5-Substituted indole 3-amide derivatives, their preparation and use

Abstract

The present invention relates to a method for preparing 5-substituted indole-3-amide derivatives and their use, which belong to the pharmaceutical field. The present invention provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof. Such compounds significantly inhibit the activity of RIPK1 kinase, exhibit high selectivity, and have excellent safety. They are RIPK1 kinase inhibitors and can be used to treat diseases, including, but not limited to, inflammation, immune disorders, tumors, and neurodegenerative diseases. Experiments using a TNFα-induced SIRS model have demonstrated that the compounds of the present invention inhibit RIPK1 kinase in vivo, and pharmacokinetic results show that this series of compounds has good pharmacokinetic properties. The present invention provides new strategies and means for the treatment of diseases by targeting RIPK1. JPEG2023541263000202.jpg6688

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to 5-substituted indole-3-amide derivatives and their preparation methods and uses. [Background technology]

[0002] Recently discovered, programmed cell necrosis (necroptosis) is a novel form of programmed cell death that differs from apoptosis in that it is caspase-independent. It is regulated by death signals and exhibits necrotic-like structural features. Unlike apoptosis, programmed cell necrosis does not form apoptotic bodies or aggregate chromatin. In contrast to necrosis, programmed cell necrosis is a type of regulated cell death regulated by multiple genes. After the addition of the caspase inhibitor Z-VAD-FMK to an in vitro culture system, programmed cell necrosis can be induced by TNF. The morphological characteristics of necrosis are cell swelling, rupture, and release of intracellular contents, followed by inflammation and an immune response. In addition to TNF, ligands for TLR3 and TLR4, as well as some bacterial and viral infections, can also induce programmed cell necrosis.

[0003] Receptor-interacting protein kinase 1 (RIPK1) is a protein with specific serine / threonine kinase activity. It has an N-terminal kinase domain similar to other protein kinases but possesses distinct binding domains. Studies have shown that RIPK1 is a key regulator of programmed cell necrosis, controlling it through the RIPK1 / RIPK3 / MLKL signaling axis. Multiple death receptors, such as TNFR, FAS, TRAILR, and Toll-like receptors, can trigger upstream signals for programmed cell necrosis upon inflammatory factor stimulation or exogenous infection. When the activity of cIAPs and caspases is limited, RIPK1 and RIPK3 form the necrosome. RIPK3 further recruits MLKL, which then self-oligomerizes, translocates to the plasma membrane, and creates a "hole" in the plasma membrane, leading to the release of cellular contents and disruption of ionic balance, ultimately resulting in the onset of cell necrosis.

[0004] Programmed cell necrosis is closely related to the development and progression of inflammation, autoimmune diseases, neurodegenerative diseases, and tumors. For example, research has shown that programmed cell necrosis is an important factor in the development of systemic inflammatory response syndrome (SIRS). SIRS is a systemic inflammatory response that causes the body to lose control and destroy itself when infectious or non-infectious factors act on the body. Critically ill patients are prone to SIRS due to a reduced capacity for compensatory anti-inflammatory responses and impaired metabolic function. Meanwhile, extensive research on TNFα-induced SIRS disease models has demonstrated a strong correlation with RIPK1-dependent programmed cell necroptosis. Inflammatory bowel disease (IBD) is a chronic, nonspecific, immune-mediated intestinal inflammation caused by environmental, genetic, infectious, and immune factors. Although the pathogenic mechanism remains unclear, excessive apoptosis of intestinal epithelial cells, damage to the intestinal mucosal barrier, and increased permeability of intestinal epithelial cells are thought to be one of the causes of IBD. Some studies have shown that programmed cell necrosis plays an important role in the pathogenesis of IBD. Programmed cell necrosis also plays an important role in the pathogenesis of several autoimmune diseases, such as rheumatoid arthritis (RA), psoriasis, and multiple sclerosis (MS). Activated microglia play a key role in the development of Alzheimer's disease (AD). RIPK1 is highly expressed in microglia, and RIPK1 inhibitors can effectively protect neurons from Aβ-induced programmed cell necrosis in vitro. In addition to Alzheimer's disease, programmed necrosis is also involved in the development and progression of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD). In 2016, Strilic et al. first discovered that tumor cells can induce vascular endothelial programmed cell necrosis, which allows tumor cells to pass through the vascular wall and achieve distant metastasis through the blood circulation. This is an important cause of tumor metastasis, and experiments have shown that RIPK1 inhibitors can effectively inhibit tumor metastasis.Additionally, studies have shown that RIPK1 kinase can promote the differentiation of resistant macrophages in the pancreatic cancer tumor microenvironment, and that inhibition of RIPK1 induces the differentiation of immunogenic macrophages in the pancreatic cancer tumor microenvironment, leading to adaptive immune activation and tumor protection.

[0005] From the above, RIPK1 is an important therapeutic target for diseases associated with programmed cell necrosis, such as inflammation, autoimmune diseases, neurodegenerative diseases, and tumors, and RIPK1 inhibitors are expected to be potential therapeutic agents for these diseases. Summary of the Invention [Problem to be solved by the invention]

[0006] In response to the need for the development of new drugs for diseases associated with programmed cell necrosis, the present invention provides 5-substituted indole-3-amide derivatives and their preparation and use. The compounds of the present invention can inhibit RIPK1 kinase in vivo, and pharmacokinetic results show that this series of compounds has good pharmacokinetic properties. The present invention provides new strategies and means for targeting RIPK1 to treat related diseases such as inflammation, autoimmune diseases, neurodegenerative diseases, and tumors. [Means for solving the problem]

[0007] A compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] [ka]

[0009] (In the formula, X 1 , X 3 independently -CR 6 -, N, X 2 is -NR 1 -, -CH=CH-, where R 1is hydrogen, substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C1-C 10 Ether groups, substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C6-C 20 aryl group, and substituted or unsubstituted 3- to 20-membered heteroaryl group, wherein the substituents are selected from deuterium, C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R 2B is selected from the following formula:

[0010] [ka]

[0011] (In the formula, R 2 is one or two R 21 or an unsubstituted C0-C6 alkylene group, wherein R 21 is a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted, C3-C 10 selected from cycloalkyl, cyano, hydroxy, carboxy, halogen, or nitro groups, wherein the substituents are cyano, hydroxy, carboxy, halogen, or nitro groups; The B ring may contain one, two, or three R 22 C4~C substituted with 10 Aryl group or unsubstituted C4-C 10 an aryl group, one, two or three R 22 or an unsubstituted 4- to 10-membered heteroaryl group substituted with one, two, or three R 22 C3~C substituted with 10 Cycloalkyl or unsubstituted C3-C 10 cycloalkyl groups, where R 22 are each independently substituted or unsubstituted C1 to C 10alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen or a nitro group, or two R 22 are linked to form a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, wherein the substituents are C1 to C 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group. R 3 is hydrogen, substituted or unsubstituted C1-C 10 alkyl groups, wherein the substituents are cyano, hydroxy, carboxy, halogen, or nitro groups; or R 2B and R 3 and are linked to form a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, and the substituents are C1 to C 10 Alkyl groups, C4-C 10 an aryl group, one or two R 31 C4~C substituted with 10 an aryl group, a cyano group, a hydroxy group, a carboxy group, a halogen, or a nitro group, wherein the R 31 is C 1~ C 10 selected from alkyl groups or halogens; R 4 , R 5 and R 6 are each independently hydrogen, C1 to C 10 selected from an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen or a nitro group; The A ring may have one or two R A C4~C substituted with 10 Aryl group or unsubstituted C4-C 10 an aryl group, one or two R A or an unsubstituted 4- to 10-membered heteroaryl group, wherein R A is a substituted or unsubstituted amino group, a group represented by the following formula, a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted, C4-C 10aryl group, a substituted or unsubstituted 4- to 10-membered heteroaryl group, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, wherein the substituents are selected from -R A2 -R A3 , R A4 , C1~C 10 C1-C substituted with alkyl and halogen 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group, where R A4 -R A2 -R A3 and an unsubstituted 3- to 10-membered heterocycloalkyl group,

[0012] [ka]

[0013] R A1 is a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C1-C 10 Alkenyl groups, substituted or unsubstituted C3-C 10 cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C2-C6 ether groups, and substituted or unsubstituted C2-C6 amine groups, wherein the substituents are selected from C1-C 10 C1-C substituted with alkyl and hydroxy groups 10 Alkyl groups, C1-C 10 an ester group, a 3- to 10-membered heterocycloalkyl group, an amino group, an amine group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A2 is selected from a substituted or unsubstituted C0-C6 alkylene group, a carbonyl group, wherein the substituent is a C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A3 is selected from substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, wherein the substituents are C1 to C10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group.

[0014] Preferably, the compound of formula (I) is represented by formula (II).

[0015] [ka]

[0016] (In the formula, R 1 is hydrogen, substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted, C3-C 10 Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C6-C 20 aryl group, substituted or unsubstituted 3- to 20-membered heteroaryl group, wherein the substituents are selected from C1 to C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R 2 is one R 21 or an unsubstituted C0-C6 alkylene group, wherein R 21 is a substituted or unsubstituted C1-C 10 selected from alkyl, cyano, hydroxy, carboxy, halogen, or nitro groups, wherein the substituents are cyano, hydroxy, carboxy, halogen, or nitro groups; The B ring may contain one, two, or three R 22 C4~C substituted with 10 Aryl group or unsubstituted C4-C 10 an aryl group or one, two or three R 22 or an unsubstituted 4- to 10-membered heteroaryl group, wherein R 22 are each independently substituted or unsubstituted C1 to C 10alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen or a nitro group, or two R 22 are linked to form a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, wherein the substituents are C1 to C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R 3 is hydrogen, substituted or unsubstituted C1-C 10 alkyl groups, wherein the substituents are cyano, hydroxy, carboxy, halogen, or nitro groups; or R 2 and R 3 and are linked to form a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, wherein the substituents are C1 to C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; X 1 , X 3 are independently selected from CH, N; Ring A is selected from a C4-C10 aryl group or an unsubstituted C4-C10 aryl group substituted with one or two R A, a 4-10 membered heteroaryl group or an unsubstituted 4-10 membered heteroaryl group substituted with one or two R A, wherein R A is selected from an amino group, a group represented by the following formula, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C4-C10 aryl group, a substituted or unsubstituted 4-10 membered heteroaryl group, and a substituted or unsubstituted 3-10 membered heterocycloalkyl group, wherein the substituents are -R A2-R A3, R A4, a C1-C10 alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group, and wherein R A4 is selected from a 3-10 membered heterocycloalkyl group substituted with -R A2-R A3 or an unsubstituted 3-10 membered heterocycloalkyl group;

[0017] [ka]

[0018] R A1 is a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C1-C 10 Alkenyl groups, substituted or unsubstituted C3-C 10 a cycloalkyl group, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C2-C6 ether group, wherein the substituents are selected from C1-C 10 an alkyl group, a 3- to 10-membered heterocycloalkyl group, an amino group, an amine group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A2 is selected from a substituted or unsubstituted C0-C6 alkylene group, a carbonyl group, wherein the substituent is a C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A3 is selected from substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, wherein the substituents are C1 to C 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group.

