Alkyne aromatic heterocyclic urea derivative and application thereof

Abstract

The invention discloses an alkyne aromatic heterocyclic urea derivative, and particularly relates to a free alkali, an isomer or a pharmaceutically acceptable salt of the derivative and other substance forms. Furthermore, the invention also discloses a preparation method and pharmaceutical application of the alkyne aromatic heterocyclic urea derivative, and the alkyne aromatic heterocyclic urea derivative can be used as an RIPK1 inhibitor for treating diseases related to abnormal expression of a mediated RIPK1 signal channel, including but not limited to tumors, inflammatory diseases or diseases accompanied by inflammatory reactions, autoimmune diseases, neurodegenerative diseases and the like, and has a broad application prospect. The clinical development value is great.

Description

Technical Field

[0001] This invention belongs to the field of small molecule targeted chemical drug technology, and relates to an alkyne aromatic heterocyclic urea derivative, specifically involving the free base, isomers or pharmaceutically acceptable salts of this type of compound; furthermore, this invention also discloses the preparation method of this type of alkyne aromatic heterocyclic urea compound and its pharmaceutical use, which can be used as RIPK1 inhibitors to treat diseases related to abnormal expression of the RIPK1 signaling pathway, including but not limited to tumors, inflammatory diseases or diseases accompanied by inflammatory responses, autoimmune diseases and neurodegenerative diseases. Background Technology

[0002] Receptor-interacting protein kinase 1 (RIPK1) is a serine / threonine protein kinase. Its C-terminus contains a death domain. Through self-binding or binding to other molecules containing death domains (such as TRADD, Fas, and TNFRI), it participates in signal transduction following TNF and FasL stimulation, mediates NF-κB activation, and induces apoptosis. Its function is regulated by ubiquitination, zinc finger proteins, and heat shock proteins.

[0003] Diseases or conditions regulated by receptor-interacting protein kinase 1 (RIK1) in a dependent manner include: hematologic and solid organ malignancies (GenesDev. 2013, 27, 1640-1649), bacterial and viral infections (CellHost & Microbe, 2014, 15, 23-35), including but not limited to tuberculosis and influenza (Cell, 2013, 153, 1-14). In summary, RKI1, as a key regulator of apoptosis, participates not only in signal transduction promoting cell survival but also in various pathways of programmed cell death signal transduction. RKI1 inhibitors have potential therapeutic effects for treating various diseases such as cancer, neurodegenerative diseases, and autoimmune diseases.

[0004] Currently, receptor-interacting protein kinase 1 inhibitors under development globally are mainly divided into three categories based on their compound structure: indole (e.g., Necrostatin-1s), benzo[a]aza[s], and others. Both GSK-2982772 and GSK-963 and GSK547 are currently in the preclinical or clinical research stage, and no drugs have been marketed yet. Their future market potential is considerable.

[0005] Professor Yuan Junying is a leading authority and pioneer in the field of receptor-interacting protein kinase 1 (RIMP 1) inhibitors. Her discovery of Necrostatin-1s in 2005, the first small-molecule RIMP 1 inhibitor, has been widely used in research on the role and mechanism of RIMP 1 in human diseases and animal models. In 2008, her mechanism of action as a necrotizing statin was determined, thus identifying it as a key regulator of programmed necrosis. The highest level of research and development for this class of drugs globally is in the preclinical stage.

[0006] Patent WO2014125444 discloses a novel benzo[a]aza The derivatives, obtained through screening of gene-coding libraries, led to the approval of GSK-2982772, the world's first receptor-interacting protein kinase 1 inhibitor, for clinical trials in the same year. In 2016, GSK-2982772 entered Phase II clinical trials for the following indications: psoriasis, rheumatoid arthritis, and ulcerative colitis. In addition to GSK-2982772, GSK-3145095 underwent a Phase II clinical trial on November 16, 2018, for the treatment of pancreatic cancer. However, the study of GSK-3145095 for pancreatic cancer was terminated on September 12, 2019.

[0007] Patent WO2016185423 discloses a pyrazole amide derivative, with GSK-963 as the representative compound. However, its poor oral efficacy limited its development. Subsequently, this compound was used as a lead compound for structural optimization, resulting in GSK-547. However, this molecule did not enter clinical trials due to poor pharmacokinetic data.

[0008]

[0009] Inhibitors of receptor-interacting protein kinase 1 (RIMP 1) based on the three main structures mentioned above suffer from drawbacks such as low selectivity, strong toxicity, and poor drug-likeness. Researchers both domestically and internationally continue to modify the structures of these compounds, hoping to find safer and more effective RMP 1 inhibitors to fill the gap in drugs targeting this target. A search revealed patent literature related to GSK-2982772 and related structural modifications and improvements to GSK-2982772, as exemplified below:

[0010] Patent WO2014125444 discloses a compound with structural formula 1, characterized by a benzo[a]aza[a] core. Cyclic rings, and nitrogen-containing rings The rings connected are benzene rings or nitrogen-containing six-membered aromatic heterocycles, benzo[a]aza The ring is connected to ring A via an amide bond, and ring A is connected to ring B via an -L- bond. The representative compound is GSK-2982772.

[0011]

[0012] In summary, how to develop a novel receptor-interacting protein kinase 1 inhibitor with good biological activity and significant effects on one or more diseases such as inflammation and tumors, and how to develop an innovative Chinese drug with independent intellectual property rights based on this, is a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0013] The technical problem to be solved by the present invention is to provide a novel alkyne-aromatic heterocyclic urea derivative that can inhibit the activity of receptor-interacting protein kinase 1 and has significant antitumor and / or anti-inflammatory activities.

[0014] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0015] An alkyne aromatic heterocyclic urea derivative, which is a compound, isomer or pharmaceutically acceptable salt thereof represented by formula (I):

[0016]

[0017] In the formula:

[0018] R is selected from H, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 3-10 Cycloalkenyl, when C is described in R 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, 5-8 quinone heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic groups, C 3-10 When a cycloalkenyl group has substituents, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group; further, the aforementioned C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 When an alkynyl group has substituents, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C2-6 alkenyl or C 2-6 alkynyl group;

[0019] The 5-8 membered heteroaryl group described in R does not contain a pyridine ring or a pyrimidine ring;

[0020] R1 can be independently H, halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, or substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when the C in R1 1-6 Alkyl, C 1-6 When an alkoxy group is present, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0021] X is N or C; Y is O or C;

[0022] The heteroaryl or heterocyclic group contains at least one heteroatom, which is selected from N, O or S;

[0023] But excluding

[0024] Preferably, it is a compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0025]

[0026] In the formula:

[0027] R is selected from

[0028] R1 and R2 are each independently hydrogen, halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo group, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when the C in R1 and R2 1-6 Alkyl, C 1-6 When an alkoxy group is present, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0029] Y is selected from O or C.

