1, 2-diaza-5-formamide compound as well as preparation method and application thereof

Abstract

The invention discloses a 1, 2-diaza # imgabs 0 #-5-formamide compound as well as a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to a (3aR, 4R, 8R, 8aR)-2, 2, 6-trimethyl-N-phenylhexahydro-5H-4, 8-epoxy-1, 3-dioxolame [4, 5-d]-1, 2-diaza # imgabs 1 #-5-formamide compound as well as a preparation method and application thereof in an anti-tumor aspect. The general formula of the 1, 2-diaza # imgabs2 #-5-formamide compound is shown in the specification, and in the general formula, X is selected from NH, O, S, NHCO, CH2NHCO and NHCONH; r is selected from hydrogen, C1-C4 alkyl groups, C1-C4 alkoxy groups, halogen, halogen-substituted C1-C4 alkyl groups, halogen-substituted C1-C4 alkoxy groups, phenyl groups, naphthyl groups formed by the phenyl groups, C1-C4 acyloxy groups, C1-C4 amido groups and C1-C4 alkylthio groups; the number of R can be one or more. The compound disclosed by the invention is simple and convenient in synthesis method and suitable for industrial production, and a biological activity test shows that the compound has anti-tumor activity and can be applied to preparation of anti-tumor drugs. # imgabs3 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-phenylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide compound preparation method and its application in anti-tumor. Background Art

[0002] Cancer has now become a major challenge to human health and is an important factor leading to human death. The occurrence of tumors is an uncontrolled cell proliferation and an abnormal behavior of one's own cells, which is often related to some abnormal signal transduction regulation mechanisms. In the diagnosis and treatment of cancer, a variety of technologies such as surgery and drug therapy have been developed, and toxic drugs and targeted drugs have been developed one after another. However, traditional chemotherapy drugs often have strong toxic side effects and serious adverse reactions. The emergence of small molecule targeted drugs has alleviated the serious toxic side effects of chemotherapy drugs to a certain extent, but as the administration time increases, targeted drugs are prone to drug resistance. Therefore, researchers of chemotherapy drugs need to continuously develop new candidate drug molecules so that cancer treatment can continue. The following drugs are currently on the market:

[0003] Sorafenib: Sorafenib is a multi-target inhibitor with a bis-aryl urea structure, which is associated with a reduced rate of tumor growth and liver function deterioration in HCV-induced hepatocellular carcinoma. Sorafenib treatment is associated with improved survival in patients with advanced liver cancer, mainly by reducing the rate of tumor growth and liver function deterioration in patients infected with hepatitis C virus (Kolamunnage-Dona R, Berhane S, Potts H, Williams EH, Tanner J, Janowitz T, Hoare M, Johnson P. Sorafenib is associated with a reduced rate of tumour growth and liver function deterioration in HCV-induced hepatocellular carcinoma. Journal of Hepatology, 2021, 75(4): 879-887.).

[0004] Lenvatinib: Lenvatinib is a drug developed by Japan's Eisai Co., Ltd. for the treatment of locally recurrent or metastatic, radioactive iodine-refractory, and progressive differentiated thyroid cancer. It is an oral multi-target receptor tyrosine kinase (RTK) inhibitor and was approved for marketing by the U.S. FDA on February 13, 2015. Lenvatinib can inhibit vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (SCFR), etc., thereby cutting off the blood and nutrient supply of cancer cells and causing cancer cells to die (Al-Salama ZT, Syed YY, Scott LJ. Lenvatinib: a review in hepatocellular carcinoma. Drugs. 2019, 79(6): 665-674.).

[0005] Entrectinib: Entrectinib is an oral, selective tyrosine kinase inhibitor (TRKI) that targets locally advanced or metastatic solid tumors carrying tropomyosin receptor kinase (NTRK) 1 / 2 / 3 or proto-oncogene tyrosine protein kinase 1 (ROS1). Entrectinib can pass through the blood-brain barrier, block the activity of TRKA / B / C and ROS1 protein kinases, and cause cancer cells carrying ROS1 or NTRK gene fusion proteins to die. Entrectinib is effective in patients with primary and metastatic central nervous system (CNS) tumors, and has no adverse off-target activity (Jiang Q, Li M, Li H, Chen L. Entrectinib, a new multi-target inhibitor for cancer therapy. Biomedicine & Pharmacotherapy, 2022, 150: 112974.).

[0006] Cabozantinib: Cabozantinib is a receptor tyrosine kinase inhibitor that effectively inhibits tumor occurrence, development and angiogenesis. Its anti-tumor mechanism is the effective inhibition of factors such as MET, AXL, VEGFR1-3, etc. (Maroto P, Porta C, Capdevila J, Apolo AB, Viteri S, Rodriguez-Antona C, Martin L, Castellano D. Cabozantinib for the treatment of solid tumors: a systematic review. Therapeutic Advances in Medical Oncology, 2022, 14: 17588359221107112.).

[0007] Urea compounds have a great impact and far-reaching significance in cancer. Due to their wide range of biological applications, they have received considerable attention in recent years. Typical anti-tumor drugs such as sorafenib and lenvatinib have aryl urea structures as marketed drugs with pharmacophores. Some studies have shown that aryl urea structures are easy to interact with target proteins because they have a planar aromatic skeleton and hydrogen bond donors and acceptors. Therefore, aryl urea structures are a good druggable structure. Summary of the invention

[0008] The primary purpose of the present invention is to provide a 1,2-diazepine -5-carboxamide compound or a pharmaceutically acceptable salt thereof, the 1,2-diazepine -5-carboxamide compounds, specifically (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-phenylhexahydro-5H-4,8-epoxy[1,3]dioxolane[4,5-d][1,2]diazepine -5-formamide compounds, the present invention also provides the 1,2-diaza -5-carboxamide compounds or their pharmaceutically acceptable salts in the preparation of anti-tumor drugs. A 1,2-diazepine as shown in general formula I -5-carboxamide compounds or pharmaceutically acceptable salts thereof;

[0009]

[0010] Wherein, X is selected from NH, O, S, NHCO, CH2NHCO, NHCONH; R is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, halogen-substituted C1-C4 alkyl, halogen-substituted C1-C4 alkoxy, phenyl, naphthyl formed with the phenyl group, C1-C4 acyloxy, C1-C4 amide, C1-C4 alkylthio; R can be one or more.

[0011] Furthermore, X is selected from NH, O, S, NHCO, NHCONH, CH2NHCO; R is selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, phenyl, naphthyl formed with the attached phenyl, propionyloxy, acetamido, methylthio; R can be one or more.

[0012] Further, X is selected from NH, O, S, NHCO, NHCONH, CH2NHCO; R is selected from hydrogen, 4-trifluoromethoxy, 4-fluoro, 4-chloro-3-trifluoromethyl, 3-chloro-4-fluoro, 4-methoxy, 3-trifluoromethyl, 4-trifluoromethyl, 3-chloro, 3-methyl, 4-methyl, 4-propyl, 2-methoxy-4-propyl, 4-phenyl, 1-naphthyl with the connected phenyl, 2-naphthyl with the connected phenyl, 4-propionyloxy, 4-acetamido, 4-methylthio.

[0013] The present invention preferably uses the following compounds:

[0014] (3aR,4R,8R,8aR)-N-{4-{3-[4-(trifluoromethoxy)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0015] (3aR,4R,8R,8aR)-N-{4-[3-(4-fluorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0016] (3aR,4R,8R,8aR)-N-{4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0017] (3aR,4R,8R,8aR)-N-{4-[3-(3-chloro-4-fluorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0018] (3aR,4R,8R,8aR)-N-{4-[3-(4-methoxyphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0019] (3aR,4R,8R,8aR)-N-{4-[3-(3-trifluoromethylphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0020] (3aR,4R,8R,8aR)-N-{4-[3-(3-chlorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0021] (3aR,4R,8R,8aR)-N-{4-[3-(3-methylphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0022] (3aR,4R,8R,8aR)-N-{4-{3-[3-(naphthalen-1-yl)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0023] (3aR,4R,8R,8aR)-N-{4-[3-(biphenyl-4-yl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0024] 4-{3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-carboxamido)phenyl]ureido}phenylpropionate;

[0025] (3aR,4R,8R,8aR)-N-[3-(Benzylcarbamoyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0026] (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[3-(naphthalen-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0027] (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[3-(p-tolylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0028] (3aR,4R,8R,8aR)-N-{3-[(4-methoxyphenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0029] (3aR,4R,8R,8aR)-N-{3-[(4-Fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0030] (3aR,4R,8R,8aR)-N-{3-[(4-fluorobenzyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0031] (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-{3-{[4-(trifluoromethoxy)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0032] (3aR,4R,8R,8aR)-N-{3-[(4-trifluoromethyl)phenyl]carbamoyl}phenyl-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0033] (3aR,4R,8R,8aR)-N-{3-{[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0034] (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-{4-{9-[4-(trifluoromethoxy)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0035] (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[4-(p-toluidinecarbonyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0036] (3aR,4R,8R,8aR)-N-{4-[(4-Fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0037] (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[4-(naphthalen-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0038] (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-{4-[4-(trifluoromethyl)phenyl)carbamoyl]phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0039] (3aR,4R,8R,8aR)-N-{4-[(3-chloro-4-fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0040] (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-{4-{[3-(trifluoromethyl)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0041] (3aR,4R,8R,8aR)-N-(4-phenoxyphenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0042] (3aR,4R,8R,8aR)-N-[4-(p-Tolylthio)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0043] (3aR,4R,8R,8aR)-N-[4-(p-Toluylamino)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0044] (3aR,4R,8R,8aR)-N-{4-[4-(methylthio)phenoxy]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0045] (3aR,4R,8R,8aR)-N-[4-(Naphthalen-2-yloxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0046] (3aR,4R,8R,8aR)-N-(4-Acetamidophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0047] (3aR,4R,8R,8aR)-N-[4-(4-methoxyphenoxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0048] (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[4-(p-tolyloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide;

[0049] (3aR,4R,8R,8aR)-N-[4-(2-methoxy-4-propylphenoxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide;

[0050] (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[4-(naphthalen-1-yloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-Carboxamide.

