Benzoxazepine compounds as RIPK1 inhibitors

Abstract

The present invention relates to benzoxazepine 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 receptor-interacting protein kinase-1 (RIPK1) inhibitors. More specifically, the present invention provides novel heterocyclic compounds as RIPK1 inhibitors, pharmaceutical compositions containing such compounds, and methods for treating or preventing RIPK1-mediated related diseases and dysfunctions by using the compounds. 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 signal transduction. RIPK1 is a 76 kDa protein with an N-terminal kinase domain, a C-terminal death domain, and a middle 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 role. On the one hand, it can act as a scaffold to promote the activation of the MAPK and NF-κB signaling pathways, thereby promoting inflammation, cell survival, and inhibiting apoptosis; on the other hand, abnormally regulated RIPK1 activity will cause cell necrosis. RIPK1 is a major regulator of the cellular determinants of NF-κB signal transduction and death responses, and NF-κB signaling responds to a wide range of inflammatory and pro-death stimuli in human diseases (Degterev, A., et.al. Proc. Natl. Acad. Sci. USA, 2019, 116(20), 9714-9722).

[0004] RIPK1 is widely expressed in various cell types, with the highest abundance in adipose, endothelial, and perivascular cell clusters, and is also expressed in immune cell clusters (dendritic cells, macrophages, and T cells). Studies have found that the activation of RIPK1 kinase exists 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 safety concerns in the treatment of central nervous system diseases. RIPK1 inhibitors can safely improve the harmful TNF response 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 deficiencies of TNF antibodies.

[0005] Studies have shown that the RIPK1 small molecule inhibitor Necrostatin-1 (Nec-1), which is known in the art, can effectively block programmed necrosis of cells (Degterev et al. Nat. Chem. Biol. 2005; 1: 112-119.), and has shown effective therapeutic effects in various inflammatory diseases. DNL-758 (SAR443122) is being developed for peripheral autoimmune diseases such as moderate to severe subacute or discoid / chronic cutaneous lupus erythematosus and moderate to severe ulcerative colitis in adults. AbbVie has also initiated a study to evaluate the efficacy and safety of ABBV-668 in subjects with moderate to severe ulcerative colitis. Eli Lilly is also conducting a Phase IIa trial of R552 in moderate to severe active rheumatoid arthritis (RA). The brain-penetrating RIPK1 inhibitor DNL-788 is used for amyotrophic lateral sclerosis and so on. These trials have laid the foundation for promoting the clinical application of RIPK1 inhibitors.

[0006] RIPKl inhibitors are of great significance in the art, especially in inhibiting inflammatory diseases (such as Crohn's disease, ulcerative colitis, etc.), sepsis, and acute ischemic injury (such as septicemia, severe Covid-19, acute ischemic brain injury, etc.), tumors, autoimmune 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. et 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), or an optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from a 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, or wherein R a is selected from a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, a 4- to 10-membered heterocyclic group containing 1 to 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl, aryl, and heterocyclic group are unsubstituted or substituted with 1 to 3 substituents, and the substituents are each independently selected from a hydroxyl group, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 oxyalkyl, or a 4- to 10-membered heterocyclic group; R 2 is selected from C1-C8 alkyl; R 3 is selected from hydrogen, halogen, or C1-C8 alkyl; X is selected from N or CR b ; wherein R b is selected from hydrogen, halogen, or C1-C8 alkyl; Y is selected from a single bond, O, S, NH, or C(R c R d ), wherein R c and R d are each independently selected from hydrogen, fluorine, or C1-C4 alkyl; Z is selected from C1-C8 alkyl, C3-C8 cycloalkyl, or 6- to 10-membered aryl, wherein the alkyl, cycloalkyl, and aryl are unsubstituted or substituted with 1 to 3 substituents, and the substituents are each independently selected from halogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0009] Preferably, the present invention relates to a compound of formula (I) as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, a 4- to 8-membered heterocyclic group, phenyl, or wherein R aSelected from 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, 4- to 8-membered heterocyclic group containing 1 to 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl, phenyl, and heterocyclic group are unsubstituted or substituted with 1 to 3 substituents, and the substituents are each independently selected from hydroxy, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 oxyalkyl, or 4- to 8-membered heterocyclic group; R 2 Selected from C1-C6 alkyl; R 3 Selected from hydrogen, fluorine, chlorine, bromine, or C1-C6 alkyl; X is selected from N or CR b ; wherein R b Selected from hydrogen, fluorine, chlorine, bromine, or C1-C6 alkyl; Y is selected from a single bond, O, NH, or C(R c R d ), where R c and R d are each independently selected from hydrogen or C1-C4 alkyl; Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 6- to 8-membered aryl, wherein the alkyl, cycloalkyl, and aryl are unsubstituted or substituted with 1 to 3 substituents, and the substituents are each independently selected from fluorine, chlorine, bromine, C1-C4 alkyl, C3-C6 cycloalkyl;

[0010] More preferably, the present invention relates to a compound of formula (I) as described above, or an optical isomer or pharmaceutically acceptable salt thereof, wherein: R 1 Selected from 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, 4- to 6-membered heterocyclic group, phenyl, or wherein R a Selected from 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, 4- to 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl, phenyl, and heterocyclic group are unsubstituted or substituted with 1 to 3 substituents, and the substituents are each independently selected from hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 oxyalkyl, or 4- to 6-membered heterocyclic group; R 2 Selected from C1-C4 alkyl; R 3 Selected from hydrogen, fluorine, chlorine, or C1-C4 alkyl; X is selected from N or CR b ; wherein R b Selected from hydrogen, fluorine, chlorine, or C1-C4 alkyl; Y is selected from a single bond, O, NH, or -CH2-; Z is selected from C1-C4 alkyl, C3-C5 cycloalkyl or phenyl, wherein the alkyl, cycloalkyl and phenyl are unsubstituted or substituted by 1-3 substituents, and the substituents are each independently selected from fluorine, chlorine, methyl, cyclopropyl;

[0011] More preferably, the present invention relates to a compound of formula (I) as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from a 5-6 membered heteroaryl, a 4-6 membered heterocyclic group containing 1-3 heteroatoms of nitrogen and oxygen, or wherein R a is selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen and oxygen, a 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from nitrogen and oxygen, and the heteroaryl and heterocyclic group are unsubstituted or substituted by 1-3 substituents, and the substituents are each independently selected from hydroxyl, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 oxyalkyl or a 4-6 membered heterocyclic group; R 2 is selected from methyl; R 3 is selected from hydrogen or fluorine; X is selected from N or CR b ; wherein R b is selected from hydrogen, fluorine; Y is selected from NH. Z is selected from

[0012] More preferably, the present invention relates to a compound of formula (I) as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from wherein R a is selected from R 2 is selected from methyl; R 3 is selected from hydrogen or fluorine; X is selected from N or CR b ; wherein R b is selected from fluorine; Y is selected from NH; Z is selected from

[0013] Most preferably, the present invention relates to a compound of formula (I) as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, which is selected from:

[0014] The present invention further relates to a pharmaceutical composition, which comprises the compound of formula I or an isomer thereof or a pharmaceutically acceptable salt thereof according to any one of the embodiments of the present invention, optionally one or more other RIPK1 inhibitors, and one or more pharmaceutically acceptable carriers.

[0015] The present invention also relates to the use of the compound of formula I according to any one of the embodiments of the present invention, its optical isomer or its pharmaceutically acceptable salt or the pharmaceutical composition according to the present invention in the preparation of a drug for treating or preventing a RIPK1-mediated disease or disorder or a disease or disorder caused by necroptosis.