[0019] Preferably, the compound of formula (I) is represented by formula (III) or formula (IV).

[0020] [ka]

[0021] (In the formula, R 1 is selected from hydrogen and C1-C4 alkyl groups, and R 23 is selected from hydrogen and methyl groups, and the B ring has one or two R 22 and an unsubstituted phenyl group, wherein R 22 are each independently selected from F, Cl, a cyano group, a methyl group, a trifluoromethyl group, a methoxy group, and a trifluoromethoxy group.

[0022] Preferably, the compound of formula (I) is represented by formula (V).

[0023] [ka]

[0024] (In the formula, X 1 , X 3 independently -CR 6 -, N, X 2 is -NR 1 -, -CH=CH-, wherein R 1 is hydrogen, substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted, C3-C 10 Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C6-C 20 aryl group, substituted or unsubstituted 3- to 20-membered heteroaryl group, wherein the substituents are selected from C1 to C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; L 3 is selected from substituted or unsubstituted C1-C4 alkylene groups, wherein the substituents are C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R 33 is hydrogen, substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted, C3-C 10 Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C6-C 10 aryl groups, wherein the substituents are C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R 4 , R 5 and R 6 are each independently hydrogen, C1 to C 10selected from an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen or a nitro group; The A ring may have one or two R A C4~C substituted with 10 Aryl group or unsubstituted C4-C 10 an aryl group, one or two R A or an unsubstituted 4- to 10-membered heteroaryl group, wherein R A represents an amino group, a group represented by the formula: 10 Alkyl groups, substituted or unsubstituted, C4-C 10 aryl group, a substituted or unsubstituted 4- to 10-membered heteroaryl group, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, and the substituents are selected from -R A2 -R A3 , R A4 , C1~C 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group, where R A4 -R A2 -R A3 and an unsubstituted 3- to 10-membered heterocycloalkyl group,

[0025] [ka]

[0026] R A1 is a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C1-C 10 Alkenyl groups, substituted or unsubstituted C3-C 10 a cycloalkyl group, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C2-C6 ether group, wherein the substituents are selected from C1-C 10 Alkyl groups, C1-C 10 an ester group, a 3- to 10-membered heterocycloalkyl group, an amino group, an amine group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A2 is selected from a substituted or unsubstituted C0-C6 alkylene group, a carbonyl group, wherein the substituent is a C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A3 is selected from substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, wherein the substituents are C1 to C 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group. Preferably, R 33 is selected from a phenyl group, a phenyl group substituted with one or two substituents, wherein said substituents are selected from F, Cl or a methyl group.

[0027] Preferably, the compound of formula (I) is represented by formula (VI).

[0028] [ka]

[0029] (In the formula, X 1 , X 3 are independently -CR 6 -, N, X 2 is -NR 1 -, -CH=CH-, X 3 is selected from CH, N, R 1 is hydrogen, substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted, C3-C 10 Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C6-C 20 aryl group, substituted or unsubstituted 3- to 20-membered heteroaryl group, wherein the substituents are selected from C1 to C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; L 4is selected from substituted or unsubstituted C1-C3 alkylene groups, wherein the substituents are C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R 3 is hydrogen, substituted or unsubstituted C1-C 10 alkyl groups, wherein the substituents are cyano, hydroxy, carboxy, halogen, or nitro groups; R 4 , R 5 and R 6 are each independently hydrogen, C1 to C 10 selected from an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen or a nitro group; The A ring may have one or two R A C4~C substituted with 10 Aryl group or unsubstituted C4-C 10 an aryl group, one or two R A or an unsubstituted 4- to 10-membered heteroaryl group, wherein R A represents an amino group, a group represented by the formula: 10 Alkyl groups, substituted or unsubstituted, C4-C 10 aryl group, a substituted or unsubstituted 4- to 10-membered heteroaryl group, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, wherein the substituents are selected from -R A2 -R A3 , R A4 , C1~C 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group, where R A4 -R A2 -R A3 and an unsubstituted 3- to 10-membered heterocycloalkyl group,

[0030] [ka]

[0031] RA1 is a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C1-C 10 Alkenyl groups, substituted or unsubstituted C3-C 10 a cycloalkyl group, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C2-C6 ether group, wherein the substituents are selected from C1-C 10 an alkyl group, a 3- to 10-membered heterocycloalkyl group, an amino group, an amine group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A2 is selected from a substituted or unsubstituted C0-C6 alkylene group, a carbonyl group, wherein the substituent is a C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A3 is selected from substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, wherein the substituents are C1 to C 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group. Preferably, the L 4 is selected from C1 to C2 alkylene groups. Preferably, the X 3 is selected from CH and N. Preferably, R 1 is selected from hydrogen, a C1 to C4 alkyl group, and a C3 ether group. Preferably, the R 4 , R 5 and R 6 are each independently selected from hydrogen and F. Preferably, the A ring contains one or two R A a 5- to 9-membered heteroaryl group substituted with or an unsubstituted 5- to 9-membered heteroaryl group, one or two R A and an unsubstituted 6-membered aryl group, wherein R Ais an amino group, an amino group substituted with a C1-C4 alkyl group, an amino group substituted with -CF3, an amino group substituted with -CHF2, a group represented by the following formula, a methyl group, -R A2 -R A3 a 5- to 6-membered heteroaryl group substituted with or an unsubstituted 5- to 6-membered heteroaryl group, R A4 methyl group substituted with -R A2 -R A3 and an unsubstituted phenyl group,

[0032] [ka]

[0033] where R A4 -R A2 -R A3 and R is selected from a 6-membered heterocycloalkyl group substituted with or an unsubstituted 6-membered heterocycloalkyl group. A1 is selected from a C2-C5 alkyl group, a C4 alkyl group substituted with Cl, a methyl group substituted with a 5-membered heterocycloalkyl group, a vinyl group, a vinyl group substituted with an N,N-dimethylamine group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl group substituted with one or two F groups, a 4-6-membered heterocycloalkyl group, a 4-6-membered heterocycloalkyl group substituted with a hydroxy group, a 4-5-membered heterocycloalkyl group substituted with —CH2OH, a 6-membered heterocycloalkyl group substituted with a methyl group, a methoxy group, a methoxy group substituted with F, a C2-C3 ether group, and a propylamine group substituted with a hydroxy group; R A2 is selected from a C0-C1 alkylene group and a carbonyl group, R A3 is selected from 6-membered heterocycloalkyl groups substituted with methyl groups or unsubstituted 6-membered heterocycloalkyl groups.

[0034] Preferably, the A ring is selected from the groups shown in the formula:

[0035] [ka]

[0036] (In the formula, L 1 is selected from S or NH, L 2 are each independently selected from CH or N. Preferably, the A ring is selected from the groups shown in the formula:

[0037] [ka]

[0038] Preferably, R 2 is one or two R 21 or an unsubstituted C0-C2 alkylene group, wherein R 21 is selected from a methyl group, The B ring may contain one, two, or three R 22 C6~C substituted with 10 Aryl group or unsubstituted C6-C 10 an aryl group, one, two or three R 22 a 5- to 9-membered heteroaryl group substituted with one, two, or three R 22 C9~C substituted with 10 Cycloalkyl or unsubstituted C9-C 10 cycloalkyl groups, where R 22 are each independently selected from a C1-C4 alkyl group, a methoxy group, a halogen, a methyl group substituted with a halogen, a methoxy group substituted with a halogen, a cyano group, a nitro group, and a group represented by the following formula, wherein the halogen is selected from F, Cl, and Br:

[0039] [ka]

[0040] Preferably, R 3 is selected from hydrogen.

[0041] Preferably, the compound of formula (I) is represented by formula (VII).

[0042] [ka]

[0043] (In the formula, R 1 is hydrogen, substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted, C3-C 10 Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C6-C 20 aryl group, substituted or unsubstituted 3- to 20-membered heteroaryl group, wherein the substituents are selected from C1 to C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R 31 is selected from C1 to C6 alkylene groups, R 32 is one, two or three R 311 C4~C substituted with 10 Aryl group or unsubstituted C4-C 10 aryl groups, where R 311 are each independently selected from a C1 to C6 alkoxy group, or two R 311 are linked to form a 4- to 10-membered heterocycloalkyl group, X 1 , X 3 are independently selected from CH and N; The A ring may have one or two R A C4~C substituted with 10 Aryl group or unsubstituted C4-C 10 an aryl group, one or two R A or an unsubstituted 4- to 10-membered heteroaryl group, wherein R A represents an amino group, a group represented by the formula: 10 Alkyl groups, substituted or unsubstituted, C4-C10 aryl group, a substituted or unsubstituted 4- to 10-membered heteroaryl group, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, wherein the substituents are selected from -R A2 -R A3 , R A4 , C1~C 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group, where R A4 -R A2 -R A3 and an unsubstituted 3- to 10-membered heterocycloalkyl group,

[0044] [ka]

[0045] R A1 is a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C1-C 10 Alkenyl groups, substituted or unsubstituted C3-C 10 a cycloalkyl group, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C2-C6 ether group, wherein the substituents are selected from C1-C 10 an alkyl group, a 3- to 10-membered heterocycloalkyl group, an amino group, an amine group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A2 is selected from a substituted or unsubstituted C0-C6 alkylene group, a carbonyl group, wherein the substituent is a C1-C 10 an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen atom, or a nitro group; R A3 is selected from substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, wherein the substituents are C1 to C 10 alkyl group, cyano group, hydroxy group, carboxy group, halogen, or nitro group. Preferably, -R 31 -R 32is selected from the group shown in the formula:

[0046] [ka]

[0047] Preferably, the compounds represented by formulas (I) to (VII) are specifically as follows:

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056]

change

[0057]

change

[0058]

change

[0059]

change

[0060]

change

[0061]

change

[0062]

change

[0063]

change

[0064]

change

[0065]

change

[0066]

change

[0067] [ka]

[0068] [ka]

[0069] [ka]

[0070] [ka]

[0071] The present invention further provides a process for preparing the above compounds, which is carried out by the following reaction steps:

[0072] [ka]

[0073] or

[0074] [ka]

[0075] (In the formula, R 2B , R 4 , R 5 , X 1 , X 2 , X 3 and ring A are the same as above.) Preferably, the synthesis process of the intermediate A is as follows: The raw material A, potassium acetate, bis(pinacolato)diboron, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex were dissolved in anhydrous dioxane, and the reaction system was purged with an inert gas, followed by reaction. After completion of the reaction, the reaction solution was concentrated, stirred, and subjected to column chromatography to obtain a product. The process for synthesizing the compound of formula I using the intermediate A and the raw material B is as follows: Intermediate A, raw material B, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, tricyclohexylphosphine, and cesium carbonate were dissolved in a dioxane / water mixture, the reaction system was purged with an inert gas, and then the reaction was allowed to proceed. After the reaction was completed, the reaction solution was concentrated, stirred, and subjected to column chromatography to obtain a product. The synthesis process of the intermediate B is as follows: The raw material B, potassium acetate, bis(pinacolato)diboron, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex were dissolved in anhydrous dioxane, and the reaction system was purged with an inert gas, followed by reaction. After completion of the reaction, the reaction solution was concentrated, stirred, and subjected to column chromatography to obtain a product. The process for synthesizing the compound of formula I using the intermediate B and the raw material A is as follows: Intermediate B, raw material A, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, tricyclohexylphosphine, and cesium carbonate are dissolved in a dioxane / water mixture, and the reaction system is purged with an inert gas. After the reaction is complete, the reaction solution is concentrated, stirred, and subjected to column chromatography to obtain the product.