[0051] A pharmaceutical composition comprises as an active ingredient a compound represented by formula I of the present invention, its prodrug and pharmaceutically active metabolite, and any one of its pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier or diluent.

[0052] "Pharmaceutically acceptable salts" refers to conventional acid addition salts or base addition salts which retain the biological effectiveness and properties of the compounds of formula I and which are formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, nitrates, phosphates, sulfates, perchlorates, thiocyanates, bisulfates, persulfates, borates, formates, acetates, propionates, valerates, pivalates, caproates, heptanoates, caprylates, isooctanoates, undecanoates, laurates, palmitates, stearates, oleates, cyclopropionates, oxalates, malonates, succinates, maleates, fumarates, adipates, azelaates, acrylates, crotonates, tiglates, itaconates, sorbates, cinnamates, glycolates, lactates, malates, tartrates, citrates, tartrates, mandelates, benzilates, tropicates, ascorbic acids, gluconates, glucoheptonates, glucarates, mannonates, lactobionates, benzoates, phthalates, terephthalates, furoates, nicotinates, isonicotinates, Salicylate, acetylsalicylate, butyrate, gallate, caffeate, ferulate, picrate, camphorate, camphorsulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, p-toluenesulfonate, p-aminobenzenesulfonate, sulfamate, taurine, 2-hydroxyethanesulfonate, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartate, asparagine, glutamate, lysine, glutamine, methionine, serine, threonine, cysteine, proline, histidine, arginine, edetate, pyruvate, α-ketoglutarate, alginate, cyclopentanepropionate, 3-phenylpropionate, 3-cyclohexylpropionic acid, 2-naphthoate, 2-naphthalenesulfonate, pamoate, lauryl sulfate, glycerophosphate, lauryl sulfate, pectinate, etc. Basic salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts of organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine salts, etc., and basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; aralkyl halides such as benzyl and phenethyl bromide, etc. Preferred acids for forming acid addition salts include hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, p-aminobenzenesulfonic acid.

[0053] The preparation route of the preferred compound of the present invention is:

[0054] Synthesis route 1:

[0055]

[0056] R in the synthetic route 1 is the corresponding group at the corresponding position of the compound YA01-YA11.

[0057] Synthesis route 2:

[0058]

[0059] R in the second synthetic route is the corresponding group at the corresponding position of compounds MA01-MA09.

[0060] Synthesis route three:

[0061]

[0062] R in the synthetic route 3 is the corresponding group at the corresponding position of compounds MB01-MB07.

[0063] Synthesis route 4:

[0064]

[0065] X and R in the synthetic route 4 are the corresponding groups at the corresponding positions of compounds MC01-MC10.

[0066] The present invention also provides 1,2-diazepine represented by formula I -5-formamide compounds or pharmaceutically acceptable salts thereof or the above pharmaceutical compositions are used in the preparation of A549 cell, A375 cell, MCF-7 cell and Calu-3 cell proliferation inhibitors.

[0067] The present invention also provides 1,2-diazepine represented by formula I -5-carboxamide compounds or their pharmaceutically acceptable salts or the above pharmaceutical compositions are used in the preparation of anti-tumor drugs. The tumors include lung cancer, melanoma, breast cancer, human lung adenocarcinoma cells and ovarian cancer.

[0068] Beneficial effects of the present invention:

[0069] The present invention discloses a series of novel 1,2-diazapines -5-carboxamide compounds, which show different degrees of proliferation inhibition activity on tumor cell lines such as A549 (lung cancer cells), A375 (melanoma cells), MCF-7 (breast cancer cells) and Calu-3 (lung adenocarcinoma cells) in in vitro experiments. The present invention provides a new strategy and potential drug for cancer treatment. The synthesis method of the compound of the present invention is simple and suitable for industrial production. The biological activity test shows that the compound has anti-tumor activity and can be used in the preparation of anti-tumor drugs. DETAILED DESCRIPTION

[0070] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0071] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents and instruments used, they are all conventional reagent products that can be purchased commercially.

[0072] Example 1: (3aR, 4R, 8R, 8aR)-N-{4-{3-[4-(trifluoromethoxy)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA01)

[0073] Step A: Preparation of (3aR,6R,6aR)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolane-4-ol

[0074] Weigh D-ribose (10.0 g, 66.7 mmol) and place it in a flask. Add 50 mL of acetone, slowly drop 0.5 mL of sulfuric acid in an ice bath, stir and react at room temperature for 1.5 hours, then add triethylamine to neutralize the reaction solution. After most of the acetone is evaporated under reduced pressure, 11.87 g of a slightly yellow viscous liquid is obtained by column chromatography (PE:EA=2:1), with a yield of 93.7%.

[0075] Step B: Preparation of [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolan-4-yl]methyl p-toluenesulfonate

[0076] Weigh (3aR, 6R, 6aR)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolane-4-ol (11.87 g, 62.4 mmol) into a flask, add pyridine to dissolve, slowly add p-toluenesulfonyl chloride (14.28 g, 74.9 mmol) in pyridine to the reaction system under ice bath, stir and react overnight at room temperature. Dilute the reaction solution with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, evaporate most of the ethyl acetate under reduced pressure, and separate by column chromatography (PE:EA=5:1) to obtain 14.00 g of white solid, with a yield of 67.3%.

[0077] Step C: (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation

[0078] [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl]methyl p-toluenesulfonate (0.35 g, 1.0 mmol), methylhydrazine sulfate (0.17 g, 1.2 mmol), acetonitrile (2 mL), triethylamine (TEA, 0.55 mL, 4.0 mmol) were added to a flask and stirred at 35°C under nitrogen protection for overnight reaction. Most of the acetonitrile was evaporated under reduced pressure and separated by column chromatography (PE:EA=2:1) ​​to obtain 0.133 g of a slightly yellow waxy solid with a yield of 66.3%. (c 0.7,CHCl3). 1 H NMR (400MHz, CDCl3) δ4.88–4.86(m,1H),4.86–4.81(m,1H),4.80–4.73(m,1H),4.27(td,J=2.1,0. 9Hz,1H),2.75–2.71(m,1H),2.36(dd,J=11.3,2.0Hz,1H),2.34(s,3H),1.47(s,3H),1.35(s,3H). 13 C NMR(101MHz, CDCl3)δ111.42,91.50,82.78,82.73,78.76,59.98,46.24,26.02,24.54.HRMS(ESI)m / z:Calcd for C9H 17 N2O3([M+H] + )201.12337.

[0079] Step D: (3aR,4R,8R,8aR)-N-(4-nitrophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of 5-formamide

[0080] Weigh triphosgene (BTC, 0.2 g, 0.67 mmol) and dichloromethane (DCM, 10 mL) into a flask, slowly drop p-nitroaniline (1.4 g, 2.0 mmol) in dichloromethane, then slowly drop triethylamine (0.4 g, 4.0 mmol) in dichloromethane, then slowly drop (3aR, 4R, 8R, 8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine (1.0 g, 1.0 mmol) of dichloromethane solution was stirred at room temperature overnight. After most of the dichloromethane was evaporated under reduced pressure, 1.56 g of yellow solid was obtained by column chromatography (DCM:EA=10:1), with a yield of 85.6%; Mp: 203.1-205.3℃; 1 H NMR(400MHz, DMSO-d6)δ9.85(s,1H),8.18(d,J=9.3Hz,2H),7.90(d,J=9.3Hz,2H),5.86–5.81(m,1H),5.10–5.02( m,2H),4.25–4.19(m,1H),3.40(dd,J=13.7,3.4Hz,1H),2.88–2.81(m,1H),2.79(s,3H),1.38(s,3H),1.32(s,3H). 13 C NMR (101MHz, DMSO-d6) δ155.39,146.25,142.11,125.10,119.26,112.37,87.23,82.44,81.73,79.46,52.28,45.96,26.37,25.00.

[0081] Step E: (3aR,4R,8R,8aR)-N-(4-aminophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of 5-formamide

[0082] Weigh (3aR,4R,8R,8aR)-N-(4-nitrophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide (0.36 g, 1.0 mmol) was placed in a flask, 0.18 g of palladium carbon was added, and an appropriate amount of ethanol was added to dissolve it. Hydrogen was introduced, and the reaction was stirred for 48 hours. After the ethanol was evaporated under reduced pressure, a yellow solid was obtained through column chromatography (PE:EA=1:1), with a yield of 74.8%; Mp: 182.1-183.4℃; 1H NMR(400MHz, DMSO-d6)δ8.83(s,1H),7.13(d,J=8.7Hz,2H),6.48(d,J=8.7Hz,2H),5.82–5.77(m,1H),5.05–5.00(m,2H), 4.79(s,2H),4.17–4.13(m,1H),3.36(dd,J=13.7,3.1Hz,1H),2.81–2.76(m,1H),2.75(s,3H),1.37(s,3H),1.32(s,3H). 13 C NMR (101MHz, DMSO-d6) δ155.96,144.92,128.33,122.09,114.23,112.17,87.38,82.55,81.68,79.27,51.94,45.86,26.40,25.01.

