Benzazepinone compound and use thereof

Abstract

Disclosed in the present invention is a benzazepinone compound. The present invention particularly relates to substance forms of the compound such as a free base, an isomer or a pharmaceutically acceptable salt thereof. Further disclosed in the present invention are a method for preparing the benzazepinone compound and the use of the benzazepinone compound. The compound can be used as an RIPK1 inhibitor for the treatment of diseases, including, but not limited to, tumors, related to the abnormal expression of an RIPK1-mediated signaling pathway, and has a great clinical development value.

Description

Benzazepin*ketone compounds and uses thereof Technical Field

[0001] The present invention belongs to the technical field of small molecule targeted chemical drugs and relates to a benzazepine Ketone compounds, 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 the RIPK1 signaling pathway, 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. By binding to itself or to other death domain-containing molecules (such as TRADD, Fas, and TNFRI), RIPK1 participates in signal transduction following TNF and FasL stimulation, mediating NF-κB activation and inducing apoptosis. Its function is regulated by ubiquitination, zinc finger proteins, and heat shock proteins.

[0003] Diseases or conditions regulated in part by receptor-interacting protein kinase 1-dependent apoptosis, necrosis, or cytokine production include: hematological and solid organ malignancies (Genes Dev. 2013, 27, 1640-1649), bacterial 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 (RIPK1) is a key regulator of apoptosis, participating not only in cell survival signaling but also in multiple pathways of programmed cell death signaling. RIPK1 inhibitors have potential therapeutic effects in treating a variety of diseases, such as cancer, neurodegenerative diseases, and autoimmune diseases.

[0004] The receptor-interacting protein kinase 1 inhibitors currently under development worldwide are mainly divided into three categories based on the compound structure: indole (e.g. Necrostatin-1s), benzazepine The pyrazole class (e.g. GSK-2982772) and pyrazole amide class (e.g. GSK-963, GSK547) are currently in the preclinical research or clinical research stage, and no drugs have been marketed yet. 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, discovered in 2005, is the first small-molecule receptor-interacting protein kinase 1 inhibitor and has been widely used to study the role and mechanism of receptor-interacting protein kinase 1 in human diseases and animal models. In 2008, the mode of action of necrotizing statins was determined, thus establishing it as a key regulator of programmed necrosis. The most advanced development stage of this class of drugs globally is in the preclinical stage.

[0006] Patent WO2014125444 discloses a novel benzazepine This type of derivative is obtained by screening the gene-encoded library. 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 entering Phase II clinical trials are: psoriasis, rheumatoid arthritis, and treatment of ulcerative colitis; in addition to GSK-2982772, GSK-3145095 was put into 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 being GSK-963. However, its poor oral efficacy limited its development. Subsequently, this compound was used as a lead compound for structural optimization to obtain GSK-547. However, this molecule ultimately did not enter the clinic due to poor pharmacokinetic data.

[0008] 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. Domestic and foreign researchers continue to modify the compound structure 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.

[0009] After searching, the patent literature regarding GSK-2982772 and structural modifications and improvements related to GSK-2982772 are as follows:

[0010] 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, benzene and azepine 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.

[0011] Patent CN112079839 discloses a compound of formula 3, which is characterized by: a parent nitrogen nucleus The nitrogen on the ring is fused with the benzene ring (or six-membered aromatic heterocycle) on the left to form a tricyclic structure. Representative compound 15 has an IC 50 =2.6nM, and its oral bioavailability is only 44.8±7.4%. For oral drugs, its bioavailability needs to be improved urgently.

[0012] In summary, how to develop a new receptor-interacting protein kinase 1 inhibitor with good biological activity and significant effects in 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.

[0013] Summary of the Invention

[0014] The technical problem to be solved by the present invention is to provide a novel benzazepine Ketone derivatives 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 The ketone compound is a compound represented by formula I, an isomer thereof or a pharmaceutically acceptable salt thereof:

[0017] Wherein: Ring A is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring, and Ring A is substituted by at least one replace;

[0018] Ring B is selected from a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group, and is substituted by at least one substituent R2;

[0019] X and Y are each independently selected from CR4, OR4, SR4 or NR4, and X and Y are not NR4 at the same time;

[0020] R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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 Halogenated alkyl, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl;

[0021] R2 is selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0022] L is selected from a 5-6 membered heteroaromatic ring substituted by at least one substituent, the substituent being 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 Halogenated alkyl, 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;

[0023] W is selected from the group consisting of a linker, -(CH2) n -、-O-、-(CH2) n O(CH2) m -、-CO-、-(CH2) n CO(CH2) m - one of;

[0024] R3 is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring substituted by at least one substituent, wherein the substituent is selected from one or more of the following groups: hydrogen, 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 Halogenated alkyl, 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;

[0025] R4 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0026] 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;

[0027] The 5-10 membered heteroaromatic ring, the 5-8 membered heteroaryl group, and the 3-6 membered heterocyclic group contain at least one heteroatom, and the heteroatom is selected from N, O, or S.

[0028] Preferably, it is a compound represented by Formula II, an isomer, or a pharmaceutically acceptable salt thereof:

[0029] Wherein: X is selected from CR4, OR4 or SR4;

[0030] R1 is selected from C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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 Halogenated alkyl, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl;

[0031] 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 Halogenated alkyl, 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;

[0032] W is selected from -(CH2) n One of -, -O-, -CO-;

[0033] R4, R5, R6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0034] n is selected from 1, 2, 3 or 4;

[0035] The 5-10 membered heteroaromatic ring, the 5-8 membered heteroaryl group, and the 3-6 membered heterocyclic group contain at least one heteroatom, and the heteroatom is selected from N, O, or S.

[0036] More preferably, it is a compound represented by formula II-1, an isomer, or a pharmaceutically acceptable salt thereof:

[0037] Wherein: X is selected from CR4, OR4 or SR4;

[0038] R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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 Halogenated alkyl, 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 1-6Alkoxysulfoxide, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl;

[0039] R4, R5, R6 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

[0040] More preferably, in formula II-1, X is selected from CH2.

[0041] More preferably, in formula II-1, R5 and R6 are independently selected from hydrogen or halogen.

[0042] More preferably, in formula II-1, R1 is selected from the following structures:

[0043] More preferably, it is a compound represented by formula II-2, an isomer, or a pharmaceutically acceptable salt thereof:

[0044] Wherein: X is selected from CR4, OR4 or SR4;

[0045] R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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 Halogenated alkyl, 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 1-6Alkoxysulfoxide, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl;

[0046] R4, R5, R6 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

[0047] More preferably, in formula II-2, X is selected from CH2.

[0048] More preferably, in formula II-2, R5 and R6 are independently selected from hydrogen or halogen.

[0049] More preferably, in formula II-2, R1 is selected from the following structures:

[0050] More preferably, it is a compound represented by formula II-3, an isomer, or a pharmaceutically acceptable salt thereof:

[0051] Wherein: X is selected from CR4, OR4 or SR4;

[0052] R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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 Halogenated alkyl, 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 1-6Alkoxysulfoxide, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl;

[0053] R4, R5, R6 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

[0054] More preferably, in formula II-3, X is selected from CH2.

[0055] More preferably, in formula II-3, R5 and R6 are independently selected from hydrogen or halogen.

[0056] More preferably, it is a compound represented by formula II-4, an isomer, or a pharmaceutically acceptable salt thereof:

[0057] Wherein: X is selected from CR4, OR4 or SR4;

[0058] R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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 Halogenated alkyl, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl;

[0059] R4, R5, R6 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

[0060] More preferably, in formula II-4, X is selected from CH2.

[0061] More preferably, in formula II-4, R5 and R6 are independently selected from hydrogen or halogen.

[0062] More preferably, it is a compound represented by formula II-5, an isomer, or a pharmaceutically acceptable salt thereof:

[0063] Wherein: X is selected from CR4, OR4 or SR4;

[0064] R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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 Halogenated alkyl, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl;

[0065] R4, R5, R6, R7 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

[0066] More preferably, in formula II-5, X is selected from CH2.

[0067] More preferably, in formula II-5, R5, R6, and R7 are independently selected from hydrogen or halogen.

[0068] The present invention also provides a benzazepine Ketone compounds include the following compounds numbered I-1 to I-13, II-1 to II-4, III-1 to III-32, IV-1, V-1 to V-2, VI-1, VII-1, VIII-1, IX-1, X-1, XI-1, XII-1, XIII-1 to XIII-2, XIV-1, XV-1, and XVI-1, or pharmaceutically acceptable salts thereof:

[0069] Compound I-1: 5-benzyl-N-[9-(cyclopropylethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0070] Compound I-2: 5-benzyl-N-[4-oxyylidene-9-(pyridin-2-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0071] Compound I-3: 5-benzyl-N-[4-oxyylidene-9-(pyridin-3-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0072] Compound I-4: 5-benzyl-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0073] Compound I-5: 5-benzyl-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0074] Compound I-6: 5-benzyl-N-[4-oxyylidene-9-(3,4,5,6-tetrahydro-2H-pyran-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0075] Compound I-7: 5-benzyl-N-[9-(3-hydroxy-3-methylbut-1-ynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0076] Compound I-8: 5-[(4-fluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0077] Compound I-9: 5-[(4-chlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0078] Compound I-10: 5-[(2-chlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0079] Compound I-11: 5-[(2-fluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0080] Compound I-12: 5-[(2,6-difluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0081] Compound I-13: 5-[(2,6-dichlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0082] Compound II-1: 5-benzyl-N-[4-oxyylidene-10-(pyridin-2-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0083] Compound II-2: 5-benzyl-N-[4-oxyylidene-10-(pyridin-3-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0084] Compound II-3: 5-benzyl-N-[10-(cyclopropylethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0085] Compound II-4: 5-benzyl-N-[4-oxyylidene-10-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0086] Compound III-1: 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0087] Compound III-2: 1-[(2,6-difluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide;

[0088] Compound III-3: 1-benzyl-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide;

[0089] Compound III-4: 1-[(2,6-difluorophenyl)methyl]-N-[9-(3-hydroxy-3-methylbut-1-ynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide;

[0090] Compound III-5: 1-[(2,6-difluorophenyl)methyl]-N-[9-(3-methoxyprop-1-ynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide;

[0091] Compound III-6: N-[9-(cyclopropylethynyl)-4-oxylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-1-[(2,6-difluorophenyl)methyl]-1,2,4-triazacyclopentane-3-carboxamide;

[0092] Compound III-7: 1-[(2-fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0093] Compound III-8: 1-[(4-fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0094] Compound III-9: 1-[(2,4-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0095] Compound III-10: 1-[(2,5-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0096] Compound III-11: 1-[(3,5-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0097] Compound III-12: 1-[(3,4-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0098] Compound III-13: 1-[(2-methylphenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0099] Compound III-14: 1-[(4-methylphenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0100] Compound III-15: 1-[(2,6-difluorophenyl)methyl]-N-(4-oxyylidene-9-(piperidin-4-ylethynyl)-1,2,3,4,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl)-1,2,4-triazacyclopentane-3-carboxamide;

[0101] Compound III-16: tert-Butyl 4-((3-(1-(2,6-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-9-yl)ethynyl)piperidine-1-carboxamide;

[0102] Compound III-17: 1-(2,6-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0103] Compound III-18: 1-(3,5-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0104] Compound III-19: 1-(2,5-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0105] Compound III-20: 1-(2,4-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0106] Compound III-21: 1-(2-fluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0107] Compound III-22: 1-(2-methylbenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0108] Compound III-23: 1-(3,4-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0109] Compound III-24: 1-(4-fluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0110] Compound III-25: 1-(4-methylbenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0111] Compound III-26: 1-(2,6-difluorobenzyl)-N-(9-ethynyl-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0112] Compound III-27: 1-(2,6-difluorobenzyl)-N-(9-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0113] Compound III-28: 1-(2,6-difluorobenzyl)-N-(9-((5-formyl-1-vinyl-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0114] Compound III-29: 1-(2,6-difluorobenzyl)-N-(9-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0115] Compound III-30: 1-(2,6-difluorobenzyl)-N-(9-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0116] Compound III-31: N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indol-5-yl)-1-(pyridin-2-ylmethyl)-1H-1,2,4-triazole-3-carboxamide;

[0117] Compound III-32: 1-(4-benzyl)-N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide;

[0118] Compound IV-1: 1-benzyl-N-[4-oxyylidene-10-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0119] Compound V-1: N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-6-phenoxypicolinamide;

[0120] Compound V-2: N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-5-phenoxypicolinamide;

[0121] Compound VI-1: 5-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-3,4,6,7-tetrahydro-2H-[1,4]oxazepano[2,3,4-hi]indol-3-yl}-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0122] Compound VII-1: 5-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-3,4,6,7-tetrahydro-2H-[1,4]thiazepano[2,3,4-hi]indol-3-yl}-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0123] Compound VIII-1: N-{7,7-difluoro-9-[(1-methylpyrazol-4-yl)ethynyl]-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;

[0124] Compound IX-1: 5-benzyl-N-[8-(cyclopropylethynyl)-4-oxyylidene-3,4,6,7-tetrahydro-2H-[1,4]oxazepano[2,3,4-hi]indol-3-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide;

[0125] Compound X-1: 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-3,4,6,7-tetrahydro-2H-[1,4]oxazepano[2,3,4-hi]indol-3-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0126] Compound XI-1: 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-3,4,6,7-tetrahydro-2H-[1,4]thiazepano[2,3,4-hi]indol-3-yl}-1,2,4-triazacyclopentane-3-carboxamide;

[0127] Compound XII-1: N-{7,7-difluoro-9-[(1-methylpyrazol-4-yl)ethynyl]-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;

[0128] Compound XIII-1: 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}pyrazole-3-carboxamide;

[0129] Compound XIII-2: 1-[(4-fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}pyrazole-3-carboxamide;

[0130] Compound XIV-1: 5-(2-benzyl-3-chloro-7-oxylidene-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-yl)-9-[(1-methylpyrazol-4-yl)ethynyl]-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-4-one;

[0131] Compound XV-1: 4-[(3-fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}pyrazole-1-carboxamide;

[0132] Compound XVI-1: 4-[(3-fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-3,4,6,7-tetrahydro-2H-[1,4]oxazepano[2,3,4-hi]indol-3-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide.

[0133] The aforementioned compounds numbered I-1 to I-13, II-1 to II-4, VI-1, VII-1, VIII-1, IX-1, or pharmaceutically acceptable salts thereof, have the following structural formulas:

[0134] The aforementioned compounds numbered III-1 to III-32, IV-1, X-1, XI-1, and XII-1, or pharmaceutically acceptable salts thereof, have the following structural formulas:

[0135] The compound numbered V-1 or a pharmaceutically acceptable salt thereof has the following structural formula:

[0136] The compound numbered V-2 or a pharmaceutically acceptable salt thereof has the following structural formula:

[0137] The aforementioned compounds numbered XIII-1 and XIII-2 or their pharmaceutically acceptable salts have the following structural formulas:

[0138] The compound numbered XIV-1 or a pharmaceutically acceptable salt thereof has the following structural formula:

[0139] The aforementioned compounds numbered XV-1, XVI-1 or pharmaceutically acceptable salts thereof have the following structural formulas:

[0140] 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.

[0141] The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are encompassed, for example, by enantiomers and diastereomers. Compounds of the present invention containing asymmetric carbon atoms may be isolated in optically pure or racemic forms. Optically pure forms may be obtained by resolution of racemic mixtures or by synthesis using chiral starting materials or reagents.

[0142] The terms used herein for compounds containing the aforementioned general structure have the following meanings:

[0143] The "pharmaceutically acceptable salts" of the present invention refer to salts of the compounds of the present invention, prepared by reacting the compounds having specific substituents discovered by the present invention with 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. Examples include 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, and the like.

[0144] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0145] 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 alkyls. The alkyl group may be optionally substituted one or more times with halogen or hydroxy.

[0146] The term "C 1-6 "Fluoroalkyl" 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, and 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.

[0147] 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 with halogen.

[0148] The term "C 1-6 "Fluoroalkoxy" 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 "fluorine-containing alkoxy" include, but are not limited to, trifluoromethoxy and difluoromethoxy.

[0149] The term "C 1-6 "Monoalkylamino" refers to C 1-6 Monoalkyl-substituted amino, wherein alkyl is as defined above. As used herein, "C 1-6 Examples of "monoalkylamino" include, but are not limited to, methylamino, ethylamino, propylamino, cyclopropylamino, and isopropylamino.

[0150] The term "C 1-6 "Dialkylamino" refers to two C 1-6 Alkyl-substituted amino, wherein alkyl is as defined above. As used herein, "C 1-6 Examples of "dialkylamino" include, but are not limited to, dimethylamino, diethylamino, aziridine, azetidinyl, azopentyl, and azohexanyl.

[0151] The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

[0152] 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.

[0153] 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, pharmaceutically acceptable salts, prodrugs (esters or phosphates), stereoisomers, deuterated substances and solvates of the compound.

[0154] 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 and gelatin, wetting agents such as glycerol, disintegrants such as agar and calcium carbonate, absorption accelerators such as quaternary ammonium compounds, surfactants such as cetyl alcohol, adsorption carriers such as sugars (sucrose, lactose), kaolin and bentonite, lubricants such as talc, etc., and flavoring agents, sweeteners, etc. may also be added if necessary.

[0155] The following routes 1 to 5 are overviews of the overall reaction routes of the aforementioned compounds of the present invention:

[0156] Route 1: Preparation of series I target compounds

[0157] Wherein R1, R5, and R6 are defined as above.

[0158] The specific reaction process is as follows:

[0159] Starting materials A-1 and A-2 react under alkaline conditions to obtain intermediate A-3; 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 acid (polyphosphoric acid, methanesulfonic acid, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid) to obtain tricyclic compound A-4 by sealed tube reaction or microwave reaction; 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 intermediate A-5; under acidic conditions, intermediate A-5 is reduced to the ketone carbonyl using triethylsilane to obtain intermediate A-6; In the presence of TMSI (iodotrimethylsilane), 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 A is coupled with a substituted alkyne under the catalysis of a transition palladium metal catalyst to obtain an alkyne-substituted tricyclic compound (Ia); the substituted phenylacetylhydrazine (Ib) undergoes a substitution reaction with intermediate Ic to obtain intermediate Id; intermediate Id then 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 Ia and If undergo an amide condensation reaction to obtain the final target products I-1 to I-13.

