provides a use of the compound of the first aspect or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotope-labeled compounds thereof, or the pharmaceutical composition of the third aspect, characterized in that the use is for preparing a medicament, wherein the medicament is used for:

[0058] 1) Detection and / or prevention and / or treatment of kinase-related diseases;

[0059] 2) Detection and / or prevention and / or treatment of immune, inflammatory and / or infection-related diseases;

[0060] 3) Detection and / or prevention and / or treatment of diseases related to ischemia and / or reperfusion injury;

[0061] 4) Detection and / or prevention and / or treatment of degenerative diseases;

[0062] 5) Detection and / or prevention and / or treatment of tumor-related diseases;

[0063] 6) Detection and / or prevention and / or treatment of cell necrosis-related diseases;

[0064] 7) Detection and / or prevention and / or treatment of metabolic-related diseases; or

[0065] 8) Detection and / or prevention and / or treatment of eye diseases.

[0066] In a sixth aspect, the present invention provides a use of the compound of the first aspect or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, prodrugs, hydrates or solvates thereof, isotope-labeled compounds thereof, or the pharmaceutical composition of the third aspect, characterized in that it is used to prepare a medicament for detecting and / or preventing and / or treating a disease selected from the group consisting of:

[0067] Systemic juvenile idiopathic arthritis, Behçet's disease, interleukin-1 converting enzyme-associated febrile syndrome, sepsis, alopecia areata, allergic diseases, hepatitis B, hepatitis C, multiple sclerosis, pulmonary sarcoidosis, pulmonary fibrosis, pneumonia, mycobacterial infection, celiac disease, Sjögren's syndrome, osteoarthritis, hidradenitis suppurativa, necrotizing enterocolitis, acute pancreatitis, spondyloarthritis, colitis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, bacterial infection, influenza, chronic obstructive pulmonary disease, viral infection, sepsis, dermatitis, staphylococcal infection, autoimmune disease, systemic lupus erythematosus, systemic inflammatory response syndrome, systemic scleroderma, prion disease, adrenocortical disease Degeneration, nephritis, Stevens-Johnson syndrome, surgical infection, atopic dermatitis, Wegener's granulomatosis, systemic lupus erythematosus, asthma, COVID-19 infection, vasculitis, periodontitis, inflammatory bowel disease, pancreatitis, transplant 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-related dementia syndrome, Tauopathy, Alzheimer's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, multiple sclerosis, frontotemporal dementia, Farber disease, Friedreich's ataxia, Guillain-Barré syndrome, Henry Tinton disease, primary lateral sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, tuberous sclerosis, progressive supranuclear palsy, progressive muscular atrophy, schizophrenia, demyelinating disease, chronic inflammatory demyelinating polyneuropathy, Niemann-Pick disease, corticobasal degeneration, lysosomal storage disease, Sandhoff disease, ganglioneuropathy, neuronal ceroid lipofuscinosis, postoperative cognitive impairment, bipolar disorder, diabetic neuropathy, pain (nerve pain), delirium, depression, peripheral neuropathy, autism, trauma, traumatic brain injury, ischemia, traumatic retinal injury, cerebrovascular accident, stroke, geographic atrophy, acetaminophen poisoning, acute liver failure, acute kidney injury, acute respiratory distress syndrome Inhalation distress syndrome, intracranial hemorrhage, cerebral hemorrhage, cerebral ischemia, ischemia, ischemic injury, anoxic brain damage, hypoxia, burns, burn shock, ischemia-reperfusion injury of solid organs, cisplatin-induced renal injury, smoking-induced injury, myocardial infarction, heart failure, toxic epidermal necrolysis, acute tubular necrosis, heart failure, mutations in NF-κB key regulatory genes, leukemia, myeloid leukemia, lymphocytic leukemia, T-cell leukemia, lymphoma, T-cell lymphoma, nasopharyngeal carcinoma, epidermoid carcinoma, pituitary adenoma, biliary carcinosarcoma, bile duct carcinoma, multiple myeloma, solid tumors in children, Hodgkin's disease, non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, cancer of the anal region, testicular cancer, cervical cancer, uterine cancer, endometrial cancer,Ovarian cancer, bone cancer, osteosarcoma, melanoma, environmentally induced cancers, spinal tumors, thyroid cancer, parathyroid cancer, glioblastoma, colorectal cancer, Kaposi's sarcoma, squamous cell carcinoma, brain glioma, endocrine system cancer, urethral cancer, bladder cancer, skin cancer, cutaneous or intraocular malignant melanoma, prostate cancer, triple-negative breast cancer, glioma, kidney or ureter cancer, renal pelvis cancer, adrenal gland cancer, solid organ malignancies, esophageal cancer, fallopian tube cancer, head and / or neck cancer, vulvar cancer, stomach cancer, gastrointestinal stromal tumors , small intestinal cancer, hematological malignancies, pancreatic cancer, hereditary aortic aneurysm, vaginal cancer, penile cancer, rectal cancer, tumor angiogenesis, maculopathy, macular hole, macular telangiectasia, dry eye, progressive retinal atrophy, Leber congenital amaurosis, cystic macular edema, age-related macular degeneration, glaucoma, retinal neurodegeneration, ischemic optic neuropathy, ischemic retinal disease, diabetic retinopathy, retinitis pigmentosa, retinal photoreceptor diseases, retinal degenerative diseases, optic nerve diseases, retinal detachment Irregular eye disease, iatrogenic retinal damage, retinal vascular disease, cone-rod dystrophy, choroideremia, fundus disease, ocular vascular disease, Usher syndrome, type 1 diabetes mellitus, nonalcoholic fatty liver disease, vitiligo, sialoside storage disease, irritable bowel syndrome, Danon disease, cholesterol ester storage disease, Wolman disease, hypolipidemia, atherosclerosis, multiple sulfatase deficiency, Fabry disease, Gaucher disease, myelofibrosis, osteoporosis, cystinosis, muscular dystrophy, polyglutamine disease, Krabbe disease, chronic kidney disease , Menkes disease, cystic fibrosis, Pompe disease, Tay-Sachs disease, lysosomal acid lipase deficiency, aspartylglucosaminuria, gout, Wilson's disease, mitochondrial disorders, fucosidosis, metachromatic leukodystrophy, bathosomal acid lipase deficiency, mucopolysaccharidosis, mucolipidosis, pycnodystrophy, hemochromatosis, Niemann-Pick disease, Heme-oxidized IRP2 ubiquitin ligase-1 deficiency, osteonecrosis, catenella ubiquitin chain assembly complex deficiency syndrome, ciliopathy, etc. ,