[0083] Step F: (3aR,4R,8R,8aR)-N-{4-{3-[4-(trifluoromethoxy)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA01)

[0084] Weigh triphosgene (0.0593 g, 0.2 mmol) and add it to a 50 mL round-bottom flask. Weigh p-trifluoromethoxyaniline (0.1063 g, 0.6 mmol) and add it to a constant pressure dropping funnel. Slowly dropwise add triethylamine (0.1214 g, 1.2 mmol). Slowly dropwise add (3aR, 4R, 8R, 8aR)-N-(4-aminophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine. -5-Formamide (0.1003 g, 0.3 mmol) was added to a constant pressure dropping funnel and added dropwise to the above reaction flask. After the addition was complete, the reaction was allowed to proceed overnight. 0.06 g of a slightly yellow solid was obtained by column chromatography (DCM:EA=5:1) with a yield of 59.8%; Mp: 246.8-249.6°C; 1H-NMR(400MHz,DMSO-d6)δ9.17(s,1H),9.03(s,1H),8.67(s,1H),7.65(d,J =8.9Hz,2H),7.61(d,J=9.0Hz,2H),7.48(d,J=9.0Hz,2H),7.36(d,J=9.0Hz ,2H),5.89–5.77(m,1H),5.10–4.99(m,2H),4.21–4.12(m,1H),3.39(dd,J= 13.6,3.1Hz,1H),2.85–2.79(m,1H),2.78(s,3H),1.38(s,3H),1.32(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ158.88,156.52,155.83,153.13,136.62,136.60,135.11,133.83,120.69,120.34,120.27,119.01,115.80,115.5 8,112.23,87.34,82.53,81.70,79.34,52.05,45.90,40.62,40.41,40 .20,40.00,39.79,39.65,39.58,39.37,26.41,25.03; MS:544.1([M+H] + ).

[0085] Example 2: (3aR, 4R, 8R, 8aR)-N-{4-[3-(4-fluorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA02)

[0086] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced by p-fluoroaniline to obtain 0.06 g of a white solid with a yield of 41.4%; MP: 191.3-193.7°C; 1H-NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.62(s,1H),8.52(s,1H),7.46(d,J =5.2Hz,2H),7.44(d,J=5.2Hz,2H),7.34(d,J=9.0Hz,2H),7.12(d,J=8.9Hz ,2H),5.85–5.79(m,1H),5.09–5.01(m,2H),4.20–4.14(m,1H),3.38(dd,J= 13.6,3.1Hz,1H),2.83–2.80(m,1H),2.78(s,3H),1.38(s,3H),1.32(s,3H); 13 C-NMR (101MHz, DMSO-d6) δ158.88, 156.52, 154.48 (d, J = 271.5Hz), 136.61 (d, J = 2.2Hz), 135.11, 133.83, 120.31 (d, J = 7.7Hz), 119.85 (d, J = 169.1Hz), 115.69 (d, J = 22.3Hz), 112.23, 87.34, 82.53, 81.70, 79.34, 52.05, 45.90, 26.41, 25.03; MS: 469.9 ([MH] - ).

[0087] Example 3: (3aR, 4R, 8R, 8aR)-N-{4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA03)

[0088] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with 3-trifluoromethyl-4-chloroaniline to obtain 0.276 g of a white solid with a yield of 99.7%; MP: 136.2-142.7°C; 1H-NMR(400MHz,DMSO-d6)δ9.19(s,1H),9.10(s,1H),8.71(s,1H),8.12(d, J=2.2Hz,1H),7.67–7.56(m,2H),7.48(d,J=9.0Hz,2H),7.37(d,J=9.0Hz,2 H),5.86–5.79(m,1H),5.09–5.01(m,2H),4.21–4.15(m,1H),3.39(dd,J=1 3.6,3.2Hz,1H),2.84–2.80(m,1H),2.78(s,3H),1.39(s,3H),1.33(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ155.83,152.89,139.96,134.56,134.28,132.39,123.38,122.55,12 0.63,119.45,112.24,87.33,82.53,81.70,79.35,52.06,45.89,26.39,25.00; MS:553.7([MH] - ).

[0089] Example 4: (3aR, 4R, 8R, 8aR)-N-{4-[3-(3-chloro-4-fluorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA04)

[0090] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with 3-chloro-4-fluoroaniline to obtain 0.1156 g of a white solid with a yield of 45.7%; MP: 224.8-226.3°C; 1 H-NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.82(s,1H),8.63(s,1H),7.81(dd, J=6.8,2.4Hz,1H),7.47(d,J=9.0Hz,2H),7.35(d,J=9.0Hz,2H),7.33–7.21( m,2H),5.86–5.81(m,1H),5.08–5.03(m,2H),4.20–4.16(m,1H),3.39(dd,J= 13.6,3.2Hz,1H),2.83–2.81(m,1H),2.78(s,3H),1.39(s,3H),1.33(s,3H); 13C-NMR (101MHz, DMSO-d6) δ155.88,153.02,152.72(d,J=240.7Hz),137.65,134.84,134.10,120.69,119.87,119.60(d,J=18.1Hz),1 19.25, 118.88 (d, J = 6.9Hz), 117.34 (d, J = 21.4Hz), 112.26, 87.35, 82.55, 81.72, 79.37, 52.07, 45.93, 26.43, 25.05; MS: 503.8 ([MH] - ).

[0091] Example 5: (3aR, 4R, 8R, 8aR)-N-{4-[3-(4-methoxyphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA05)

[0092] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with 4-methoxyaniline to obtain 0.0905 g of a white solid with a yield of 37.4%; MP: 190.3-194.7°C; 1 H-NMR (400MHz, DMSO-d6) δ9.14 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 7.44 (d, J = 9. 0Hz,2H),7.35(d,J=3.2Hz,2H),7.32(d,J=3.2Hz,2H),6.86(d,J=9.0Hz,2H),5 .86–5.79(m,1H),5.12–5.00(m,2H),4.22–4.13(m,1H),3.71(s,3H),3.38(dd, J=13.7,3.2Hz,1H),2.83–2.79(m,1H),2.78(s,3H),1.38(s,3H),1.32(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ155.88,154.84,153.28,133.64,133.33,120.74,120.39,118.8 4,114.45,112.26,82.56,81.71,79.37,55.65,52.06,45.94,26.44,25.05; MS:481.9([MH] - ).

[0093] Example 6: (3aR, 4R, 8R, 8aR)-N-{4-[3-(3-trifluoromethylphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA06)

[0094] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with 3-trifluoromethylaniline to obtain 0.2368 g of a white solid with a yield of 90.8%; MP: 142.5-143.7°C; 1 H-NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.98(s,1H),8.66(s,1H),8.02(s,1H) ,7.59–7.49(m,2H),7.48(d,J=9.0Hz,2H),7.37(d,J=9.0Hz,2H),7.29(d,J=7 .9Hz,1H),5.86–5.81(m,1H),5.07–5.02(m,2H),4.21–4.15(m,1H),3.39(dd, J=13.6,3.2Hz,1H),2.83–2.79(m,1H),2.78(s,3H),1.38(s,3H),1.32(s,3H); 13 C-NMR (101MHz, DMSO-d6) δ155.89,153.04,141.21,134.76,134.17,130.37,129.99(q,J=33.1,31.7Hz),124.73(q,J=272.1H z),122.20,120.69,119.31,118.39,114.50,112.26,87.34,82.56,81.72,79.38,52.07,45.93,26.43,25.03; MS:519.9([MH] - ).

[0095] Example 7: (3aR, 4R, 8R, 8aR)-N-{4-[3-(3-chlorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA07)

[0096] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with 3-chloroaniline to obtain 0.1864 g of white solid. Yield: 76.4%; MP: 245.3-246.6°C; 1H-NMR (400MHz, DMSO-d6) δ9.16(s,1H),8.74(s,1H),8.57(s,1H),7.52–7.42(m,4H),7.34(d,J=8.9Hz,2H),7.31(d,J=8.9Hz,2H),5.87–5 .80(m,1H),5.07–5.02(m,2H),4.20–4.15(m,1H),3.38(dd,J=13.6,3.2Hz,1H),2.82–2.79(m,1H),2.78(s,3H),1.38(s,3H),1.32(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ155.88,152.97,139.34,134.97,133.99,129.09,125.63,120.72,12 0.10,119.11,112.26,87.35,82.55,81.71,79.37,52.08,45.93,26.44,25.05; MS:485.8([MH] - ).

[0097] Example 8: (3aR, 4R, 8R, 8aR)-N-{4-[3-(3-methylphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA08)

[0098] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with 3-methylaniline to obtain 0.1803 g of a white solid with a yield of 77.1%; MP: 223.2-225.2°C; 1 H-NMR (400MHz, DMSO-d6) δ9.15(s,1H),8.51(s,2H),7.45(d,J=8.9Hz,2H),7.39–7.29(m,4H),7.08(d,J=8.2Hz,2H),5.88–5.81(m,1H),5.08 –5.03(m,2H),4.21–4.15(m,1H),3.39(dd,J=13.6,3.2Hz,1H),2.83–2.80(m,1H),2.83–2.79(m,1H),2.24(s,3H),1.39(s,3H),1.33(s,3H); 13C-NMR(101MHz,DMSO-d6)δ155.89,153.13,137.75,135.32,133.72,130.94,129.65,120.74,118.8 8,118.68,112.26,87.36,82.56,81.72,79.37,52.07,45.94,26.44,25.05,20.84; MS:468.1([M+H] + ).

[0099] Example 9: (3aR, 4R, 8R, 8aR)-N-{4-{3-[3-(naphthalen-1-yl)]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA09)

[0100] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with 1-naphthylamine to obtain 0.0620 g of a white solid with a yield of 24.6%; Mp: 180.5-182.8°C; 1 H-NMR (400MHz, DMSO-d6) δ9.18(s,1H),8.95(s,1H),8.72(s,1H),8.13(d,J=8.3Hz,1H),8.02( dd,J=7.7,1.1Hz,1H),7.93(dd,J=8.1,1.4Hz,1H),7.65–7.52(m,3H),7.49(d,J=9.0Hz,2H),7 .46(d,J=8.0Hz,1H),7.41(d,J=9.0Hz,2H),5.87–5.80(m,1H),5.08–5.03(m,2H),4.21–4.15( m,1H),3.40(dd,J=13.6,3.2Hz,1H),2.83–2.80(m,1H),2.78(s,3H),1.38(s,3H),1.33(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ155.85,134.89,128.89,126.34,126.30,126.12,123.21,121.76,120.77 ,118.85,117.63,112.24,87.36,82.54,81.71,79.35,52.06,45.91,26.42,25.03; MS:504.1([M+H] + ).