[0076] The present invention further provides the use of the above-mentioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a RIPK1 inhibitor.

[0077] The present invention provides the use of the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating inflammation, an immune disorder, a neurodegenerative disorder, or a tumor.

[0078] Preferably, the medicament is used for the treatment of inflammatory responses, immune disorders, neurodegenerative disorders or tumors associated with programmed cell necrosis.

[0079] Preferably, the inflammation is colitis.

[0080] The present invention further provides a pharmaceutical composition, which is a formulation prepared using the above-mentioned compound, or its stereoisomer, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials. Programmed cell necrosis, as defined in the present invention, is a form of spontaneous, orderly cell death determined by genes. Specifically, it refers to a suicide protection measure initiated by gene control when cells are stimulated by internal or external environmental factors. It involves the induced activation of several molecular mechanisms and genetic programming, and this method eliminates non-essential cells in the body or cells immediately prior to the onset of speciation. TNF, TLR3 and TLR4 ligands, certain bacterial and viral infections, etc., can induce programmed cell necrosis.

[0081] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, Ohio) naming systems.

[0082] Regarding the definitions of terms used in the present invention, unless otherwise specified, the initial definitions provided for groups or terms described herein apply to the corresponding groups or terms throughout the specification. For terms not specifically defined herein, those skilled in the art can assign their meanings based on the disclosure and context.

[0083] "Substituted" means that a hydrogen atom in a molecule is replaced with another atom or molecule.

[0084] The minimum and maximum carbon atom content in the hydrocarbon group is represented by a prefix, for example, the prefix C a ~C b The alkyl group in the above expression refers to any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1-C4 alkyl group" refers to an alkyl group containing 1 to 4 carbon atoms, and in particular, "C0-C b When an alkylene group is defined as "," it means that there is no need for an alkylene group at that site.

[0085] The term "alkyl group" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, a C1-C6 alkyl group is an alkyl group having 1 to 6 member atoms, e.g., 1 to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Examples of alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. The alkyl group may be part of another group, e.g., a C1-C6 alkoxy group.

[0086] "Cycloalkyl group" refers to a saturated or partially saturated cyclic group containing 3 to 14 carbon atoms, no cyclic heteroatoms, and single or multiple rings (including fused, bridged, and spiro systems). In the case of polycyclic ring systems containing aromatic and non-aromatic rings without cyclic heteroatoms, the term "cycloalkyl group" applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8-tetrahydronaphthalen-5-yl). "Cycloalkyl group" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.

[0087] The term "alkenyl group" refers to a linear or branched hydrocarbon group having 2 to 10 carbon atoms, and in some embodiments, 2 to 6 or 2 to 4 carbon atoms, and having at least one vinyl unsaturation site (>C=C<). For example, (C a ~C b ) The alkenyl group means an alkenyl group having a to b carbon atoms, and includes, for example, a vinyl group, a propenyl group, an isopropenyl group, and a 1,3-butadienyl group.

[0088] An "alkynyl group" refers to a linear or branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl group" is also intended to include hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6) alkynyl groups include ethynyl and propynyl groups.

[0089] "Halogen" is fluorine, chlorine, bromine or iodine.

[0090] The terms "heterocycle" and "heterocycloalkyl group" refer to a saturated or non-aromatic unsaturated ring containing at least one heteroatom. The heteroatom is a nitrogen atom, an oxygen atom, or a sulfur atom.

[0091] The term "heteroaryl group" refers to an aromatic unsaturated ring group containing at least one heteroatom, such as nitrogen, oxygen, or sulfur.

[0092] An "ether group" refers to a group formed by removing one hydrogen atom from a carbon atom of an ether compound. A C2-C6 ether group means that the total number of carbon atoms in the hydrocarbon groups connected to both ends of the oxygen atom in the ether compound is 2 to 6.

[0093] The term "amine group" refers to a group obtained by removing one H from an amine compound. The term "amine compound" refers to a compound in which some or all of the hydrogen atoms in an ammonia molecule are substituted with hydrocarbon groups, and the term "C2-C6 amine group" means that the total number of carbon atoms in the hydrocarbon groups connected to both ends of the oxygen atom in the amine compound is 2 to 6.

[0094] An "ester group" refers to a group formed by removing one hydrogen atom from the carbon atom of an ester compound. An ester compound is a compound formed by removing water from an acid and an alcohol, and has the functional group "-COO-". C1 to C 10 The ester group means that the total number of carbon atoms in the amine compound is 1 to 10.

[0095] "R a and R b "form a heterocycle with R" means that R a and R b At least one atom in each of these is connected by a chemical bond, so that in the general formula, R a and R b The atom or atom chain commonly connected to R a and R b This means that the heterocycle is formed with

[0096] "Stereoisomer" includes enantiomers and diastereomers.

[0097] In the present invention, a horizontal line connected to a symbol representing a substituent represents a covalent bond. For example, "-R" means that R is linked to another group by one covalent bond. "-R-" means that R is linked to another group by two covalent bonds. "-R A2 -R A3 " is R A3 is connected to R by one covalent bond A2 and R A2 is connected to R by two covalent bonds A3 and other groups.

[0098] The term "pharmaceutically acceptable" means that the carrier, carrier, diluent, auxiliary material, and / or formed salt is chemically or physically compatible with the other ingredients that normally make up a dosage form of a drug, and is physiologically compatible with the receptor.

[0099] The terms "salt" and "pharmaceutically useful salt" refer to acid and / or base salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and alkalis, including zwitterionic salts (internal salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds or their stereoisomers with an appropriate amount (e.g., an equivalent amount) of acid or alkali. These salts can be prepared by forming a precipitate in a solution and recovering it by filtration, recovering it after evaporating the solvent, or reacting it in an aqueous medium followed by lyophilization. The salts of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate salts of the compounds.

[0100] In some embodiments, one or more compounds of the present invention can be used in combination with each other.The compounds of the present invention can also be used in combination with any other active agent to prepare drugs or pharmaceutical compositions for regulating cell function or treating disease.When a group of compounds is used, these compounds can be administered to a subject simultaneously, separately, or sequentially.

[0101] Obviously, according to the above content of the present invention, various other forms of modifications, substitutions or alterations can be made by those skilled in the art in the light of their common technical knowledge and common practices without departing from the above basic technical idea of ​​the present invention.

[0102] The above content of the present invention will be described in more detail below through specific embodiments as examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. The technology realized based on the above content of the present invention belongs to the scope of the present invention. [Brief explanation of the drawings]

[0103] [Figure 1] 1 is a kinase selectivity profile of compound 34 of the present invention. [Figure 2] 1 is a kinase selectivity profile of compound 94 of the present invention. [Figure 3] FIG. 10 is a curve diagram of cell viability in Example 5. [Figure 4] 1 shows the effect of compounds 46 and 94 on the necrosis signal pathway in Example 6. [Figure 5] 1 shows the results of protecting a mouse SIRS model induced by TNFα with compounds 46 and 94 in Example 7. [Figure 6] 1 shows concentration-response curves of compound terfenadine (left) and compound 94 (right) in Example 8. [Figure 7] 1 shows the experimental results of comparing the colon lengths of mice in Example 8. [Figure 8] 1 shows concentration-response curves of the inhibitory effects of compound terfenadine (left) and compound 94 (right) on hERG current in Example 10. DETAILED DESCRIPTION OF THE INVENTION

[0104] The present disclosure will now be further described with reference to examples. The depictions of specific exemplary embodiments of the present disclosure are for purposes of explanation and illustration. These depictions are not intended to limit the disclosure to the precise forms disclosed, and clearly, many modifications and variations are possible in accordance with the teachings of the present specification. The exemplary embodiments are selected and depicted to illustrate certain principles of the present disclosure and their practical applications, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure and various options and modifications. [Example]

[0105] The experimental methods used in the following examples are all conventional methods unless otherwise specified.

[0106] Unless otherwise specified, all materials, reagents, etc. used in the following examples are commercially available products.

[0107] NMR measurements were performed using a BRUKER 400MR DD2 nuclear magnetic resonance spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS). Liquid chromatography-mass spectrometry (LC-MS) measurements were performed using an Agilent 1200 Infinity II-InfinityLab LC / MSD mass spectrometer. HPLC measurements were performed using an Agilent 1200 Infinity II high-pressure liquid chromatograph (Sunfire C18 5µm 150 x 4.6mm column). Thin-layer chromatography silica gel plates were Yantai Jiangyou Silica Gel Development Co., Ltd.'s HSGF254 silica gel plates, with a diameter of 0.9mm to 1mm. The TLC silica gel plate used was a GF254 silica gel plate from YuCheng Chemical (Shanghai) Co., Ltd., with a 0.2-0.25 mm diameter. The column chromatography carrier used was a 300-400 mesh silica gel from Qingdao Hailang Silica Desiccant Co., Ltd. The flash column used was a Claricep Flash amorphous silica gel purification column from Agela & Phenomenex. In the examples of the present invention, the reagents 1-propanephosphonic anhydride and methylmagnesium bromide were purchased from Shanghai Macklin Biochemical Technology Co., Ltd., 4N hydrochloric acid dioxane solution was purchased from Panjin Yanfeng Technology Co., Ltd., 1M borane tetrahydrofuran solution, N,N-diisopropylethylamine, and (S)-tert-butylsulfenamide were purchased from Adamas Reagent Co., Ltd., and other reagents and starting materials were purchased from Shanghai Haohong Biomedical Technology Co., Ltd. or could be synthesized using methods known in the art.Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon gas atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in °C.

