Amidated compounds having ripk1 inhibitory activity, methods of making and uses thereof

Abstract

Disclosed are an amide compound having RIPK1 inhibitory activity, a preparation method therefor, and a use thereof. The amide compound has a structure as shown in general formula I, and definitions of substituents are described in the specification and claims. The amide compound of the present application can be used for treating conditions and diseases such as inflammatory diseases, ischemic diseases, neurodegenerative diseases, tumors, and the like associated with RIPK1.

Description

Technical Field

[0001] This invention relates to amide compounds having receptor-interacting protein kinase 1 (RIPK1) inhibitory activity, their preparation methods and uses, particularly the use of such compounds or pharmaceutical compositions containing such compounds and therapeutic agents for treating inflammatory diseases, ischemic diseases, neurodegenerative diseases, tumors and other conditions and diseases associated with receptor-interacting protein kinase 1 (RIPK1). Background Technology

[0002] Protein kinases are proteins (enzymes) that regulate various cellular functions by phosphorylating specific amino acids on proteins. Proteins regulate their activity and binding capacity to their phosphate groups through conformational changes. The activity of a protein kinase refers to the rate at which the kinase binds a phosphate group to a substrate; this rate can be measured by detecting the amount of substrate converted into a product within a given time. Substrate phosphorylation occurs at the activation site of the protein kinase. Based on the types of amino acid residues phosphorylated in the substrate protein, protein kinases can be classified into five classes: serine / threonine protein kinases, tyrosine protein kinases, histidine protein kinases, tryptophan protein kinases, and aspartic / glutamic protein kinases. Serine / threonine protein kinases are enzymes that catalyze the phosphorylation of serine / threonine residues on various substrate proteins; tyrosine kinases are proteases that catalyze the transfer of adenosine triphosphate (ATP) to tyrosine residues in proteins. Pathological conditions associated with protein kinases include inflammatory diseases, immune diseases, cardiovascular diseases, and tumors, among others.

[0003] Cell death primarily includes apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death processes associated with autophagy and unprogrammed necrosis. Necrotosis, also known as programmed cell death or programmed necrosis, is a novel form of cell death discovered in recent years. Programmed necrosis is a highly inflammatory form of cell death that leads to the release of dangerous molecular patterns from cells and is considered an important pathological factor in various degenerative and inflammatory diseases. These diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degeneration, 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 components mediating necroptosis.

[0004] RIPK1 kinase is widely recognized as a potential therapeutic target for diseases related to programmed cell death. First-in-class RIPK1 inhibitors, such as Necrostatin-1 (Nec-1) and its analogues, have demonstrated clear efficacy in preclinical studies against various degenerative diseases, inflammation, and cancer. For example, it has alleviating effects on Alzheimer's disease, Parkinson's disease, Huntington's disease, and age-related macular degeneration; it has protective effects against psoriasis, retinitis pigmentosa, inflammatory bowel disease, autoimmune diseases, tadalafil-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 kidney injury, and traumatic brain injury; it can at least partially alleviate other diseases related to RIPK1-dependent apoptosis, necrosis, or cytokine production, including hematologic and solid organ malignancies, bacterial and viral infections (including tuberculosis, influenza, etc.), and lysosomal storage diseases (especially Gaucher disease). Another RIPK1 inhibitor, GSK2982772, is also in clinical trials for the treatment of various autoimmune diseases.

[0005] There is a demand for kinase inhibitors, especially RIPK1 kinase inhibitors, for use as pharmaceutical agents. However, existing inhibitors targeting programmed necrosis-associated kinases all have varying degrees of drawbacks, such as poor selectivity, insufficient in vivo inhibitory activity, poor pharmacokinetic properties, and low oral bioavailability. Some also cannot cross the blood-brain barrier to enter the central nervous system. These shortcomings limit their further research and clinical application. There is still a need in this field for more novel kinase inhibitors with novel chemical structures, better physicochemical properties, and more prominent pharmacodynamic and pharmacokinetic properties as candidate drugs for the detection, prevention, and treatment of diseases involving necrosis-associated kinases (such as RIPK1). Summary of the Invention

[0006] The purpose of this invention is to provide an inhibitor of RIPK1 kinase.

[0007] A first aspect of the present invention provides a compound of general formula (I) or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, or an isotopically labeled compound thereof.

[0008]

[0009] Z1 is selected independently from the following group each time it appears:

[0010]

[0011] Wherein, ring E is a 5-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N, O or S; wherein ring E is optionally substituted by 1 to 2 substituents selected from the following: D, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkoxy and halo-C1-C8 alkoxy, and wherein if the nitrogen atom in ring E is substituted, the substituent is not D, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, having an O or S atom directly bonded to the N atom;

[0012] Ring G is a 4- to 7-membered carbon ring, a C5-C14 aromatic ring, or a 4- to 7-membered heterocyclic ring or a 4- to 7-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N, O or S; preferably, ring G is a 5-membered carbon ring, or a 5-membered heterocyclic ring having 1 to 3 heteroatoms selected from N, O or S.

[0013] R 1 Each occurrence is independently composed of 1 to 5 identical or different R's. 1a Substituted or unsubstituted subgroups: C3-C14 cycloalkyl, 3-14 heterocyclic, C5-C14 aryl, 5-14 heteroaryl;

[0014] R 3 Each occurrence is independently composed of 1 to 5 identical or different R's. 3a Substituted or unsubstituted subgroups: C3-C14 cycloalkyl, 3-14 heterocyclic, C5-C14 aryl, 5-14 heteroaryl;

[0015] R is independently selected from H, D, C1-C8 alkyl, and halo-C1-C8 alkyl each time it appears;

[0016] Ring A is a six-membered heteroaryl ring; V1, V2, V3, and V4 are independently selected from the following groups: N, CR v N→O or N→S; at least one of V1, V2, and V3 is not CR. v ;

[0017] Ring Q is selected from C5-C14 aryl (such as C6-C14 aryl) and 5-14 heteroaryl with 1 to 3 heteroatoms selected from N, O or S;

[0018] Each time m appears, it is independently selected from 1, 2, 3, 4;

[0019] Each time n appears, it is independently selected from 0, 1, 2, and 3;

[0020] Each time p appears, it is independently selected from 0, 1, 2, 3, 4;

[0021] R vEach time it appears, it is independently selected from: H, D, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, C2-C8 alkenyl, halo-C2-C8 alkenyl, C2-C8 alkenyloxy, halo-C2-C8 alkenyloxy, C2-C8 alkynyl, halo-C2-C8 alkynyloxy, C2-C8 alkynyloxy, C3-C14 cycloalkyl, 3-14 member Heterocyclic groups, hydroxyl groups, hydroxyl-substituted C1-C8 alkyl groups, mercapto groups, mercapto-substituted C1-C8 alkyl groups, amino-substituted C1-C8 alkyl groups, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)(C1-C8 alkyl), cyano groups, cyano-substituted C1-C8 alkyl groups, NH2C(=O)-, (C1-C8 alkyl)-NHC(=O)-, (C1-C8 alkyl)(C1-C8 alkyl)NC(=O)-;

[0022] R 1a R 3a R 2 Each time it appears, it is independently assigned to 1-5 R values. 1a1 Substituted or unsubstituted subgroups: R 1a2 Oxide (=O), thioide (=S);

[0023] R 4 R 5a R 5b R 6 R 7 Each time it appears, it is independently assigned to 1-5 R values. 1a1 Replaced or unreplaced R 1a2 ;

[0024] R 1a2Each time it appears, it is independently selected from: H, D, halogen, CD3, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, C2-C8 alkenyl, halo-C2-C8 alkenyloxy, C2-C8 alkenyloxy, halo-C2-C8 alkenyloxy, C2-C8 alkynyl, halo-C2-C8 alkynyloxy, C3-C14 cycloalkyl, 3-14 membered heterocyclic, C6-C14 aryl, 5-14 membered heteroaryl. Benzo5-14 heteroaryl, hydroxyl, hydroxyl-substituted C1-C8 alkyl, mercapto, mercapto-substituted C1-C8 alkyl, amino, amino-substituted C1-C8 alkyl, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)(C1-C8 alkyl), cyano, cyano-substituted C1-C8 alkyl, -COOH, -(C1-C8 alkyl)-COOH, -C(=O)O-(C1-C8 alkyl), -(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)(C1-C8 alkyl)-, (C1-C 8-alkyl)-NHC(=O)-, (C1-C8 alkyl)(C1-C8 alkyl)NC(=O)-, (C1-C8 alkyl)-NHC(=O)-(C1-C8 alkyl)-, (C1-C8 alkyl)(C1-C8 alkyl)NC(=O)-(C1-C8 alkyl)-, HC(=O)NH-, HC(=O)N(C1-C8 alkyl)-, (C1-C8 alkyl)-C(=O)NH-, (C1-C8 alkyl)-C(=O)N(C1-C8 alkyl)-;

[0025] Each R 1a1 Each time it appears, it is independently selected from: H, D, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group;

[0026] Optional two R 1a1 They can form 3-6 membered ring structures together with the atoms they are attached to;

[0027] R 9 Each time it appears, it is randomly selected from 1-5 R's. 9a2 Replaced or unreplaced R 9a1 ;

[0028] R9a1 R 9a2 Optional 1-5 R 9a3 replace;

[0029] R 9a3 For "-Linker-R" 9a4 The above Linker is selected from: non-existent, bond, O, NH, NR. 9a4 , -C(=O)O-, -C(=O)NH-, -C(=O)NR 9a4 - 3-14 membered cycloalkyl, 3-14 membered heterocyclic, C6-C14 aryl, 5-14 membered heteroaryl;