[0101] Example 10: (3aR, 4R, 8R, 8aR)-N-{4-[3-(biphenyl-4-yl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (YA10)

[0102] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with 4-aminobiphenyl to obtain 0.2200 g of a white solid with a yield of 83.1%; MP: 214.9-216.6°C; 1 H-NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.73(s,1H),8.59(s,1H),7.68–7.57(m,4H),7.57–7.34(m,8H),7.34–7.26(m,1H),5.89–5.82 (m,1H),5.09–5.01(m,2H),4.22–4.14(m,1H),3.39(dd,J=13.6,3.2Hz,1H),2.83–2.79(m,1H),2.78(s,3H),1.39(s,3H),1.33(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ155.84,152.99,135.11,133.85,129.32,127.43,127.22,126.54,120.7 1,119.00,118.91,112.24,87.34,82.54,81.71,79.35,52.06,45.90,26.41,25.02; MS:527.9([MH] - ).

[0103] Example 11: 4-{3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of 5-formamido]phenyl}ureido}phenylpropionate (YA11)

[0104] Referring to the preparation method of Example 1, the p-trifluoromethoxyaniline in step F was replaced with p-aminophenol to obtain (3aR, 4R, 8R, 8aR)-N-{4-[3-(3-methylphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide was a white solid. The intermediate was heated to reflux with propionic anhydride for 4 h without purification. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated and separated by column chromatography (DCM:EA=5:1) to obtain 0.0900 g of a white solid with a yield of 34.2%; MP: 236.8-239.5°C; 1 H-NMR(400MHz,DMSO-d6)δ9.18(s,1H),9.05(s,1H),8.67(s,1H),7.88(d,J=8.4Hz ,2H),7.58(d,J=8.4Hz,2H),7.48(d,J=8.5Hz,2H),7.36(d,J=8.6Hz,2H),5.88–5. 81(m,1H),5.09–4.99(m,2H),4.27(q,J=7.1Hz,2H),4.21–4.13(m,1H),3.39(dd,J =13.7,3.2Hz,1H),2.82–2.80(m,1H),2.78(s,3H),1.38(s,3H),1.35–1.28(m,6H); 13 C-NMR(101MHz,DMSO-d6)δ165.89,155.83,152.66,144.91,134.68,130.81,123.02,120.67,119.22,11 7.64,112.24,87.34,82.54,81.71,79.35,60.71,52.06,45.90,26.40,25.02,14.72; MS:548.1([M+Na] + ).

[0105] Example 12: (3aR, 4R, 8R, 8aR)-N-[3-(Benzylcarbamoyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA01)

[0106] Step G: (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of 5-formamide

[0107] Weigh 6.85g of m-aminobenzoic acid into a 250mL round-bottom flask, add 73mL of ethanol, add 5mL of concentrated sulfuric acid under ice bath, put the round-bottom flask in a water bath to control the temperature at 80°C, and add a drying tube. Use TLC to detect that the reaction is complete, add triethylamine to adjust the pH to 7, concentrate by rotary evaporation, dilute with 100mL of water, extract with 100mL of ethyl acetate, dry, and filter to obtain ethyl m-aminobenzoate with a yield of 67.2%. Weigh triphosgene (1.98 g, 6.67 mmol) in a 500 mL flask and dissolve it in 50 mL of dichloromethane. Weigh ethyl m-aminobenzoate in a 100 mL beaker and dissolve it in 50 mL of dichloromethane. Slowly add dropwise with a constant pressure dropping funnel. After the addition is complete, weigh triethylamine (4.05 g, 40 mmol) in a 100 mL beaker and dissolve it in dichloromethane. Slowly add dropwise with a constant pressure dropping funnel. Weigh (3aR, 4R, 8R, 8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine (i.e., the product of step C in Example 1) (2.00 g, 10 mmol), after the dropwise addition, the reaction was allowed to proceed overnight at room temperature. TLC monitoring (DCM:EA=10:1) showed that the reaction was almost complete. Column chromatography (DCM:EA=25:1) was used to separate 3.54 g of solid, with a yield of 90.44%; MP: 117.8-118.7°C; MS: 392.18088 ([M+H] + ).

[0108] Step H: (3aR,4R,8R,8aR)-N-[3-(hydroxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of 5-formamide

[0109] Weigh (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide (3.91 g, 10 mmol) was placed in a 50 mL beaker, lithium hydroxide (0.718 g, 30 mmol) was added, 30 mL of water was added, and the mixture was stirred at room temperature for 5 min, then transferred to a 50 °C oil bath and reacted for 1 h. The reaction was basically complete as monitored by TLC, and the insoluble matter was removed by filtration. The pH was adjusted to 3-4 with concentrated hydrochloric acid under ice bath. A large amount of solid precipitated, which was filtered and dried to obtain 1.90 g of brown solid, with a yield of 52.28%; MP: 216.9-217.6 °C; MS: 364.14960 ([M+H] + ).

[0110] Step I: (3aR,4R,8R,8aR)-N-[3-(Benzylcarbamoyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine Preparation of 5-formamide

[0111] Weigh (3aR,4R,8R,8aR)-N-[3-(hydroxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide (0.36 g, 1 mmol) was placed in a 10 mL flask, and EDCI (0.23 g, 1.2 mmol), HOBT (0.16 g, 1.2 mmol), DMF 5 mL, and TEA 0.12 g were added. After stirring for 30 min, benzylamine (0.12 g, 1.1 mmol) was added. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC the next day. The reaction was almost complete. 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. The mixture was washed with water and then with saturated brine, dried, filtered, and subjected to column chromatography (PE:EA=1:1) to obtain 0.3781 g of a white solid with a yield of 82.45%; MP: 184.4-185.5°C; 1 H-NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.97(s,1H),8.03(s,1H),7.79(dd,J=8.1,1.3Hz, 1H),7.52(d,J=7.7Hz,1H),7.38–7.34(m,1H),7.33–7.29(m,4H),7.24(d,J=5.0Hz,1H),5. 87–5.81(m,1H),5.10–5.00(m,2H),4.47(d,J=6.0Hz,2H),4.25–4.12(m,1H),3.39(dd,J=1 3.7,3.2Hz,1H),2.90–2.79(m,1H),2.78(s,3H),1.38(s,3H),1.33(s,3H); MS:450.9([MH] - ).

[0112] Example 13: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-[3-(naphthalen-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA02)

[0113] Referring to the preparation method of Example 12, benzylamine was replaced with 1-naphthylamine to obtain 0.2502 g of a white solid with a yield of 51.21%; MP: 150.1-151.1°C; 1 H-NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.51(s,1H),8.20(s,1H),7.98(d,J=9.6Hz, 2H),7.89(dd,J=13.1,7.9Hz,2H),7.75(d,J=7.8Hz,1H),7.59–7.54(m,4H),7.49–7.4 5(m,1H),5.90–5.83(m,1H),5.11–5.03(m,2H),4.23–4.18(m,1H),3.42(dd,J=13.7,3 .3Hz,1H),2.90–2.83(m,1H),2.81(s,3H),1.39(s,3H),1.33(s,3H); MS:489.1([M+H] + ).

[0114] Example 14: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-[3-(p-tolylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA03)

[0115] Referring to the preparation method of Example 12, benzylamine was replaced with p-toluidine to obtain 0.3201 g of a white solid with a yield of 69.80%; Mp: 106.2-107.5°C; 1 H-NMR(400MHz,chloroform-d)δ8.64(s,1H),8.02(s,1H),7.89(s,1H),7.75(d,J=7. 7Hz,1H),7.53(d,J=8.5Hz,3H),7.41–7.36(m,1H),7.16(d,J=8.2Hz,2H),6.27–6.14( m,1H),5.10–5.05(m,1H),5.05–4.94(m,1H),4.33–4.24(m,1H),3.61–3.50(m,1H),2 .90(s,3H),2.82–2.71(m,1H),2.34(s,3H),1.51(s,3H),1.37(s,3H); MS:450.8([MH] - ).

[0116] Example 15: (3aR, 4R, 8R, 8aR)-N-{3-[(4-methoxyphenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA04)

[0117] Referring to the preparation method of Example 12, benzylamine was replaced with 4-methoxyaniline to obtain 0.3160 ​​g of a white solid with a yield of 67.40%; Mp: 97.3-98.9°C; 1 H-NMR(400MHz,DMSO-d6)δ10.09(s,1H),9.46(s,1H),8.09–8.05(m,1H),7.85–7.80(m,1 H),7.66(d,J=9.0Hz,2H),7.58–7.54(m,1H),7.43–7.39(m,1H),6.92(d,J=8.0Hz,2H),5. 87–5.83(m,1H),5.09–5.05(m,2H),4.22–4.18(m,1H),3.76–3.73(m,3H),3.40(dd,J=13 .7,3.2Hz,1H),2.86–2.81(m,1H),2.80(s,3H),1.39(s,3H),1.33(s,3H); MS:466.9([MH] - ).

[0118] Example 16: (3aR, 4R, 8R, 8aR)-N-{3-[(4-fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA05)

[0119] Referring to the preparation method of Example 12, benzylamine was replaced with 4-fluoroaniline to obtain 0.3077 g of a white solid with a yield of 67.40%; Mp: 97.6-98.4°C; 1H-NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.48(s,1H),8.09(s,1H),7.85(d,J=7.9H z,1H),7.81–7.74(m,2H),7.57(d,J=7.9Hz,1H),7.46–7.39(m,1H),7.23–7.16(m,2 H),5.89–5.82(m,1H),5.11–5.03(m,2H),4.23–4.17(m,1H),3.40(dd,J=13.7,3.3 Hz,1H),2.89–2.81(m,1H),2.80(s,3H),1.39(s,3H),1.33(s,3H); MS:457.0([M+H] + ).