[0108] Example 1 Preparation of Compound 34 of the Invention (Method I)

[0109] [ka]

[0110] i: N,N-Dimethylformamide, (S)-1-(3-fluorophenyl)ethylamine, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N-diisopropylethylamine, 65°C, 8 hours, yield 85%. ii: pyridine, cyclopropylcarbonyl chloride, triethylamine, 0°C to room temperature, 6 hours, yield 90%, iii: Anhydrous dioxane, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, potassium acetate, bis(pinacolato)diboron, 95°C, 24 hours, 60% yield. iv: 1,4-dioxane / water=10:1, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, tricyclohexylphosphine, cesium carbonate, 100°C, 16 hours, yield 75%.

[0111] The specific operation steps include:

[0112] Preparation of (S)-5-bromo-N-(1-(3-fluorophenyl)ethyl)-1H-indole-3-amide (Intermediate 2): 5-Bromoindole-3-carboxylic acid (4.5 g, 18.8 mmol), 1-hydroxybenzotriazole (HOBT) (3 g, 21.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (4.3 g, 23.4 mmol) were dissolved in 60 mL of N,N-dimethylformamide, and then N,N-diisopropylethylamine (3.6 mL, 23.4 mmol) was added. The carboxylic acid was activated at room temperature for 0.5 hours, and then (S)-1-(3-fluorophenyl)ethylamine (2.8 g, 19.8 mmol) was added, and the reaction was heated to 65°C for 8 hours. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated, extracted with dichloromethane and sodium thiosulfate solution, the organic phase was washed with water, washed with saturated sodium chloride solution, and then dried by adding sodium sulfate. After suction filtration and drying, column chromatography was performed to obtain intermediate 2 (5.7 g, white solid) in 85% yield. 1 H NMR (400 MHz, DMSO- d6) δ 11.46 (s, 1H), 8.35 (s, 1H), 8.19 (d, J = 5.9 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.11-7.02 (m, 2H), 7.00 (s, 1H), 6.97 (d, J = 7.0 Hz, 1H), 5.21-5.11 (m, 1H), 1.47 (d, J = 7.1 Hz, 3H).

[0113] Preparation of N-(6-bromobenzo[d]thiazol-2-yl)cyclopropylcarboxamide (Intermediate 4): 1 g of intermediate 3 (1.0 g, 4.4 mmol) was dissolved in 15 mL of dry pyridine, and 1.4 mL of triethylamine (575 mg, 5.7 mmol) was added. 370 μL of cyclopropylcarbonyl chloride (499 mg, 4.8 mmol) was slowly added dropwise at 0°C. The temperature was gradually raised to room temperature and the reaction was carried out for 6 hours. The reaction solution was directly concentrated and extracted with dichloromethane and saturated sodium carbonate solution. The organic phase was washed with water and saturated sodium chloride solution, then dried over sodium sulfate, and purified by column chromatography to obtain intermediate 4 (1.2 g, pale yellow solid) in 90% yield. 1 H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.11 (d, J = 6.9 Hz, 1H), 7.55 (s, 1H), 7.02 (d, J = 5.4 Hz, 1H), 1.23 (d, J = 11.0 Hz, 1H), 1.16 (dt, J = 7.4 3.9 Hz, 2H), 0.93 (td, J = 7.0, 3.9 Hz, 2H).

[0114] Preparation of N-(6-(pinacolborate)benzo[d]thiazol-2-yl)cyclopropylcarboxamide (Intermediate 5): Intermediate 4 (10 g, 33.8 mmol), potassium acetate (6.6 g, 67.6 mmol), 12 g of bis(pinacolato)diboron (12 g, 47.2 mmol), and 2.8 g of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.8 g, 3.4 mmol) were dissolved in 200 mL of anhydrous dioxane. The reaction system was purged with nitrogen gas three times, and then the reaction was carried out at 95°C for 24 hours. The reaction was monitored using a developing solvent of petroleum ether:ethyl acetate = 20:1. After completion of the reaction, the reaction solution was concentrated, stirred homogeneously, and purified by column chromatography using an eluent of petroleum ether:ethyl acetate = 80:1 to obtain Intermediate 5 (6.9 g, white solid) in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.45 (d, J = 6.7 Hz, 1H), 8.03 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 1.21 (d, J = 11.2 Hz, 1H), 1.33 (s, 12H), 1.11 (dt, J = 7.4 3.9 Hz, 2H), 0.99 (td, J = 7.0, 3.9 Hz, 2H).

[0115] Preparation of (S)-5-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)-1H-indole-3-carboxamide (compound 34): Intermediate 2 (400 mg, 1.1 mmol), Intermediate 5 (580 mg, 1.7 mmol), 133 mg of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (133 mg, 0.16 mmol), 41 mg of tricyclohexylphosphine (45 mg, 0.16 mmol), and 780 mg of cesium carbonate (780 mg, 2.4 mmol) were added to 100 mL of 1,4-dichloro-2,4-diphenylphosphine. The product was dissolved in a mixture of oxane and water (10:1), and the reaction system was purged with nitrogen gas three times. The reaction was then carried out at 100°C for 16 hours. The reaction was monitored using a developing solvent of ethyl acetate:petroleum ether = 1:1. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated, stirred uniformly, and subjected to column chromatography. The product was purified using an eluent of ethyl acetate:petroleum ether = 5:1 to obtain compound 34 (318 mg, an almost white solid) in a 58% yield. 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 11.66 (s, 1H), 8.43 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.81-7.75 (m, 2H), 7.70 (dd, J = 8.5, 1.6 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 14.1, 8.1 Hz, 2H), 7.25 (t, J = 9.4 Hz, 2H), 7.09-7.00 (m, 1H), 5.75 (s, 1H), 5.27-5.15 (m, 1H), 2.06 (d, J = 11.0 Hz, 1H), 0.96 (d, J = 5.1 Hz, 4H).

[0116] Example 2 Preparation of Compound 94 of the Invention (Method II).

[0117] [ka]

[0118] i: N,N-Dimethylformamide, iodomethane, cesium carbonate, 80°C, 8 hours, 90%. ii: Methanol, water, sodium hydroxide, 60°C, 3 hours, 95% iii: N,N-dimethylformamide, (S)-1-(3-fluorophenyl)ethylamine, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N-diisopropylethylamine, 65°C, 8 hours, 85%, iv: 1,4-dioxane / water = 5:1, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, tricyclohexylphosphine, cesium carbonate, 95°C, 12 hours, 75%, v: Pyridine, cyclopropanecarbonyl chloride, triethylamine, 0°C to room temperature, 6 hours, 90%, vi: 1,4-dioxane / water=10:1, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, tricyclohexylphosphine, cesium carbonate, 95°C, 12 hours, 75%.

[0119] The specific operation steps include:

[0120] Preparation of methyl 5-bromo-1-methyl-1H-indole-3-carboxylate (intermediate 2): Intermediate 1 (1.0 g, 3.9 mmol), iodomethane (700 mg, 4.9 mmol), and cesium carbonate (1.8 g, 5.5 mmol) were dissolved in 30 mL of N,N-dimethylformamide and reacted for 8 hours at 80°C under a nitrogen atmosphere. The reaction was monitored using a 1:3 mixture of ethyl acetate and petroleum ether as a developing solvent. After completion of the reaction, the reaction mixture was directly concentrated, stirred homogeneously, and subjected to column chromatography. Purification with a 1:1 mixture of ethyl acetate and petroleum ether afforded Intermediate 2 (937 mg, white solid) in 90% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.7, 1.9 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H).

[0121] Preparation of 5-bromo-1-methyl-1H-indole-3-carboxylic acid (intermediate 3): Intermediate 2 (507 mg, 1.9 mmol) was dissolved in 20 ml of methanol, and 10 ml of a 2 mol / L sodium hydroxide solution was added. The mixture was stirred at 60°C for 3 hours and reacted. The reaction was monitored using a developing solvent of ethyl acetate:petroleum ether = 1:1. After completion of the reaction, the reaction solution was directly concentrated, diluted with water, and then adjusted to pH 4 to precipitate a solid. The solid was suction filtered and dried to obtain intermediate 3 (432 mg, white solid) in 90% yield. This was used directly in the next step without further purification.

[0122] Preparation of (S)-5-bromo-N-(1-(3-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide (Intermediate 4) Intermediate 3 (987 mg, 3.9 mmol), 1-hydroxybenzotriazole (HOBT) (806 mg, 5.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.0 g, 5.8 mmol) were dissolved in 20 ml of N,N-dimethylformamide, and then N,N-diisopropylethylamine (1.0 g, 7.8 mmol) was added. The carboxylic acid was activated at room temperature for 0.5 hours, and then (S)-1-(3-fluorophenyl)ethylamine (650 mg, 4.6 mmol) was added. The reaction was heated to 65 ° C. and reacted for 8 hours. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated, extracted with dichloromethane and sodium thiosulfate solution, the organic phase was washed with water, washed with saturated sodium chloride solution, added sodium sulfate, dried, suction filtered, and then subjected to column chromatography to obtain intermediate 4 (1.2 g, white solid) in 84% yield. 1 H NMR (400 MHz, DMSO) δ 8.34 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.37-7.30 (m, 2H), 7.22 (t, J = 9.0 Hz, 2H), 7.05 (d, J = 9.3 Hz, 1H), 5.17 (d, J = 7.5 Hz, 1H), 3.84 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H).

[0123] Preparation of (S)-N-(1-(3-fluorophenyl)ethyl)-1-methyl-5-(pinacolborate)-1H-indole-3-carboxamide (Intermediate 5): Intermediate 4 (2.0 g, 5.3 mmol), potassium acetate (1.1 g, 11.2 mmol), bis(pinacolato)diboron (1.7 g, 6.9 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (410 mg, 0.5 mmol) were dissolved in 50 mL of anhydrous dioxane. The reaction system was purged with nitrogen gas three times, and then the reaction was carried out at 95°C for 12 hours. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, concentrated, stirred homogeneously, and purified by column chromatography using an eluent of petroleum ether:ethyl acetate = 1:1 to obtain Intermediate 5 (1.3 g, pale yellow solid) in 60% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.14 (s, 1H), 7.48 (t, J = 6.8 Hz, 2H), 7.36 (dd, J = 14.1, 8.0 Hz, 1H), 7.22 (t, J = 9.5 Hz, 2H), 7.06-6.99 (m, 1H), 5.19-5.11 (m, 1H), 3.84 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.30 (s, 12H).

