Heterocyclic compounds as RIPK1 inhibitors

Abstract

The present invention relates to heterocyclic compounds, pharmaceutical compositions containing the same, processes for their preparation, and their use as RIPK1 inhibitors. The compound is a compound as shown in formula (I), or an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof. The invention also relates to the use of said compounds for the treatment or prevention of related diseases and dysfunctions mediated by RIPK1 and to methods of using the same to treat said diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to heterocyclic compounds, pharmaceutical compositions containing the same and their use as inhibitors of receptor interacting protein kinase 1 (RIPK1). More specifically, the present invention provides novel heterocyclic compounds as RIPK1 inhibitors, pharmaceutical compositions containing such compounds and methods for using the compounds to treat or prevent diseases and functional disorders mediated by RIPK1. The present invention also relates to methods for preparing the compounds. Background Art

[0002] Receptor-interacting protein kinase 1 (RIPK1) is a serine / threonine protein kinase involved in innate immune signaling. RIPK1 is a 76 kDa protein with an N-terminal kinase domain, a C-terminal death domain, and an intermediate domain with a RHIM (receptor-interacting protein homotypic interaction motif). The C-terminal death domain mediates homodimerization and heterodimerization with other death domain-containing proteins, and the N-terminal kinase domain mediates trans-autophosphorylation to promote self-activation.

[0003] RIPK1 has a dual immunomodulatory effect. On the one hand, it can act as a scaffold to promote the activation of MAPK and NF-κB signaling pathways, thereby promoting inflammatory responses, cell survival, and inhibiting cell apoptosis; on the other hand, abnormally regulated RIPK1 activity will cause cell necrosis. RIPK1 is a major regulator of NF-κB signaling and cellular determinants of death responses. NF-κB signaling responds to a wide range of inflammatory and pro-death stimuli in human diseases (Degterev, A., et.al. PNAS, 2019, 116(20), 9714-9722).

[0004] RIPK1 is widely expressed in various cell types, and is most abundantly expressed in adipose, endothelial, and perivascular cell clusters. It is also expressed in immune cell clusters (dendritic cells, macrophages, and T cells). Studies have found that activation of RIPK1 kinase is present in pathological samples of autoimmune diseases and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). Anti-tumor necrosis factor-α (TNF-α) drugs have achieved significant clinical success in the treatment of human peripheral inflammatory diseases such as rheumatoid arthritis, colitis, and psoriasis. However, since tumor necrosis factor receptor 2 (TNFR2) mediates nerve regeneration, there are unsafe factors in the treatment of central nervous system diseases. RIPK1 inhibitors can safely improve harmful TNF responses in the central nervous system without affecting TNFR2. Therefore, RIPK1 inhibitors have the potential to become drugs to replace TNF antibodies to make up for the shortcomings of TNF antibodies.

[0005] Studies have shown that Necrostatin-1 (Nec-1), a small molecule inhibitor of RIPK1 known in the art, can effectively block programmed cell necrosis (Degterev et al. Nat. Chem. Biol. 2005; 1: 112-119.), and has shown effective therapeutic effects in a variety of inflammatory diseases. GSK2982772 is being developed for peripheral autoimmune diseases such as psoriasis, rheumatoid arthritis (RA) and ulcerative colitis. The brain-penetrating RIPK1 inhibitor DNL-788 is used for amyotrophic lateral sclerosis, etc. These experiments have laid the foundation for advancing the clinical application of RIPK1 inhibitors.

[0006] RIPK1 inhibitors are of great significance in this field, especially in inhibiting inflammatory diseases (such as Crohn's disease, ulcerative colitis, etc.), sepsis and acute ischemic injury (such as sepsis, severe Covid-19, acute ischemic brain injury, etc.), tumors, autoimmune system diseases (such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, etc.) and neurodegenerative diseases (such as multiple sclerosis, Huntington's disease, Duchenne muscular dystrophy, frontotemporal dementia, Alzheimer's disease, Parkinson's disease, etc.) (Lauren M. etc. al. Nature Reviews Drug Discovery, 19 (2020), 553–571).

[0007] Therefore, there is still a need to develop small-molecule RIPK1 inhibitors with excellent activity. Summary of the invention

[0008] The present invention relates to a compound of formula (I), an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof. in: R 1 is selected from fluorine, cyano, alkynyl, wherein the alkynyl is unsubstituted or substituted by one or more R x substituted 5-6 membered heteroaryl, wherein R x Each is independently selected from fluorine, chlorine, cyano, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C1-C4 alkyl, wherein the C3-C6 cycloalkyl and C1-C4 alkyl are unsubstituted or substituted with one to three fluorine or cyano groups; R 2 Selected from hydrogen, fluorine, chlorine, cyano, unsubstituted or C1-C4 alkyl or C3-C6 cycloalkyl substituted by one to three fluorine or cyano groups; X is selected from CR 5 , N, where R 5 Selected from hydrogen, fluorine, chlorine, cyano, unsubstituted or C1-C4 alkyl or C3-C6 cycloalkyl substituted by one to three fluorine or cyano groups; Y is selected from CR 6a R 6b , O, S or NR 6a , where R 6a and R 6b are each independently selected from hydrogen, halogen, C1-C6 alkyl, or R 6a and R 6b They may form together a C3-C8 cycloalkyl group or a 4- to 8-membered heterocyclic group; R 3 , R 4 R is each independently selected from hydrogen, fluorine, chlorine, cyano, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C6-C10 aryl, or 5-6-membered heteroaryl, wherein the C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C6-C10 aryl, and 5-6-membered heteroaryl are unsubstituted or substituted with one to three fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl; or 3 and R 4 may together form a C3-C8 cycloalkyl or 4- to 8-membered heterocyclyl which is optionally unsubstituted or substituted by one to three substituents selected from fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5-6-membered heteroaryl, C3-C6 cycloalkyl and 4- to 6-membered heterocyclyl; n is selected from 1-2; A is a 6-9 membered lactam heterocyclic ring containing 1-3 heteroatoms selected from N, O and S.

[0009] Preferably, the present invention relates to a compound of formula (I) as described above, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, which has formula (II): R 1 is selected from fluorine, cyano, alkynyl, wherein the alkynyl is unsubstituted or substituted by one or more R x substituted 5-6 membered heteroaryl, wherein R x Each is independently selected from fluorine, chlorine, cyano, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C1-C4 alkyl, wherein the C3-C6 cycloalkyl and C1-C4 alkyl are unsubstituted or substituted with one to three fluorine or cyano groups; R 2 Selected from hydrogen, fluorine, chlorine, cyano, unsubstituted or C1-C4 alkyl or C3-C6 cycloalkyl substituted by one to three fluorine or cyano groups; X is selected from CR 5 , N, where R 5 Selected from hydrogen, fluorine, chlorine, cyano, unsubstituted or C1-C4 alkyl or C3-C6 cycloalkyl substituted by one to three fluorine or cyano groups; R 3 , R 4 R is each independently selected from hydrogen, fluorine, chlorine, cyano, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C6-C10 aryl, or 5-6-membered heteroaryl, wherein the C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C6-C10 aryl, and 5-6-membered heteroaryl are unsubstituted or substituted with one to three fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl; or 3 and R 4 They may together form a C3-C8 cycloalkyl or 4- to 8-membered heterocyclic group which is optionally unsubstituted or substituted by one to three substituents selected from fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5-6-membered heteroaryl, C3-C6 cycloalkyl and 4- to 6-membered heterocyclic group.

[0010] More preferably, the present invention relates to a compound of formula (II) as described above, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 Selected from fluorine, cyano; R 2 Selected from hydrogen, unsubstituted or substituted by one to three fluorine or cyano C1-C3 alkyl or cyclopropane; X is selected from CR 5 , N, where R 5 is selected from hydrogen and fluorine; R 3 , R 4 R is each independently selected from hydrogen, fluorine, chlorine, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C6-C10 aryl, or 5-6-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C6-C10 aryl, and 5-6-membered heteroaryl are unsubstituted or substituted with one to three fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl; or 3 and R 4 They may together form a C3-C8 cycloalkyl or 4- to 8-membered heterocyclic group which is optionally unsubstituted or substituted by one to three substituents selected from fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5-6-membered heteroaryl, C3-C6 cycloalkyl and 4- to 6-membered heterocyclic group.

