Benzoazaketone derivative and application thereof

Abstract

The invention discloses a benzo-aza # imgabs0 # ketone derivative, and particularly relates to substance forms such as free alkali, an isomer or pharmaceutically acceptable salt of the derivative. Furthermore, the invention also discloses a preparation method and pharmaceutical application of the benzaza # imgabs1 # ketone derivative, and the benzaza # imgabs1 # ketone derivative can be used as an RIPK1 inhibitor for treating diseases related to abnormal expression of a mediated RIPK1 signal channel, including but not limited to tumors, and has great clinical development value.

Description

Technical Field

[0001] The present invention belongs to the technical field of small molecule targeted chemical drugs and relates to a benzazepine Ketone derivatives, specifically the free base, isomers or pharmaceutically acceptable salts of the compounds; further, the present invention also discloses the benzazepine The preparation method and pharmaceutical use of ketone compounds can be used as RIPK1 inhibitors to treat diseases related to abnormal expression of RIPK1 signaling pathways, including but not limited to tumors. Background Art

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

[0003] Diseases or conditions that are partially regulated by receptor interacting protein kinase 1, dependent apoptosis, necrosis or cytokine production include: blood and solid organ malignancies (Genes Dev. 2013, 27, 1640-1649), bacterial infections and viral infections (Cell Host & Microbe, 2014, 15, 23-35), including but not limited to tuberculosis and influenza (Cell, 2013, 153, 1-14). In summary, receptor interacting protein kinase 1 is a key regulator of apoptosis, which is not only involved in the signal transduction of cell survival, but also in the signal transduction of programmed cell death in multiple pathways. Receptor interacting protein kinase 1 inhibitors have potential therapeutic effects for the treatment of various diseases such as cancer, neurodegenerative diseases, autoimmune diseases, etc.

[0004] At present, the receptor-interacting protein kinase 1 inhibitors under research in the world are mainly divided into three categories based on the compound structure: indole (for example: Necrostatin-1s), benzazepine The pyrazole amide class (for example: GSK-2982772) and pyrazole amide class (for example: GSK-963, GSK547) are currently in the preclinical research or clinical research stage, and no marketed drugs have yet appeared, so the future market potential is considerable.

[0005] Professor Yuan Junying is an authority and pioneer in the field of receptor-interacting protein kinase 1 inhibitors. Necrostatin-1s, which he discovered in 2005, is the first small molecule receptor-interacting protein kinase 1 inhibitor and has been widely used in the study of the role and mechanism of receptor-interacting protein kinase 1 in human diseases and animal models. In 2008, it was determined that it is the mode of action of necrotizing statins, thus determining it as a key regulator of programmed necrosis. The highest research and development status of this type of drug in the world is in the preclinical stage.

[0006] Patent WO2014125444 discloses a novel benzazepine In the same year, the world's first receptor interacting protein kinase 1 inhibitor, GSK-2982772, was approved for clinical trials. In 2016, GSK-2982772 was promoted to Phase II clinical trials. The indications for Phase II clinical trials were: psoriasis, rheumatoid arthritis, and treatment of ulcerative colitis. In addition to GSK-2982772, GSK-3145095 was tested in Phase II clinical trials on November 16, 2018 for the treatment of pancreatic cancer. On September 12, 2019, the research on GSK-3145095 for the treatment of pancreatic cancer was terminated.

[0007] Patent WO2016185423 discloses a pyrazole amide derivative, the representative compound is GSK-963, but its poor oral effect limits its development. Subsequently, this compound was used as a lead compound for structural optimization to obtain GSK-547. This molecule did not enter the clinic due to poor pharmacokinetic data.

[0008]

[0009] Receptor-interacting protein kinase 1 inhibitors based on the above three main structures have defects such as low selectivity, strong toxic side effects, and poor drugability. Researchers at home and abroad continue to modify the structure of compounds based on their structures, hoping to find safer and more effective receptor-interacting protein kinase 1 inhibitors to fill the gap in drugs for this target.

[0010] After searching, the patent literature about GSK-2982772 and the structural modification and improvement of GSK-2982772 are as follows:

[0011] Patent WO2014125444 discloses a compound of formula 1, which has the following structural characteristics: the parent nucleus is a benzazepine Ring, with nitrogen The rings connected are benzene rings or nitrogen-containing six-membered aromatic heterocycles, benzazepine The ring is connected to ring A via an amide bond, and ring A is connected to ring B via -L-. The representative compound is GSK-2982772.

[0012]

[0013] In summary, how to develop a new receptor interacting protein kinase 1 inhibitor with good biological activity and significant effects on one or more of anti-inflammatory and anti-tumor diseases, and on this basis develop a Chinese innovative drug with independent intellectual property rights, is a technical problem that technicians in this field urgently need to solve. Summary of the invention

[0014] The technical problem to be solved by the present invention is to provide a novel structure of benzazepine Ketone derivatives that can inhibit the activity of receptor interacting protein kinase 1 and have significant anti-tumor and / or anti-inflammatory activities.

[0015] In order to solve the above technical problems, the technical solutions provided by the present invention are as follows:

[0016] A benzazepine Ketone derivatives are compounds represented by formula (I), isomers or pharmaceutically acceptable salts thereof:

[0017]

[0018] Where:

[0019] Ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl;

[0020] R1 is selected from halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, when C in R1 is 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 When aryl and 5-14 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone, C 1-6 Alkoxysulfoxide, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-14 5- to 14-membered aryl or heteroaryl;

[0021] Ring B is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, ring B is substituted by at least one substituent R2;

[0022] X and Y are each independently selected from CR4, OR4, SR4 or NR4, and X and Y are not NR4 at the same time;

[0023] R2 is selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0024] L is selected from substituted or unsubstituted 5-6 membered heteroaryl. When the 5-6 membered heteroaryl in L has a substituent, it may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide;

[0025] W is selected from a linker, -(CH2) n -、-O-、-(CH2) n O(CH2) m -, -CO- or -(CH2) n CO(CH2)m -;

[0026] R3 is selected from substituted or unsubstituted C 6-14 Aryl or 5-14 membered heteroaryl, when C in R3 is 6-14 When aryl and 5-14 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide;

[0027] R4 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide;

[0028] n and m are each independently selected from 0, 1, 2, 3 or 4, and n and m are not 0 at the same time;

[0029] The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0030] Preferably, it is a compound represented by Formula I, an isomer, or a pharmaceutically acceptable salt thereof:

[0031]

[0032] Where:

[0033] Ring A is selected from C6-10 Aryl or 5-10 membered heteroaryl;

[0034] Ring B is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, ring B is substituted by at least one substituent R2;

[0035] X and Y are each independently selected from CR4, OR4, SR4 or NR4, and X and Y are not NR4 at the same time;

[0036] R2 is selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0037] L is selected from substituted or unsubstituted 5-6 membered heteroaryl. When the 5-6 membered heteroaryl in L has a substituent, it may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Haloalkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide;

[0038] W is selected from a linker, -(CH2) n -、-O-、-(CH2) n O(CH2) m -, -CO- or -(CH2) n CO(CH2) m -;

[0039] R3 is selected from substituted or unsubstituted C 6-14 Aryl or 5-14 membered heteroaryl, when C in R3 is 6-14 When aryl and 5-14 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide;

[0040] R4 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide;

[0041] n and m are each independently selected from 0, 1, 2, 3 or 4, and n and m are not 0 at the same time;

[0042] The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0043] Preferably, it is a compound represented by Formula II, an isomer, or a pharmaceutically acceptable salt thereof:

[0044]

[0045] Where:

[0046] X is selected from CR4, OR4 or SR4;

[0047] L is selected from triazole, pyridine, pyrazole or pyrazolotetrahydropyridone substituted with at least one substituent; the substituent is selected from one or more of the following groups: hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C1-6 Haloalkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide;

[0048] W is selected from -(CH2) n -, -O- or -CO-;

[0049] R4 and R5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Haloalkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide;

[0050] n is selected from 1, 2, 3 or 4;

[0051] q is selected from 1, 2, 3, 4 or 5;

[0052] The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0053] Preferably, it is a compound represented by formula II-1, an isomer, or a pharmaceutically acceptable salt thereof:

[0054]

[0055] Where:

[0056] R5 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl;

[0057] q is selected from 1, 2, 3, 4 or 5.

[0058] Preferably, it is a compound represented by formula II-2, an isomer, or a pharmaceutically acceptable salt thereof:

[0059]

[0060] Where:

[0061] R5 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl;

[0062] q is selected from 1, 2, 3, 4 or 5.

[0063] Preferably, it is a compound represented by formula II-3, an isomer, or a pharmaceutically acceptable salt thereof:

[0064]

[0065] Where:

[0066] R5 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl;

[0067] q is selected from 1, 2, 3, 4 or 5.

[0068] The present invention also provides a benzazepine Ketone derivatives include the following compounds numbered I, II-1 to II-10, III-1 to III-4, IV-1, V-1 to V-2 or their pharmaceutically acceptable salts:

[0069] Compound I-1: 5-benzyl-N-(10-bromo-4-oxyylidene-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl)-4H-1,2,4-triazacyclopentazone-3-carboxamide;

[0070] Compound II-1: N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl)-1-[(2,6-difluorophenyl)methyl]-1,2,4-triazacyclopentazone-3-carboxamide;

[0071] Compound II-2: 1-benzyl-N-(9-bromo-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptanol[3,2,1-hi]indol-5-yl)-1,2,4-triazacyclopentane-3-carboxamide;

[0072] Compound II-3: N-(9-bromo-4-oxyde-1,2,3,4,6,7-hexahydroazepine[3,2,1-hi]indol-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0073] Compound II-4: N-(9-bromo-4-oxyde-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0074] Compound II-5: N-(9-bromo-4-oxyde-1,2,3,4,6,7-hexahydroazepine[3,2,1-hi]indol-3-yl)-1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0075] Compound II-6: N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0076] Compound II-7: N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(3,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0077] Compound II-8: N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0078] Compound II-9: N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0079] Compound II-10: N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(4-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0080] Compound III-1: 5-benzyl-N-(9-bromo-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptanol[3,2,1-hi]indol-5-yl)-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0081] Compound III-2: N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl)-5-[(4-fluorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0082] Compound III-3: N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl)-5-[(4-chlorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0083] Compound III-4: N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl)-5-[(2,6-difluorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0084] Compound IV-1: N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl)-2-[(2,6-difluorophenyl)methyl]-1,2,4-triazacyclopentane-3-carboxamide;

[0085] Compound V-1: N-(9-bromo-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-6-phenoxypicolinamide;

[0086] Compound V-2: N-(9-bromo-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-4-phenoxypicolinamide;

[0087] Compound VI-1: 1-(2,6-difluorophenyl)-N-(4-oxo-9-(2-oxa-6-diazospiro[3,3]heptane-6-yl)-1,2,3,4,6,7-hexahydroazepine[3,2,1-hi]indol-3-yl)-1H-1,2,4-triazole-3-amide.