[0160] Transition metal palladium catalysts: including but not limited to bis(triphenylphosphine)palladium(II) dichloride, allylpalladium(II) chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl2), palladium(II) acetate, palladium(π-cinnamyl) chloride dimer [(cinnamyl)PdCl]2.

[0161] Typically, the coupling reaction is carried out in the presence of a metal catalyst (including but not limited to a metal palladium catalyst and a metal copper catalyst (such as cuprous iodide)), a phosphine ligand (including but not limited to a BINAP ligand, a DPPF ligand, a Xantphos ligand, a DPBP ligand, an X-phos ligand, a cBRIDP ligand) and a base (including but not limited to triethylamine, pyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate), and in a suitable solvent (including but not limited to N,N-dimethylformamide, dimethylacetamide, acetonitrile, dimethoxyethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, 2 wt% TPGs-750-w / H2O) at elevated temperature or reflux conditions.

[0162] In the amide condensation reaction in the third synthesis scheme, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0163] Route 2: Preparation of target compounds II series

[0164] Wherein R1, R5, and R6 are defined as above.

[0165] The specific reaction process is as follows:

[0166] The starting material B-1 is reduced with sodium cyanoborohydride under acidic conditions to obtain intermediate B-2; subsequently, 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 to the ketone carbonyl group using triethylsilane to obtain intermediate B-6; intermediate B-6 is catalyzed by the Lewis acid TMSI ( In the presence of trimethylsilyl iodide), an iodine atom is introduced at the ortho position of the amide to obtain intermediate B-7; the iodide B-7 undergoes a substitution reaction in ammonia methanol to obtain intermediate B; intermediate B is coupled with a substituted alkyne under the catalysis of a transition metal palladium catalyst to obtain an alkyne-substituted tricyclic compound IIa; the substituted phenylacetylhydrazine (Ib) undergoes a substitution reaction with intermediate Ic to obtain intermediate Id; intermediate Id then 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 IIa and intermediate If undergo an amide condensation reaction to obtain the final target products II-1 to II-4.

[0167] Transition metal palladium catalysts: including but not limited to bis(triphenylphosphine)palladium(II) dichloride, allylpalladium(II) chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl2), palladium(II) acetate, palladium(π-cinnamyl) chloride dimer [(cinnamyl)PdCl]2.

[0168] Typically, the coupling reaction is carried out in the presence of a metal catalyst (including but not limited to a metal palladium catalyst and a metal copper catalyst (such as cuprous iodide)), a phosphine ligand (including but not limited to a BINAP ligand, a DPPF ligand, a Xantphos ligand, a DPBP ligand, an X-phos ligand, a cBRIDP ligand) and a base (including but not limited to triethylamine, pyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate), and in a suitable solvent (including but not limited to N,N-dimethylformamide, dimethylacetamide, acetonitrile, dimethoxyethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, 2 wt% TPGs-750-w / H2O) at elevated temperature or reflux conditions.

[0169] In the amide condensation reaction in the third synthesis scheme, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0170] Route 3: Preparation of target compounds of series III

[0171] Wherein R1, R5, and R6 are defined as above.

[0172] The specific reaction process is as follows:

[0173] Starting materials A-1 and A-2 undergo a substitution reaction under alkaline conditions to obtain intermediate A-3; 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 microwave reaction; 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 intermediate A-5; under acidic conditions, intermediate A-5 is reduced to the ketone carbonyl using triethylsilane to obtain intermediate A-6; in the presence of a Lewis acid T In the presence of MSI (iodotrimethylsilane), 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 A is coupled with a substituted alkyne under the catalysis of a transition metal catalyst palladium to obtain an alkyne-substituted tricyclic compound (III-prol); the substituted benzyl bromide (IIIb) undergoes a substitution reaction with triazolecarboxylic acid methyl ester (IIIa) to obtain intermediate IIIc; intermediate IIIc is then hydrolyzed under alkaline conditions to obtain a substituted triazolecarboxylic acid (IIId); intermediate III-prol undergoes an amide condensation reaction with IIId to obtain the final products III-1 to III-16.

[0174] Transition metal palladium catalysts: including but not limited to bis(triphenylphosphine)palladium(II) dichloride, allylpalladium(II) chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl2), palladium(II) acetate, palladium(π-cinnamyl) chloride dimer [(cinnamyl)PdCl]2.

[0175] Typically, the coupling reaction is carried out in the presence of a metal catalyst (including but not limited to a metal palladium catalyst and a metal copper catalyst (such as cuprous iodide)), a phosphine ligand (including but not limited to a BINAP ligand, a DPPF ligand, a Xantphos ligand, a DPBP ligand, an X-phos ligand, a cBRIDP ligand) and a base (including but not limited to triethylamine, pyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate), and in a suitable solvent (including but not limited to N,N-dimethylformamide, dimethylacetamide, acetonitrile, dimethoxyethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, 2 wt% TPGs-750-w / H2O) at elevated temperature or reflux conditions.

[0176] In the amide condensation reaction in the third synthesis scheme, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0177] Route 4: Preparation of IV series target compounds

[0178] Wherein R1, R5, and R6 are defined as above.

[0179] The specific reaction process is as follows:

[0180] The starting material B-1 is reduced with sodium cyanoborohydride under acidic conditions to obtain intermediate B-2; subsequently, 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 to ketone carbonyl using triethylsilane to obtain intermediate B-6; intermediate B-6 is catalyzed by Lewis acid catalyst (including but not limited to aluminum trichloride, ferric chloride, boron trifluoride, niobium pentachloride, HFIP, oxalyl chloride and trifluoromethanesulfonate, etc. ... In the presence of acid TMSI (iodotrimethylsilane), an iodine atom is introduced at the ortho position of the amide to obtain intermediate B-7; the iodide B-7 undergoes a substitution reaction in ammonia methanol to obtain intermediate B; intermediate B is coupled with a substituted alkyne under the catalysis of a transition metal catalyst palladium to obtain an alkyne-substituted tricyclic compound IV-prol; the substituted benzyl bromide (IIIb) undergoes a substitution reaction with triazolecarboxylic acid methyl ester (IIIa) to obtain intermediate IIIc; intermediate IIIc is then hydrolyzed under alkaline conditions to obtain a substituted triazolecarboxylic acid (IIId); intermediate IV-prol undergoes an amide condensation reaction with IIId to obtain the final target product IV-1.

[0181] Transition metal palladium catalyst (including but not limited to bis(triphenylphosphine)palladium(II) dichloride, allylpalladium(II) chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl2), palladium(II) acetate, palladium(π-cinnamyl) chloride dimer [(cinnamyl)PdCl]2).

[0182] Typically, the coupling reaction is carried out in the presence of a metal catalyst (including but not limited to a metal palladium catalyst and a metal copper catalyst (such as cuprous iodide)), a phosphine ligand (including but not limited to a BINAP ligand, a DPPF ligand, a Xantphos ligand, a DPBP ligand, an X-phos ligand, a cBRIDP ligand) and a base (including but not limited to triethylamine, pyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate), and in a suitable solvent (including but not limited to N,N-dimethylformamide, dimethylacetamide, acetonitrile, dimethoxyethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, 2 wt% TPGs-750-w / H2O) at elevated temperature or reflux conditions.

[0183] In the amide condensation reaction in the third synthesis scheme, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0184] Route 5: Preparation of V series target compounds

[0185] Wherein R1 is defined as described above.

[0186] The specific reaction process is as follows:

[0187] Starting materials A-1 and A-2 undergo a substitution reaction under alkaline conditions to obtain intermediate A-3; intermediate A-3 is subjected to ring closure using a sealed tube reaction or microwave reaction under the catalysis of 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; 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 intermediate A-5; under acidic conditions, intermediate A-5 is reduced to the ketone carbonyl group using triethylsilane. Obtain intermediate A-6; in the presence of Lewis acid TMSI (iodotrimethylsilane), 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 A is coupled with a substituted alkyne under the catalysis of a transition metal catalyst palladium to obtain an alkyne-substituted tricyclic compound (V-prol); intermediate Va undergoes a substitution reaction with Vb to obtain intermediate Vc; intermediate Vc is subsequently hydrolyzed under alkaline conditions to obtain intermediate substituted pyridinecarboxylic acid Vd; intermediate V-prol undergoes an amide condensation reaction with Vd to obtain final products V-1 to V-2.

[0188] Transition metal palladium catalysts: including but not limited to bis(triphenylphosphine)palladium(II) dichloride, allylpalladium(II) chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl2), palladium(II) acetate, palladium(π-cinnamyl) chloride dimer [(cinnamyl)PdCl]2.

[0189] Typically, the coupling reaction is carried out in the presence of a metal catalyst (including but not limited to a metal palladium catalyst and a metal copper catalyst (such as cuprous iodide)), a phosphine ligand (including but not limited to a BINAP ligand, a DPPF ligand, a Xantphos ligand, a DPBP ligand, an X-phos ligand, a cBRIDP ligand) and a base (including but not limited to triethylamine, pyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate), and in a suitable solvent (including but not limited to N,N-dimethylformamide, dimethylacetamide, acetonitrile, dimethoxyethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, 2 wt% TPGs-750-w / H2O) at elevated temperature or reflux conditions.

[0190] In the amide condensation reaction in the third synthesis scheme, the amide condensation agent selected includes but is not limited to: a combination of HOBT and EDCI, HATU, T3P, etc.

[0191] Compared with the prior art, the present invention has the following beneficial effects:

[0192] ① In vitro activity tests have shown that the vast majority of the molecules in this patent exhibit excellent anti-tumor activity;

[0193] ② The compounds of the present application not only exhibit effective anti-systemic inflammatory activity, but also exhibit better activity than the positive control compound GSK2982772;

[0194] ③ Compared with the compound in Example 13 of CN201910518248X, some of the target compounds of the present invention have significantly improved exposure and bioavailability and have good pharmacokinetic characteristics.

[0195] In summary, the compounds of the present application have significant anti-tumor activity and / or anti-inflammatory activity as well as good pharmacokinetic activity, and have great clinical application prospects. DETAILED DESCRIPTION

[0196] The following are specific embodiments of the present invention to further describe the technical solution of the present invention, but the scope of protection 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 scope of protection of the present invention.

[0197] 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.

[0198] The reaction starting materials and common intermediates involved in the embodiments of the present invention can be purchased commercially or prepared in-house. The preparation process of the starting materials and common intermediates that need to be prepared in-house is described in detail as follows:

[0199] Explanation of the abbreviations of solvents or materials used:

[0200] NBS: N-bromosuccinimide; TMEDA: tetramethylethylenediamine; TMSI: trimethylsilyl iodide; DMF: N,N-dimethylformamide; I2: iodine; DCM: dichloromethane; NH3 / MeOH: methanolic ammonia solution; EtOH: ethanol; Xylenes: xylenes; 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.

[0201] 1. Preparation of Common Intermediate A

[0202] Step 1: Synthesis of compound A-3

[0203] In a 250 mL eggplant-shaped flask, starting material A-1 (5.96 g, 50 mmol) was dissolved in 60 mL of anhydrous pyridine. Stirring was performed under ice-cooling, and starting material A-2 (5.00 g, 50 mmol) was slowly added portionwise. After nitrogen was replaced, the ice-cooling bath was removed, and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. The mixture was acidified with 6 M hydrochloric acid and extracted three times with EA. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to afford compound A-3 (10.5 g) as a pink solid in a 95.8% yield.

[0204] MS (m / z): 220.1 [M+H] + .

[0205] Step 2: Synthesis of compound A-4

[0206] In a 50 mL microwave reaction vial, intermediate A-3 (1.75 g, 8.0 mmol) was dissolved in 15 mL of trifluoromethanesulfonic acid solution. A catalytic amount of AlCl₃ was added portionwise, the nitrogen atmosphere was replaced, and the mixture was placed in a microwave reactor at 160°C for 1 h. Thin-layer chromatography confirmed that the reaction was essentially complete. The mixture was adjusted to neutral to alkaline with sodium hydroxide solution, extracted with DCM, and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product was purified by column chromatography to afford compound A-4 (2.40 g) as a gray solid in a 34.5% yield.

[0207] MS (m / z): 202.1 [M+H] + .

[0208] Step 3: Synthesis of Compound A-5

[0209] In a 250 mL eggplant-shaped flask, intermediate A-4 (3.6 g, 18.0 mmol) was dissolved in 60 mL of anhydrous DMF. NBS (6.37 g, 36 mmol) was then added portionwise to the reaction system. The nitrogen atmosphere was replaced and the reaction was allowed to proceed overnight at room temperature. Thin-layer chromatography confirmed the substantial reaction of the starting material. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to afford compound A-5 as a yellow solid, which was used directly in the next step without further purification.

[0210] MS (m / z): 280.1 [M+H] + .

[0211] Step 4: Synthesis of Compound A-6

[0212] In a 250 mL eggplant-shaped flask, A-5 (5.0 g, 18 mmol) was dissolved in 60 mL of anhydrous trifluoroacetic acid under an ice bath. Triethylsilane (10.4 g, 90 mmol) was slowly added in portions while cooling. After replacing the nitrogen atmosphere, the ice bath was removed and the mixture was slowly returned to room temperature. Finally, the mixture was transferred to a 45°C oil bath and allowed to react overnight. Thin-layer chromatography confirmed that the reaction of the starting material was essentially complete. The system was adjusted to pH > 7 by adding saturated sodium bicarbonate. The reaction was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain compound A-6 (2.43 g) as a gray-green solid. The combined yield of Steps 3 and 4 was 51.05%.

[0213] MS (m / z): 266.1 [M+H] + .

[0214] Step 5: Synthesis of Compound A-7

[0215] In a 250 mL eggplant-shaped flask, intermediate A-6 (0.81 g, 3.04 mmol) was dissolved in 30 mL of dichloromethane and stirred under ice. TMEDA (1.06 g, 9.12 mmol) and TMSI (1.83 g, 9.12 mmol) were slowly added portionwise. After replacing the nitrogen atmosphere, the mixture was stirred under ice for 2 h. I2 (1.08 g, 4.26 mmol) was added, the nitrogen atmosphere was replaced, and the mixture was stirred under ice for 2 h. Thin-layer chromatography confirmed that the reaction was essentially complete. The reaction was quenched with saturated sodium bicarbonate and extracted with DCM. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound A-7 as a gray solid, which was used directly in the next reaction without further purification.

[0216] MS (m / z): 391.9 [M+H] + .

[0217] Step 6: Synthesis of Compound A

[0218] In a 100 mL eggplant-shaped flask, intermediate A-7 from the previous step was dissolved in 45 mL of NH3 / MeOH solution. The nitrogen atmosphere was replaced three times under vacuum. The flask was placed in a 45°C oil bath and sealed to react overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. The system was then dried and the crude product was purified by column chromatography to obtain compound A (0.4 g) as a brown solid. The combined yield of Steps 5 and 6 was 46.87%.

[0219] MS (m / z): 281.1 [M+H] + .

[0220] 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).

[0221] 2. Preparation of Common Intermediate B

[0222] Step 1: Synthesis of compound B-2

[0223] In a 100 mL eggplant-shaped flask, starting material B-1 (1.95 g, 10 mmol) was dissolved in 40 mL of acetic acid. After nitrogen was replaced, NaBH3CN (1.89 g, 30 mmol) was added portionwise in an ice bath and allowed to react at room temperature for 4 hours. Thin-layer chromatography confirmed that the reaction was essentially complete. Aqueous sodium hydroxide solution was added dropwise to adjust the pH to >7. The mixture was extracted three times with EA. 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 crude liquid. The organic layer was dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound B-2 (1.87 g), a pale yellow liquid in a yield of 94.8%.

[0224] MS (m / z): 198.2 [M+H] + .

[0225] Step 2: Synthesis of compound B-4

[0226] In a 100 mL eggplant-shaped flask, intermediate B-2 (1.87 g, 9.5 mmol) was dissolved in 20 mL of anhydrous pyridine and stirred under an ice bath. After nitrogen was replaced, compound B-3 (0.95 g, 9.5 mmol) was added portionwise. The ice bath was removed and the mixture was allowed to react overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. The mixture was acidified with 6 M hydrochloric acid and extracted three times with EA. 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 crude brown liquid. The organic layer was dried and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound B-4 (2.79 g) as a pink solid in a 99.7% yield.

[0227] MS (m / z): 298.3 [M+H] + .

[0228] Step 3: Synthesis of compound B-5

[0229] In a 50 mL microwave reaction vial, intermediate B-4 (2.79 g, 9.4 mmol) was dissolved in 45 mL of trifluoromethanesulfonic acid solution. A catalytic amount of AlCl was then added to the reaction system, the nitrogen atmosphere was replaced, and the reaction was set at 160°C in a microwave reactor for 1 h. Thin-layer chromatography confirmed that the reaction was essentially complete. The mixture was adjusted to alkalinity with 1 M sodium hydroxide solution and extracted with DCM. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product, compound B-5 (1.56 g), as a gray solid. This was carried on to the next step without purification.

[0230] MS (m / z): 280.1 [M+H] + .

[0231] Step 4: Synthesis of compound B-6

[0232] In a 100 mL eggplant-shaped flask, the purified intermediate B-5 (1.56 g, 5.6 mmol) was dissolved in 50 mL of trifluoroacetic acid. The mixture was cooled in an ice bath and triethylsilane (3.24 g, 27.9 mmol) was slowly added. After nitrogen was replaced, the mixture was heated to 45°C and allowed to react overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. The pH was adjusted to >7 by adding saturated sodium bicarbonate. The mixture was extracted with EA, and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product was purified by silica gel column chromatography to obtain compound B-6 (1.35 g), a pale yellow liquid, in a yield of 91.2%.

[0233] MS (m / z): 266.0 [M+H] + .

[0234] Step 5: Synthesis of compound B-7

[0235] In a 100 mL eggplant-shaped flask, intermediate B-6 (1.35 g, 5.1 mmol) was dissolved in 50 mL of dichloromethane and stirred on ice. TMEDA (1.52 g, 13.1 mmol) and TMSI (2.62 g, 13.1 mmol) were added portionwise. After replacing the nitrogen atmosphere, the mixture was stirred on ice for 2 h. I2 (1.81 g, 7.1 mmol) was added, the nitrogen atmosphere was replaced, and the mixture was stirred on ice for 2 h. Thin-layer chromatography confirmed that the reaction of the starting material was essentially complete. 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 spin-dried to obtain solid B-7, which was used directly in the next reaction without further purification.