[0124] Preparation of N-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropylcarboxamide (Intermediate 7): Intermediate 6 (1.0 g, 4.7 mmol) was dissolved in 15 ml of dry pyridine, 1.4 mL of triethylamine (949 mg, 9.4 mmol) was added, and cyclopropanecarbonyl chloride (541 mg, 5.2 mmol) was slowly added dropwise at 0°C. The temperature was gradually raised to room temperature and the reaction was carried out for 6 hours. The reaction solution was directly concentrated and extracted with dichloromethane and saturated sodium carbonate solution. The organic phase was washed with water and then with saturated sodium chloride solution, followed by addition of sodium sulfate, drying, and purification by column chromatography to obtain Intermediate 7 (1.2 g, yellow solid) in 90% yield. 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.40 (d, J = 7.1 Hz, 1H), 7.82 (s, 1H), 7.09 (d, J = 5.9 Hz, 1H), 1.27 (d, J = 11.5 Hz, 1H), 1.21 (dt, J = 7.6, 3.9 Hz, 2H), 0.96 (td, J = 7.0, 3.9 Hz, 2H).

[0125] Preparation of (S)-5-(2-(cyclopropylcarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide (compound 94): Intermediate 7 (280 mg, 1.0 mmol), Intermediate 5 (422 mg, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (85 mg, 0.1 mmol), tricyclohexylphosphine (28 mg, 0.1 mmol), and cesium carbonate (390 mg, 1.2 mmol) were dissolved in 100 mL of a 1,4-dioxane / water (10:1) mixture. The reaction system was purged with nitrogen gas three times, and then the reaction was carried out at 100 °C for 12 hours. The reaction was monitored using a 3:1 mixture of ethyl acetate and petroleum ether as a developing solvent. The polarity of the product was observed to be higher than that of the raw materials. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated, stirred homogeneously, and subjected to column chromatography. The mixture was purified using a 10:1 mixture of ethyl acetate and petroleum ether to obtain compound 94 (372 mg, white solid) in 75% yield. 1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.83 (d, J = 7.1 Hz, 1H), 8.53 (s, 1H), 8.37 (d, J = 8.0 Hz, 2H), 8.22 (s, 1H), 7.86 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.46-7.40 (m, 1H), 7.37 (dd, J = 14.2, 7.8 Hz, 2H), 7.25 (t, J = 9.7 Hz, 2H), 7.05 (t, J = 8.6 Hz, 1H), 5.22 (dd, J = 14.3, 6.9 Hz, 1H), 3.90 (s, 3H), 2.07 (s, 1H), 0.96 (d, J = 5.3 Hz, 4H).

[0126] Example 3 Preparation of Compound 142 of the Invention (Method III)

[0127] [ka]

[0128] i: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide, pyridine, 80°C, 12 hours, yield 80%.

[0129] The specific operation steps include:

[0130] Preparation of (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide (141): Compound 141 can be prepared following the procedural steps shown in Method II. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 7.0 Hz, 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 7.73-7.60 (m, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.37 (q, J = 7.4 Hz, 1H), 7.32-7.12 (m, 3H), 7.04 (td, J = 8.7, 2.6 Hz, 1H), 5.99 (s, 2H), 5.20 (q, J = 7.3 Hz, 1H), 3.89 (s, 3H), 1.49 (d, J = 7.1 Hz, 3H).

[0131] Preparation of 5-(2-(2,2-difluorocyclopropane-1-carboxamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((S)-1-(3-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide (142) Compound 141 (150 mg, 0.35 mmol) and 2,2-difluorocyclopropanecarboxylic acid (85 mg, 0.70 mmol) were dissolved in 15 ml of dry pyridine, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (229 mg, 50% ethyl acetate solution) was added at room temperature. The temperature was gradually raised to 80°C and the reaction was carried out for 6 hours. The reaction solution was directly concentrated, homogenized with dichloromethane, and purified by column chromatography to obtain 142 (149 mg, pale yellow solid) in 80% yield. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.93 (d, J = 7.0 Hz, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.45 (d, J = 8.1 Hz, 1H), 8.29 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.80 (dd, J = 8.6, 1.9 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 7.2, 2.0 Hz, 1H), 7.46-7.39 (m, 1H), 7.35-7.28 (m, 2H), 7.15-7.05 (m, 1H), 5.27 (t, J = 7.4 Hz, 1H), 3.95 (d, J = 13.0 Hz, 3H), 2.10 (d, J = 7.1 Hz, 1H), 1.55 (d, J = 7.0 Hz, 3H), 1.31-1.18 (m, 2H).

[0132] Example 4 Preparation of Compound 162 of the Invention (Method IV)

[0133] [ka]

[0134] i: Methyl chloroformate, N,N-diisopropylethylamine, dichloromethane, room temperature, 6 hours, 90%. ii: (R)-3-pyrrolidinol, pyridine, 100°C, 16 hours, 80%.

[0135] Preparation of (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-1-methyl-1H-indole-3-carboxamide (141): Compound 141 can be prepared following the procedural steps shown in Method II. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 7.0 Hz, 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 7.73-7.60 (m, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.37 (q, J = 7.4 Hz, 1H), 7.32-7.12 (m, 3H), 7.04 (td, J = 8.7, 2.6 Hz, 1H), 5.99 (s, 2H), 5.20 (q, J = 7.3 Hz, 1H), 3.89 (s, 3H), 1.49 (d, J = 7.1 Hz, 3H).

[0136] Preparation of methyl (S)-(7-(3-((1-(3-fluorophenyl)ethyl)carbamoyl)-1-methyl-1H-indol-5-yl)-(1,2,4]triazolo[1,5-a]pyridin-2-yl)carbamate (166) Intermediate 141 (513 mg, 1.2 mmol) was placed in a flask, and 10 ml of dichloromethane, 1 ml of N,N-diisopropylethylamine (310 mg, 2.4 mmol), and methyl chloroformate (131 mg, 1.4 mmol) were added in that order. The mixture was stirred at room temperature for 6 hours to react, and the reaction was monitored using a developing solvent of dichloromethane:methanol=20:1. After completion of the reaction, the reaction solution was directly concentrated, stirred uniformly, and purified using a silica gel column to obtain intermediate 166 (525 mg, a light yellow solid) in a 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.89-8.80 (m, 1H), 8.53 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.23 ​​(s, 1H), 7.86 (s, 1H), 7.78-7.63 (m, 2H), 7.50-7.35 (m, 2H), 7.25 (t, J = 9.7 Hz, 2H), 7.04 (d, J = 10.0 Hz, 1H), 5.22 (s, 1H), 3.91 (s, 3H), 3.70 (s, 3H), 1.50 (d, J = 7.1 Hz, 3H).

[0137] Preparation of N-((S)-1-(3-fluorophenyl)ethyl)-5-(2-((R)-3-hydroxypyrrolidine-1-carboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-indole-3-carboxamide (162): 100 mg of intermediate 166 (100 mg, 0.2 mmol) was dissolved in pyridine, 50 mg of (R)-3-pyrrolidinol (52 mg, 0.6 mmol) was added, and the reaction was heated to 100 °C for 16 hours. The reaction was monitored using a developing solvent of dichloromethane:methanol = 20:1. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase column chromatography to obtain 162 (86 mg, white solid) in 80% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.80 (d, J = 7.1 Hz, 1H), 8.53 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.72 (dd, J = 8.6, 1.9 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.45-7.33 (m, 2H), 7.29-7.20 (m, 2H), 7.05 (ddd, J = 10.3, 8.2, 2.7 Hz, 1H), 5.22 (q, J = 7.3 Hz, 1H), 4.98 (d, J = 3.4 Hz, 1H), 4.30 (s, 1H), 3.90 (s, 3H), 3.49 (s, 3H), 3.31 (s, 1H), 1.96-1.88 (m, 1H), 1.81 (s, 1H), 1.49 (d, J = 7.0Hz, 3H).

[0138] Other compounds of the present invention can all be synthesized in a manner similar to that of Examples 1 to 4, with the synthetic methods and structural characterizations used being as shown in the table below.

[0139] [Table 1]

[0140] [Table 2]

[0141] [Table 3]

[0142] [Table 4]

[0143] [Table 5]

[0144]

Table 6

[0145]

Table 7

[0146]

Table 8

[0147]

Table 9

[0148]

Table 10

[0149]

Table 11

[0150]

Table 12

[0151]

Table 13

[0152]

Table 14

[0153]

Table 15

[0154] Table 16

[0155]

Table 17

[0156]

Table 18

[0157]

Table 19

[0158] Table 20

[0159] Table 21

[0160] Table 22

[0161] Table 23

[0162] Table 24

[0163] Table 25

[0164] Table 26

[0165] Table 27

[0166] Table 28

[0167] Table 29

[0168] Table 30

[0169] Table 31

[0170] Table 32

[0171]

Table 33

[0172] Table 34

[0173] Table 35

[0174] Table 36

[0175] Table 37

[0176] Table 38

[0177] Table 39

[0178] Table 40

[0179] Table 41

[0180] Table 42

[0181] Table 43

[0182] Table 44

[0183] Table 45

[0184] Table 46

[0185] Table 47

[0186] Table 48

[0187] Table 49

[0188]

Table 50

[0189] Table 51

[0190] Table 52

[0191] Table 53

[0192] Table 54

[0193] Table 55

[0194] Table 56

[0195] Table 57

[0196] Table 58

[0197] Table 59

[0198] Table 60

[0199] Table 61

[0200] Table 62

[0201] Table 63

[0202] Table 64

[0203] Table 65

[0204] Table 66

[0205] Table 67

[0206] Table 68

[0207] Table 69

[0208] Table 70

[0209] Table 71

[0210] Table 72

[0211] Table 73

[0212] Table 74

[0213] Table 75

[0214] Table 76

[0215] Table 77

[0216] Table 78

[0217] Table 79

[0218] Table 80

[0219] Table 81

[0220] Table 82

[0221] Table 83

[0222] Table 84

[0223] Table 85

[0224] Table 86

[0225] Table 87

[0226] Table 88

[0227] [Table 89]

[0228] Example 5 In vitro kinase assay and protection against programmed cell death of compounds according to the present invention In vitro kinase assays were performed using the Kinase Profiler service provided by Eurofins. The experimental method was as follows: A test small molecule compound (0.001-10 μM), a test protein kinase, and a substrate, 10 mM magnesium acetate and [γ- 33 The reaction mixture was incubated simultaneously with a buffer containing [P-ATP], and the Mg\ATP mix was added to initiate the reaction. After incubation at room temperature for a specific period, 3% phosphate solution was added to the buffer to terminate the reaction. Then, 10 μL of the reaction mixture was aspirated and dropped onto a P30 filter paper, which was washed three times with 75 mM phosphate solution and once with methanol. After air-drying the P30 filter paper, scintillation fluid was added and scintillation counting was performed. The activity inhibition of the compound was measured using the half-maximal inhibitory concentration (IC50). 50 and IC 50 The value of is obtained by fitting the inhibition rate corresponding to each concentration gradient.