[0088] The aforementioned compounds numbered I-1, III-1 to III-4 or their pharmaceutically acceptable salts, have the following structural formulas:

[0089]

[0090]

[0091]

[0092] The aforementioned compounds numbered II-1 to II-10 or their pharmaceutically acceptable salts, the structural formulas of which are shown below:

[0093]

[0094]

[0095]

[0096] The compound numbered IV-1 or a pharmaceutically acceptable salt thereof, the structural formula of which is shown below:

[0097]

[0098] The aforementioned compound numbered V-1 or a pharmaceutically acceptable salt thereof, the structural formula of which is shown below:

[0099]

[0100] The aforementioned compound numbered V-2 or a pharmaceutically acceptable salt thereof, the structural formula of which is shown below:

[0101]

[0102] The "compounds" of the present invention include, but are not limited to, the following forms of the compounds: free base, stereoisomers, geometric isomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters or phosphates), etc.

[0103] The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0104] The terms used in this article have the following meanings for compounds containing the above general structure:

[0105] The "pharmaceutically acceptable salts" of the present invention refer to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium salts, ammonium or organic amines. For example: alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts, etc.

[0106] In addition to the form of salts, compounds provided by the present invention also exist in prodrug form. Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0107] The term "C 1-6 "Alkyl" refers to a straight or branched alkane containing 1 to 6 carbon atoms, unless a different number of atoms is specified. Examples of "alkyl" used in the present invention include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl and tert-butyl. "Alkyl" also includes substituted alkyl. The alkyl may be optionally substituted one or more times by halogen or hydroxy.

[0108] The term "C 1-6 "Fluorinated alkyl" refers to an alkyl group containing fluorine atoms, wherein the alkyl group is as defined above. As used herein, "C 1-6 Examples of "fluorinated alkyl" include, but are not limited to, trifluoromethyl, difluoromethyl, 2.2.2-trifluoroethyl. 1-6 "Fluorinated alkyl" also includes C 1-6 Substituted fluorinated alkyl. 1-6 The substituted fluorinated alkyl group may be optionally substituted one or more times with halogen.

[0109] The term "C 1-6"Alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. "Alkoxy" also includes substituted alkoxy. Alkoxy may be optionally substituted one or more times by halogen.

[0110] The term "C 1-6 "Fluorine-containing alkoxy" refers to an -O-alkyl group containing a fluorine atom, wherein the alkyl group is as defined above. As used herein, "C 1-6 Examples of the "fluorine-containing alkoxy group" include, but are not limited to, trifluoromethoxy and difluoromethoxy.

[0111] The term "C 1-6 "Monoalkylamino" means C 1-6 Monoalkyl-substituted amino, wherein alkyl is as defined above. 1-6 Examples of "monoalkylamino" include, but are not limited to, methylamino, ethylamino, propylamino, cyclopropylamino, isopropylamino.

[0112] The term "C 1-6 "Dialkylamino" refers to two C 1-6 Alkyl-substituted amino, wherein alkyl is as defined above. 1-6 Examples of "dialkylamino" include, but are not limited to, dimethylamino, diethylamino, aziridine, azetidinyl, azopentyl, azidine.

[0113] The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

[0114] The present invention relates to a compound comprising the above-mentioned benzazepine Ketone compounds, pharmaceutically acceptable salts, pharmaceutical compositions, stereoisomers and anti-inflammatory and anti-tumor uses thereof.

[0115] The present invention also provides a pharmaceutical composition, comprising at least one active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient can be selected from any one or more of the compound of the general formula I structure and its preferred compounds, the pharmaceutically acceptable salts, prodrugs (esters or phosphates), stereoisomers, deuterated substances and solvates of the compound.

[0116] The "pharmaceutically acceptable carrier" refers to conventional drug carriers in the pharmaceutical field, including conventional diluents and excipients such as water, fillers such as starch, binders such as cellulose derivatives, gelatin, wetting agents such as glycerol, disintegrants such as agar, calcium carbonate, absorption promoters such as quaternary ammonium compounds, surfactants such as cetyl alcohol, adsorption carriers such as sugars (sucrose, lactose), kaolin and soap clay, lubricants such as talc, etc., and flavoring agents, sweeteners, etc. may be added if necessary.

[0117] The following routes 1 to 5 are overviews of the overall reaction routes of the aforementioned compounds of the present invention:

[0118] Route 1: Preparation of series I target compounds

[0119]

[0120] Wherein R5 is defined as described above.

[0121] The specific reaction process is as follows:

[0122] The starting material B-1 is reduced with sodium cyanoborohydride under acidic conditions to obtain intermediate B-2; then, intermediate B-2 reacts with intermediate B-3 under alkaline conditions to obtain amide intermediate B-4; intermediate B-4 is catalyzed by a Lewis acid catalyst (including but not limited to aluminum trichloride, ferric chloride, boron trifluoride, niobium pentachloride, HFIP, oxalyl chloride and trifluoromethanesulfonate, etc.) or acid (polyphosphoric acid, methanesulfonic acid, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid) to obtain tricyclic compound B-5 by sealed tube reaction or microwave reaction; under acidic conditions, intermediate B-5 is reduced with triethylsilane The original ketone carbonyl is obtained to obtain intermediate B-6; in the presence of Lewis acid TMSI (trimethylsilyl iodide), an iodine atom is introduced into the ortho position of the amide of intermediate B-6 to obtain intermediate B-7; the iodide B-7 undergoes a substitution reaction in ammonia methanol to obtain intermediate B; the substituted phenylacetyl hydrazine (Ib) undergoes a substitution reaction with intermediate Ic to obtain intermediate Id; then intermediate Id undergoes a ring-closure reaction at high temperature to obtain a substituted triazole carboxylate (Ie); intermediate Ie is hydrolyzed under alkaline conditions to obtain a substituted triazole carboxylic acid (If); intermediate B and If undergo an amide condensation reaction to obtain the final product I.

[0123] In the amide condensation reaction in the synthesis scheme 3, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0124] Route 2: Preparation of target compounds of series II

[0125]

[0126] Wherein R5 is defined as described above.

[0127] The specific reaction process is as follows:

[0128] Starting materials A-1 and A-2 undergo substitution reaction under alkaline conditions to obtain intermediate A-3; intermediate A-3 is subjected to ring closure by sealed tube reaction or microwave reaction under the catalytic action of Lewis acid catalyst (including but not limited to aluminum trichloride, ferric chloride, boron trifluoride, niobium pentachloride, HFIP, oxalyl chloride and trifluoromethanesulfonate, etc.) or acid (polyphosphoric acid, methanesulfonic acid, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid) to obtain tricyclic compound A-4; intermediate A-4 is brominated by NBS (N-bromosuccinimide), and a bromine atom is introduced at the para position of the nitrogen atom on the benzene ring to obtain intermediate A-5; intermediate A-3 is subjected to ring closure by sealed tube reaction or microwave reaction under the catalytic action of Lewis acid catalyst (including but not limited to aluminum trichloride, ferric chloride, boron trifluoride, niobium pentachloride, HFIP, oxalyl chloride and trifluoromethanesulfonate, etc. ... -5 uses triethylsilane to reduce the ketone carbonyl group to obtain intermediate A-6; in the presence of Lewis acid TMSI (trimethylsilane iodide), an iodine atom is introduced into the ortho position of the amide of intermediate A-6 to obtain intermediate A-7; the iodide A-7 undergoes a substitution reaction in ammonia methanol to obtain intermediate A; the substituted benzyl bromide (IIIb) undergoes a substitution reaction with triazolecarboxylic acid methyl ester (IIIa) to obtain intermediate IIIc; intermediate IIIc is subsequently hydrolyzed under alkaline conditions to obtain substituted triazolecarboxylic acid (IIId); intermediate A undergoes an amide condensation reaction with IIId to obtain the final products II-1 to II-10.

[0129] In the amide condensation reaction in the synthesis scheme 3, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0130] Route 3: Preparation of target compounds of series III

[0131]

[0132] Wherein R5 is defined as described above.

[0133] The specific reaction process is as follows:

[0134] The starting materials A-1 and A-2 undergo a substitution reaction under alkaline conditions to obtain an intermediate A-3; the intermediate A-3 is catalyzed by a Lewis acid catalyst (including but not limited to aluminum trichloride, ferric chloride, boron trifluoride, niobium pentachloride, HFIP, oxalyl chloride and trifluoromethanesulfonate, etc.) or an acid (polyphosphoric acid, methanesulfonic acid, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid) to obtain a tricyclic compound A-4 by a sealed tube reaction or a microwave reaction; the intermediate A-4 is brominated with NBS (N-bromosuccinimide) to introduce a bromine atom at the para position of the nitrogen atom on the benzene ring to obtain an intermediate A-5; under acidic conditions, the intermediate A-5 is used Triethylsilane reduces the ketone carbonyl group to obtain intermediate A-6; in the presence of Lewis acid TMSI (trimethyl iodosilane), an iodine atom is introduced into the ortho position of the amide of intermediate A-6 to obtain intermediate A-7; the iodide A-7 undergoes a substitution reaction in ammonia methanol to obtain intermediate A; the substituted phenylacetyl hydrazine (Ib) undergoes a substitution reaction with intermediate Ic to obtain intermediate Id; then intermediate Id undergoes a ring-closure reaction at high temperature to obtain intermediate Ie; intermediate Ie is hydrolyzed under alkaline conditions to obtain a substituted triazole carboxylic acid (If); intermediate A and If undergo an amide condensation reaction to obtain the final target products III-1 to III-4.

[0135] In the amide condensation reaction in the synthesis scheme 3, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0136] Route 4: Preparation of target compounds of series IV

[0137]

[0138] Wherein R5 is defined as described above.

[0139] The specific reaction process is as follows:

[0140] Starting materials A-1 and A-2 undergo substitution reaction under alkaline conditions to obtain intermediate A-3; intermediate A-3 is subjected to ring closure by sealed tube reaction or microwave reaction under the catalysis of Lewis acid catalyst (including but not limited to aluminum trichloride, ferric chloride, boron trifluoride, niobium pentachloride, HFIP, oxalyl chloride and trifluoromethanesulfonate, etc.) or acid (polyphosphoric acid, methanesulfonic acid, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid) to obtain tricyclic compound A-4; intermediate A-4 is brominated by NBS (N-bromosuccinimide), and a bromine atom is introduced at the para position of the nitrogen atom on the benzene ring to obtain intermediate A-5; under acidic conditions , intermediate A-5 is reduced to the ketone carbonyl group using triethylsilane to obtain intermediate A-6; in the presence of Lewis acid TMSI (trimethylsilane iodide), an iodine atom is introduced into the ortho position of the amide of intermediate A-6 to obtain intermediate A-7; the iodide A-7 undergoes a substitution reaction in ammonia methanol to obtain intermediate A; the substituted benzyl bromide (IIIb) undergoes a substitution reaction with triazolecarboxylic acid methyl ester (IIIa) to obtain intermediate IXc; intermediate IXc is then hydrolyzed under alkaline conditions to obtain substituted triazolecarboxylic acid (IXd); intermediate A and IXd undergo an amide condensation reaction to obtain the final product IV-1.

[0141] In the amide condensation reaction in the synthesis scheme 3, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0142] Note: When preparing intermediates IIId and IXd, the same raw materials and the same route are used, and two triazole ester fragments, IIId and IXd, can be obtained through column chromatography purification.