[0011] Further preferably, the present invention relates to a compound of formula (II) as described above, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 Selected from fluorine, cyano; R 2 is selected from hydrogen, C1-C2 alkyl which is unsubstituted or substituted by one to three fluorine groups; X is selected from CR 5 , N, where R 5 is selected from hydrogen and fluorine; R 3 , R 4 Each is independently selected from hydrogen, fluorine, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are unsubstituted or substituted by one to three fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C8 aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl or 4 to 6 membered heterocyclyl; or R 3 and R 4They may together form a C3-C8 cycloalkyl or 4- to 8-membered heterocyclic group which is optionally unsubstituted or substituted by one to three substituents selected from fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5-6-membered heteroaryl, C3-C6 cycloalkyl and 4- to 6-membered heterocyclic group.

[0012] More preferably, the present invention relates to a compound of formula (II) as described above, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 Selected from fluorine, cyano; R 2 is selected from hydrogen, C1-C2 alkyl; X is selected from CR 5 , N, where R 5 is selected from hydrogen and fluorine; R 3 , R 4 are each independently selected from hydrogen, fluorine, C1-C4 alkyl, wherein the C1-C4 alkyl is unsubstituted or substituted by one to three fluorines; or R 3 and R 4 Together they may form a C3-C6 cycloalkyl group or a 4- to 6-membered heterocyclic group which is optionally unsubstituted or substituted by one to three fluorine groups.

[0013] Still more preferably, the present invention relates to a compound of formula (II) as described above, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 Selected from fluorine, cyano; R 2 is selected from hydrogen, methyl; X is selected from CR 5 , N, where R 5 is selected from hydrogen and fluorine; R 3 , R 4 are each independently selected from hydrogen, methyl, difluoroethyl; or R 3 and R 4 Can be formed together

[0014] Most preferably, the present invention relates to a compound of formula (II) as described above, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, which is selected from:

[0015] The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) as described in any embodiment of the present invention, an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0016] The present invention also relates to the use of a compound of formula (I) according to any embodiment of the present invention, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof in the preparation of a medicament for use as a RIPK1 inhibitor.

[0017] The present invention also relates to the use of a compound of formula (I) according to any embodiment of the present invention, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing related diseases and dysfunctions mediated by RIPK1, wherein the related diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, acute nervous system diseases, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic fatty liver disease, alcoholic fatty liver disease, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, pancreatic cancer, bacterial infection, hematological malignancies, solid organ malignancies, etc.

[0018] The present invention also relates to the use of the pharmaceutical composition according to the present invention in the preparation of a drug, wherein the drug is used to treat or prevent related diseases mediated by RIPK1, such as ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic fatty hepatitis, alcoholic fatty hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, cancer (such as pancreatic cancer), bacterial infection, blood malignancies, solid organ malignancies, etc. In particular, rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0019] The present invention also relates to a method for treating or preventing related diseases mediated by RIPK1, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound or its optical isomer or its pharmaceutically acceptable salt according to any embodiment of the present invention, or the pharmaceutical composition of the present invention, wherein the related diseases are, for example, ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic fatty hepatitis, alcoholic fatty hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, cancer (e.g., pancreatic cancer), bacterial infection, hematological malignancies, solid organ malignancies, etc.; in particular, rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0020] Another aspect of the present invention relates to a compound described in any embodiment of the present invention, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, for use in treating or preventing related diseases mediated by RIPK1, such as ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic fatty hepatitis, alcoholic fatty hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, cancer (e.g. pancreatic cancer), bacterial infection, hematological malignancies, solid organ malignancies, etc.; in particular, rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0021] Another aspect of the present invention relates to a pharmaceutical composition, which comprises a compound of formula I or an optical isomer thereof or a pharmaceutically acceptable salt thereof as described in any embodiment of the present invention, optionally one or more other RIPK1 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients, which is used to treat or prevent related diseases mediated by RIPK1, such as ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic fatty hepatitis, alcoholic fatty hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, cancer (e.g. pancreatic cancer), bacterial infection, hematological malignancies, solid organ malignancies, etc.; in particular, rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0022] According to the present invention, the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, and injections.

[0023] The pharmaceutical preparation of the present invention can be administered in the form of a dosage unit containing a predetermined amount of active ingredient per dosage unit. This unit can contain, for example, 0.5 mg to 1 gram, preferably 1 mg to 700 mg, particularly preferably 5 mg to 300 mg of the compound of the present invention according to the disease, administration method and age, body weight and condition of the patient for treatment, or the pharmaceutical preparation can be administered in the form of a dosage unit containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit preparations are those containing the active ingredient of the daily dose or divided dose or its corresponding fraction as indicated above. In addition, this type of pharmaceutical preparation can be prepared using methods known in the pharmaceutical field.

[0024] The pharmaceutical preparations of the present invention may be suitable for administration by any desired suitable method, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) administration. Such preparations may be prepared using all methods known in the pharmaceutical art, for example, by combining the active ingredient with one or more excipients or one or more adjuvants. Preparation process

[0025] The present invention also provides a method for preparing the compound.

[0026] Intermediate Process 1 X, R 2 is defined as above; first step: Compounds (I) and (II) are dissolved in a solvent (such as methanol) and reacted at room temperature for 1 to 4 hours under the protection of an inert gas (such as nitrogen or argon). A reducing agent (such as sodium borohydride) is added and reacted at 0 to 30°C for 0.1 to 2 hours to obtain compound (III); Step 2: Compound (III) is dissolved in a solvent (such as N,N-dimethylformamide), a base (such as sodium hydride, etc.) is added, and the mixture is reacted at 0 to 30° C. for 1 to 4 hours to obtain compound (IV).

[0027] Intermediate Process 2 X, R 2 is defined as above; first step: Compounds (V) and (II) are dissolved in a solvent (such as dichloroethane), and under the protection of an inert gas (such as nitrogen or argon), a reducing agent (such as sodium cyanoborohydride) and a promoter (such as acetic acid) are added, and the mixture is reacted at room temperature for 1 to 4 hours to obtain compound (VI); Step 2: Compound (VI) is dissolved in a solvent (such as water and ethyl acetate), and di-tert-butyl dicarbonate and a base (such as sodium hydroxide) are added to react at room temperature for 1 to 6 hours to obtain compound (VII); Step 3: Dissolve compound (VII) in a solvent (such as dichloromethane), add a phosphine reagent (such as triphenylphosphine) and an azo reagent (such as diisopropyl azodicarboxylate), and stir at room temperature for 2 to 16 hours to obtain compound (VIII); Step 4: Compound (VIII) is dissolved in a solvent (such as dichloromethane or 1,4-dioxane), an acid (such as trifluoroacetic acid or hydrochloric acid) is added, and the mixture is stirred at room temperature for 1 to 5 hours to obtain compound (IV).

[0028] Compound preparation process X, R 2 , R 3 With R 4 is defined as above; first step: Compound (IX) is dissolved in a solvent (such as dichloromethane), and under the protection of an inert gas (such as nitrogen or argon), an activating reagent (such as 1-chloro-N,N,2-trimethylprop-1-en-1-amine) is added, and the reaction is carried out at room temperature for 0.5 to 4 hours. The reaction solution is added to a solution (such as dichloromethane) containing compound (IV) and a base (such as triethylamine), and the reaction is carried out at room temperature for 1 to 8 hours to obtain compound (X); Step 2: Compound (X) is dissolved in a solvent (such as dichloromethane), an acid (such as hydrochloric acid) is added, and the mixture is stirred at room temperature for 1 to 30 minutes, and the excess acid is removed by distillation under reduced pressure. The residue is dissolved in a solvent (such as dichloromethane), and a catalyst (1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinyl) (dichlorobenzylidene) (tricyclohexylphosphine) ruthenium) is added under the protection of an inert gas (such as nitrogen or argon), and the mixture is reacted at 20 to 60°C for 1 to 5 hours to obtain compound (XI); Step 3: Dissolve compound (XI), a cyano reagent (such as zinc cyanide), a catalyst (such as tris(dibenzylideneacetone)dipalladium) and a ligand (such as bistriphenylphosphinoferrocene) in a solvent (such as N,N-dimethylformamide), and heat in an oil bath to 80-130° C. under the protection of an inert gas (such as nitrogen or argon) for 2-16 hours to obtain compound (XII); Step 4: Compound (XII) is dissolved in a solvent (such as methanol), a catalyst (palladium on carbon) is added, and the mixture is reacted at room temperature for 0.5 to 4 hours in the presence of a reducing agent (such as hydrogen) to obtain compound (XIII). DETAILED DESCRIPTION

[0029] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings: Groups not specifically defined in the present invention have the meanings generally recognized in the art by those skilled in the art.