[0016] The present invention also relates to the use of the compound of formula I according to any one of the embodiments of the present invention or its optical isomer or its pharmaceutically acceptable salt in the preparation of a drug for treating or preventing RIPK1-mediated related diseases, such as ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, 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, hematological malignancies, solid organ malignancies, etc. Especially rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0017] The present invention also relates to the use of the pharmaceutical composition according to the present invention in the preparation of a drug for treating or preventing RIPK1-mediated related diseases, such as ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, 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, hematological malignancies, solid organ malignancies, etc. Especially rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0018] The present invention also relates to a method for treating or preventing RIPK1-mediated related diseases, which comprises administering to a patient in need a therapeutically effective amount of the compound or its optical isomer or its pharmaceutically acceptable salt described in any one embodiment of the present invention, or the pharmaceutical composition described in the present invention. The related diseases include, for example, ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, 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, hematological malignancies, solid organ malignancies, etc.; especially rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0019] Another aspect of the present invention relates to the compound, or its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt described in any one embodiment of the present invention, which is used for treating or preventing RIPK1-mediated related diseases. The related diseases include, for example, ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, 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, hematological malignancies, solid organ malignancies, etc.; especially rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0020] Another aspect of the present invention relates to a pharmaceutical composition, which comprises the compound of formula I or its optical isomer or its pharmaceutically acceptable salt described in any one 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 for treating or preventing RIPK1-mediated related diseases. The related diseases include, for example, ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, 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, hematological malignancies, solid organ malignancies, etc.; especially rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, etc.

[0021] According to the present invention, the drug can be any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, and injections.

[0022] The pharmaceutical preparation of the present invention can be administered in unit dosage form containing a predetermined amount of the active ingredient per dosage unit. Such units can contain, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, and particularly preferably from 5 mg to 300 mg of the compound of the present invention, depending on the condition to be treated, the method of administration, and the age, weight, and condition of the patient. Or the pharmaceutical preparation can be administered in unit dosage form containing a predetermined amount of the active ingredient per dosage unit. Preferred unit dosage preparations are those containing the active ingredient in the daily dose or divided dose or corresponding fractions as indicated above. In addition, pharmaceutical preparations of this type can be prepared using methods well known in the pharmaceutical art.

[0023] The pharmaceutical preparation of the present invention can be adapted for administration by any desired and suitable method, such as by oral (including buccal or sublingual), rectal, nasal, topical (including oral, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) methods. All methods known in the pharmaceutical art can be used to prepare such preparations, for example, by combining the active ingredient with one or more excipients or one or more adjuvants. Preparation Process

[0024] The present invention also provides a method for preparing the compound.

[0025] Process 1: R 3 With X defined as described above, Z is selected from C1-C8 alkyl, C3-C8 cycloalkyl; The first step: Compound (I) and (II) are dissolved in a solvent (such as tetrahydrofuran or methanol), an acid (such as glacial acetic acid) is added, and the reaction is carried out at 0 °C to room temperature for 0.5 to 2 hours. Then a reducing agent (such as sodium cyanoborohydride) is added, and the reaction is carried out at room temperature for 2 to 12 hours to obtain compound (III); The second step: Compound (III) is dissolved in a solvent (such as water), a base (such as sodium hydroxide or lithium hydroxide, etc.) is added, and the mixture is stirred at a temperature of room temperature to 50 °C for 1 to 5 hours to obtain compound (IV);

[0026] Process 2: R 3 The definitions of, X and Z are as described above; The first step: Under nitrogen protection, compound (V), compound (VI), a base (such as cesium carbonate), a ligand (such as 2 - dicyclohexylphosphino - 2',4',6' - triisopropylbiphenyl), and a catalyst (such as palladium acetate) are added to a solvent (such as dioxane). The system is evacuated and replaced with nitrogen three times, heated to 80 - 120 °C and reacted for 4 - 16 hours to obtain compound (VII); Step 2: Under nitrogen protection, compound (VII), zinc cyanide, a ligand (such as 1,1' - bis(diphenylphosphino)ferrocene), and a catalyst (such as tris(dibenzylideneacetone)dipalladium) are added to a solvent (such as N,N - dimethylacetamide). The system is evacuated and replaced with nitrogen three times, heated to 100 - 120 °C and reacted for 6 - 16 hours to obtain compound (VIII); Step 3: Compound (VIII) is dissolved in a solvent (such as water), a base (such as sodium hydroxide or lithium hydroxide, etc.) is added, and stirred at room temperature for 16 hours to obtain compound (IV);

[0027] Process 3: R 1 、R 2 、R 3 、X and Z are defined as described above; Step 1: Compound (IX) (synthesis reference: Journal of Medicinal Chemistry (2017), 60(4), 1247 - 1261) and bis(pinacolato)diboron are dissolved in a solvent (such as dioxane). Under the protection of an inert gas (such as nitrogen or argon), a catalyst (such as 1,1' - bis(diphenylphosphino)ferrocene dichloropalladium) and a base (such as potassium acetate) are added. The system is evacuated and replaced with nitrogen three times, and reacted at 80 - 100 °C in an oil bath for 3 - 16 hours to obtain compound (X); Step 2: Compound (X) and (XI) are dissolved in dioxane. Under the protection of an inert gas (such as nitrogen or argon), a base (such as sodium carbonate) and a catalyst (such as 1,1' - bis(diphenylphosphino)ferrocene dichloropalladium) are added. The system is evacuated and replaced with nitrogen three times, and reacted at 80 - 100 °C in an oil bath for 3 - 16 hours to obtain compound (XII); Step 3: Compound (XII) is dissolved in a solvent (such as dioxane), an acid (such as hydrochloric acid) is added, and stirred at room temperature for 2 - 3 hours to obtain compound (XIII); Step 4: Dissolve compound (XIII), compound (IV), a condensing agent (such as 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate), and a base (such as triethylamine) in a solvent (such as N,N-dimethylformamide), and stir at room temperature for 2 - 16 hours to obtain compound (XIV);

[0028] Process 4: R a and R 2 and R 3 The definitions of X and Z are as described above; The first step: Dissolve compound (IX) in a solvent (such as dioxane), add an acid (such as hydrochloric acid), and stir at room temperature for 2 - 3 hours to obtain compound (XV); The second step: Dissolve compound (XV), compound (IV), a condensing agent (such as 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate), and a base (such as triethylamine) in a solvent (such as N,N-dimethylformamide), and stir at room temperature for 2 - 16 hours to obtain compound (XVI); The third step: Dissolve compounds (XVI) and (XVII) in a solvent (such as N,N-dimethylformamide), under the protection of an inert gas (such as nitrogen or argon), add a base (such as triethylamine), a catalyst (such as copper iodide), a ligand (such as triphenylphosphine), and a catalyst (such as palladium acetate), evacuate the system and replace it with nitrogen three times, and react at 80 - 100 °C in an oil bath for 4 - 16 hours to obtain compound (XVIII); Detailed implementation mode

[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 commonly represented in the art known to those skilled in the art.

[0030] The expression "Cx-Cy" used in the present invention represents the range of the number of carbon atoms, where both x and y are integers. For example, C3-C8 cycloalkyl represents a cycloalkyl having 3 - 8 carbon atoms, and -C0-C2 alkyl represents an alkyl having 0 - 2 carbon atoms, where -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-chain and branched-chain groups having 1 to 20 carbon atoms, such as straight-chain and branched-chain groups having 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 can 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 "hydroxyalkyl" refers to an alkyl-OH group, that is, a group in which any position of the alkyl group (including straight-chain alkyl and branched-chain alkyl) is substituted by a hydroxyl group, wherein the alkyl group has the meaning defined above.