[0143]

[0144] Route 5: Preparation of V series target compounds

[0145]

[0146] The specific reaction process is as follows:

[0147] The starting materials A-1 and A-2 undergo a substitution reaction under alkaline conditions to obtain an intermediate A-3; the intermediate A-3 is catalyzed by a Lewis acid catalyst (including but not limited to aluminum trichloride, ferric chloride, boron trifluoride, niobium pentachloride, HFIP, oxalyl chloride and trifluoromethanesulfonate, etc.) or an acid (polyphosphoric acid, methanesulfonic acid, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid) to obtain a tricyclic compound A-4 by a sealed tube reaction or a microwave reaction; the intermediate A-4 is brominated with NBS (N-bromosuccinimide) to introduce a bromine atom at the position opposite to the nitrogen atom on the benzene ring to obtain an intermediate Under acidic conditions, the intermediate A-5 is reduced to the ketone carbonyl using triethylsilane to obtain intermediate A-6; in the presence of Lewis acid TMSI (trimethylsilane iodide), an iodine atom is introduced into the ortho position of the amide of intermediate A-6 to obtain intermediate A-7; the iodide A-7 undergoes a substitution reaction in ammonia methanol to obtain intermediate A; intermediate Va and Vb undergo a substitution reaction to obtain intermediate Vc; intermediate Vc is then hydrolyzed under alkaline conditions to obtain intermediate substituted pyridine carboxylic acid Vd; intermediate A and Vd undergo an amide condensation reaction to obtain the final products V-1 to V-2.

[0148] In the amide condensation reaction in the synthesis scheme 3, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc. DETAILED DESCRIPTION

[0149] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0150] In addition, all operations involving raw materials that are easily oxidized or hydrolyzed are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be used directly without further purification.

[0151] The reaction starting materials and common intermediates involved in the embodiments of the present invention can be purchased commercially or prepared by themselves. The preparation process of the starting materials and common intermediates that need to be prepared by themselves is described in detail as follows:

[0152] Explanation of the abbreviations of the solvents or materials used:

[0153] NBS: N-bromosuccinimide; TMEDA: tetramethylethylenediamine; TMSI: trimethylsilyl iodide; DMF: N,N-dimethylformamide; I2: iodine; DCM: dichloromethane; NH3 / MeOH: methanolic ammonia solution; EtOH: ethanol; Xylenes: xylene; LiOH: lithium hydroxide; THF-H2O: tetrahydrofuran-water solution; NaBH3CN: sodium cyanoborohydride; AcOH: acetic acid; TFA: trifluoroacetic acid; HOBT: 1-hydroxybenzotriazole; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM: N-methylmorpholine; K2CO3: potassium carbonate; Cu: copper; Cs2CO3: cesium carbonate; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPE A: N,N-diisopropylethylamine; T3P: 1-propylphosphonic anhydride; THF: tetrahydrofuran; EA: ethyl acetate; BINAP ligand: S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine ligand; DPPF ligand: 1,1'-bis(diphenylphosphino)ferrocene ligand; Xantphos ligand: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene ligand; DPBP ligand: 2,2′-bis(diphenylphosphino)benzophenone ligand; X-phos ligand: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl ligand; cBRIDP ligand: dicyclohexyl(2,2-diphenyl-1-methylcyclopropyl)phosphine ligand; HFIP: hexafluoroisopropanol.

[0154] 1. Preparation of Common Intermediate A

[0155]

[0156] Step 1: Synthesis of compound A-3

[0157] In a 250mL eggplant-shaped bottle, the starting material A-1 (5.96g, 50mmol) was dissolved in 60mL of anhydrous pyridine, stirred under an ice bath, and the starting material A-2 (5.00g, 50mmol) was slowly added in batches. After replacing the nitrogen, the ice bath was removed and the reaction was restored to room temperature overnight. The raw material was basically reacted completely by thin layer chromatography, and 6M hydrochloric acid was added to adjust it to acidity, EA was extracted three times, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by column chromatography to obtain pink solid compound A-3 (10.5g) with a yield of 95.8%.

[0158] MS (m / z): 220.1 [M+H] + .

[0159] Step 2: Synthesis of compound A-4

[0160] In a 50mL microwave reaction bottle, the intermediate A-3 (1.75g, 8.0mmol) was dissolved in 15mL trifluoromethanesulfonic acid solution, and a catalytic amount of AlCl3 was added in batches, the nitrogen was replaced, and the mixture was placed in a microwave reactor, and the temperature was set to 160°C for 1h. The raw material was basically reacted by thin layer chromatography, and sodium hydroxide solution was added to adjust the mixture to neutral or alkaline, and DCM was used for extraction. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by column chromatography to obtain a gray solid compound A-4 (2.40g) with a yield of 34.5%.

[0161] MS (m / z): 202.1 [M+H] + .

[0162] Step 3: Synthesis of Compound A-5

[0163] In a 250mL eggplant-shaped bottle, the intermediate A-4 (3.6g, 18.0mmol) was dissolved in 60mL of anhydrous DMF, and then NBS (6.37g, 36mmol) was added to the reaction system in batches, the nitrogen was replaced, and the reaction was allowed to proceed overnight at room temperature. The reaction of the raw material was basically complete according to TLC, and water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by column chromatography to obtain a yellow solid compound A-5, which was directly used in the next step without further purification.

[0164] MS (m / z): 280.1 [M+H] + .

[0165] Step 4: Synthesis of Compound A-6

[0166] In a 250mL eggplant-shaped bottle, A-5 (5.0g, 18mmol) was dissolved in 60mL anhydrous trifluoroacetic acid under ice bath, and triethylsilane (10.4g, 90mmol) was slowly added in batches under cooling. After replacing nitrogen, the ice bath was removed and slowly restored to room temperature, and finally transferred to a 45°C oil bath for reaction overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, saturated sodium bicarbonate was added to the system to adjust pH>7, ethyl acetate was extracted, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by column chromatography to obtain gray-green solid compound A-6 (2.43g), and the total yield of step 3 and step 4 was 51.05%.

[0167] MS (m / z): 266.1 [M+H] + .

[0168] Step 5: Synthesis of Compound A-7

[0169] In a 250mL eggplant-shaped bottle, the intermediate A-6 (0.81g, 3.04mmol) was dissolved in 30mL dichloromethane, stirred under ice bath, and TMEDA (1.06g, 9.12mmol) and TMSI (1.83g, 9.12mmol) were slowly added in batches. After replacing nitrogen, the mixture was stirred under ice bath for 2h. I2 (1.08g, 4.26mmol) was added, nitrogen was replaced, and the mixture was stirred under ice bath for 2h. The reaction of the raw material was basically complete according to TLC. The system was quenched by adding saturated sodium bicarbonate, extracted with DCM, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain a gray solid compound A-7, which was directly used for the next step without further purification.

[0170] MS (m / z): 391.9 [M+H] + .

[0171] Step 6: Synthesis of Compound A

[0172] In a 100 mL eggplant-shaped bottle, the intermediate A-7 in the previous step was dissolved in NH3 / MeOH (45 mL) solution, the nitrogen was replaced by vacuum three times, and the mixture was placed in a 45°C oil bath, and the tube was sealed and reacted overnight. The reaction of the raw material was basically complete by thin layer chromatography, the system was spin-dried, and the crude product was purified by column chromatography to obtain a brown solid compound A (0.4 g). The total yield of step 5 and step 6 was 46.87%.

[0173] MS (m / z): 281.1 [M+H] + .

[0174] 1 H NMR(400MHz,DMSO-d6)δ8.40(br,2H),7.37(s,1H),7.28(s,1H),4.28-4.21(m,1H),4.18-4.12(m,1 H),3.95-3.85(m,1H),3.38-3.34(m,2H),3.24-3.21(m,2H),2.14-2.06(m,1H),2.07-1.94(m,1H).

[0175] 2. Preparation of Common Intermediate B

[0176]

[0177] Step 1: Synthesis of compound B-2

[0178] In a 100mL eggplant-shaped bottle, the starting material B-1 (1.95g, 10mmol) was dissolved in 40mL acetic acid. After replacing the nitrogen, NaBH3CN (1.89g, 30mmol) was added in batches under ice bath conditions, and the reaction was restored to room temperature for 4 hours. Thin layer chromatography detected that the raw material was basically reacted completely, and the system was adjusted to pH>7 by adding sodium hydroxide aqueous solution, and EA was extracted three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown liquid crude product. The organic layer was dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain a light yellow liquid compound B-2 (1.87g) with a yield of 94.8%.

[0179] MS (m / z): 198.2 [M+H] + .

[0180] Step 2: Synthesis of compound B-4

[0181] In a 100mL eggplant-shaped bottle, the intermediate B-2 (1.87g, 9.5mmol) was dissolved in 20mL of anhydrous pyridine, stirred under an ice bath, and after replacing nitrogen, compound B-3 (0.95g, 9.5mmol) was added in batches, and the ice bath was removed and the reaction was allowed to proceed overnight at room temperature. Thin layer chromatography detected that the raw materials were basically reacted completely, and 6M hydrochloric acid was added to adjust to acidity, EA was extracted three times, the organic phases were combined, the organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown liquid crude product, and the organic layer was dried and concentrated. The crude product was purified by silica gel column chromatography to obtain a pink solid compound B-4 (2.79g) with a yield of 99.7%.

[0182] MS (m / z): 298.3 [M+H] + .

[0183] Step 3: Synthesis of compound B-5

[0184] In a 50mL microwave reaction bottle, the intermediate B-4 (2.79g, 9.4mmol) was dissolved in 45mL trifluoromethanesulfonic acid solution, and then a catalytic amount of AlCl3 was added to the reaction system, the nitrogen was replaced, and the reaction was set at 160°C in a microwave reactor for 1h. The raw material was basically reacted completely by thin layer chromatography, and 1M sodium hydroxide solution was added to adjust to alkalinity, DCM was extracted, the organic phases were combined, the organic phases were washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product, which was a gray solid compound B-5 (1.56g), which was directly used for the next step without purification.

[0185] MS (m / z): 280.1 [M+H] + .

[0186] Step 4: Synthesis of compound B-6

[0187] In a 100mL eggplant-shaped bottle, the purified intermediate B-5 (1.56g, 5.6mmol) was dissolved in 50mL trifluoroacetic acid, cooled in an ice bath, triethylsilane (3.24g, 27.9mmol) was slowly added, and after replacing nitrogen, the mixture was transferred to 45°C for overnight reaction. The raw material was basically reacted completely by thin layer chromatography, and the system was adjusted to pH>7 by adding saturated sodium bicarbonate, extracted with EA, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain a light yellow liquid compound B-6 (1.35g) with a yield of 91.2%.

[0188] MS (m / z): 266.0 [M+H] + .

[0189] Step 5: Synthesis of compound B-7

[0190] In a 100 mL eggplant-shaped bottle, the intermediate B-6 (1.35 g, 5.1 mmol) was dissolved in 50 mL of dichloromethane, stirred under an ice bath, and TMEDA (1.52 g, 13.1 mmol) and TMSI (2.62 g, 13.1 mmol) were added in batches. After replacing the nitrogen, the mixture was stirred under an ice bath for 2 h. I2 (1.81 g, 7.1 mmol) was added, the nitrogen was replaced, and the mixture was stirred under an ice bath for 2 h. The reaction of the raw material was basically complete according to TLC. Water was added dropwise to quench the reaction, and the mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain a solid B-7, which was directly used for the next step without further purification.

[0191] MS (m / z): 391.9 [M+H] + .