[0068] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal, or similar purpose. Due to space limitations, they will not be listed here one by one. Specific implementation methods

[0069] After extensive and intensive research, the inventors unexpectedly discovered compounds represented by Formula (I) and / or Formula (II) with novel structures and significant kinase inhibitory activity. These kinase inhibitors exhibit excellent RIPK1 inhibitory activity and are therefore useful in preparing pharmaceutical compositions for detecting and / or preventing and / or treating cell death and / or related diseases. Based on this, the inventors completed the present invention.

[0070] the term

[0071] Unless expressly stated otherwise, the terms used according to the present invention and herein have the following meanings:

[0072] The term "C1-C6" refers to a ring having 1, 2, 3, 4, 5, or 6 carbon atoms, "C1-C8" refers to a ring having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and so on. "5-8 membered" refers to a ring having 5-8 ring atoms, and so on.

[0073] "Substituent" refers to an atom or group that can replace a hydrogen atom in the substituted substance. Examples include, but are not limited to, deuterated, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, isocyanato, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, thioxo, -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)2R o NR n S(=O)2NR o R p 、-OR n 、-SR n 、-OC(=O)R n 、-OC(=O)NR n Ro 、-OC(=O)OR n 、-S(=O)NR n R o 、-S(=O)2NR 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)2R n 、-P(=O)2R n 、-NP(=O)R n R o 、-NP(=O)R n R o 、-NP(=O)2R n 、-NP(=O)2R n etc., where R n 、R o 、R p is independently selected at each occurrence from the group consisting of H, D, C1-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 aryl, halogenated C3-C12 aryl, C3-C12 heteroaryl, halogenated C3-C12 heteroaryl; optionally, R n 、R o The atoms to which they are attached may form a ring structure. It will be understood by those skilled in the art that the combinations of substituents and substituted substances contemplated by the present invention are those that are stable or chemically feasible.