[0030] The notation "Cx-Cy" used in the present invention represents the range of carbon atom numbers, wherein x and y are both integers, for example, C3-C8 cycloalkyl represents a cycloalkyl group having 3-8 carbon atoms, and C0-C2 alkyl represents an alkyl group having 0-2 carbon atoms, wherein -C0 alkyl refers to a chemical single bond.

[0031] In the present invention, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms, for example, straight and branched groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, and various branched isomers thereof. The alkyl group may be optionally substituted or unsubstituted.

[0032] In the present invention, the term "alkoxy" refers to an alkyl-O- group, wherein the alkyl group has the meaning defined above.

[0033] In the present invention, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, which includes 3 to 20 ring atoms, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, but excluding -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, 3 to 12 ring atoms are included, wherein 1 to 4 are heteroatoms, more preferably, the heterocyclyl ring contains 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, most preferably 5-membered rings or 6-membered rings, wherein 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, and most preferably 1 to 2 are heteroatoms. Non-limiting examples of heterocyclyls include oxetane, oxacyclohexane, azetidinyl, morpholinyl, 2-morpholinyl, dihydropyrazolyl, etc. The heterocyclyl group may be optionally substituted or unsubstituted.

[0034] In the present invention, the term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. Preferably, it is 5 to 10 yuan. More preferably, the heteroaryl is 5 or 6 yuan, such as pyrazolyl, imidazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl, etc.), thiazolyl, pyrazinyl, oxazolyl, isoxazolyl, pyridyl, etc. The heteroaryl group can be optionally substituted or unsubstituted.

[0035] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0036] In the present invention, "optional" or "optionally" means that the event or circumstance described subsequently may but need not occur, and the description includes occasions where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes situations where the heterocyclic group is substituted with an alkyl group and situations where the heterocyclic group is not substituted with an alkyl group.

[0037] The substituents include but are not limited to the various groups described above.

[0038] The compounds claimed in the present invention include not only the compounds themselves but also optical isomers of the compounds or pharmaceutically acceptable salts thereof.

[0039] The "pharmaceutical composition" of the present invention refers to a mixture containing one or more compounds of the present invention or their optical isomers or pharmaceutically acceptable salts and other chemical components. Other components include pharmaceutically acceptable carriers, diluents and excipients. The purpose of the pharmaceutical composition is to promote administration to an organism, facilitate the absorption of the active ingredients and thus exert biological activity.

[0040] When used in the specification, the term "comprising" includes "consisting of".

[0041] The "room temperature" mentioned in the present invention refers to 15-30°C.

[0042] The "pharmaceutically acceptable salts" of the present invention are discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and are obvious to pharmaceutical chemists. The salts are substantially non-toxic and can provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc.

[0043] The pharmaceutically acceptable salts of the present invention can be synthesized by general chemical methods.

[0044] Generally, salts can be prepared by reacting a free base or acid with an equal chemical equivalent or excess of an acid (inorganic or organic) or base in a suitable solvent or solvent combination.

[0045] The "optical isomers" of the present invention include meso-forms, racemates, enantiomers, diastereomers, and mixtures thereof of the compounds of formula (I) of the present invention.

[0046] The present invention includes any polymorphs and any hydrates or other solvates of the compound or its salt.

[0047] In the present invention, the term "patient" generally refers to mammals, especially humans.

[0048] In the present invention, the term "therapeutically effective amount" refers to an amount of the compound of the present invention that can effectively treat or prevent diseases mediated by RIPK1. Example

[0049] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0050] The structures of all compounds of the present invention can be determined by nuclear magnetic resonance ( 1 H NMR) and / or mass spectrometry (MS).

[0051] 1 H NMR chemical shifts (δ) are reported in PPM (parts per million). NMR was performed on a Bruker AVANCE III-400 MHz spectrometer. A suitable solvent was selected from deuterated chloroform (CDCl3 ), deuterated methanol (CD 3 OD), deuterated dimethyl sulfoxide (DMSO-d 6 ), and tetramethylsilane (TMS) was used as the internal standard.

[0052] Low-resolution mass spectra (MS) were measured by Agilent 1260 HPLC / 6120 mass spectrometer using Agilent ZORBAXX DB-C18, 4.6×50 mm, 3.5 μm.

[0053] Gradient elution condition 1: 0 min: 95% solvent A1 and 5% solvent B1, 1-2 min: 5% solvent A1 and 95% solvent B1; 2.01-2.50 min: 95% solvent A1 and 5% solvent B1. The percentage is the volume percentage of a certain solvent in the total solvent volume. Solvent A1: 0.01% formic acid aqueous solution; Solvent B1: 0.01% formic acid in acetonitrile solution; The percentage is the volume percentage of the solute in the solution.

[0054] The thin layer silica gel plate is Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses Yantai Huanghai 100-200 or 200-300 mesh silica gel as a carrier.

[0055] Preparative liquid chromatography (prep-HPLC) used Waters SQD2 mass spectrometer-guided high pressure liquid chromatography separation instrument, XBridge-C18; 30X 150mm preparative column, 5μm; Method 1: acetonitrile-water (0.2% formic acid), flow rate 25 mL / min; Method 2: acetonitrile-water (0.8% ammonium bicarbonate), flow rate 25 mL / min; The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Bid Pharmaceutical, Shanghai Aladdin Chemical, Shanghai Myrrel Chemical, Bailingwei Chemical, Anaiji Chemical and other companies.

[0056] Unless otherwise specified in the examples, all the solvents used in the reactions were anhydrous solvents purchased from Anergy Chemical and J&K Chemical. The transfer and use of all anhydrous solvents were carried out under argon protection unless otherwise specified.

[0057] Unless otherwise specified in the examples, all reactions were carried out under argon or nitrogen atmosphere.

[0058] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0059] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0060] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0061] Unless otherwise specified in the examples, the reaction temperature is room temperature, which ranges from 15°C to 30°C.

[0062] The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction were A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0063] The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents.

[0064] The reagents used in the biological experiment of the present invention are: DMSO (D5879-500ML) purchased from Sigma, Fetal Bovine Serum (FSP500) purchased from ExCell Bio, DPBS (14190-144), RPMI Medium 1640 (72400-047), Luminescent Cell Viability Assay( Luminescent cell viability detection kit (G7571, G7573) was purchased from Promega. Preparation of intermediates

[0065] Intermediate 1 (R)-3-Allyl-9-bromo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine first step (R)-2-(((5-bromo-4-chloropyridin-3-yl)methyl)amino)pent-4-en-1-ol 1-1 5-Bromo-4-chloronicotinaldehyde (2.83 g, 12.90 mmol) (Synthesis reference: WO2012066061 A1) was dissolved in methanol (30 mL), (R)-2-aminopent-4-en-1-ol (1.80 g, 18.00 mmol) (Synthesis reference: WO2022109573A1) was added, and the mixture was reacted at room temperature for 4 hours under nitrogen protection. The mixture was cooled to 0°C in an ice-water bath, and sodium borohydride (0.98 g, 25.80 mmol) was added in batches, and the reaction was continued at 0°C for 1 hour. Saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. The organic phase was filtered to remove the desiccant and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:3) to give the target compound (R)-2-(((5-bromo-4-chloropyridin-3-yl)methyl)amino)pent-4-en-1-ol 1-1 (1.36 g, yellow oil), yield: 35%.

[0066] MS m / z(ESI):305&307[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.60(s,1H),8.41(s,1H),5.69-5.62(m,1H),5.07-5.03(m,2H),4.45-4.41(m,1H),3.94 -3.88(m,2H),3.65-3.61(m,1H),3.36-3.31(m,1H),2.71-2.67(m,1H),2.22-2.18(m,2H). Step 2 (R)-3-allyl-9-bromo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine 1 (R)-2-(((5-bromo-4-chloropyridin-3-yl)methyl)amino)pent-4-en-1-ol 1a (1.36 g, 4.50 mmol) was dissolved in anhydrous DMF (30 mL), cooled to 0°C in an ice-water bath, and sodium hydride (60% dispersed in mineral oil, 0.54 g, 13.40 mmol) was slowly added in batches. After the addition was completed, the mixture was reacted at 0°C for 1 hour. Saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction, and water (100 mL) was added to dilute it. It was extracted with ethyl acetate (40 mL x 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column chromatography (Biotage combi-flash, C18 column, water / acetonitrile = 66 / 34) to give the target product (R)-3-allyl-9-bromo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine 1 (0.90 g, yellow oil) in a yield of 74%.

[0067] MS m / z(ESI):269&271[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.46(s,1H),8.13(s,1H),5.78-5.71(m,1H),5.12-5.07(m,2H),4.45-4.41 (m,1H),3.94(s,2H),3.68-3.63(m,1H),3.2-3.17(m,1H),2.21-2.06(m,2H).