[0236] MS (m / z): 391.9 [M+H] + .

[0237] Step 6: Synthesis of Compound B

[0238] In a 250 mL eggplant-shaped flask, intermediate B-7 was dissolved in 100 mL of NH3 / MeOH solution, the atmosphere was replaced with nitrogen, and the mixture was sealed and reacted at 45°C overnight. Thin-layer chromatography confirmed the reaction was essentially complete. The reaction solution was dried and the crude product was purified by silica gel column chromatography to obtain compound B (1.12 g) as a brown solid powder in a 78.5% yield.

[0239] MS (m / z): 281.0 [M+H] + .

[0240] Example 1: Preparation of the target compound 5-benzyl-N-[9-(cyclopropylethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-1)

[0241] Step 1: Synthesis of compound Id-1

[0242] In a 100 mL eggplant-shaped reaction flask, starting material Ib-1 (1.8 g, 12 mmol) was dissolved in a mixture of 7.5 mL of ethanol and 22.5 mL of diethyl ether. Cooled in an ice bath, starting material Ic (1.8 g, 12.4 mmol) was slowly added dropwise. After complete addition, the atmosphere was replaced with nitrogen, the ice bath was removed, and the mixture was slowly warmed to room temperature for 2 hours. Thin-layer chromatography confirmed the reaction was essentially complete, and the mixture was filtered and washed with diethyl ether. After drying under reduced pressure, compound Id-1 (1.8 g) was obtained as a pale yellow solid in a 60.2% yield. This was used in the next step without purification.

[0243] MS (m / z): 250.1 [M+H] + .

[0244] Step 2: Synthesis of compound Ie-1

[0245] In a 100 mL eggplant-shaped reaction flask, intermediate Id-1 (1.8 g, 7.2 mmol) was dissolved in 20 mL of anhydrous xylene. A reflux condenser and water separator were installed and the reaction was carried out at 170°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, where a large amount of solid precipitated. 40 mL of diethyl ether was added and the mixture was slurried in an ice bath. The residue was filtered and rinsed with diethyl ether to obtain compound Ie-1 (1.0 g) as a pale yellow solid in a yield of 59.8%. This was used in the next reaction without purification.

[0246] MS (m / z): 232.1 [M+H] + .

[0247] Step 3: Synthesis of Compound If-1

[0248] In a 100 mL eggplant-shaped reaction flask, intermediate Ie-1 (1.0 g, 4.3 mmol) was dissolved in 20 mL of anhydrous THF. Lithium hydroxide (455 mg, 10.8 mmol) was then dissolved in 4 mL of water and slowly added dropwise to the reaction system. The reaction was allowed to proceed overnight at room temperature. Thin-layer chromatography confirmed that the starting material had reacted substantially completely. The THF was removed under reduced pressure, 6 mL of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 1-2. A white solid gradually precipitated. The solid was slurried, filtered, and the residue washed with water to afford compound If-1 (873 mg) as a pale white solid in a 99.4% yield. The solid was used in the next step without purification.

[0249] MS (m / z): 204.1 [M+H] + .

[0250] 1H NMR (400MHz, DMSO-d6) δ14.35(s,1H),7.49-7.01(m,5H),4.07(s,2H).

[0251] Step 4: Preparation of Compound Ia-1

[0252] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0253] Intermediate A (0.5 mmol, 1 eq.), ethynylcyclopropane (1.2 eq.), and triethylamine (2 mL) were dissolved in 5 mL of DMF, purged with nitrogen, and stirred for 10 minutes. Under nitrogen, cuprous iodide (0.25 eq.) and bistriphenylphosphine palladium dichloride (0.25 eq.) were added. After further purging with nitrogen, the reaction was allowed to warm overnight. Thin-layer chromatography confirmed the reaction was essentially complete. The mixture was filtered through celite, washed with methanol, and the filtrate was concentrated to dryness. The crude product was used directly in the next reaction without further purification.

[0254] MS (m / z): 267.1 [M+H] + .

[0255] The above-mentioned cuprous iodide and bistriphenylphosphine palladium dichloride are metal synergistic catalysis. According to the common sense of those skilled in the art, it can be known that: generally, the coupling reaction is carried out under the combined action of a metal catalyst (including but not limited to a metal palladium catalyst and a metal copper catalyst (such as cuprous iodide), such as the cuprous iodide and bistriphenylphosphine palladium dichloride used in this embodiment), a phosphine ligand (including but not limited to a BINAP ligand, a DPPF ligand, a Xantphos ligand, a DPBP ligand, an X-phos ligand, a cBRIDP ligand) and a base (including The reaction is carried out in the presence of, but not limited to, triethylamine, pyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate, such as triethylamine used in this embodiment, and in an appropriate solvent (including but not limited to N,N-dimethylformamide, dimethylacetamide, acetonitrile, dimethoxyethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, 2wt% TPGs-750-w / H2O, such as N,N-dimethylformamide used in this embodiment) at elevated temperature or reflux. This reaction belongs to a classic metal-catalyzed coupling reaction, and those skilled in the art can make adaptive modifications to one or more of the transition metal palladium catalyst, phosphine ligand, base, and solvent of the present invention according to the characteristics of the reaction substrate.

[0256] Transition metal palladium catalysts: including but not limited to bis(triphenylphosphine)palladium(II) dichloride, allylpalladium(II) chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl2), palladium(II) acetate, palladium(π-cinnamyl) chloride dimer [(cinnamyl)PdCl]2.

[0257] Step 5: Preparation of target compound I-1

[0258] In a 50 mL eggplant-shaped flask, the purified intermediate Ia-1 (29 mg, 0.11 mmol), HOBT (16 mg, 0.12 mmol), EDCI (22 mg, 0.12 mmol), and NMM (32 mg, 0.31 mmol) were dissolved in DCM (5 mL) in this order, and the atmosphere was purged with nitrogen three times. After stirring at room temperature for 10 minutes, If-1 (32 mg, 0.16 mmol) dissolved in DCM (4 mL) was added under nitrogen, and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the title compound I-1 (10 mg) as a white solid in a yield of 20.8%.

[0259] MS (m / z): 452.1 [M+H] + .

[0260] 1 H NMR(400MHz,Chloroform-d)δ8.44(d,J=6.0Hz,1H),7.31-7.26(m,4H),7.26-7.24(m,2H) ,7.09(d,J=7.2Hz,2H),4.56(t,J=8.4Hz,1H),4.49-4.43(m,1H),4.19(s,2H),3.88(q,J= 10.2Hz,1H),3.26(d,J=14.4Hz,1H),3.12-3.06(m,1H),3.04-2.94(m,2H),2.42(d,J=13. 8Hz,1H),2.03(d,J=13.8Hz,1H),1.46-1.41(m,1H),0.88-0.86(m,2H),0.80-0.79(m,2H).

[0261] Example 2: Preparation of the target compound 5-benzyl-N-[4-oxyylidene-9-(pyridin-2-ylethynyl)-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-2)

[0262] Step 1: Preparation of compound Ia-2

[0263] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0264] Referring to the "Preparation Method of Ia-1" in Example 1, the intermediate "ethynylcyclopropane" was replaced with "2-ethynylpyridine", and the rest of the method was referred to the "Preparation Method of Ia-1" in Example 1 to prepare compound Ia-2 (84 mg) with a yield of 36.8%.

[0265] MS (m / z): 304.1 [M+H] + .

[0266] Step 2: Preparation of target compound I-2

[0267] Refer to the “Preparation method of compound If-1” in Example 1 to prepare intermediate If-1.

[0268] In a 50 mL eggplant-shaped flask, intermediate Ia-2 (84 mg, 0.28 mmol), HOBT (42 mg, 0.31 mmol), EDCI (59 mg, 0.31 mmol), and NMM (85 mg, 0.83 mmol) were dissolved in DCM (5 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, If-1 (85 mg, 0.42 mmol) dissolved in DCM (5 mL) was added under nitrogen and allowed to react overnight at room temperature. Thin-layer chromatography confirmed that the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (3 times with 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the title compound I-2 (10 mg) as a white solid in a yield of 7.35%.

[0269] MS (m / z): 489.1 [M+H] + .

[0270] 1H NMR(400MHz,Chloroform-d)δ8.57(d,J=4.8Hz,1H),8.37(d,J=6.0Hz,1H),7. 71(t,J=7.8Hz,1H),7.49(d,J=7.8Hz,1H),7.26-7.18(m,9H),4.54(dd,J=10.2 ,6.0Hz,1H),4.46-4.40(m,1H),4.13(s,2H),3.86(q,J=10.2Hz,1H),3.29-3. 23(m,1H),3.11-2.94(m,3H),2.39(dt,J=13.8,4.8Hz,1H),2.04-1.98(m,1H).

[0271] Example 3: Preparation of the target compound 5-benzyl-N-[4-oxyylidene-9-(pyridin-3-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-3)

[0272] Step 1: Preparation of compound Ia-3

[0273] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0274] Referring to the "Preparation Method of Ia-1" in Example 1, the intermediate "ethynylcyclopropane" was replaced with "3-ethynylpyridine", and the rest of the method was referred to the "Preparation Method of Ia-1" in Example 1 to prepare compound Ia-3 (52 mg) with a yield of 30.7%.

[0275] MS (m / z): 304.1 [M+H] + .

[0276] Step 2: Preparation of target compound I-3

[0277] Refer to the “Preparation method of compound If-1” in Example 1 to prepare intermediate If-1.

[0278] In a 50 mL eggplant-shaped flask, intermediate Ia-3 (52 mg, 0.17 mmol), HOBT (26 mg, 0.19 mmol), EDCI (36 mg, 0.19 mmol), and NMM (53 mg, 0.52 mmol) were dissolved in anhydrous DCM (3 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, If-1 (53 mg, 0.26 mmol) dissolved in DCM (3 mL) was added under nitrogen and allowed to react at room temperature overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the title compound I-3 (5 mg) as a white solid in a yield of 5.88%.

[0279] MS (m / z): 489.1 [M+H] + .

[0280] 1 H NMR(400MHz,Chloroform-d)δ8.75(s,1H),8.55(dd,J=6.0,1.6Hz,1H),8.45(d,J=6.0Hz,1H), 7.80(dt,J=8.0,2.0Hz,1H),7.33-7.31(m,4H),7.30-7.27(m,5H),4.66-4.59(m,1H),4.51(ddd ,J=13.2,10.4,3.2Hz,1H),4.20(s,2H),3.94(dt,J=12.0,10.0Hz,1H),3.36(ddd,J=18.0,12. 4,5.6Hz,1H),3.23-3.09(m,2H),3.09-3.02(m,1H),2.48(d,J=14.0Hz,1H),2.15-2.03(m,1H).

[0281] Example 4: Preparation of the target compound 5-benzyl-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-4)

[0282] Step 1: Preparation of compound Ia-4

[0283] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0284] Referring to the "Preparation Method of Ia-1" in Example 1, the intermediate "ethynylcyclopropane" was replaced with "4-ethynylpyridine", and the rest of the method was referred to the "Preparation Method of Ia-1" in Example 1 to prepare compound Ia-4 (89 mg) with a yield of 12.3%.

[0285] MS (m / z): 304.1 [M+H] + .

[0286] Step 2: Preparation of target compound I-4

[0287] Refer to the “Preparation method of compound If-1” in Example 1 to prepare intermediate If-1.

[0288] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (89 mg, 0.3 mmol), HOBT (45 mg, 0.33 mmol), EDCI (63 mg, 0.33 mmol), and NMM (91 mg, 0.9 mmol) were dissolved in anhydrous DCM (3 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, If-1 (40 mg, 0.20 mmol) dissolved in DCM (3 mL) was added under nitrogen and allowed to react at room temperature overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. 20 mL of water was added to the system, and the layers were extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford I-4 (20 mg) as a white solid in a 13.7% yield.

[0289] MS (m / z): 489.1 [M+H] + .

[0290] 1 H NMR(400MHz,Chloroform-d)δ8.65-8.53(m,2H),8.46(d,J=6.0Hz,1H),7.38(d ,J=5.2Hz,2H),7.34-7.27(m,6H),7.24-7.23(m,1H),4.62(dd,J=10.4,6.0Hz,1 H),4.51(ddd,J=13.2,10.4,3.2Hz,1H),4.21(s,2H),3.97-3.90(m,1H),3.34(d t,J=12.4,6.0Hz,1H),3.23-2.98(m,4H),2.51-2.44(m,1H),2.14-2.05(m,1H).

[0291] Example 5: Preparation of the target compound 5-benzyl-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-4H-1,2,4-triazacyclopentane-3-carboxamide (I-5)

[0292] Step 1: Preparation of compound Ia-5

[0293] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0294] Referring to the "Preparation Method of Ia-1" in Example 1, the intermediate "ethynylcyclopropane" was replaced with "N-methyl-4-alkynylpyrazole", and the remaining methods were referred to the "Preparation Method of Ia-1" in Example 1 to prepare compound Ia-5 (75 mg) with a yield of 29.4%.

[0295] MS (m / z): 307.1 [M+H] + .

[0296] Step 2: Preparation of target compound I-5

[0297] Refer to the “Preparation method of compound If-1” in Example 1 to prepare intermediate If-1.

[0298] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (75 mg, 0.25 mmol), If-1 (102 mg, 0.50 mmol), HATU (190 mg, 0.5 mmol), and DIPEA (161 mg, 1.25 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the layers were extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the title compound I-5 (15 mg) as a white solid in a 12.3% yield.

[0299] MS (m / z): 492.2 [M+H] + .

[0300] 1H NMR(400MHz,Chloroform-d)δ8.46(d,J=6.0Hz,1H),7.63(s,1H),7.54(s,1H) ),7.35-7.26(m,5H),7.25-7.21(m,1H),7.19(d,J=2.8Hz,2H),4.64-4.56(m, 1H),4.48(dt,J=11.2,10.0,3.2Hz,1H),4.20(s,2H),3.95-3.87(m,4H),3.3 7-3.25(m,1H),3.19-2.93(m,3H),2.44(d,J=13.6Hz,1H),2.12-2.00(m,1H).

[0301] Example 6: Preparation of the target compound 5-benzyl-N-[4-oxyylidene-9-(3,4,5,6-tetrahydro-2H-pyran-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-6)

[0302] Step 1: Preparation of compound Ia-6

[0303] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0304] Referring to the “Preparation Method of Ia-1” in Example 1, the intermediate “ethynylcyclopropane” was replaced with “4-acetylenepyran”, and the rest of the method was referred to the “Preparation Method of Ia-1” in Example 1 to prepare compound Ia-6 (118 mg) with a yield of 100%.

[0305] MS (m / z): 311.1 [M+H] + .

[0306] Step 2: Preparation of target compound I-6

[0307] Refer to the “Preparation method of compound If-1” in Example 1 to prepare intermediate If-1.

[0308] In a 50 mL eggplant-shaped flask, intermediate Ia-6 (118 mg, 0.38 mmol), If-1 (154 mg, 0.76 mmol), HATU (288 mg, 0.76 mmol), and DIPEA (147 mg, 1.14 mmol) were dissolved in anhydrous DMF (5 mL). The nitrogen atmosphere was fully replaced and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the layers were extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the title compound I-6 (16 mg) as a white solid in a 4.0% yield.

[0309] MS (m / z): 496.2 [M+H] + .

[0310] 1 H NMR(400MHz,DMSO-d6)δ8.62(d,J=6.8Hz,1H),7.38-7.20(m,5H),7.13(d,J=13.2Hz,2H),4.51(ddd ,J=9.6,6.8,2.0Hz,1H),4.23(ddd,J=11.6,10.4,4.4Hz,1H),4.12(s,2H),3.87-3.75(m,3H),3.44( ddd,J=11.6,9.2,2.8Hz,3H),3.10-2.95(m,4H),2.87(tt,J=8.8,4.0Hz,1H),2.19(ddd,J=11.6,6. 0,3.2Hz,1H),2.05(ddt,J=14.0,10.0,5.6Hz,1H),1.82(dq,J=12.4,4.0Hz,2H),1.62-1.53(m,2H).

[0311] Example 7: Preparation of the target compound 5-benzyl-N-[9-(3-hydroxy-3-methylbut-1-ynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-7)

[0312] Step 1: Preparation of compound Ia-7

[0313] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0314] Referring to the “Preparation Method of Ia-1” in Example 1, the intermediate “ethynylcyclopropane” was replaced with “2-methyl-3-butyn-2-ol”, and the rest of the method was referred to the “Preparation Method of Ia-1” in Example 1 to prepare compound Ia-7 (98 mg) with a yield of 34.5%.

[0315] MS (m / z): 311.1 [M+H] + .

[0316] Step 2: Preparation of target compound I-7

[0317] Refer to the “Preparation method of compound If-1” in Example 1 to prepare intermediate If-1.

[0318] In a 50 mL eggplant-shaped flask, intermediate Ia-7 (48 mg, 0.17 mmol), If-1 (52 mg, 0.25 mmol), HATU (129 mg, 0.34 mmol), and DIPEA (66 mg, 0.51 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound I-7 (5 mg) as a white solid in a 6.3% yield.

[0319] MS (m / z): 470.3 [M+H] + .

[0320] 1 H NMR (400MHz, DMSO-d6) δ14.42(s,1H),8.63(s,1H),7.35-7.23(m,5H),7.12(d,J=13.2Hz,2H),5.42(s,1H),4.51(t,J=8.4Hz,1H),4. 30-4.19(m,1H),4.12(s,2H),3.85(q,J=10.4Hz,1H),3.10-2.98(m,4H),2.19(d,J=13.6Hz,1H),2.06(d,J=12.4Hz,1H),1.45(s,6H).

[0321] Example 8: Preparation of the target compound 5-[(4-fluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-8)

[0322] Step 1: Preparation of compound If-2

[0323] Referring to the preparation method of compound If-1 in Example 1, only the starting material "2-phenylacetohydrazide" was replaced with "2-(4-fluorophenyl)-acetohydrazide". 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.