[0074] "Substitution" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those that are stable or chemically feasible. The substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, 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)2R o NR n S(=O)2NR 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)2NR 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)2R n 、-P(=O)2R n 、-NP(=O)R n R o 、-NP(=O)R n R o 、-NP(=O)2R n 、-NP(=O)2R n etc., where R n 、R o 、R p The definition of is the same as above.

[0075] "Alkyl" refers to a saturated aliphatic hydrocarbon group, which may be straight or branched. The alkyl group may be independently substituted with one or more substituents as 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, 1,1-dimethylpropyl, and 3-methylpentyl. Alkyl groups may be optionally substituted or unsubstituted.

[0076] "Alkenyl" is a straight or branched hydrocarbon group in which at least one C—C is sp 2 Double bond, wherein the alkenyl group can be independently optionally substituted with one or more substituents described in the present invention, specific examples of which include, but are not limited to, vinyl, allyl, butyl, Etc. Alkenyl groups may be optionally substituted or unsubstituted.

[0077] "Alkynyl" refers to a straight or branched hydrocarbon group in which 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 of which 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.

[0078] "Ring structure" refers to a monocyclic or polycyclic structure. It is usually two or more fragments connected on an atom in a ring structure connected to form a closed structure, including but not limited to cycloalkanes, heterocycloalkanes, cyclic lactams, aromatic hydrocarbons, heteroaromatic hydrocarbons, parallel rings, bridged rings, spirocyclic structures, 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-benzoxazepine-5(2H)-one, naphthalene, anthracene, phenanthrene, quinoline, pyrrolopyridine, pyrazolopyridine, indole, dihydroindole, steroid ring, porphyrin ring, etc. The ring structure may be optionally substituted or unsubstituted. When it appears as a substituent, it means that one or more hydrogen atoms on the monocyclic or polycyclic ring are removed, so that it can serve as a substituent of the substituted substance.

[0079] "Halogen" refers to F, Cl, Br or I.

[0080] "Halo" means substituted with one or more halogens.

[0081] "Aryl" refers to a carbocyclic aromatic system containing one or more rings, which do not contain heteroatoms. Optionally, the aryl group may be fused to a heteroaryl group, a heterocyclic group, or other ring structure. Examples include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl,

[0082] The aryl group may be optionally substituted or unsubstituted. When the aryl group is described as "C6-C14 aryl", it means that the aromatic ring connecting the aryl group and the parent structure has 6-14 carbon atoms, but the aryl group may be optionally fused with another ring structure, wherein the other ring structure refers to a ring structure having 3-18 ring atoms, and the other ring structure may be optionally substituted or unsubstituted.

[0083] "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. Optionally, the aryl group may be fused to an aryl group, a heterocyclic group, a cycloalkyl group or other ring structure. Examples include (but are not limited to) furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, The heteroaryl group may be optionally substituted or unsubstituted. When the heteroaryl group is described as a "5-14 membered heteroaryl group", it means that the heteroaryl ring connected to the parent structure has 5-14 ring atoms, but the heteroaryl group may be optionally fused with another ring structure, wherein the other ring structure refers to a ring structure having 3-18 ring atoms, and the other ring structure may be optionally substituted or unsubstituted.