[0068] The synthetic steps of Intermediate 2-6 refer to Intermediate 1, wherein the corresponding amine is used instead of (R)-2-aminopent-4-en-1-ol in the first step.

[0069] Intermediate 2 (R)-9-Bromo-3-vinyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine

[0070] MS m / z(ESI):255&257[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.48(s,1H),8.16(s,1H),5.80-5.72(m,1H),5.33-5.18(m,2H),4.45-4.42(m,1H),4.05-3.93(m,2H),3.80-3.70(m,2H).

[0071] Intermediate 3 (S)-9-Bromo-3-vinyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine

[0072] MS m / z(ESI):255&257[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.48(s,1H),8.16(s,1H),5.80-5.72(m,1H),5.33-5.18(m,2H),4.45-4.42(m,1H),4.05-3.93(m,2H),3.80-3.70(m,2H).

[0073] Intermediate 4 (R)-9-Chloro-8-methyl-3-vinyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine first step (4,5-dichloro-6-methylpyridin-3-yl)methanol 4-1 The compound 4,5-dichloro-6-methylnicotinic acid methyl ester (synthesis reference: WO2010098344 A1) (0.44 g, 2.00 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0°C in an ice-water bath, and diisobutylaluminum hydride (1M hexane solution, 6.00 mL, 6.00 mmol) was added under nitrogen protection, and reacted at room temperature for 0.5 hours. Water (25 mL) was added to quench the reaction, and it was extracted with ethyl acetate (25 mL×3). The combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude target product (4,5-dichloro-6-methylpyridin-3-yl)methanol 4-1 (0.35 g, yellow liquid). The product did not need to be purified and was used directly in the next step.

[0074] MS m / z(ESI): 192,194&196[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.38(s,1H),4.74(s,2H),2.61(s,3H). Step 2 4,5-Dichloro-6-methylnicotinaldehyde 4-2 The compound (4,5-dichloro-6-methylpyridin-3-yl)methanol 4-1 (0.35 g, 1.79 mmol) was dissolved in anhydrous dichloromethane (10 mL), and active manganese dioxide (0.44 g, 5.00 mmol) was added under nitrogen protection, and the reaction was carried out at room temperature for 1 hour. The reaction solution was filtered using diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude target product 4,5-dichloro-6-methylnicotinaldehyde 4-2 (0.30 g, yellow liquid). The product did not need to be purified and was used directly in the next step.

[0075] MS m / z(ESI):190,192&194[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ10.36(s,1H),8.75(s,1H),2.69(s,3H). Step 3 (R)-9-Chloro-8-methyl-3-vinyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine The synthesis steps of intermediate 4 refer to intermediate 1, wherein in the first step, 4,5-dichloro-6-methylnicotinaldehyde 4-2 is used instead of 5-bromo-4-chloronicotinaldehyde, and (R)-2-aminobut-3-en-1-ol (synthesis reference: WO2014022752 A1) is used instead of (R)-2-aminopent-4-en-1-ol.

[0076] MS m / z(ESI):225&227[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ7.98(s,1H),5.77-5.73(m,1H),5.29-5.20(m,2H),4.73-4.47(m,1H),4.04-3.94(m,2H),3.82-3.70(m,2H),2.51(s,3H).

[0077] Intermediate 5 9-Fluoro-3-vinyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine

[0078] MS m / z(ESI):195[M+1]; 1 H NMR (400 MHz, CDCl 3)δ8.33-8.29(m,1H),8.14(s,1H),5.96-5.75(m,1H),5.47-5.18(m,2H),4.50(m,1H),4.08(m,2H),3.91-3.73(m,2H).

[0079] Intermediate 6 (R)-7,9-Difluoro-3-vinyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylic acid tert-butyl ester first step (R)-2,4-difluoro-6-(((1-hydroxybut-3-en-2-yl)amino)methyl)phenol 6-1 Compound 3,5-difluoro-2-hydroxybenzaldehyde (0.96 g, 6.00 mmol), (R)-2-aminobut-3-ene-1-ol hydrochloride (1.24 g, 10.00 mmol, synthesis reference: WO2014022752 A1) and triethylamine (2.5 g, 25.00 mmol) were added to anhydrous 1.2-dichloroethane (15 mL) in sequence and stirred at room temperature for 1 hour under nitrogen protection. Acetic acid (1.80 g, 30.00 mmol) and sodium cyanoborohydride (0.95 g, 15.00 mmol) were added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution (20 mL) was added to quench, extracted with dichloromethane (25 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered to remove the desiccant. The reaction mixture was concentrated under reduced pressure to give the target product (R)-2,4-difluoro-6-(((1-hydroxybut-3-en-2-yl)amino)methyl)phenol 6-1 (1.30 g, light yellow liquid, crude product). The product did not need to be purified and was used directly in the next step. MS m / z (ESI): 230 [M+1]; Step 2 (R)-tert-butyl (3,5-difluoro-2-hydroxybenzyl)(1-hydroxybut-3-en-2-yl)carbamate Compound (R)-2,4-difluoro-6-(((1-hydroxybut-3-en-2-yl)amino)methyl)phenol 6-1 (1.30 g, 5.68 mmol), di-tert-butyl dicarbonate (4.36 g, 20.00 mmol), sodium hydroxide (0.80 g, 20.00 mmol) were dissolved in water (10 mL) and ethyl acetate (15 mL) in turn, and stirred at room temperature for 3 hours. Ethyl acetate (25 mL×3) was used for extraction, and the combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain the target product (R)-(3,5-difluoro-2-hydroxybenzyl)(1-hydroxybut-3-en-2-yl)carbamic acid tert-butyl ester 6-2 (0.85 g, light yellow liquid), with a yield of 44%.

[0080] MS m / z(ESI):330[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ6.77-6.71(m,1H),6.64-6.60(m,1H),5.77-5.72(m,1H),5.18-5.14(m,1H),5.08 -5.03(m,1H),4.43-4.40(m,1H),4.26-4.21(m,2H),3.75-3.71(m,2H),1.41(s,9H). Step 3 (R)-7,9-difluoro-3-vinyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylic acid tert-butyl ester Compound (R)-(3,5-difluoro-2-hydroxybenzyl)(1-hydroxybut-3-en-2-yl)carbamic acid tert-butyl ester 6-2 (0.33 g, 1.00 mmol) and triphenylphosphine (0.42 g, 1.60 mmol) were dissolved in anhydrous dichloromethane (10 mL). Diisopropyl azodicarboxylate (0.40 g, 2.00 mmol) was added dropwise to the reaction solution under nitrogen protection. Stir at room temperature for 3 hours, add water (25 mL) to quench the reaction, and extract with dichloromethane (25 mL × 3). The combined organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the target product (R)-7,9-difluoro-3-vinyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylic acid tert-butyl ester 6 (0.22 g, yellow liquid) with a yield of 71%.

[0081] MS m / z(ESI):312[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ6.69-6.61(m,2H),5.79-5.74(m,1H),5.32-5.28(m,2H),5.08-5.03(m,1H),4.43-4.40(m,2H),4.18-4.12(m,2H),1.41(s,9H).

[0082] The synthetic steps of Intermediate 7-8 refer to Intermediate 6, wherein different aldehydes are used in place of 3,5-difluoro-2-hydroxybenzaldehyde in the first step.

[0083] Intermediate 7 (R)-tert-Butyl 9-fluoro-3-vinyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

[0084] MS m / z(ESI):354&356[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ7.42(d,J=7.8Hz,1H),7.10-7.07(m,1H),6.86-6.82(m,1H),5.94-5.88(m,1H),5.37-5.35(m,2H),5.09-4.10(m,5H),1.40(s,9H).

[0085] Intermediate 8 (R)-tert-Butyl 9-bromo-7-fluoro-3-vinyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

[0086] MS m / z(ESI):372[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ7.15-7.05(m,1H),6.85-6.75(m,1H),5.92-5.69(m,1H),5.44-5.20(m,2H),4.99-4.90(m,1H),4.78-3.88(m,4H),1.35(s,9H).

