1,2-diazepane-5-carboxamide compounds, and preparation method and application thereof

Abstract

The application discloses a 1,2-diazepane-5-carboxamide compound and 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-dioxolan[4,5-d]-1,2-diazepane-5-carboxamide compound and a preparation method and application thereof in the aspect of resisting tumors. The 1,2-diazepane-5-carboxamide compound has the general formula shown below, 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 consisting of the connected phenyl, C1-C4 acyloxy, C1-C4 acylamino, C1-C4 alkylthio; and R can be one or more. The synthesis method of the compound is simple, suitable for industrial production, and biological activity tests show that the compound has the antitumor activity, and can be applied to the preparation of antitumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-phenylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazepine Preparation methods of 5-formamide compounds and their applications in antitumor therapy. Background Technology

[0002] Cancer has become a major challenge to human health and a leading cause of death. Tumor development is an uncontrolled proliferation of cells, an abnormal behavior of the cells themselves, often related to dysregulation of signal transduction mechanisms. The diagnosis and treatment of cancer have seen advancements in various techniques, including surgery and drug therapy, with the development of drugs ranging from toxic to targeted therapies. However, traditional chemotherapy drugs often have strong toxic side effects and severe adverse reactions. The emergence of small-molecule targeted drugs has alleviated the severe toxic side effects of chemotherapy drugs to some extent, but with prolonged administration, targeted drugs are prone to developing drug resistance. Therefore, researchers in chemotherapy need to continuously develop new candidate drug molecules to ensure the continuation of cancer treatment. Currently, the following drugs are on the market:

[0003] Sorafenib: Sorafenib is a multi-target inhibitor with a diaryl urea structure. It is associated with a reduced rate of tumor growth and liver function deterioration in hepatitis C virus-induced hepatocellular carcinoma. Sorafenib treatment is associated with improved survival in patients with advanced hepatocellular carcinoma, 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 tumor 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 Eisai Co., Ltd. of Japan 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 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), and stem cell factor receptor (SCFR), thereby cutting off the blood and nutrient supply to cancer cells and causing cancer cell death (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 crosses the blood-brain barrier, blocking the activity of TRKA / B / C and ROS1 protein kinases, leading to the death of cancer cells carrying ROS1 or NTRK gene fusion proteins. Entrectinib is effective in both primary and metastatic central nervous system (CNS) tumors and has no adverse off-target activities (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 development, progression, and angiogenesis. Its anti-tumor mechanism is the effective inhibition of factors such as MET, AXL, and VEGFR1-3 (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 significant impact and profound implications in cancer research, and have received considerable attention in recent years due to their wide range of biological applications. Typical anti-tumor drugs such as sorafenib and lenvatinib are marketed drugs with arylurea structures as pharmacophores. Some studies have shown that arylurea, due to its planar aromatic backbone and the presence of both hydrogen bond donors and acceptors, readily interacts with target proteins, making it a favorable drug-forming structure. Summary of the Invention

[0008] The primary objective of this invention is to provide a 1,2-diazazonium chloride solution. 5-Formamide compounds or pharmaceutically acceptable salts thereof, wherein the 1,2-diaza... -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]diaza -5-formamide compounds, the present invention also provides the 1,2-diaza-type compounds. Use of 5-formamide compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs. A 1,2-diazamethoxycarbamate, as shown in general formula I... 5-Formamide compounds or their pharmaceutically acceptable salts;

[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 with the attached phenyl group, C1-C4 acyloxy, C1-C4 amide, C1-C4 alkylthio; R can be one or more.

[0011] Further, 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, propionyloxy, acetamido, and methylthio; R can be one or more.

[0012] Furthermore, 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 with the attached phenyl group, naphthyl-2-yl with the attached phenyl group, 4-propionyloxy, 4-acetamido, 4-methylthio.