[0084] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The first ring structure to which the cycloalkyl is directly attached to the substituted substance is non-aromatic. Examples of monocyclic cycloalkyls (but not limited to the following examples) include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctynyl, etc.; examples of polycyclic cycloalkyls (but not limited to the following examples) include spirocyclic, fused, and bridged cycloalkyls. Optionally, the cycloalkyl may be fused with an aromatic, heterocyclic, cycloalkyl, or other ring structure to form a spirocyclic ring. Examples of fused with other ring structures to form a spirocyclic ring (but not limited to the following examples) include:

[0085] The cycloalkyl group may be optionally substituted or unsubstituted. When the cycloalkyl group is described as "C3-C14 cycloalkyl", it means that the cycloalkyl ring connected to the parent structure has 3-14 carbon atoms, but the cycloalkyl group may be optionally fused with other ring structures or form a spirocycle, and the other ring structure refers to a ring structure with 3-18 ring atoms, and the other ring structure may be optionally substituted or unsubstituted.

[0086] "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, etc.). Examples include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, 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 the heterocyclyl. The heterocyclyl group may be optionally substituted or unsubstituted. When the heteroalkyl group is described in the form of a "3-14 membered heterocyclyl", it means that the heterocyclyl ring connected to the parent structure has 3-14 ring atoms, but the heterocyclyl can be optionally fused with other ring structures or form a spiro ring, and the other ring structure refers to a ring structure with 3-18 ring atoms, and the other ring structure can be optionally substituted or unsubstituted.

[0087] "Tautomers" refer to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversions via proton migration, such as 1H-indazole and 2H-indazole, and 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0088] "Stereoisomers" are molecules with identically connected atoms but arranged differently in space. For example, two compounds containing a chiral center may have identical two-dimensional connections, such as R-glyceraldehyde and S-glyceraldehyde, or R-serine and S-serine.

[0089] "Enantiomers" refer to stereoisomers that are mirror images of each other and are non-superimposable, such as R-serine and S-serine.

[0090] "Diastereoisomers" are stereoisomers that have two or more chiral centers and are not mirror images of each other, such as tartaric acid.

[0091] "Atropisomers" refer to a group of conformational isomers that arise from hindered rotation about a single bond, such as the stereoisomers of 6,6'-dinitro-2,2'-biphenyldicarboxylic acid.

[0092] "Optical isomers" refer to compounds that have two or more molecules with the same two-dimensional connection but exhibit different optical properties due to differences in configuration, such as levamlodipine and dextroamlodipine.

[0093] "Racemate" refers to compounds that have the same two-dimensional connection but are optical isomers of each other. When mixed together, they ultimately exhibit an optically inactive substance. This is better than racemic amlodipine.

[0094] The term "amino acid acyl" refers to the conversion of the carboxyl group of an amino acid into an acyl group, which is then linked to a substituent of a substituted substance through the acyl group. Exemplary examples include, but are not limited to, the following: the structure of a glycine acyl group is obtained by converting the carboxyl group of glycine (NH2-CH2-COOH) into an acyl group to obtain a glycine acyl group (NH2-CH2-C(=O)-). The amino acids include, but are not limited to, α-amino acids, β-amino acids, γ-amino acids, and ω-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, β-alanine, and the like.

[0095] The term "glycosyl" refers to a substituent formed by providing a hemiacetal hydroxyl group on a monosaccharide or oligosaccharide. The monosaccharide includes aldose and ketose. The monosaccharide includes triose, tetrose, pentose, hexose, and heptose. The oligosaccharide, also known as oligosaccharide, refers to a compound containing 2-11 monosaccharides, each of which is polymerized by a glycosidic bond. Examples of the monosaccharide or polysaccharide are as follows (but not limited to the following examples): erythrose, thulose, arabinose, ribose, xylose, lyxose, glucose, mannose, fructose, galactose, lactose, sucrose, maltose, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

[0096] Pharmaceutically acceptable salts of the present invention can be salts formed by positively charged groups on anion and formula (I) compound. Suitable anion is chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate or maleate. Similarly, salts can be formed by negatively charged groups on cation and formula (I) compound. Suitable cation includes sodium ion, potassium ion, magnesium ion, calcium ion and ammonium ion, such as tetramethylammonium ion.

[0097] In another preferred embodiment, "pharmaceutically acceptable salts" refer to salts formed by the compound 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, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic 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 and isethionic acid; or sodium salts, potassium salts, calcium salts, aluminum salts or ammonium salts formed by the compound of formula (I) with an inorganic base; or methylamine salts, ethylamine salts or ethanolamine salts formed by the compound of general formula I with an organic base.