[0034] In the present invention, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which includes 3 to 20 ring atoms, such as 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 heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but does not include ring moieties of -O-O-, -O-S-, or -S-S-, and the remaining ring atoms are carbon. Preferably, it includes 3 to 12 ring atoms, among which 1 to 4 are heteroatoms, more preferably the heterocyclic group ring contains 3 to 10 ring atoms, more preferably includes 3 to 8 ring atoms, most preferably a 5-membered ring or a 6-membered ring, 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 monocyclic heterocyclic groups include oxetanyl, cyclohexanyl, azetidinyl, morpholinyl, 2-morpholinyl, dihydropyrazolyl, etc. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. The heterocyclic group can be optionally substituted or unsubstituted.

[0035] In the present invention, the term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably, it is 5- to 10-membered. More preferably, the heteroaryl is 5-membered or 6-membered, such as pyrazolyl, imidazolyl, triazolyl, pyridyl, etc. The heteroaryl can be optionally substituted or unsubstituted.

[0036] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0037] In the present invention, "optionally" or "optionally" means that the subsequent described event or circumstance may but does not necessarily occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but does not necessarily exist, and this description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

[0038] The substituents include but are not limited to the various groups described above.

[0039] The compounds claimed in the present invention include not only the compounds themselves, but also the optical isomers or pharmaceutically acceptable salts thereof.

[0040] The "pharmaceutical composition" described in the present invention refers to a mixture containing one or more compounds described in the present invention, or their optical isomers, or their pharmaceutically acceptable salts, and other chemical components. Other components such as pharmaceutically acceptable carriers, diluents and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to organisms, facilitate the absorption of the active ingredient and thus exert biological activity.

[0041] When used in the specification, the term "comprising" includes "consisting of".

[0042] The "room temperature" described in the present invention refers to 15 - 30 °C.

[0043] The "pharmaceutically acceptable salts" described in the present invention are discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 1977, 66, 1 - 19, and are obvious to pharmaceutical chemists. The salts are substantially non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc.

[0044] The pharmaceutically acceptable salts of the present invention can be synthesized by general chemical methods.

[0045] Generally, the preparation of salts can be carried out by reacting a free base or acid with an equi - chemical equivalent or an excess of acid (inorganic acid or organic acid) or base in a suitable solvent or solvent composition.

[0046] The "optical isomers" described in the present invention include mesomers, racemates, enantiomers, diastereoisomers of the compounds of formula (I) of the present invention, and their mixture forms, etc.

[0047] The present invention includes any polymorphs of the compounds or their salts, as well as any hydrates or other solvates.

[0048] In the present invention, the term "patient" generally refers to a mammal, particularly a human.

[0049] In the present invention, the term "therapeutically effective amount" refers to the amount of the compound of the present invention that can effectively treat or prevent related diseases mediated by RIPK1. Examples

[0050] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0051] The structures of all compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and / or mass spectrometry (MS).

[0052] 1 The chemical shift (δ) of 1H NMR is recorded in PPM (parts per million). NMR is performed using a Bruker AVANCE III-400MHz spectrometer. Suitable solvents are selected from chloroform-d (CDCl3), methanol-d (CD3OD), dimethyl sulfoxide-d 6 ) etc., and tetramethylsilane is used as an internal standard (TMS).

[0053] Low-resolution mass spectrometry (MS) is determined using an Agilent 1260HPLC / 6120 mass spectrometer, using an Agilent ZORBAXXDB-C18, 4.6×50mm, 3.5μm.

[0054] Gradient elution condition 1: 0 minute: 95% solvent A1 and 5% solvent B1, 1-2 minutes: 5% solvent A1 and 95% solvent B1; 2.01-2.50 minutes: 95% solvent A1 and 5% solvent B1. The percentages are the volume percentages of a certain solvent in the total solvent volume. Solvent A1: 0.01% formic acid aqueous solution; Solvent B1: acetonitrile solution of 0.01% formic acid; the percentages are the volume percentages of the solute in the solution.

[0055] The thin-layer silica gel plate is the Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses Yantai Huanghai 100-200 or 200-300 mesh silica gel as the carrier.

[0056] Preparative liquid chromatography (prep-HPLC) uses a Waters SQD2 mass spectrometry-guided high-pressure liquid chromatography separation instrument, XBridge-C18; 30X 150mm preparative column, 5μm;

[0057] 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;

[0058] The known starting materials of the present invention can be used or synthesized according to methods known in the art, or can be purchased from companies such as Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Bide Pharmatech, Shanghai Aladdin Chemistry, Shanghai Merck Chemical, J&K Scientific, Energy Chemical, etc.

[0059] Unless otherwise specified in the examples, the solvents used in the reactions are anhydrous solvents. Among them, anhydrous tetrahydrofuran uses commercially available tetrahydrofuran, with sodium chunks as the water remover and benzophenone as the indicator. Under argon protection, it is refluxed until the solution turns blue - violet, then distilled and collected, and stored at room temperature under argon protection. Other anhydrous solvents are purchased from Energy Chemical and J&K Scientific. Unless otherwise specified, the transfer and use of all anhydrous solvents need to be carried out under argon protection.

[0060] Unless otherwise specified in the examples, the reactions are carried out under an argon or nitrogen atmosphere.

[0061] An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0062] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0063] For the hydrogenation reaction, it is usually evacuated, filled with hydrogen, and this operation is repeated 3 times.

[0064] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 15°C - 30°C.

[0065] The progress of the reactions in the examples is monitored by thin - layer chromatography (TLC). The developing agent systems used in the reactions are A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compounds.

[0066] The eluent systems for column chromatography used to purify the compounds and the developing agent systems for thin - layer chromatography include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of triethylamine and acidic or basic reagents can also be added for adjustment.

[0067] The reagents used in the biological experiments 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) purchased from Promega. Preparation of intermediates

[0068] Intermediate 1 2,4-Difluoro-5-(isopropylamino)benzoic acid First step Methyl 2,4-difluoro-5-(isopropylamino)benzoate Dissolve methyl 5-amino-2,4-difluorobenzoate (1.00 g, 5.35 mmol) in tetrahydrofuran (10 mL), add methanol (10 mL) and acetone (0.37 g, 8.04 mmol) under nitrogen protection. Stir at 0 °C for 20 minutes, add glacial acetic acid (0.32 g, 5.33 mmol), continue to stir at 0 °C for 30 minutes, and then add sodium cyanoborohydride (1.01 g, 16.03 mmol). Then let the reaction warm up to room temperature overnight. Evaporate the organic solvent, dissolve the residue in water (20 mL), extract the aqueous phase with ethyl acetate (10 mL × 3), and wash the combined organic phases with saturated brine (10 mL × 2). Dry the organic phase with anhydrous sodium sulfate, filter off the desiccant, and remove the solvent under reduced pressure. The crude product is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target product methyl 2,4-difluoro-5-(isopropylamino)benzoate (0.40 g, colorless oil). Yield: 32.7%.

[0069] MS m / z (ESI): 230 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.22-7.18 (m, 1H), 6.84-6.78 (m, 1H), 3.90 (s, 3H), 3.68-3.64 (m, 1H), 1.24 (d, J = 6.0 Hz, 6H). Second step 2,4-Difluoro-5-(isopropylamino)benzoic acid Methyl 2,4-difluoro-5-(isopropylamino)benzoate (0.40 g, 1.75 mmol) was dissolved in tetrahydrofuran (10 mL), and an aqueous lithium hydroxide solution (2 M, 10 mL) was added. The mixture was stirred at 50 °C for 2 hours, and the organic solvent was evaporated to dryness. The residue was dissolved in water (20 mL). The aqueous phase was adjusted to a pH of approximately 4 with 1 M dilute hydrochloric acid and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the solvent was removed under reduced pressure to obtain the target product 2,4-difluoro-5-(isopropylamino)benzoic acid (0.35 g, white solid, crude product).

[0070] MS m / z (ESI): 216 [M + 1]; 1 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.26 (m, 1H), 6.87 - 6.82 (m, 1H), 3.69 - 3.63 (m, 1H), 1.25 (d, J = 6.0 Hz, 6H).