[0324] MS (m / z): 222.1 [M+H] + .

[0325] 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).

[0326] Step 2: Preparation of target compound I-8

[0327] Refer to the "Preparation method of compound Ia-4" in Example 4 to prepare intermediate Ia-4.

[0328] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (95 mg, 0.31 mmol), If-2 (139 mg, 0.63 mmol), HATU (238 mg, 0.63 mmol), and DIPEA (121 mg, 0.94 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (3 times with 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound I-8 (21 mg) as a white solid in a 13.3% yield.

[0329] MS (m / z): 507.2 [M+H] + .

[0330] 1 H NMR(600MHz,DMSO-d6)δ14.41(s,1H),8.85-8.44(m,3H),7.56-7.43(m,2H),7.42-7.24(m,4H),7.21-7.09(m,2H),4.58- 4.55(m,1H),4.29-4.21(m,1H),4.12(s,2H),3.92-3.87(m,1H),3.14-3.02(m,4H),2.23-2.19(m,1H),2.13-2.06(m,1H).

[0331] Example 9: Preparation of the target compound 5-[(4-chlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-9)

[0332] Step 1: Preparation of compound If-3

[0333] 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". The rest of the method was the same to prepare compound If-3 (1.07 g) with a total yield of 90.3% in three steps.

[0334] MS (m / z): 238.0 [M+H] + .

[0335] 1 H NMR (400MHz, DMSO-d6) δ7.43-7.24(m,4H),4.05(s,2H),3.47(s,2H).

[0336] Step 2: Preparation of target compound I-9

[0337] Refer to the "Preparation method of compound Ia-4" in Example 4 to prepare intermediate Ia-4.

[0338] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (91 mg, 0.3 mmol), If-3 (85 mg, 0.36 mmol), T3P (50% wt in DMF, 286 mg, 0.45 mmol), and DIPEA (193 mg, 1.5 mmol) were dissolved in DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature for 3 h. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (3 times with 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound I-9 (20 mg) as a white solid in a 12.8% yield.

[0339] MS (m / z): 523.2 [M+H] + .

[0340] 1H NMR(400MHz,DMSO-d6)δ14.41(s,1H),8.80-8.53(m,3H),7.61-7.46(m,2H),7.45-7.10(m,6H),4.59-4.54(m,1 H),4.29-4.22(m,1H),4.13(s,2H),3.93-3.86(m,1H),3.18-2.98(m,4H),2.25-2.16(m,1H),2.15-2.04(m,1H).

[0341] Example 10: Preparation of the target compound 5-[(2-chlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-10)

[0342] Step 1: Preparation of compound If-4

[0343] Referring to the preparation method of compound If-1 in Example 1, only the starting material "2-phenylacetohydrazide" was replaced with "2-(2-chlorophenyl)-acetohydrazide". The rest of the method was the same to prepare compound If-4 (335 mg) with a total yield of 56.6% in three steps.

[0344] 1 H NMR (400MHz, DMSO-d6) δ14.21(s,1H),8.21(s,1H),7.50-7.25(m,4H),4.19(s,2H).

[0345] MS (m / z): 238.0 [M+H] + .

[0346] Step 2: Preparation of target compound I-10

[0347] Refer to the "Preparation method of compound Ia-4" in Example 4 to prepare intermediate Ia-4.

[0348] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (50 mg, 0.17 mmol), If-4 (85 mg, 0.25 mmol), HATU (126 mg, 0.33 mmol), and DIPEA (106 mg, 0.83 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (3 times with 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound I-10 (7 mg) as a white solid in an 8.1% yield.

[0349] MS (m / z): 523.3 [M+H] + .

[0350] 1 H NMR (400MHz, DMSO-d6) δ14.51(br,1H),8.62(d,J=5.2Hz,3H),7.63-7.18(m,8H),4.56(t,J=8.4Hz,1H), 4.24(s,3H),3.90(q,J=10.8Hz,1H),3.18-2.95(m,4H),2.21(d,J=13.6Hz,1H),2.09(d,J=11.6Hz,1H).

[0351] Example 11: Preparation of the target compound 5-[(2-fluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-11)

[0352] Step 1: Preparation of compound If-5

[0353] Referring to the preparation method of compound If-1 in Example 1, only the starting material "2-phenylacetohydrazide" was replaced with "2-(2-fluorophenyl)-acetohydrazide". The rest of the method was the same to prepare compound If-5 (230 mg) with a total yield of 40.5% in three steps.

[0354] MS (m / z): 222.1 [M+H] + .

[0355] 1 H NMR (600MHz, DMSO-d6) δ13.45(s,1H),7.38-7.12(m,5H),4.10(s,2H).

[0356] Step 2: Preparation of target compound I-11

[0357] Refer to the "Preparation method of compound Ia-4" in Example 4 to prepare intermediate Ia-4.

[0358] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (50 mg, 0.17 mmol), If-5 (55 mg, 0.25 mmol), HATU (126 mg, 0.33 mmol), and DIPEA (64 mg, 0.50 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound I-11 (6 mg) as a white solid in a 7.2% yield.

[0359] MS (m / z): 507.3 [M+H] + .

[0360] 1 H NMR(400MHz, DMSO-d6)δ14.30(br,1H),8.62(d,J=5.6Hz,3H),7.68-6.97(m,8H),4.57(t,J=8.8Hz, 1H),4.28-4.15(m,3H),3.93-3.86(m,1H),3.19-2.99(m,4H),2.26-2.16(m,1H),2.15-2.03(m,1H).

[0361] Example 12: Preparation of the target compound 5-[(2,6-difluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-12)

[0362] Step 1: Preparation of compound If-6

[0363] 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". 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.

[0364] MS (m / z): 240.0 [M+H] + .

[0365] 1 H NMR (600MHz, DMSO-d6) δ13.79(s,1H),7.87-6.94(m,4H),4.04(s,2H).

[0366] Step 2: Preparation of target compound I-12

[0367] Refer to the "Preparation method of compound Ia-4" in Example 4 to prepare intermediate Ia-4.

[0368] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (120 mg, 0.40 mmol), If-6 (142 mg, 0.60 mmol), HATU (304 mg, 0.80 mmol), and DIPEA (155 mg, 1.20 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound I-12 (32 mg) as a white solid in a 15.2% yield.

[0369] MS (m / z): 525.2 [M+H] + .

[0370] 1 H NMR (400MHz, DMSO-d6) δ14.31 (s, 1H), 8.67-8.61 (m, 3H), 7.49 (d, J = 5.2Hz, 2H), 7.45-7.35 (m, 3H), 7.13 (t, J = 7.6Hz, 2H), 4.61 -4.52(m,1H),4.28-4.21(m,1H),4.14(s,2H),3.89(q,J=10.2Hz,1H),3.13-3.03(m,4H),2.21-2.17(m,1H),2.13-2.07(m,1H).

[0371] Example 13: Preparation of the target compound 5-[(2,6-dichlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (I-13)

[0372] Step 1: Preparation of compound If-7

[0373] Referring to the preparation method of compound If-1 in Example 1, only the starting material "2-phenylacetohydrazide" was replaced with "2-(2,6-dichlorophenyl)-acetohydrazide". The rest of the method was the same to prepare compound If-7 (310 mg) with a total yield of 36.9% in three steps.

[0374] MS (m / z): 238.0 [M+H] + .

[0375] Step 2: Preparation of target compound I-13

[0376] Refer to the "Preparation method of compound Ia-4" in Example 4 to prepare intermediate Ia-4.

[0377] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (170 mg, 0.56 mmol), If-7 (182 mg, 0.607 mmol), HATU (426 mg, 1.12 mmol), and DIPEA (218 mg, 1.68 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound I-13 (20 mg) as a white solid in a 6.4% yield.

[0378] MS (m / z): 557.3 [M+H] + .

[0379] 1 H NMR(400MHz,DMSO-d6)δ14.61(s,1H),8.65-8.60(m,2H),7.57-7.47(m,4H),7. 38(t,J=9.2Hz,3H),5.35(s,1H),4.56(s,1H),4.40(s,2H),4.25(td,J=10.8,1 0.4,4.4Hz,1H),3.90(q,J=10.4Hz,1H),3.23(d,J=7.2Hz,1H),2.87(d,J=7.2H z,1H),2.20(d,J=12.8Hz,1H),2.11(s,1H),2.00(q,J=7.2Hz,1H),1.77(s,1H).

[0380] Example 14: Preparation of the target compound 5-benzyl-N-[4-oxyylidene-10-(pyridin-2-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (II-1)

[0381] Step 1: Preparation of compound IIa-1

[0382] Intermediate B was prepared by referring to the “Preparation method of common intermediate B”.

[0383] Referring to the “Preparation Method of Ia-2” in Example 2, the intermediate “A” was replaced with the intermediate “B”, and the rest of the method was referred to the “Preparation Method of Ia-2” in Example 2 to prepare compound IIa-1 (100 mg) with a yield of 55.2%.

[0384] MS (m / z): 304.1 [M+H] + .

[0385] Step 2: Preparation of target compound II-1

[0386] Refer to the “Preparation method of compound If-1” in Example 1 to prepare intermediate If-1.

[0387] In a 50 mL eggplant-shaped flask, intermediate IIa-1 (94 mg, 0.31 mmol), HOBT (46 mg, 0.34 mmol), EDCI (65 mg, 0.34 mmol), and NMM (94 mg, 0.93 mmol) were dissolved in DCM (3 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, If-1 (91 mg, 0.45 mmol) dissolved in DCM (3 mL) was added under nitrogen and allowed to react at room temperature overnight. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (3 times with 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound II-1 (20 mg) as a white solid in a yield of 13.2%.

[0388] MS (m / z): 489.2 [M+H] + .

[0389] 1H NMR(600MHz,Chloroform-d)δ8.55(d,J=4.8Hz,1H),8.41(d,J=7.2Hz,1H),7.64(t,J=7.8H z,1H),7.46(d,J=7.8Hz,1H),7.33-7.20(m,6H),7.18-7.12(m,2H),6.98(d,J=7.8Hz,1H), 4.52(t,J=8.4Hz,1H),4.47-4.39(m,1H),4.14(s,2H),3.86(q,J=10.8Hz,1H),3.3-3.24(m ,1H),3.23-3.14(m,2H),3.02(d,J=16.8Hz,1H),2.37(d,J=13.2Hz,1H),2.04-1.97(m,1H).

[0390] Example 15: Preparation of the target compound 5-benzyl-N-[4-oxyylidene-10-(pyridin-3-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (II-2)

[0391] Step 1: Preparation of compound IIa-2

[0392] Intermediate B was prepared by referring to the “Preparation method of common intermediate B”.

[0393] Referring to the “Preparation Method of Ia-3” in Example 3, the intermediate “A” was replaced with the intermediate “B”, and the remaining methods were referred to the “Preparation Method of Ia-3” in Example 3 to prepare compound IIa-2 (110 mg) with a yield of 61.3%.

[0394] MS (m / z): 304.1 [M+H] + .

[0395] Step 2: Preparation of target compound II-2

[0396] Refer to the "Preparation method of compound If-1" in Example 1 to prepare intermediate If-1 (106 mg).

[0397] In a 50 mL eggplant-shaped flask, intermediate IIa-2 (105 mg, 0.35 mmol), HOBT (52 mg, 0.38 mmol), EDCI (73 mg, 0.38 mmol), and NMM (105 mg, 1.04 mmol) were dissolved in DCM (3 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, If-1 (106 mg, 0.52 mmol) dissolved in DCM (3 mL) was added under nitrogen and allowed to react overnight at room temperature. Thin-layer chromatography confirmed the near-complete reaction of the starting materials. 20 mL of water was added to the system, and the layers were extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to yield the target compound II-2 (21 mg) as a white solid in a 12.4% yield.

[0398] MS (m / z): 489.2 [M+H] + .

[0399] 1 H NMR(400MHz,Chloroform-d)δ8.75(d,J=2.0Hz,1H),8.56(dd,J=4.8,1.6Hz,1H),8.49(d,J=6.0Hz,1H),7.8 1(dt,J=8.0,2.0Hz,1H),7.35-7.26(m,6H),7.25-7.21(m,1H),7.17(d,J=8.0Hz,1H),7.06(d,J=8.0Hz,1H) ,4.61(dd,J=10.4,6.0Hz,1H),4.57-4.51(m,1H),4.22(s,2H),3.96(q,J=10.4Hz,1H),3.36(ddd,J=18.0,1 2.4,5.6Hz,1H),3.28-3.19(m,2H),3.11(dt,J=18.0,4.0Hz,1H),2.47(d,J=13.6Hz,1H),2.13-2.06(m,1H).

[0400] Example 16: Preparation of the target compound 5-benzyl-N-[10-(cyclopropylethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (II-3)

[0401] Step 1: Preparation of compound IIa-3

[0402] Intermediate B was prepared by referring to the “Preparation method of common intermediate B”.

[0403] Referring to the “Preparation Method of Ia-1” in Example 1, the intermediate “A” was replaced with the intermediate “B”, and the rest of the method was referred to the “Preparation Method of Ia-1” in Example 1 to prepare compound IIa-3 (110 mg) with a yield of 68.2%.

[0404] MS (m / z): 267.1 [M+H] + .

[0405] Step 2: Preparation of target compound II-3

[0406] Refer to the “Preparation method of compound If-1” in Example 1 to prepare intermediate If-1.

[0407] In a 50 mL eggplant-shaped flask, intermediate IIa-3 (103 mg, 0.39 mmol), HOBT (57 mg, 0.43 mmol), EDCI (81 mg, 0.43 mmol), and NMM (117 mg, 1.16 mmol) were dissolved in anhydrous DCM (4 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, If-1 (117 mg, 0.58 mmol) dissolved in DCM (4 mL) was added under nitrogen and allowed to react overnight at room temperature. Thin-layer chromatography confirmed that the starting materials had essentially reacted. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using preparative liquid chromatography to afford the target compound II-3 (10 mg) as a white solid in a 5.7% yield.

[0408] MS (m / z): 452.2 [M+H] + .

[0409] 1 H NMR(600MHz,Chloroform-d)δ8.46(d,J=6.0Hz,1H),7.31(d,J=4.2Hz,4H),7.27-7.23(m,2H),7 .00(d,J=7.8Hz,1H),6.95(d,J=7.8Hz,1H),4.57(dd,J=10.2,6.0Hz,1H),4.58-4.55(m,1H),4.1 9(s,2H),3.88(q,J=10.8Hz,1H),3.35-3.29(m,1H),3.12-3.04(m,3H),2.47-2.41(m,1H),2.07( dt,J=12.0,10.2,4.2Hz,1H),1.47(dt,J=8.4,3.6Hz,1H),0.91-0.89(m,2H),0.80-0.79(m,2H).

[0410] Example 17: Preparation of the target compound 5-benzyl-N-[4-oxyylidene-10-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (II-4)

[0411] Step 1: Preparation of compound IIa-4

[0412] Intermediate B was prepared by referring to the “Preparation method of common intermediate B”.

[0413] Referring to the “Preparation Method of Ia-4” in Example 4, the intermediate “A” was replaced with the intermediate “B”, and the rest of the method was the same as that in the “Preparation Method of Ia-4” in Example 4 to prepare compound IIa-4 (45 mg) with a yield of 27.6%.

[0414] MS (m / z): 304.1 [M+H] + .

[0415] Step 2: Preparation of target compound II-4

[0416] Intermediate If-1 was prepared by referring to the “Preparation method of intermediate If-1” in Example 1.

[0417] In a 50 mL eggplant-shaped flask, intermediate IIa-4 (40 mg, 0.13 mmol), HOBT (20 mg, 0.15 mmol), EDCI (28 mg, 0.15 mmol), and NMM (40 mg, 0.40 mmol) were dissolved in DCM (2 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, If-1 (40 mg, 0.20 mmol) dissolved in DCM (2 mL) was added under nitrogen and allowed to react overnight at room temperature. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the layers were extracted with DCM (3 times with 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound II-4 (6 mg) as a white solid in a 9.3% yield.

[0418] MS (m / z): 489.2 [M+H] + .

[0419] 1H NMR(400MHz,Chloroform-d)δ11.85(s,1H),8.56-8.38(m,2H),7.80-6.79(m,9H),5.34(s,1H),4.60-4.4 7(m,1H),4.13-3.91(m,2H),3.32-2.97(m,2H),2.40-2.02(m,2H),1.80-1.58(m,2H),1.22-1.20(m,2H).

[0420] Example 18: Preparation of the target compound 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-1)

[0421] Step 1: Synthesis of compound IIIc-1

[0422] In a 100 mL eggplant-shaped reaction flask, starting material IIIa-1 (1.9 g, 15 mmol) and potassium carbonate (4.14 g, 30 mmol) were dissolved in 15 mL of anhydrous DMF. Cooled in an ice bath, IIIb-1 (3.73 g, 18 mmol) was slowly added dropwise. After the addition was complete, the atmosphere was replaced with nitrogen, the ice bath was removed, and the mixture was slowly returned to room temperature and allowed to react overnight. Thin-layer chromatography confirmed that the starting material had essentially reacted. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound IIIc-1 (1.42 g) as a white solid in a 37.4% yield. This was used directly in the next reaction without purification.

[0423] MS (m / z): 254.1 [M+H] + .

[0424] Step 2: Synthesis of compound IIId-1

[0425] In a 100 mL eggplant-shaped reaction flask, intermediate IIIc-1 (1.42 g, 5.6 mmol) was dissolved in 32 mL of anhydrous THF. Lithium hydroxide (270 mg, 11.2 mmol) was then dissolved in 8 mL 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 mixture was allowed to react overnight at room temperature. Thin-layer chromatography confirmed that the starting material had reacted substantially completely. The THF was removed under reduced pressure, 8 mL of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 1-2. A white solid gradually precipitated. The solid was slurried, filtered, and the residue washed with water to afford IIId-1 (1.05 g) as a pale white solid in a 78.5% yield. This solid was used in the next step without purification.

[0426] MS (m / z): 240.1 [M+H] + .

[0427] 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).

[0428] Step 3: Preparation of target compound III-1

[0429] Refer to the “Preparation method of compound Ia-5” in Example 5 to prepare intermediate Ia-5.