[0030] Each R 9a1 R 9a2Each time it appears, it is independently selected from: H, D, halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkynyl, C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, (C3-C14 cycloalkyl)-(C1-C8 alkyl)-, (C3-C14 cycloalkyl)oxy, (C3-C14 cycloalkyl)-(C1-C8 alkyl)oxy, (C3-C14 cycloalkyl)oxy(C1-C8 alkyl) (C3-C14 cycloalkyl)thio, (C3-C14 cycloalkyl)-(C1-C8 alkyl)thio, (C3-C14 cycloalkyl)thio(C1-C8 alkyl)-, (C3-C14 cycloalkyl)NH-, (C3-C14 cycloalkyl)-(C1-C8 alkyl)-NH-, (C3-C14 cycloalkyl)-NH-(C1-C8 alkyl)-, (C3-C14 cycloalkyl)-C(=O)-, (C3-C14 cycloalkyl)-(C1-C8 alkyl)-C(=O)-, (C3-C14 cycloalkyl)C(=O)-(C1-C8 alkyl)-, (C3-C14 cycloalkyl)-C(=O)O-, (C3-C14 cycloalkyl)-(C1-C8 alkyl) -C(=O)O-, (C3-C14 cycloalkyl)-C(=O)O-(C1-C8 alkyl)-, (C3-C14 cycloalkyl)-OC(=O)-, (C3-C14 cycloalkyl)-(C1-C8 alkyl)-OC(=O)-, (C3-C14 cycloalkyl)-OC(=O)-(C1-C8 alkyl)-, (C3-C14 cycloalkyl)-C(=O)NH-, (C3-C14 cycloalkyl)-(C1-C8 alkyl)-C(=O)NH-, (C3-C14 cycloalkyl)-C(=O)NH-(C1-C8 alkyl)-, (C3-C14 cycloalkyl)-NHC(=O)-, (C3-C14 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-(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)-(C1-C8 alkyl)-(C3-C14 cycloalkyl)-, (C1-C8 alkyl)-(C3-C14 cycloalkyl)-(C1-C8 alkyl)-, 3-14 membered heterocyclic group, (3-14 membered heterocyclic group)-(C1-C8 alkyl)-, (3-14 membered heterocyclic group)oxy group ... (3-14-membered heterocyclic)-(C1-C8 alkyl)-oxy, (3-14-membered heterocyclic)oxy-(C1-C8 alkyl)-, (3-14-membered heterocyclic)thio, (3-14-membered heterocyclic)-(C1-C8 alkyl)-thio, (3-14-membered heterocyclic)thio-(C1-C8 alkyl)-, (3-14-membered heterocyclic)NH-, (3-14-membered heterocyclic))(C1-C8 alkyl)NH-, (3-14-membered heterocyclic)-NH-(C1-C8 alkyl)-, (3-14-membered heterocyclic)-C(=O)-, (3-14-membered heterocyclic)-(C1-C8 alkyl)-C(=O)-, (3-14-membered heterocyclic)-C(=O)-(C1-C8 alkyl ...(C1-C8 alkyl)-, (3-14-membered heterocyclic)-(C1-C8 alkyl)-(C1-C8 alkyl)-(C1-C8 alkyl)-(C1-C8 alkyl)-(C1-C8 alkyl)-(C1- (3-14-membered heterocyclic)-C(=O)O-, (3-14-membered heterocyclic)-(C1-C8 alkyl)-C(=O)O-, (3-14-membered heterocyclic)-C(=O)O-(C1-C8 alkyl)-, (3-14-membered heterocyclic)-OC(=O)-, (3-14-membered heterocyclic)-(C1-C8 alkyl)-OC(=O)-, (3-14-membered heterocyclic)-OC(=O)-(C1-C8 alkyl)-, (3-14-membered heterocyclic)-C(=O)NH-, (3-14-membered heterocyclic)-(C1-C8 alkyl)-C(=O)NH-, (3-14-membered heterocyclic)-C(=O)NH-(C1-C8 alkyl)-, (3-14-membered heterocyclic)-NHC(=O)-,(3-14-membered heterocyclic)-(C1-C8 alkyl)-NHC(=O)-, (3-14-membered heterocyclic)-NHC(=O)-(C1-C8 alkyl)-, (C1-C8 alkyl)-(3-14-membered heterocyclic)-, hydroxy(3-14-membered heterocyclic)-, (C1-C8 alkoxy)-(3-14-membered heterocyclic)-, hydroxy(C1-C8 alkyl)-(3-14-membered heterocyclic)-, mercapto(C3-C14 cycloalkyl), (C1-C8 alkylthio)-(3-14-membered heterocyclic)-, mercapto(C1-C8 alkyl)-(3-14-membered heterocyclic)-, amino(3-14-membered heterocyclic), (C1-C8 alkyl)NH-(3-14-membered heterocyclic)-, amino(C1-C8 Alkyl)-(3-14 membered heterocyclic)-, HC(=O)-(3-14 membered heterocyclic)-, (C1-C8 alkyl)-C(=O)-(3-14 membered heterocyclic)-, HC(=O)-(C1-C8 alkyl)-(3-14 membered heterocyclic)-, HC(=O)O-(3-14 membered heterocyclic)-, (C1-C8 alkyl)-C(=O)O-(3-14 membered heterocyclic)-, HC(=O)O-(C1-C8 alkyl)-(3-14 membered heterocyclic)-, HOC(=O)-(3-14 membered heterocyclic)-, (C1-C8 alkyl)-OC(=O)-(3-14 membered heterocyclic)-, HO-C(=O)-(C1-C8 alkyl)-(3-14 membered heterocyclic)- , HC(=O)NH-(3-14 membered heterocyclic)-, (C1-C8 alkyl)C(=O)NH-(3-14 membered heterocyclic)-, HC(=O)NH-(C1-C8 alkyl)-(3-14 membered heterocyclic)-, NH2C(=O)-(3-14 membered heterocyclic)-, (C1-C8 alkyl)NHC(=O)-(3-14 membered heterocyclic)-, NH2C(=O)-(C1-C8 alkyl)-(3-14 membered heterocyclic)-, (C1-C8 alkyl)-(3-14 membered heterocyclic)-(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)-, 5-14 heteroaryl, (5-14 heteroaryl)-(C1-C8 alkyl)-, (5-14 heteroaryl)oxy, (5-14 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)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)-, hydroxyl, hydroxyl-substituted C1-C8 alkyl, mercapto, mercapto-substituted C1-C8 alkyl, ammonia C1-C8 alkyl groups substituted with alkyl, amino, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)(C1-C8 alkyl), cyano, cyano-substituted C1-C8 alkyl groups, -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)- with one or two C1-C8 alkyl substituted, NH2C(O)- with one or two C1-C8 cycloalkyl substituted, NH2C(O)- with one or two C6-C14 aryl substituted, NH2C(O)- with one or two 5-14 heteroaryl substituted, NH2C(O)- with one or two 4-10 heterocyclic substituted, NH NH2C(O)-(C1-C8 alkyl)-, NH2C(O)-(C1-C8 alkyl)- with one or two C1-C8 alkyl substituted groups, NH2C(O)-(C1-C8 alkyl)- with one or two C1-C8 cycloalkyl substituted groups, NH2C(O)-(C1-C8 alkyl)- with one or two C6-C14 aryl substituted groups, NH2C(O)-(C1-C8 alkyl)- with one or two 5-14 heteroaryl substituted groups, NH2C(O)-(C1-C8 alkyl)- with one or two 4-10 heterocyclic substituted groups, oxo(=O), thio(=S);

[0031] R 9a4Selected from: H, D, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C2-C8 alkenyl, halo-C2-C8 alkenyl, C2-C8 ynyl, halo-C2-C8 ynyl, (C1-C15 alkyl)-OC(=O)-, (C6-C14 aryl)-OC(=O)-, (4-12-membered heterocyclic)-OC(=O)-, (5-14-membered heteroaryl)-OC(=O)-, (C1-C15 alkyl)-C(=O)-, (C6-C14 aryl)-C(=O)-, (4-12-membered heterocyclic)-C(=O)-, (5-14-membered heteroaryl)-C(=O)-, (C1-C15 alkyl)-C(=O)O-, (C6-C14 aryl) ( )-C(=O)O-, (4-12-membered heterocyclic)-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 heterocyclic)-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 heterocyclic)-C(=O)-, (halogenated 5-14-membered heteroaryl)-C(=O)-, (halogenated C1-C15 alkyl)-C(=O)O-, (halogenated C6-C1 4-aryl)-C(=O)O-, (halogenated 4-12-membered heterocyclic)-C(=O)O-, (halogenated 5-14-membered heteroaryl)-C(=O)O-, C1-C8 alkyl-substituted (C1-C15 alkyl)-OC(=O)-, C1-C8 alkyl-substituted (C6-C14 aryl)-OC(=O)-, C1-C8 alkyl-substituted (4-12-membered heterocyclic)-OC(=O)-, C1-C8 alkyl-substituted (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 (4- (12-membered heterocyclic)-C(=O)-, (5-14-membered heteroaryl)-C(=O)-, (C1-C8 alkyl-substituted)-C(=O)O-, (C1-C8 alkyl-substituted)-C6-C14 aryl)-C(=O)O-, (4-12-membered heterocyclic)-C(=O)O-, (5-14-membered heteroaryl)-C(=O)O-, (C1-C8 alkyl)3-Si-(C1-C8 alkyl)-O-(C1-C8 alkylene)-, (C1-C8 alkyl)-OC(=O)-(C1-C8 alkyl)C(=O)O-, halogen-substituted or unsubstituted (C1-C8 alkyl)-OC(=O)-(C1-C8 alkyl)C(=O)O-,Halogen-substituted or unsubstituted (C1-C8 alkyl)-OC(=O)-(C3-C14 cycloalkyl)C(=O)O-, glycosyl, -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, -O--P(=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, halo-C1-C16 alkyl, C6-C14 aryl, halo-C6-C14 aryl;

[0032] Among them, two Rs are optional 9a1 They can form 4-15 membered ring structures together with the atoms they are attached to;

[0033] Among them, two Rs are optional 9a2 They can form 4-15 membered ring structures together with the atoms they are attached to;

[0034] R 8 It is not H, D, or alkyl, and R 8 Each time it appears, select independently from the following group:

[0035] (a) by 1-5 R 9a2 Replaced or unreplaced R 9a1 At this time R 9a1 Not H, C1-C8 alkyl;

[0036] (b) by 1-5 R 9a2 Substituted C1-C8 alkyl groups, wherein at least one of the R groups is substituted on the C1-C8 alkyl group. 9a2 Not H, C1-C8 alkyl;

[0037] (c) by 1-5 R 9a3 0-5 R 9a2 Substituted C1-C16 alkyl groups, wherein at least one of the R groups is substituted on the C1-C8 alkyl group. 9a3 It is not H or C1-C8 alkyl.

[0038] In another preferred embodiment, the compound is selected from formulas (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), and (III-8):

[0039]

[0040]

[0041] Among them, W1 is independently selected from the following group each time it appears: -CH2-, -O-;

[0042] W2 is selected independently from the following group each time it appears: -NH-, -O-, -S-;

[0043] R, R 1 R 2 V1, V2, V3, V4, R 8 R 9 The definitions of m, n, ring A, and ring Q are as described above.

[0044] In another preferred embodiment, the compound is selected from the compounds shown in formula (IV-1) and formula (IV-2):

[0045]

[0046] Among them, R 1 R 2 V4, R v R 8 R 9 The definition is as described above.