[0071] The synthesis of intermediate 2 to 3 refers to the synthetic procedure of intermediate 1.

[0072] Intermediate 2 5-Cyclopentylamino-2,4-difluorobenzoic acid MS m / z (ESI): 242 [M + 1]; 1 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.26 (m, 1H), 6.87 - 6.81 (m, 1H), 3.84 - 3.78 (m, 1H), 2.12 - 2.04 (m, 2H), 1.79 - 1.61 (m, 4H), 1.54 - 1.48 (m, 2H).

[0073] Intermediate 3 2,4-Difluoro-5-(2-fluorophenylamino)benzoic acid MS m / z (ESI): 268 [M + 1]; 1 1H NMR (400 MHz, CDCl3) δ 7.92 - 7.88 (m, 1H), 7.26 - 7.21 (m, 1H), 7.16 - 7.08 (m, 2H), 7.02 - 6.95 (m, 2H), 5.75 (brs, 1H).

[0074] Intermediate 4 5-Fluoro-4-(isopropylamino)picolinate The first step 2-Chloro-5-fluoro-N-isopropylpyridin-4-amine Compound 2-chloro-5-fluoro-4-iodopyridine (5.14 g, 20.00 mmol) and 1,4-dioxane (60 mL) were mixed. Under nitrogen protection, isopropylamine (1.48 g, 25.00 mmol), cesium carbonate (1.30 g, 25.00 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.95 g, 2.00 mmol) and palladium acetate (0.23 g, 1.00 mmol) were added. The mixture was stirred at 100 °C for 15 h. This mixture was quenched with 50 mL of water, 50 mL of dichloromethane was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (25 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 6:1) to obtain the target product 2-chloro-5-fluoro-N-isopropylpyridin-4-amine (0.80 g, yellow solid), yield: 21%.

[0075] MS m / z (ESI): 189&191 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 4.0 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.26 (brs, 1H), 3.68 - 3.60 (m, 1H), 1.28 (d, J = 6.0 Hz, 6H). The second step 5-Fluoro-4-(isopropylamino)picolinitrile Compound 2-chloro-5-fluoro-N-isopropylpyridin-4-amine (0.19 g, 1.00 mmol) and N,N-dimethylacetamide (4 mL) were mixed. Under nitrogen protection, zinc cyanide (0.14 g, 1.20 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.05 g, 0.10 mmol), and tris(dibenzylideneacetone)dipalladium (0.09 g, 0.10 mmol) were added, and the mixture was stirred at 120 °C for 15 hours. This mixture was quenched with 25 mL of water and 25 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (25 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure to obtain the crude product. Purification by silica gel column (petroleum ether / ethyl acetate = 5:1) gave the target product 5-fluoro-4-(isopropylamino)pyridine-2-carbonitrile (0.04 g, yellow solid), yield: 22%.

[0076] MS m / z (ESI): 180 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 4.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.50 (brs,, 1H), 3.72 - 3.64 (m, 1H), 1.30 (d, J = 6.0 Hz, 6H). The third step 5-Fluoro-4-(isopropylamino)picolinic acid Compound 5-fluoro-4-(isopropylamino)pyridine-2-carbonitrile (40 mg, 0.22 mmol) and methanol (4 mL) were mixed. Under nitrogen protection, aqueous sodium hydroxide solution (4 M, 2 mL) was added, and the mixture was stirred at 70 °C for 4 hours. After cooling to room temperature, this mixture was quenched with dilute hydrochloric acid (1 M, 10 mL), and then 15 mL of dichloromethane was added. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (15 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure to obtain the target product 5-fluoro-4-(isopropylamino)picolinic acid (0.04 g, yellow solid, crude product).

[0077] MS m / z (ESI): 199 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 4.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 4.13 - 4.08 (m, 1H), 1.25 (d, J = 6.0 Hz, 6H).

[0078] The synthesis of intermediates 5 to 7 refers to the synthesis steps of intermediate 4, in which isopropylamine is replaced by different amines in the first step.

[0079] Intermediate 5 4-(Cyclopentylamino)-5-fluoropicolinic acid MS m / z(ESI): 225 [M+1]; 1 H NMR(400MHz, DMSO-d6) δ 8.99(d, J = 4.0Hz, 1H), 8.41(d, J = 5.8Hz, 1H), 7.48(s, 1H), 4.20 - 4.11(m, 1H), 2.09 - 1.78(m, 2H), 1.74 - 1.58(m, 4H), 1.53 - 1.28(m, 2H).

[0080] Intermediate 6 5-Fluoro-4-(phenylamino)picolinic acid MS m / z(ESI): 233 [M+1]; 1 H NMR(400MHz, DMSO-d6) δ 10.94(s, 1H), 8.29(d, J = 5.2Hz, 1H), 7.31(d, J = 7.2Hz, 1H), 7.22 - 7.13(m, 2H), 7.12 - 7.03(m, 2H), 7.00 - 6.91(m, 1H).

[0081] Intermediate 7 4-((Cyclopropylmethyl)amino)-5-fluoropicolinic acid MS m / z(ESI): 211 [M+1]; 1 H NMR(400MHz, DMSO-d6) δ 9.05(s, 1H), 8.36(d, J = 5.4Hz, 1H), 7.43(d, J = 7.6Hz, 1H), 3.34 - 3.18(m, 2H), 1.06 - 0.98(m, 1H), 0.50 - 0.34(m, 2H), 0.31 - 0.09(m, 2H).

[0082] Intermediate 8 (S)-7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-5-methyl-3-tritylamino-2,3-dihydrobenz[b][1,4]oxazepin-4(5H)-one The first step (S)-5-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-tritylamino-2,3-dihydrobenzo[b][1,4]oxazin-4(5H)-one Dissolve (S)-5-methyl-7-bromo-3-tritylamino-2,3-dihydrobenzo[b][1,4]oxazin-4(5H)-one (2.00 g, 3.90 mmol) (synthesis reference: WO2021173917 A1) in 1,4-dioxane (30 mL). Under nitrogen protection, add bis(pinacolato)diboron (5.00 g, 19.68 mmol), potassium acetate (1.15 g, 11.73 mmol), and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (0.29 g, 0.39 mmol). After addition, react at 100 °C for 3 hours. Cool to room temperature, rotary evaporate the organic solvent under reduced pressure. The residue is dissolved in water (20 mL), and the aqueous phase is extracted with ethyl acetate (10 mL × 3). The combined organic phases are washed with saturated brine (10 mL × 2). Dry the organic phase with anhydrous sodium sulfate, filter off the desiccant, and evaporate the solvent under reduced pressure. The crude product is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target product (S)-5-methyl-7- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-tritylamino-2,3-dihydrobenzo[b][1,4]oxazin-4(5H)-one (2.00 g, white solid), yield: 91.4%.

[0083] MS m / z (ESI): 561 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.55~7.53 (m, 1H), 7.39 - 7.37 (m, 6H), 7.32~7.31 (m, 1H), 7.23 - 7.14 (m, 9H), 7.01 (d, J = 8.0 Hz, 1H), 4.49 - 4.45 (m, 1H), 4.40 - 4.35 (m, 1H), 3.59 - 3.52 (m, 1H), 3.33 (d, J = 8.0 Hz, 1H), 2.93 (s, 3H), 1.36 (s, 12H). The second step (S)-7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-5-methyl-3-tritylamino-2,3-dihydrobenzo[b][1,4]oxazin-4(5H)-one (S)-5-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-tritylamino-2,3-dihydrobenzo[b][1,4]oxazin-4(5H)-one (0.50 g, 0.89 mmol) was dissolved in dioxane (10 mL), and water (2 mL) was added. Under nitrogen protection, 2-(5-bromopyridin-2-yl)propan-2-ol (0.38 g, 1.79 mmol), sodium carbonate (0.28 g, 2.68 mol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (65 mg, 0.09 mmol) were added. After the addition, the reaction was carried out at 100 °C for 4 hours. The organic solvent was evaporated to dryness, and the residue was dissolved in water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure to obtain the crude product. The target product (S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-methyl-3-tritylamino-2,3-dihydrobenzo[b][1,4]oxazin-4(5H)-one (0.40 g, white solid) was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1), and the yield was 78.7%.