[0120] Example 17: (3aR, 4R, 8R, 8aR)-N-{3-[(4-fluorobenzyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA06)

[0121] Referring to the preparation method of Example 12, benzylamine was replaced with 4-fluorobenzylamine to obtain 0.2642 g of a white solid with a yield of 56.15%; Mp: 207.5-208.6°C; 1 H-NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.97(s,1H),8.02(s,1H),7.78(d,J=7.4Hz ,1H),7.50(d,J=7.8Hz,1H),7.39–7.32(m,3H),7.18–7.11(m,2H),5.86–5.80(m,1H ),5.09–5.01(m,2H),4.44(d,J=5.9Hz,2H),4.22–4.16(m,1H),3.39(dd,J=13.7,3. 3Hz,1H),2.86–2.79(m,1H),2.78(s,3H),1.38(s,3H),1.33(s,3H); MS:468.9([MH] - ).

[0122] Example 18: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-{3-{[4-(trifluoromethoxy)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA07)

[0123] Referring to the preparation method of Example 12, benzylamine was replaced with 4-trifluoromethoxyaniline to obtain 0.2333 g of a white solid with a yield of 44.65%; MP: 106.2-107.8°C; 1 H-NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.54(s,1H),8.20(dd,J=16.8,8.7Hz, 1H),8.03–7.82(m,4H),7.74(dd,J=17.3,8.9Hz,2H),7.35(d,J=8.6Hz,1H),5. 86(s,1H),5.12–5.01(m,2H),4.27–4.16(m,1H),3.41(dd,J=13.7,3.3Hz,1H), 2.88–2.76(m,4H),1.39(d,J=2.8Hz,3H),1.33(d,J=2.3Hz,3H); MS:520.8([MH] - ).

[0124] Example 19: (3aR, 4R, 8R, 8aR)-N-{3-[(4-trifluoromethyl)phenyl]carbamoyl}phenyl-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA08)

[0125] Referring to the preparation method of Example 12, benzylamine was replaced with 4-trifluoromethylaniline to obtain 0.1780 g of a white solid with a yield of 35.32%; MP: 89.9-90.4°C; 1 H-NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.49(s,1H),8.23(s,1H),8.15–8.08(m,1H ),8.06(d,J=8.5Hz,1H),7.87(d,J=8.2Hz,1H),7.62–7.58(m,2H),7.48–7.43(m,2H) ,5.88–5.81(m,1H),5.11–5.02(m,2H),4.22–4.18(m,1H),3.41(dd,J=13.7,3.3Hz, 1H),2.87–2.81(m,1H),2.81–2.77(m,3H),1.39(s,3H),1.33(s,3H); MS:504.8([MH] - ).

[0126] Example 20: (3aR, 4R, 8R, 8aR)-N-{3-{[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MA09)

[0127] Referring to the preparation method of Example 12, benzylamine was replaced with 3-trifluoromethyl-4-chloroaniline to obtain 0.3148 g of a white solid with a yield of 58.08%; MP: 114.1-115.5°C; 1 H-NMR(400MHz,DMSO-d6)δ9.85(s,0H),9.54(s,1H),8.20(dd,J=16.0,8.7Hz,1H),8.03–7.82(m,3H),7.80–7.67(m,2H),7.63–7.46(m,1H),5.89 –5.80(m,1H),5.13–4.98(m,2H),4.26–4.18(m,1H),3.45–3.37(m,1H),2 .93–2.82(m,1H),2.80(s,3H),1.39(s,3H),1.33(s,3H); MS:538.9([MH] - ).

[0128] Example 21: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-{4-{9-[4-(trifluoromethoxy)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MB01)

[0129] Refer to the preparation method of Example 12, and replace the m-aminobenzoic acid in step G with p-aminobenzoic acid, and replace the (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine in step H with -5-formamide was replaced by (3aR,4R,8R,8aR)-N-[4-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide, the benzylamine in step I was replaced with 4-trifluoromethoxyaniline to obtain 0.7144 g of a white solid with a yield of 89.24%; MP: 138.4-139.5°C; 1H-NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.54(s,1H),8.20(dd,J=16.8,8.7Hz, 1H),8.04–7.80(m,4H),7.74(dd,J=17.3,8.9Hz,2H),7.35(d,J=8.6Hz,1H),5. 92–5.80(m,1H),5.14–4.97(m,2H),4.27–4.15(m,1H),3.41(dd,J=13.7,3.3Hz ,1H),2.89–2.82(m,1H),2.81(s,3H),1.39(s,3H),1.33(s,3H); MS:520.8([MH] - ).

[0130] Example 22: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-[4-(p-toluidine carboxylate)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MB02)

[0131] Refer to the preparation method of Example 12, and replace the m-aminobenzoic acid in step G with p-aminobenzoic acid, and replace the (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine in step H with -5-formamide was replaced by (3aR,4R,8R,8aR)-N-[4-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide, benzylamine in step I was replaced with p-toluidine to obtain 0.5980 g of white solid, yield 75.30%; MP: 208.2-209.1°C; 1H-NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.52(s,1H),7.91(d,J=8.6Hz,2H),7.7 4(d,J=8.6Hz,2H),7.65(d,J=8.3Hz,2H),7.14(d,J=8.2Hz,2H),5.88–5.82(m,1 H),5.10–5.02(m,2H),4.23–4.17(m,1H),3.41(dd,J=13.6,3.3Hz,1H),2.88–2. 81(m,1H),2.80(s,3H),2.27(s,3H),1.39(s,3H),1.33(s,3H); MS:453.1([M+H] + ).

[0132] Example 23: (3aR, 4R, 8R, 8aR)-N-{4-[(4-fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MB03)

[0133] Refer to the preparation method of Example 12, and replace the m-aminobenzoic acid in step G with p-aminobenzoic acid, and replace the (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine in step H with -5-formamide was replaced by (3aR,4R,8R,8aR)-N-[4-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide, the benzylamine in step I was replaced with 4-fluoroaniline to obtain 0.4478 g of a white solid with a yield of 66.40%; MP: 185.5-186.1°C; 1 H-NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.53(s,1H),7.91(d,J=8.7Hz,2H),7.85–7.68(m,4H),7.24–7.13(m,2H),5.90–5.78(m,1H),5.15 –4.98(m,2H),4.26–4.15(m,1H),3.41(dd,J=13.6,3.3Hz,1H),2.95–2.81(m,1H),2.80(s,3H),1.39(s,3H),1.33(s,3H); MS:457.1([M+H]+ .

[0134] Example 24: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-[4-(naphthalen-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MB04)

[0135] Refer to the preparation method of Example 12, and replace the m-aminobenzoic acid in step G with p-aminobenzoic acid, and replace the (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine in step H with -5-formamide was replaced by (3aR,4R,8R,8aR)-N-[4-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide, the benzylamine in step I was replaced with 1-naphthylamine to obtain 0.5299 g of a white solid with a yield of 48.70%; MP: 150.2-151.6°C; 1 H-NMR(400MHz,chloroform-d)δ8.70(s,1H),8.28(s,1H),8.00–7.85(m,5H),7.73(d,J=8.2Hz,1H),7.63(d,J=8.2Hz,2H),7.54–7.45(m,3H),6.28 –6.13(m,1H),5.06–4.91(m,2H),4.33–4.23(m,1H),3.62–3.49(m,1H),2 .89(s,3H),2.83–2.70(m,1H),1.51(s,3H),1.37(s,3H); MS:489.1([M+H] + ).

[0136] Example 25: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-{4-[4-(trifluoromethyl)phenyl)carbamoyl]phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of 5-formamide (MB05)

[0137] Refer to the preparation method of Example 12, and replace the m-aminobenzoic acid in step G with p-aminobenzoic acid, and replace the (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine in step H with -5-formamide was replaced by (3aR,4R,8R,8aR)-N-[4-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide, the benzylamine in step I was replaced with 4-trifluoromethylaniline to obtain 0.36 g of a white solid with a yield of 71.22%; MP: 129.8-130.5°C; 1 H-NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.54(s,1H),8.39–8.02(m,2H),8. 02–7.92(m,2H),(m,2H),7.91–7.73(m,2H),7.73–7.57(m,2H),5.88–5.81 (m,1H),5.11–5.02(m,2H),4.26–4.18(m,1H),3.41(dd,J=12.4,10.2Hz,1 H),2.85(dd,1H),2.80(s,3H),1.39(s,3H),1.33(s,3H); MS:507.1([M+H] + ).

[0138] Example 26: (3aR, 4R, 8R, 8aR)-N-{4-[(3-chloro-4-fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MB06)

[0139] Refer to the preparation method of Example 12, and replace the m-aminobenzoic acid in step G with p-aminobenzoic acid, and replace the (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine in step H with -5-formamide was replaced by (3aR,4R,8R,8aR)-N-[4-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide, the benzylamine in step I was replaced with 3-chloro-4-fluoroaniline to obtain 0.3822 g of a white solid with a yield of 77.84%; MP: 153.5-154.4°C; 1 H-NMR (400MHz, DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.54(s,1H),8.08(dd,J=6.9,2.6Hz,1H ),7.95(dd,J=27.4,8.9Hz,2H),7.76(d,J=8.8Hz,2H),7.45–7.36(m,1H),5.89 –5.82(m,1H),5.10–5.02(m,2H),4.39–4.09(m,0H),3.41(dd,J=13.7,3.3Hz,1 H),2.86–2.82(m,1H),2.79(s,3H),1.39(s,3H),1.33(s,3H); MS:491.0([M+H] + ).