[0013] The following compounds are preferred in this invention:

[0014] (3aR,4R,8R,8aR)-N-{4-{3-[4-(trifluoromethoxy)phenyl]ureo}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0015] (3aR,4R,8R,8aR)-N-{4-[3-(4-fluorophenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0016] (3aR,4R,8R,8aR)-N-{4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureo}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

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

[0018] (3aR,4R,8R,8aR)-N-{4-[3-(4-methoxyphenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0019] (3aR,4R,8R,8aR)-N-{4-[3-(3-trifluoromethylphenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0020] (3aR,4R,8R,8aR)-N-{4-[3-(3-chlorophenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0021] (3aR,4R,8R,8aR)-N-{4-[3-(3-methylphenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0022] (3aR,4R,8R,8aR)-N-{4-{3-[3-(naphthyl-1-yl)phenyl]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 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-dioxolane[4,5-d]-1,2-diaza 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-diaza -5-Formamido)phenyl]ureo]phenylpropionate;

[0025] (3aR,4R,8R,8aR)-N-[3-(benzylcarbamoyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0026] (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-[3-(naphthyl-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0027] (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-diaza 5-Formamide;

[0028] (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-diaza 5-Formamide;

[0029] (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-diaza 5-Formamide;

[0030] (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-diaza 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-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0032] (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-diaza 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-dioxolane[4,5-d]-1,2-diaza 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-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0035] (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-[4-(p-toluamide carboxyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide;

[0036] (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-diaza 5-Formamide;

[0037] (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-[4-(naphthyl-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 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-dioxolane[4,5-d]-1,2-diaza 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-dioxolane[4,5-d]-1,2-diaza 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-dioxolane[4,5-d]-1,2-diaza 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-diaza 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-diaza 5-Formamide;

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

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

[0048] (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-diaza 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-diaza 5-Formamide;

[0050] (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-[4-(naphthyl-1-yloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide.

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

[0052] "Pharmaceutical acceptable salt" refers to a conventional acid addition salt or base addition salt that retains the biological potency and properties of a compound of formula I and is formed with a suitable nontoxic organic or inorganic acid or organic or inorganic base. Acid addition salts include hydrochlorides, hydrobroms, hydroiodates, nitrates, phosphates, sulfates, perchlorates, thiocyanates, hydrogen sulfates, persulfates, borates, formates, acetates, propionates, valerates, neovalerates, hexanoates, heptanoates, octanoates, isooctanoates, undecanoates, laurates, palmitates, stearates, oleates, cyclopropionates, oxalates, malonates, succinates, maleates, fumarates, adipates, azelaates, acrylates, strawberry salts, crotonates, tigrinates, itacrates, sorbates, cinnamates, glycolates, lactates, malates, tartrates, citrates, tartrites, mandelates, diphenylglycolates, tropine, ascorbate, gluconate, glucono-p-ethyl, gluconate, mannitol, lactobionate, benzoates, phthalates, paraphthalates, furoate, nicotinic acid, and isonicotinic acid. Salicylate, acetylsalicylate, butyrate, gallate, caffeate, ferulic acid, picrate, camphorate, camphor sulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, p-toluenesulfonate, p-aminobenzenesulfonate, aminosulfonate, 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-naphthylcarboxate, 2-naphthylsulfonate, dihydroxynaphthylate, lauryl sulfate, glycerol phosphate, lauryl sulfate, pectin esters, etc. Alkaline salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts of organic bases such as dicyclohexylamine salts and N-methyl-D-glucosamine salts. Furthermore, the basic nitrogen-containing group can be quaternized with reagents such as lower alkyl halides, such as chloro, bromine, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and dipentyl sulfates; long-chain halides, such as chloro, bromine, and iodides of decyl, lauryl, myristyl, and stearoyl groups; and aralkyl halides, such as bromides of benzyl and phenethyl groups. Preferred acids for forming acid addition salts include hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, and p-aminobenzenesulfonic acid.

[0053] The preferred preparation route of the compound of this invention is as follows:

[0054] Synthesis Route 1:

[0055]

[0056] In synthetic route one, R represents the corresponding group at the corresponding position in compounds YA01-YA11.

[0057] Synthesis Route 2:

[0058]

[0059] In synthetic route two, R represents the corresponding group at the corresponding position of compounds MA01-MA09.