[0047] In another preferred embodiment, ring Q is selected from phenyl;

[0048] Ring A is a 6-membered heteroaryl group having 1 to 3 heteroatoms selected from N, O or S, preferably ring A is pyridyl and V1 is N;

[0049] R 8 It is a C1-C8 alkoxy, cyano, -CONH2, hydroxy, amino, or -CONH (C3-C6 cycloalkyl); optionally surrounded by 1-5 R... 9a2 Replacement, where each R 9a2Independently selected from: C1-C8 alkyl, hydroxyl, -CONH2, -OCO phenyl, -CONH (C3-C6 cycloalkyl);

[0050] R 9 It can be H, halogen, halogenated C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy;

[0051] R is H or a C1-C4 alkyl group;

[0052] Ring E is a 5-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N, O or S;

[0053] Ring G is a 5-membered heterocycle having 1 to 3 heteroatoms selected from N, O or S;

[0054] R 1 Each occurrence is independently composed of 1-3 identical or different R's. 1a Substituted or unsubstituted subgroups: C3-C6 cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; each R 1a Each time it appears, it is independently a halogen, a halo-C1-C4 alkyl, a C1-C4 alkyl, a halo-C1-C4 alkoxy, or a C1-C4 alkoxy.

[0055] R 2 Each time it appears, it is independently H, halogen, C1-C4 alkyl, or C1-C4 alkoxy; or two Rs. 2 They can form 3-6 membered ring structures together with the atoms they are attached to;

[0056] R 3 Each occurrence is independently composed of 1 to 3 identical or different R's. 3a Substituted or unsubstituted subgroups: C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; each R 3a Each time it appears, it is independently a halogen, a halo-C1-C4 alkyl, a C1-C4 alkyl, a halo-C1-C4 alkoxy, or a C1-C4 alkoxy.

[0057] R 4 Each time it appears, it is independently H, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, halo-C1-C4 alkoxy or C1-C4 alkoxy;

[0058] R 6 Each time it appears, it is independently H, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, halo-C1-C4 alkoxy or C1-C4 alkoxy;

[0059] R 7Each time it appears, it is independently H, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, halo-C1-C4 alkoxy or C1-C4 alkoxy;

[0060] R 5a Each time it appears, it is independently H, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, or C1-C4 alkoxy.

[0061] In another preferred embodiment, the compound is selected from one of the compounds listed in claim 5.

[0062] A second aspect of the present invention provides a method for preparing the compound represented by formula (I) of the first aspect, wherein the synthesis steps include at least one of the reaction formulas 1 and 2:

[0063] [Reaction Formula 1]

[0064]

[0065] [Reaction 2]

[0066]

[0067] Among them, R a 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);

[0068] R b Selected from: H, -C(=O)-Z1, R 9a4 ;

[0069] R c R d Selected from: -OH, halogen, -Mg-X, -Li, -Na, -K, -B(OH)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl, 1,3,2-dioxaborane-2-yl, 1,3,2-dioxaborane-2-yl, benzo[d][1,3,2]-dioxaborane-2-yl;

[0070] X is selected from F, Cl, Br, and I;

[0071] R, Z1, V1, V2, V3, V4, R 8 R 9 R 9a4The definitions of m, n, ring A, and ring Q are as described above.

[0072] A third aspect of the present invention provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and one or more of the compounds described in the first aspect or their stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, or isotopically labeled compounds.

[0073] A 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 thereof, their prodrugs, their hydrates or solvates, or the pharmaceutical composition described in the third aspect.

[0074] A fifth aspect of the invention provides the use of the compound of the first aspect or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, isotopically labeled compounds or pharmaceutical compositions of the third aspect for the preparation of a medicament used for: 1) detecting and / or preventing and / or treating kinase-related diseases; 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 degenerative diseases; 5) detecting and / or preventing and / or treating tumor-related diseases; 6) detecting and / or preventing and / or treating cell necrosis-related diseases; 7) detecting and / or preventing and / or treating metabolic-related diseases; or 8) detecting and / or preventing and / or treating eye diseases.

[0075] A fifth aspect of the invention provides the use of the compounds of the first aspect or their stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, isotopically labeled compounds or pharmaceutical compositions of the third aspect for the preparation of medicaments for the detection and / or prevention and / or treatment of diseases selected from the group consisting of:

[0076] Systemic juvenile idiopathic arthritis, Behcet's disease, interleukin-1 converting enzyme-related fever syndrome, sepsis, alopecia areata, allergic diseases, 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, regional ileitis, antiphospholipid syndrome, Crohn's disease, ulcerative colitis, 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, prions, adrenocortical... Degeneration, nephritis, Schlewynn syndrome, surgical infection, atopic dermatitis, Wegener's granulomatosis, systemic lupus erythematosus, asthma, COVID-19, vasculitis, periodontitis, inflammatory bowel disease, pancreatitis, organ transplant exclusion, 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 ganglioside storage disease, GM2 ganglioside storage disease, AIDS-related dementia syndrome, Tau proteinosis, Alzheimer's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, multiple sclerosis, frontotemporal dementia, Faber's disease, Friedreich ataxia, Guillain-Barré syndrome, Huntington's 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 diseases, chronic inflammatory demyelinating polyneuropathy, Niemann-Pick disease, corticobasal degeneration, lysosomal storage diseases, Sandhoff's disease, ganglion cell diseases, neuronal ceroid lipofuscin deposition, postoperative cognitive impairment, bipolar disorder, diabetic neuropathy, pain (neuralgic pain), delirium, depression, peripheral neuropathy, autism, trauma, traumatic brain injury, focal ischemia, traumatic retinal injury, cerebrovascular accident, stroke, genomic atrophy, acetaminophen poisoning, acute liver failure, acute kidney injury, acute respiratory distress syndrome. Syndrome, intracranial hemorrhage, cerebral hemorrhage, cerebral ischemia, ischemia, ischemic injury, hypoxic brain injury, hypoxia, burns, burn shock, ischemia-reperfusion injury of solid organs, cisplatin-induced kidney injury, smoking-induced injury, myocardial infarction, heart failure, toxic epidermal necrolysis, acute tubular necrosis, heart failure, NF-κB key regulatory gene mutation, leukemia, myeloid leukemia, lymphocytic leukemia, T-cell leukemia, lymphoma, T-cell lymphoma, nasopharyngeal carcinoma, epidermoid carcinoma, pituitary adenoma, biliary carcinosarcoma, cholangiocarcinoma, multiple myeloma, childhood solid tumors, Hodgkin's disease, non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, anal region cancer, testicular cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancerBone cancer, osteosarcoma, melanoma, environmentally induced cancers, spinal tumors, thyroid cancer, parathyroid cancer, glioblastoma, colorectal cancer, Kaposi's sarcoma, squamous cell carcinoma, glioma, endocrine system cancers, urethral cancer, bladder cancer, skin cancer, malignant melanoma of the skin or eye, prostate cancer, triple-negative breast cancer, glioma, kidney or ureter cancer, renal pelvis cancer, adrenal cancer, malignant tumors of solid organs, esophageal cancer, fallopian tube cancer, head and / or neck cancer, vulvar cancer, gastric cancer, gastrointestinal stromal tumors, small intestine Cancer, hematologic malignancies, pancreatic cancer, hereditary aortic aneurysms, vaginal cancer, penile cancer, rectal cancer, tumor angiogenesis, macular degeneration, macular hole, macular telangiectasia, dry eye syndrome, progressive retinal atrophy, Leber's congenital amaurosis, cystic macular edema, age-related macular degeneration, glaucoma, retinal neurodegeneration, ischemic optic neuropathy, ischemic retinopathy, diabetic retinopathy, retinitis pigmentosa, retinal photoreceptor diseases, retinal degenerative diseases, optic nerve diseases, retinal detachment. Iatrogenic retinal injury, retinal vascular disease, cone-rod dystrophy, choroidal agenesis, fundus diseases, ocular vascular diseases, Ussell's syndrome, type 1 diabetes, non-alcoholic fatty liver disease, vitiligo, sialic acid storage disease, irritable bowel syndrome, Danon's disease, cholesterol ester storage disease, Wollman's disease, hypolipidemia, atherosclerosis, multiple sulfatase deficiency, Fabry disease, Gaucher disease, myelofibrosis, osteoporosis, cystine storage disease, muscular dystrophy, polyglutamine disorders, Krabby's disease, chronic kidney disease. Menx disease, cystic fibrosis, Pompeii disease, Tay-Sachs II disease, lysosomal acid lipase deficiency, aspartic glucosamineuria, gout, Wilson's disease, mitochondrial diseases, fucoside storage disease, metachromatic leukodystrophy, hygrosomal acid lipase deficiency, mucopolysaccharidosis, mucolipidemia, osteogenesis imperfecta condensans, hemochromatosis, Niemann-Pick disease, Heme-oxidized IRP2 ubiquitin ligase-1 deficiency, osteonecrosis, chain ubiquitin chain assembly complex deficiency syndrome, cilia.

[0077] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described 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, equivalent, or similar purpose. Due to space limitations, they will not be described in detail here. Specific implementation methods

[0078] Through long-term and in-depth research, the inventors unexpectedly developed a compound of general formula (I) with a novel structure and significant kinase inhibitory activity. This kinase inhibitor exhibits excellent RIPK1 inhibitory activity and can therefore be used to prepare pharmaceutical compositions for the detection and / or prevention and / or treatment of diseases involving cell death and / or related conditions. Based on this, the inventors completed this invention.

[0079] the term

[0080] Unless otherwise expressly indicated, the terms used in this invention and herein have the following meanings:

[0081] The terms "C1-C6" refer to having 1, 2, 3, 4, 5, or 6 carbon atoms, "C1-C8" refers to having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and so on. "5-8" refers to having 5-8 ring atoms, and so on.

[0082] A "substituent" refers to an atom or group that can replace a hydrogen atom in a substituted compound. Examples are as follows (but are not limited to): deuterated, alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, isocyanate, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, 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 Each time it appears, it is independently selected 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 Together with the atoms they are attached to, they can form ring structures. Those skilled in the art will understand that the combinations of substituents and substituted substances contemplated in this invention are those stable or chemically feasible combinations.

[0083] "Substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents at each position may be the same or different. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Such substituents include (but are not limited to): alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, 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 is the same as above.

[0084] "alkyl" refers to a saturated aliphatic hydrocarbon group, which may be straight-chain or branched. The alkyl group may be independently substituted by one or more substituents described in this invention. 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. The alkyl group may be optionally substituted or unsubstituted.