[0430] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (110 mg, 0.36 mmol), IIId-1 (172 mg, 0.72 mmol), HATU (273 mg, 0.72 mmol), and DIPEA (233 mg, 1.80 mmol) were dissolved in anhydrous DMF (8 mL). The atmosphere was fully replaced with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the title compound III-1 (80 mg) as a white solid in a yield of 42.24%.

[0431] MS (m / z): 527.2 [M+H] + .

[0432] 1 H NMR(400MHz,Chloroform-d)δ8.39(d,J=6.0Hz,1H),8.14(s,1H),7.63(s,1H),7.54(s,1 H),7.38(tt,J=8.4,6.4Hz,1H),7.19(d,J=3.6Hz,2H),6.97(t,J=8.0Hz,2H),5.49(s,2H ),4.62(dd,J=10.2,6.0Hz,1H),4.50(ddd,J=12.0,10.2,3.2Hz,1H),3.91(s,4H),3.38( ddd,J=18.0,12.8,5.6Hz,1H),3.20-2.96(m,3H),2.54-2.45(m,1H),2.08-1.99(m,1H).

[0433] Example 19: Preparation of the target compound 1-[(2,6-difluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide (III-2)

[0434] Refer to the “Preparation method of compound Ia-4” in Example 4 to prepare intermediate Ia-4; refer to the “Preparation of compound IIId-1” in Example 18 to prepare intermediate IIId-1.

[0435] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (210 mg, 0.7 mmol), HOBT (103 mg, 0.76 mmol), EDCI (146 mg, 0.76 mmol), and NMM (210 mg, 2.1 mmol) were dissolved in anhydrous DCM (5 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, IIId-1 (248 mg, 1.04 mmol) dissolved in DCM (5 mL) was added under nitrogen and allowed to react overnight at room temperature. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (3 times with 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound III-2 (30 mg) as a white solid in a yield of 17.8%.

[0436] MS (m / z): 525.2 [M+H] + .

[0437] 1 H NMR(400MHz,Chloroform-d)δ8.60(d,J=5.2Hz,2H),8.38(d,J=6.0Hz,1H),8.15(s, 1H),7.43-7.34(m,3H),7.29(s,2H),6.98(t,J=8.0Hz,2H),5.50(s,2H),4.68-4.60( m,1H),4.52(ddd,J=12.0,10.2,3.2Hz,1H),3.94(dt,J=12.0,10.2Hz,1H),3.41(ddd ,J=18.0,12.4,5.6Hz,1H),3.23-2.99(m,3H),2.55-2.49(m,1H),2.11-2.00(m,1H).

[0438] Example 20: Preparation of the target compound 1-benzyl-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacycloheptaino[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide (III-3)

[0439] Step 1: Preparation of compound IIId-2

[0440] Referring to the preparation method of compound IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "benzyl bromide". The rest of the method was the same to prepare compound IIId-2 (811 mg) with a total yield of 40.0% for two steps.

[0441] MS (m / z): 204.1 [M+H] + .

[0442] 1 H NMR (600MHz, DMSO-d6) δ13.32(s,1H),8.79(s,1H),7.46-7.20(m,5H),5.48(s,2H).

[0443] Step 2: Preparation of target compound III-3

[0444] Refer to the "Preparation method of compound Ia-4" in Example 4 to prepare intermediate Ia-4.

[0445] In a 50 mL eggplant-shaped flask, intermediate Ia-4 (95 mg, 0.31 mmol), IIId-2 (127 mg, 0.63 mmol), HATU (238 mg, 0.63 mmol), and DIPEA (121 mg, 0.94 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react overnight at room temperature. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the title compound III-3 (21 mg) as a white solid in a 13.7% yield.

[0446] MS (m / z): 489.2 [M+H] + .

[0447] 1H NMR(600MHz,DMSO-d6)δ8.84(s,1H),8.68-8.56(m,3H),7.56-7.46(m,2H),7.44-7.25(m,7H),5.50(s,2H),4.5 7-4.53(m,1H),4.30-4.23(m,1H),3.93-3.86(m,1H),3.17-3.00(m,4H),2.23-2.20(m,1H),2.11-2.04(m,1H).

[0448] Example 21: Preparation of the target compound 1-[(2,6-difluorophenyl)methyl]-N-[9-(3-hydroxy-3-methylbut-1-ynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide (III-4)

[0449] Refer to Example 7 “Preparation of Compound Ia-7” to prepare intermediate Ia-7; refer to Example 18 “Preparation of Compound IIId-1” to prepare intermediate IIId-1.

[0450] In a 50 mL eggplant-shaped flask, intermediate Ia-7 (50 mg, 0.18 mmol), IIId-1 (63 mg, 0.26 mmol), HATU (134 mg, 0.35 mmol), and DIPEA (68 mg, 0.53 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound III-4 (10 mg) as a white solid in an 11.4% yield.

[0451] MS (m / z): 506.3 [M+H] + .

[0452] 1H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.58(d,J=6.8Hz,1H),7.52(p,J=7.6Hz,1H),7.27-7.06(m,4H),5.58(s,2H),5.42(s,1H),4.48(t,J =8.4Hz,1H),4.24(td,J=11.2,4.4Hz,1H),3.85(q,J=10.4Hz,1H),3.15-2.93(m,4H),2.21-2.16(m,1H),2.08-1.98(m,1H),1.45(s,6H).

[0453] Example 22: Preparation of the target compound 1-[(2,6-difluorophenyl)methyl]-N-[9-(3-methoxyprop-1-ynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide (III-5)

[0454] Step 1: Preparation of compound III-5-1

[0455] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0456] Referring to the “Preparation Method of Ia-1” in Example 1, the intermediate “ethynylcyclopropane” was replaced with “3-methoxy-1-propyne”, and the rest of the method was referred to the “Preparation Method of Ia-1” in Example 1 to prepare compound III-5-1 (160 mg) with a yield of 59.3%.

[0457] MS (m / z): 271.2 [M+H] + .

[0458] Step 2: Preparation of target compound III-5

[0459] Refer to the "Preparation of Compound IIId-1" in Example 18 to prepare Intermediate IIId-1.

[0460] In a 50 mL eggplant-shaped flask, intermediate III-5-1 (51 mg, 0.20 mmol), IIId-1 (48 mg, 0.20 mmol), HATU (152 mg, 0.40 mmol), and DIPEA (78 mg, 0.60 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully replaced with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the title compound III-5 (5 mg) as a white solid in a 5.1% yield.

[0461] MS (m / z): 492.3 [M+H] + .

[0462] 1 H NMR(400MHz, DMSO-d6)δ8.86(s,1H),8.59(d,J=6.8Hz,1H),7.56-7.48(m,1H),7.29-7.12(m,4H),5.58(s,2H),4.50(ddd,J=9.6,6.8,2.0Hz,1H),4 .31(s,2H),4.27-4.19(m,1H),3.85(q,J=10.4Hz,1H),3.32(s,3H),3.13 -2.97(m,4H),2.21(d,J=3.6Hz,1H),2.05(ddd,J=14.4,10.8,4.4Hz,1H).

[0463] Example 23: Preparation of the target compound N-[9-(cyclopropylethynyl)-4-oxyylidene-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 (III-6)

[0464] Refer to the “Preparation of Compound Ia-1” in Example 1 to obtain Compound Ia-1; refer to the “Preparation of Compound IIId-1” in Example 18 to obtain Intermediate IIId-1.

[0465] In a 50 mL eggplant-shaped flask, intermediate Ia-1 (120 mg, 0.45 mmol), IIId-1 (160 mg, 0.67 mmol), HATU (342 mg, 0.90 mmol), and DIPEA (175 mg, 1.35 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound III-6 (53 mg) as a white solid in a 24.2% yield.

[0466] MS (m / z): 488.2 [M+H] + .

[0467] 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.57(d,J=6.4Hz,1H),7.51(q,J=7.6Hz,1H ),7.33-6.95(m,4H),5.57(s,2H),4.47(t,J=8.4Hz,1H),4.22(td,J=11.2,4.0Hz ,1H),3.83(q,J=10.4Hz,1H),3.15-2.87(m,4H),2.17(d,J=13.6Hz,1H),2.03(t, J=12.4Hz,1H),1.51(p,J=6.8,1H),0.86(d,J=8.0Hz,2H),0.69(d,J=5.2Hz,2H).

[0468] Example 24: Preparation of the target compound 1-[(2-fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-7)

[0469] Step 1: Preparation of compound IIId-3

[0470] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-1-fluorobenzene". 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.

[0471] MS (m / z): 222.1 [M+H] +.

[0472] 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).

[0473] Step 2: Preparation of target compound III-7

[0474] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0475] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (107 mg, 0.35 mmol), IIId-3 (78 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (137 mg, 1.05 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react overnight at room temperature. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound III-7 (10 mg) as a white solid in a 5.5% yield.

[0476] MS (m / z): 510.3 [M+H] + .

[0477] 1H NMR(600MHz, DMSO-d6)δ8.82(s,1H),8.60(d,J=6.6Hz,1H),8.03(s,1H),7.65(s,1H),7.45-7.41(m,1H),7.39-7.36(m,1H),7.29-7.17 (m,4H),5.57(s,2H),4.53-4.50(m,1H),4.29-4.23(m,1H),3.89-3.83(m,4H),3.15-2.96(m,4H),2.24-2.17(m,1H),2.11-2.01(m,1H).

[0478] Example 25: Preparation of the target compound 1-[(4-fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-8)

[0479] Step 1: Preparation of compound IIId-4

[0480] Referring to the preparation of intermediate IIId-1 in Example 18, 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.

[0481] 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).

[0482] MS (m / z): 222.1 [M+H] + .

[0483] Step 2: Preparation of target compound III-8

[0484] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0485] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (107 mg, 0.35 mmol), IIId-4 (78 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (137 mg, 1.05 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound III-8 (12 mg) as a white solid in a 6.5% yield.

[0486] MS (m / z): 510.3 [M+H] + .

[0487] 1H NMR(600MHz,DMSO-d6)δ8.82(s,1H),8.60(d,J=6.6Hz,1H),8.03(s,1H),7.65(s,1H),7.43-7.36(m,2H),7.26-7.15(m,4H),5 .49(s,2H),4.53-4.50(m,1H),4.27-4.23(m,1H),3.89-3.84(m,4H),3.13-2.97(m,4H),2.22-2.18(m,1H),2.09-2.02(m,1H).

[0488] Example 26: Preparation of the target compound 1-[(2,4-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-9)

[0489] Step 1: Preparation of compound IIId-5

[0490] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "4-(bromomethyl)-1,3-difluorobenzene". 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.

[0491] MS (m / z): 240.1 [M+H] + .

[0492] 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).

[0493] Step 2: Preparation of target compound III-9

[0494] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0495] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (107 mg, 0.35 mmol), IIId-5 (84 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (137 mg, 1.05 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react overnight at room temperature. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound III-9 (15 mg) as a white solid in a 10.2% yield.

[0496] MS (m / z): 528.3 [M+H] + .

[0497] 1 H NMR(600MHz,DMSO-d6)δ8.81(s,1H),8.59(d,J=6.6Hz,1H),8.03(s,1H),7.65(s,1H),7.51-7.47(m,1 H),7.32(td,J=10.2,3.0Hz,1H),7.23(s,1H),7.20(s,1H),7.14(td,J=8.4,2.4Hz,1H),5.54(s,2H), 4.53 -4.50(m,1H),4.29-4.20(m,1H),3.89-3.83(m,4H),3.14-2.96(m,4H),2.22-2.18(m,1H),2.08-2.02(m,1H).

[0498] Example 27: Preparation of the target compound 1-[(2,5-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-10)

[0499] Step 1: Preparation of compound IIId-6

[0500] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-1,4-difluorobenzene". The rest of the method was the same to prepare compound IIId-6 (510 mg) with a total yield of 21.3% for two steps.

[0501] MS (m / z): 240.1 [M+H]+ .

[0502] 1 H NMR (600MHz, DMSO-d6) δ13.34(s,1H),8.79(s,1H),7.39-7.22(m,3H),5.55(s,2H).

[0503] Step 2: Preparation of target compound III-10

[0504] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0505] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (107 mg, 0.35 mmol), IIId-6 (84 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (137 mg, 1.05 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound III-10 (14 mg) as a white solid in a 9.7% yield.

[0506] MS (m / z): 528.3 [M+H] + .

[0507] 1 H NMR(600MHz,DMSO-d6)δ8.83(s,1H),8.61(d,J=6.6Hz,1H),8.03(s,1H),7.65(s,1H),7.33-7.28(m,3H),7.23(s,1H),7.20(s,1H ),5.56(s,2H),4.53-4.50(m,1H),4.28-4.22(m,1H),3.89-3.84(m,4H),3.15-2.96(m,4H),2.24-2.17(m,1H),2.09-2.02(m,1H).

[0508] Example 28: Preparation of the target compound 1-[(3,5-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-11)

[0509] Step 1: Preparation of compound IIId-7

[0510] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "3-(bromomethyl)-1,5-difluorobenzene". The rest of the method was the same to prepare compound IIId-7 (1.06 g) with a total yield of 44.4% for two steps.

[0511] MS (m / z): 240.1 [M+H] + .

[0512] 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).

[0513] Step 2: Preparation of target compound III-11

[0514] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0515] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (107 mg, 0.35 mmol), IIId-7 (84 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (137 mg, 1.05 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to afford the target compound III-11 (17 mg) as a white solid in a 12.6% yield.

[0516] MS (m / z): 528.3 [M+H] + .

[0517] 1H NMR(600MHz,DMSO-d6)δ8.84(s,1H),8.63(d,J=6.6Hz,1H),8.03(s,1H),7.65(s,1H),7.34-7.15(m,3H),7.11-7.07(m,2H),5 .54(s,2H),4.54-4.51(m,1H),4.30-4.21(m,1H),3.89-3.84(m,4H),3.15-2.97(m,4H),2.23-2.19(m,1H),2.11-2.01(m,1H).

[0518] Example 29: Preparation of the target compound 1-[(3,4-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-12)

[0519] Step 1: Preparation of compound IIId-8

[0520] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "4-(bromomethyl)-1,2-difluorobenzene". 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.

[0521] MS (m / z): 240.1 [M+H] + .

[0522] 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).

[0523] Step 2: Preparation of target compound III-12

[0524] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0525] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (107 mg, 0.35 mmol), IIId-8 (84 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (137 mg, 1.05 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully replaced with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain the target compound III-12 (18 mg) as a white solid in a yield of 13.2%.

[0526] MS (m / z): 528.3 [M+H] + .

[0527] 1 H NMR(600MHz,DMSO-d6)δ8.82(s,1H),8.61(d,J=6.6Hz,1H),8.03(s,1H),7.65(s,1H),7.54-7.40(m,2H),7.31-7.12(m,3H),5 .50(s,2H),4.54-4.51(m,1H),4.28-4.23(m,1H),3.88-3.84(m,4H),3.15-2.97(m,4H),2.22-2.18(m,1H),2.10-2.01(m,1H).

[0528] Example 30: Preparation of the target compound 1-[(2-methylphenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-13)

[0529] Step 1: Preparation of compound IIId-9

[0530] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-1-methylbenzene". The rest of the method was the same to prepare compound IIId-9 (1.16 g) with a total yield of 51.9% for two steps.

[0531] MS (m / z): 218.1 [M+H] + .

[0532] 1H 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).

[0533] Step 2: Preparation of target compound III-13

[0534] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0535] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (107 mg, 0.35 mmol), IIId-9 (76 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (137 mg, 1.05 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound III-13 (19 mg) as a white solid in a 15.4% yield.

[0536] MS (m / z): 506.3 [M+H] + .

[0537] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.61(d,J=6.4Hz,1H),8.04(s,1H),7.66(s,1H),7.33-7.15(m,5H),7.09(d,J=7.6Hz,1H),5.52( s,2H),4.54-4.50(m,1H),4.29-4.23(m,1H),3.90-3.83(m,4H),3.13-2.97(m,4H),2.33(s,3H),2.26-2.17(m,1H),2.11-2.01(m,1H).

[0538] Example 31: Preparation of the target compound 1-[(4-methylphenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide (III-14)

[0539] Step 1: Preparation of compound IIId-10

[0540] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced by "4-(bromomethyl)-1-methylbenzene". 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.

[0541] MS (m / z): 218.1 [M+H] + .

[0542] 1 H 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).

[0543] Step 2: Preparation of target compound III-14

[0544] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0545] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (107 mg, 0.35 mmol), IIId-10 (76 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (137 mg, 1.05 mmol) were dissolved in anhydrous DMF (5 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound III-14 (15 mg) as a white solid in a 14.2% yield.

[0546] MS (m / z): 506.3 [M+H] + .

[0547] 1 H NMR(400MHz, DMSO-d6)δ8.81(s,1H),8.59(d,J=6.4Hz,1H),8.03(s,1H),7.66(s,1H),7.33-7.11(m,6H),5.44(s,2H),4.54 -4.49(m,1H),4.29-4.22(m,1H),3.90-3.82(m,4H),3.12-2.98(m,4H),2.29(s,3H),2.23-2.17(m,1H),2.09-2.00(m,1H).

[0548] Example 32: Preparation of the target compound 1-[(2,6-difluorophenyl)methyl]-N-(4-oxyylidene-9-(piperidin-4-ylethynyl)-1,2,3,4,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl)-1,2,4-triazacyclopentane-3-carboxamide (III-15)

[0549] Step 1: Preparation of compound III-16-1

[0550] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0551] Referring to the “Preparation Method of Ia-1” in Example 1, the intermediate “ethynylcyclopropane” was replaced with “1-Boc-4-ethynylpiperidine”, and the remaining methods were referred to the “Preparation Method of Ia-1” in Example 1 to prepare compound III-16-1 (228 mg) with a yield of 27.9%.

[0552] MS (m / z): 410.1 [M+H] + .

[0553] Step 2: Preparation of target compound III-15

[0554] Intermediate IIId-1 was prepared by referring to the “Preparation method of intermediate IIId-1” in Example 18.