[0229] In vitro protection experiments against HT-29 programmed cell death were carried out by the inventors themselves.

[0230] 1) Experimental materials DMEM medium is purchased from Gibco, penicillin and streptomycin are purchased from Hyclone, TNFα is purchased from Peprotech, Smac mimetic and Z-VAD-FMK are purchased from Selleck, and CCK8 is purchased from Medchem Express.

[0231] 2) Experimental method HT-29 cells (colon cancer cells) are cultured in DMEM + 10% FBS + penicillin / streptomycin medium. At the time of the experiment, HT-29 cells in the logarithmic growth phase are harvested and a specific number of cells per well (adherent cells are typically 8 x 10 cells) are cultured. 3 Cells were seeded into a 96-well plate at 1000 x g (cells / well) and cultured overnight in a cell incubator at 37°C and 5% CO2. The next day, test compounds were diluted to the corresponding concentrations with culture medium and added to the corresponding wells of the 96-well plate. Each sample was replicated in triplicate, with a solvent control group and a blank control group containing only culture medium. After drug administration, cells were induced with the TNFα / Smac mimetic / Z-VAD-FMK combination for 24 h. Then, 10 μl of CCK8 solution was added per well and incubated in an incubator for 1–3 h. Absorbance at 495 nm was measured using a microplate reader, and the necrosis protection rate of the drug was calculated using the following formula: Cell necrosis protection rate = [(X-C0) / (C-C0)] × 100%.

[0232] where C, C0, and X represent the average absorbance values ​​of the solvent control group, the blank control group, and the drug-treated group, respectively. Finally, the cell viability curves were fitted using Graphpad Prism 5.0 software, and the EC50 of the test compounds to inhibit programmed cell death was calculated. 50 The results are shown in Table 2, where +++++ is the IC 50 or EC 50 <0.001 μM, ++++ denotes IC >0.01 μM 50 or EC 50 ≥ 0.001 μM, and +++ indicates 0.1 μM > IC 50 or EC 50 ≥ 0.01 μM, and ++ indicates 1 μM > IC 50 or EC 50 ≥ 0.1 μM, + indicates IC 50 or EC 50 ≥ 1 μM.

[0233] [Table 90]

[0234] [Table 91]

[0235] [Table 92]

[0236] [Table 93]

[0237] [Table 94]

[0238] [Table 95]

[0239] [Table 96]

[0240] [Table 97]

[0241] [Table 98]

[0242] [Table 99]

[0243] The preferred compounds 34 and 94 were subjected to single concentration inhibition measurement at a concentration of 10 μM against 422 existing kinases (including mutants) from Eurofins, and the IC50 Measurements were carried out and the results (tests were carried out by Eurofins and activity data was provided) are shown in Tables 3 and 4:

[0244] [Table 100]

[0245] [Table 101]

[0246] [Table 102]

[0247] [Table 103]

[0248] [Table 104]

[0249] [Table 105]

[0250] [Table 106]

[0251] [Table 107]

[0252] [Table 108]

[0253] [Table 109]

[0254] Based on the data in Tables 3 and 4, the selectivity profiles of compounds 34 and 94 were plotted (see http: / / bcb.med.usherbrooke.ca / kinomerenderLig.php for plotting flow and operation), and are shown in Figures 1 and 2. Here, red circular spots indicate kinases with significant inhibitory activity, with larger red spot radiuses indicating stronger inhibitory activity against the kinase, and smaller red spot radiuses indicating weaker inhibitory activity against the kinase. Tables 3 and 4 and Figures 1 and 2 indicate that compounds 34 and 94 have good kinase selectivity.

[0255] As shown in Figure 3, compound 94 inhibited the programmed necrosis model of HT-29 cells. 50 The EC value was 0.012 nM, and compounds 34 and 46 in the same series inhibited the programmed necrosis model in HT-29 cells. 50 The values ​​were 0.117 nM and 0.070 nM, respectively. These experimental results demonstrate that compound 94 of the present invention and compounds in the same series can protect HT-29 cells from necrosis-like apoptosis induced by TSZ.

[0256] Example 6 Regulation of the RIPK1 signal pathway by compounds 94 and 46 of the present invention 1) Experimental materials TNFα was purchased from Peprotech, Smac mimetic and Z-VAD-FMK were purchased from Selleck, RIPA lysis solution was purchased from Beyotime Biotechnology Institute, cocktail was purchased from MCE, PMSF protease inhibitor, sodium dodecyl sulfonate (SDS), and glycine were purchased from Sigma, acrylamide, trimethylolaminomethane (Tris), ammonium persulfate (APS), and N,N,N',N'-tetramethylethylenediamine (TEMED) were all purchased from Wuhan Servicebio Technology Co., Ltd.

[0257] 2) Experimental method Total cellular protein extraction: Cell supernatants were treated with the corresponding concentrations of compound 94, 46, or blank solvent. Cells were then induced with the TNFα / Smac mimetic / Z-VAD-FMK combination for a specified period. The supernatant was then discarded, washed three times with pre-chilled PBS or saline, and lysed immediately after adding an appropriate volume of RIPA lysis solution (containing 1% cocktail and 1% PMSF protease inhibitor) on ice for 15 min. After 15 min, the cell lysate was scraped off with a scraper, transferred to a 1.5 ml EP tube, and disrupted using an ultrasonicator. The tube was then placed in a low-temperature high-speed centrifuge and centrifuged (12,000 rpm for 15 min) to remove cell debris. Protein quantification was performed using the BCA method. A calibration curve was created using protein standards, and the protein concentration of each sample was calculated from the calibration curve. The protein concentration of each group was then equalized by calculation. 5x protein loading buffer was added and the tube was placed in a dry incubator at 100°C for 10 min. The sample was then directly loaded onto a lane for electrophoresis or aliquoted and stored at -20°C for further use, avoiding repeated freezing and thawing of the protein sample.

[0258] After preparing the protein samples, the proteins were separated by polyacrylamide gel electrophoresis (SDS-PAGE). The polyacrylamide gel preparation formula is shown in Table 5, and separation is typically performed using a 10% separating gel. After electrophoresis, the proteins were thoroughly transferred to a PVDF membrane using a trough-type wet transfer. The PVDF membrane was then blocked in 5% nonfat dry milk (prepared with TBS / T) at room temperature for at least 2 hours. A band containing the protein corresponding to the desired molecular weight was obtained on the PVDF membrane. The primary antibody was then diluted according to the dilution ratio recommended in the antibody manual and the protein band was incubated overnight at 4°C. The next day, each band was removed and rinsed with TBS / T buffer (5 min, 3 times). Then, a 1:5000 diluted HRP-labeled secondary antibody was added and incubated at 37°C with shaking for 1 hour. After that, excess antibody was eluted and removed with TBS / T. HRP substrate was evenly dropped onto the PVDF membrane, which was then developed using a high-speed gel imaging system and photographed.

[0259] [Table 110]

[0260] 3) Experimental results The results are shown in Figure 4. Compounds 94 and 46 inhibited the phosphorylation of RIPK1 itself, thereby affecting the phosphorylation of downstream RIPK3 and MLKL. Furthermore, this inhibitory activity was concentration-dependent, consistent with protective activity at the cellular level, indicating that compounds 94 and 46 exert their inhibitory effect on programmed necrosis by blocking the programmed necrosis signaling pathway.

[0261] Example 7 Protective effects of compounds 94 and 46 of the present invention on TNFα-induced mouse SIRS model 1) Experimental materials TNFα is purchased from Peprotech, castor oil is purchased from MCE, and sterile saline is purchased from Chengdu Baisheng Kechuang Biotechnology Co., Ltd.

[0262] 2) Experimental method The modeling dose of TNFα was 500 μg / kg, prepared in sterile saline, and injected via the tail vein. Mouse body temperature was measured using a gun-type infrared thermometer. The solvent was 25% ethanol castor oil and 75% saline. Oral administration was used. Compounds 94, 46, and the RIPK1-positive compound GSK2982772 were all administered orally at 40 mg / kg before model creation. Body temperature and survival status of the mice were recorded hourly, and further records were kept for 11 h, 24 h, and 48 h after administration. Survival curves were fitted using Graphpad Prism 5.0 software.

[0263] 3) Experimental results To verify whether compounds 94 and 46 possess anti-RIPK1 activity and inhibitory activity against programmed necrosis in vivo, we used SIRS, a representative inflammation model. Systemic inflammatory response syndrome (SIRS) is a systemic inflammatory response that damages and destroys the body through infection or other factors. In critically ill patients, SIRS is easily induced due to a decrease in the body's compensatory anti-inflammatory response capacity and impaired metabolic function. Meanwhile, long-term studies have demonstrated a high correlation between TNFα-induced SIRS disease models and RIPK1-dependent apoptosis and programmed necrosis.

[0264] In this experiment, a TNFα-induced SIRS mouse model was established to evaluate the in vivo activity of the compounds of the present invention. The modeling dose of TNFα was 500 μg / kg, prepared in sterile saline, and injected into the mice via tail vein. Because measuring the rectal temperature of mice may cause mechanical injury to the mice and interfere with the experimental results, the mice's body temperature was measured using a gun-type infrared thermometer, and their survival status was monitored. Compounds 94 and 46 were administered at a dose of 40 mg / kg once before establishing the model. The vehicle group (vehicle) was administered the corresponding vehicle control.

[0265] The experimental results are shown in Figure 5. Within a short time after tail vein injection of TNFα, mice in the vehicle group showed symptoms such as a continuous drop in body temperature and decreased activity, and began to die within 24 hours. In contrast, in the groups treated with compounds 94 and 46, except for one individual mouse, all mice maintained normal body temperature within 11 hours after TNFα injection, and the vitality of the mice was significantly superior to that of the vehicle group. The overall mortality rate was significantly reduced compared to the vehicle group. Furthermore, compound 94 demonstrated a better protective effect than the active compound GSK2982772. Compounds 94 and 46 exerted significant anti-inflammatory effects by inhibiting RIPK1 in vivo, demonstrating resistance to high-dose TNFα-induced mortality in mice.

[0266] Example 8 Protective effect of compound 94 of the present invention on DSS-induced IBD model in mice 1) Experimental materials Dextran sulfate sodium salt (DSS, 36,000-50,000 KD) was purchased from Shanghai Yeasen Biotech Co., Ltd., 0.CT tissue fixative was purchased from Servicebio Technology Co., Ltd., PEG300 and Tween-80 were purchased from MCE, and DMSO was purchased from Sigma.