[0030] Preferably, it is a compound of formula (II-1), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0031]

[0032] In the formula:

[0033] R is selected from

[0034] R1 and R2 are each independently hydrogen, halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo group, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when the C in R1 and R2 1-6 Alkyl, C 1-6 When an alkoxy group is present, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

[0035] Preferably, it is a compound of formula (II-2), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0036]

[0037] In the formula:

[0038] R is selected from

[0039] R1 and R2 are each independently hydrogen, halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo group, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when the C in R1 and R2 1-6 Alkyl, C 1-6 When an alkoxy group is present, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

[0040] Preferably, it is a compound of formula (II-2A), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0041]

[0042] In the formula:

[0043] R1 is selected from hydrogen, methyl, or -OCH3;

[0044] Ra R b R c Each is independently selected from H or F.

[0045] Preferably, R1 is selected from hydrogen or methyl.

[0046] Preferred, Selected from

[0047] Preferably, it is a compound of formula (III), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0048]

[0049] In the formula:

[0050] R is selected from

[0051] R1 and R2 are each independently hydrogen, halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo group, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when the C in R1 and R2 1-6 Alkyl, C 1-6 When an alkoxy group is present, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0052] Y is selected from O or C.

[0053] Preferably, it is a compound of formula (III-1), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0054]

[0055] In the formula:

[0056] R is selected from

[0057] R1 and R2 are each independently hydrogen, halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo group, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when the C in R1 and R2 1-6 Alkyl, C 1-6 When an alkoxy group is present, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

[0058] Preferably, it is a compound of formula (III-2), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0059]

[0060] In the formula:

[0061] R is selected from

[0062] R1 and R2 are each independently hydrogen, halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo group, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when the C in R1 and R2 1-6 Alkyl, C 1-6 When an alkoxy group is present, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

[0063] Preferably, it is a compound of formula (III-2A), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0064]

[0065] In the formula:

[0066] R1 is selected from hydrogen, methyl, or -OCH3;

[0067] R a R b R c Each is independently selected from H or F.

[0068] Preferably, R1 is selected from hydrogen or methyl.

[0069] Preferred, Selected from

[0070] The present invention also provides an alkyne aromatic heterocyclic urea derivative, such as the following compounds or pharmaceutically acceptable salts thereof:

[0071] (S)-N-(5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-3-phenylisooxazolidine-2-carboxamide;

[0072] (S)-N-(5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-3-phenylisooxazolidine-2-carboxamide; (S)-N-(3-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide;

[0073] (S)-N-(3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide;

[0074] (S)-N-(2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide;

[0075] (S)-N-(5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-2-methoxyphenyl)-3-phenylisooxazolidine-2-carboxamide;

[0076] (S)-N-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide;

[0077] (S)-N-(5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-2-phenylpyrrolidine-1-carboxamide;

[0078] (S)-N-(3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-2-phenylpyrrolidine-1-carboxamide.

[0079]

Terminology Definition

[0080] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0081] The "compound" described in this invention includes, but is not limited to, compounds in the following forms: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0082] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0083] In this invention, "isomer" refers to stereoisomers or tautomers unless otherwise specified. Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include, but are not limited to, enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and transisomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons.

[0084] In this invention, "isotope" refers to a compound of this invention, unless otherwise specified, existing in an isotopically traced or enriched form, containing one or more atoms whose atomic weight or mass number differs from the atomic weight or mass number of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Commonly used isotopes for isotopic labeling include hydrogen isotopes, including but not limited to... 2 H and 3 H; Carbon isotopes: including but not limited to 13 C and 14 C; Chlorine isotopes: including but not limited to 35 Cl and 37 Cl; Fluorine isotopes: including but not limited to 18 F; Iodine isotopes: including but not limited to 123 I and 125 I; Nitrogen isotopes: including but not limited to 13 N and 15 N; oxygen isotopes: including but not limited to 15 O、 17 O and 18 O; sulfur isotopes: including but not limited to35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues, especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0085] In this invention, "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, which are compounds with specific substituents discovered in this invention, and are compatible with 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucohepose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, hydroxyethanesulfonic acid, lactic acid, lactose, and dodecyl sulfonic acid. A base addition salt can be obtained by contacting a compound in its neutral form with a sufficient amount of base in a pure solution or a suitable inert solvent when it contains a relatively acidic functional group, such as maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, or organic amine salts. Examples include alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkyl sulfonates, aryl sulfonates, organic acid salts, and amino acid salts.

[0086] In this invention, "prodrug" refers to a prodrug of the compound of this invention that readily undergoes a chemical change under physiological conditions to be converted into the compound of this invention. Furthermore, prodrugs can be converted into the compound of this invention in the in vivo environment through chemical or biochemical methods.

[0087] The terms used in this article have the following meanings:

[0088] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0089] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group composed of carbon and hydrogen atoms, such as C... 1-6Alkyl groups, including but not limited to methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), and hexyl (n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, and 2,2-dimethylbutyl).

[0090] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, possessing at least one double bond. For example, "C..." 2-6 "Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, etc.

[0091] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, with at least one triple bond. For example, "C..." 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 1,3-butyrynyl, 1-pentynyl, 3-methyl-1-butynyl, 1,3-pentyrynyl, 1,4-pentyrynyl, 1-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 3,3-dimethyl-1-butynyl, 3-ethyl-1-butynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 3-methyl-1,4-pentyrynyl, 1,5-hexadiynyl, etc.

[0092] The term "cycloalkyl" refers to a monocyclic alkyl group composed of carbon and hydrogen atoms, such as C1. 3-8 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0093] The term "alkoxy" refers to a straight-chain or branched alkyl group linked by an oxygen atom, such as C... 1-6 Alkoxy groups, including but not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, and neopentoxy), and hexoxy (n-hexoxy, 2-methylpentoxy, 3-methylpentoxy, 2,3-dimethylbutoxy, and 2,2-dimethylbutoxy).

[0094] The term "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic ring with 6-14 carbon atoms, possessing a fully conjugated π-electron system, including but not limited to benzene rings, naphthalene rings, anthracene rings, etc., with benzene rings being preferred.

[0095] The term "aryl" refers to a monocyclic or fused polycyclic group with 6-14 carbon atoms, possessing a fully conjugated π-electron system, including but not limited to phenyl, naphthyl, anthracene, etc., with phenyl being preferred.

[0096] The term "heterocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., spirocyclic, bridged ring, etc.) containing 3-10 ring atoms, and having a non-aromatic structure. The polycyclic ring may consist entirely of non-aromatic rings, or at least one ring may be aromatic while the rest are non-aromatic. The aforementioned 3-10 ring atoms contain one or more (e.g., 2, 3, 4 or more) heteroatoms, with the remainder being carbon atoms selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic ring may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. Non-limiting examples of "heteroaromatic" include, but are not limited to, azirrocyclopropane, oxacyclopropane, thioherrocyclopropane, azirrocyclobutane, oxacyclobutane, thioherrocyclobutane, furan, piperidine, piperazine, morpholine, pyrrole, thiomorpholine, etc.