[0085] "Alkenyl" refers to a straight-chain or branched hydrocarbon group, wherein at least one C group is sp. 2 The double bond, wherein the alkenyl group may be independently and optionally replaced by one or more substituents described in this invention, wherein specific examples include, but are not limited to, vinyl, allyl, allyl, and alkyl groups. And so on. The alkenyl group can be optionally substituted or unsubstituted.

[0086] "Alynyl" refers to a straight-chain or branched hydrocarbon group, wherein at least one C-C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described in this invention, specific examples including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be optionally substituted or unsubstituted.

[0087] "Ring structure" refers to monocyclic or polycyclic structures. Typically, it is a closed structure formed by the connection of two or more segments on a single atom in a ring structure. Examples include, but are not limited to, cycloalkanes, heterocyclic alkanes, cyclic lactams, aromatics, heteroaromatics, fused rings, bridged rings, and spirocyclic structures, such as cyclopropane, cyclobutane, oxacyclobutane, cyclopentane, cyclohexane, adamantane, cyclohexene, cyclooctyne, pyrazole, benzene, pyridine, 3,4-dihydro-1,4-benzoxazolopyridine-5(2H)-one, naphthalene, anthracene, phenanthrene, quinoline, pyrrolopyridine, pyrazolopyridine, indole, dihydroindole, steroidal rings, and porphyrin rings. The ring structure can 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, thus allowing it to act as a substituent for the substituted substance.

[0088] "Halogen" refers to F, Cl, Br, or I. "Halogenated" means substituted by one or more halogens.

[0089] "Aryl" refers to a carbocyclic aromatic system containing one or more rings, wherein the rings do not contain heteroatoms. Optionally, the aryl group may be fused with a heteroaryl, heterocyclic, or other ring structure. Examples are as follows (but are not limited to): phenyl, naphthyl, tetrahydronaphthyl, ... 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 connected to the parent structure has 6-14 carbon atoms, but the aryl group may optionally be fused with other ring structures, which refer to ring structures with 3-18 ring atoms, and these other ring structures may be optionally substituted or unsubstituted.

[0090] "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 atoms. Optionally, the aryl group may be fused with an aryl, heterocyclic, cycloalkyl, or other ring structure. Examples are as follows (but not limited to): furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, 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 group", it means that the heteroaryl group and the parent structure together form a heteroaryl ring with 5-14 ring atoms. However, the heteroaryl group may optionally be fused with other ring structures, which refer to ring structures with 3-18 ring atoms. These other ring structures may be optionally substituted or unsubstituted.

[0091] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The first ring structure directly attached to the substituted compound is non-aromatic. Examples of monocyclic cycloalkyl groups (but not limited to the following): cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, cyclooctyynyl, etc.; Examples of polycyclic cycloalkyl groups (but not limited to the following): spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Optionally, the cycloalkyl group may be fused with an aryl, heterocyclic, cycloalkyl, or other cyclic structure to form a spirocyclic ring. Examples of fusion with other cyclic structures to form a spirocyclic ring (but not limited to the following): 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. However, the cycloalkyl group may optionally be fused with other ring structures or form a spiro ring. The other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.

[0092] "Heterocyclic group" refers to a monocyclic or polycyclic cyclic structure in which at least one ring atom is a heteroatom (e.g., O, N, S atoms, etc.) and is saturated or partially unsaturated. Examples are as follows (but not limited to): tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroliyl, tetrahydrothiophenyl, piperidinyl, piperazine, aziridine, aziridine-butyl, aziridine-heptyl, morpholinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, etc. The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is the heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted. When the heteroalkyl group is described as a "3-14 membered heterocyclic group", it means that the heterocyclic group connected to the parent structure has 3-14 ring atoms. However, the heterocyclic group may be fused with other ring structures or form a spirocyclic ring. The other ring structures refer to ring structures with 3-18 ring atoms. The other ring structures may be optionally substituted or unsubstituted.

[0093] "Tautomers" refer to structural isomers with different energies that can cross a low energy barrier and thus interconvert. For example, proton tautomers (i.e., proton transfers) include interconversion through proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomers include interconversion through some bonding electron recombination. "Stereoisomers" refer to molecules with atoms of the same connectivity but different spatial arrangements. For example, two compounds containing one chiral center and having the same two-dimensional connectivity, such as R-glyceraldehyde and S-glyceraldehyde, R-serine and S-serine. "Enantiomers" refer to stereoisomers that are mirror images of each other and cannot be superimposed. For example, R-serine and S-serine. "Diabeta-isomers" refer to stereoisomers with two or more chiral centers and non-mirror image relationships between molecules. For example, tartaric acid. "Restricted rotation isomers" refer to a group of conformational isomers of a molecule that exist because rotation around a single bond is hindered. For example, the various stereoisomers of 6,6'-dinitro-2,2'-biphenyldicarboxylic acid. "Optical isomers" refer to compounds that have the same two-dimensional linkage but exhibit different optical properties due to differences in configuration. For example, levorotatory amlodipine and dextrorotatory amlodipine. "Racemates" refer to compounds that have the same two-dimensional linkage but are optical isomers of each other; when mixed together, they ultimately exhibit no optical activity. Racemic amlodipine is an example.

[0094] The term "amino acid acyl group" refers to the conversion of the carboxyl group of an amino acid into an acyl group, through which the acyl group is attached to a substituent in the substituted product. Exemplary examples include, but are not limited to, the structure of a glycine acyl group, which is obtained by converting the carboxyl group of glycine (NH2-CH2-COOH) into an acyl group, yielding 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, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, pyrrolidone, β-alanine, etc.

[0095] The term "glycosyl" refers to a substituent formed by providing a hemiacetal hydroxyl group in a monosaccharide or oligosaccharide. The monosaccharides include aldoses and ketoses. The monosaccharides include trioses, tetroses, pentoses, hexoses, and heptoses. The oligosaccharides, also known as oligosaccharides, refer to compounds containing 2-11 monosaccharides polymerized by glycosidic bonds. Examples of monosaccharides or polysaccharides are as follows (but not limited to): erythrose, threose, arabinose, ribose, xylose, lysolose, glucose, mannose, fructose, galactose, lactose, sucrose, maltose, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

[0096] The pharmaceutically acceptable salts described in this invention can be salts formed by anion and a positively charged group on a compound of Formula I. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, or maleate. Similarly, salts can be formed by cations and negatively charged groups on a compound of Formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium ions.

[0097] In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt formed by a 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, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid; or a sodium, potassium, calcium, aluminum, or ammonium salt formed by a compound of Formula I with an inorganic base; or a methylamine, ethylamine, or ethanolamine salt formed by a 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 the compound of the present invention or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, or isotopically labeled compounds.

[0100] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to 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 of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0101] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that 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 and with the compounds of the present invention without significantly reducing the efficacy of the compounds. 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0102] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0103] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local 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 components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0105] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0106] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0107] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0108] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol 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 of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0111] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

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

[0113] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0114] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions (such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0115] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this 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)hexafluorophosphate urea

[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: tetrakis(triphenylphosphine)palladium

[0121] DPPA: Diphenyl azidophosphate; 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] 128 mg of 5-(3-bromo-4-methylphenoxy)-2-methylpentane-2-ol, 1.3 equivalents of pinacol 2-aminopyridine-4-boronic acid, 33 mg of Pd(dppf)Cl2, and 141 mg of Na2CO3 were added to a mixture of 1.5 mL of 1,4-dioxane and 0.5 mL of water. Argon gas was purged, and the mixture was reacted at 90 °C for 2 hours under an argon atmosphere. The resulting reaction mixture was poured into water, extracted three times with ethyl acetate, and the combined ethyl acetate layers were washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give (IM-1), yield: 95 mg, 71%. 1 H NMR (400MHz, CDCl3) δ8.08(dd,J=5.2,0.8Hz,1H),7.15(d,J=8.4Hz,1H),6.83(dd,J=8.4,2.7Hz,1H),6.74(d,J=2.8Hz,1H),6.62(dd,J= 5.3,1.5Hz,1H),6.48–6.40(m,1H),4.49(s,2H),3.98(t,J=6.3Hz,2H),2.19(s,3H),1.93–1.84(m,2H),1.68–1.60(m,2H),1.26(s,6H).

[0127] Example 2:

[0128]

[0129] 52 mg of (IM-1), 33 mg of (Acid-1), 82 mg of HATU, and 60 μL of TEA were dissolved in 1 mL of DMF, and the mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was poured into water, extracted three times with ethyl acetate, and the combined ethyl acetate layers were washed five times with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to give (I-1), yield: 21 mg, 24%. 1 H NMR(400MHz, Acetone-d6)δ9.59(s,1H),8.39(dd,J=5.1,0.8Hz,1H),8.37–8.29(m,1H),7.46–7.33(m,3H),7.33–7.2 8(m,2H),7.23(d,J=8.4Hz,1H),7.16(dd,J=5.1,1.6Hz,1H),6.91(dd,J=8.4,2.7Hz,1H),6.85(d,J=2.7Hz,1H),5.70–

[0130] 5.62(m,1H),4.02(t,J=6.6Hz,2H),3.42–3.31(m,1H),3.27(s,1H),3.25–3.16(m,1H),3.15–3.06(m,1H) ,2.78–2.67(m,1H),2.23(s,3H),1.92–1.82(m,2H),1.63–1.56(m,2H),1.19(s,6H).LC-MS:512.3([M+H] + ).

[0131] Example 3:

[0132]

[0133] Using a method similar to that in Example 2, (I-2) was obtained by using (IM-1) and (Acid-2) as starting materials. 1H NMR (400MHz, Acetone-d6) δ13.06(s,1H),8.47–8.35(m,2H),7.72–7.60(m,5H),7.22(d,J=8.4Hz,1H),7.14(dd,J=5.1,1.4Hz,1H),6.97–6.80(m ,3H),4.01(t,J=6.6Hz,2H),3.24(s,1H),2.35–2.29(m,3H),2.23(s,3H) ,1.91–1.82(m,2H),1.65–1.56(m,2H),1.18(s,6H).LC-MS:513.4([M+H] + ).

[0134] Example 4:

[0135]

[0136] Using a method similar to that in Example 2, (I-4) was obtained by using (IM-1) and (Acid-4) as starting materials. 1 H NMR(400MHz,DMSO-d6)δ13.09(s,1H),8.40(d,J=5.2Hz,1H),8.38(s,1H),8.24(s,1H) ,7.62(s,5H),7.23(d,J=8.4Hz,1H),7.15(d,J=5.1Hz,1H),6.91(dd,J=8.4,2.6Hz,1H ),6.78(d,J=2.6Hz,1H),6.68(s,1H),4.17(s,1H),3.95(t,J=6.4Hz,2H),2.18(s,3H) ,2.08(s,3H),1.80–1.68(m,2H),1.53–1.42(m,2H),1.09(s,6H).LC-MS:512.3([M+H] + ).