[0087] Intermediate 9 2-(2,2-Difluoroethyl)pent-4-enoic acid Dissolve pentyl-4-enoic acid (2.00 g, 20 mmol) in anhydrous tetrahydrofuran (20 mL), cool the reaction solution to -78 ° C with a dry ice ethanol bath under nitrogen protection, slowly add lithium diisopropylamide (2M tetrahydrofuran / n-hexane solution, 22 mL, 44.0 mmol), and slowly warm to room temperature for 1.5 hours after the addition. Use a dry ice ethanol bath to cool to -78 ° C again, and slowly add 2,2-difluoroethyl trifluoromethanesulfonic anhydride (5.14 g, 24 mmol). React at this temperature for 1 hour, then slowly warm to room temperature and continue to react for 2 hours. Add saturated aqueous ammonium chloride solution (20 mL) to quench, and extract with ethyl acetate (25 mL x2). The aqueous phase was adjusted to pH <2 with 4M dilute hydrochloric acid aqueous solution, extracted with ethyl acetate (25mL x 3), and the combined organic phase was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound 2-(2,2-difluoroethyl)but-3-enoic acid (1.42g, yellow oil, crude product). The product did not need to be purified and was used directly in the next step.

[0088] MS m / z(ESI):163[M-1]; 1 H NMR (400 MHz, CDCl 3 )δ6.08-5.71(m,2H),5.16-5.12(m,2H),2.77-2.74(m,1H),2.50-2.45(m,1H),2.41-2.30(m,1H),2.28-2.21(m,1H),2.03-1.98(m,1H).

[0089] Example 1 (6aR)-10-methyl-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile (the compound is monochiral, but the chirality of the methyl group is uncertain); first step 1-((R)-3-Allyl-9-bromo-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)-2-methylbut-3-en-1-one 1-1 Dissolve 2-methylbut-3-enoic acid (0.11 g, 1.10 mmol) in anhydrous dichloromethane (5 mL), cool to 0°C in an ice-water bath, slowly add 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.17 g, 1.4 mmol) under nitrogen protection, and react at room temperature for 1 hour. The above reaction solution was added to a dichloromethane (5 mL) solution of (R)-3-allyl-9-bromo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine (Intermediate 1) (0.27 g, 1.00 mmol) and triethylamine (0.20 g, 2.00 mmol) at 0°C, and reacted at room temperature for 3.5 hours. Dichloromethane (25 mL) was added to dilute, and the organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to give the target compound 1-((R)-3-allyl-9-bromo-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)-2-methylbut-3-en-1-one 1-1 (0.16 g, light yellow oil) in a yield of 45%. MS m / z (ESI): 351 & 353 [M+1]. Step 2 (6aR)-4-bromo-10-methyl-6,6a,7,10-tetrahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one 1-2 1-((R)-3-allyl-9-bromo-2,3-dihydropyrido[3,4-f][1,4]oxazepine-4(5H)-yl)-2-methylbut-3-en-1-one 1-1 (0.16 g, 0.45 mmol) was dissolved in dichloromethane (10 mL), and a hydrochloric acid dioxane solution (4M, 0.46 mL, 1.84 mmol) was added, and stirred at room temperature for 10 minutes. The solvent and excess hydrochloric acid were removed by rotary evaporation under reduced pressure, and the residue was dissolved in anhydrous dichloromethane (30 mL), and 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinyl) (dichlorobenzylidene) (tricyclohexylphosphine) ruthenium (77 mg, 0.09 mmol) was added. The reaction was carried out at 40°C for 2.5 hours under nitrogen protection. The reaction was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target compound (6aR)-4-bromo-10-methyl-6,6a,7,10-tetrahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one 1-2a (40 mg, yellow oil, yield 27%, second peak, the compound is single chiral, but the chirality of the methyl group is uncertain);

[0090] MS m / z(ESI):323&325[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.52(s,1H),8.28(s,1H),5.75-5.71(m,1H),5.64-5.61(m,1H),5.30-5.27(m,1H),4.67- 4.58(m,3H),4.52-4.48(m,1H),3.45-3.41(m,1H),2.30-2.13(m,2H),1.46(d,J=7.2Hz,3H). (6aR)-4-Bromo-10-methyl-6,6a,7,10-tetrahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one 1-2b (30 mg, yellow oil, yield 20%, first peak, the compound is monochiral, but the chirality of the methyl group is uncertain).

[0091] MS m / z(ESI):323&325[M+1]; 1 H NMR (400 MHz, CDCl 3)δ8.48(s,1H),8.26(s,1H),5.61-5.57(m,1H),5.46-5.42(m,1H),5.37-5.33(m,1H),5.00-4.95(m,1 H),4.63-4.58(m,1H),4.48-4.44(m,2H),3.79-3.76(m,1H),2.26-2.22(m,2H),1.25(d,J=7.2Hz,3H). Step 3 (6aR)-10-methyl-11-carbonyl-6a,7,10,11-tetrahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 1-3 (the compound is monochiral, but the chirality of the methyl group is uncertain) (6aR)-4-bromo-10-methyl-6,6a,7,10-tetrahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one 1-2a (40 mg, 0.12 mmol) and anhydrous N,N-dimethylformamide (4 mL) were added to the sealed tube, followed by zinc cyanide (0.14 g, 1.20 mmol), bistriphenylphosphinoferrocene (28 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium (21 mg, 0.02 mmol), and the mixture was reacted at 120°C for 4.5 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (30 mL), and the organic phase was washed with saturated brine (20 mL x 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to give the target compound (6aR)-10-methyl-11-carbonyl-6a,7,10,11-tetrahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 1-3a (15 mg, yellow oil, yield 46%, the compound is monochiral, but the chirality of the methyl group is uncertain).

[0092] MS m / z(ESI):270[M+1]; 1 H NMR (400 MHz, CDCl 3)δ8.60(s,1H),8.53(s,1H),5.76-5.71(m,1H),5.67-5.65(m,1H),5.35-5.31(m,1H),4.77-4.69(m,2 H),4.58-4.52(m,2H),3.48-3.42(m,1H),2.30-2.26(m,1H),2.20-2.15(m,1H),1.47(d,J=7.2Hz,3H). Step 4 (6aR)-10-methyl-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 1 (the compound is monochiral, but the chirality of the methyl group is uncertain) Dissolve (6aR)-10-methyl-11-carbonyl-6a,7,10,11-tetrahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 1-3a (15 mg, 0.05 mmol) in methanol (5 mL), add palladium carbon (5% supported on activated carbon, 10 mg). Vacuum and replace hydrogen three times, and react at room temperature for 1 hour under a hydrogen balloon (1 atmosphere). Filter to remove palladium carbon, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to give the target compound (6aR)-10-methyl-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 1a (10.5 mg, white solid, yield 84%, the compound is monochiral, but the chirality of the methyl group is uncertain).

[0093] MS m / z(ESI):272[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.59(s,1H),8.52(s,1H),5.18-5.14(m,1H),4.65-4.59(m,2H),4.55-4.51(m,1H),4.38-4.35(m,1 H),2.96-2.91(m,1H),1.97-1.83(m,2H),1.72-1.62(m,3H),1.47-1.42(m,1H),1.27(d,J=7.2Hz,3H).

[0094] Example 2 (6aR)-10-methyl-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile (the compound is monochiral, but the chirality of the methyl group is uncertain) Referring to the third and fourth steps in Example 1, the raw material 1-2a was replaced by 1-2b to obtain the target compound (6aR)-10-methyl-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 2 (the compound is single chiral, but the chirality of the methyl group is uncertain).

[0095] MS m / z(ESI):272[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.57(s,1H),8.49(s,1H),5.50-5.46(m,1H),4.75-4.68(m,1H),4.49-4.44(m,3H),2.82- 2.79(m,1H),2.00-1.93(m,1H),1.80-1.73(m,3H),1.47-1.39(m,2H),1.15(d,J=7.2Hz,3H).

[0096] Example 3 (6aR)-10-(2,2-difluoroethyl)-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile (the compound is monochiral, but the chirality of the difluoroethyl group is uncertain) first step (6aR)-4-bromo-10-(2,2-difluoroethyl)-6,6a,9,10-tetrahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one 3-1 Referring to the first and second steps of Example 1, the raw material 2-methylbut-3-enoic acid was replaced with 2-(2,2-difluoroethyl)pent-4-enoic acid (Intermediate 9), and (R)-3-allyl-9-bromo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine (Intermediate 1) was replaced with (R)-9-bromo-3-vinyl-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine Zhuo (Intermediate 2) to obtain the target compound (6aR)-4-bromo-10-(2,2-difluoroethyl)-6,6a,9,10-tetrahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one 3-1a (preparative thin layer chromatography (petroleum ether:ethyl acetate=3:1), the second peak, the compound is single chiral, but the chirality of the difluoroethyl group is uncertain);

[0097] MS m / z(ESI):373[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.49(s,1H),8.23(s,1H),6.10-5.79(m,2H),5.63-5.58(m,1H),5.45-5.28(m,2H),4.79 -4.56(m,3H),3.55-3.46(m,1H),2.56-2.42(m,2H),2.28-2.18(m,1H),1.87-1.71(m,1H). (6aR)-10-(2,2-difluoroethyl)-11-carbonyl-6a,7,10,11-tetrahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 3-1b (preparative thin layer chromatography (petroleum ether:ethyl acetate=3:1), the first peak, the compound has a single chirality, but the chirality of the difluoroethyl group is uncertain).