[0192] Step 6: Synthesis of Compound B

[0193] In a 250 mL eggplant-shaped bottle, the intermediate B-7 was dissolved in NH3 / MeOH (100 mL) solution, the nitrogen was replaced, and the tube was sealed and reacted overnight at 45°C. Thin layer chromatography showed that the raw material was basically reacted. The reaction solution was spin-dried and the crude product was purified by silica gel column chromatography to obtain brown solid powder compound B (1.12 g) with a yield of 78.5%.

[0194] MS (m / z): 281.0 [M+H] + .

[0195] Example 1: Preparation of the target compound 5-benzyl-N-(10-bromo-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-4H-1,2,4-triazacyclopentane-3-carboxamide (I-1)

[0196] The synthetic route of the target compound I-1 is as follows:

[0197]

[0198] Step 1: Synthesis of compound Id-1

[0199] In a 100mL eggplant-shaped reaction bottle, the starting material Ib-1 (1.8g, 12mmol) was dissolved in a mixed solvent of 7.5mL ethanol and 22.5mL ether. Cool under ice bath conditions, slowly add the starting material Ic (1.8g, 12.4mmol), after the addition is complete, replace the nitrogen, remove the ice bath, slowly warm to room temperature and react for 2 hours. Thin layer chromatography detected that the raw material was basically reacted, filtered, and washed with ether. After drying under reduced pressure, a light yellow solid compound Id-1 (1.8g) was obtained with a yield of 60.2%, which was directly used for the next step without purification.

[0200] MS (m / z): 250.1 [M+H] + .

[0201] Step 2: Synthesis of compound Ie-1

[0202] In a 100mL eggplant-shaped reaction bottle, the intermediate Id-1 (1.8g, 7.2mmol) was dissolved in 20mL of anhydrous xylene, and a reflux condenser and a water separator were set up to react at 170°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature and a large amount of solid precipitated. 40mL of ether was added to slurry in an ice bath. The residue was filtered and rinsed with ether to obtain a light yellow solid compound Ie-1 (1.0g) with a yield of 59.8%. It was directly used for the next step without purification.

[0203] MS (m / z): 232.1 [M+H] + .

[0204] Step 3: Synthesis of Compound If-1

[0205] In a 100mL eggplant-shaped reaction bottle, the intermediate Ie-1 (1.0g, 4.3mmol) was dissolved in 20mL of anhydrous THF solution. Then lithium hydroxide (455mg, 10.8mmol) was dissolved in 4mL of water and slowly added dropwise to the reaction system. The reaction was allowed to proceed overnight at room temperature. Thin layer chromatography detected that the raw materials were basically reacted completely, THF was removed under reduced pressure, 6mL of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 1-2. A white solid was gradually precipitated, and the residue was slurried, filtered, and washed with water to obtain a light white solid compound If-1 (873mg) with a yield of 99.4%. It was directly used for the next step without purification.

[0206] MS (m / z): 204.1 [M+H] + .

[0207] 1 H NMR (400MHz, DMSO-d6) δ14.35(s,1H),7.49-7.01(m,5H),4.07(s,2H).

[0208] Step 4: Synthesis of target compound I-1

[0209] Compound B was prepared by referring to “Common Intermediate B”.

[0210] In a 50mL eggplant-shaped bottle, intermediate B (140mg, 0.5mmol), If-1 (152mg, 0.75mmol), HATU (380mg, 1.0mmol), DIPEA (198mg, 1.5mmol) were dissolved in anhydrous DMF (10mL), nitrogen was fully replaced, and the reaction was allowed to proceed overnight at room temperature. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, and ethyl acetate was extracted and separated (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain the target compound I-1 (16mg) as a white solid with a yield of 6.9%.

[0211] MS (m / z): 466.1 [M+H] + .

[0212] 1 H NMR(400MHz,Chloroform-d)δ8.47(s,1H),7.36-7.31(m,5H),7.22(d,J=5.6Hz,1H),7.14(s,1H),6.93(s,1H) ,4.49(s,2H),4.22(s,2H),3.91(d,J=10.4Hz,1H),3.24(s,1H),3.03-2.93(m,3H),2.37(s,1H),2.01(s,1H).

[0213] Example 2: Preparation of the target compound N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-1-[(2,6-difluorophenyl)methyl]-1,2,4-triazacyclopentane-3-carboxamide (II-1)

[0214]

[0215] Step 1: Synthesis of compound IIIc-1

[0216] In a 100mL eggplant-shaped reaction bottle, the starting material IIIa-1 (1.9g, 15mmol) and potassium carbonate (4.14g, 30mmol) were dissolved in 15mL of anhydrous DMF solvent. Cool in an ice bath, slowly add IIIb-1 (3.73g, 18mmol), replace nitrogen after the addition, remove the ice bath and slowly return to room temperature to react overnight. Thin layer chromatography detected that the raw material was basically reacted, water was added to quench the reaction, ethyl acetate was extracted (3*50mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid compound IIIc-1 (1.42g) with a yield of 37.4%. It was directly used for the next step without purification.

[0217] MS (m / z): 254.1 [M+H] + .

[0218] Step 2: Synthesis of compound IIId-1

[0219] In a 100mL eggplant-shaped reaction bottle, the intermediate IIIc-1 (1.42g, 5.6mmol) was dissolved in 32mL of anhydrous THF solution. Then lithium hydroxide (270mg, 11.2mmol) was dissolved in 8mL of water and slowly added dropwise to the reaction system under an ice bath. After the addition was complete, the ice bath was removed and the temperature was restored to room temperature for overnight reaction. Thin layer chromatography detected that the raw material was basically reacted completely, THF was removed under reduced pressure, 8mL of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 1-2. A white solid was gradually precipitated, slurried, filtered, and the filter residue was washed with water to obtain a light white solid IIId-1 (1.05g), with a yield of 78.5%. It was directly used for the next step without purification.

[0220] MS (m / z): 240.1 [M+H] + .

[0221] 1 H NMR (600MHz, DMSO-d6) δ13.33(s,1H),8.81(s,1H),7.54-7.49(m,1H),7.23-7.13(m,2H),5.56(s,2H).

[0222] Step 3: Preparation of target compound II-1

[0223] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0224] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-1 (172mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and separated (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-1 (5mg) with a yield of 6.5%.

[0225] MS (m / z): 502.0 [M+H] + .

[0226] 1 H NMR(400MHz,Chloroform-d)δ8.38(d,J=6.0Hz,1H),8.14(s,1H),7.38(tt,J=8.4,6.4Hz,1H),7. 20(d,J=5.2Hz,2H),7.01-6.94(m,2H),5.49(s,2H),4.59(dd,J=10.2,6.0Hz,1H),4.50(ddd,J=12 .0,10.2,3.2Hz,1H),3.90(dt,J=12.0,10.2Hz,1H),3.37(ddd,J=18.0,12.4,6.0Hz,1H),3.20-2 .94(m,3H),2.48(dddd,J=13.2,5.6,3.6,1.6Hz,1H),2.03(dddd,J=14.0,12.4,10.2,4.4Hz,1H).

[0227] Example 3: Preparation of the target compound 1-benzyl-N-(9-bromo-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-1,2,4-triazacyclopentane-3-carboxamide (II-2)

[0228]

[0229] Step 1: Preparation of compound IIId-2

[0230] Referring to the preparation method of compound IIId-1 in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "benzyl bromide", and the rest of the method was the same to prepare compound IIId-2 (811 mg) with a total yield of 40.0% in two steps.

[0231] MS (m / z): 204.1 [M+H] + .

[0232] 1 H NMR (600MHz, DMSO-d6) δ13.32(s,1H),8.79(s,1H),7.46-7.20(m,5H),5.48(s,2H).

[0233] Step 2: Preparation of target compound II-2

[0234] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0235] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-2 (146mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-2 (6mg) with a yield of 7.5%.

[0236] MS (m / z): 466.1 [M+H] + .

[0237] 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.59(d,J=6.4Hz,1H),7.50-7.17(m,7H),5.50(s,2H),4.50(t,J=8.4Hz,1H),4.25(dt, J=11.2,4.0Hz,1H),3.84(q,J=10.4Hz,1H),3.05(ddd,J=21.6,13.6,5.6Hz,4H),2.19(d,J=13.2Hz,1H),2.11-1.97(m,1H).

[0238] Example 4: Preparation of the target compound N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (II-3)

[0239]

[0240] Step 1: Preparation of compound IIId-3

[0241] Referring to the preparation of intermediate IIId-1 in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-1-fluorobenzene", and the rest of the method was the same to prepare compound IIId-3 (1.56 g) with a total yield of 47.1% for two steps.

[0242] MS (m / z): 222.1 [M+H] + .

[0243] 1 H NMR (600MHz, DMSO-d6) δ13.31(s,1H),8.79(s,1H),7.51-7.35(m,2H),7.29-7.19(m,2H),5.56(s,2H).

[0244] Step 2: Preparation of target compound II-3

[0245] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0246] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-3 (159mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-3 (5mg) with a yield of 6.5%.

[0247] MS (m / z): 484.1 [M+H] + .

[0248] 1 H NMR (400MHz, DMSO-d6) δ8.83 (s, 1H), 8.60 (d, J = 6.4Hz, 1H), 7.46-7.31 (m, 3H), 7.30-7.20 (m, 3H), 5.57 (s ,2H),4.52-4.47(m,1H),4.28-4.21(m,1H),3.88-3.80(m,1H),3.16-2.94(m,4H),2.20-2.15(m,1H),2.10 -1.98(m,1H).

[0249] Example 5: Preparation of the target compound N-(9-bromo-4-oxyde-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (II-4)

[0250]

[0251] Step 1: Preparation of compound IIId-4

[0252] Referring to the preparation of intermediate IIId-1 in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-4-fluorobenzene". The rest of the method was the same to prepare compound IIId-4 (1.65 g) with a total yield of 50.0% for two steps.

[0253] 1 H NMR (600MHz, DMSO-d6) δ13.30(s,1H),8.79(s,1H),7.42-7.38(m,2H),7.24-7.19(m,2H),5.48(s,2H).

[0254] MS (m / z): 222.1 [M+H] + .

[0255] Step 2: Preparation of target compound II-4

[0256] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0257] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-4 (159mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-4 (10mg) with a yield of 9.3%.

[0258] MS (m / z): 484.0 [M+H] + .

[0259] 1H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.60(d,J=6.4Hz,1H),7.46-7.36(m,2H),7.33(d,J=2.0Hz,1H),7.29-7.14(m,3H),5.4 9(s,2H),4.52-4.47(m,1H),4.28-4.22(m,1H),3.88-3.80(m,1H),3.16-2.95(m,4H),2.22-2.15(m,1H),2.09-1.98(m,1H).

[0260] Example 6: Preparation of the target compound N-(9-bromo-4-oxyde-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (II-5)

[0261]

[0262] Step 1: Preparation of compound IIId-5

[0263] Referring to the preparation of intermediate IIId-1 in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "4-(bromomethyl)-1,3-difluorobenzene", and the rest of the method was the same to prepare compound IIId-5 (1.29 g) with a total yield of 54.0% for two steps.

[0264] MS (m / z): 240.1 [M+H] + .

[0265] 1 H NMR (600MHz, DMSO-d6) δ13.31(s,1H),8.78(s,1H),7.51-7.46(m,1H),7.34-7.29(m,1H),7.16-7.12(m,1H),5.53(s,2H).