[0555] In a 50 mL eggplant-shaped flask, intermediate III-16-1 (147 mg, 0.36 mmol), IIId-1 (172 mg, 0.72 mmol), HATU (273 mg, 0.72 mmol), and DIPEA (233 mg, 1.80 mmol) were dissolved in anhydrous DMF (8 mL). The atmosphere was fully replaced with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed that the reaction was essentially complete. 20 mL of water was added to the system, and the layers were extracted with ethyl acetate (20 mL*3 times). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. After concentration under reduced pressure, the residue was deprotected with TFA / DCM (5 mL). The system was concentrated and purified by preparative liquid chromatography to obtain the target compound III-15 (10 mg) as a white solid in a yield of 5.26%.

[0556] MS (m / z): 531.2 [M+H] + .

[0557] 1H NMR (400MHz, DMSO-d6) δ8.85 (s, 1H), 8.58 (d, J = 6.4Hz, 1H), 8.37 (s, 1H), 7.56-7. 48(m,1H),7.19(t,J=8.0Hz,2H),7.16(s,1H),7.12(s,1H),5.58(s,2H),4.50-4. 45(m,1H),4.27-4.20(m,1H),3.88-3.80(m,1H),3.13-2.93(m,6H),2.85-2.81(m ,3H),2.20-2.16(m,1H),2.08-1.97(m,1H),1.92-1.89(m,2H),1.68-1.56(m,2H).

[0558] Example 33: Preparation of the target compound tert-butyl 4-((3-(1-(2,6-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-9-yl)ethynyl)piperidine-1-carboxamide (III-16)

[0559] Step 1: Preparation of compound III-16-1

[0560] Refer to the "Preparation of Compound III-16-1" in Example 32 to prepare Compound III-16-1.

[0561] MS (m / z): 410.1 [M+H] + .

[0562] Step 2: Preparation of target compound III-16

[0563] Intermediate IIId-1 was prepared by referring to the “Preparation method of intermediate IIId-1” in Example 18.

[0564] In a 50 mL eggplant-shaped flask, intermediate III-16-1 (147 mg, 0.36 mmol), IIId-1 (172 mg, 0.72 mmol), HATU (273 mg, 0.72 mmol), and DIPEA (233 mg, 1.80 mmol) were dissolved in anhydrous DMF (8 mL). The atmosphere was fully replaced with nitrogen and the mixture was allowed to react at room temperature overnight. Thin-layer chromatography confirmed the reaction was essentially complete. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the target compound III-16 (10 mg) as a white solid in a 9.5% yield.

[0565] MS (m / z): 631.3 [M+H] + .

[0566] 1 H NMR(600MHz,DMSO-d6)δ8.85(s,1H),8.58(d,J=6.6Hz,1H),7.54-7.49(m,1H),7.19(t,J=7.8Hz,2H),7. 15(s,1H),7.11(s,1H),5.57(s,2H),4.48-4.46(m,1H),4.25-4.21(m,1H),3.83(q,J=10.2Hz,1H),3.65 -3.61(m,2H),3.19-3.10(m,2H),3.08-2.93(m,4H),2.86-2.80(m,1H),2.19-2. 14(m,1H),2.06-1.98(m,1H),1.82-1.78(m,2H),1.51-1.48(m,2H),1.40(s,9H).

[0567] Example 34: Preparation of the target compound 1-(2,6-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-17)

[0568] Step 1: Preparation of compound Ia-8

[0569] Referring to the "Preparation of Intermediate Ia-5" in Example 5, only the raw material "N-methyl-4-alkynylpyrazole" was replaced with "N-difluoromethyl-4-alkynylpyrazole". The rest of the method was the same to prepare compound Ia-8.

[0570] MS (m / z): 343.2 [M+H] + .

[0571] Step 2: Preparation of target compound III-17

[0572] Referring to the synthetic method of step 3 of Example 18, only the preparation of intermediate Ia-5 was replaced by Ia-8, and the rest of the method remained unchanged to obtain the target compound III-17 (59 mg) with a yield of 10.28%.

[0573] MS (m / z): 564.2 [M+H] + .

[0574] 1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.63(s,1H),8.60(d,J=6.8Hz,1H),8.04 (s,1H),7.84(t,J=58.8Hz,1H),7.52(p,J=7.6Hz,1H),7.26(d,J=10.4Hz,2H) ,7.19(t,J=8.0Hz,2H),5.58(s,2H),4.54-4.47(m,1H),4.28-4.22(m,1H),3. 87(q,J=10.4Hz,1H),3.13-3.00(m,4H),2.21-2.03(m,1H),2.11-2.01(m,1H).

[0575] Example 35: Preparation of the target compound 1-(3,5-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-18)

[0576] Step 1: Preparation of compound IIId-7

[0577] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "3-(bromomethyl)-1,5-difluorobenzene". The rest of the method was the same to prepare compound IIId-7 (1.06 g) with a total yield of 44.4% for two steps.

[0578] MS (m / z): 240.1 [M+H] + .

[0579] Step 2: Preparation of target compound III-18

[0580] Referring to the synthetic method of step 3 of Example 18, only the preparation intermediate Ia-5 was replaced by Ia-8, and only the preparation intermediate IIId-1 was replaced by IIId-7. The rest of the method remained unchanged to prepare the target compound III-18 (41 mg) with a yield of 13.68%.

[0581] MS (m / z): 564.2 [M+H] + .

[0582] 1H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.64(d,J=8.4Hz,2H),8.04(s,1H),7.84(t,J=58.8Hz,1H),7.36 -7.19(m,3H),7.09(d,J=6.0Hz,2H),5.54(s,2H),4.54(t,J=8.0Hz,1H),4.26(td,J=11.2,10. 4,4.0Hz,1H),3.88(q,J=10.4Hz,1H),3.20-2.95(m,4H),2.27-2.16(m,1H),2.15-2.00(m,1H).

[0583] Example 36: Preparation of the target compound 1-(2,5-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-19)

[0584] Step 1: Preparation of compound IIId-11

[0585] Referring to the preparation of intermediate IIId-1 in Example 18, compound IIId-11 was prepared by replacing the raw material "2-(bromomethyl)-1,3-difluorobenzene" with "2,5-difluorobenzyl bromide" and following the same method.

[0586] MS (m / z): 240.1 [M+H] + .

[0587] Step 2: Preparation of target compound III-19

[0588] Referring to the synthetic method of step 3 of Example 18, only the preparation intermediate Ia-5 was replaced by Ia-8, and only the preparation intermediate IIId-1 was replaced by IIId-11. The rest of the method remained unchanged to prepare the target compound III-19 (36 mg) with a yield of 9.68%.

[0589] MS (m / z): 564.2 [M+H] + .

[0590] 1H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.63(s,1H),8.62(d,J=6.8,1H),8.04(s,1H),7.84(t,J=58.8Hz,1H),7.36 -7.25(m,5H),5.56(s,2H),4.56-4.51(m,1H),4.29-4.23(m,1H),3.87(q,J=10.4Hz,1H),3.13-2.99(m,4H),2.24 -2.18(m,1H),2.11-2.01(m,1H).

[0591] Example 37: Preparation of the target compound 1-(2,4-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-20)

[0592] Step 1: Preparation of compound IIId-5

[0593] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "4-(bromomethyl)-1,3-difluorobenzene". 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.

[0594] MS (m / z): 240.1 [M+H] + .

[0595] Step 2: Preparation of target compound III-20

[0596] Referring to the synthetic method of step 3 of Example 18, only the preparation intermediate Ia-5 was replaced by Ia-8, and only the preparation intermediate IIId-1 was replaced by IIId-5. The rest of the method remained unchanged to prepare the target compound III-20 (38 mg) with a yield of 10.57%.

[0597] MS (m / z): 564.2 [M+H] + .

[0598] 1H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.63(s,1H),8.61(d,J=6.4Hz,1H),8.04( s,1H),7.84(t,J=58.8Hz,1H),7.53-7.47(m,1H),7.35-7.30(m,1H),7.28-7.25 (m,2H),7.17-7.12(m,1H),5.55(s,2H),4.55-4.50(m,1H),4.29-4.22(m,1H),3 .87(q,J=10.8Hz,1H),3.13-3.01(m,4H),2.26-2.16(m,1H),2.11-2.01(m,1H).

[0599] Example 38: Preparation of the target compound 1-(2-fluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-21)

[0600] Step 1: Preparation of compound IIId-3

[0601] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-1-fluorobenzene". 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.

[0602] MS (m / z): 222.1 [M+H] + .

[0603] 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).

[0604] Step 2: Preparation of target compound III-21

[0605] Referring to the synthetic method of step 3 of Example 18, only the preparation intermediate Ia-5 was replaced by Ia-8, and only the preparation intermediate IIId-1 was replaced by IIId-3. The rest of the method remained unchanged to prepare the target compound III-21 (38 mg) with a yield of 10.57%.

[0606] MS (m / z): 546.2 [M+H]+ .

[0607] 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.63(s,1H),8.62(d,J=6.8Hz,1H),8.04(s,1H),7.84(t,J=58.8Hz,1H),7.46-7.36(m,2H),7.28-7.22 (m,4H),5.57(s,2H),4.55-4.50(m,1H),4.29-4.22(m,1H),3.87(q,J= 10.4Hz,1H),3.14-2.99(m,4H),2.23-2.17(m,1H),2.11-2.00(m,1H).

[0608] Example 39: Preparation of the target compound 1-(2-methylbenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-22)

[0609] Step 1: Preparation of compound IIId-9

[0610] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "2-(bromomethyl)-1-methylbenzene". The rest of the method was the same to prepare compound IIId-9 (1.16 g) with a total yield of 51.9% for two steps.

[0611] MS (m / z): 218.1 [M+H] + .

[0612] 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).

[0613] Step 2: Preparation of target compound III-22

[0614] Referring to the synthetic method of step 3 of Example 18, only the preparation intermediate Ia-5 was replaced by Ia-8, and only the preparation intermediate IIId-1 was replaced by IIId-9. The rest of the method remained unchanged to prepare the target compound III-22 (23 mg) with a yield of 8.75%.

[0615] MS (m / z): 542.3 [M+H] + .

[0616] 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),8.64(s,1H),8.62(d,J=6.4Hz,1H),8.05(s,1H),7.84(t,J=58.8Hz,1H),7.30-7.19(m,5H),7.09(d,J=7.6Hz,1 H),5.52(s,2H),4.56-4.51(m,1H),4.30-4.23(m,1H),3.88(q,J=10.4Hz, 1H),3.16-2.99(m,4H),2.34(s,3H),2.25-2.17(m,1H),2.12-2.01(m,1H).

[0617] Example 40: Preparation of the target compound 1-(3,4-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-23)

[0618] Step 1: Preparation of compound IIId-8

[0619] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "4-(bromomethyl)-1,2-difluorobenzene". 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.

[0620] MS (m / z): 240.1 [M+H] + .

[0621] 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).

[0622] Step 2: Preparation of target compound III-23

[0623] Referring to the synthetic method of step 3 of Example 18, only the preparation intermediate Ia-5 was replaced by Ia-8, and only the preparation intermediate IIId-1 was replaced by IIId-8. The rest of the method remained unchanged to prepare the target compound III-23 (47 mg) with a yield of 9.25%.

[0624] MS (m / z): 564.2 [M+H] + .

[0625] 1 H NMR(400MHz, DMSO-d6)δ8.83(s,1H),8.66-8.60(m,2H),8.04(s,1H),7.84(t,J=58.8Hz,1H),7.52-7.42(m,2H),7.30-7.24(m,2H),7.23-7.1 9(m,1H),5.50(s,2H),4.56-4.51(m,1H),4.29-4.23(m,1H),3.74(q,J =10.0Hz,1H),3.13-3.01(m,4H),2.23-2.19(m,1H),2.12-2.02(m,1H).

[0626] Example 41: Preparation of the target compound 1-(4-fluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-24)

[0627] Step 1: Preparation of compound IIId-4

[0628] Referring to the preparation of intermediate IIId-1 in Example 18, 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.

[0629] 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).

[0630] MS (m / z): 222.1 [M+H] + .

[0631] Step 2: Preparation of target compound III-24

[0632] Referring to the synthetic method of step 3 of Example 18, only the preparation intermediate Ia-5 was replaced by Ia-8, and only the preparation intermediate IIId-1 was replaced by IIId-4. The rest of the method remained unchanged to prepare the target compound III-24 (40 mg) with a yield of 10.45%.

[0633] MS (m / z): 546.2 [M+H] + .

[0634] 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.62(d,J=8.4Hz,2H),8.04(s,1H),7.84(t,J=58.8Hz,1H),7.45 -7.36(m,2H),7.30-7.18(m,4H),5.50(s,2H),4.57-4.50(m,1H),4.30-4.21(m, 1H),3.93-3.82(m,1H),3.19-2.95(m,4H),2.25-2.16(m,1H),2.12-2.00(m,1H).

[0635] Example 42: Preparation of the target compound 1-(4-methylbenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-25)

[0636] Step 1: Preparation of compound IIId-10

[0637] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced by "4-(bromomethyl)-1-methylbenzene". 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.

[0638] MS (m / z): 218.1 [M+H] + .

[0639] 1 H 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).

[0640] Step 2: Preparation of target compound III-25

[0641] Referring to the synthetic method of step 3 of Example 18, only the preparation intermediate Ia-5 was replaced by Ia-8, and only the preparation intermediate IIId-1 was replaced by IIId-10. The rest of the method remained unchanged to prepare the target compound III-25 (38 mg) with a yield of 9.82%.

[0642] MS (m / z): 543.2 [M+H] + .

[0643] 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.63(s,1H),8.61(d,J=6.4Hz,1H),8.04(s,1H),7.84(t,J=58.8Hz,1H),7.30-7.16(m,6H),5.44(s, 2H),4.57-4.50(m,1H),4.30-4.21(m,1H),3.87(q,J=10.4Hz,1H),3.18-2.96(m,4H),2.29(s,3H),2.25-2.16(m,1H),2.12-2.00(m,1H).

[0644] Example 43: Preparation of the target compound 1-(2,6-difluorobenzyl)-N-(9-ethynyl-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-26)

[0645] Step 1: Preparation of compound Ia-9

[0646] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0647] Referring to the “Preparation Method of Ia-1” in Example 1, the intermediate “ethynylcyclopropane” was replaced with “TBDMS acetylene”, and the remaining methods were referred to the “Preparation Method of Ia-1” in Example 1 to prepare compound Ia-9 (85 mg) with a yield of 32.4%.

[0648] MS (m / z): 227.1 [M+H] + .

[0649] Step 2: Preparation of target compound III-26

[0650] Referring to the synthetic method of step 3 of Example 18, only the intermediate Ia-5 was replaced by Ia-9, and the rest of the method remained unchanged to prepare the target compound III-26 (25 mg) with a yield of 5.14%.

[0651] MS (m / z): 448.2 [M+H] + .

[0652] 1 H NMR (400MHz, DMSO-d6) δ8.85 (s, 1H), 8.59 (d, J = 6.4Hz, 1H), 7.52 (p, J = 7.2Hz, 1H), 7.28-7.12 (m, 4H), 5.57 (s, 2H), 4.52-4. 47(m,1H),4.27-4.20(m,1H),4.09(s,1H),3.85(q,J=10.4Hz,1H),3.09-2.97(m,4H),2.22-2.13(m,1H),2.09-1.97(m,1H).

[0653] Compound III-26a:

[0654] MS (m / z): 484.1 [M+H] + .

[0655] 1 H NMR (400MHz, DMSO-d6) δ8.85 (s, 1H), 8.59 (d, J = 6.8Hz, 1H), 7.55-7.48 (m, 1H), 7.4 5(d,J=2.0Hz,1H),7.38(d,J=2.0Hz,1H),7.18(t,J=8.1Hz,2H),6.00(d,J=2.4Hz,1 H), 5.57 (s, 2H), 5.53 (d, J = 2.4 Hz, 1H), 4.53-4.49 (m, 1H), 4.29-4.22 (m, 1H), 3.92-3.84 (m, 1H), 3.15-3.00 (m, 4H), 2.22-2.16 (m, 1H), 2.10-2.00 (m, 1H). Compound III-26b:

[0656] MS (m / z): 466.1 [M+H] + .

[0657] 1H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.62(d,J=6.8Hz,1H),7.71(s,2H),7.52(p,J=7.2Hz,1H),7.19(t,J=8.0Hz,2H),5.58(s,2H), 4.62-4.51(m,1H),4.29-4.23(m,1H),3.92(q,J=10.4Hz,1H),3.22-3.03(m,4H),2.53(s,3H),2.26-2.17(m,1H),2.13-2.05(m,1H).

[0658] Example 44: Preparation of the target compound 1-(2,6-difluorobenzyl)-N-(9-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1H-1,2,4-triazole-3-carboxamide (III-27)

[0659] Step 1: Preparation of compound Ia-10

[0660] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0661] Referring to the "Preparation Method of Ia-1" in Example 1, the intermediate "ethynylcyclopropane" was replaced with "3-ethynyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine", and the rest of the method was referred to the "Preparation Method of Ia-1" in Example 1 to prepare compound Ia-10 (85 mg) with a yield of 22.4%.

[0662] MS (m / z): 349.2 [M+H] + .

[0663] Step 2: Preparation of target compound III-27

[0664] Referring to the synthetic method of step 3 of Example 18, only the intermediate Ia-5 was replaced by Ia-10, and the rest of the method remained unchanged to prepare the target compound III-27 (3 mg) with a yield of 3.14%.

[0665] MS (m / z): 570.1 [M+H] + .

[0666] 1H NMR (400MHz, DMSO-d6) δ8.86 (s, 1H), 8.59 (d, J = 6.4Hz, 1H), 7.70 (s, 1H), 7.56-7.49(m,1H),7.27-7.15(m,4H),5.58(s,2H),4.89(s,2H),4.53-4.4 8(m,1H),4.28-4.22(m,1H),4.15-4.12(m,2H),4.09-4.07(m,2H),3.86(q ,J=10.4Hz,1H),3.11-2.99(m,4H),2.23-2.15(m,1H),2.10-2.00(m,1H).

[0667] Example 45: Preparation of the target compound 1-(2,6-difluorobenzyl)-N-(9-((5-formyl-1-vinyl-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-28)

[0668] Step 1: Preparation of compound Ia-11

[0669] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0670] Referring to the “Preparation Method of Ia-1” in Example 1, the intermediate “ethynylcyclopropane” was replaced with “4-ethynyl-1-vinyl-1H-pyrazole-5-carboxaldehyde”, and the remaining methods were referred to the “Preparation Method of Ia-1” in Example 1 to prepare compound Ia-11 (185 mg) with a yield of 33.7%.