[0097] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., spirocyclic, bridged, etc.) group containing 3-10 ring atoms, and having a non-aromatic structure. The polycyclic group may consist entirely of non-aromatic rings, or at least one ring may be aromatic while the rest are non-aromatic. The aforementioned 3-10 ring atoms contain one or more (e.g., 2, 3, 4, or more) heteroatoms, with the remainder being carbon atoms selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic group may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. Non-limiting examples of "heterocyclic group" include, but are not limited to, azirropropyl, oxadiropropyl, thioherropropyl, azirrobutyl, oxadirobutyl, thioherrobutyl, furanyl, piperidinyl, piperazinyl, morpholinyl, pyrroleyl, and thiomorpholinyl.

[0098] The term "heteroaromatic ring" refers to an aromatic monocyclic or polycyclic ring (e.g., fused ring) containing 5-14 ring atoms, wherein the aforementioned 5-14 ring atoms contain one or more (e.g., 2, 3, 4 or more) heteroatoms, and the remainder are carbon atoms selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic ring may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. The aforementioned "heteroaromatic ring" preferably contains 5-14, 5-10, or 5-8 ring atoms, more preferably 5-6 ring atoms. Non-limiting examples of "heteroaromatic rings" include, but are not limited to, tetrahydrofuran, thiophene, oxazole, thiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazinyl, pyridazine, quinoline, indole, benzofuran, benzothiophene, benzimidazole, benzopyridine, benzopyrimidine, benzopyrazine, etc.

[0099] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic (e.g., fused ring) group containing 5-14 ring atoms, wherein the aforementioned 5-14 ring atoms contain one or more (e.g., 2, 3, 4 or more) heteroatoms, and the remainder are carbon atoms selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic group may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. The aforementioned "heteroaryl" preferably contains 5-14, 5-12, 5-10, or 5-8 ring atoms, more preferably 5-6 ring atoms. Non-limiting examples of "heteroaryl" include, but are not limited to, tetrahydrofuranyl, thiophenyl, oxazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, etc.

[0100] Preparation of compounds

[0101] This invention also provides methods for preparing the above-mentioned compounds, but is not limited to the following methods:

[0102] The specific embodiments described below are for illustrative purposes only and should not be construed as limiting the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0103] The following routes 1 and 2 are an overview of the overall reaction routes of the aforementioned compounds of this invention:

[0104] Route 1: Preparation of the I-series target compounds

[0105]

[0106] X, R, and R1 are defined as described above.

[0107] The specific reaction process is as follows:

[0108] Starting material A-1 undergoes nucleophilic substitution with Boc-hydroxylamine to give intermediate A-2, which further undergoes a cyclization reaction to give intermediate A-3, followed by deprotection to give intermediate A-4.

[0109] Starting material B-1 is deprotected to obtain intermediate B-2, which then reacts with phenyl chloroformate to obtain intermediate B-3. Subsequently, intermediate B-3 undergoes amine-ester exchange with intermediate A-4 to obtain intermediate B-4. Intermediate B-4 undergoes a Sonogashira reaction with alkyne to obtain a series of I compounds.

[0110] Route 2: Preparation of Series II Target Compounds

[0111]

[0112] X, R, and R1 are defined as described above.

[0113] The specific reaction process is as follows:

[0114] Starting material B-1 is deprotected to obtain intermediate B-2, which then reacts with phenyl chloroformate to obtain intermediate B-3. Subsequently, intermediate B-3 undergoes amine-ester exchange with intermediate A-5 to obtain intermediate B-5. Intermediate B-5 undergoes a sonagashira reaction with alkyne to obtain a series of II compounds.

[0115] The present invention also provides a pharmaceutical composition comprising at least one compound as described above or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one or more pharmaceutically acceptable carriers.

[0116] The term "pharmaceutical composition" as used in this invention refers to a formulation comprising one or more compounds of the invention or salts thereof, and a carrier, in commonly accepted terms in the art, for delivering a bioactive compound to an organism (e.g., a human). The purpose of a pharmaceutical composition is to facilitate drug delivery to an organism.

[0117] The routes of administration for the compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions described in this invention include, but are not limited to, oral, rectal, transmucosal, enteral, or local, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

[0118] The present invention also provides the use of the preparation of the compounds or pharmaceutical compositions described above in the preparation or prevention of diseases mediated by receptor-interacting protein kinase activity.

[0119] Preferably, the aforementioned receptor-interacting protein kinase activity-mediated diseases are diseases related to alterations in receptor-interacting protein kinase 1 activity.

[0120] More preferably, the aforementioned diseases are tumors, inflammatory diseases or diseases accompanied by inflammatory responses, autoimmune diseases, and neurodegenerative diseases, etc.

[0121] More preferably, the aforementioned tumors are selected from colorectal cancer, lung cancer, liver cancer, pancreatic cancer, breast cancer, lymphoma, melanoma, etc.

[0122] Further preferably, the aforementioned diseases are selected from systemic inflammatory response syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic fatty liver disease, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerocholangitis, nephritis, etc. Celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, allergic diseases, asthma, multiple sclerosis, amyotrophic lateral sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 convertase-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, or periodontitis, etc.

[0123] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0124] Based on receptor-interacting protein kinase 1 (RIMP1), this invention has developed a series of novel alkyne-based aromatic heterocyclic urea compounds. These compounds are characterized by simple preparation routes and readily available raw materials. A series of related biological experiments were conducted on the compounds, and the results all show that these compounds have significant inhibitory effects on RIMP1 and can be used as lead molecules for the prevention or treatment of RIMP1-related diseases.

[0125] Instruction manual illustrations

[0126] Figure 1 Figure showing body temperature changes in a mouse model of TNF-α-induced systemic inflammatory response syndrome (SIRS) for efficacy evaluation.

[0127] Figure 2 Animal survival rate graph for efficacy evaluation test of TNF-α-induced systemic inflammatory response syndrome (SIRS) mouse model. Detailed Implementation

[0128] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0129] Furthermore, all operations involving readily oxidizable or hydrolyzable raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0130] All reaction starting materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or prepared in-house. The preparation process of the starting materials and common intermediates that need to be prepared in-house is detailed below:

[0131] Explanation of abbreviations for solvents or materials used:

[0132] NaH: Sodium hydride; DMF: N,N-dimethylformamide; DCM: Dichloromethane; LiOH: Lithium hydroxide; THF-H2O: Tetrahydrofuran-aqueous solution; NaBH3CN: Sodium cyanoborohydride; AcOH: Acetic acid; TFA: Trifluoroacetic acid; HOBT: 1-hydroxybenzotriazole; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM: N-methylmorpholine; K2CO3: Potassium carbonate; Cu: Copper; Cs2CO3: Cesium carbonate; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; T3P: 1-propylphosphonic anhydride; THF: Tetrahydrofuran; EA: Ethyl acetate.