[0098] MS m / z(ESI):373[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.61(s,1H),8.44(s,1H),6.12-6.06(m,1H),6.03-5.72(m,1H),5.65-5.61(m,1H),5.34-5.30(m,1H),4.67 -4.61(m,2H),3.99-3.95(m,1H),3.87-3.81(m,1H),2.54-2.38(m,3H),2.27-2.19(m,1H),1.87-1.71(m,1H). Step 2 (6aR)-10-(2,2-difluoroethyl)-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 3 (the compound is monochiral, but the chirality of the difluoroethyl group is uncertain) Referring to Example 1, (6aR)-4-bromo-10-methyl-6,6a,7,10-tetrahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one 1-2a was replaced with (6aR)-4-bromo-10-(2,2-difluoroethyl)-6,6a,9,10-tetrahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one The target compound (6aR)-10-(2,2-difluoroethyl)-11-carbonyl-6a,7,10,11-tetrahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-4-carbonitrile 3 was obtained by purifying the product with the oxadifluoroethyl group and the oxadifluoroethyl group.

[0099] MS m / z(ESI):322[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.60(s,1H),8.49(s,1H),6.07-5.75(m,1H),5.45-5.42(m,1H),4.73-4.67(m,1H),4.55-4.43(m, 3H),2.97-2.91(m,1H),2.52-2.39(m,1H),2.01-1.96(m,1H),1.89-1.74(m,4H),1.55-1.35(m,2H).

[0100] Example 4 (6aR)-10-(2,2-difluoroethyl)-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile (the compound is monochiral, but the chirality of the difluoroethyl group is uncertain) Referring to Example 3, the raw material 3-1a was replaced with 3-1b to obtain the target compound (6aR)-10-(2,2-difluoroethyl)-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile 4 (the compound is single chirality, but the chirality of the difluoroethyl group is uncertain).

[0101] MS m / z(ESI):322[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.62(s,1H),8.55(s,1H),6.02-5.72(m,1H),4.93-4.78(m,2H),4.58-4.46(m, 2H),4.32-4.23(m,1H),3.00-2.93(m,1H),2.33-2.22(m,1H),2.09-1.55(m,7H).

[0102] The synthetic steps of Examples 5 to 16 refer to the process of Example 1.

[0103] Example 5 (R)-11-Oxo-6a,7,8,9-tetrahydro-6H,11H,13H-spiro[azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-10,1'-cyclopropane]-4-carbonitrile

[0104] MS m / z(ESI):284[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.56(s,1H),8.49(s,1H),5.26-5.15(m,1H),4.85-4.39(m,4H),2.19-2.05(m,1H),1.96-1.83(m, 1H),1.80-1.63(m,2H),1.50-1.39(m,2H),1.22-1.11(m,1H),0.90-0.73(m,2H),0.59-0.44(m,1H).

[0105] Example 6 (R)-10,10-Dimethyl-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile

[0106] MS m / z(ESI):286[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.58(s,1H),8.49(s,1H),5.37-5.33(m,1H),4.75-4.71(m,1H),4.55-4.50(m,3H) ,1.97-1.93(m,1H),1.78-1.74(m,1H),1.68-1.60(m,4H),1.38(s,3H),1.32(s,3H).

[0107] Example 7 (S)-10,10-Dimethyl-11-carbonyl-6a,7,8,9,10,11-hexahydro-6H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-4-carbonitrile

[0108] MS m / z(ESI):286[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.58(s,1H),8.48(s,1H),5.47-5.28(m,1H),4.87-4.66(m,1H),4.60-4.45(m,3H) ,1.95-1.82(m,1H),1.80-1.68(m,1H),1.66-1.54(m,4H),1.38(s,3H),1.32(s,3H).

[0109] Example 8 (R)-11-Carbonyl-6a,7,8,9,11,13-hexahydro-6H-spiro[azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-10,1'-cyclobutane]-4-carbonitrile

[0110] MS m / z(ESI):298[M+1]; 1 H NMR (400 MHz, CDCl 3)δ8.58(s,1H),8.50(s,1H),5.48-5.39(m,1H),4.67-4.58(m,1H),4.50-4.39(m,2H),4.13-4.09(m,1H),2.94 -2.85(m,1H),2.38-2.26(m,1H),2.27-2.17(m,1H),2.07-1.83(m,5H),1.83-1.70(m,2H),1.32-1.26(m,2H).

[0111] Example 9 (R)-3',3'-difluoro-11-carbonyl-6a,7,8,9,11,13-hexahydro-6H-spiro[azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-10,1'-cyclobutane]-4-carbonitrile

[0112] MS m / z(ESI):334[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.60(s,1H),8.50(s,1H),5.42(d,J=16.4Hz,1H),4.71-4.65(m,1H),4.60-4.42(m,2H),4.06-3.97(m,1H),3. 61-3.39(m,1H),2.94-2.84(m,1H),2.76-2.66(m,1H),2.34-2.24(m,1H),2.00-1.70(m,4H),1.43-1.26(m,2H).

[0113] Example 10 (R)-11-Oxo-6a,7,8,9-tetrahydro-6H,11H,13H-spiro[azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-10,1'-cyclohexane]-4-carbonitrile

[0114] MS m / z(ESI):326[M+1]; 1 H NMR (400 MHz, CDCl 3)δ8.57(s,1H),8.48(s,1H),5.48-5.44(m,1H),4.72-4.69(m,1H),4.59-4.52(m, 3H),2.52-2.40(m,4H),2.23-2.17(m,4H),1.84-1.78(m,4H),1.49-1.39(m,4H).

[0115] Embodiment 11 (R)-11-Carbonyl-2',3',5',6a,6',7,8,9-octahydro-6H,11H,13H-spiro[azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-10,4'-pyran]-4-carbonitrile

[0116] MS m / z(ESI):328[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.50(s,1H),8.42(s,1H),5.38-5.34(m,1H),4.65-4.62(m,1H),4.49-4.44(m,3H),3.89-3.85(m, 1H),3.66-3.62(m,1H),3.54-3.51(m,2H),2.37-2.32(m,1H),1.88-1.73(m,3H),1.50-1.30(m,6H).

[0117] Example 12 (R)-3-Methyl-11-carbonyl-6a,7,8,9-tetrahydro-6H,11H,13H-spiro[azepino[2,1-c]pyrido[3,4-f][1,4]oxazepine-10,1'-cyclopropane]-4-carbonitrile

[0118] MS m / z(ESI):298[M+1]; 1 H NMR (400 MHz, CDCl 3)δ8.26(s,1H),5.09-5.04(m,1H),4.68-4.60(m,2H),4.50-4.42(m,2H),2.58(s,3H),2.04-2.00(m,1H),1.86 -1.80(m,1H),1.74-1.70(m,2H),1.48-1.42(m,2H),1.19-1.15(m,1H),0.86-0.81(m,2H),0.53-0.50(m,1H).

[0119] Example 13 (R)-4-Fluoro-10,10-dimethyl-6,6a,7,8,9,10-hexahydro-11H,13H-azepino[2,1-c]pyrido[3,4-f][1,4]oxazepin-11-one

[0120] MS m / z(ESI):279[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ8.26-8.23(m,1H),8.14(s,1H),5.37(d,J=16.2Hz,1H),4.70-4.53(m,1H),4.51- 4.35(m,3H),1.92-1.81(m,1H),1.77-1.67(m,1H),1.65-1.51(m,4H),1.27(s,6H).