[0084] MS m / z(ESI): 570 [M + 1]; 1 H NMR(400 MHz, CDCl3) δ 8.67 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 8.2 Hz, J = 2.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.42 - 7.40 (m, 6H), 7.28 - 7.12 (m, 11H), 7.04 (d, J = 2.0 Hz, 1H), 4.80 (s, 1H), 4.59 - 4.55 (m, 1H), 4.45 - 4.40 (m, 1H), 3.63 - 3.56 (m 1H), 3.36 (d, J = 8.0 Hz, 1H), 2.95 (s, 3H), 1.24 (s, 6H).

[0085] The synthesis of intermediate 9 - 10 refers to the synthesis steps of intermediate 8.

[0086] Intermediate 9 (S)-7-(6-(2-Hydroxy-2-methylpropyl)pyridin-3-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazin-4(5H)-one MS m / z(ESI): 584 [M + 1]; 1 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 7.42 - 7.40 (m, 6H), 7.28 - 7.12 (m, 12H), 7.04 (d, J = 2.4 Hz, 1H), 5.49 (s, 1H), 4.59 - 4.55 (m, 1H), 4.45 - 4.40 (m, 1H), 3.63 - 3.56 (m, 1H), 3.36 (d, J = 8.8 Hz, 1H), 2.98 (s, 2H), 2.95 (s, 3H), 1.27 (s, 6H).

[0087] Intermediate 10 (S)-7-(1-(2-Hydroxy-2-methylpropyl)-2-oxo-1,2-dihydropyridin-4-yl)-5-methyl-3-tritylamino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one MS m / z (ESI): 600 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 7.45 - 7.32 (m, 7H), 7.31 - 7.08 (m, 12H), 6.77 (d, J = 1.6 Hz, 1H), 6.43 (dd, J = 7.2 Hz, J = 2.0 Hz, 1H), 4.59 - 4.54 (m, 1H), 4.46 - 4.40 (m, 1H), 4.15 - 4.14 (m, 1H), 4.09 (s, 2H), 2.92 (s, 3H), 1.31 (s, 6H).

[0088] Example 1 (S)-2,4-Difluoro-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(isopropylamino)benzamide (S)-3-Amino-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazin-4(5H)-one (20 mg, 0.07 mmol) (synthesis reference: WO2021046407 A1) was dissolved in N,N-dimethylformamide (3 mL), and 2,4-difluoro-5-(isopropylamino)benzoic acid (Intermediate 1) (15 mg, 0.07 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (53 mg, 0.14 mmol), and N,N-diisopropylethylamine (27 mg, 0.21 mmol) were added with stirring at 25 °C. Stir at 25 °C for 2 hours, evaporate the solvent, dissolve the residue in water (20 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases and wash with saturated brine (10 mL × 2). Dry the organic phase over anhydrous sodium sulfate, filter off the desiccant, and remove the solvent under reduced pressure to obtain the crude product. Purify by preparative silica gel plate (petroleum ether / ethyl acetate = 1:1) to obtain the target product (S)-2,4-difluoro-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazin-3-yl)-5-(isopropylamino)benzamide (11.4 mg, white solid), yield: 33.8%.

[0089] MS m / z (ESI): 486 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 7.81 - 7.76 (m, 1H), 7.33 - 7.22 (m, 3H), 7.17 - 7.09 (m, 1H), 6.86 - 6.81 (m, 1H), 5.10 - 5.05 (m, 1H), 4.95 - 4.93 (m, 2H), 4.83 - 4.79 (m, 3H), 4.31 - 4.26 (m, 1H), 3.66 - 3.63 (m, 1H), 3.43 (s, 3H), 2.95 (brs, 1H), 1.20 (d, J = 4.4 Hz, 6H).

[0090] The synthesis of Examples 2 - 6 refers to the synthesis procedure of Example 1.

[0091] Example 2 (S)-5-(Cyclopentylamino)-2,4-difluoro-N-(7-(3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazin-3-yl)benzamide MS m / z (ESI): 512 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.81 - 7.76 (m, 1H), 7.32 - 7.24 (m, 3H), 7.17 (d, J = 8.8 Hz, 1H), 6.85 - 6.80 (m, 1H), 5.11 - 5.05 (m, 1H), 4.94 - 4.92 (m, 2H), 4.83 - 4.79 (m, 3H), 4.31 - 4.26 (m, 1H), 3.80 - 3.77 (m, 1H), 3.43 (s, 3H), 2.05 - 2.02 (m, 2H), 1.72 - 1.62 (m, 4H), 1.46 - 1.43 (m, 2H).

[0092] Example 3 (S)-2,4-difluoro-5-((2-fluorophenyl)amino)-N-(7-(3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzamide MS m / z (ESI): 538 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.83 - 7.79 (m, 1H), 7.75 - 7.70 (m, 1H), 7.25 - 7.22 (m, 2H), 7.16 - 7.11 (m, 1H), 7.09 - 6.83 (m, 5H), 5.02 - 4.95 (m, 1H), 4.87 - 4.85 (m, 2H), 4.74 - 4.70 (m, 3H), 4.24 - 4.19 (m, 1H), 3.36 (s, 3H).

[0093] Example 4 (S)-2,4-difluoro-N-(7-(1-(2-hydroxy-2-methylpropyl)-2-oxo-1,2-dihydropyridin-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(isopropylamino)benzamide MS m / z (ESI): 555 [M+1]; 11H NMR (400 MHz, CDCl3) δ 7.83 - 7.78 (m, 1H), 7.48 - 7.41 (m, 3H), 7.30 - 7.22 (m, 2H), 6.87 - 6.81 (m, 2H), 6.47 - 6.44 (m, 1H), 5.14 - 5.12 (m, 1H), 4.86 - 4.81 (m 1H), 4.35 - 4.29 (m, 1H), 4.09 (s, 2H), 3.66 - 3.63 (m 1H), 3.49 (s, 3H), 1.31 (s, 6H), 1.21 (d, J = 6.0 Hz, 6H).

[0094] Example 5 (S)-2,4-difluoro-N-(7-(6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(isopropylamino)benzamide MS m / z (ESI): 539 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.84 - 7.79 (m, 2H), 7.44 - 7.39 (m, 2H), 7.32 - 7.23 (m, 3H), 6.85 - 6.83 (m, 1H), 5.20 - 5.14 (m, 1H), 4.87 - 4.82 (m, 1H), 4.33 - 4.21 (m, 1H), 3.66 - 3.61 (m, 1H), 3.50 (s, 3H), 2.99 (s, 2H), 2.82 - 2.80 (m, 1H), 1.27 (s, 6H), 1.21 (d, J = 6.0 Hz, 6H).

[0095] Example 6 (S)-2,4-difluoro-N-(7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(isopropylamino)benzamide MS m / z (ESI): 525 [M+1]; 11H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.87 - 7.79 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.33 - 7.23 (m, 2H), 6.86 - 6.84 (m, 1H), 5.20 - 5.15 (m, 1H), 4.87 - 4.83 (m, 1H), 4.34 - 4.29 (m, 1H), 3.68 - 3.63 (m, 1H), 3.50 (s, 3H), 1.60 (s, 6H), 1.21 (d, J = 6.0 Hz, 6H).