[0060] Synthesis Route 3:

[0061]

[0062] In synthetic route three, R represents the corresponding group at the corresponding positions of compounds MB01-MB07.

[0063] Synthesis Route 4:

[0064]

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

[0066] The present invention also provides 1,2-diazazidene as shown in Formula I. The use of 5-formamide compounds or pharmaceutically acceptable salts thereof or the above-described pharmaceutical compositions in the preparation of A549, A375, MCF-7 and Calu-3 cell proliferation inhibitors.

[0067] The present invention also provides 1,2-diazazidene as shown in Formula I. The use of 5-formamide compounds or pharmaceutically acceptable salts thereof, or the above-described pharmaceutical compositions, in the preparation of antitumor drugs. The tumors include lung cancer, melanoma, breast cancer, human lung adenocarcinoma cells, and ovarian cancer.

[0068] The beneficial effects of this invention are:

[0069] This invention discloses a series of novel 1,2-diazazides 5-Formamide compounds, in vitro, exhibited varying degrees of inhibitory activity against tumor cell lines such as A549 (lung cancer cells), A375 (melanoma cells), MCF-7 (breast cancer cells), and Calu-3 (lung adenocarcinoma cells). This invention provides a novel strategy and potential drugs for cancer treatment. The compounds of this invention are simple to synthesize and suitable for industrial production. Bioactivity tests show that these compounds possess antitumor activity and can be applied to the preparation of antitumor drugs. Detailed Implementation

[0070] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0071] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents and instruments used, unless otherwise specified, are all commercially available conventional reagent products.

[0072] Example 1: (3aR,4R,8R,8aR)-N-{4-{3-[4-(trifluoromethoxy)phenyl]ureoyl}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 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] 10.0 g (66.7 mmol) of D-ribose was weighed and placed in a flask. 50 mL of acetone was added, and 0.5 mL of sulfuric acid was slowly added dropwise under ice bath conditions. The mixture was stirred at room temperature for 1.5 h, and then triethylamine was added to neutralize the reaction solution to neutral. After most of the acetone was distilled off under reduced pressure, 11.87 g of a pale yellow viscous liquid was 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-dioxolane-4-yl]methyl-p-methylbenzenesulfonate

[0076] Weigh 11.87 g (62.4 mmol) of (3aR,6R,6aR)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolane-4-ol (62.4 mmol) into a flask, dissolve it in pyridine, and slowly add a pyridine solution of p-toluenesulfonyl chloride (14.28 g, 74.9 mmol) to the reaction system under ice bath conditions. Stir the reaction mixture overnight at room temperature. Dilute the reaction solution with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry to 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, yield 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-diaza Preparation

[0078] [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-yl]methyl p-toluenesulfonate (0.35 g, 1.0 mmol), methylhydrazine sulfate (0.17 g, 1.2 mmol), acetonitrile (2 mL), and triethylamine (TEA, 0.55 mL, 4.0 mmol) were added to a flask and reacted overnight at 35 °C under nitrogen protection with stirring. After most of the acetonitrile was distilled off under reduced pressure, the mixture was separated by column chromatography (PE:EA = 2:1) to give 0.133 g of a pale 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-diaza Preparation of 5-formamide