[0133] I. Preparation of common intermediate A-4

[0134]

[0135] Step 1: Synthesis of compound A-2

[0136] Starting material A-1 (1.7 g, 10 mmol) was added to a round-bottom flask, followed by 60 mL of DMF, and then Boc-hydroxylamine (2.66 g, 20 mmol). The mixture was stirred and cooled in an ice bath. NaH (880 mg, 22 mmol) was then slowly added under ice bath conditions, and the reaction was purged with nitrogen at room temperature. After the reaction was complete as monitored by TLC, water was added dropwise to quench the reaction in an ice bath. The mixture was extracted with EA (50 mL x 3 times), and the organic phase was separated, dried, concentrated, and purified by column chromatography to give intermediate A-2 (2.38 g), with a yield of 90.0%.

[0137] MS (m / z): 268.2 [M+H]+ .

[0138] Step 2: Synthesis of compound A-3

[0139] Intermediate A-2 (2.38 g, 8.9 mmol) was added to a reaction flask, followed by 45 mL of DCM solvent and TEA (3.71 mL, 26.7 mmol). Methanesulfonic anhydride (2.33 g, 13.38 mmol) was added under ice-bath cooling, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete as monitored by TLC, the system was concentrated and purified by column chromatography to obtain intermediate A-3 (1.64 g), with a yield of 74.0%.

[0140] MS (m / z): 250.2 [M+H] + .

[0141] Step 3: Synthesis of compound A-4

[0142] Intermediate A-3 (1.6 g, 6.42 mmol) was added to a reaction flask, followed by 30 mL of DCM, and then 15 mL of 4N HCl in dioxane solution. The reaction was allowed to proceed at room temperature. After the reaction was completed by TLC monitoring, sodium bicarbonate solution was added to adjust the pH to neutral. The mixture was then extracted with DCM (50 mL x 3 times), and the organic phase was separated, dried, and concentrated to obtain a yellow solid, which was intermediate A-4 (870 mg), with a yield of 90.3%. This solid was used directly in the next reaction without further purification.

[0143] MS (m / z): 150.1 [M+H] + .

[0144] II. Preparation of the common intermediate B-4-A

[0145]

[0146] Step 1: Synthesis of compound B-2-A

[0147] Starting material B-1-A (172 mg, 0.6 mmol) was added to a reaction flask, followed by 3 mL of DCM, and then 1 mL of 4N HCl in dioxane solution. The reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, sodium bicarbonate solution was added to adjust the pH to neutral. The mixture was then extracted with DCM (5 mL x 3 times), and the organic phase was separated, dried, and concentrated to obtain a yellow solid, which was intermediate B-2-A. This intermediate was used directly in the next reaction without further purification.

[0148] MS (m / z): 172.9 [M+H] + .

[0149] Step 2: Synthesis of compound B-3-A

[0150] Intermediate B-2-A was added to a reaction flask, followed by 5 mL of acetonitrile. Then, phenyl chloroformate (103 mg, 0.66 mmol) and pyridine (47.5 mg, 0.6 mmol) were added under ice bath conditions. After the addition was complete, nitrogen gas was purged, and the reaction was allowed to proceed to the next step at room temperature. After the reaction was completed as monitored by TLC, the system was used directly for the next reaction without any further treatment.

[0151] MS (m / z): 293.0 [M+H] + .

[0152] Step 3: Synthesis of compound B-4-A

[0153] TEA (182 mg, 1.8 mmol) and intermediate A-4 (103 mg, 0.7 mmol) were added to the previous step system, and the reaction was carried out at room temperature after purging with nitrogen. After the reaction was completed by TLC monitoring, the reaction was quenched with water, extracted with EA (50 mL, 3 times), the organic phase was separated, dried and concentrated, and purified by column chromatography to give intermediate B-4-A (203 mg), with a yield of 93.5%.

[0154] MS (m / z): 348.0 [M+H] + .

[0155] III. Preparation of the common intermediate B-4-B

[0156]

[0157] Following the preparation method of B-4-A, the only difference was that the starting material tert-butyl (5-bromopyridin-3-yl) carbamate was replaced with tert-butyl (3-bromophenyl) carbamate. The rest of the method was the same, and intermediate B-4-B was obtained by deprotection and amine exchange.

[0158] MS (m / z): 347.0 [M+H] + .

[0159] IV. Preparation of the common intermediate B-4-C

[0160]

[0161] Following the preparation method of B-4-A, only the starting material tert-butyl (5-bromopyridin-3-yl)carbamate was replaced with tert-butyl (5-bromo-2-methylphenyl)carbamate, and the rest of the method was the same. After deprotection and amine exchange, intermediate B-4-C was obtained.

[0162] MS (m / z): 361.0 [M+H] + .

[0163] V. Preparation of the common intermediate B-4-D

[0164]

[0165] Following the preparation method of B-4-A, only the starting material tert-butyl (5-bromopyridin-3-yl) carbamate was replaced with tert-butyl (5-bromo-2-methoxyphenyl) carbamate, and the rest of the method was the same. After deprotection and amine exchange, intermediate B-4-D was obtained.

[0166] MS (m / z): 377.0 [M+H] + .

[0167] VI. Preparation of the common intermediate B-4-E

[0168]

[0169] Following the preparation method of B-4-A, only intermediate A-4 was replaced with raw material A-5, and the rest of the method was the same, with deprotection and amine exchange to obtain intermediate B-4-E.

[0170] VII. Preparation of the common intermediate B-4-F

[0171]

[0172] Referring to the preparation method of B-4-A, the starting material tert-butyl (5-bromopyridin-3-yl)carbamate was replaced with tert-butyl (3-bromophenyl)carbamate, intermediate A-4 was replaced with starting material A-5, and the rest of the method was the same. After deprotection and ester exchange, intermediate B-4-F was obtained.

[0173] MS (m / z): 346.1 [M+H] + .

[0174] Example 1: Preparation of the target compound (S)-N-(5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-3-phenylisoxazolidine-2-carboxamide (I-1)

[0175] The synthetic route for target compound I-1 is as follows:

[0176]

[0177] Intermediate B-4-A (100 mg, 0.288 mmol), alkyne substrate (46 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the diatomaceous earth filter aid system was used, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to give a white solid I-1 (43 mg), with a yield of 40.2%.

[0178] MS(m / z): 374.1 [M+H] + .

[0179] 1 H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.78(s,1H),8.33(s,1H),8.18(s,1H),8.12(s,1H),7.73(s,1H),7.38( m,4H),7.28(t,J=8.0Hz,1H),5.45-5.35(m,1H),4.29(t,J=8.0Hz,1H),3.97-3.88(m,1H),3.86(s,3H),2.94 -2.81(m,1H),2.31-2.18(m,1H).

[0180] Example 2: Preparation of the target compound (S)-N-(5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-3-phenylisoxazolidine-2-carboxamide (I-2)

[0181] The synthetic route for the target compound I-2 is as follows:

[0182]

[0183] Intermediate B-4-A (100 mg, 0.288 mmol), alkyne substrate (61 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the mixture was filtered through a diatomaceous earth filter, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to give a white solid I-2 (25 mg), with a yield of 21.2%.

[0184] MS(m / z): 410.1 [M+H] + .