[0266] Step 2: Preparation of target compound II-5

[0267] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0268] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-5 (172mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-5 (11mg) with a yield of 10.4%.

[0269] MS (m / z): 502.2 [M+H] + .

[0270] 1 H NMR(400MHz, DMSO-d6)δ8.82(s,1H),8.60(d,J=6.4Hz,1H),7.50(td,J=8.8,6.4Hz,1H),7.38-7.26(m,3H),7.15(td,J=8.4,2.8Hz, 1H),5.55(s,2H),4.52-4.47(m,1H),4.28-4.22(m,1H),3.88-3.80(m,1H),3.15-2.95(m,4H),2.22-2.13(m,1H),2.0-1.99(m,1H).

[0271] Example 7: Preparation of the target compound N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (II-6)

[0272]

[0273] Step 1: Preparation of compound IIId-6

[0274] Referring to the preparation of intermediate IIId-1 in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-1,4-difluorobenzene", and the rest of the method was the same to prepare compound IIId-6 (510 mg) with a total yield of 21.3% in two steps.

[0275] MS (m / z): 240.1 [M+H] + .

[0276] 1H NMR (600MHz, DMSO-d6) δ13.34(s,1H),8.79(s,1H),7.39-7.22(m,3H),5.55(s,2H).

[0277] Step 2: Preparation of target compound II-6

[0278] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0279] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-6 (172mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-6 (18mg) with a yield of 12.6%.

[0280] MS (m / z): 502.2 [M+H] + .

[0281] 1 H NMR (400MHz, DMSO-d6) δ8.84 (s, 1H), 8.62 (d, J = 6.4Hz, 1H), 7.39-7.23 (m, 5H), 5.56 (s, 2H), 4.52-4.47 (m ,1H),4.28-4.22(m,1H),3.84(q,J=10.4Hz,1H),3.16-2.95(m,4H),2.22-2.15(m,1H),2.09-1.99(m,1H).

[0282] Example 8: Preparation of the target compound N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(3,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (II-7)

[0283]

[0284] Step 1: Preparation of compound IIId-7

[0285] Referring to the "Preparation of Intermediate IIId-1" in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "3-(bromomethyl)-1,5-difluorobenzene", and the rest of the method was the same to prepare compound IIId-7 (1.06 g) with a total yield of 44.4% in two steps.

[0286] MS (m / z): 240.1 [M+H] + .

[0287] 1 H NMR (600MHz, DMSO-d6) δ13.34(s,1H),8.80(s,1H),7.26-7.22(m,1H),7.09-7.06(m,2H),5.53(s,2H).

[0288] Step 2: Preparation of target compound II-7

[0289] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0290] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-7 (172mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-7 (13mg) with a yield of 7.5%.

[0291] MS (m / z): 502.2 [M+H] + .

[0292] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.63(d,J=6.4Hz,1H),7.42-7.19(m,3H),7.09(d,J=6.8Hz,2H),5.54(s,2H ),4.51(s,1H),4.26(d,J=13.6Hz,1H),3.85(d,J=10.8Hz,1H),3.07(t,J=18.0Hz,4H),2.19(s,1H),2.07(s,1H).

[0293] Example 9: Preparation of the target compound N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide (II-8)

[0294]

[0295] Step 1: Preparation of compound IIId-8

[0296] Referring to the "Preparation of Intermediate IIId-1" in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "4-(bromomethyl)-1,2-difluorobenzene", and the rest of the method was the same to prepare compound IIId-8 (1.08 g) with a total yield of 45.2% for two steps.

[0297] MS (m / z): 240.1 [M+H] + .

[0298] 1 H NMR (600MHz, DMSO-d6) δ13.31(s,1H),8.79(s,1H),7.53-7.42(m,2H),7.21-7.18(m,1H),5.49(s,2H).

[0299] Step 2: Preparation of target compound II-8

[0300] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0301] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-8 (172mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-8 (15mg) with a yield of 11.5%.

[0302] MS (m / z): 502.2 [M+H] + .

[0303] 1H NMR (600MHz, DMSO-d6) δ8.82(s,1H),8.60(d,J=6.6Hz,1H),7.52-7.44(m,2H),7.34(d,J=1.8Hz,1H),7.27(d,J=1.8Hz,1H),7.22-7.20 (m,1H),5.50(s,2H),4.52-4.49(m,1H),4.28-4.23(m,1H),3.88-3.82(m,1H),3.15-2.97(m,4H),2.22-2.17(m,1H),2.08-2.02(m,1H).

[0304] Example 10: Preparation of the target compound N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide (II-9)

[0305]

[0306] Step 1: Preparation of compound IIId-9

[0307] Referring to the "Preparation of Intermediate IIId-1" in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-1-methylbenzene", and the rest of the method was the same to prepare compound IIId-9 (1.16 g) with a total yield of 51.9% in two steps.

[0308] MS (m / z): 218.1 [M+H] + .

[0309] 1 H NMR (600MHz, DMSO-d6) δ13.31(s,1H),8.74(s,1H),7.30-7.16(m,3H),7.09-7.08(m,1H),5.49(s,2H),2.31(s,3H).

[0310] Step 2: Preparation of target compound II-9

[0311] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0312] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-9 (156mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-9 (15mg) with a yield of 12.1%.

[0313] MS (m / z): 480.3 [M+H] + .

[0314] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.60(d,J=6.4Hz,1H),7.34(d,J=2.0Hz,1H),7.28-7.18(m,4H),7.09(d,J=7.6Hz,1H),5.51(s, 2H),4.52-4.47(m,1H),4.29-4.22(m,1H),3.89-3.81(m,1H),3.12-2.95(m,4H),2.33(s,3H),2.24-2.16(m,1H),2.10-1.98(m,1H).

[0315] Example 11: Preparation of the target compound N-(9-bromo-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(4-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide (II-10)

[0316]

[0317] Step 1: Preparation of compound IIId-10

[0318] Referring to the "Preparation of Intermediate IIId-1" in Example 2, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "4-(bromomethyl)-1-methylbenzene", and the rest of the method was the same to prepare compound IIId-10 (930 mg) with a total yield of 43.1% for two steps.

[0319] MS (m / z): 218.1 [M+H] + .

[0320] 1H NMR (400MHz, DMSO-d6) δ13.28(s,1H),8.78(s,1H),7.23-7.17(m,4H),5.42(s,2H),2.28(s,3H).

[0321] Step 2: Preparation of target compound II-10

[0322] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0323] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IIId-10 (156mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound II-10 (15mg) with a yield of 9.5%.

[0324] MS (m / z): 480.1 [M+H] + .

[0325] 1 H NMR (600MHz, DMSO-d6) δ8.80(s,1H),8.57(d,J=6.6Hz,1H),7.33(d,J=1.8Hz,1H),7.27(d,J=2.4Hz,1H),7.25-7.17(m,4H),5.44(s, 2H),4.52-4.48(m,1H),4.29-4.22(m,1H),3.87-3.82(m,1H),3.15-2.98(m,4H),2.29(s,3H),2.21-2.17(m,1H),2.08-2.00(m,1H).

[0326] Example 12: Preparation of the target compound 5-benzyl-N-(9-bromo-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-4H-1,2,4-triazacyclopentane-3-carboxamide (III-1)

[0327]

[0328] Refer to the “Preparation method of common intermediate A” to prepare intermediate A; refer to the “Preparation of compound If-1” in Example 1 to prepare compound If-1.

[0329] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), If-1 (146mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound III-1 (10mg) with a yield of 10.3%.

[0330] MS (m / z): 466.1 [M+H] + .

[0331] 1 H NMR(400MHz,Chloroform-d)δ8.42(d,J=6.0Hz,1H),7.33-7.32(m,4H),7.28-7 .27(m,2H),7.22(s,1H),7.19(s,1H),4.59-4.55(m,1H),4.53-4.47(m,1H),4.1 9(s,2H),3.90(dt,J=12.0,10.0Hz,1H),3.32(ddd,J=18.0,12.4,5.6Hz,1H),3 .20-3.06(m,2H),3.04-2.98(m,1H),2.45(d,J=13.6Hz,1H),2.11-2.00(m,1H).

[0332] Example 13: Preparation of the target compound N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-5-[(4-fluorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide (III-2)

[0333]

[0334] Step 1: Preparation of compound If-2

[0335] Referring to the "Preparation method of compound If-1" in Example 1, only the starting material "2-phenylacetylhydrazine" was replaced with "2-(4-fluorophenyl)-acetylhydrazine", and the rest of the method was the same to prepare compound If-2 (475 mg) with a total yield of 43.1% in three steps.

[0336] MS (m / z): 222.1 [M+H] + .

[0337] 1 H NMR (400MHz, DMSO-d6) δ13.76(s,1H),8.32(s,1H),7.56-6.78(m,4H),4.11-4.03(m,2H).

[0338] Step 2: Preparation of target compound III-2

[0339] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0340] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), If-2 (159mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound III-2 (12mg) with a yield of 11.3%.

[0341] MS (m / z): 484.1 [M+H] + .

[0342] 1 H NMR (400MHz, DMSO-d6) δ14.35(br,1H),8.61(s,1H),7.38-7.29(m,3H),7.27(d,J=2.4Hz,1H),7.18-7.12(m,2H),4.52-4 .49(m,1H),4.26-4.22(m,1H),4.11(s,2H),3.87-3.82(m,1H),3.15-2.97(m,4H),2.19-2.16(m,1H),2.08-2.02(m,1H).

[0343] Example 14: Preparation of the target compound N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-5-[(4-chlorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide (III-3)

[0344]

[0345] Step 1: Preparation of compound If-3

[0346] Referring to the "Preparation method of compound If-1" in Example 1, only the starting material "2-phenylacetohydrazide" was replaced with "2-(4-chlorophenyl)-acetohydrazide", and the rest of the method was the same to prepare compound If-3 (1.07g), with a total yield of 90.3% in three steps.

[0347] MS (m / z): 238.0 [M+H] + .

[0348] 1 H NMR (400MHz, DMSO-d6) δ7.43-7.24(m,4H),4.05(s,2H),3.47(s,2H).

[0349] Step 2: Preparation of target compound III-3

[0350] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0351] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), If-3 (170mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound III-3 (12mg) with a yield of 9.3%.

[0352] MS (m / z): 500.0 [M+H] + .

[0353] 1H NMR(400MHz,DMSO-d6)δ14.47(s,1H),8.63(s,1H),7.44-7.36(m,2H),7.35-7.22(m,4H),4.53-4.49(m,1H), 4.27-4.21(m,1H),4.12(s,2H),3.89-3.81(m,1H),3.15-2.96(m,4H),2.21-2.14(m,1H),2.10-2.00(m,1H).

[0354] Example 15: Preparation of the target compound N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-5-[(2,6-difluorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide (III-4)

[0355]

[0356]

[0357] Step 1: Preparation of compound If-6

[0358] Referring to the "Preparation method of compound If-1" in Example 1, only the starting material "2-phenylacetohydrazide" was replaced with "2-(2,6-difluorophenyl)-acetohydrazide", and the rest of the method was the same to prepare compound If-6 (270 mg) with a total yield of 16.8% in three steps.

[0359] MS (m / z): 240.0 [M+H] + .

[0360] 1 H NMR (600MHz, DMSO-d6) δ13.79(s,1H),7.87-6.94(m,4H),4.04(s,2H).