[0267] 2) Experimental method Female C57BL / 6 mice weighing 17–20 g were used. Experimental groups were given DSS (2.5% wt / vol) in their drinking water and allowed to drink ad libitum for 7 days (days 0–7). Fresh DSS solution was replaced on days 2, 4, and 6. On day 7, all water was replaced with normal drinking water, and mice were randomly assigned (7 mice per group) to either the vehicle group (10% DMSO, 40% PEG300, 5% Tween-80, 45% saline), the GSK3145095 group (40 mg / kg), or the Compound 94 group (40 mg / kg) and orally administered the corresponding vehicle. The control group received normal drinking water daily and, from day 7, received the corresponding vehicle orally. Mouse weight and survival rates were recorded daily. Survival curves were fitted using Graphpad Prism 5.0 software. On day 12, the mice (2 mice each) were sacrificed and the changes in the length of the mouse colon were observed.

[0268] 3) Experimental results In this study, we selected IBD, a representative model of colitis, to verify whether compound 94 possesses anti-RIPK1 activity and inhibitory activity against programmed necrosis in an in vivo autoimmune disease model. Inflammatory bowel diseases (IBD) are chronic, nonspecific intestinal inflammatory diseases characterized by abnormal immune-mediated intestinal inflammation resulting from environmental, genetic, infectious, and immunological factors. The pathogenesis of IBD remains unknown. The major pathological types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). Although the etiology of IBD remains unknown, excessive apoptosis of intestinal epithelial cells, damage to the intestinal mucosal barrier, and increased permeability of intestinal epithelial cells are thought to be factors contributing to the development of IBD. Necrosis has been shown to play an important role in the pathogenesis of IBD.

[0269] Seven days after model creation, mice in the experimental group showed pathological symptoms such as bloody stool and weight loss, indicating successful model creation. As shown in Figure 6, seven days after model creation, mice were randomly assigned to groups and administered drugs. Body weight continued to decrease and some mice died in the vehicle and GSK3145095 groups, while mice in the compound 94 group gradually recovered weight and no deaths occurred by day 14, and their vitality was significantly greater than that of the vehicle group. As shown in Figure 7, mice (two mice per group) were sacrificed on day 12. The colon length of the vehicle group mice was significantly shorter than that of the control group, while the colon length of the compound 94 group mice was longer than that of the vehicle group and almost equal to that of the control group. Compound 94 alleviated DSS-induced colon shortening in mice, demonstrating a more effective treatment than the active drug GSK3145095. Compound 94 was shown to exert significant anti-inflammatory effects by inhibiting RIPK1 in vivo and to alleviate DSS-induced colitis in mice.

[0270] Example 9 In vivo pharmacokinetic studies of representative compounds of the present invention 1) Experimental method An appropriate amount of representative compound was accurately weighed and dissolved in 5% DMSO, 40% PEG400, and 55% saline to a final volume. The solution was then homogenized by vortexing or sonication to obtain a clear 1 mg / mL dosing solution. The rat dose (10 mg / kg) was calculated based on body weight and administered via intravenous or intragastric gavage. Blood samples were collected from the rats at various time points: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous administration, and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after intragastric gavage. Approximately 0.20 mL of blood was collected from the jugular vein or other appropriate method at the corresponding time points. The blood samples were placed on ice after collection and centrifuged to separate plasma within 1 hour (centrifugation conditions: 6800 g, 6 min, 2-8°C). The collected plasma samples were stored in a refrigerator at −80°C before analysis, and the remaining plasma samples after analysis were kept in a refrigerator at −80°C for one month.

[0271] From the plasma concentration data at each time point, AUC(0-t), T1 / 2, and C max , T max Pharmacokinetic parameters such as C and MRT were calculated. When the plasma drug concentration-time curve was plotted, the BLQ was always 0. When calculating the pharmacokinetic parameters, the concentration before administration was set to 0, and C max BLQ up to (including "No peak") is calculated as 0, and C max Any BLQs (including "No peak") that appear after this will not be involved in the calculation. This experiment will be conducted at Shanghai Medicilon Inc.

[0272] 2) Experimental results The results are shown in Table 6. As can be seen, after a single oral administration of 10 mg / kg of the representative compounds, rats showed good oral absorption of all six representative compounds, with oral bioavailability reaching up to 60.85%. Initial pharmacokinetic experiments showed that after a single administration of the compounds, the drug concentration accumulated in the body could reach the half-maximal inhibitory concentration value of RIPK1 and necrosis signaling pathway inhibition, indicating that this series of compounds is a promising RIPK1 inhibitor for development.

[0273] [Table 111]

[0274] Example 10 Effect of Compound 94 of the Present Invention on the hERG Potassium Ion Channel 1) Experimental method Stabilized HEK-hERG cells were washed with DPBS, digested with Trypsin or Tryple solution, resuspended in culture medium, and stored in a centrifuge tube for further use. Prior to patch clamp recording, the cells were dropped onto a small culture dish to ensure that the cells had a consistent density and were single-cell isolated.

[0275] hERG currents were recorded using the whole-cell patch clamp technique. Cell suspensions were harvested, placed in small culture dishes, and placed on an inverted microscope stage. After allowing the cells to adhere to the wall, they were perfused with extracellular solution at a recommended flow rate of 1–2 mL / min. Glass microelectrodes were stretched in two stages using a microelectrode stretcher. After filling with intracellular solution, the water entry resistance was 2–5 MΩ.

[0276] After establishing whole-cell recording mode, the clamp voltage was maintained at -80 mV. A depolarizing voltage of +60 mV was applied for 850 ms, followed by a repolarization to -50 mV for 1275 ms to elicit hERG tail currents. This pulse process was repeated every 15 s throughout the experiment.

[0277] After the current stabilized, extracellular continuous perfusion was performed, starting with the low concentration and continuing until the drug effect stabilized, followed by perfusion of the next concentration. This experiment measured the blocking effect (N≧2) of Compound 94 (0.3, 1, 3, 10, 30 μM) and the positive compound terfenadine on the hERG tail current.

[0278] The drug effect was defined as stable if the change in the current value of the last five stimulation bars in the administration phase at each concentration was less than 10% of the mean value (if the current was 200 pA or more) or less than 30% of the mean value (if the current was less than 200 pA). If the drug effect was unstable, data for that concentration was not collected.

[0279] PatchMaster software controlled stimulus delivery and signal acquisition, and the patch clamp amplifier amplified the signal with a 10 KHz filter.

[0280] Further data analysis and curve fitting were performed using FitMaster, EXCEL, Graphpad Prism, and SPSS 21.0. All data were expressed as mean and standard deviation.

[0281] During data processing, the peak value of the tail current and its baseline were corrected when determining the blocking effect on hERG. The effect of each compound at different concentrations was expressed as the tail current inhibition rate. Inhibition rate % = 100 × (peak value of tail current before administration - peak value of tail current after administration) / peak value of tail current before administration. A SD of ≤ 15 for the inhibition rate at each concentration in all cells was considered acceptable (excluding abnormal data).

[0282] I C 50 The values ​​are fitted by the Hill equation (if applicable).

[0283]

number

[0284] This study was conducted by Shanghai Medicilon Inc.

[0285] 2) Experimental results The concentration-response curve of the inhibitory effect of tefenadine, a positive compound, on the hERG current is shown in Figure 8. As a result, the effect of tefenadine on the hERG potassium channel is concentration-dependent, and the IC value of the inhibitory effect of tefenadine on the hERG current obtained by fitting the Hill equation was 50 The value was 0.045 μM (N=3), which was consistent with literature reports.

[0286] The final concentrations of Compound 94 were 0.3, 1, 3, 10, and 30 μM, and the final concentration of DMSO in the extracellular solution was 0.3%. The concentration-response curve of the inhibitory effect of Compound 94 on the hERG current is shown in Figure 8. Under these experimental conditions, Compound 94 had no significant inhibitory effect on the hERG potassium channel current at any of the detected concentrations (0.3, 1, 3, 10, and 30 μM). At 30 μM, the average inhibitory rate on the hERG potassium channel current was 3.40% (N=3). This indicates that the IC value of Compound 94's inhibitory effect on the hERG current was 0.50. 50 The values ​​exceeded 30 μM, indicating that Compound 94 does not cause side effects due to significant inhibitory effects on hERG potassium channel current.

[0287] As described above, the compounds of the present invention can protect HT-29 cells from TSZ-induced necrosis-like apoptosis and have good kinase selectivity. Their mechanism of action is to inhibit the phosphorylation of RIPK1 itself, affecting the phosphorylation of its downstream RIPK3 and MLKL, thereby blocking the programmed necrosis signaling pathway and inhibiting programmed necrosis. The compounds of the present invention exert significant anti-inflammatory effects by inhibiting RIPK1 in vivo, and do not significantly inhibit hERG potassium channel current at any concentration, resulting in no side effects due to significant inhibition of hERG potassium channel current. Therefore, the compounds of the present invention have potential as active ingredients in RIPK1 inhibitors and anti-inflammatory drugs.

Claims

1. A compound represented by formula (I), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, X １ , X ３ is independently -CR ６ - and X ２ is -NR １ -, where R １ is hydrogen, substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C １ ~C １０ ether groups, wherein the substituents are selected from deuterium, C １ ~C １０ is an alkyl group, R ２Ｂ is selected from the following formula: 【Chemistry 2】 (In the formula, R ２ is a single bond, one or two R ２１ C1 to C substituted with ６ Alkylene group or unsubstituted C1-C ６ alkylene groups, where R ２１ is a substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C ３ ~C １０ selected from cycloalkyl groups, cyano groups, hydroxy groups, carboxy groups, halogens, or nitro groups, where the substituents are cyano groups, hydroxy groups, carboxy groups, halogens, or nitro groups; The B ring may contain one, two or three R ２２ C substituted with ４ ~C １０ Aryl group or unsubstituted C ４ ~C １０ an aryl group, one, two or three R ２２ or an unsubstituted 4- to 10-membered heteroaryl group substituted with one, two or three R ２２ C substituted with ３ ~C １０ Cycloalkyl group or unsubstituted C ３ ~C １０ cycloalkyl groups, where R ２２ each independently represents a substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C １ ~C ６ or two R ２２ are linked to form a substituted or unsubstituted 4-10 membered heterocycloalkyl group, wherein the substituents are C １ ~C １０ It is an alkyl group, a cyano group, a hydroxyl group, a carboxyl group, a halogen, or a nitro group. R ３ is hydrogen, substituted or unsubstituted C １ ~C １０ alkyl groups, wherein the substituents are cyano, hydroxy, carboxy, halogen or nitro groups; or R ２Ｂ and R ３ and are linked to form a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, wherein the substituents are C １ ~C １０ Alkyl group, C ４ ~C １０ an aryl group, one or two R ３１ C substituted with ４ ~C １０ an aryl group, a cyano group, a hydroxy group, a carboxy group, a halogen, or a nitro group, wherein R ３１ is C １～Ｃ１０ selected from an alkyl group or a halogen; R ４ , R ５ and R ６ are each independently hydrogen, C １ ~C １０ selected from an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen or a nitro group; The A ring is selected from the groups represented by the formula: 【Chemistry 3】 Here, L １ is selected from S or NH; R Ａ is selected from a substituted or unsubstituted amino group, a group represented by the formula: １ ~C １０ Alkyl group, halogen-substituted C １ ~C １０ is selected from an alkyl group, or a hydroxy group; 【Chemistry 4】 R Ａ１ is a substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted C ２ ~C ６ Ether group, substituted or unsubstituted C ２ ~C ６ amine groups, wherein the substituents are selected from １ ~C １０ is an alkyl group, a hydroxyl group, or a halogen.