[0121] Embodiment 14 (R)-2,4-Difluoro-6a,7,8,9-tetrahydro-6H,11H,13H-spiro[azepino[2,1-c]benzo[f][1,4]oxazepin-10,1'-cyclopropane]-11-one first step (R)-7,9-Difluoro-3-vinyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride 14a Tert-butyl ((R)-7,9-difluoro-3-vinyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (Intermediate 7) (0.22 g, 0.70 mmol) was dissolved in methanol (5 mL), and a dioxane hydrochloride solution (4 M, 4 mL) was added. The mixture was stirred at room temperature for 3 hours under nitrogen protection. The mixture was concentrated under reduced pressure to give the target product (R)-7,9-difluoro-3-vinyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride 14a (0.14 g, white solid, crude product), which was used directly in the next step without purification. MS m / z (ESI): 212 [M+1]; Step 2 (R)-2,4-difluoro-6a,7,8,9-tetrahydro-6H,11H,13H-spiro[azepino[2,1-c]benzo[f][1,4]oxazepin-10,1'-cyclopropane]-11-one 14 Referring to the synthetic steps of Example 1, 2-methylbut-3-enoic acid was replaced with 1-allylcyclopropane-1-carboxylic acid, and (R)-3-allyl-9-bromo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine was replaced with (R)-7,9-difluoro-3-vinyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride to obtain the target product (R)-2,4-difluoro-6a,7,8,9-tetrahydro-6H,11H,13H-spiro[azepino[2,1-c]benzo[f][1,4]oxazepine-10,1'-cyclopropane]-11-one 14.

[0122] MS m / z(ESI):294[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ6.76-6.70(m,2H),5.13-5.09(m,1H),4.64-4.57(m,1H),4.53-4.49(m,1H),4.49-4.45(m,1H),4.36-4.31(m,1H) ,1.86-1.80(m,2H),1.69-1.62(m,2H),1.58-1.52(m,2H),1.25-1.19(m,1H),0.91-0.86(m,2H),0.53-0.50(m,1H).

[0123] The synthetic steps of Examples 15-16 refer to Example 14, except that ((R)-7,9-difluoro-3-vinyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylic acid tert-butyl ester was replaced with the corresponding intermediate.

[0124] Embodiment 15 (R)-2-Fluoro-11-carbonyl-6a,7,8,9-tetrahydro-6H,11H,13H-spiro[azepino[2,1-c]benzo[f][1,4]oxazepine-10,1'-cyclopropane]-4-carbonitrile

[0125] MS m / z(ESI):301[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ7.11-6.97(m,2H),5.05-5.01(m,1H),4.62-4.56(m,1H),4.51-4.43(m,2H),4.35-4.30(m,1H),2.05-1.98(m,1H) ,1.79-1.74(m,1H),1.73-1.59(m,2H),1.44-1.32(m,2H),1.17-1.08(m,1H),0.78-0.73(m,2H),0.48-0.39(m,1H).

[0126] Example 16 (R)-11-Carbonyl-6a,7,8,9-tetrahydro-6H,11H,13H-spiro[azepino[2,1-c]benzo[f][1,4]oxazepine-10,1'-cyclopropane]-4-carbonitrile

[0127] MS m / z(ESI):283[M+1]; 1 H NMR (400 MHz, CDCl 3 )δ7.42-7.36(m,2H),6.96-6.92(m,1H),5.17-5.13(m,1H),4.65-4.62(m,1H),4.61-4.54(m,2H),4.43-4.39(m,1H) ,2.10-2.01(m,1H),1.84-1.70(m,3H),1.46-1.40(m,2H),1.20-1.15(m,1H),0.85-0.81(m,2H),0.52-0.49(m,1H). Biological experiments

[0128] Example 1: RIPK1 kinase inhibitory activity detection experimental method: This experiment uses the ADP-Glo ​​kinase activity detection method to test the inhibitory effect of the compound on RIPK1 kinase activity and obtain the half inhibitory concentration IC of the compound on RIPK1 kinase activity50 First, dilute the enzyme reaction buffer. Dilute the enzyme reaction buffer stock solution (5x) in the ADP-Glo ​​Kinase Assay Kit purchased from Promega with deionized water, and add a final concentration of 1 mM DTT and 5 mM MnCl 2 The compound was serially diluted 4-fold with DMSO and then diluted 40-fold with enzyme reaction buffer; recombinant human RIPK1 protein was purchased from SignalChem, and monkey RIPK1 recombinant protein was purchased from Abcam. 4 μL of compound solution and 2 μL of RIPK1 kinase solution diluted with reaction buffer were added to the 384-well plate. The final concentrations of human and monkey RIPK1 were 1 ng / μL and 4 ng / mL, respectively. After mixing well, the plate was incubated at room temperature for 30 minutes. Then, 2 μL of ATP solution diluted with reaction buffer was added. After incubation at room temperature for 2 hours, 5 μL of ADP-Glo ​​was added to each well, and the plate was incubated at room temperature for another 40 minutes. Finally, 10 μL of enzyme detection reagent in the kit was added to each well, and the plate was incubated at room temperature for another 30 minutes. The chemiluminescent signal of each well was detected using an Envision multi-function microplate reader (Perkin Elmer, Waltham, MA).

[0129] Example 2: Experimental study on TNF-α-induced p-RIPK1 activation in different species Experimental method: This experiment used the ultrasensitive electrochemiluminescence method of MesoScale Discovery (MSD) to test the inhibitory effect of the compound on the p-RIPK1 level and to obtain the half inhibitory concentration IC of the compound on the p-RIPK1 level. 50 . Peripheral blood mononuclear cells (PBMC) of healthy human and cynomolgus monkey were purchased from Shanghai Aoneng Biotechnology Co., Ltd. Rat and mouse bone marrow cells (BMDM) were isolated from the femur and tibia of rats or mice. The compound was diluted 5-fold to 8 concentration points, with the highest final concentration of 5000nM. 0.5-1×10 5 The cells were cultured in plates derived from PBMC or BMDM, and then TNF-α, Z-VAD-FMK, and SM-164 were added, respectively, and placed at 37°C, 5% CO 2 The cells were incubated in an incubator for 3 hours, and DMSO treatment was used as a control. The cells were then washed with PBS and added with cell lysis buffer, lysed on ice for 30 minutes, and then transferred to a centrifuge tube and centrifuged at 12,000 rpm for 10 minutes. After centrifugation, the cell lysate was collected and protein quantification was performed using the BCA method.

[0130] The p-RIPK level in the cell lysate was determined using the Meso Scale Discovery (MSD) method. The biotinylated RIPK1 capture antibody was diluted in PBS and added to a 96-well streptavidin plate from MSD at 4°C overnight. The plate was blocked with MSD's blocking buffer for 2 hours, and then incubated with 20-40 μL of lysis buffer at room temperature for 2 hours. Phospho-RIPK1antibody (Cell Signaling #31122) was diluted in the blocking buffer and added as the detection antibody, and incubated at room temperature for 1 hour; SULFO-labeled goat anti-rabbit antibody (MSD, R32AB-1) was diluted 500-1000 times in the blocking buffer, and continued to incubate at room temperature for 45 minutes, and then 100 μL of twice-diluted detection buffer (R92TC-3) was added. After incubation, the electrochemical signal was read on the MSD MesoSector Imager S600.

[0131] The results of enzyme activity detection are shown in Table 1 Table 1: Enzyme activity test results of RIPK1 (reference compound is Example 29 in US11203600B2 patent) Compound No. <![CDATA[RIPK1 Monkey_IC 50 (nM)]]> <![CDATA[RIPK1 Human_IC 50 (nM)]]> 1 17 42 3 19 37 5 7.3 11.2 6 13.5 16 19 20 Example 29 (US11203600 B2) 188 78 The structure of compound 29 in US11203600B2 is as follows:

[0132] From the data in Table 1, the activity of the compound of this patent is significantly improved compared with Example 29 (US11203600B2).

[0133] Example 3: Programmed necrosis of I2.1 cells I2.1 cells are Jurkat cells with FADD gene knockout, which are suitable for studying programmed cell necrosis under TNF-α-induced conditions. Experimental method: I2.1 cells (purchased from ATCC, catalog number CRL-2572; cultured at 37°C with 5% CO 2 The cells were incubated in a cell culture incubator in 1640 culture medium and plated on a 384-well white plate. The compounds were diluted 4-fold in a gradient series with a final starting concentration of 500 nM. 40 ng / mL of TNF-α and the test drugs were incubated with the cells for 24 hours, wherein Example 29 (US11203600B2) was used as a positive control, and DMSO (D5879-500ML, purchased from Sigma) was used as the control well. The cell viability was determined using the Cell-TiterGlo kit based on the change in ATP content. The cell viability was determined, and the value represented the percentage of cell viability in the drug-treated wells compared to the control wells, where the higher the value, the stronger the cell viability (drug action viability calculation = drug-treated wells / control wells*100%).

[0134] Example 4: Programmed necrosis of HT-29 cells Experimental method: HT-29 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP30001L) were cultured at 37°C with 5% CO 2 The cells were plated in a 384-well white plate in a cell culture incubator with 1640 culture medium. The compounds were diluted 4-fold in a series with a final starting concentration of 500 nM. 100 ng / mL TNF-α, Q-VD-Oph (10 μM), SM-164 (1 μM) and the test drugs were incubated with the cells for 48 hours. Example 29 (US11203600B2) was used as a positive control, and DMSO was used in the control wells.