[0361] Step 2: Preparation of target compound III-4

[0362] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0363] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), If-6 (172mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound III-4 (15mg) with a yield of 9.3%.

[0364] MS (m / z): 502.1 [M+H] + .

[0365] 1 H NMR (400MHz, DMSO-d6) δ14.50(br,1H),8.61(d,J=6.8Hz,1H),7.44-7.38(m,1H),7.33(d,J=2.0Hz,1H),7.26(d,J=2.0Hz,1H),7.16-7.0 9(m,2H),4.53-4.48(m,1H),4.26-4.20(m,1H),4.13(s,2H),3.88-3.81(m,1H),3.13-2.95(m,4H),2.18-2.13(m,1H),2.20-2.10(m,1H).

[0366] Example 16: Preparation of the target compound N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-2-[(2,6-difluorophenyl)methyl]-1,2,4-triazacyclopentane-3-carboxamide (IV-1)

[0367]

[0368] Note: When preparing intermediates IIId and IXd, the same raw materials and the same route are used, and two triazole ester fragments, IIId and IXd, can be obtained through column chromatography purification.

[0369]

[0370] Refer to the “Preparation method of common intermediate A” to prepare intermediate A; refer to the “Preparation of intermediate compound IIId-1” in Example 2 to prepare intermediate IXd-1.

[0371] In a 50mL eggplant-shaped bottle, intermediate A (100mg, 0.36mmol), IXd-1 (172mg, 0.72mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, 20mL of water was added to the system, ethyl acetate was extracted and separated (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound IV-1 (10mg) with a yield of 11.5%.

[0372] MS (m / z): 502.1 [M+H] + .

[0373] 1 H NMR(400MHz,Chloroform-d)δ8.65(d,J=6.0Hz,1H),7.86(s,1H),7.33-7.29(m,1H) ,7.25-7.19(m,2H),6.96-6.88(m,2H),6.04(d,J=2.4Hz,2H),4.60-4.50(m,2H),3.9 5-3.90(m,1H),3.37(ddd,J=18.0,12.6,6.0Hz,1H),3.20-3.09(m,2H),3.01(ddd,J= 16.2, 10.2, 3.0Hz, 1H), 2.50 (dddd, J=13.8, 5.6, 3.6, 1.8Hz, 1H), 2.15-2.07 (m, 1H).

[0374] Example 17: Preparation of the target compound N-(9-bromo-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-6-phenoxypyridineamide (V-1)

[0375]

[0376] Step 1: Synthesis of compound Vc-2

[0377] In a microwave reaction bottle, methyl compound Va-2, compound Vb, copper powder and cesium carbonate were dissolved in 20 mL of anhydrous DMF solvent. Microwave reaction was carried out at 100°C for 30 min. DCM was added for dilution, washed with 10% sodium hydroxide solution, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, dried and concentrated, and flash purified to obtain white solid Vc-2.

[0378] Step 2: Synthesis of compound Vd-2

[0379] In a 100mL eggplant-shaped reaction bottle, the intermediate Vc-2 was dissolved in 4mL of anhydrous THF solution. Then lithium hydroxide was dissolved in 1mL of water and slowly added dropwise to the reaction system under an ice bath. After the addition was complete, the ice bath was removed and the reaction was restored to room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, THF was removed under reduced pressure, 2mL of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 1-2. A white solid was gradually precipitated, pulped, filtered, and the filter residue was washed with water to obtain a light white solid Vd-2, which was directly used for the next step without purification.

[0380] Step 3: Preparation of target compound V-1

[0381] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0382] In a 50mL eggplant-shaped bottle, dissolve intermediate A (112mg, 0.4mmol), Vd-2 (103.2mg, 0.48mmol), HATU (304mg, 0.8mmol), and DIPEA (258mg, 2.0mmol) in DMF (5mL) in turn, and replace nitrogen three times. Under nitrogen protection, react at room temperature overnight. Thin layer chromatography detected that the raw materials were basically reacted completely, and 20mL of water was added to the system, and DCM was extracted and layered (20mL*3 times). The organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound V-1 (20mg) with a yield of 10.5%.

[0383] MS (m / z): 478.1 [M+H] + .

[0384] 1 H NMR (400MHz, DMSO-d6) δ8.66(d,J=6.0Hz,1H),8.05(t,J=7.6Hz,1H),7.81(d,J=7.2Hz,1H),7.49(t,J=7.6Hz,2H),7.39-7.09( m,6H),4.46-4.41(m,1H),4.30-4.23(m,1H),3.82(q,J=10.2Hz,1H),3.18-2.96(m,4H),2.26-2.16(m,1H),2.01-1.94(m,1H).

[0385] Example 18: Preparation of the target compound N-(9-bromo-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-4-phenoxypyridineamide (V-2):

[0386]

[0387] Step 1: Preparation of compound Vd-3

[0388] Referring to the “Preparation of Compound Vd-2” in Example 17, only the starting material “methyl 5-chloropicolinate” was replaced with “methyl 4-chloropicolinate”, and the rest of the method was the same to prepare Compound Vd-3 (86 mg) with a two-step yield of 6.3%.

[0389] MS (m / z): 216.0 [M+H] + .

[0390] Step 2: Preparation of Compound V-2

[0391] Intermediate A was prepared by referring to “Preparation method of common intermediate A”.

[0392] In a 50mL eggplant-shaped bottle, the intermediate Ia-5 (110mg, 0.36mmol), Vd-3 (78mg, 0.36mmol), HATU (273mg, 0.72mmol), DIPEA (233mg, 1.80mmol) were dissolved in anhydrous DMF (8mL), nitrogen was fully replaced, and the reaction was carried out at room temperature overnight. The raw materials were basically reacted completely by thin layer chromatography, 20mL of water was added to the system, and ethyl acetate was extracted and layered (20mL*3 times), the organic phases were combined, washed with saturated sodium chloride solution, dried and filtered with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain a white solid target compound X-2 (15mg) with a yield of 10.8%.

[0393] MS (m / z): 478.1 [M+H] + .

[0394] 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=6.4Hz,1H),8.48(d,J=2.8Hz,1H),8.06(d,J=8.4Hz,1H),7.55-7.44(m,3H),7.38-7.15 (m,5H),4.56-4.50(m,1H),4.32-4.25(m,1H),3.90-3.82(m,1H),3.17-2.97(m,4H),2.29-2.22(m,1H),2.08-1.95(m,1H).

[0395] Example 19: Preparation of the target compound 1-(2,6-difluorophenyl)-N-(4-oxo-9-(2-oxa-6-diazospiro[3,3]heptane-6-yl)-1,2,3,4,6,7-hexahydroazepine[3,2,1-hi]indol-3-yl)-1H-1,2,4-triazole-3-amide (VI-1)

[0396]

[0397] Step 1: Preparation of compound C-1

[0398] 398 mg of intermediate A-6 (1.5 mmol) was added to a 100 mL eggplant-shaped bottle, followed by 15 mL of dioxane, 179 mg of spirocyclic raw material (1.8 mmol), 438 mg of potassium tert-butoxide (3.9 mmol), and 280 mg of ligand BINAP (0.45 mmol). After nitrogen was fully replaced, 137 mg of Pd-cata. (0.15 mmol) was added, and nitrogen was replaced again, and the reaction was carried out at 100° C. overnight. TLC monitored the reaction to be complete, water was added to quench, diatomaceous earth was used for filtration, and the filter residue was washed with DCM. The filtrate was separated, extracted, dried, and concentrated, and the target intermediate C-1 (300 mg) was obtained by column chromatography with a yield of 70.4%.

[0399] MS (m / z): 285.2 [M+H] + .

[0400] Step 2: Preparation of compound C-2

[0401] Referring to the preparation method of intermediate A-7 in common intermediate A, only intermediate A-6 was replaced by intermediate C-1. The rest of the method was the same to obtain the target intermediate, which was directly used in the next step without purification.

[0402] MS (m / z): 411.1 [M+H] + .

[0403] Step 3: Preparation of Compound C

[0404] Referring to the preparation method of common intermediate A, only intermediate A-7 was replaced by intermediate C-2, and the rest of the method was the same to obtain the target intermediate (190 mg), and the yield of the 2-step intermediate was 63.5%.

[0405] Step 4: Preparation of Compound VI-1

[0406] Referring to the preparation method of Example 2, intermediate A was replaced by intermediate C, and the rest of the method was the same to obtain the target molecule (25 mg) with a yield of 7.58%.

[0407] MS (m / z): 521.2 [M+H]+ .

[0408] 1 H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.50(d,J=6.4Hz,1H),7.52(tt,J=8.4,6.8Hz,1H), 7.18(t,J=8.0Hz,2H),6.30(d,J=2.4Hz,1H),6.10(d,J=2.4Hz,1H),5.57(s,2H),4.70(s, 4H),4.36(ddd,J=10.4,6.0,2.0Hz,1H),4.24(ddd,J=11.6,10.0,3.6Hz,1H),3.91(s,4H ),3.73(dt,J=12.0,9.6Hz,1H),3.10-2.85(m,4H),2.21-2.13(m,1H),2.03-1.91(m,1H).

[0409] Example 20: Preparation of reference compound 5-benzyl-N-[(3S)-5-methyl-4-oxyde-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazepan-3-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (GSK2982772):

[0410]

[0411] For the specific synthesis route, please refer to patent CN201580044931.

[0412] MS (m / z): 378.1 [M+H] + .

[0413] 1 H NMR(400MHz,Chloroform-d)δ8.11(d,J=7.2Hz,1H),7.44-7.04(m,10H),5.04(dt,J=11.2,7.2H z,1H),4.66(dd,J=9.6,7.2Hz,1H),4.26(t,J=10.8Hz,1H),4.12(d,J=3.0Hz,2H),3.41(s,3H).

[0414] Example 21: Compounds inhibit TNF-α-induced programmed necrosis in U937 cells

[0415] 1. Experimental reagents: RPMI-1640 culture medium, fetal bovine serum, penicillin-streptomycin double antibody, TNF-α (MCE, HY-P7058), BV6 (MCE, HY-16701), Z-VAD-FMK (MCE, HY-16658B), CCK-8 (Dalian Meilun Biotechnology Co., Ltd., MA0218).

[0416] 2. Experimental instruments: medical low-temperature refrigerator (thermo fisher scientific, 902-ULTS), electric constant temperature water bath (Shanghai Yiheng Scientific Instrument Co., Ltd., CD-420), low-speed centrifuge (Anhui Zhongke Zhongjia Scientific Instrument Co., Ltd., SC-3616), carbon dioxide incubator (Shanghai Yiheng Scientific Instrument Co., Ltd., BPN-150CH (UV)), inverted microscope (Olympus, CKX53), multi-function microplate reader (Thermo Tecan, SPARK), Class II biological safety cabinet (Sujing Antai, BSC-1304ⅡA2), desktop cell counter (Thermo Fisher Scientific, CountessⅡ).

[0417] 3. Cell culture: U937 cells (human histiocytic lymphoma cells) were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution at 37°C in a saturated humidity incubator with 5% CO2. The cell culture flasks were placed vertically in the incubator. Taking T25 culture flasks as an example, the culture medium in the flask was 6-8 mL, and the medium was changed 3-4 times a week.