[0185] 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 8.83 (d, J = 2.4Hz, 1H), 8.73 (s, 1H), 8.38-8.33 (m, 1H), 8.24-8.23 (m ,1H),8.11(s,1H),7.86(t,J=58.8Hz,1H),7.42-7.34(m,4H),7.31-7.25(m,1H),5.43-5.39(m,1H),4.31 -4.26(m,1H),3.95-3.89(m,1H),2.93-2.83(m,1H),2.30-2.21(m,1H).

[0186] Example 3: Preparation of the target compound (S)-N-(3-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisoxazolidine-2-carboxamide (I-3)

[0187] The synthetic route for the target compound I-3 is as follows:

[0188]

[0189] Intermediate B-4-B (100 mg, 0.288 mmol), alkyne substrate (61 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the diatomaceous earth filter aid system was used, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to obtain a white solid I-3 (41 mg), with a yield of 35.1%.

[0190] MS (m / z): 409.1 [M+H] + .

[0191] 1H NMR (400MHz, DMSO-d6) δ9.55(s,1H),8.68(s,1H),8.08(s,1H),8.02-7.80(m,2H),7.73-7.63(m,1H),7.46-7.24(m,6H),7.17(d,J=8 .0Hz,1H),5.41(dd,J=8.0,4.0Hz,1H),4.35-4.17(m,1H),3.89(q,J=8.0Hz,1H),2.86(p,J=8.0Hz,1H),2.24(dq,J=16.0,8.0Hz,1H).

[0192] Example 4: Preparation of the target compound (S)-N-(3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisoxazolidine-2-carboxamide (I-4)

[0193] The synthetic route for the target compound I-4 is as follows:

[0194]

[0195] Intermediate B-4-B (100 mg, 0.288 mmol), alkyne substrate (46 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the mixture was filtered through a diatomaceous earth filter, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to give a white solid I-4 (35 mg), with a yield of 32.7%.

[0196] MS (m / z): 373.2 [M+H] + .

[0197] 1H NMR(400MHz, DMSO-d6)δ9.50(s,1H),8.07(s,1H),7.82(s,1H),7.68(s,1H),7.63(d,J=8.0Hz,1H),7.43-7.33(m,4H),7.29(dd,J=8.0,8.0Hz,2H),7 .12(d,J=8.0Hz,1H),5.41(dd,J=8.0,4.0Hz,1H),4.25(td,J=8.0,4.0Hz, 1H),3.93-3.86(m,1H),3.85(s,3H),2.92-2.79(m,1H),2.31-2.15(m,1H).

[0198] Example 5: Preparation of the target compound (S)-N-(2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisoxazolidine-2-carboxamide (I-5)

[0199] The synthetic route for the target compound I-5 is as follows:

[0200]

[0201] Intermediate B-4-D (108 mg, 0.288 mmol), alkyne substrate (46 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the diatomaceous earth filter aid system was used, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to give a white solid I-5 (27 mg), with a yield of 23.5%.

[0202] MS (m / z): 403.2 [M+H] + .

[0203] 1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.11(s,1H),8.04(s,1H),7.66(s,1H), 7.38(m,4H),7.32-7.24(m,1H),7.19(d,J=8.0,1H),7.09(d,J=8.0Hz,1H),5. 39(dd,J=8.0,4.0Hz,1H),4.29(td,J=8.0,4.0Hz,1H),3.99-3.93(m,1H),3.9 2(s,3H),3.84(s,3H),2.89(td,J=16.0,12.0,8.0Hz,1H),2.32-2.19(m,1H).

[0204] Example 6: Preparation of the target compound (S)-N-(5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-2-methoxyphenyl)-3-phenylisoxazolidine-2-carboxamide (I-6)

[0205] The synthetic route for the target compound I-6 is as follows:

[0206]

[0207] Intermediate B-4-D (108 mg, 0.288 mmol), alkyne substrate (61 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the diatomaceous earth filter aid system was used, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to give a white solid I-6 (40 mg), with a yield of 31.8%.

[0208] MS (m / z): 439.2 [M+H] + .

[0209] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.52(s,1H),8.16(s,1H),8.05(s,1H),7.83(t,J=60Hz,1H),7.38(m,4H),7.27(d,J =8.0,2H),7.12(d,J=8.0Hz,1H),5.42-5.35(m,1H),4.30(t,J=8.0Hz,1H),3.93(s,4H),2.89(m,1H),2.33-2.17(m,1H).

[0210] Example 7: Preparation of the target compound (S)-N-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisoxazolidine-2-carboxamide (I-7)

[0211] The synthetic route for the target compound I-7 is as follows:

[0212]

[0213] Intermediate B-4-C (104 mg, 0.288 mmol), alkyne substrate (46 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the diatomaceous earth filter aid system was used, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to give a white solid I-7 (30 mg), with a yield of 27.1%.

[0214] MS (m / z): 387.2 [M+H] + .

[0215] 1 H NMR (400MHz, DMSO-d6) δ8.90(s,1H),8.05(s,1H),7.67(s,1H),7.52(s,1H),7.43-7.33(m,4H),7.30-7.26(m,1H),7.24(d,J=8.0Hz,1H),7.18( dd,J=8.0,4.0Hz,1H),5.40(dd,J=8.0,4.0Hz,1H),4.26(td,J=8.0,4.0 Hz,1H),4.03-3.92(m,1H),3.84(s,3H),2.94-2.81(m,1H),2.25(s,4H).

[0216] Example 8: Preparation of the target compound (S)-N-(5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-2-phenylpyrrolidine-1-carboxamide (II-1)

[0217] The synthetic route for target compound II-1 is as follows:

[0218]

[0219] Intermediate B-4-E (100 mg, 0.288 mmol), alkyne substrate (46 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the diatomaceous earth filter aid system was used, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to give a white solid II-1 (24 mg), with a yield of 22.6%.

[0220] MS(m / z): 372.1 [M+H] + .

[0221] 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.53(s,1H),8.23(s,1H),8.10(s,1H),8.06(s,1H),7.71(s,1H),7.32(t,2H),7.22(d,3H),5.10(d, J=4.0Hz,1H),3.85(s,3H),3.79(td,J=12.0,8.0,4.0Hz,1H),3.65-3.56(m,1H),2.40-2.24(m,1H),2.01-1.82(m,2H),1.81-1.69(m,1H).

[0222] Example 9: Preparation of the target compound (S)-N-(3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-2-phenylpyrrolidine-1-carboxamide (II-2)

[0223] The synthetic route for target compound II-2 is as follows:

[0224]

[0225] Intermediate B-4-F (99 mg, 0.288 mmol), alkyne substrate (46 mg, 0.432 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (145 mg, 1.44 mmol) were added to a reaction flask. 4 mL of DMF was added, and the nitrogen atmosphere was completely purged. Pd-catalyst (20 mg, 0.029 mmol) was then added, followed by further nitrogen purging. The reaction was then carried out overnight at 90 °C. After the reaction was complete as monitored by TLC, the diatomaceous earth filter aid system was used, the filter residue was washed with EA, water was added to separate the layers, the organic phase was separated, further dried and concentrated, and the residue was purified to give a white solid II-2 (30 mg), with a yield of 27.8%.