[0140] Example 27: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-{4-{[3-(trifluoromethyl)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine Preparation of 5-formamide (MB07)

[0141] Refer to the preparation method of Example 12, and replace the m-aminobenzoic acid in step G with p-aminobenzoic acid, and replace the (3aR,4R,8R,8aR)-N-[3-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine in step H with -5-formamide was replaced by (3aR,4R,8R,8aR)-N-[4-(ethoxycarbonyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide, the benzylamine in step I was replaced with 3-trifluoromethylaniline to obtain 0.2730 g of a white solid with a yield of 53.95%; MP: 138.3-139.5°C; 1H-NMR(400MHz,chloroform-d)δ8.70(s,1H),8.19(d,J=8.6Hz,1H),8.00(s,1H ),7.84(dd,J=25.8,8.3Hz,2H),7.72(d,J=8.8Hz,1H),7.58–7.44(m,3H),7.39( s,1H),6.29–6.12(m,1H),5.20–4.91(m,2H),4.38–4.21(m,1H),3.67–3.47(m, 1H),2.92(s,3H),2.83–2.72(m,1H),1.51(s,3H),1.37(s,3H); MS:507.1([M+H] + ).

[0142] Example 28: (3aR, 4R, 8R, 8aR)-N-(4-phenoxyphenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC01)

[0143] Weigh triphosgene (0.20 g, 0.67 mmol) and dichloromethane into a flask, slowly drop a dichloromethane solution of 4-aminodiphenyl ether (CAS: 139-59-3) (0.37 g, 2.0 mmol), then slowly drop a dichloromethane solution of triethylamine (0.40 mL, 4.0 mmol), then slowly drop (3aR, 4R, 8R, 8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine A solution of (the product of step C in Example 1) (0.20 g, 1.0 mmol) in dichloromethane was stirred and reacted overnight at room temperature. After most of the dichloromethane was evaporated under reduced pressure, 0.2137 g of a white solid was obtained by column chromatography (DCM:EA=20:1), with a yield of 77.40%; MP: 159.6-160.5°C; 1 H-NMR (400MHz, DMSO-d6) δ9.29(s,1H),7.59(d,J=9.0Hz,2H),7.36(dd,J=8.7,7.4Hz,2H),7.12–7.06(m,1H),7.04–6.92(m,4H),5.87–5. 80(m,1H),5.11–5.02(m,2H),4.22–4.16(m,1H),3.39(dd,J=13.6,3.2Hz,1H),2.84–2.80(m,1H),2.78(s,3H),1.38(s,3H),1.33(s,3H):13 C NMR(101MHz,DMSO-d6)δ158.01,135.49,130.38,123.28,121.66,119.80,118.15, 112.25,87.35,82.52,81.70,79.36,52.08,45.88,26.40,25.03; MS:412.1([M+H] + ).

[0144] Example 29: (3aR, 4R, 8R, 8aR)-N-[4-(p-tolylthio)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC02)

[0145] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-(p-tolylthio)aniline (CAS: 22865-52-7) to obtain 0.4415 g of a white solid with a yield of 86.10%; MP: 153.0-154.1°C; 1 H-NMR (400MHz, DMSO-d6) δ9.38(s,1H),7.62(d,J=8.7Hz,2H),7.28(d,J=8.7Hz,2H),7.18–7.08(m,4H),5.85–5.80(m,1H),5.07–5. 02(m,2H),4.26–4.12(m,1H),3.38(dd,J=13.6,3.3Hz,1H),2.84–2.79(m,1H),2.77(s,3H),2.26(s,3H),1.38(s,3H),1.32(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ155.69,139.47,136.69,133.43,132.93,130.45,129.99,127.46,1 20.83,112.27,87.34,82.49,81.71,79.38,52.13,45.88,26.40,25.03,21.01; MS:439.8([MH] - ).

[0146] Example 30: (3aR, 4R, 8R, 8aR)-N-[4-(p-toluylamino)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC03)

[0147] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced by N 1 -(p-Tolyl)benzene-1,4-diamine (CAS: 33227-76-8) to give 0.3118 g of white solid, yield 73.46%; MP: 160.1-161.6°C; 1 H-NMR(400MHz, DMSO-d6)δ9.06(s,1H),7.81(s,1H),7.37(d,J=8.9Hz,2H),7.01(d,J=8.3Hz,2H),6.97–6.88(m,4H),5.85–5.80(m,1H),5 .07–5.02(m,2H),4.22–4.12(m,1H),3.38(dd,J=13.6,3.2Hz,1H),2.82–2.78(m,1H),2.77(s,3H),2.21(s,3H),1.38(s,3H),1.32(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ155.87,142.01,139.59,131.74,129.99,128.25,121.52,117.48,11 6.87,112.21,87.40,82.55,81.71,79.33,52.03,45.88,26.42,25.03,20.71; MS:425.1([M+H] + ).

[0148] Example 31: (3aR, 4R, 8R, 8aR)-N-{4-[4-(methylthio)phenoxy]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC04)

[0149] Step J: Preparation of 4-[4-(methylthio)phenoxy]aniline

[0150] 4-Methylthiophenol (1.40 g, 10.0 mmol), 4-chloronitrobenzene (1.73 g, 11.0 mmol), K2CO3 (6.91 g, 50.0 mmol) and 30 mL of acetone were mixed and heated under reflux for 2 h. After the reaction, the mixture was poured into 50 mL of water, and then extracted with ethyl acetate three times. The organic phases were combined, washed with brine, and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to obtain 1.90 g of 4-(methylthio)-4'-nitrodiphenyl ether as a pale yellow oil with a yield of 72.7%. The obtained 4-(methylthio)-4'-nitrodiphenyl ether as a pale yellow oil (1.90 g, 7.3 mmol), ferric chloride hexahydrate (1.97 g, 7.3 mmol) and 3 g of activated carbon were placed in a 100 mL round-bottom flask, and 25 mL of anhydrous ethanol was added. The temperature was set to 80°C. Under heating and stirring conditions, hydrazine hydrate (3.03 mL, 50 mmol) was added dropwise and refluxed for 12 h. After ethanol was distilled off under reduced pressure, a light yellow solid was obtained, which was separated by column chromatography (PE:EA=8:1) to obtain 4-[4-(methylthio)phenoxy]aniline as a light yellow solid (1.20 g), with a yield of 71.01%. 1 H-NMR (400MHz, CDCl3) δ2.48(d,J=1.2Hz,3H),3.60(s,2H),6.70(d,J=8.8Hz,2H),6 .88(d,J=8.8Hz,2H),6.92(d,J=8.7Hz,2H),7.22(d,J=8.8Hz,2H); MS:232.3([M+H] + ).

[0151] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-[4-(methylthio)phenoxy]aniline (CAS: 69360-39-0) to obtain 0.2314 g of a white solid with a yield of 51.23%; MP: 142.2-143.1°C; 1 H-NMR (400MHz, DMSO-d6) δ9.28(s,1H),7.58(d,J=9.0Hz,2H),7.28(d,J=8.8Hz,2H),6.94(dd,J=8.8,8.1Hz,4H),5.86–5.81(m,1H),5.0 8–5.03(m,2H),4.21–4.15(m,1H),3.39(dd,J=13.6,3.2Hz,1H),2.85–2.79(m,1H),2.78(s,3H),2.45(s,3H),1.38(s,3H),1.32(s,3H); 13C-NMR(101MHz,DMSO-d6)δ155.86,155.79,151.89,135.45,132.00,128.97,121.66,119.52,11 9.14,112.25,87.34,82.52,81.70,79.36,52.08,45.88,26.40,25.03,16.32; MS:458.0([M+H] + ).

[0152] Example 32: (3aR, 4R, 8R, 8aR)-N-[4-(naphthalen-2-yloxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC05)

[0153] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 2-(4-aminophenoxy)naphthalene (CAS: 71311-83-6) to obtain 0.2883 g of a white solid with a yield of 62.47%; MP: 168.6-169.1°C; 1 H-NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 7.92 (dd, J=19.2, 8.9Hz, 2H), 7.78 (d, J= 8.2Hz,1H),7.63(d,J=9.0Hz,2H),7.53–7.40(m,2H),7.28(d,J=7.2Hz,2H),7.1 0–7.03(m,2H),5.89–5.80(m,1H),5.12–5.01(m,2H),4.23–4.17(m,1H),3.40(d d,J=13.6,3.2Hz,1H),2.86–2.80(m,1H),2.79(s,3H),1.39(s,3H),1.33(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ156.03,155.90,151.55,135.75,134.39,130.46,129.94,128.08,127.41,127.10,125.03 ,121.70,120.14,119.72,112.69,112.25,87.39,82.52,81.71,79.38,52.09,45.88,26.41,25.03; MS:462.1([M+H] + ).

[0154] Example 33: (3aR, 4R, 8R, 8aR)-N-(4-acetamidophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC06)

[0155] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced with N-(4-(4-aminophenoxy)phenyl)acetamide (CAS: 2687-41-4) to obtain 0.2866 g of a white solid with a yield of 61.17%; MP: 169.9-170.8°C; 1 H-NMR (400MHz, DMSO-d6) δ9.90(s,1H),9.26(s,1H),7.55(d,J=9.0Hz,4H),6.91(dd,J=9.1,2.9Hz,4H),5.85–5.80(m,1H),5.09–5. 01(m,2H),4.21–4.15(m,1H),3.38(dd,J=13.6,3.2Hz,1H),2.84–2.79(m,1H),2.78(s,3H),2.02(s,3H),1.38(s,3H),1.32(s,3H); 13 C-NMR(101MHz,DMSO-d6)δ168.42,155.87,152.91,152.60,135.26,135.02,121.65,121.04,118.9 8,118.96,112.24,87.35,82.52,81.70,79.35,52.07,45.88,26.40,25.03,24.32; MS:466.9([MH] - ).