[0418] 4. Experimental methods: CCK-8 method was used to detect the inhibitory effect of compounds on TNF-α-induced programmed necrosis of U937 cells, and to screen compounds with receptor interacting protein kinase 1 inhibitory activity.

[0419] 4.1 Cell plating:

[0420] (1) Turn on the water bath and adjust the temperature to 37°C. Take the culture medium out of the refrigerator and place it in the water bath to preheat. Take an appropriate amount for use.

[0421] (2) Transfer the cell suspension to a 15 mL sterile centrifuge tube and centrifuge at 850 rpm for 4 min to collect U937 cells;

[0422] (3) Carefully discard the supernatant, add an appropriate amount of culture medium, gently pipette to even out the cells, prepare a single-cell suspension, and count;

[0423] (4) Dilute the cells to 4×10 5 / mL, 90 μL / well was plated in a 96-well plate, so that the cell density in the 96-well plate was 3.6×104 pcs / well, placed in an incubator at 37°C, 5% CO2, saturated humidity for 6 hours, then added with drugs;

[0424] 4.2 Compound dilution and dosing:

[0425] (1) TNF-α was dissolved in PBS to a 100 μg / mL storage solution and aliquoted; Z-VAD-FMK was dissolved in DMSO to a 10 mM storage solution and aliquoted; BV6 was dissolved in DMSO to a 10 mM storage solution and aliquoted; GSK2982772 was dissolved in DMSO to a 10 mM storage solution and aliquoted; Take one tube of each of the above reagent storage solutions and place it at -20°C for use, and store the rest at -80°C and use within the shelf life.

[0426] (2) preparing RPMI-1640 medium containing TNF-α, BV6, and Z-VAD-FMK, 5 μL per well, so that the final concentrations of TNF-α, BV6, and Z-VAD-FMK are 20 ng / mL, 2 μM, and 20 μM;

[0427] (3) The culture medium of each target compound was diluted into 8 concentration gradients by three-fold dilution method, and each concentration was repeated, with 5 μL in each well, and the final concentration was 1000.00 / 333.33 / 111.11 / 37.04 / 12.35 / 4.12 / 1.37 / 0.46 nM;

[0428] (4) Take out the 96-well plate with 90 μL of cell suspension from the incubator, set up a positive control group, a test compound group, and a DMSO (5‰) control group, add 5 μL of RPMI-1640 culture medium containing TNF-α, BV6, and Z-VAD-FMK and 5 μL of culture medium containing the test compound to the positive control group and the test compound group. After culturing for 18 hours after drug addition, perform the CCK-8 experiment.

[0429] (5) Take out the 96-well plate, carefully add 10 μL of CCK-8 reagent to each well, incubate at 37°C for 2 h to 4 h, and measure the absorbance at a wavelength of 450 nm;

[0430] 5. Evaluation of the compound's inhibitory activity on TNF-α-induced U937 programmed necrosis

[0431] Cell survival rate % = (OD value of treatment group - OD value of blank background) / (OD value of DMSO group - OD value of blank background) * 100

[0432] Compound EC 50 The calculations were processed using Graphpad prism 6 software, and the experimental results of the exemplary compounds are shown in Table 1.

[0433] Example 22: Compounds inhibit TNF-α-induced programmed necrosis in HT-29 cells

[0434] 1. Experimental reagents: McCoy's 5A medium, fetal bovine serum, penicillin-streptomycin double antibody, trypsin, PBS, TNF-α (MCE, HY-P7058), BV6 (MCE, HY-16701), Z-VAD-FMK (MCE, HY-16658B), SRB kit (Shanghai Beibo Biotechnology Co., Ltd., BB-4208-500T).

[0435] 2. Experimental instruments: medical low-temperature refrigerator (thermo fisher scientific, 902-ULTS), electric constant temperature water bath (Shanghai Yiheng Scientific Instrument Co., Ltd., CD-420), low-speed centrifuge (Anhui Zhongke Zhongjia Scientific Instrument Co., Ltd., SC-3616), carbon dioxide incubator (Shanghai Yiheng Scientific Instrument Co., Ltd., BPN-150CH (UV)), inverted microscope (Olympus, CKX53), multi-function microplate reader (Thermo Tecan, SPARK), Class II biological safety cabinet (Sujing Antai, BSC-1304ⅡA2), desktop cell counter (Thermo Fisher Scientific, CountessⅡ).

[0436] 3. Cell culture: HT-29 cells (human colon cancer cells) were cultured in McCoy's 5A culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution at 37°C in a saturated humidity incubator with 5% CO2. The medium was changed and the cells were passaged 3-4 times a week.

[0437] 4. Experimental methods: The SRB method was used to detect the inhibitory effect of compounds on TNF-α-induced HT-29 cell programmed necrosis (necroptosis) and to screen compounds with receptor interacting protein kinase 1 inhibitory activity.

[0438] 4.1 Cell plating:

[0439] (1) Turn on the water bath and adjust the temperature to 37°C. Take the culture medium, pancreatic enzyme, etc. out of the refrigerator and place them in the water bath to preheat. Take an appropriate amount for use.

[0440] (2) Use a sterile pipette to discard the old culture medium in the bottle, wash it three times with PBS, and add 1 mL of trypsin (25 cm 2The culture flask was gently shaken to allow trypsin to flow over all the cell surfaces. Digestion was performed in a 37°C incubator. After 2 minutes of digestion, the culture flask was placed under a microscope for observation. When the cytoplasm shrank, the intercellular space increased, and the cells became round, the culture flask was immediately stood up and 4 mL of serum-containing culture medium was added to terminate the digestion.

[0441] (3) Transfer the cell suspension to a 15 mL sterile centrifuge tube and centrifuge at 1000 rpm for 4 min to collect HT-29 cells;

[0442] (4) Carefully discard the supernatant, add an appropriate amount of culture medium, gently pipette to even out the cells, prepare a single-cell suspension, and count;

[0443] (5) Dilute the cells to 3×10 5 / mL, 100 μL / well was plated in a 96-well plate, so that each well of the 96-well plate had 3×10 cells. 4 The cells were placed in an incubator at 37°C, 5% CO2, and saturated humidity for 24 hours before adding the drug.

[0444] 4.2 Compound dilution and dosing:

[0445] (1) TNF-α was dissolved in PBS to a 100 μg / mL storage solution and aliquoted; Z-VAD-FMK was dissolved in DMSO to a 10 mM storage solution and aliquoted; BV6 was dissolved in DMSO to a 10 mM storage solution and aliquoted; GSK2982772 was dissolved in DMSO to a 10 mM storage solution and aliquoted; Take one tube of each of the above reagent storage solutions and place it at -20°C for use, and store the rest at -80°C and use within the shelf life.

[0446] (2) Prepare McCoy's 5A culture medium containing TNF-α, BV6 and Z-VAD-FMK. Add 90 μL of the culture medium containing the test compound to each well of the positive control group and the test compound group, and then add 10 μL of the culture medium containing the test compound to make the final concentrations of TNF-α, BV6 and Z-VAD-FMK 20 ng / mL, 2 μM and 20 μM. Add 90 μL of McCoy's 5A complete culture medium to the DMSO (5‰) control group, and then add 10 μL of DMSO to make the final concentration of 5‰;

[0447] (3) The culture medium of each target compound was diluted into 8 concentration gradients by three-fold dilution method, and each concentration was repeated, with 10 μL in each well, and the final concentration was 1000.00 / 333.33 / 111.11 / 37.04 / 12.35 / 4.12 / 1.37 / 0.46 nM;

[0448] (4) Take out the 96-well plate after culturing for 24 hours from the incubator, carefully aspirate the culture medium in the 96-well plate, set up a positive control group, a test compound group, and a DMSO (5‰) control group, and add 10 μL of the corresponding compound to each group. After culturing for 18 hours after drug addition, perform the SRB experiment;

[0449] (5) Take out the 96-well plate and detect the absorbance according to the instructions of the SRB kit;

[0450] 5. Evaluation of the compound's inhibitory activity against TNF-α-induced HT-29 programmed necrosis

[0451] Cell survival rate % = (OD value of treatment group - OD value of blank background) / (OD value of DMSO group - OD value of blank background) * 100

[0452] Compound EC 50 The calculations were processed using Graphpad prism 6 software, and the experimental results of the exemplary compounds are shown in Table 1.

[0453] Table 1. Inhibitory activity of compounds on HT-29 and U937 cells

[0454]

[0455] Note: ++++≤10nM; 10nM<+++≤100nM; 100nM<++≤200nM; +>200nM.

[0456] Example 23: Inhibitory effect of compounds on hERG ion channels

[0457] 1. Cell culture

[0458] hERG ion channel was stably expressed in HEK293 cells.

[0459] Materials: 0.25% trypsin; DPBS (calcium-free, magnesium-free); DMEM / F-12 (10% FBS+P / S); cells in logarithmic growth phase;

[0460] Operation process:

[0461] 1. 0.25% trypsin; DPBS (calcium-free, magnesium-free); DMEM / F-12 (10% FBS+P / S) were placed in a 37°C constant temperature water bath and preheated for use.

[0462] 2. Take out the cells from the 37℃ CO2 constant temperature incubator and use a pipette to remove the old culture medium in the culture dish.

[0463] 3. Use a pipette to transfer 1 mL of DPBS wash solution to wash twice (Note: place the pipette tip against the wall of the culture dish and add slowly), then gently rotate the culture dish on the table to aspirate the wash solution to completely remove the fetal bovine serum.

[0464] 4. Add 180 μL of trypsin for digestion, gently rotate the culture dish on the table to ensure that the trypsin covers the bottom of the culture dish. Place the cell culture dish in a CO2 constant temperature incubator at 37°C for digestion.

[0465] 5. Take out the digested cells, and then use a pipette to absorb 1 mL of DMEM / F12 (10% FBS+P / S) culture medium, add it along the bottom of the culture dish with appropriate force, and blow it gently, and use a 200 μL pipette to gently blow away the cells.

[0466] 6. Take a certain amount of cells and transfer them to a new 35mm culture dish. Shake the dish so that the cells are evenly dispersed.

[0467] 7. Label the cell type, generation, date, etc. on the lid of the culture dish and place it in a 37°C 5% CO2 incubator for culture.

[0468] 2. Test sample configuration

[0469] The test sample was dissolved in dimethyl sulfoxide (DMSO) to prepare a 9mM storage solution and stored in a -20°C refrigerator. On the day of the test, it was dissolved in the extracellular fluid and prepared to the required concentration. The concentration for electrophysiological testing was 10μM.

[0470] Electrophysiological testing of intracellular and extracellular fluid formula

[0471] Extracellular fluid (mM): NaCl, 137; KCl, 4; CaCl, 1.8; MgCl, 1; HEPES, 10; Glucose, 10. Adjust pH to 7.34 with NaOH. Store at 2-8°C.

[0472] The intracellular solution (mM) is: potassium aspartate, 130; magnesium chloride, 5; ethylene glycol tetraacetic acid (EGTA), 5; N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10. The pH is adjusted to 7.4 with potassium hydroxide. The cells are divided into 1 mL centrifuge tubes and stored in a -80°C refrigerator.

[0473] 3. Electrophysiological testing experimental steps

[0474] All assays were performed at room temperature. Cells were transferred to a perfusion tank and perfused with extracellular solution. Intracellular solution was thawed on the day of the experiment. Electrodes were pulled using PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, and noise was filtered at one-fifth of the sampling frequency.