[0137] Example 5:

[0138]

[0139] Using a method similar to that in Example 2, (I-5) was obtained by using (IM-1) and (Acid-5) as starting materials. 1H NMR (400MHz, Methanol-d4) δ8.54(d,J=1.7Hz,1H),8.29(d,J=5.5Hz,2H),7. 57–7.45(m,3H),7.32(d,J=7.5Hz,2H),7.21(d,J=8.1Hz,1H),7.11(d,J=5.2H z,1H),6.89(d,J=9.0Hz,1H),6.80(s,1H),3.99(t,J=6.4Hz,2H),2.22(s,3H ),1.85(s,2H),1.65–1.59(m,2H),1.22(d,J=1.6Hz,6H).LC-MS:515.3([M+H] + ).

[0140] Example 6:

[0141]

[0142] Using a method similar to that in Example 2, (I-6) was obtained by using (IM-1) and (Acid-6) as starting materials. 1 H NMR (400MHz, DMSO-d6) δ12.94 (s, 1H), 11.36 (s, 1H), 8.43 (d, J = 5.2Hz, 1H), 8.16 (s, 1H) ),7.59–7.50(m,4H),7.47(d,J=6.5Hz,1H),7.24(t,J=7.5Hz,2H),6.96–6.88(m,1H), 6.80(d,J=2.7Hz,1H),4.17(d,J=1.7Hz,1H),3.99–3.92(m,2H),2.18(s,3H),1.74(t, J=7.8Hz,2H),1.47(dd,J=10.4,5.7Hz,2H),1.09(d,J=1.7Hz,6H).LC-MS:516.3([M+H] + ).

[0143] Example 7:

[0144]

[0145] Using a method similar to that in Example 2, (I-7) was obtained by using (IM-1) and (Acid-7) as starting materials. 1H NMR (400MHz, Methanol-d4) δ8.34(s,1H),8.26(s,1H),7.71(d,J=7.6Hz,2H),7.57(d,J=8.0Hz,2H),7.53(d,J=6.9Hz,1H),7.24(d,J=8.4Hz,1H),7.17(s ,1H),7.02(s,1H),6.92(d,J=8.4Hz,1H),6.83(s,1H),4.02(s,2H),2.62(s, 3H),2.25(s,3H),1.87(s,2H),1.65(s,2H),1.24(s,6H).LC-MS:513.3([M+H] + ).

[0146] Example 8:

[0147]

[0148] Using a method similar to that in Example 2, (I-8) was obtained by using (IM-1) and (Acid-8) as starting materials. 1 H NMR(400MHz, Methanol-d4)δ8.48(d,J=2.7Hz,1H),8.38(d,J=5.1Hz,1H),8.22–8.13( m,2H),7.66–7.49(m,5H),7.23(d,J=8.4Hz,1H),7.15(dd,J=5.1,1.6Hz,1H),6.91(dd ,J=8.4,2.7Hz,1H),6.82(d,J=2.6Hz,1H),6.72(d,J=9.6Hz,1H),4.01(t,J=6.4Hz,2H ),2.24(s,3H),1.91–1.83(m,2H),1.68–1.61(m,2H),1.24(s,6H).LC-MS:498.1([M+H] + ).

[0149] Example 9:

[0150]

[0151] Using a method similar to that in Example 2, (I-9) was obtained by using (IM-1) and (Acid-9) as starting materials. 1H NMR(400MHz, Acetone-d6)δ9.59(s,1H),8.39(dd,J=5.1,0.8Hz,1H),8.37–8.29(m,1H),7.46–7.33(m,3H),7.3 3–7.28(m,2H),7.23(d,J=8.4Hz,1H),7.16(dd,J=5.1,1.6Hz,1H),6.91(dd,J=8.4,2.7Hz,1H),6.85(d,J=2.7H z,1H),5.70–5.62(m,1H),4.02(t,J=6.6Hz,2H),3.42–3.31(m,1H),3.27(s,1H),3.25–3.16(m,1H),3.15–3.06 (m,1H),2.78–2.67(m,1H),2.23(s,3H),1.92–1.82(m,2H),1.63–1.56(m,2H),1.19(s,6H).LC-MS:512.3([M+H] + ).

[0152] Example 10:

[0153]

[0154] Using a method similar to that in Example 2, (I-10) was obtained by using (IM-1) and (Acid-10) as starting materials. 1 HNMR(400MHz, Acetone-d6)δ9.59(s,1H),8.39(dd,J=5.1,0.8Hz,1H),8.37–8.29(m,1H),7.46–7.33(m,3H),7. 33–7.28(m,2H),7.23(d,J=8.4Hz,1H),7.16(dd,J=5.1,1.6Hz,1H),6.91(dd,J=8.4,2.7Hz,1H),6.85(d,J=2.7H z,1H),5.70–5.62(m,1H),4.02(t,J=6.6Hz,2H),3.42–3.31(m,1H),3.27(s,1H),3.25–3.16(m,1H),3.15–3.06 (m,1H),2.78–2.67(m,1H),2.23(s,3H),1.92–1.82(m,2H),1.63–1.56(m,2H),1.19(s,6H).LC-MS:512.3([M+H] + ).

[0155] Example 11:

[0156]

[0157] Using a method similar to that in Example 2, (I-11) was obtained by using (IM-1) and (Acid-11) as starting materials. 1 HNMR(400MHz, Methanol-d4)δ8.38(d,J=5.1Hz,1H),8.27(s,1H),7.44(dq,J=8.7,5.1,4.3 Hz,1H),7.28–7.16(m,5H),6.92(dd,J=8.4,2.7Hz,1H),6.82(d,J=2.7Hz,1H),5.86(dd,J= 8.6,5.8Hz,1H),4.01(t,J=6.4Hz,2H),3.28–3.11(m,2H),2.82–2.72(m,1H),2.24(s,3H), 1.93–1.81(m,2H),1.67–1.62(m,2H),1.23(s,6H),0.94–0.87(m,1H).LC-MS:530.4([M+H] + ).

[0158] Example 12:

[0159]

[0160] Using a method similar to that in Example 2, (I-12) was obtained by using (IM-1) and (Acid-12) as starting materials. 1 HNMR (400MHz, DMSO-d6) δ9.90 (s, 1H), 8.42 (d, J = 5.1Hz, 1H), 8.10 (d, J = 1.3Hz, 1H), 7. 38(dd,J=8.7,5.4Hz,2H),7.30–7.19(m,4H),6.93(dd,J=8.4,2.7Hz,1H),6.80(d,J=2 .7Hz,1H),5.67(t,J=7.2Hz,1H),4.19(s,1H),3.97(t,J=6.6Hz,2H),3.26–3.01(m,4H ),2.19(s,3H),1.80–1.70(m,2H),1.52–1.43(m,2H),1.10(s,6H).LC-MS:530.4([M+H] + ).

[0161] Example 13:

[0162]

[0163] Using a method similar to that in Example 2, (I-13) was obtained by using (IM-1) and (Acid-13) as starting materials. 1 HNMR(400MHz,Methanol-d4)δ8.38(d,J=5.2Hz,1H),8.28(s,1H),7.46(td,J=8.0,5.8Hz,1H),7 .23(d,J=8.4Hz,1H),7.18(d,J=5.2Hz,1H),7.16–7.06(m,3H),6.92(dd,J=8.4,2.8Hz,1H),6.83 (d,J=2.7Hz,1H),5.69–5.63(m,1H),4.01(t,J=6.4Hz,2H),3.25–3.07(m,2H),2.78–2.68(m,1H ),1.92–1.81(m,2H),1.69–1.61(m,2H),1.23(s,6H),0.92(t,J=6.7Hz,1H).LC-MS:530.4([M+H] + ).

[0164] Example 14:

[0165]

[0166] Using a method similar to that in Example 2, (I-14) was obtained by using (IM-1) and (Acid-14) as starting materials. 1 HNMR(400MHz, Methanol-d4)δ8.36(d,J=5.2Hz,1H),8.25(s,1H),7.54–7.43(m,1H),7.22( d,J=8.4Hz,1H),7.16(dd,J=5.1,1.5Hz,1H),7.08(t,J=9.0Hz,2H),6.90(dd,J=8.4,2.7Hz ,1H),6.81(d,J=2.7Hz,1H),6.06(dd,J=9.2,5.7Hz,1H),3.99(t,J=6.4Hz,2H),3.31–3.14 (m,2H),2.93–2.83(m,2H),2.23(s,3H),1.91–1.82(m,2H),1.68–1.60(m,2H),1.23(s,6H).

[0167] Example 15:

[0168]

[0169] Using a method similar to that in Example 2, (I-15) was obtained by using (IM-1) and (Acid-15) as starting materials.1 HNMR(400MHz, DMSO-d6)δ9.94(s,1H),8.42(d,J=5.1Hz,1H),8.11(d,J=1.5Hz,1H),7.54–7.44( m,1H),7.31–7.19(m,3H),7.12(t,J=7.1Hz,1H),6.93(dd,J=8.5,2.7Hz,1H),6.80(d,J=2.6Hz, 1H),5.92(dd,J=8.6,5.8Hz,1H),4.18(s,1H),3.96(t,J=6.5Hz,2H),3.33–3.24(m,1H),3.22–3 .06(m,2H),2.75–2.64(m,1H),2.19(s,3H),1.81–1.70(m,2H),1.53–1.44(m,2H),1.10(s,6H).

[0170] Example 16:

[0171]

[0172] Using a method similar to that in Example 2, (I-16) was obtained by using (IM-1) and (Acid-16) as starting materials. 1 HNMR(400MHz,DMSO-d6)δ9.94(s,1H),8.43(d,J=5.1Hz,1H),8.12(s,1H),7.33–7.20( m,3H),7.17–7.10(m,2H),6.93(dd,J=8.4,2.7Hz,1H),6.81(d,J=2.7Hz,1H),5.69(t, J=7.3Hz,1H),4.18(s,1H),3.97(t,J=6.4Hz,2H),3.28–3.11(m,2H),3.11–3.00(m,1H ),2.69–2.56(m,1H),2.19(s,3H),1.81–1.71(m,2H),1.53–1.42(m,2H),1.10(s,6H).