[0156] Example 34: (3aR, 4R, 8R, 8aR)-N-[4-(4-methoxyphenoxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC07)

[0157] Referring to the preparation method of 4-[4-(methylthio)phenoxy]aniline in step J of Example 31, 4-methylthiophenol was replaced with 4-methoxyphenol to obtain 4-[4-(methoxy)phenoxy]aniline as a white solid in a yield of 80.20%; MS: 216.3 ([M+H] + ).

[0158] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced by 4-[4-(methoxy)phenoxy]aniline to obtain 0.1513 g of a white solid with a yield of 34.27%; MP: 170.7-171.3°C; 1 H-NMR(400MHz,DMSO-d6)δδ9.24(s,1H),7.56–7.49(m,2H),6.94(s,4H),6.89–6.83(m,2H),5.85–5.79(m,1H),5.08–5.00(m, 2H),4.20–4.14(m,1H),3.73(s,3H),3.38(dd,J=13.5,2.9Hz,1H),2.83–2.79(m,1H),2.77(s,3H),1.38(s,3H),1.32(s,3H); 13 C NMR(101MHz,DMSO-d6)δ155.69,153.31,150.79,134.68,121.66,120.31,118.37,115.45 ,112.24,87.34,82.52,81.69,79.35,55.86,52.06,45.88,26.40,25.02; MS:442.0([M+H] + ).

[0159] Example 35: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-[4-(p-tolyloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC08)

[0160] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-amino-4'-methyldiphenyl ether (CAS: 41295-20-9) to obtain 0.3823 g of a white solid with a yield of 89.85%; MP: 128.8-129.9°C; 1 H-NMR (400MHz, DMSO-d6) δ9.27(s,1H),7.56(d,J=9.0Hz,2H),7.16(d,J=8.2Hz,2H),6.88(dd,J=22.7,8.7Hz,4H),5.86–5.81(m,1H),5.08–5.02 (m,2H),4.21–4.15(m,1H),3.39(dd,J=13.6,3.2Hz,1H),2.84–2.79(m,1 H),2.78(s,3H),2.27(s,3H),1.38(s,3H),1.32(s,3H); MS:426.1([M+H]+ ).

[0161] Example 36: (3aR, 4R, 8R, 8aR)-N-[4-(2-methoxy-4-propylphenoxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC09)

[0162] Referring to the preparation method of 4-[4-(methylthio)phenoxy]aniline in step J of Example 31, 4-methylthiophenol was replaced with 2-methoxy-4-propylphenol to obtain 4-(2-methoxy-4-propylphenoxy)aniline as a white solid in a yield of 65.44%; MS: 258.3 ([M+H] + ).

[0163] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-(2-methoxy-4-propylphenoxy)aniline to obtain 0.2066 g of a white solid with a yield of 42.72%; MP: 127.7-128.6°C; 1 H-NMR (400MHz, DMSO-d6) δ9.18 (s, 1H), 7.52–7.41 (m, 2H), 7.34 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 1. 9Hz,1H),6.87(dd,J=8.1,3.2Hz,1H),6.76–6.73(m,2H),5.87–5.77(m,1H),5.09–4.99(m,2H) ,4.21–4.13(m,1H),3.73–3.70(m,3H),3.38(dd,J=13.6,3.2Hz,1H),2.84–2.77(m,1H),2.77( s,3H),2.57–2.53(m,2H),1.65–1.58(m,2H),1.38(s,3H),1.32(s,3H),0.91(t,J=7.4Hz,3H); 13 C-NMR (101MHz, DMSO-d6) δ155.89,153.81,151.32,142.54,139.78,133.90,121.65,121.24,121.11,121.03,120.30,117. 06,116.60,113.86,112.23,87.34,82.53,81.69,79.34,52.04,45.87,37.56,26.39,25.01,24.59,14.18; MS:484.1([M+H] + ).

[0164] Example 37: (3aR, 4R, 8R, 8aR)-2,2,6-trimethyl-N-[4-(naphthalen-1-yloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine - Preparation of 5-formamide (MC10)

[0165] Referring to the preparation method of 4-[4-(methylthio)phenoxy]aniline in step J of Example 31, 4-methylthiophenol was replaced with 1-naphthol to obtain 4-(naphthalene-1-yloxy)aniline as a white solid in a yield of 56.82%. MS: 236.3 ([M+H] + ).

[0166] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-(naphthalen-1-yloxy)aniline to obtain 0.2942 g of a white solid with a yield of 63.75%; MP: 189.9-190.6°C; 1 H-NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.14(d,J=8.3Hz,1H),7.97(d,J=7.5Hz,1H),7. 68(d,J=8.2Hz,1H),7.65–7.50(m,4H),7.48–7.39(m,1H),7.01(d,J=9.0Hz,2H),6.87(d ,J=6.6Hz,1H),5.87–5.77(m,1H),5.11–5.00(m,2H),4.28–4.10(m,1H),3.39(dd,J=13. 6,3.2Hz,1H),2.85–2.79(m,1H),2.78(s,3H),1.38(s,3H),1.32(s,3H); MS:459.9([MH] - ).

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] Example 39: Pharmacological Example

[0173] (1) Experimental methods

[0174] Step A: Cell recovery

[0175] The cryopreserved tubes containing non-small cell lung cancer cells A549, melanoma cells A375, human breast cancer cells MCF-7, and human lung adenocarcinoma cells Calu-3 were taken out of the liquid nitrogen tank, shaken and dissolved in a 37.0℃ water bath, and the dissolved cryopreserved solution was transferred to a 15mL centrifuge tube containing culture medium, centrifuged at 1050rpm for 3min, the supernatant was discarded, 1mL of complete culture medium was added to resuspend the cells, and inoculated into a 75mL culture bottle pre-filled with warm complete culture medium. After shaking the culture bottle to evenly distribute the cells, it was placed in an incubator at 37.0℃ and 5% CO2 for culture, and the cell morphology and growth were observed at regular intervals.

[0176] Step B: Cell passaging

[0177] When the cells in the culture flask grow to 80%-90%, discard the culture medium, add 3mL 0.25% trypsin solution and digest in a 37.0℃ incubator for 2min, add 6mL culture medium to terminate digestion, blow the flask wall repeatedly, transfer the detached cells to a 15mL centrifuge tube, centrifuge at 1050rpm for 3min, discard the supernatant, add complete culture medium containing 10% fetal bovine serum to resuspend the cells, prepare a single cell suspension, blow evenly, and count. Press 100μL 2-5*10 3 The cells were inoculated into 96-well culture plates, and the edge wells were filled with sterile PBS to avoid edge effects. The plates were placed in an incubator at 37.0°C and 5% CO2 for 24 hours.

[0178] Step C: Cytotoxicity and proliferation inhibition

[0179] After the cells in the above 96-well culture plate were cultured in an incubator for 24 hours, the culture medium was discarded and replaced with 200 μL of complete culture medium containing the sample for a further 72 hours. 3-5 concentration gradients were set for each group of samples, and 3 replicate wells were set for each concentration. 20 μL of MTT solution (5 mg / mL, prepared with PBS, pH = 7.4) was added to each well and incubated for another 4 hours. 150 μL of DMSO was added to each well and shaken for 3 minutes to fully dissolve the crystals. The light absorption value of each well was measured on an ELISA reader at 490 nm, 570 nm or 630 nm, and the results were recorded. The cellular drug response of the sample (the concentration required to obtain 50% maximum cellular effect, EC 50 ) was obtained by calculating the experimental data using the software GraphPad Prism8.0.1.

[0180]

[0181]

[0182] Among the above target compounds, all compounds showed different degrees of tumor cell proliferation inhibition activity against A549, A375, MCF-7 and Calu-3 cell lines. Among them, YA01, YA03, YA07, YA10, MA01, MA06 and MC06 had significant proliferation inhibition activity against A549 cell line, and YA03 and YA08 had significant proliferation inhibition activity against Calu-3 cell line. Their EC 50 All were below 10μM.

[0183] Formulation Examples

[0184] The following formulation examples are merely illustrative of the scope of the present invention, but are not intended to limit the scope of the present invention in any way. The active compounds described in the following examples are compounds YA01-YA11, MA01-MA09, MB01-MB07, and MC01-MC10 prepared in the above examples.

[0185] Example 40: Tablet Formulation

[0186] Active compound 25-1000 mg, starch 45 mg, microcrystalline cellulose 35 mg, polyvinyl pyrrolidone (as a 10% aqueous solution) 4 mL, sodium carboxymethyl cellulose 4.5 mg, magnesium stearate 0.5 mg, talc 1 mg.

[0187] Example 18: Suspension Concentrate Formulation

[0188] Active compound 0.1-1000 mg, sodium carboxymethyl cellulose 50 mg, syrup 1.25 mg, sodium benzoate 0.1 mg, flavoring agent 25 mg, coloring agent 5 mg, add purified water to 5 mL.

[0189] Example 19: Aerosol Formulation

[0190] Active compound 0.25 mg, ethanol 25-75 mL, propellant 22 (chlorodifluoromethane) 70 mg.

[0191] Example 20: Suppository Formulation

[0192] Active compound 250mg, saturated fatty acid glycerides 2000mL.

[0193] Example 21: Injectable Formulation

[0194] Active compound 50 mg, isotonic saline solution 1000 mL.

[0195] Example 22: Ointment Formulation

[0196] 0.025 g of micronized active compound, 10 g of liquid paraffin, and add soft white wax to 100 g.

[0197] Example 23: Ointment Formulation

[0198] 0.025 g of active compound, 5 g of propylene glycol, 5 g of sorbitan sesquioleate, 10 g of liquid paraffin, and add soft white wax to 100 g.