[0475] The test article is administered by perfusion using a perfusion system that uses its own gravity. During the initial recording period, the peak current amplitude is observed for at least 1 minute until it stabilizes. During this period, the CV% of all peak current amplitudes should be less than 10% to exclude the ups and downs of the initial current. The average of the peak current amplitudes recorded in the last 3 times during the initial recording period is used as the current peak of the negative control. After the initial current stabilizes, the test sample is administered from a low concentration until the peak current recorded in the 3 times stabilizes again or after continuous administration for 5 minutes, the peak current after administration is "unchanged" from that before administration. We define the following two situations as "stable" or "unchanged": 1) if the absolute average of the peak current of 3 consecutive scans exceeds 200pA and the CV value is less than 10%, 2) or the average of the peak current of 3 consecutive scans is between 200pA and 50pA and the CV value is less than 30%. Then the next higher concentration is administered for testing.

[0476] The average peak current of the last three scans of each concentration is used as the peak current of the concentration for data analysis. If the steady state cannot be reached within 5 minutes, the average peak current of the last three scans at this time is used as the peak current of the concentration for data analysis. At the same time, the cell should be discarded and no longer used for higher concentration detection. At least one single cell should be repeated for each concentration.

[0477] 4. Voltage pulse program

[0478] The cells were clamped at -80 mV, then depolarized to 40 mV with a 4 s square wave, and then hyperpolarized to -40 mV with a 2 s square wave to obtain hERG tail currents. This procedure was repeated every 20 s.

[0479] 5. Data processing and fitting

[0480] For each cell, the average of the last three current peaks during the monitoring period (before administration of the test drug) was used as the current peak of the negative control. When each concentration was detected, the average of the last three current peaks was used as the current peak under the action of the concentration for data analysis statistics. The blocking rate of each detection concentration on hERG current was calculated by the following formula:

[0481] (1-peak current recorded after compound perfusion / peak current recorded before compound perfusion) × 100%

[0482] The percentage inhibition of hERG currents at the same test concentration was averaged for all cells recorded.

[0483] IC50 50 The values ​​are fitted by the Hill1 equation (OriginPro):

[0484] Y=START+(END-START)*x^n / (k^n+x^n)

[0485] Where Y = blocking rate of current after perfusion of the test substance; x = concentration of the test substance; k = half inhibitory concentration IC 50 ; START = the blocking percentage recorded after perfusion of the initial concentration of the test substance; END = the blocking percentage recorded when the test substance reaches the plateau phase; n = the number of binding sites of the test substance to different binding sites of the ion channel (Cooperative site).

[0486] Data were analyzed using Excel and OriginPro.

[0487] Table 2. Blocking rate of compounds on hERG ion channels

[0488]

[0489] Example 24: Pharmacokinetics of the compound in SD rats

[0490] 1. Experimental Animals

[0491] SD rats, male, 6-8 weeks old, were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Zhejiang) 2019-0001. The animals were kept in the SPF animal room of Hangzhou Baicheng Pharmaceutical Technology Co., Ltd., experimental animal use license number: SYXK (Zhejiang) 2021-0014, and the animals were used after at least one week of breeding. All experiments were carried out in strict accordance with the relevant regulations on experimental animals.

[0492] 2. Experimental reagents and equipment

[0493] 2.1 Experimental reagents: Dimethyl sulfoxide (DMSO) was purchased from SIGMA-ALDRICH, ammonium acetate and Kolliphor EL were purchased from Aladdin, saline was purchased from Zhejiang Kangjier Pharmaceutical Co., Ltd., and methanol, acetonitrile and formic acid were purchased from Merck.

[0494] 2.2 Experimental materials: Centrifuge tubes of various specifications were purchased from Biosharp; pipettes of various specifications were purchased from Eppendorf.

[0495] 2.3 Experimental equipment: Exion AD-SCIEX TRIPE QUADTM 5500 was purchased from AB SCIEX.

[0496] 3 Experimental plan

[0497] 3.1. Preparation of compound dosing solution:

[0498] 3.1.1 Intravenous injection solution: GSK2982772 and compound VI-1 were prepared into 0.2 mg / mL dosing solution using 5% DMSO + 10% kolliphor EL + 85% Saline as solvent.

[0499] 3.1.2 Intragastric administration solution: GSK2982772 and compound VI-1 were prepared into 0.5 mg / mL administration solution using 5% DMSO + 10% kolliphor EL + 85% Saline as solvent.

[0500] 3.2 Administration of drugs to SD rats

[0501] 1) SD rats were fasted but not watered for at least 12 hours. The oral administration dose was 5.0 mg / kg, and the administration volume was 10 mL / kg; the intravenous administration dose was 0.5 mg / kg, and the administration volume was 2.5 mL / kg. Food was given four hours after administration.

[0502] 4. Experimental Procedure

[0503] After administration of SD rats, about 300 μL of blood was collected from the orbit of each animal, and EDTA-Na2 was used for anticoagulation. The blood was collected at 2 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration of the test substance in the intravenous administration group; the blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration of the test substance in the oral administration group. After collection, the blood was placed in an ice bath and centrifuged within 1 h to separate the plasma (centrifugation conditions: 2000 × g, 10 min, 4 ° C). After protein precipitation treatment, 50 μL of plasma samples were taken and analyzed by UHPLC-MS injection. The test data were analyzed and processed by WinNonLin8.1 pharmacokinetic software to obtain pharmacokinetic parameters.

[0504] 5. Experimental Results

[0505] The pharmacokinetic parameters of the compounds of the present invention are shown in Table 3:

[0506] Conclusion: Compound VI-1 of the present invention has good oral exposure after oral administration, high bioavailability, and a good half-life. After intravenous administration, compound VI-1 has a good half-life, a good clearance rate, and a relatively large steady-state apparent distribution, indicating that the compound has a larger tissue distribution in SD rats than GSK2982772.

[0507] In summary, compound VI-1 has good pharmacokinetic characteristics.

[0508] NA: Not determined.

[0509] Table 3. Pharmacokinetic parameters of the tested compounds

[0510] #imgpt61#

Claims

1. A Benzazepine Ketone derivatives are compounds represented by formula (I), isomers or pharmaceutically acceptable salts thereof: Where: Ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl; R1 is selected from halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, when the C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 When aryl and 5-14 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone, C 1-6 Alkoxysulfoxide, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-14 5- to 14-membered aryl or heteroaryl; Ring B is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, ring B is substituted by at least one substituent R2; X and Y are each independently selected from CR4, OR4, SR4 or NR4, and X and Y are not NR4 at the same time; R2 is selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; L is selected from substituted or unsubstituted 5-6 membered heteroaryl. When the 5-6 membered heteroaryl in L has a substituent, it may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide; W is selected from a linker, -(CH2) n -、-O-、-(CH2) n O(CH2) m -, -CO- or -(CH2) n CO(CH2) m -; R3 is selected from substituted or unsubstituted C 6-14 aryl or 5-14 membered heteroaryl, when the C 6-14 When aryl and 5-14 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide; R4 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide; n and m are each independently selected from 0, 1, 2, 3 or 4, and n and m are not 0 at the same time; The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

2. The benzazepine according to claim 1 A ketone derivative, characterized in that The compound, isomer or pharmaceutically acceptable salt thereof represented by formula I: Where: Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl; Ring B is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, ring B is substituted by at least one substituent R2; X and Y are each independently selected from CR4, OR4, SR4 or NR4, and X and Y are not NR4 at the same time; R2 is selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; L is selected from substituted or unsubstituted 5-6 membered heteroaryl. When the 5-6 membered heteroaryl in L has a substituent, it may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide; W is selected from a linker, -(CH2) n -、-O-、-(CH2) n O(CH2) m -, -CO- or -(CH2) n CO(CH2) m -; R3 is selected from substituted or unsubstituted C 6-14 aryl or 5-14 membered heteroaryl, when the C 6-14 When aryl and 5-14 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide; R4 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide; n and m are each independently selected from 0, 1, 2, 3 or 4, and n and m are not 0 at the same time; The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

3. The benzazepine according to claim 2 A ketone derivative, characterized in that The compound represented by formula II, its isomers, or its pharmaceutically acceptable salt: Where: X is selected from CR4, OR4 or SR4; L is selected from triazole, pyridine, pyrazole or pyrazolotetrahydropyridone substituted with at least one substituent; the substituent is selected from one or more of the following groups: hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, hydroxy, cyano, amide, sulfone, sulfoxide, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide; W is selected from -(CH2) n -, -O- or -CO-; R4 and R5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Alkylamide, C 1-6 Alkylsulfone, C 1-6 Alkyl sulfoxide, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy hydroxyl, C 1-6 Alkoxyamino, C 1-6 Alkoxyamide, C 1-6 Alkoxysulfone or C 1-6 Alkoxysulfoxide; n is selected from 1, 2, 3 or 4; q is selected from 1, 2, 3, 4 or 5; The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

4. The benzazepine according to claim 3 A ketone derivative, characterized in that The compound represented by formula II-1, its isomers, or its pharmaceutically acceptable salt: Where: R5 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl; q is selected from 1, 2, 3, 4 or 5.

5. The benzazepine according to claim 3 A ketone derivative, characterized in that The compound represented by formula II-2, its isomers, or its pharmaceutically acceptable salt: Where: R5 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl; q is selected from 1, 2, 3, 4 or 5.

6. The benzazepine according to claim 3 A ketone derivative, characterized in that The compound represented by formula II-3, its isomers, or its pharmaceutically acceptable salt: Where: R5 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl; q is selected from 1, 2, 3, 4 or 5.

7. A Benzazepine Ketone derivatives are compounds, isomers or pharmaceutically acceptable salts thereof having the following structures: 5-Benzyl-N-(10-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-4H-1,2,4-triazacyclopentane-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-1-[(2,6-difluorophenyl)methyl]-1,2,4-triazacyclopentane-3-carboxamide; 1-Benzyl-N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-1,2,4-triazacyclopentane-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(3,5-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(3,4-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(2-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1-(4-methylbenzyl)-1H-1,2,4-triazole-3-carboxamide; 5-Benzyl-N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-4H-1,2,4-triazacyclopentane-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-5-[(4-fluorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-5-[(4-chlorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-5-[(2,6-difluorophenyl)methyl]-4H-1,2,4-triazacyclopentane-3-carboxamide; N-(9-bromo-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-2-[(2,6-difluorophenyl)methyl]-1,2,4-triazacyclopentane-3-carboxamide; N-(9-bromo-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-6-phenoxypicolinamide; N-(9-bromo-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-4-phenoxypicolinamide; 1-(2,6-difluorophenyl)-N-(4-oxo-9-(2-oxa-6-diazospiro[3,3]heptane-6-yl)-1,2,3,4,6,7-hexahydroazepin[3,2,1-hi]indol-3-yl)-1H-1,2,4-triazole-3-amide.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 as an active ingredient, and at least one pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a drug for preventing or treating a disease associated with receptor-interacting protein kinase.

10. The use according to claim 9, characterized in that: The disease is a disease associated with altered receptor interacting protein kinase 1 activity.

11. The use according to claim 10, characterized in that: The disease is selected from tumors, including but not limited to colorectal cancer, lung cancer, liver cancer, pancreatic cancer, breast cancer, lymphoma, melanoma, etc.

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