[0096] Example 7 (S)-2,4-Difluoro-5-(isopropylamino)-N-(5-methyl-7-(1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzamide The first step (S)-3-Amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride Compound (S)-(tert-butyl (7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate) (synthesis reference: Journal of Medicinal Chemistry (2017), 60(4), 1247 - 1261) (1.00 g, 2.70 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 40 mmol, 10 mL), stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure to obtain (S)-3-amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (0.83 g, yellow solid, crude product). MS m / z (ESI): 271 & 273 [M + 1]; The second step (S)-N-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2,4-difluoro-5-(isopropylamino)benzamide (S)-3-Amino-7-bromo-5-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-one hydrochloride (0.11 g, 0.37 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2,4-difluoro-5-(isopropylamino)benzoic acid (80 mg, 0.37 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g, 0.74 mmol), and N,N-diisopropylethylamine (0.14 g, 1.09 mmol) were added with stirring at 25 °C. The mixture was stirred at 25 °C for 2 h, the solvent was evaporated to dryness, the residue was dissolved in water (20 mL), and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure to obtain the crude product. The target product (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl)-2,4-difluoro-5-(isopropylamino)benzamide (0.10 g, white solid) was obtained by preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1), yield: 57.8%

[0097] MS m / z (ESI): 468 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 7.79-7.74 (m, 1H), 7.36-7.34 (m, 2H), 7.27-7.23 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.84~6.83 (m, 1H), 5.11-5.05 (m, 1H), 4.81-4.77 (m, 1H), 4.29-4.23 (m, 1H), 3.68-3.60 (m, 2H), 3.43 (s, 3H), 1.21 (d, J = 6.0 Hz, 6H). The third step (S)-2,4-Difluoro-5-isopropylamino-N-(5-methyl-7-(1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl)benzamide The compound (S)-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2,4-difluoro-5-(isopropylamino)benzamide (50 mg, 0.11 mmol), 3-ethynyl-1-methyl-1H-1,2,4-triazole (synthesis reference: Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1975), (3), 690-3) (57 mg, 0.53 mmol) and triethylamine (2 mL) were dissolved in N,N-dimethylformamide (2 mL). Under nitrogen protection, palladium acetate (5 mg, 0.02 mmol), copper(I) iodide (4 mg, 0.02 mmol) and triphenylphosphine (28 mg, 0.11 mmol) were added. The mixture was purged with nitrogen three times and stirred at 85 °C for 16 hours. After cooling to room temperature, the mixture was poured into water (20 mL), diluted with 10 mL of ethyl acetate, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (10 mL × 3), and the combined organic layers were washed with saturated brine (10 mL × 2). The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure to obtain the crude product. The residue was prepared by liquid phase to obtain the target product (S)-2,4-difluoro-5-isopropylamino-N-(5-methyl-7-(1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzamide (36 mg, black solid), yield: 68.6%.

[0098] MS m / z (ESI): 495 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.75 - 7.71 (m, 1H), 7.41 - 7.38 (m, 2H), 7.19 - 7.16 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.79 - 6.74 (m, 1H), 5.05 - 5.00 (m, 1H), 4.81 - 4.74 (m, 1H), 4.25 - 4.20 (m, 1H), 3.90 (s, 3H), 3.61 - 3.55 (m, 1H), 3.38 (s, 3H), 1.14 (d, J = 6.0 Hz, 6H).

[0099] The synthesis of Examples 8 - 11 refers to the synthesis procedure of Example 7.

[0100] Example 8 (S)-2,4-Difluoro-5-(isopropylamino)-N-(5-methyl-4-oxo-7-(pyridin-2-yl)ethynyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl)benzamide MS m / z (ESI): 491 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.4 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.66 - 7.61 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.41 - 7.38 (m, 2H), 7.22 - 7.11 (m, 3H), 6.79 - 6.73 (m, 1H), 5.06 - 5.00 (m, 1H), 4.78 - 4.74 (m, 1H), 4.25 - 4.20 (m, 1H), 3.61 - 3.54 (m, 1H), 3.38 (s, 3H), 1.14 (d, J = 6.0 Hz, 6H).

[0101] Example 9 (S)-2,4-Difluoro-5-(cyclopentylamino)-N-(5-methyl-7-(1-methyl-1H-1,2,4-triazol-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl)benzamide MS m / z (ESI): 521 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.82 - 7.80 (m, 1H), 7.49 - 7.44 (m, 2H), 7.19 (d, J = 8.8 Hz, 1H), 6.85 - 6.78 (m, 1H), 5.15 - 5.06 (m, 1H), 4.85 - 4.81 (m, 1H), 4.32 - 4.27 (m, 1H), 3.97 (s, 3H), 3.83 - 3.76 (m, 1H), 3.45 (s, 3H), 2.99 - 2.96 (m, 1H), 1.77 - 1.66 (m, 4H), 1.63 - 1.59 (m, 4H).

[0102] Example 10 (S)-2,4-Difluoro-5-(isopropylamino)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl)benzamide MS m / z (ESI): 498 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.81 - 7.76 (m, 1H), 7.28 - 7.23 (m, 2H), 7.13 - 7.10 (m, 1H), 6.86 - 6.80 (m, 1H), 5.09 - 5.04 (m, 1H), 4.82 - 4.78 (m 1H), 4.29 - 4.23 (m, 1H), 3.98 - 3.93 (m, 2H), 3.65 - 3.53 (m, 3H), 3.44 (s, 3H), 2.87 - 2.83 (m, 1H), 1.95 - 1.90 (m, 2H), 1.78 - 1.73 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H).

[0103] Example 11 (S)-2,4-Difluoro-5-isopropylamino-N-(5-methyl-7-(oxetan-3-yl ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzamide MS m / z (ESI): 470 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.81 - 7.76 (m, 1H), 7.29 - 7.23 (m, 2H), 7.15 - 7.12 (m, 1H), 6.86 - 6.80 (m, 1H), 5.09 - 5.05 (m, 1H), 4.91 - 4.78 (m 5H), 4.30 - 4.24 (m, 1H), 4.10 - 4.06 (m, 1H), 3.70 - 3.62 (m, 1H), 3.44 (s, 3H), 1.21 (d, J = 6.0 Hz, 6H).

[0104] The synthesis of Examples 12 - 16 refers to the synthesis steps of Example 1.

[0105] Example 12 (S)-5-Fluoro-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(isopropylamino)pyridine-2-carboxamide MS m / z (ESI): 469 [M+1]; 11H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 4.98 - 4.92 (m, 1H), 4.86 - 4.84 (m 2H), 4.75 - 4.71 (m, 2H), 4.65 - 4.61 (m, 2H), 4.41 - 4.39 (m, 1H), 4.26 - 4.21 (m, 1H), 3.72 - 3.67 (m, 1H), 3.34 (s, 3H), 1.19 (d, J = 6.0 Hz, 6H).

[0106] Example 13 (S)-5-Fluoro-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(cyclopentylamino)pyridine-2-carboxamide MS m / z (ESI): 495 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.20 - 7.14 (m, 1H), 5.09 - 4.98 (m, 1H), 4.97 - 4.92 (m, 2H), 4.84 - 4.78 (m, 2H), 4.75 - 4.68 (m, 1H), 4.48 (s, 1H), 4.36 - 4.28 (m, 1H), 3.96 - 3.85 (m, 1H), 3.43 (s, 3H), 2.15 - 2.01 (m, 2H), 1.80 - 1.57 (m, 4H), 1.56 - 1.42 (m, 2H).