[0135] The cell viability was determined using the Cell-TiterGlo kit based on ATP viability assay. For cell viability assay, the value represents the percentage of cell viability in the drug-treated wells compared to the control wells, where the higher the value, the stronger the cell viability (drug action activity calculation = drug-treated wells / control wells*100%).

[0136] Example 5: Programmed necrosis of L-929 cells Experimental method: L-929 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60878) were cultured at 37°C with 5% CO 2 The cells were incubated in a cell culture box in MEM medium and plated on a 384-well white plate. The compound was diluted 4-fold in a gradient series, and the final starting concentration was 10000nM. 40ng / mL TNFα, Q-VD-Oph (10μM) and the test drug were incubated with the cells for 24 hours. Example 29 was used as a positive control, and DMSO was used for the control wells. The cell viability was determined using the Cell-TiterGlo kit based on ATP viability assay. For the cell viability assay, the value represents the percentage of cell viability in the drug-treated wells compared to the control wells, where the higher the value, the stronger the cell viability (drug action activity calculation = drug-treated well / control well*100%).

[0137] The results of the cell experiments are shown in Table 2 Table 2: Cellular activity detection results of RIPK1

[0138] The data in Table 2 further show that some compounds of the present invention still maintain high inhibitory activity in rodent L929 cells, and their HT29 and I2.1 activities are better than those of Example 29 (US11203600B2).

[0139] From the above experimental results, it can be seen that the example compounds of the present invention can effectively inhibit the activity of RIPK1. They can be used to treat or prevent related diseases and dysfunctions mediated by RIPK1, especially central nervous system diseases, such as rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc.

[0140] It is obvious to those skilled in the art that the present disclosure is not limited to the above illustrative embodiments, and that it may be embodied in other specific forms without departing from the essential characteristics of the present disclosure. Therefore, it is expected that these embodiments are considered illustrative and non-restrictive in all respects, and that reference should be made to the appended claims rather than to the above embodiments, and that all changes within the equivalent meaning and scope of the claims are included therein.

Claims

1. A compound of formula (I), an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, in: R 1 is selected from fluorine, cyano, alkynyl, wherein the alkynyl is unsubstituted or substituted by one or more R x substituted 5-6 membered heteroaryl, wherein R x Each is independently selected from fluorine, chlorine, cyano, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C1-C4 alkyl, wherein the C3-C6 cycloalkyl and C1-C4 alkyl are unsubstituted or substituted with one to three fluorine or cyano groups; R 2 Selected from hydrogen, fluorine, chlorine, cyano, unsubstituted or C1-C4 alkyl or C3-C6 cycloalkyl substituted by one to three fluorine or cyano groups; X is selected from CR 5 , N, where R 5 Selected from hydrogen, fluorine, chlorine, cyano, unsubstituted or C1-C4 alkyl or C3-C6 cycloalkyl substituted by one to three fluorine or cyano groups; Y is selected from CR 6a R 6b , O, S or NR 6a , where R 6a and R 6b are each independently selected from hydrogen, halogen, C1-C6 alkyl, or R 6a and R 6b They may form together a C3-C8 cycloalkyl group or a 4- to 8-membered heterocyclic group. R 3 , R 4 R is each independently selected from hydrogen, fluorine, chlorine, cyano, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C6-C10 aryl, or 5-6-membered heteroaryl, wherein the C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C6-C10 aryl, and 5-6-membered heteroaryl are unsubstituted or substituted with one to three fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl; or 3 and R 4 They may together form a C3-C8 cycloalkyl or 4- to 8-membered heterocyclic group which is optionally unsubstituted or substituted by one to three substituents selected from fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5-6-membered heteroaryl, C3-C6 cycloalkyl and 4- to 6-membered heterocyclic group. n is selected from 1-2. A is a 6-9 membered lactam heterocyclic ring containing 1-3 heteroatoms selected from N, O and S.

2. The compound according to claim 1, its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt, which has formula (II): R 1 is selected from fluorine, cyano, alkynyl, wherein the alkynyl is unsubstituted or substituted by one or more R x substituted 5-6 membered heteroaryl, wherein R x Each is independently selected from fluorine, chlorine, cyano, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C1-C4 alkyl, wherein the C3-C6 cycloalkyl and C1-C4 alkyl are unsubstituted or substituted with one to three fluorine or cyano groups; R 2 Selected from hydrogen, fluorine, chlorine, cyano, unsubstituted or C1-C4 alkyl or C3-C6 cycloalkyl substituted by one to three fluorine or cyano groups; X is selected from CR 5 , N, where R 5 Selected from hydrogen, fluorine, chlorine, cyano, unsubstituted or C1-C4 alkyl or C3-C6 cycloalkyl substituted by one to three fluorine or cyano groups; R 3 , R 4 R is each independently selected from hydrogen, fluorine, chlorine, cyano, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C6-C10 aryl, or 5-6-membered heteroaryl, wherein the C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C6-C10 aryl, and 5-6-membered heteroaryl are unsubstituted or substituted with one to three fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl; or 3 and R 4 They may together form a C3-C8 cycloalkyl or 4- to 8-membered heterocyclic group which is optionally unsubstituted or substituted by one to three substituents selected from fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5-6-membered heteroaryl, C3-C6 cycloalkyl and 4- to 6-membered heterocyclic group.

3. The compound according to claim 2, its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt, in: R 1 Selected from fluorine, cyano; R 2 Selected from hydrogen, unsubstituted or substituted by one to three fluorine or cyano C1-C3 alkyl or cyclopropane; X is selected from CR 5 , N, where R 5 is selected from hydrogen and fluorine; R 3 , R 4 R is each independently selected from hydrogen, fluorine, chlorine, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C6-C10 aryl, or 5-6-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C6-C10 aryl, and 5-6-membered heteroaryl are unsubstituted or substituted with one to three fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclyl; or 3 and R 4 They may together form a C3-C8 cycloalkyl or 4- to 8-membered heterocyclic group which is optionally unsubstituted or substituted by one to three substituents selected from fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5-6-membered heteroaryl, C3-C6 cycloalkyl and 4- to 6-membered heterocyclic group.

4. The compound according to claim 2, its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt, in: R 1 Selected from fluorine, cyano; R 2 is selected from hydrogen, C1-C2 alkyl which is unsubstituted or substituted by one to three fluorine groups; X is selected from CR 5 , N, where R 5 is selected from hydrogen and fluorine; R 3 , R 4 Each is independently selected from hydrogen, fluorine, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are unsubstituted or substituted by one to three fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C8 aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl or 4 to 6 membered heterocyclyl; or R 3 and R 4 They may together form a C3-C8 cycloalkyl or 4- to 8-membered heterocyclic group which is optionally unsubstituted or substituted by one to three substituents selected from fluorine, chlorine, cyano, amine, C1-C4 alkyl, C1-C4 alkoxy, C6-C10 aryl, 5-6-membered heteroaryl, C3-C6 cycloalkyl and 4- to 6-membered heterocyclic group.

5. The compound according to claim 2, its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt, in: R 1 Selected from fluorine, cyano; R 2 is selected from hydrogen, C1-C2 alkyl; X is selected from CR 5 , N, where R 5 is selected from hydrogen and fluorine; R 3 , R 4 are each independently selected from hydrogen, fluorine, C1-C4 alkyl, wherein the C1-C4 alkyl is unsubstituted or substituted by one to three fluorines; or R 3 and R 4 Together they may form a C3-C6 cycloalkyl group or a 4- to 6-membered heterocyclic group which is optionally unsubstituted or substituted by one to three fluorine groups.

6. The compound according to claim 2, its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt, in: R 1 Selected from fluorine, cyano; R 2 is selected from hydrogen, methyl; X is selected from CR 5 , N, where R 5 is selected from hydrogen and fluorine; R 3 , R 4 are each independently selected from hydrogen, methyl, difluoroethyl; or R 3 and R 4 Can be formed together 7. The compound according to claim 2, its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt, which is selected from:

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

9. Use of the compound according to any one of claims 1 to 7 or its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt in the preparation of a medicament for use as a RIPK1 inhibitor.

10. Use of a compound according to any one of claims 1 to 7 or its isomers, prodrugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts in the preparation of a medicament for treating or preventing related diseases and dysfunctions mediated by RIPK1, wherein the related diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, acute nervous system diseases, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, pancreatic cancer, bacterial infection, hematological malignancies, solid organ malignancies, etc.

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