[0226] MS(m / z): 371.1 [M+H] + .

[0227] 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),8.05(s,1H),7.67(d,2H),7.43(d,J=8.0Hz,1H),7.36-7.26(m,2H),7.25-7.15(m,4H),6.99(d,J=8.0Hz, 1H),5.10(dd,J=8.0,4.0Hz,1H),3.84(s,3H),3.81-3.73(m,1H),3.61 -3.52(m,1H),2.36-2.24(m,1H),1.96-1.82(m,2H),1.79-1.70(m,1H).

[0228] Example 10: Compound inhibits TNF-α-induced programmed necrosis in U937 cells

[0229] 1. Experimental reagents: RPMI-1640 medium, fetal bovine serum, penicillin-streptomycin antibiotics, TNF-α (MCE, HY-P7058), BV6 (MCE, HY-16701), Z-VAD-FMK (MCE, HY-16658B), CCK-8 (Dalian Meilun Biotechnology Co., Ltd., MA0218).

[0230] 2. Experimental instruments: Medical low-temperature freezer (Thermo Fisher Scientific, 902-ULTS), electric thermostatic water bath (Shanghai Yiheng Scientific Instrument Co., Ltd., CD-420), low-speed centrifuge (Anhui Zhongke Zhongjia Scientific Instrument Co., Ltd., SC-3616), carbon dioxide incubator (Shanghai Yiheng Scientific Instrument Co., Ltd., BPN-150CH(UV)), inverted microscope (Olympus, CKX53), multi-functional microplate reader (Thermo Tecan, SPARK), Class II biosafety cabinet (Sujing Antai, BSC-1304ⅡA2), benchtop cell counter (Thermo Fisher Scientific, CountessⅡ).

[0231] 3. Cell culture: U937 cells (human histiocytic lymphoma cells) were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution in a saturated humidity incubator at 37°C and 5% CO2. The cell culture flasks were placed vertically in the incubator. Taking a T25 culture flask as an example, the culture medium in the flask was 6-8 mL. The medium was changed and passaged 3-4 times a week.

[0232] 4. Experimental methods: The CCK-8 assay was used to detect the inhibitory effect of compounds on TNF-α-induced necroptosis in U937 cells, and compounds with receptor-interacting protein kinase 1 inhibitory activity were screened.

[0233] 4.1 Cell plating:

[0234] (1) Turn on the water bath and set the temperature to 37°C. Take the culture medium out of the refrigerator and put it into the water bath to preheat it. Take an appropriate amount for use.

[0235] (2) Transfer the cell suspension to a 15 mL sterile centrifuge tube, centrifuge at 850 rpm for 4 min, and collect U937 cells;

[0236] (3) Carefully discard the supernatant, add an appropriate amount of culture medium, gently blow with a pipette to make the cells uniform, prepare a single-cell suspension, and count them;

[0237] (4) Dilute the cells to 4 × 10⁻⁶ 5 90 μL / well was seeded into 96-well plates to achieve a cell density of 3.6 × 10⁶ cells / well. 4 Each cell / well was incubated in a 37°C, 5% CO2, and saturated humidity incubator for 6 hours before adding the drug.

[0238] 4.2 Compound dilution and dosing:

[0239] (1) TNF-α was dissolved in PBS to prepare a 100 μg / mL stock solution and aliquoted; Z-VAD-FMK was dissolved in DMSO to prepare a 10 mM stock solution and aliquoted; BV6 was dissolved in DMSO to prepare a 10 mM stock solution and aliquoted; GSK2982772 was dissolved in DMSO to prepare a 10 mM stock solution and aliquoted; one tube of each of the above reagent stock solutions was placed at -20℃ for use, and the rest were stored at -80℃ and used within the shelf life.

[0240] (2) Prepare RPMI-1640 medium containing TNF-α, BV6 and Z-VAD-FMK, 5 μL per well, so that the final concentrations of TNF-α, BV6 and Z-VAD-FMK are 20 ng / mL, 2 μM and 20 μM respectively.

[0241] (3) The culture medium for each target compound was diluted three times to form eight concentration gradients. Each concentration was replicated in wells with 5 μL per well. The final concentrations were 1000.00 / 333.33 / 111.11 / 37.04 / 12.35 / 4.12 / 1.37 / 0.46 nM.

[0242] (4) Remove the 96-well plate containing 90 μL of cell suspension from the incubator. Set up a positive control group, a test compound group, and a DMSO (5‰) control group. Add 5 μL of RPMI-1640 culture medium containing TNF-α, BV6, and Z-VAD-FMK and 5 μL of culture medium containing the test compound to the positive control group and the test compound group. Incubate for 18 h after drug addition before performing the CCK-8 experiment.

[0243] (5) Take out the 96-well plate, carefully add 10 μL of CCK-8 reagent to each well, incubate at 37℃ for 2 h to 4 h, and detect the absorbance value at 450 nm wavelength;

[0244] 5. Evaluation of the activity of the compound in inhibiting TNF-α-induced programmed necrosis of U937 cells.

[0245] Cell viability % = (OD value of treatment group - OD value of blank background) / (OD value of DMSO group - OD value of blank background) * 100

[0246] Compound EC 50 The calculations were performed using Graphpad Prism 6 software, and the experimental results for the example compounds are shown in Table 1.

[0247] Example 11: Compound inhibits TNF-α-induced programmed necrosis in HT-29 cells

[0248] 1. Experimental reagents: McCoy's 5A medium, fetal bovine serum, penicillin-streptomycin antibiotics, trypsin, PBS, TNF-α (MCE, HY-P7058), BV6 (MCE, HY-16701), Z-VAD-FMK (MCE, HY-16658B), SRB kit (Shanghai Bebo Biotechnology Co., Ltd., BB-4208-500T).

[0249] 2. Experimental instruments: Medical low-temperature freezer (Thermo Fisher Scientific, 902-ULTS), electric thermostatic water bath (Shanghai Yiheng Scientific Instrument Co., Ltd., CD-420), low-speed centrifuge (Anhui Zhongke Zhongjia Scientific Instrument Co., Ltd., SC-3616), carbon dioxide incubator (Shanghai Yiheng Scientific Instrument Co., Ltd., BPN-150CH(UV)), inverted microscope (Olympus, CKX53), multi-functional microplate reader (Thermo Tecan, SPARK), Class II biosafety cabinet (Sujing Antai, BSC-1304ⅡA2), benchtop cell counter (Thermo Fisher Scientific, CountessⅡ).

[0250] 3. Cell culture: HT-29 cells (human colon cancer cells) were cultured in McCoy's 5A medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution in a saturated humidity incubator at 37°C and 5% CO2. The medium was changed and passaged 3-4 times per week.

[0251] 4. Experimental methods: The SRB method was used to detect the inhibitory effect of compounds on TNF-α-induced necroptosis in HT-29 cells, and compounds with receptor-interacting protein kinase 1 inhibitory activity were screened.