[0107] Example 14 (S)-4-((Cyclopropylmethyl)amino)-5-fluoro-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridine-2-carboxamide MS m / z (ESI): 481 [M+1]; 11H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 7.2 Hz, 1H), 8.09 (d, J = 4.0 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.16 (d, J = 8.8 Hz, 1H), 5.07 - 4.98 (m, 1H), 4.96 - 4.91 (m, 2H), 4.83 - 4.77 (m, 2H), 4.74 - 4.68 (m, 1H), 4.65 (s, 1H), 4.37 - 4.26 (m, 1H), 3.42 (s, 3H), 3.14 - 3.04 (m, 2H), 1.15 - 1.01 (m, 1H), 0.66 - 0.55 (m, 2H), 0.34 - 0.21 (m, 2H).

[0108] Example 15 (S)-5-Fluoro-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(phenylamino)pyridine-2-carboxamide MS m / z (ESI): 503 [M+1]; 1 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 7.2 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.33 - 7.28 (m, 2H), 7.24 - 7.12 (m, 4H), 6.31 (d, J = 2.8 Hz, 1H), 5.07 - 4.96 (m, 1H), 4.95 - 4.90 (m, 2H), 4.82 - 4.76 (m, 2H), 4.74 - 4.66 (m, 1H), 4.35 - 4.26 (m, 1H), 3.43 (s, 3H).

[0109] Example 16 (S)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(isopropylamino)pyridine-2-carboxamide MS m / z (ESI): 451 [M+1]; 1H NMR(400MHz, CDCl3)δ8.87(d,J=7.2Hz,1H),8.15(d,J=5.6Hz,1H),7.35-7.30(m, 2H),7.21(s,1H),7.15(d,J=8.4Hz,1H),6.47(d,J=3.2Hz,1H),5.09-5.03(m,1H) ,4.95(d,J=6.4Hz,2H),4.80(d,J=6.4Hz,2H),4.73-4.68(m,1H),4.36-4.30(m,1 H),4.22(d,J=6.4Hz,1H),3.75-3.68(m,1H),3.43(s,3H),1.22(d,J=6.0Hz,6H).

[0110] Embodiment 17 (S)-5-Fluoro-4-(isopropylamino)-N-(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-one-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridine-2-carboxamide first step (S)-3-Amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (S)-(7-bromo-5-methyl-4-carbonyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamic acid tert-butyl ester (Synthesis reference: Journal of Medicinal Chemistry (2017), 60(4), 1247-1261) (0.20 g, 0.54 mmol), a solution of hydrogen chloride in dioxane (4M, 8 mL) and methanol (2 mL) were mixed and stirred at room temperature for 1 hour. The mixture was desolvated under reduced pressure, and a saturated aqueous sodium bicarbonate solution (10 mL) was added to the residue, extracted with dichloromethane (10 mL×3), and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the target product (S)-3-amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (0.13 g, white solid) was obtained with a yield of 89%. MS m / z (ESI): 271&273 [M+1]; Step 2 (S)-N-(7-Bromo-5-methyl-4-carbonyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-fluoro-4-(isopropylamino)pyridine-2-carboxamide (S)-3-amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (0.13 g, 0.48 mmol), 5-fluoro-4-(isopropylamino)-1-picolinic acid (0.11 g, 0.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.18 g, 0.96 mmol), hydroxybenzotriazole (0.13 g, 0.96 mmol) and N,N-dimethylformamide (5 mL) were mixed and stirred at room temperature for 16 hours. The mixture was quenched with water (20 mL), extracted with ethyl acetate (15 mL×3), and washed with saturated brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the solvent was removed under reduced pressure to obtain the target product (S)-N-(7-bromo-5-methyl-4-carbonyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-fluoro-4-(isopropylamino)pyridine-2-carboxamide (0.16 g, white solid), yield: 74%. MS m / z (ESI): 451 [M+1]; Step 3 (S)-5-Fluoro-4-(isopropylamino)-N-(5-methyl 7-((1-methyl-1-1H-pyrazol-4-yl)ethynyl)-4-one-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridine-2-carboxamide (S)-N-(7-bromo-5-methyl-4-carbonyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-fluoro-4-(isopropylamino)pyridine-2-carboxamide (45 mg, 0.10 mmol), 4-ethynyl-1-methyl-1H-pyrazole (0.11 g, 1.00 mmol), anhydrous triethylamine (3 mL) and anhydrous N,N-dimethylformamide (3 mL) were mixed, and cuprous iodide (19 mg, 0.10 mmol) and bistriphenylphosphine palladium dichloride (14 mg, 0.02 mmol) were added under nitrogen protection, replaced with nitrogen three times, and stirred at 90°C for 16 hours. The mixture was cooled to room temperature, desolventized under reduced pressure, and ammonia water (8 mL) was added to the residue, extracted with ethyl acetate (5 mL×3), and washed with saturated brine (5 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized to obtain a crude product. Purification on a preparative silica gel plate (petroleum ether / ethyl acetate = 1:1) gave the target product (S)-5-fluoro-4-(isopropylamino)-N-(5-methyl 7-((1-methyl-1-1H-pyrazol-4-yl)ethynyl)-4-one-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)pyridine-2-carboxamide (11 mg, white solid), yield: 23%.

[0111] MS m / z(ESI):477[M+1]; 1 H NMR (400MHz, CDCl3) δ8.77(d,J=7.2Hz,1H),8.07(d,J=2.4Hz,1H),7.66(s,1H),7.57(s,1H),7.39(d,J=7.2Hz,1H),7.36-7.30(m,2H),7.15( d,J=8.7Hz,1H),5.10-5.00(m,1H),4.77-4.65(m,1H),4.38-4.25(m,2 H),3.93(s,3H),3.84-3.71(m,1H),3.44(s,3H),1.26(d,J=6.0Hz,6H).

[0112] The synthesis of Example 18 follows the synthesis steps of Example 17.

[0113] Embodiment 18 (S)-5-Fluoro-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-keto-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(isopropylamino)pyridine-2-carboxamide MS m / z(ESI):497[M+1]; 1 H NMR (400MHz, CDCl3) δ8.76(d,J=7.2Hz,1H),8.08(s,1H),7.38(d,J=7.2Hz,1H),7.32-7.36(m,2H),7.15(d,J=8.8Hz,1H),5.07-5.02(m,1H),4.73 -4.68(m,1H),4.34-4.28(m,2H),4.03-3.98(m,2H),3.76-3.72(m,3H),3 .43(s,3H),2.08-2.02(m,2H),1.98-1.92(m,2H),1.27(d,J=6.0Hz,6H).

[0114] Example 19: Experimental method for programmed necrosis of U-937 cells: U-937 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60277) were cultured in a cell culture incubator at 37°C with 5% CO2, in 1640 culture 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 2000nM, 100ng / mL TNFα, Q-VD-Oph (10μM) and the test drug were incubated with the cells for 48 hours, GSK2982772 was used as a positive control, and DMSO was used for the control wells. The cell viability was determined using the Cell-TiterGlo kit (purchased from Promega) based on ATP viability assay. The cell viability assay value represents the percentage of cell viability in the drug-treated well compared to the control well, where the higher the value, the stronger the cell viability (drug action activity calculation = drug-treated well / control well*100%). EC 50 The value was defined as the compound concentration that produced 50% of the maximum effect concentration. The drug activity data were fitted using a 4-parameter logistic equation, and the EC was calculated using XLfit 5.4 software from IDBS. 50 .

[0115] Example 20: Experimental method for programmed necrosis of L-929 cells: L-929 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60878) were cultured in a cell culture incubator at 37°C with 5% CO2, in MEM culture medium, and plated on a 384-well white plate. The compound was diluted 4-fold in a gradient series with a final starting concentration of 10000nM, 40ng / mL TNFα, Q-VD-Oph (10μM) and the test drug were incubated with the cells for 24 hours, GSK2982772 was used as a positive control, and DMSO was used for the control wells. The viability of the cells was determined using the Cell-TiterGlo kit based on ATP viability assay. The cell viability assay value represents the percentage of cell viability in the drug-treated well to the control well, where the higher the value, the stronger the cell viability (drug action activity calculation = drug-treated well / control well*100%). EC 50 The value was defined as the compound concentration that produced 50% of the maximum effect concentration. The drug activity data were fitted using a 4-parameter logistic equation, and the EC was calculated using XLfit 5.4 software from IDBS. 50 .