[0671] MS (m / z): 347.2 [M+H] + .

[0672] Step 2: Preparation of target compound III-28

[0673] Referring to the synthetic method of step 3 of Example 18, only the intermediate Ia-5 was replaced by Ia-11, and the rest of the method remained unchanged to prepare the target compound III-28 (20 mg) with a yield of 13.34%.

[0674] MS (m / z): 568.2 [M+H] + .

[0675] 1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.60(d,J=6.8Hz,1H),7.86(s,1H),7.55-7.50(m,1H) ,7.40-7.33(m,1H),7.31(d,J=1.6Hz,1H),7.26(d,J=1.6Hz,1H),7.23-7.16(m,2H),5.69( d,J=15.6Hz,1H),5.63(s,1H),5.58(s,2H),4.98(d,J=8.8Hz,1H),4.54-4.49(m,1H),4.29 -4.23(m,1H),3.91-3.84(m,1H),3.14-3.00(m,4H),2.25-2.16(m,1H),2.11-2.01(m,1H).

[0676] Example 46: Preparation of the target compound 1-(2,6-difluorobenzyl)-N-(9-((1-(oxetane-3-yl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-29)

[0677] Step 1: Preparation of compound Ia-12

[0678] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0679] Referring to the "Preparation Method of Ia-1" in Example 1, the intermediate "ethynylcyclopropane" was replaced with "4-ethynyl-1-(oxetane-3-yl)-1H-pyrazole", and the remaining methods were referred to the "Preparation Method of Ia-1" in Example 1 to prepare compound Ia-12 (122 mg) with a yield of 25.7%.

[0680] MS (m / z): 349.2 [M+H] + .

[0681] Step 2: Preparation of target compound III-29

[0682] Referring to the synthetic method of step 3 of Example 18, only the intermediate Ia-5 was replaced by Ia-12, and the rest of the method remained unchanged to prepare the target compound III-29 (9 mg) with a yield of 6.34%.

[0683] MS (m / z): 570.2 [M+H] + .

[0684] 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.59(d,J=6.4Hz,1H),8.25(s,1H),7.82(s,1H),7.56-7.48(m,1H),7.23-7.14(m,4H),5.62-5.50(m,3H ),4.94-4.86(m,4H),4.52-4.48(m,1H),4.28-4.21(m,1H),3.86(q,J= 10.4Hz,1H),3.14-2.97(m,4H),2.23-2.15(m,1H),2.10-1.99(m,1H).

[0685] Example 47: Preparation of the target compound 1-(2,6-difluorobenzyl)-N-(9-((1-(cyclobutane-3-yl)-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-30)

[0686] Step 1: Preparation of compound Ia-13

[0687] Intermediate A was prepared by referring to the “Preparation method of common intermediate A”.

[0688] Referring to the "Preparation Method of Ia-1" in Example 1, the intermediate "ethynylcyclopropane" was replaced with "4-ethynyl-1-(cyclobutane-3-yl)-1H-pyrazole", and the remaining methods were referred to the "Preparation Method of Ia-1" in Example 1 to prepare compound Ia-13 (122 mg) with a yield of 27.5%.

[0689] MS (m / z): 347.1 [M+H] + .

[0690] Step 2: Preparation of target compound III-30

[0691] Referring to the synthetic method of step 3 of Example 18, only the intermediate Ia-5 was replaced by Ia-13, and the rest of the method remained unchanged to prepare the target compound III-30 (9 mg) with a yield of 6.41%.

[0692] MS (m / z): 568.2 [M+H] + .

[0693] 1H NMR(400MHz, DMSO-d6)δ8.85(s,1H),8.59(d,J=6.4Hz,1H),8.18(s,1H),7.69(s,1H),7.56-7.48(m,1H),7.24- 7.15(m,4H),5.58(s,2H),4.83(p,J=8.4Hz,1H),4.52-4.48(m,1H),4.28-4.21(m,1H),3.91-3.82(m,1H),3.15 -2.98(m,4H),2.48-2.33(m,4H),2.23-2.14(m,1H),2.09-2.02(m,1H),1.83-1.74(m,2H).

[0694] Example 48: Preparation of the target compound N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,4,5,6,7-hexahydroazepine[3,2,1-hi]indol-5-yl)-1-(pyridin-2-ylmethyl)-1H-1,2,4-triazole-3-carboxamide (III-31)

[0695] Step 1: Preparation of compound IIId-12

[0696] Referring to the preparation of intermediate IIId-1 in Example 18, compound IIId-12 was prepared by replacing the raw material "2,6-difluorobenzyl bromide" with "2-(bromomethyl)pyridine" and following the same method.

[0697] MS (m / z): 205.1 [M+H] + .

[0698] Step 2: Preparation of target compound III-31

[0699] Referring to the synthetic method of step 3 of Example 18, only the intermediate IIId-1 was replaced by IIId-12, and the rest of the method remained unchanged to prepare the target compound III-31 (73 mg) with a yield of 19.52%.

[0700] MS (m / z): 493.1 [M+H] + .

[0701] 1H NMR (400MHz, DMSO-d6) δ8.85 (s, 1H), 8.63 (d, J = 6.8Hz, 1H), 8.57-8.51 (m, 1 H),8.04(s,1H),7.84(td,J=7.6,1.6Hz,1H),7.66(s,1H),7.38-7.34(m,2H) ,7.22(d,J=10.8Hz,2H),5.63(s,2H),4.57-4.50(m,1H),4.29-4.23(m,1H), 3.91-3.83(m,4H),3.13-3.00(m,4H),2.23-2.19(m,1H),2.12-2.00(m,1H).

[0702] Example 49: Preparation of the target compound 1-(4-benzyl)-N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide (III-32)

[0703] Step 1: Preparation of compound IIId-2

[0704] Referring to the preparation method of compound IIId-1 in Example 18, only the starting material "2-(bromomethyl)-1,3-difluorobenzene" was replaced with "benzyl bromide". The rest of the method was the same to prepare compound IIId-2 (811 mg) with a total yield of 40.0% for two steps.

[0705] MS (m / z): 204.1 [M+H] + .

[0706] 1 H NMR (600MHz, DMSO-d6) δ13.32(s,1H),8.79(s,1H),7.46-7.20(m,5H),5.48(s,2H).

[0707] Step 2: Preparation of target compound III-32

[0708] Referring to the synthetic method of step 3 of Example 18, only the intermediate IIId-1 was replaced by IIId-2, and the rest of the method remained unchanged to prepare the target compound III-31 (80 mg) with a yield of 21.38%.

[0709] MS (m / z): 492.1 [M+H] + .

[0710] 1H NMR (600MHz, DMSO-d6) δ8.84(s,1H),8.61(d,J=6.6Hz,1H),8.03(s,1H),7.65(s,1H),7.42-7.30(m,5H),7.22(d,J=15.6 Hz,2H),5.50(s,2H),4.53-4.50(m,1H),4.27-4.10(m,1H),3.87-3.83(m,4H),3.13-2.97(m,4H),2.25-2.18(m,1H),2.09 -2.02(m,1H).

[0711] Example 50: Preparation of the target compound 1-benzyl-N-[4-oxyylidene-10-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazacyclohepta[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (IV-1)

[0712] The synthetic route of target compound IV-1 is as follows:

[0713] Refer to Example 17 “Preparation of Compound IIa-4” to prepare Compound IIa-4; Refer to Example 20 “Preparation of Compound IIId-2” to prepare Compound IIId-2.

[0714] In a 50 mL eggplant-shaped flask, intermediate IIa-4 (40 mg, 0.13 mmol), HOBT (20 mg, 0.15 mmol), EDCI (28 mg, 0.15 mmol), and NMM (40 mg, 0.40 mmol) were dissolved in anhydrous DCM (2 mL) and the atmosphere was fully replaced with nitrogen. After stirring at room temperature for 10 minutes, IIId-2 (41 mg, 0.20 mmol) dissolved in DCM (2 mL) was added under nitrogen and allowed to react overnight at room temperature. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with DCM (3 times with 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound IV-1 (10 mg) as a white solid in a 15.3% yield.

[0715] MS (m / z): 489.2 [M+H] + .

[0716] 1H NMR(400MHz,Chloroform-d)δ8.90(s,1H),8.56-8.38(m,2H),7.80-6.79(m,9H),5.34(s,1H),4.60-4.4 7(m,1H),4.13-3.91(m,2H),3.32-2.97(m,2H),2.40-2.02(m,2H),1.98-1.88(m,2H),1.82-1.76(m,2H).

[0717] Example 51: Preparation of the target compound N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-6-phenoxypicolinamide (V-1)

[0718] The synthetic route of target compound V-1 is as follows:

[0719] Step 1: Preparation of compound Vd-2

[0720] Referring to the preparation of intermediate Vd-1 in Example 36, only the starting material "methyl 5-chloropicolinate" was replaced by "methyl 6-chloropicolinate". The rest of the method was the same to prepare compound Vd-2 (250 mg) with a two-step yield of 38.7%.

[0721] MS (m / z): 489.2 [M+H] + .

[0722] Step 2: Preparation of target compound V-1

[0723] Compound Ia-5 was prepared by referring to the “Preparation of Compound Ia-5” in Example 5.

[0724] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (110 mg, 0.36 mmol), Vd-2 (155 mg, 0.72 mmol), HATU (273 mg, 0.72 mmol), and DIPEA (233 mg, 1.80 mmol) were dissolved in anhydrous DMF (8 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react overnight at room temperature. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the title compound V-1 (18 mg) as a white solid in a 10.0% yield.

[0725] MS (m / z): 504.2 [M+H] + .

[0726] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=6.0Hz,1H),8.12-7.99(m,2H),7.81(d,J=7.2Hz,1H),7.67(s,1H),7.54-7.44(m,2H),7.36-7.12(m,6 H),4.50-4.42(m,1H),4.32-4.22(m,1H),3.87-3.80(m,4H),3.20-3.12(m,1H),3.10-2.94(m,3H),2.27-2.18(m,1H),2.04-1.91(m,1H).

[0727] Example 52: Preparation of the target compound N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-5-phenoxypicolinamide (V-2)

[0728] Step 1: Synthesis of compound Vc-1

[0729] In a microwave reaction vial, methyl compound Va-1 (515 mg, 3 mmol), compound Vb (424 mg, 4.5 mmol), copper powder (19.2 mg, 0.3 mmol), and cesium carbonate (2.93 g, 9 mmol) were dissolved in 20 mL of anhydrous DMF. The reaction was microwaved at 100°C for 30 min. The product was diluted with DCM, washed with 10% sodium hydroxide solution, washed with water, and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a flash column to obtain Vc-1 (140 mg) as a white solid in a yield of 20.4%.

[0730] MS (m / z): 230.1 [M+H] + .

[0731] Step 2: Synthesis of Compound Vd-1

[0732] In a 100 mL eggplant-shaped reaction flask, intermediate Vc-1 (140 mg, 0.61 mmol) was dissolved in 4 mL of anhydrous THF. Lithium hydroxide (30 mg, 1.22 mmol) was then dissolved in 1 mL 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 mixture was allowed to react overnight at room temperature. Thin-layer chromatography confirmed that the reaction was essentially complete. The THF was removed under reduced pressure, 2 mL of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 1-2. A white solid gradually precipitated. The solid was slurried, filtered, and the residue washed with water to afford Vd-1 (113 mg) as a pale white solid in an 86.0% yield. The solid was used in the next step without purification.

[0733] MS (m / z): 216.1 [M+H] + .

[0734] Step 3: Preparation of target compound V-2

[0735] Compound Ia-5 was prepared by referring to Example 5 “Preparation of Compound Ia-5”.

[0736] In a 50 mL eggplant-shaped flask, intermediate Ia-5 (110 mg, 0.36 mmol), Vd-1 (155 mg, 0.72 mmol), HATU (273 mg, 0.72 mmol), and DIPEA (233 mg, 1.80 mmol) were dissolved in anhydrous DMF (8 mL). The atmosphere was fully purged with nitrogen and the mixture was allowed to react overnight at room temperature. Thin-layer chromatography confirmed the substantial reaction of the starting materials. 20 mL of water was added to the system, and the layers were extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography to afford the target compound V-2 (10 mg) as a white solid in a 9.5% yield.

[0737] MS (m / z): 504.2 [M+H] + .

[0738] 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=6.4Hz,1H),8.49(d,J=2.8Hz,1H),8.14-7.96(m,2H),7.67(s,1H),7.56-7.41(m,3H),7.35- 7.12(m,5H),4.59-4.52(m,1H),4.32-4.26(m,1H),3.92-3.84(m,4H),3.21-2.96(m,4H),2.31-2.23(m,1H),2.14-2.02(m,1H).

[0739] Example 53: Preparation of the target compound 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}pyrazole-3-carboxamide (XIII-1)

[0740] Step 1: Preparation of compound IIId-13

[0741] Referring to the preparation of intermediate IIId-1 in Example 18, only the starting material "1,2,4-triazole-3-methyl ester" was replaced with "pyrazole-3-methyl ester". The rest of the method was the same to prepare compound IIId-13 (530 mg) with a total yield of 35.1% for two steps.

[0742] MS (m / z): 239.1 [M+H] + .

[0743] Step 2: Preparation of target compound XIII-1

[0744] Referring to the synthetic method of step 3 of Example 18, only the intermediate IIId-1 was replaced by IIId-13, and the rest of the method remained unchanged to prepare the target compound XIII-1 (45 mg) with a yield of 7.58%.

[0745] MS (m / z): 527.2 [M+H] + .

[0746] 1 H NMR(400MHz, DMSO-d6)δ8.16(d,J=6.4Hz,1H),8.03(s,1H),7.90(d,J=2.4Hz ,1H),7.66(s,1H),7.50(tt,J=8.4,6.8Hz,1H),7.19(q,J=8.8,8.0Hz,4H),6 .66(d,J=2.4Hz,1H),5.49(s,2H),4.52-4.43(m,1H),4.30-4.20(m,1H),3.8 5(s,4H),3.15-2.95(m,4H),2.18(dd,J=13.6,2.0Hz,1H),2.07-1.96(m,1H).

[0747] Example 54: Preparation of reference compound 5-benzyl-N-[(3S)-5-methyl-4-oxylidene-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazepan-3-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide (GSK2982772):

[0748] For the specific synthesis route, please refer to patent CN201580044931.

[0749] MS (m / z): 378.1 [M+H] + .

[0750] 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).

[0751] Example 55: Preparation of reference compound 1-[(2,6-difluorophenyl)methyl]-N-(4-oxyylidene-1,2,4,5,6,7-hexahydroazacycloheptano[3,2,1-hi]indol-5-yl)-1,2,4-triazacyclopentane-3-carboxamide (Compound of Example 13 in CN201910518248X):

[0752] For the specific synthesis route, please refer to patent CN201910518248X.

[0753] MS (m / z): 424.2 [M+H] + .

[0754] 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.56(d,J=6.4Hz,1H),7.52(p,J=7.2Hz,1H ),7.19(t,J=8.0Hz,2H),7.13(d,J=7.2Hz,1H),7.05(d,J=7.6Hz,1H),6.98(t,J =7.2Hz,1H),5.57(s,2H),4.46(t,J=8.4Hz,1H),4.26(dt,J=10.8,6.8Hz,1H),3 .82(q,J=10.4Hz,1H),3.15-2.95(m,4H),2.25-2.16(m,1H),2.10-1.98(m,1H).

[0755] Example 56: Compounds inhibit TNF-α-induced programmed necrosis in U937 cells

[0756] 1. 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).

[0757] 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), multifunctional microplate reader (Thermo Tecan, SPARK), Class II biological safety cabinet (Sujing Antai, BSC-1304ⅡA2), and desktop cell counter (Thermo Fisher Scientific, Countess Ⅱ).

[0758] 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. Cell culture flasks were placed upright in the incubator. For example, in a T25 flask, the volume of culture medium in the flask was 6-8 mL. The medium was changed 3-4 times per week for subculture.

[0759] 4. Experimental methods: CCK-8 assay was used to detect the inhibitory effect of compounds on TNF-α-induced necroptosis in U937 cells, and to screen compounds with receptor interacting protein kinase 1 inhibitory activity.

[0760] 4.1 Cell plating:

[0761] (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.

[0762] (2) Transfer the cell suspension to a 15 mL sterile centrifuge tube and centrifuge at 850 rpm for 4 min to collect U937 cells;

[0763] (3) Carefully discard the supernatant, add an appropriate amount of culture medium, gently pipette to evenly distribute the cells, prepare a single-cell suspension, and count;

[0764] (4) Dilute the cells to 4×10 5 / mL, 90 μL / well was plated in a 96-well plate to make the cell density in the 96-well plate 3.6×104 Each well was placed in a 37°C, 5% CO2, saturated humidity incubator and cultured for 6 hours before drug addition.

[0765] 4.2 Compound dilution and dosing:

[0766] (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 store it at -20°C for use, and store the rest at -80°C and use within the shelf life.

[0767] (2) RPMI-1640 medium containing TNF-α, BV6, and Z-VAD-FMK was prepared, 5 μL per well, so that the final concentrations of TNF-α, BV6, and Z-VAD-FMK were 20 ng / mL, 2 μM, and 20 μM, respectively;

[0768] (3) The culture medium of each target compound was diluted into 8 concentration gradients by three-fold dilution method, and each concentration was repeated in duplicate, with 5 μL per well, and the final concentrations were 1000.00 / 333.33 / 111.11 / 37.04 / 12.35 / 4.12 / 1.37 / 0.46 nM;

[0769] (4) Remove the 96-well plate containing 90 μL of cell suspension from the incubator and 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 and test compound groups. After incubation for 18 h, perform the CCK-8 assay.

[0770] (5) Remove the 96-well plate and carefully add 10 μL of CCK-8 reagent to each well. Incubate at 37°C for 2–4 h and measure the absorbance at 450 nm.

[0771] 5. Evaluation of the compound's inhibitory activity against TNF-α-induced programmed necrosis in U937 cells

[0772] Cell survival rate % = (OD value of treatment group - OD value of blank background) / (OD value of DMSO group - OD value of blank background) * 100

[0773] 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.