[0173] Example 17:

[0174]

[0175] Using a method similar to that in Example 2, (I-17) was obtained by using (IM-1) and (Acid-17) as starting materials. 1HNMR(400MHz,Chloroform-d)δ9.57(s,1H),8.42(t,J=1.1Hz,1H),8.37(d,J=5.1Hz,1H),7.29(s,1H ),7.20(d,J=8.4Hz,1H),7.15–7.01(m,4H),6.88(dd,J=8.3,2.8Hz,1H),6.84(d,J=2.7Hz,1H),6.71( ddd,J=8.6,5.7,3.0Hz,1H),5.72(dd,J=8.7,5.4Hz,1H),4.01(t,J=6.3Hz,2H),3.40–3.29(m,1H),3 .25–3.05(m,2H),2.78–2.67(m,1H),2.27(s,3H),1.95–1.84(m,2H),1.69–1.66(m,2H),1.28(s,6H).

[0176] Example 18:

[0177]

[0178] Using a method similar to that in Example 2, (I-18) was obtained by using (IM-1) and (Acid-18) as starting materials. 1 HNMR(400MHz, Methanol-d4)δ8.39(d,J=5.1Hz,1H),8.30(s,1H),7.23(d,J=8.4Hz,1H),7.18( dd,J=5.2,1.4Hz,1H),6.91(dd,J=8.5,2.7Hz,1H),6.83(d,J=2.7Hz,1H),4.38(dt,J=9.2,5.1H z,1H),4.00(t,J=6.4Hz,2H),3.02–2.93(m,2H),2.89–2.80(m,2H),2.66–2.53(m,1H),2.25(s ,3H),2.03–1.73(m,8H),1.67–1.60(m,2H),1.51–1.41(m,2H),1.23(s,6H),1.11–0.86(m,2H).

[0179] Example 19:

[0180]

[0181] Using a method similar to that in Example 2, (I-19) was obtained from (IM-1) and (Acid-19) as starting materials. LC-MS: 513.3 ([M+H]) + ).

[0182] Example 20:

[0183]

[0184] Using a method similar to that in Example 2, (I-20) was obtained by using (IM-1) and (Acid-20) as starting materials. 1 HNMR(400MHz,Chloroform-d)δ9.56(s,1H),8.43–8.40(m,1H),8.37(d,J=5.1Hz,1H),7. 47–7.41(m,3H),7.23–7.17(m,3H),7.08(dd,J=5.2,1.5Hz,1H),6.88(dd,J=8.3,2.8Hz,1 H),6.84(d,J=2.7Hz,1H),6.13(dd,J=55.4,6.2Hz,1H),5.78(td,J=6.6,3.1Hz,1H),4.0 1(t,J=6.3Hz,2H),3.52–3.38(m,1H),3.17–3.01(m,2H),2.83(s,3H),2.27(s,3H),1.96–

[0185] 1.86(m,2H),1.68(dd,J=7.6,3.6Hz,2H),1.63(s,9H).

[0186] Example 21:

[0187]

[0188] Using a method similar to that in Example 2, (I-21) was obtained by using (IM-1) and (Acid-21) as starting materials. 1 HNMR(400MHz,Chloroform-d)δ9.57(s,1H),8.40(dd,J=1.6,0.8Hz,1H),8.37(dd,J=5.1,0.8Hz, 1H),7.45–7.37(m,3H),7.30(d,J=2.4Hz,1H),7.20(d,J=8.4Hz,1H),7.08(dd,J=5.2,1.5Hz,1H), 6.88(dd,J=8.3,2.7Hz,1H),6.83(d,J=2.7Hz,1H),6.19–5.98(m,1H),5.57–5.51(m,1H),4.01(t, J=6.3Hz,2H),3.76–3.61(m,1H),3.07–2.99(m,1H),2.26(s,3H),1.96–1.86(m,2H),1.28(s,6H).

[0189] Example 22:

[0190]

[0191] Using a method similar to that in Example 2, (I-22) was obtained by using (IM-1) and (Acid-22) as starting materials. 1 HNMR(400MHz, Acetone-d6)δ9.58(s,1H),8.38(d,J=5.1Hz,1H),8.34(s,1H),7.44–7.37(m,4H),7.3 6–7.29(m,1H),7.24(d,J=8.4Hz,1H),7.15(dd,J=5.1,1.5Hz,1H),6.92(dd,J=8.4,2.8Hz,1H),6.86( d,J=2.7Hz,1H),4.65(dd,J=8.9,7.4Hz,1H),4.54–4.43(m,1H),4.41–4.32(m,1H),4.03(t,J=6.6Hz, 2H),3.47–3.35(m,1H),3.26(s,1H),2.24(s,3H),1.94–1.83(m,2H),1.66–1.58(m,2H),1.19(s,6H).

[0192] Example 23:

[0193]

[0194] Using a method similar to that in Example 2, (I-23) was obtained by using (IM-1) and (Acid-23) as starting materials. 1 HNMR (400MHz, Acetone-d6) δ9.58(s,1H),8.39(d,J=5.1Hz,1H),8.32(s,1H),7.45(d,J=8.1H z,2H),7.36(d,J=8.1Hz,2H),7.24(d,J=8.4Hz,1H),7.16(d,J=5.1Hz,1H),6.92(d,J=8.5Hz,1 H),6.85(s,1H),5.70(t,J=7.3Hz,1H),4.02(t,J=6.7Hz,2H),3.45–3.32(m,1H),3.29–3.07( m,3H),2.79–2.68(m,1H),2.23(s,3H),1.87(t,J=8.3Hz,2H),1.67–1.54(m,2H),1.19(s,6H).

[0195] Example 24:

[0196]

[0197] Using a method similar to that in Example 2, (I-24) was obtained by using (IM-1) and (Acid-24) as starting materials. 1 HNMR(400MHz, Acetone-d6)δ9.60(s,1H),8.39(d,J=5.1Hz,1H),8.33(s,1H),7.48–7.39(m,3H),7.30(dd ,J=7.3,2.1Hz,1H),7.24(d,J=8.4Hz,1H),7.16(dd,J=5.0,1.6Hz,1H),6.92(dd,J=8.4,2.7Hz,1H),6.85 (d,J=2.7Hz,1H),5.70(dd,J=8.3,6.2Hz,1H),4.02(t,J=6.6Hz,2H),3.46–3.34(m,1H),3.32–3.17(m,2H ),3.17–3.07(m,1H),2.82–2.72(m,1H),2.23(s,3H),1.94–1.79(m,2H),1.67–1.54(m,2H),1.18(s,6H).

[0198] Example 25:

[0199]

[0200] Using a method similar to that in Example 2, (I-25) was obtained by using (IM-1) and (Acid-25) as starting materials. 1HNMR(400MHz,Chloroform-d)δ9.54(s,1H),8.41(dd,J=1.4,0.8Hz,1H),8.34(dd,J=5.1,0.8Hz,1H),7.44(dd,J=7.9,1.4Hz ,1H),7.30(td,J=7.7,1.8Hz,1H),7.25–7.21(m,1H),7.18(d,J=8.4Hz,1H),7.05(dd,J=5.1,1.5Hz,1H),6.86(dd,J=8.3,2.8 Hz,1H),6.82(d,J=2.7Hz,1H),6.73(dd,J=7.7,1.7Hz,1H),5.90(dd,J=8.6,5.1Hz,1H),3.99(t,J=6.3Hz,2H),3.43–3.32(m ,1H),3.10(t,J=7.4Hz,2H),2.80(s,1H),2.69–2.59(m,1H),2.24(s,3H),1.94–1.83(m,2H),1.68–1.64(m,2H),1.60(s,6H).

[0201] Example 26:

[0202]

[0203] Using a method similar to that in Example 2, (I-26) was obtained by using (IM-1) and (Acid-26) as starting materials. 1 HNMR (400MHz, Acetone-d6) δ9.59(s,1H),8.40(d,J=5.1Hz,1H),8.35(d,J=1.4Hz,1H),7.24(d,J=8.4H z,1H),7.16(dd,J=5.2,1.6Hz,1H),6.92(dd,J=8.4,2.8Hz,1H),6.86(d,J=2.7Hz,1H),4.43(td,J=8.0, 4.8Hz,1H),4.03(t,J=6.6Hz,2H),3.30(s,1H),3.00–2.91(m,3H),2.58–2.47(m,1H),2.36–2.26(m,1H) ,2.24(s,3H),2.03–1.96(m,1H),1.93–1.84(m,2H),1.81–1.72(m,1H),1.68–1.45(m,8H),1.19(s,6H).

[0204] Example 27:

[0205]

[0206] Using a method similar to that in Example 2, (I-27) was obtained by starting with (IM-2) and (Acid-1). 1 HNMR(400MHz, Acetone-d6)δ9.64(s,1H),8.33(d,J=1.4Hz,1H),8.30(d,J=5.6Hz,1H),7.4 3–7.33(m,3H),7.32–7.24(m,3H),6.96(dd,J=8.4,2.7Hz,1H),6.88(d,J=2.7Hz,1H),5.65 (dd,J=8.3,5.9Hz,1H),4.01(t,J=6.6Hz,2H),3.40–3.28(m,2H),3.25–3.14(m,1H),3.14– 3.03(m,1H),2.73(s,1H),2.15(s,3H),1.91–1.82(m,2H),1.62–1.56(m,2H),1.18(s,6H).

[0207] Example 28:

[0208]

[0209] Using a method similar to that in Example 2, (I-28) was obtained by starting with (IM-3) and (Acid-1). 1 HNMR (400MHz, Acetone-d6) δ10.13(s,1H),9.70(d,J=2.5Hz,1H),8.33(d,J=2.5Hz,1H) ,7.46–7.35(m,3H),7.32–7.23(m,3H),7.06(d,J=2.6Hz,1H),6.96(d,J=8.7Hz,1H),5.6 6(t,J=7.1Hz,1H),4.04(t,J=6.6Hz,2H),3.43–3.31(m,1H),3.30(s,1H),3.26–3.17(m, 1H),3.16–3.06(m,1H),2.31(s,3H),1.92–1.85(m,2H),1.64–1.58(m,2H),1.19(s,6H).

[0210] Example 29:

[0211]

[0212] Using a method similar to that in Example 2, (I-29) was obtained by starting with (IM-4) and (Acid-1). 1HNMR (400MHz, Acetone-d6) δ10.12(s,1H),9.70(d,J=2.4Hz,1H),8.33(d,J=2.4Hz,1H),7.46 –7.36(m,3H),7.32–7.23(m,3H),7.06(d,J=2.7Hz,1H),6.96(dd,J=8.3,2.7Hz,1H),5.69–5. 62(m,1H),4.04(t,J=6.6Hz,2H),3.42–3.32(m,1H),3.28(s,1H),3.26–3.17(m,1H),3.17–3. 06(m,1H),2.77–2.66(m,1H),2.31(s,3H),1.93–1.83(m,2H),1.65–1.58(m,2H),1.19(s,6H).