[0098] Pharmaceutical composition

[0099] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more therapeutically effective amounts of a compound of the present invention or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, or isotope-labeled compounds thereof.

[0100] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 50-200 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0101] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0102] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0103] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0105] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0106] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0107] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0108] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0109] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0110] Dosage forms for topical administration of the compounds of this invention 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 that may be required.

[0111] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0112] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0113] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0114] Below in conjunction with specific embodiment, further elaborate the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the invention.The experimental method of unreceipt specific conditions in the following examples is usually according to normal conditions (such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York:Cold Spring Harbor Laboratory Press, 1989) described in the conditions) or according to the conditions suggested by the manufacturer.Unless otherwise stated, percentage and umber are weight percentage and weight parts.

[0115] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0116] Abbreviation Definition

[0117] HATU: N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate

[0118] DMF: N,N-dimethylformamide; TEA: triethylamine; DIPEA: diisopropylethylamine

[0119] DMAC: N,N-dimethylacetamide; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0120] NBS: N-bromosuccinimide; NMP: N-methylpyrrolidone; Pd(PPh3)4: tetrakistriphenylphosphine palladium

[0121] DPPA: diphenylphosphoryl azide; 4-DMAP: 4-dimethylaminopyridine; NaBH3CN: sodium cyanoborohydride

[0122] PTSA: p-toluenesulfonic acid; MeOH: methanol; EtOH: ethanol; Boc2O: di-tert-butyl dicarbonate

[0123] DMSO: dimethyl sulfoxide; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0124] Example 1:

[0125]

[0126] 30 mg of (IM-1), 35 mg of (Acid-1), and 78 mg of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, CAS: 148893-10-1) were dissolved in 3 mL of N,N-dimethylformamide (DMF). 50 μL of diisopropylethylamine (DIPEA) was added with stirring, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed five times with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography to obtain 47 mg of I-1 (yield: 92.1%). 1HNMR(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] +

[0127] Using the same synthetic method, different amino compounds and carboxyl compounds were used as starting materials to obtain the following compounds:

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137] Experimental Example 2: Effects of Compounds on RIPK1 Kinase Activity at the Molecular Level

[0138] In a 384-well plate, add 2 μL of enzyme and 1 μL of different concentrations of compound. At the same time, set up 0% kinase activity control wells without kinase and compound and 100% kinase activity control wells without compound. Incubate at room temperature for 10 minutes. Then add 2 μL of ATP + substrate peptide mixture (substrate final concentration 100 μg / mL, ATP final concentration 10 μM) and incubate at 37°C for 1 hour. Add 5 μL of ADP-Glo ​​to each well. TM Reagent, incubate at room temperature for 40 minutes to remove unreacted ATP. Add 10 μL of Kinase Detection Reagent to each well and incubate at room temperature for 30-60 minutes to convert the ADP generated in the reaction into ATP. Detect the fluorescence signal (luminescence: integration time 0.5 s). Calculate the inhibition rate, IC, for each well by averaging the 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.

[0139] Table 1: Inhibitory activity of compounds against RIPK1 enzyme

[0140]

[0141]

[0142] Among them, + represents IC 50 Less than (≤) 0.1 μM

[0143] As can be seen from Table 1, the compounds of the present invention have a significant inhibitory effect on RIPK1 enzyme.

[0144] Experimental Example 3: Effect of Compounds on the Recovery of I2.1 Cell Necrosis

[0145] The I2.1 cell line (a FADD mutant of human acute T-cell leukemia Jurkat cells, in which FADD protein is missing and TNFα alone can induce programmed necrosis) was tested using a CCK-8 cell counting kit (Dojindo).