[0116] Example 21: Programmed necrosis of HT-29 cells Experimental method: HT-29 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP30001L) were cultured in a cell culture incubator at 37°C containing 5% CO2 in 1640 culture medium. The cells were plated on a 384-well white plate. The compound was diluted 4-fold in a gradient series with a final starting concentration of 500nM. 100ng / mL TNFα, Q-VD-Oph (10μM), SM-164 (1μΜ) and the test drugs were incubated with the cells for 48 hours. GSK2982772 was used as a positive control and DMSO was used in the control wells.

[0117] The cell viability was determined using the Cell-TiterGlo kit based on ATP viability assay. The cell viability assay 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%). EC 50 The value was defined as the compound concentration that produced 50% of the maximum effect concentration. The drug activity data were fitted using a 4-parameter logistic equation, and the EC was calculated using XLfit 5.4 software from IDBS. 50 .

[0118] Example 22 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 TNFα-induced conditions. Experimental method: I2.1 cells (purchased from ATCC, catalog number CRL-2572) were cultured in a cell culture incubator at 37°C with 5% CO2 in 1640 culture medium and plated on a 384-well white plate. The compound was diluted 4-fold with a final starting concentration of 500nM. 40ng / mL of TNFα and the test drugs were incubated with the cells for 24 hours, where GSK2982772 was used as a positive control, and DMSO (D5879-500ML, purchased from Sigma) was used in the control wells.

[0119] The cell viability was determined using the Cell-TiterGlo kit based on the change in ATP content. The cell viability determination 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%). EC 50 The value was defined as the compound concentration that produced 50% of the maximum effect concentration. The drug activity data were fitted using a 4-parameter logistic equation, and the EC was calculated using XLfit 5.4 software from IDBS. 50 .

[0120] The results of the cell experiments are shown in Table 1 Table 1: Cell activity test results of the compounds of the present invention

[0121] From the above experimental results, it can be seen that the example compounds of the present invention can effectively inhibit programmed cell necrosis, thereby effectively inhibiting the activity of RIPK1, and can be used to treat or prevent related diseases and functional disorders mediated by RIPK1, such as rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc.

[0122] 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), or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 selected from 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, 6- to 10-membered aryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, or wherein R a selected from 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, 4- to 10-membered heterocyclic group containing 1 to 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl, aryl, and heterocyclic group are unsubstituted or substituted with 1 to 3 substituents, and the substituents are each independently selected from hydroxy, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 oxyalkyl, or 4- to 10-membered heterocyclic group; R 2 selected from C1-C8 alkyl groups; R 3 selected from hydrogen, a halogen or a C1-C8 alkyl group; X is selected from N or CR b ; wherein R b is selected from hydrogen, halogen or C1-C8 alkyl; Y is selected from a single bond, O, S, NH, or C(R c R d ), where R c and R d are each independently selected from hydrogen, fluorine, or C1-C4 alkyl; Z is selected from C1-C8 alkyl, C3-C8 cycloalkyl or 6- to 10-membered aryl, wherein said alkyl, cycloalkyl and aryl are unsubstituted or substituted with 1-3 substituents, and wherein said substituents are each independently selected from halogen, C1-C6 alkyl or C3-C8 cycloalkyl.

2. The compound of formula (I) according to claim 1, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 selected from a 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen and oxygen, a 4- to 8-membered heterocyclic group, a phenyl group, or wherein R a selected from a 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen and oxygen, a 4- to 8-membered heterocyclic group containing 1 to 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl group, phenyl group, and heterocyclic group are unsubstituted or substituted with 1 to 3 substituents, and the substituents are each independently selected from a hydroxyl group, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C1-C8 alkoxy group, a C1-C8 oxyalkyl group, or a 4- to 8-membered heterocyclic group; R 2 selected from a C1-C6 alkyl group; R 3 selected from hydrogen, fluorine, chlorine, bromine or C1-C6 alkyl; X is selected from N or CR b ; wherein R b is selected from hydrogen, fluorine, chlorine, bromine or C1-C6 alkyl; Y is selected from a single bond, O, NH or C(R c R d ), where R c and R d are each independently selected from hydrogen or C1-C4 alkyl; Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl or 6- to 8-membered aryl, wherein said alkyl, cycloalkyl, aryl are unsubstituted or substituted with 1-3 substituents, and wherein said substituents are each independently selected from fluorine, chlorine, bromine, C1-C4 alkyl, C3-C6 cycloalkyl.

3. The compound of formula (I) according to claim 1, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 selected from 5-6-membered heteroaryl, 4-6-membered heterocyclic group, phenyl or wherein R a selected from 5-6-heteroaryl containing 1-3 heteroatoms selected from nitrogen and oxygen, 4-6-membered heterocyclic group containing 1-2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl, phenyl and heterocyclic group are unsubstituted or substituted by 1-3 substituents, and the substituents are each independently selected from hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 oxyalkyl or 4-6-membered heterocyclic group; R 2 selected from C1-C4 alkyl groups; R 3 selected from hydrogen, fluorine, chlorine or C1-C4 alkyl; X is selected from N or CR b ; wherein R b is selected from hydrogen, fluorine, chlorine or C1-C4 alkyl; Y is selected from a single bond, O, NH or -CH2-; Z is selected from C1-C4 alkyl, C3-C5 cycloalkyl or phenyl, wherein said alkyl, cycloalkyl and phenyl are unsubstituted or substituted with 1-3 substituents, and wherein said substituents are each independently selected from fluorine, chlorine, methyl, cyclopropyl.

4. The compound of formula (I) according to claim 1, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 a 5- or 6-membered heteroaryl, 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen and oxygen, or wherein R a is selected from a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen, a 4- to 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl and heterocyclic group are unsubstituted or substituted with 1 to 3 substituents, and wherein the substituents are each independently selected from hydroxy, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 oxyalkyl, or a 4- to 6-membered heterocyclic group; R 2 selected from methyl; R 3 selected from hydrogen or fluorine; X is selected from N or CR b ; wherein R b is selected from hydrogen, fluorine; Y is selected from NH. Z is selected from 5. The compound of formula (I) according to claim 1, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein: R 1 selected from wherein R a selected from R 2 selected from methyl; R 3 selected from hydrogen or fluorine; X is selected from N or CR b ; wherein R b is selected from fluorine; Y is selected from NH; Z is selected from 6. The compound of formula (I) according to claim 1, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, selected from:

7. A pharmaceutical composition comprising a compound according to any one of claims 1-6 or an optical isomer or pharmaceutically acceptable salt thereof, optionally one or more other RIPK1 inhibitors, and one or more pharmaceutically acceptable carriers.

8. Use of a compound according to any one of claims 1-6, an optical isomer thereof or a pharmaceutically acceptable salt thereof and the composition according to claim 7 in the manufacture of a medicament for the treatment or prevention of a RIPK1-mediated disease or disorder.

9. Use according to claim 8, wherein the RIPK1-mediated disease or disorder is selected from: rheumatoid arthritis, Crohn's disease, ulcerative colitis, pancreatitis, psoriasis, atopic dermatitis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, asthma, multiple sclerosis, pancreatic cancer, bacterial infection, hematological malignancies, solid organ malignancies, etc.

10. The use according to claim 8, wherein the RIPK1-mediated disease or disorder is selected from rheumatoid arthritis, ulcerative colitis, psoriasis, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis.

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