[0252] 4.1 Cell plating:

[0253] (1) Open the water bath and adjust the temperature to 37°C. Take out the culture medium, trypsin, etc. from the refrigerator and put them into the water bath to preheat. Take an appropriate amount for use.

[0254] (2) Discard the old culture medium in the bottle using a sterile pipette, wash three times with PBS, and add 1 mL of trypsin (25 cm) to the bottle. 2 (Cell culture flask), gently shake the culture flask to allow trypsin to flow to all cell surfaces, and digest in a 37°C incubator. After digestion for 2 minutes, observe the culture flask under a microscope. Once you find that the cytoplasm has shrunk, the intercellular spaces have increased, and the cells have become rounded, immediately stand the culture flask upright and add 4 mL of serum-containing culture medium to stop the digestion.

[0255] (3) Transfer the cell suspension to a 15mL sterile centrifuge tube, centrifuge at 1000rpm for 4min, and collect HT-29 cells;

[0256] (4) Carefully discard the supernatant, add an appropriate amount of culture medium, gently blow with a pipette to make the cells uniform, prepare a single-cell suspension, and count them;

[0257] (5) Dilute the cells to 3 × 10⁻⁶ 5 100 μL / well was seeded into 96-well plates, with each well containing 3 × 10⁶ cells. 4 Each sample was placed in an incubator at 37°C, 5% CO2, and saturated humidity for 24 hours before the drug was added.

[0258] 4.2 Compound dilution and dosing:

[0259] (1) TNF-α was dissolved in PBS to prepare a 100 μg / mL stock solution and aliquoted; Z-VAD-FMK was dissolved in DMSO to prepare a 10 mM stock solution and aliquoted; BV6 was dissolved in DMSO to prepare a 10 mM stock solution and aliquoted; GSK2982772 was dissolved in DMSO to prepare a 10 mM stock solution and aliquoted; one tube of each of the above reagent stock solutions was placed at -20℃ for use, and the rest were stored at -80℃ and used within the shelf life.

[0260] (2) Prepare McCoy's 5A culture medium containing TNF-α, BV6 and Z-VAD-FMK. Add 90 μL of the positive control group and the test compound group to each well, and then add 10 μL of the culture medium containing the test compound to make the final concentrations of TNF-α, BV6 and Z-VAD-FMK 20 ng / mL, 2 μM and 20 μM respectively. Add 90 μL of McCoy's 5A complete culture medium to the DMSO (5‰) control group, and then add 10 μL of DMSO to make the final concentration 5‰.

[0261] (3) The culture medium for each target compound was diluted three times to form eight concentration gradients. Each concentration was replicated in wells with 10 μL per well. The final concentrations were 1000.00 / 333.33 / 111.11 / 37.04 / 12.35 / 4.12 / 1.37 / 0.46 nM.

[0262] (4) Remove the 96-well plate from the incubator after 24 hours of incubation, carefully aspirate the culture medium from the 96-well plate, and set up a positive control group, a test compound group, and a DMSO (5‰) control group. Add 10 μL of the corresponding compound to each group. Incubate for 18 hours after adding the drug before performing the SRB experiment;

[0263] (5) Remove the 96-well plate and measure the absorbance according to the SRB kit instructions;

[0264] 5. Evaluation of the activity of the compound in inhibiting TNF-α-induced HT-29 programmed necrosis

[0265] Cell viability % = (OD value of treatment group - OD value of blank background) / (OD value of DMSO group - OD value of blank background) * 100

[0266] Compound EC 50 The calculations were performed using Graphpad Prism 6 software, and the experimental results for the example compounds are shown in Table 1.

[0267] Table 1. Inhibitory activity of compounds against HT-29 and U937 cells

[0268] Note: ++++≤10nM; 10nM<++++≤100nM; 100nM<++≤200nM;+>200nM. Example 12: Evaluation of the inhibitory capacity of RIPK1 (receptor-interacting serine / threonine protein kinase 1) enzyme. 1. Reagents, consumables and instruments

[0269]

[0270]

[0271] 2. Experimental Procedure

[0272] 1) Prepare 2×ATP / substrate solution and 2×kinase solution using kinase reaction buffer;

[0273] 2) Use an Echo 655 to transfer 100 nL of the complex dilution to a 384 detection plate; centrifuge and add 5 μL of 2× kinase solution to the 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes;

[0274] 3) Add 5 μL of 2× substrate and ATP solution to the 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 180 minutes;

[0275] 4) Transfer 5 μL of ADP-Glo ​​reagent to a 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes;

[0276] 5) Transfer 10 μL of kinase assay reagent to a 384 plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes;

[0277] 6) Use BMG to read the light emission signal.

[0278] 3. Data Analysis

[0279] 1) Composite pore inhibition rate (%inh) = 100 * (ave high control - cpd pore) / (ave high control - ave low control)

[0280] Compound IC 50 The calculations were processed using Graphpad prism 8 software, and the test results of the example compounds are shown in Table 2.

[0281] Table 2. Inhibitory activity of compounds against RIPK1

[0282]

[0283] Note: ++++ ≤ 5 nM; 5 nM < +++ ≤ 10 nM; 10 nM < ++ ≤ 100 nM; + > 100 nM.

[0284] Example 13: Pharmacodynamic evaluation test of a mouse model of TNF-α-induced systemic inflammatory response syndrome (SIRS)

[0285] 1. Experimental animals

[0286] C57BL / 6J mice, female, 8 weeks old, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd., license number: SCXK(Zhe)2024-0001. The animals were housed in the SPF animal room of Hangzhou Biochem Pharm Co., Ltd., and the experimental animal use license number: SYXK(Zhe)2023-0039. The animals were used at least one week after being raised. All experiments were carried out strictly in accordance with the relevant regulations of experimental animals.

[0287] 2. Experimental reagents and instruments

[0288]

[0289]

[0290] 3. Preparation methods of reagents and compounds:

[0291] Preparation method of the test sample: Weigh an appropriate amount of the test sample precisely, add an appropriate amount of 1% HPMC solution to prepare suspension solutions with concentrations of 0.1 mg / mL, 0.3 mg / mL, and 1 mg / mL, and prepare them freshly for use.

[0292] Positive control: Weigh an appropriate amount of the test sample GSK2982772 precisely, add an appropriate amount of 0.9% sodium chloride injection to prepare a clear solution with a concentration of 1 mg / ml, and prepare it freshly for use.

[0293] Preparation of 1% HPMC solution: Weigh 1 g of HPMC and dissolve it in 100 mL of sterilized double-distilled water, and dissolve it fully.

[0294] Preparation method of modeling agent: Accurately weigh an appropriate amount of recombinant mouse TNF-α protein as the modeling agent, add an appropriate amount of 0.9% sodium chloride injection to prepare a clear solution with a concentration of 25 μg / mL, and prepare it fresh before use.