[0213] Example 30:

[0214]

[0215] Using a method similar to that in Example 2, (I-30) was obtained by starting with (IM-5) and (Acid-1). 1 HNMR(400MHz, Acetone-d6)δ9.64(s,1H),8.44(s,1H),8.27(s,1H),7.44–7.34( m,3H),7.30(d,J=7.3Hz,2H),7.25(d,J=8.6Hz,1H),6.95(dd,J=8.4,2.6Hz,1H), 6.78(s,1H),5.66(t,J=7.3Hz,1H),4.01(t,J=6.6Hz,2H),3.39(s,1H),3.27–3. 17(m,2H),3.16–3.09(m,1H),1.91–1.84(m,2H),1.62–1.57(m,2H),1.18(s,6H).

[0216] Example 31:

[0217]

[0218] Using a method similar to that in Example 2, (I-31) was obtained by starting with (IM-6) and (Acid-1). 1HNMR(400MHz,Acetone-d6)δ9.52(s,1H),8.28(s,1H),8.11(s,1H),7.45–7.38(m,3H),7.35–7 .29(m,2H),7.25(d,J=8.4Hz,1H),6.92(dd,J=8.4,2.8Hz,1H),6.72(d,J=2.7Hz,1H),5.67(dd, J=8.3,5.9Hz,1H),4.02(t,J=6.6Hz,2H),3.44–3.34(m,1H),3.27–3.18(m,2H),3.18–3.08(m, 1H),2.81(s,3H),2.75(s,1H),2.02(s,3H),1.91–1.85(m,2H),1.64–1.59(m,2H),1.20(s,6H).

[0219] Example 32:

[0220]

[0221] Using a method similar to that in Example 2, (I-32) was obtained by using (IM-7) and (Acid-1) as starting materials. 1 HNMR (400MHz, Acetone-d6) δ9.58(s,1H),8.39(d,J=5.1Hz,1H),8.32(d,J=1.4Hz,1H),7.4 4–7.35(m,3H),7.34–7.29(m,2H),7.25(d,J=8.5Hz,1H),7.15(dd,J=5.2,1.5Hz,1H),6.92 (dd,J=8.5,2.8Hz,1H),6.85(d,J=2.8Hz,1H),5.69–5.64(m,1H),3.81(s,3H),3.44–3.33( m,1H),3.27–3.17(m,1H),3.16–3.05(m,1H),2.80(s,1H),2.79–2.69(m,1H),2.23(s,3H).

[0222] Example 33:

[0223]

[0224] Using a method similar to that in Example 2, (I-33) was obtained by starting with (IM-8) and (Acid-1). 1HNMR (400MHz, Acetone-d6) δ9.61 (s, 1H), 8.47–8.39 (m, 2H), 7.46 (d, J = 8.4Hz, 1 H),7.43–7.36(m,3H),7.33–7.30(m,2H),7.25(dd,J=5.3,1.4Hz,1H),7.07–7.02 (m,2H),5.67(dd,J=8.3,6.0Hz,1H),4.08(t,J=6.6Hz,2H),3.44–3.28(m,2H),3. 26(s,1H),3.23–3.07(m,2H),1.94–1.85(m,2H),1.65–1.57(m,2H),1.19(s,6H).

[0225] Example 34:

[0226]

[0227] Using a method similar to that in Example 2, (I-34) was obtained by using (IM-9) and (Acid-1) as starting materials. 1 HNMR(400MHz,Acetone-d6)δ9.59(s,1H),8.64(s,1H),8.41(d,J=5.3Hz,1H),7 .50–7.38(m,5H),7.37–7.30(m,4H),7.08(d,J=8.3Hz,1H),5.69(t,J=7.3Hz,1 H),4.13(t,J=6.5Hz,2H),3.45–3.33(m,1H),3.29(d,J=1.5Hz,1H),3.25–3.09 (m,2H),2.81–2.69(m,1H),1.99–1.88(m,2H),1.70–1.61(m,2H),1.22(s,6H).

[0228] Example 35:

[0229]

[0230] Using a method similar to that in Example 2, (I-35) was obtained by using (IM-10) and (Acid-1) as starting materials. 1HNMR(400MHz, Acetone-d6)δ9.58(s,1H),8.39(d,J=5.1Hz,1H),8.32(s,1H),7.45–7.34(m ,3H),7.33–7.28(m,2H),7.24(d,J=8.4Hz,1H),7.16(dd,J=5.1,1.6Hz,1H),6.95(dd,J=8.5 ,2.8Hz,1H),6.88(d,J=2.6Hz,1H),5.74–5.63(m,1H),3.83(s,2H),3.72(s,1H),3.42–3.32 (m,1H),3.28–3.18(m,1H),3.18–3.07(m,1H),2.79–2.74(m,1H),2.23(s,3H),1.28(s,6H).

[0231] Example 36:

[0232]

[0233] Using a method similar to that in Example 2, (I-36) was obtained by using (IM-11) and (Acid-1) as starting materials. 1 HNMR(400MHz, Acetone-d6)δ9.62(s,1H),8.40(d,J=5.1Hz,1H),8.36(s,1H),7.78(d,J=8.8H z,1H),7.44–7.35(m,3H),7.33–7.28(m,2H),7.20–7.13(m,2H),6.98(d,J=2.6Hz,1H),5.66( dd,J=8.3,5.9Hz,1H),4.15(t,J=6.6Hz,2H),3.41–3.33(m,1H),3.30(s,1H),3.25–3.16(m,1 H),3.16–3.06(m,2H),2.79–2.68(m,1H),1.97–1.87(m,2H),1.65–1.58(m,2H),1.19(s,6H).

[0234] Example 37:

[0235]

[0236] Using a method similar to that in Example 2, (I-37) was obtained by using (IM-12) and (Acid-1) as starting materials. 1HNMR(400MHz, Acetone-d6)δ9.58(s,1H),8.39(d,J=5.1Hz,1H),8.32(s,1H),7.45–7.34(m,3H),7.34–7 .29(m,2H),7.24(d,J=8.4Hz,1H),7.15(dd,J=5.2,1.5Hz,1H),6.92(dd,J=8.3,2.8Hz,1H),6.86(d,J=2 .7Hz,1H),5.66(dd,J=8.3,6.0Hz,1H),4.08(t,J=6.4Hz,2H),3.92–3.81(m,2H),3.43–3.26(m,3H),3.2 6–3.16(m,1H),3.16–3.07(m,1H),2.79–2.67(m,1H),2.23(s,3H),1.75–1.63(m,4H),1.32–1.25(m,3H).

[0237] Example 38:

[0238]

[0239] Using a method similar to that in Example 2, (I-38) was obtained by using (IM-13) and (Acid-1) as starting materials. 1 HNMR(400MHz,Methanol-d4)δ8.35(d,J=5.2Hz,1H),8.25(s,1H),7.43–7.35(m,3H),7 .24(dd,J=12.5,7.9Hz,3H),7.18–7.10(m,1H),6.93(dd,J=8.3,2.7Hz,1H),6.84(d,J= 2.7Hz,1H),5.60(t,J=7.1Hz,1H),4.08(t,J=5.9Hz,2H),3.25–3.15(m,1H),3.15–3.04 (m,1H),2.72(d,J=10.8Hz,1H),2.64(t,J=7.1Hz,2H),2.22(s,3H),2.13–2.05(m,2H).

[0240] Example 39:

[0241]

[0242] Using a method similar to that in Example 2, (I-39) was obtained by using (IM-14) and (Acid-1) as starting materials. 1HNMR(400MHz, Methanol-d4)δ8.35(d,J=5.2Hz,1H),8.24(s,1H),7.43–7.36(m,3H),7.26(d, J=7.4Hz,2H),7.22(d,J=8.4Hz,1H),7.15(d,J=5.2Hz,1H),6.94–6.89(m,1H),6.83(d,J=2.7H z,1H),5.60(t,J=7.2Hz,1H),4.11(t,J=4.6Hz,2H),3.73(t,J=4.6Hz,2H),3.41(d,J=1.4Hz, 3H),3.29–3.22(m,1H),3.22–3.15(m,1H),3.14–3.04(m,1H),2.75–2.63(m,1H),2.22(s,3H).

[0243] Experimental Example 40: Effects of Compounds at the Molecular Level on RIPK1 Kinase Activity

[0244] Add 2 μL of enzyme and 1 μL of different concentrations of compound to each well of a 384-well plate. Include wells with 0% kinase activity (no kinase or compound) and wells with 100% kinase activity (no compound). Incubate at room temperature for 10 min. Add 2 μL of a mixture of ATP and substrate peptide (final substrate concentration 100 μg / mL, final ATP concentration 10 μM), and incubate at 37°C for 1 h. Add 5 μL of LADP-Glo ​​to each well. TM Reagent was added and incubated at room temperature for 40 minutes to remove unreacted ATP. 10 μL of Kinase Detection Reagent was added to each well and incubated at room temperature for 30-60 minutes to convert ADP generated during the reaction into ATP. The fluorescence signal was detected (luminescence: integration time 0.5 s). The inhibition rate of each well was calculated by using the average RLU value to represent 0% kinase activity (no enzyme and compound) and 100% kinase activity (no compound). IC50 was used. 50 The values ​​were calculated using GraphPad Prism software.

[0245] Table 1: Inhibitory activity of compounds against RIPK1 enzyme

[0246]

[0247]

[0248] Where "+" represents IC 50 Less than (≤) 1μM; "-" indicates IC 50 Less than (>) 1μM

[0249] As can be seen from Table 1, the compounds of the present invention have a significant inhibitory effect on RIPK1 enzyme.

[0250] Experimental Example 41: Effect of Compounds on the Reversal of Programmed Necrosis in I2.1 Cells

[0251] The I2.1 cell line (a FADD mutant of human acute T-cell leukemia Jurkat cells, lacking the FADD protein, where TNFα alone can induce programmed cell death) was tested. Cell counting was performed using the CCK-8 cell counting kit (Dojindo).

[0252] I2.1 cells in logarithmic growth phase were seeded at an appropriate density into 96-well culture plates and cultured overnight. Different concentrations of the compound were added first, followed by 20 ng / mL TNFα stimulation one hour later. Control wells (positive control) were set up without the compound and without the stimulating factor, and control wells (negative control) were set up without the compound but with the stimulating factor. After 24 hours of compound treatment, the effect of the compound on cell proliferation was detected using a CCK-8 cell counting kit (Dojindo). 10 μL of CCK-8 reagent was added to each well, and the cells were incubated at 37°C for 2-4 hours. Readings were then performed using a SpectraMax 190 microplate reader at a wavelength of 450 nm. The recovery rate (%) of programmed cell death was calculated using the following formula:

[0253] Recovery rate (%) = (OD administration wells - OD negative control wells) / (OD positive control wells - OD negative control wells) × 100%

[0254] IC 50 The values ​​were calculated using GraphPad Prism software.