[0774] Example 57: Compounds inhibit TNF-α-induced programmed necroptosis in HT-29 cells

[0775] 1. Reagents: McCoy's 5A medium, fetal bovine serum, penicillin-streptomycin 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).

[0776] 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), multifunctional microplate reader (Thermo Tecan, SPARK), Class II biological safety cabinet (Sujing Antai, BSC-1304ⅡA2), and desktop cell counter (Thermo Fisher Scientific, CountessⅡ).

[0777] 3. Cell culture: HT-29 cells (human colon cancer cells) were cultured in McCoy's 5A medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution at 37°C in a saturated humidity incubator with 5% CO2. The medium was changed and passaged 3-4 times a week.

[0778] 4. Experimental method: The SRB method was used to detect the inhibitory effect of compounds on TNF-α-induced programmed necrosis in HT-29 cells and to screen compounds with receptor-interacting protein kinase 1 inhibitory activity.

[0779] 4.1 Cell plating:

[0780] (1) Turn on the water bath and adjust the temperature to 37°C. Take the culture medium, trypsin, etc. out of the refrigerator and place them in the water bath to preheat. Take an appropriate amount for use.

[0781] (2) Use a sterile pipette to discard the old culture medium in the bottle, wash it with PBS three times, and add 1 mL of trypsin (25 cm 2Gently shake the flask to allow trypsin to flow over all cell surfaces and digest in a 37°C incubator. After 2 minutes of digestion, place the flask under a microscope and observe. If the cytoplasm shrinks, the intercellular spaces increase, and the cells become round, immediately stand the flask upright and add 4 mL of serum-containing culture medium to terminate digestion.

[0782] (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;

[0783] (4) Carefully discard the supernatant, add an appropriate amount of culture medium, gently pipette to evenly distribute the cells, prepare a single-cell suspension, and count;

[0784] (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 contained 3×10 cells. 4 The cells were placed in an incubator at 37°C, 5% CO2 and saturated humidity for 24 hours before drug addition.

[0785] 4.2 Compound dilution and dosing:

[0786] (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 store it at -20°C for use, and store the rest at -80°C and use within the shelf life.

[0787] (2) Prepare McCoy's 5A culture medium containing TNF-α, BV6, and Z-VAD-FMK. 90 μL of culture medium containing the test compound was added to each well of the positive control group and the test compound group, and 10 μL of culture medium containing the test compound was added to make the final concentrations of TNF-α, BV6, and Z-VAD-FMK 20 ng / mL, 2 μM, and 20 μM, respectively. 90 μL of McCoy's 5A complete culture medium was added to the DMSO (5‰) control group, and then 10 μL of DMSO was added to make the final concentration 5‰.

[0788] (3) The culture medium of each target compound was diluted into 8 concentration gradients by three-fold dilution method, and each concentration was repeated in duplicate, with 10 μL per well, and the final concentrations were 1000.00 / 333.33 / 111.11 / 37.04 / 12.35 / 4.12 / 1.37 / 0.46 nM;

[0789] (4) Remove the 96-well plate from the incubator after 24 h of culture. 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. Add 10 μL of the corresponding compound to each group. Incubate for 18 h after drug addition before conducting the SRB experiment.

[0790] (5) Remove the 96-well plate and measure the absorbance according to the SRB kit instructions;

[0791] 5. Evaluation of the compound's activity in inhibiting TNF-α-induced HT-29 programmed necrosis

[0792] Cell survival rate % = (OD value of treatment group - OD value of blank background) / (OD value of DMSO group - OD value of blank background) * 100

[0793] 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.

[0794] Table 1. Inhibitory activity of compounds against HT-29 and U937 cells

[0795] Note: +++++≤5nM; 5nM<++++≤10nM; 10nM<+++≤100nM; 100nM<++≤200nM; +>200nM.

[0796] Example 58: Inhibitory effect of compounds on hERG ion channels

[0797] 1. Cell culture

[0798] hERG ion channel was stably expressed in HEK293 cells.

[0799] Materials: 0.25% trypsin; DPBS (calcium-free, magnesium-free); DMEM / F-12 (10% FBS + P / S); cells in the logarithmic growth phase;

[0800] Operation process:

[0801] 1. Preheat 0.25% trypsin, DPBS (calcium-free, magnesium-free), and DMEM / F-12 (10% FBS + P / S) in a 37°C constant temperature water bath.

[0802] 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.

[0803] 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.

[0804] 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.

[0805] 5. Remove the digested cells and use a pipette to draw 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. Use a 200 μL pipette to gently disperse the cells.

[0806] 6. Transfer a certain amount of cells into a new 35mm culture dish and shake the dish to evenly disperse the cells.

[0807] 7. Label the cell type, generation number, date, etc. on the lid of the culture dish and place it in a 37°C 5% CO2 incubator for culture.

[0808] 2. Test sample configuration

[0809] Dissolve the test sample in dimethyl sulfoxide (DMSO) to a 9 mM stock solution and store at -20°C. On the day of testing, redissolve the solution in extracellular fluid to the desired concentration. For electrophysiological testing, the concentration is 10 μM.

[0810] Electrophysiological testing of intracellular and extracellular fluid formula

[0811] 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.

[0812] The intracellular solution (mM) is aspartate, 130 mg; magnesium chloride, 5 mg; ethylene glycol tetraacetic acid (EGTA), 5 mg; and N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10 mg. Adjust the pH to 7.4 with potassium hydroxide. Aliquot into 1 mL centrifuge tubes and store at -80°C.

[0813] 3. Experimental instruments

[0814] 4. Electrophysiological testing experimental steps

[0815] 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 made using PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, and noise was filtered at one-fifth the sampling frequency.

[0816] The test article is administered using a gravity-fed perfusion system. 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 fluctuations in the initial current. The average of the peak current amplitudes recorded during the last three recordings during the initial recording period is used as the peak current of the negative control. After the initial current stabilizes, the test article is administered starting at a low concentration until the three recorded peak currents stabilize again or until the peak current remains unchanged after 5 minutes of continuous administration. We define "stable" or "unchanged" as follows: 1) if the absolute average of the peak current for three consecutive scans exceeds 200pA with a CV value of less than 10%; 2) if the average of the peak current for three consecutive scans is between 200pA and 50pA with a CV value of less than 30%. The next higher concentration is then administered.

[0817] The average peak current of the last three scans at each concentration was used as the peak current for that concentration and was used for data analysis. If steady state is not reached within 5 minutes, the average peak current of the last three scans at that time was used as the peak current for that concentration and was used for data analysis. The cell was discarded and not used for testing at higher concentrations. At least one replicate was performed on a single cell for each concentration.

[0818] 5. Voltage pulse program

[0819] The cells were clamped at -80 mV, then depolarized to 40 mV with a 4-second square wave, followed by hyperpolarization to -40 mV with a 2-second square wave. This procedure was repeated every 20 seconds.

[0820] 6. Data processing and fitting

[0821] Data were analyzed using Excel 2003 (Microsoft Corporation) and OriginPro 8.

[0822] For each cell, the mean of the last three current peaks during the monitoring period (before administration of the test drug) was used as the negative control current peak. At each concentration, the mean of the last three current peaks was used as the peak current at that concentration for statistical analysis. The blocking rate of hERG current at each concentration was calculated using the following formula:

[0823] (1-peak current recorded after compound perfusion / peak current recorded before compound perfusion) × 100%

[0824] The percentage inhibition of hERG currents at the same test concentration was averaged for all cells recorded.

[0825] Half maximal inhibitory concentration (IC) 50 The value is obtained by fitting the Hill1 equation (OriginPro 8): Y = START + (END - START) * x^n / (k^n + x^n)

[0826] 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).

[0827] Table 2. Blocking rate of hERG ion channels by compounds

[0828] Example 59: Pharmacokinetics of the compound in SD rats

[0829] 1. Experimental Animals

[0830] Male Sprague-Dawley rats, 6–8 weeks old, were purchased from Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd. (Production License No. SCXK(Zhejiang)2019-0001). Animals were housed in the SPF animal facility of Hangzhou Baicheng Pharmaceutical Technology Co., Ltd. (Laboratory Animal Use License No. SYXK(Zhejiang)2021-0014) for at least one week before use. All experiments were conducted in strict accordance with relevant regulations on laboratory animals.

[0831] 2. Experimental reagents and equipment

[0832] 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.

[0833] 2.2 Experimental materials: Centrifuge tubes of various specifications were purchased from Biosharp; pipettes of various specifications were purchased from Eppendorf.

[0834] 2.3 Experimental equipment: Exion AD-SCIEX TRIPE QUAD™ 5500 was purchased from AB SCIEX.

[0835] 3 Experimental plan

[0836] 3.1. Preparation of compound dosing solution:

[0837] 3.1.1 Intravenous dosing solution: GSK2982772, Example 13 in CN201910518248X, and compounds III-1, III-10, III-12, III-19, III-21, and III-26 were prepared into 0.2 mg / mL dosing solutions using 5% DMSO + 10% kolliphor EL + 85% Saline as the solvent.

[0838] 3.1.2 Oral administration solution: GSK2982772, Example 13 in CN201910518248X, and compounds III-1, III-10, III-12, III-19, III-21, and III-26 were all prepared into 0.5 mg / mL administration solutions using 5% DMSO + 10% kolliphor EL + 85% Saline as the solvent.

[0839] 3.2 Administration to SD rats

[0840] 1) SD rats were fasted for at least 12 hours. The oral dose was 5.0 mg / kg in a 10 mL / kg volume, and the intravenous dose was 0.5 mg / kg in a 2.5 mL / kg volume. Food was given four hours after administration.

[0841] 4. Experimental Procedure

[0842] After administration, approximately 300 μL of blood was collected from the orbital cavity of each SD rat and anticoagulated with EDTA-Na₂. Blood was collected at 2, 10, 30, 1, 2, 4, 6, 8, and 24 hours after administration of the test substance for the intravenous administration group and at 5, 15, 30, 1, 2, 4, 6, 8, and 24 hours after administration of the test substance for the oral administration group. Blood was placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 2000 × g, 10 min, 4°C). After protein precipitation, 50 μL of plasma was sampled and analyzed by UHPLC-MS. Data were analyzed using WinNonLin 8.1 pharmacokinetic software to obtain pharmacokinetic parameters.

[0843] 5. Experimental Results

[0844] The pharmacokinetic parameters of the compounds of the present invention are shown in Table 2:

[0845] Conclusion: Compounds III-1, III-10, and III-12 of the present invention have good oral exposure, high bioavailability, and good half-life after oral administration, significantly improving exposure and bioavailability compared to Example 13 in CN201910518248X. After intravenous administration, compounds III-1, III-10, and III-12 have good half-lives, good clearance rates, and relatively large steady-state apparent distributions, suggesting that the compounds have greater tissue distribution in SD rats than GSK2982772 and Example 13 in CN201910518248X. In summary, compounds III-1, III-10, and III-12 have good pharmacokinetic characteristics.

[0846] NA: Not tested.

[0847] Table 2. Pharmacokinetic parameters of the tested compounds

Claims

1. A Benzazepine The ketone compound is a compound represented by formula I, an isomer or a pharmaceutically acceptable salt thereof: in: Ring A is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring, and Ring A is substituted by at least one replace; Ring B is selected from a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group, and 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; R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl; R2 is selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; L is selected from a 5-6 membered heteroaromatic ring substituted by at least one substituent, the substituent being 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, C 1-6 Alkoxysulfoxide; W is selected from a linker, -(CH2) n -、-O-、-(CH2) n O(CH2) m -、-CO-、-(CH2) n CO(CH2) m - one of; R3 is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring substituted by at least one substituent, wherein the substituent is selected from one or more of the following groups: hydrogen, 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; 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 5-10 membered heteroaromatic ring, 5-8 membered heteroaryl group, and 3-6 membered 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 compound, characterized in that The compound represented by formula II, its isomers, or its pharmaceutically acceptable salt: Wherein: X is selected from CR4, OR4 or SR4; R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl; 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, C 1-6 Alkoxysulfoxide; W is selected from -(CH2) n One of -, -O-, -CO-; R4, R5, R6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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; The 5-10 membered heteroaromatic ring, 5-8 membered heteroaryl group, and 3-6 membered 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 compound, characterized in that The compound represented by formula II-1, its isomers, or its pharmaceutically acceptable salt: Wherein: X is selected from CR4, OR4 or SR4; R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl; R4, R5, R6 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

4. The benzazepine according to claim 2 A ketone compound, characterized in that The compound represented by formula II-2, its isomers, or its pharmaceutically acceptable salt: Wherein: X is selected from CR4, OR4 or SR4; R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl; R4, R5, R6 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

5. The benzazepine according to claim 2 A ketone compound, characterized in that The compound represented by formula II-3, its isomers, or its pharmaceutically acceptable salt: Wherein: X is selected from CR4, OR4 or SR4; R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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 Alkyl amide Base, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl; R4, R5, R6 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

6. The benzazepine according to claim 2 A ketone compound, characterized in that The compound represented by formula II-4, its isomers, or its pharmaceutically acceptable salt: Wherein: X is selected from CR4, OR4 or SR4; R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl; R4, R5, R6 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

7. The benzazepine according to claim 2 A ketone compound, characterized in that The compound represented by formula II-5, its isomers, or its pharmaceutically acceptable salt: Wherein: X is selected from CR4, OR4 or SR4; R1 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the substituent is selected from one or more of the following groups: hydrogen, 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl; R4, R5, R6, R7 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy hydroxyl.

8. A Benzazepine The ketone compound is a compound, an isomer or a pharmaceutically acceptable salt thereof having the following structure: 5-Benzyl-N-[9-(cyclopropylethynyl)-4-oxyylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[4-oxyylidene-9-(pyridin-2-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[4-oxyylidene-9-(pyridin-3-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indole-5-yl] 4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[4-oxydeoxy-9-(3,4,5,6-tetrahydro-2H-pyran-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[9-(3-hydroxy-3-methylbut-1-ynyl)-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-[(4-Fluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-[(4-chlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-[(2-chlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-[(2-Fluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-[(2,6-difluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-[(2,6-dichlorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[4-oxyylidene-10-(pyridin-2-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[4-oxyylidene-10-(pyridin-3-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[10-(cyclopropylethynyl)-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-Benzyl-N-[4-oxyylidene-10-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,6-difluorophenyl)methyl]-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide; 1-Benzyl-N-[4-oxyylidene-9-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,6-difluorophenyl)methyl]-N-[9-(3-hydroxy-3-methylbut-1-ynyl)-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,6-difluorophenyl)methyl]-N-[9-(3-methoxyprop-1-ynyl)-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-1,2,4-triazacyclopentane-3-carboxamide; N-[9-(cyclopropylethynyl)-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-[(2-Fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(4-Fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,4-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,5-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(3,5-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxydeoxy-1,2,4,5,6,7-hexahydroazepine [3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(3,4-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2-methylphenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(4-methylphenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,6-difluorophenyl)methyl]-N-(4-oxyylidene-9-(piperidin-4-ylethynyl)-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl)-1,2,4-triazacyclopentane-3-carboxamide; tert-Butyl 4-((3-(1-(2,6-difluorobenzyl)-1H-1,2,4-triazole-3-carboxamide)-4-oxyylidene-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-9-yl)ethynyl)piperidine-1-carboxamide; 1-(2,6-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(3,5-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(2,5-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(2,4-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(2-Fluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(2-methylbenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(3,4-difluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(4-fluorobenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(4-methylbenzyl)-N-(9-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(2,6-difluorobenzyl)-N-(9-ethynyl-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(2,6-difluorobenzyl)-N-(9-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1H-1,2,4-triazole-3-carboxamide; 1-(2,6-difluorobenzyl)-N-(9-((5-formyl-1-vinyl-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(2,6-difluorobenzyl)-N-(9-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-(2,6-difluorobenzyl)-N-(9-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indol-5-yl)-1-(pyridin-2-ylmethyl)-1H-1,2,4-triazole-3-carboxamide; 1-(4-benzyl)-N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-1,2,4-triazole-3-carboxamide; 1-Benzyl-N-[4-oxyylidene-10-(pyridin-4-ylethynyl)-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-6-phenoxy Pyridine amide; N-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-1,2,3,4,6,7-hexahydroazepano[3,2,1-hi]indol-3-yl)-5-phenoxypicolinamide; 5-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-3,4,6,7-tetrahydro-2H-[1,4]oxazepano[2,3,4-hi]indol-3-yl}-4H-1,2,4-triazacyclopentane-3-carboxamide; 5-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxo-3,4,6,7-tetrahydro-2H-[1,4]thiazepano[2,3,4-hi]indol-3-yl}-4H-1,2,4-triazacyclopentane-3-carboxamide; N-{7,7-difluoro-9-[(1-methylpyrazol-4-yl)ethynyl]-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; 5-Benzyl-N-[8-(cyclopropylethynyl)-4-oxylidene-3,4,6,7-tetrahydro-2H-[1,4]oxazepano[2,3,4-hi]indol-3-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxoylidene-3,4,6,7-tetrahydro-2H-[1,4]oxazepano[2,3,4-hi]indol-3-yl}-1,2,4-triazacyclopentane-3-carboxamide; 1-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-3,4,6,7-tetrahydro-2H-[1,4]thiazepano[2,3,4-hi]indol-3-yl}-1,2,4-triazacyclopentane-3-carboxamide; N-{7,7-difluoro-9-[(1-methylpyrazol-4-yl)ethynyl]-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-[(2,6-difluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxyde-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}pyrazole-3-carboxamide; 1-[(4-Fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}pyrazole-3-carboxamide; 5-(2-Benzyl-3-chloro-7-oxoylidene-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-yl)-9-[(1-methylpyrazol-4-yl)ethynyl]-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-4-one; 4-[(3-Fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxylidene-1,2,4,5,6,7-hexahydroazepano[3,2,1-hi]indol-5-yl}pyrazole-1-carboxamide; 4-[(3-Fluorophenyl)methyl]-N-{9-[(1-methylpyrazol-4-yl)ethynyl]-4-oxoylidene-3,4,6,7-tetrahydro-2H-[1,4]oxazepano[2,3,4-hi]indol-3-yl]-4H-1,2,4-triazacyclopentane-3-carboxamide.

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

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

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

12. The use according to claim 11, 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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