[0295] 4. Experimental Design:

[0296] 1) Model Introduction: Systemic inflammatory response syndrome (SIRS) is a "mediator disease" caused by the excessive release of various inflammatory mediators and cytokines after severe injury, which activates many physiological, biochemical, and immune pathways, leading to uncontrolled inflammatory responses. The inflammatory cytokine TNF-α can promote cell death through the RIPK1 signaling pathway, thereby inducing septic shock and producing SIRS. This experiment aims to conduct a pharmacodynamic evaluation of the test product's anti-TNF-α-induced SIRS mouse model and confirm the dose-response relationship of the test product.

[0297] 2) Experimental procedure:

[0298] Animal marking and grouping

[0299] After 3 days of acclimatization, the animals were weighed and randomly divided into 6 groups based on their weight. The grouping and drug dosage are shown in the table below:

[0300]

[0301] *Note: Animal numbers on the record sheet are marked on the tail with a marker pen.

[0302] Animal drug administration and modeling

[0303] Before modeling, each C57BL / 6 mouse was weighed and marked. The Dex group received a single gavage administration on the day of modeling. Other test drug groups were pre-administered with a BID (best-in-dose) frequency for 3 days, and then administered a single gavage administration 15 minutes before modeling on the fourth day. During the administration period, the Control and Model groups were given an equal volume of 1% HPMC blank solvent at the BID frequency. Mice in the Model group and each drug administration group were injected with 200 μL of recombinant murine TNF-α protein (5 μg / mouse) via the tail vein 15 minutes after the last administration, while the Control group was injected with an equal volume of physiological saline via the tail vein.

[0304] 3) Detection indicators:

[0305] General clinical observation

[0306] All animals were observed twice daily during the experiment. Observations included observation of death or near-death state, feces, feeding status, mental state, and behavioral activity. Any abnormalities were recorded promptly.

[0307] Weight record

[0308] All animals were weighed once a day during the experiment.

[0309] Rectal temperature monitoring

[0310] The rectal temperature of mice in each group was measured at six time points: before modeling and 1, 2, 4, 6, and 8 hours after modeling.

[0311] Survival Curve

[0312] The experiment ended 24 hours after modeling, and the mortality of mice in each group was recorded and survival curves were plotted.

[0313] Data collection and statistical analysis

[0314] Record the results and data of the measurements and observations required by the plan into appropriate tables, and analyze them uniformly in an Excel spreadsheet. Measurement data are expressed as mean ± standard error. All statistical analysis was performed using Prism statistical software. General data were analyzed using the one-way ANOVA method, while time-related data such as rectal temperature were analyzed using the two-way ANOVA method. A p-value ≤ 0.05 was considered statistically significant.

[0315] 5. Experimental Results

[0316] General clinical observation

[0317] No obvious abnormalities were observed in any group of animals during the experiment.

[0318] Body temperature changes

[0319] The trends of body temperature changes in each group of animals are as follows: Figure 1 As shown: Compared with the control group, the rectal temperature of Model mice gradually decreased after tail vein injection of TNF-α (P<0.001); Compared with the Model group, compound I-7 improved hypothermia in SIRS model mice at low, medium and high doses (P<0.05~P<0.001), and I-7 significantly improved hypothermia in SIRS model mice at a dose of 10 mg / kg (P<0.001), which was comparable to or slightly better than the same dose of GSK2982772 (P>0.05@1, 2, 4h) (P<0.05@6h).

[0320] Survival rate

[0321] The survival rate trends of each group of animals are as follows: Figure 2As shown, the survival rate of SIRS model mice treated with GSK2982772 at a dose of 10 mg / kg at 24 h was 16.7%, and the survival rate of SIRS model mice treated with I-7 at a dose of 10 mg / kg at 24 h was significantly improved, with the improvement being significantly better than that of GSK2982772 at the same dose.

[0322] in conclusion

[0323] Under the conditions of this experiment, the improvement in hypothermia and survival rate of SIRS mice by I-7 at the same dose was comparable to or slightly better than that of GSK2982772.

Claims

1. An alkyne aromatic heterocyclic urea derivative, which is a compound, isomer, or pharmaceutically acceptable salt thereof represented by formula (I): In the formula: R is selected from H, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 3-10 Cycloalkenyl, when C is described in R 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, 5-8 quinone heteroaryl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic groups, C 3-10 When a cycloalkenyl group has substituents, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group; further, the aforementioned C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 When an alkynyl group has substituents, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The 5-8 membered heteroaryl group described in R does not contain a pyridine ring or a pyrimidine ring; R1 can be independently H, halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, or substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, when the C in R1 1-6 Alkyl, C 1-6 When an alkoxy group is present, it can be substituted by at least one of the following groups: halogen, amino, hydroxyl, cyano, amide, sulfone, sulfoxide, oxo, C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; X is N or C; Y is O or C; The heteroaryl or heterocyclic group contains at least one heteroatom, which is selected from N, O or S; But excluding 2. The alkyne aromatic heterocyclic urea derivative according to claim 1, characterized in that, The compounds, isomers, or pharmaceutically acceptable salts of formulas (II-2A) and (III-2A) are: In the formula: R1 is selected from hydrogen, methyl, or -OCH3; R a R b R c Each is independently selected from H or F.

3. The compound according to any one of claims 1-2, or its pharmaceutical salt, characterized in that, R1 is selected from hydrogen or methyl.

4. The compound according to any one of claims 1-3, or its pharmaceutical salt, characterized in that, The Selected from 5. An alkyne aromatic heterocyclic urea derivative, which is a compound, isomer, or pharmaceutically acceptable salt thereof with the following structure: (S)-N-(5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-3-phenylisooxazolidine-2-carboxamide; (S)-N-(5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-3-phenylisooxazolidine-2-carboxamide; (S)-N-(3-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide; (S)-N-(3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide; (S)-N-(2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide; (S)-N-(5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-2-methoxyphenyl)-3-phenylisooxazolidine-2-carboxamide; (S)-N-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide; (S)-N-(5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-3-yl)-2-phenylpyrrolidine-1-carboxamide; (S)-N-(3-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-2-phenylpyrrolidine-1-carboxamide.

6. A pharmaceutical composition comprising the compound as an active ingredient as described in any one of claims 1-5, and at least one pharmaceutically acceptable carrier.

7. The use of a compound according to any one of claims 1-5 or a pharmaceutical composition according to claim 6 in the preparation of a medicament for the prevention or treatment of diseases associated with receptor-interacting protein kinases, preferably, said diseases being diseases associated with altered activity of receptor-interacting protein kinase 1.

8. The application according to claim 7, characterized in that, The diseases mentioned are selected from tumors, symptomatic diseases or diseases accompanied by inflammatory reactions, autoimmune diseases, neurodegenerative diseases, etc.

9. The application according to claim 8, characterized in that, The diseases mentioned are selected from tumors, including but not limited to colorectal cancer, lung cancer, liver cancer, pancreatic cancer, breast cancer, lymphoma, melanoma, etc.

10. The application according to claim 8, characterized in that, The diseases mentioned are selected from systemic inflammatory response syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic fatty liver disease, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerocholangitis, nephritis, and celiac disease. Autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, allergic diseases, asthma, multiple sclerosis, amyotrophic lateral sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-related febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodic syndrome, periodontitis, etc.

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