2. The compound of claim 1, characterized in that the compound of formula (I) is represented by formula (II): or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 5】 (In the formula, R １ is hydrogen or substituted or unsubstituted C １ ~C １０ alkyl, wherein the substituents are selected from １ ~C １０ is an alkyl group, R ２ is a single bond, one R ２１ C1 to C substituted with ６ Alkylene group or unsubstituted C1-C ６ alkylene groups, where R ２１ is a substituted or unsubstituted C １ ~C １０ selected from an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen group, or a nitro group, wherein the substituent is a cyano group, a hydroxy group, a carboxy group, a halogen group, or a nitro group; The B ring may contain one, two or three R ２２ C substituted with ４ ~C １０ Aryl group or unsubstituted C ４ ~C １０ an aryl group or one, two or three R ２２ or an unsubstituted 4-10 membered heteroaryl group, where R ２２ each independently represents a substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C １ ~C ６ or two R ２２ are linked to form a substituted or unsubstituted 4-10 membered heterocycloalkyl group, wherein the substituents are C １ ~C １０ an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen, or a nitro group; R ３ is hydrogen, substituted or unsubstituted C １ ~C １０ alkyl groups, wherein the substituents are cyano, hydroxy, carboxy, halogen or nitro groups; or R ２ and R ３ and are linked to form a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, wherein the substituents are C １ ~C １０ an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen, or a nitro group; X １ , X ３ is independently CH; The A ring is selected from the groups represented by the formula: 【Chemistry 6】 Here, L １ is selected from S or NH; R Ａ is selected from an amino group, a group represented by the formula: 【Chemistry 7】 R Ａ１ is a substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted C ２ ~C ６ ether groups, wherein the substituents are selected from １ ~C １０ It is an alkyl group, a hydroxyl group, or a halogen.

3. The compound of claim 1 or 2, characterized in that the compound of formula (I) is represented by formula (III) or formula (IV), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 8】 (In the formula, R １ is hydrogen, C １ ~C ４ alkyl group; R ２３ is selected from hydrogen and a methyl group, and the B ring is one or two R ２２ or an unsubstituted phenyl group, where R ２２ are each independently selected from F, Cl, a cyano group, a methyl group, a trifluoromethyl group, a methoxy group, or a trifluoromethoxy group.

4. The compound of claim 1, characterized in that the compound of formula (I) is represented by formula (V), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 9】 (In the formula, X １ , X ３ is independently -CR ６ - and X ２ is -NR １ - and The R １ is hydrogen or C １ ~C １０ is an alkyl group, L ３ is a substituted or unsubstituted C １ ~C ４ alkylene groups, wherein the substituents are selected from １ ~C １０ an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen, or a nitro group; R ３３ is hydrogen, substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C ６ ~C １０ aryl groups, wherein the substituents are selected from １ ~C １０ an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen, or a nitro group; R ４ , R ５ and R ６ are each independently hydrogen, C １ ~C １０ selected from an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen or a nitro group; The A ring is selected from the groups represented by the formula: 【Chemistry 10】 Here, L １ is selected from S or NH; R Ａ is selected from an amino group, a group represented by the formula: 【Chemistry 11】 R Ａ１ is a substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted C ２ ~C ６ ether groups, wherein the substituents are selected from C １ ~C １０ It is an alkyl group, a hydroxyl group, or a halogen.

5. R ３３ is selected from a phenyl group, a phenyl group substituted with one or two substituents, wherein the substituents are selected from F, Cl or a methyl group.

6. The compound of claim 1, characterized in that the compound of formula (I) is represented by formula (VI): or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 12】 (In the formula, X １ is -CR ６ - and X ２ is -NR １ - and X ３ is CH, The R １ is hydrogen, C １ ~C １０ alkyl groups, L ４ is a substituted or unsubstituted C １ ~C ３ alkylene groups, wherein the substituents are selected from １ ~C １０ an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen, or a nitro group; R ３ is hydrogen, substituted or unsubstituted C １ ~C １０ alkyl groups, wherein the substituents are cyano, hydroxy, carboxy, halogen or nitro groups; R ４ , R ５ and R ６ are each independently hydrogen, C １ ~C １０ selected from an alkyl group, a cyano group, a hydroxy group, a carboxy group, a halogen or a nitro group; The A ring is selected from the groups represented by the formula: 【Chemistry 13】 Here, L １ is selected from S or NH; R Ａ is selected from an amino group, a group represented by the formula: 【Chemistry 14】 R Ａ１ is a substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted C ２ ~C ６ ether groups, wherein the substituents are selected from １ ~C １０ It is an alkyl group, a hydroxyl group, or a halogen.

7. Said L ４ is C １ ~C ２ 7. The compound according to claim 6, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein the radical is selected from the group consisting of alkylene radicals.

8. R １ is hydrogen, C １ ~C ４ 7. The compound according to claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl groups.

9. The R ４ , R ５ and R ６ are each independently selected from hydrogen and F, or a stereoisomer or a pharma- ceutically acceptable salt thereof, according to any one of claims 1, 4 and 6.

10. The compound according to any one of claims 1 to 4 or 6, wherein ring A is a group represented by the following formula: 【Chemistry 15】

11. R ２ is a single bond, one or two R ２１ C1 to C substituted with ２ Alkylene group or unsubstituted C1-C ２ alkylene groups, where R ２１ is selected from a methyl group, The B ring may contain one, two or three R ２２ C substituted with ６ ~C １０ Aryl group or unsubstituted C ６ ~C １０ an aryl group, one, two or three R ２２ or an unsubstituted 5- to 9-membered heteroaryl group, or one, two or three R ２２ C substituted with ９ ~C １０ Cycloalkyl group or unsubstituted C ９ ~C １０ cycloalkyl groups, where R ２２ are each independently １ ~C ４ is selected from an alkyl group, a methoxy group, a halogen, a methyl group substituted with a halogen, a methoxy group substituted with a halogen, a cyano group, a nitro group, and a group represented by the formula: 【Chemistry 16】 3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein halogen is selected from F, Cl, and Br.

12. R ３ 2. The compound of claim 1, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein: is selected from hydrogen.

13. The compound of claim 1 or 2, characterized in that the compound of formula (I) is represented by formula (VII), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 17】 (In the formula, R １ is hydrogen, substituted or unsubstituted C １ ~C １０ alkyl groups, R ３１ is C １ ~C ６ alkylene groups, R ３２ is one, two or three R ３１１ C substituted with ４ ~C １０ Aryl group or unsubstituted C ４ ~C １０ aryl groups, where R ３１１ are each independently １ ~C ６ alkoxy groups, or two R ３１１ are linked to form a 4- to 10-membered heterocycloalkyl group; X １ , X ３ is CH, Ring A is a group represented by the following formula: 【Chemistry 18】 Here, L １ is selected from S or NH; R Ａ is selected from an amino group, a group represented by the formula: 【Chemistry 19】 R Ａ１ is a substituted or unsubstituted C １ ~C １０ Alkyl group, substituted or unsubstituted C ３ ~C １０ Cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted C ２ ~C ６ ether groups, wherein the substituents are selected from １ ~C １０ It is an alkyl group, a hydroxyl group, or a halogen.

14. -R ３１ -R ３２ 14. The compound of claim 13, wherein: R is selected from the group represented by the formula: R is a substituted or unsubstituted aryl group; 【Chemistry 20】

15. The compound below, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemical 27】 【Chemistry 28】 【Chemical Formula 29】 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical Formula 34】 【Chemistry 35】

16. A process for the preparation of a compound according to any one of claims 1 to 15, which is carried out by the following reaction steps: 【Chemical 36】 or 【Chemical 37】 (In the formula, R ２Ｂ , R ４ , R ５ , X １ , X ２ , X ３ and ring A are as defined in any one of claims 1 to 14.

17. The synthesis process of the intermediate A is as follows: The raw material A, potassium acetate, bis(pinacolato)diboron and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex are dissolved in anhydrous dioxane, the reaction system is replaced with an inert gas, and then reacted. After the reaction is completed, the reaction solution is concentrated, stirred, and subjected to column chromatography to obtain a product. The process of synthesizing the compound of formula (I) using the intermediate A and the raw material B is as follows: Intermediate A, raw material B, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, tricyclohexylphosphine, and cesium carbonate are dissolved in a dioxane / water mixture, the reaction system is replaced with an inert gas, and then reacted. After the reaction is completed, the reaction solution is concentrated, stirred, and subjected to column chromatography to obtain a product. The synthesis process of the intermediate B is as follows: The raw material B, potassium acetate, bis(pinacolato)diboron and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex are dissolved in anhydrous dioxane, the reaction system is replaced with an inert gas, and then reacted. After the reaction is completed, the reaction solution is concentrated, stirred, and subjected to column chromatography to obtain a product. The process of synthesizing the compound of formula (I) using the intermediate B and the raw material A is as follows: The preparation method according to claim 16, characterized in that intermediate B, raw material A, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, tricyclohexylphosphine and cesium carbonate are dissolved in a dioxane / water mixture, the reaction system is purged with an inert gas, and then reacted, and after completion of the reaction, the reaction solution is concentrated, stirred and subjected to column chromatography to obtain a product.

18. 16. The compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, for use in the preparation of a RIPK1 inhibitor.

19. 16. The compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, for use in the preparation of a medicament for treating inflammation, an immune disease, a neurodegenerative disease, or a tumor.

20. 20. The compound of claim 19, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, characterized in that the drug is used for the treatment of inflammatory responses associated with programmed cell necrosis, immune disorders, neurodegenerative disorders or tumors.

21. 21. The compound, or a stereoisomer or a pharma- ceutically acceptable salt thereof, according to claim 19 or 20, wherein the inflammation is colitis.

22. A pharmaceutical composition, which is a formulation prepared from a compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and pharma- ceutically acceptable auxiliary materials.

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