[0199] Example 24: Oil-in-water cream formulation

[0200] Active compound 0.025g, hexadecanol 5g, glyceryl monostearate 5g, liquid paraffin 10g, cetyl alcohol polyoxyethylene ether 2g, citric acid 0.1g, sodium citrate 0.2g, propylene glycol 35g, add water to 100g.

[0201] Example 25: Oil-in-water cream formulation

[0202] 0.025 g of micronized active compound, 15 g of soft white wax, 5 g of liquid paraffin, 5 g of hexadecanol, 2 g of Sorbimacrogolstearate (Tween 65 of specific pharmaceutical excipient grade), 0.5 g of sorbitan monostearate, 0.2 g of sorbic acid, 0.1 g of citric acid, 0.2 g of sodium citrate, add water to 100 g.

[0203] Example 26: Water-in-oil cream formulation

[0204] 0.025g active compound, 35g soft white wax, 5g liquid paraffin, 5g dehydrated sorbitan sesquioleate, 0.2g sorbic acid, 0.1g citric acid, 0.2g sodium citrate, add water to 100g.

[0205] Example 27: Lotion Formulation

[0206] Active compound 0.25 g, isopropanol 0.5 mL, carboxyvinyl polymer 3 mg, NaOH 2 mg, add water to 1 g.

[0207] Example 28: Formulation of suspension for injection

[0208] Active compound 10 mg, sodium carboxymethyl cellulose 7 mg, NaCl 7 mg, polyoxyethylene (20) sorbitan monooleate 0.5 mg, benzyl alcohol 8 mg, add sterile water to 1 mL.

[0209] Example 29: Aerosol Formulation for Oral and Nasal Inhalation

[0210] Active compound 0.1% w / w, Sorbitan trioleate 0.7% w / w, Trichlorofluoromethane 24.8% w / w, Dichlorotetrafluoroethane 24.8% w / w, Dichlorodifluoromethane 49.6% w / w.

[0211] Example 30: Nebulized solution formulation

[0212] Active compound 7 mg, propylene glycol 5 mg, add water to 10 g.

[0213] Example 31: Powder Formulation for Inhalation

[0214] Fill a clear gelatin capsule with the mixture of the following ingredients, 0.1 mg of micronized active compound, 20 mg of lactose, and inhale the powder with the aid of an inhalation device.

[0215] Example 32: Powder Formulation for Inhalation

[0216] The spheronized powder is filled into a multiple-dose powder inhaler, each dose containing 0.1 mg of the micronized active compound.

[0217] Example 33: Powder Formulation for Inhalation

[0218] The spheronized powder is filled into a multiple-dose powder inhaler, each dose containing 0.1 mg of micronized active compound and 1 mg of micronized lactose.

[0219] Example 34: Capsule Formulation

[0220] Active compound 1.0 mg, small sugar spheres 321 mg, Aquacoat ECD 30 6.6 mg, acetyl tributyl citrate 0.5 mg, Tween-80 0.1 mg, Eudragit L 100-55 17.5 mg, triethyl citrate 1.8 mg, talc 8.8 mg, defoaming agent MMS 0.1 mg.

[0221] Example 35: Capsule Seedling Formulation

[0222] Active compound 2.0 mg, small sugar spheres 305 mg, Aquocoat ECD 30 5.0 mg, acetyl tributyl citrate 0.4 mg, Tween-80 0.14 mg, Eudragit NE30 D 12.6 mg, Eudragit S100 12.6 mg, talc 0.16 mg.

[0223] Example 36: Enema Formulation

[0224] Active compound 2 mg, sodium carboxymethyl cellulose 25 mg, disodium edetate 0.5 mg, methyl parahydroxybenzoate 0.8 mg, propyl parahydroxybenzoate 0.2 mg, sodium chloride 7 mg, citric acid 1.8 mg, Tween-80 0.01 mg, add purified water to 1 mL.

[0225] Example 37: Formulation containing liposomes

[0226] A. Preparation of Infusion Formulation

[0227] Dipalmitoyl phosphatidylcholine (45 mg), dimyristoyl phosphatidylcholine (7 mg), dipalmitoyl phosphatidylglycerol (1 mg) and active compound (5 mg) were placed in a glass tube, all components were dissolved in chloroform, most of the solvent was evaporated with N2, and then the pressure was reduced, thereby forming a lipid film on the surface of the glass tube. An aqueous solution (0.9% NaCl) was added to the lipid, and liposomes were formed at a temperature higher than the phase transition temperature of the lipid. The resulting suspension contained liposomes ranging in size from extremely small vesicles to 2 μm.

[0228] B. Preparation of Formulations for Inhalation

[0229] Liposomes were prepared according to Example A, wherein the aqueous solution contained 10% lactose, and the ratio of lactose to lipid was 7:3. The liposome suspension was frozen with dry ice and freeze-dried, and the dried product was micronized to obtain particles with a mass mean aerodynamic diameter (MMAD) of about 2 μm.

[0230] The above is only a preferred embodiment of the present invention, and does not limit the present invention in other forms. Any technician familiar with the profession may use the above disclosed technical content to change or modify it into an equivalent embodiment with equivalent changes. Any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still belongs to the protection scope of the technical solution of the present invention.

Claims

1. A 1,2-diazepine as shown in general formula I -5-carboxamide compound or a pharmaceutically acceptable salt thereof, characterized in that The structure of formula I is: Wherein, X is selected from NH, O, S, NHCO, CH2NHCO, NHCONH; R is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, halogen-substituted C1-C4 alkyl, halogen-substituted C1-C4 alkoxy, phenyl, naphthyl formed with the phenyl group, C1-C4 acyloxy, C1-C4 amide, C1-C4 alkylthio; R can be one or more.

2. 1,2-diazepine according to claim 1 -5-carboxamide compound or a pharmaceutically acceptable salt thereof, characterized in that In formula I: X is selected from NH, O, S, NHCO, NHCONH, CH2NHCO; R is selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, phenyl, naphthyl formed with the attached phenyl, propionyloxy, acetamido, methylthio; R can be one or more.

3. 1,2-diazepine according to claim 2 -5-carboxamide compound or a pharmaceutically acceptable salt thereof, characterized in that In formula I: X is selected from NH, O, S, NHCO, NHCONH, CH2NHCO; R is selected from hydrogen, 4-trifluoromethoxy, 4-fluoro, 4-chloro-3-trifluoromethyl, 3-chloro-4-fluoro, 4-methoxy, 3-trifluoromethyl, 4-trifluoromethyl, 3-chloro, 3-methyl, 4-methyl, 4-propyl, 2-methoxy-4-propyl, 4-phenyl, naphthyl-1-yl formed with the connected phenyl, naphthyl-2-yl formed with the connected phenyl, 4-propionyloxy, 4-acetamido, 4-methylthio.

4. 1,2-diazepine according to claim 3 -5-carboxamide compound or a pharmaceutically acceptable salt thereof, characterized in that The 1,2-diazepine -5-Carboxamide compound is any one of the following compounds: (3aR,4R,8R,8aR)-N-{4-{3-[4-(trifluoromethoxy)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[3-(4-fluorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[3-(3-chloro-4-fluorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[3-(4-methoxyphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[3-(3-trifluoromethylphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[3-(3-chlorophenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[3-(3-methylphenyl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-{3-[3-(naphthalen-1-yl)]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[3-(biphenyl-4-yl)ureido]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; 4-{3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamido]phenyl}ureido}phenylpropionate; (3aR,4R,8R,8aR)-N-[3-(Benzylcarbamoyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[3-(naphthalen-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[3-(p-tolylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{3-[(4-methoxyphenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{3-[(4-Fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{3-[(4-fluorobenzyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-{3-{[4-(trifluoromethoxy)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{3-[(4-trifluoromethyl)phenyl]carbamoyl}phenyl-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{3-{[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-{4-{9-[4-(trifluoromethoxy)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[4-(p-toluidinecarbonyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[(4-Fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[4-(naphthalen-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-{4-[4-(trifluoromethyl)phenyl)carbamoyl]phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[(3-chloro-4-fluorophenyl)carbamoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-{4-{[3-(trifluoromethyl)phenyl]carbamoyl}phenyl}hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-(4-phenoxyphenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-[4-(p-Tolylthio)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-[4-(p-Toluylamino)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-{4-[4-(methylthio)phenoxy]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-[4-(Naphthalen-2-yloxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-(4-Acetamidophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-[4-(4-methoxyphenoxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[4-(p-tolyloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-N-[4-(2-methoxy-4-propylphenoxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazepine -5-formamide; (3aR,4R,8R,8aR)-2,2,6-Trimethyl-N-[4-(naphthalen-1-yloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepine -5-Carboxamide.

5. A pharmaceutical composition, characterized in that Comprising the 1,2-diazepine according to any one of claims 1 to 4 as an active ingredient -5-carboxamide compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent.

6. 1,2-diazepine according to any one of claims 1 to 4 -5-formamide compounds or pharmaceutically acceptable salts thereof in the preparation of anti-tumor drugs.

7. Use of the pharmaceutical composition according to claim 5 in the preparation of anti-tumor drugs.

8. The use according to claim 6 or 7, characterized in that: The tumors include lung cancer, melanoma, breast cancer, human lung adenocarcinoma cells and ovarian cancer.

9. 1,2-diazepine according to claim 4 -5-formamide compound or its pharmaceutically acceptable salt preparation method, characterized in that, The following steps are involved: Synthesis route 1: R in the synthetic route 1 is the corresponding group at the corresponding position of compound YA01-YA11; Synthesis route 2: R in the synthetic route 2 is the corresponding group at the corresponding position of compounds MA01-MA09; Synthesis route three: R in the synthetic route 3 is the corresponding group at the corresponding position of compounds MB01-MB07; Synthesis route 4: X and R in the synthetic route 4 are the corresponding groups at the corresponding positions of compounds MC01-MC10.

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