[0146] I2.1 cells in the logarithmic growth phase were seeded at an appropriate density into 96-well culture plates and cultured overnight. Compounds were then added at varying concentrations. One hour later, 20 ng / mL of TNFα was added as a stimulation. Control wells without compound or stimulation (positive control) and without compound but with stimulation (negative control) were established. After 24 hours of exposure, the effects of the compounds on cell proliferation were assessed using a CCK-8 cell counting kit (Dojindo). 10 μL of CCK-8 reagent was added to each well. After incubation at 37°C for 2-4 hours, the cells were read using a SpectraMax 190 full-wavelength microplate reader at a wavelength of 450 nm.

[0147] The recovery rate (%) of the compound on programmed cell necrosis was calculated using the following formula:

[0148] Recovery rate (%) = (OD of drug administration well - OD of negative control well) / (OD of positive control well - OD of negative control well) × 100%

[0149] IC 50 The values ​​were calculated using GraphPad Prism software.

[0150] Table 2: Response rate of compounds to I2.1 cell death

[0151]

[0152]

[0153] Among them, "+" represents IC 50 Less than (≤) 1μM; “-” indicates IC 50 Greater than (>) 1μM

[0154] It can be seen from the above test results that, compared with "Comparative Compound 1", the compound of the present invention has a significant recovery effect on Hepa1-6 cell death induced by TNFα.

[0155] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, in, Cy 1 Select from the following groups: R 5 is independently selected at each occurrence from: H, D, halogen, C1-C8 alkyl; Cy 2 Selected from 0-5 R 8 substituted C6 aryl; R 4 is independently selected at each occurrence from: H, D, CH3, CD3; Each dashed line independently represents a single bond or a double bond; Z 1 Selected from: O, S, N, NH; Z 2 Selected from C(R z2 )2、N、CR z2 ; Each R z2 independently H; Z 3 , Z 4 is C; Ring A is a C6 aromatic ring, a 5-membered heteroaromatic ring, or a 6-membered heteroaromatic ring; m is selected from 1; R 1 For "R 7 -C≡C-”; R 7 Each occurrence is independently divided into 0-5 R 1a2 Replaced R 1a1 ; R 2 does not exist; R 3 Selected from: H, D, CH3, CD3; Y is O or S; R 6 Selected from: CD3, C1-C8 alkyl, halogenated C1-C8 alkyl, C6 aryl; R 8 is independently selected at each occurrence from: H, D, halogen, C1-C8 alkyl, halo-C1-C8 alkyl; R 1a1 is independently selected at each occurrence from the group consisting of C1-C8 alkyl, C3-C14 cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, (C6-C14 aryl)-(C1-C8 alkyl)-C(=O)O-; R 1a2 Independently selected at each occurrence are: H, D, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkoxy, hydroxy, mercapto, amino, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)(C1-C8 alkyl), cyano, NH2C(=O)-, oxo(=O), thioxo(=S).

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound represented by general formula (I) has the structure represented by formula (II):

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from formula (IV-1) and (IV-2): Among them, Cy 3 Select from the following groups: Z 5 Selected from CH or N; R 1 , m, Z 1 、R 3 、Cy 2 、R 5 、R 6 Same as the definition in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from (V-3), (V-4): Among them, Z 5 Selected from CH or N; R 1a1 、R 1 、R 3 , Z 1 、Cy 2 、R 5 Same as the definition in claim 1.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R 1 At each occurrence, independently selected from the group consisting of:

6. A compound selected from the group consisting of: or 7. A method for preparing the compound of formula (I) according to claim 1, characterized in that: The synthesis steps of the compound include at least one of Reaction Formula 1 and Reaction Formula 2: [Reaction formula 1] [Reaction formula 2] in, G 2 Selected from: -OH, halogen, C1-C8 alkoxy, C6-C14 aryloxy, -OC(=O)-(C1-C8 alkoxy), -OS(=O)-(C1-C8 alkoxy), -OS(=O)2-(C1-C8 alkoxy), -OC(=O)-(C6-C14 aryloxy), -OS(=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 Same as the definition in claim 1.

8. A pharmaceutical composition, characterized in that The invention comprises: a pharmaceutically acceptable carrier and one or more compounds according to any one of claims 1 to 6 or pharmaceutically acceptable salts thereof.

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