[0255] Table 2: Recovery rate of I2.1 cell death by the compounds

[0256] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> I-1 + I-23 + I-2 + I-24 + I-9 + I-25 + I-10 + I-26 + I-11 + I-27 + I-12 + I-30 + I-13 + I-31 + I-14 + I-32 + I-15 + I-33 + I-16 + I-34 + I-17 + I-35 + I-18 + I-36 + I-20 + I-37 + I-21 + I-38 + I-22 + I-39 +

[0257] Where "+" represents IC 50 Less than (≤) 1μM; "-" indicates IC 50 Less than (>) 1μM

[0258] The experimental results above show that the compound of the present invention has a significant reversal effect on TNFα-induced I2.1 cell death.

[0259] It should be understood that after reading the above teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of general formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, Z1 is That is, the compounds are selected from: formula (III-1) and formula (III-2): in, W1 is -CH2-; R is H, D, or a C1-C8 alkyl group; R 1 For 1 to 5 identical or different R 1a Substituted or unsubstituted subgroups: C3-C14 cycloalkyl, C6-C14 aryl, 5-14 heteroaryl; R 1a Each time it appears, it is independently H, D, halogen, C1-C8 alkyl, or halogenated C1-C8 alkoxy. R 2 It is independently H, D or halogen each time it appears; Ring A is a six-membered heteroaryl ring; V1, V2, V3, and V4 are independently selected from the following groups: N, CR v At least one of V1, V2, and V3 is not CR. v ;R v Each time it appears, it is independently selected from: H, D, halogen, C1-C8 alkyl, halogenated C1-C8 alkoxy; Ring Q is phenyl; m is 1; n is selected from 0, 1, 2, and 3; R 9 Each time it appears, it is: H, halogen, C1-C8 alkyl, C1-C8 alkoxy, halo-C1-C8 alkyl; R 8 For 1-5 R 9a2 Replaced or unreplaced R 9a1 , where R 9a1 It is a C1-C8 alkoxy group; each R 9a2 Each time it appears, it is independently selected from: C1-C8 alkyl, hydroxyl, C1-C8 alkoxy, 3-14 membered heterocyclic groups.

2. The compound according to claim 1, characterized in that, The compound is the compound shown in formula (IV-1): Among them, R v It is H, a halogenated C1-C8 alkoxy group, a halogen, or a C1-C8 alkyl group; V4 is CH; R 1 R 2 R 8 R 9 The definition is as described in claim 1.

3. The compound according to claim 1, characterized in that, Ring Q is selected from phenyl; R 8 It is a C1-C8 alkoxy group; optionally surrounded by 1-5 R groups. 9a2 Replacement, where each R 9a2 Independently selected from: C1-C8 alkyl, hydroxyl; R 9 It can be H, halogen, halogenated C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; R is H or a C1-C4 alkyl group; R 1 For 1-3 identical or different R 1a Substituted or unsubstituted subgroups: C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl; each R 1a Each time it appears, it is independently a halogen, a C1-C4 alkyl, or a halo-C1-C4 alkoxy. R 2 It is either H or halogen each time it appears.

4. The compound according to claim 1, characterized in that, Ring A is pyridinyl, and V1 is N.

5. A compound or its tautomer or its pharmaceutically acceptable salt, characterized in that, The compound is selected from one of the following compounds:

6. A pharmaceutical composition, characterized in that, It comprises: a pharmaceutically acceptable carrier and one or more compounds according to any one of claims 1-5, or their tautomers or their pharmaceutically acceptable salts.

7. A receptor-interacting protein kinase 1 (RIPK1) inhibitor, characterized in that, It comprises one or more compounds according to any one of claims 1-5, or their tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 6.

8. Use of a compound according to any one of claims 1-5, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, characterized in that, Used in the preparation of a drug, said drug being used for: 1) Detection and / or prevention and / or treatment of kinase-related diseases; 2) Detection and / or prevention and / or treatment of immune, inflammatory and / or infection-related diseases; 3) Detection and / or prevention and / or treatment of ischemia and / or reperfusion injury-related diseases; 4) Detection and / or prevention and / or treatment of degenerative diseases; 5) Detection and / or prevention and / or treatment of cancer-related diseases; 6) Detection and / or prevention and / or treatment of cell necrosis-related diseases; 7) Detect and / or prevent and / or treat metabolic-related diseases; or 8) Detection and / or prevention and / or treatment of eye diseases.

9. Use of a compound according to any one of claims 1-5, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, characterized in that, Used to prepare medicines for the detection and / or prevention and / or treatment of diseases selected from the following group: Systemic juvenile idiopathic arthritis, Behcet's disease, sepsis, alopecia areata, allergic diseases, allergic diseases, hepatitis B, hepatitis C, multiple sclerosis, pulmonary sarcoidosis, pulmonary fibrosis, mycobacterial infection, celiac disease, Sjögren's syndrome, osteoarthritis, hidradenitis suppurativa, necrotizing enterocolitis, acute pancreatitis, spondyloarthritis, colitis, regional ileitis, antiphospholipid syndrome, Crohn's disease, ulcerative colitis, rheumatoid arthritis, influenza, chronic obstructive pulmonary disease, viral infections, sepsis, staphylococcal infection, systemic lupus erythematosus, systemic inflammatory response syndrome, systemic scleroderma, prions, adrenocortical degeneration, nephritis, Schleck-Jones syndrome, surgical infection, atopic dermatitis, Wegener's granulomatosis, asthma, COVID-19 Inflammation, vasculitis, periodontitis, inflammatory bowel disease, pancreatitis, organ transplant exclusion, 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 ganglioside storage disease, GM2 ganglioside storage disease, AIDS-related dementia syndrome, Tau proteinosis, Alzheimer's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, multiple sclerosis, frontotemporal dementia, Faber's disease, Friedreich ataxia, Guillain-Barré syndrome, Huntington's disease, primary lateral sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, tuberous sclerosis, progressive supranuclear palsy, progressive muscular Atrophy, schizophrenia, demyelinating diseases, chronic inflammatory demyelinating polyneuropathy, Niemann-Pick disease, corticobasal degeneration, lysosomal storage diseases, Sandhoff's disease, ganglion cell diseases, neuronal ceroid lipofuscin deposition, postoperative cognitive impairment, bipolar disorder, diabetic neuropathy, pain, delirium, depression, peripheral neuropathy, autism, trauma, traumatic brain injury, focal ischemia, traumatic retinal injury, cerebrovascular accident, stroke, geographical atrophy, acetaminophen poisoning, acute liver failure, acute kidney injury, acute respiratory distress syndrome, cerebral ischemia, ischemia, ischemic injury, hypoxic brain injury, hypoxia, burns, burn shock, ischemia-reperfusion injury of solid organs, cisplatin-induced kidney injury, smoking-induced injury. Myocardial infarction, toxic epidermal necrolysis, acute tubular necrosis, heart failure, NF-κB key regulatory gene mutation, myeloid leukemia, lymphocytic leukemia, T-cell leukemia, T-cell lymphoma, nasopharyngeal carcinoma, epidermoid carcinoma, pituitary adenoma, biliary carcinosarcoma, cholangiocarcinoma, multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, anal region cancer, testicular cancer, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, bone cancer, osteosarcoma, melanoma, spinal tumors, thyroid cancer, parathyroid cancer, glioblastoma, colorectal cancer, Kaposi's sarcoma, squamous cell carcinoma, glioma, endocrine system cancers, urethral cancer, bladder cancer, skin cancer, malignant melanoma of the skin or eye.Prostate cancer, triple-negative breast cancer, glioma, kidney or ureter cancer, renal pelvis cancer, adrenal cancer, esophageal cancer, fallopian tube cancer, head and / or neck cancer, vulvar cancer, gastric cancer, gastrointestinal stromal tumor, small bowel cancer, hematologic malignancies, pancreatic cancer, hereditary aortic aneurysm, vaginal cancer, penile cancer, rectal cancer, tumor angiogenesis, macular degeneration, macular hole, macular telangiectasia, dry eye syndrome, progressive retinal atrophy, Leber's congenital amaurosis, cystic macular edema, age-related macular degeneration, glaucoma, retinal neurodegeneration, ischemic optic neuropathy, ischemic retinopathy, diabetic retinopathy, retinitis pigmentosa, retinal photoreceptor diseases, retinal degenerative diseases, optic nerve diseases, retinal detachment, iatrogenic retinal injury, retinal vascular diseases, cone and rod dystrophy, choroidal agenesis, ocular vascular diseases, Ussell's syndrome, type I diabetes. Diabetes, non-alcoholic fatty liver disease, vitiligo, sialic acid storage disease, irritable bowel syndrome, Danon's disease, cholesterol ester storage disease, Wolman's disease, hypolipidemia, atherosclerosis, multiple sulfatase deficiency, Fabry disease, Gaucher disease, myelofibrosis, osteoporosis, cystine storage disease, muscular dystrophy, polyglutamine disease, Krabby's disease, chronic kidney disease, Menx's disease, cystic fibrosis, Pompeii disease, Tai-Sachs disease, lysosomal acid lipase deficiency, aspartate glucosamineuria, gout, Wilson's disease, mitochondrial diseases, fucoside storage disease, metachromatic leukodystrophy, mucopolysaccharidosis, mucolipidemia, osteogenesis imperfecta condensans, hemochromatosis, Niemann-Pick disease, Heme-oxidized IRP2 ubiquitin ligase-1 deficiency, osteonecrosis, chain ubiquitin chain assembly complex deficiency syndrome, ciliopathy.

10. Use of a compound according to any one of claims 1-5, its tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, characterized in that, This medicine is used to prepare drugs for the detection and / or prevention and / or treatment of diseases selected from the group consisting of: bacterial infections, neuropathic pain, lymphoma, cerebral hemorrhage, fundus diseases, malignant tumors of solid organs, autoimmune diseases, dermatitis, pneumonia, pseudobulbar palsy, and leukemia.

11. Use of a compound according to any one of claims 1-5, its tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, characterized in that, This is used to prepare medicines for the detection and / or prevention and / or treatment of diseases selected from the group consisting of: intracranial hemorrhage, childhood solid tumors, and progressive bulbar palsy.

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