[0080] Weigh triphosgene (BTC, 0.2 g, 0.67 mmol) and dichloromethane (DCM, 10 mL) into a flask. Slowly add a dichloromethane solution of p-nitroaniline (1.4 g, 2.0 mmol), followed by a dichloromethane solution of triethylamine (0.4 g, 4.0 mmol). Then slowly add (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza A solution of 1.0 g, 1.0 mmol of dichloromethane was stirred overnight at room temperature. After most of the dichloromethane was distilled off under reduced pressure, 1.56 g of a yellow solid was obtained by column chromatography (DCM:EA = 10:1), yield 85.6%; Mp: 203.1-205.3 °C. 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-diaza 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-diaza 5-Formamide (0.36 g, 1.0 mmol) was placed in a flask, 0.18 g of palladium on carbon was added, and an appropriate amount of ethanol was added to dissolve it. Hydrogen gas was introduced, and the reaction was stirred for 48 h. After the ethanol was distilled off under reduced pressure, the solid was obtained by column chromatography (PE:EA = 1:1) to give a yellow solid, yield 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]ureoyl}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 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. Add it slowly dropwise. After the addition is complete, slowly add triethylamine (0.1214 g, 1.2 mmol). After the addition is complete, add (3aR,4R,8R,8aR)-N-(4-aminophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide (0.1003 g, 0.3 mmol) was added to a constant pressure dropping funnel and then added dropwise to the above reaction flask. After the addition was complete, the reaction was allowed to proceed overnight. 0.06 g of a pale yellow solid was obtained by column chromatography (DCM:EA = 5:1), yield 59.8%; Mp: 246.8-249.6℃. 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)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (YA02)

[0086] Following the preparation method of Example 1, p-trifluoromethoxyaniline in step F was replaced with p-fluoroaniline to obtain 0.06 g of white solid, yield 41.4%; MP: 191.3-193.7℃; 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]ureoyl}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (YA03)

[0088] Following the preparation method of Example 1, replacing p-trifluoromethoxyaniline in step F with 3-trifluoromethyl-4-chloroaniline yielded 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)ureoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (YA04)

[0090] Following the preparation method of Example 1, 3-chloro-4-fluoroaniline was replaced with p-trifluoromethoxyaniline in step F to obtain 0.1156 g of white solid, yield 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)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (YA05)

[0092] Following the preparation method of Example 1, 4-methoxyaniline was replaced with p-trifluoromethoxyaniline in step F to obtain 0.0905 g of white solid, yield 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)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (YA06)

[0094] Following the preparation method of Example 1, 3-trifluoromethylaniline was replaced with p-trifluoromethoxyaniline in step F to obtain 0.2368 g of white solid, yield 90.8%; MP: 142.5-143.7℃; 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)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (YA07)

[0096] Following the preparation method of Example 1, 3-chloroaniline was replaced with p-trifluoromethoxyaniline in step F to obtain 0.1864 g of a 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)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (YA08)

[0098] Following the preparation method of Example 1, 3-methylaniline was replaced with p-trifluoromethoxyaniline in step F to obtain 0.1803 g of white solid, yield 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-(naphthyl-1-yl)]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (YA09)

[0100] Following the preparation method of Example 1, replacing p-trifluoromethoxyaniline in step F with 1-naphthylamine yielded 0.0620 g of a white solid, with a yield of 24.6%; Mp: 180.5-182.8℃; 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-diaza Preparation of 5-formamide (YA10)

[0102] Following the preparation method of Example 1, 4-aminobiphenyl was replaced with p-trifluoromethoxyaniline in step F to obtain 0.2200 g of white solid, yield 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-diaza Preparation of 5-formamido]phenyl}ureo]phenylpropionate (YA11)

[0104] Referring to the preparation method of Example 1, p-trifluoromethoxyaniline in step F was replaced with p-aminophenol to obtain (3aR,4R,8R,8aR)-N-{4-[3-(3-methylphenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza -5-Formamide, a white solid, was reacted with propionic anhydride without purification and refluxed for 4 h. 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 white solid, yield 34.2%; MP: 236.8-239.5℃. 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-diaza Preparation of 5-formamide (MA01)

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

[0107] Weigh 6.85 g of m-aminobenzoic acid into a 250 mL round-bottom flask, add 73 mL of ethanol, and add 5 mL of concentrated sulfuric acid under ice bath conditions. Place the round-bottom flask in a water bath and reflux at 80 °C, adding a drying tube. Monitor the reaction by TLC until complete. Adjust the pH to 7 with triethylamine, concentrate by rotary evaporation, dilute with 100 mL of water, extract with 100 mL of ethyl acetate, dry, and filter to obtain ethyl m-aminobenzoate in 67.2% yield. Weigh triphosgene (1.98 g, 6.67 mmol) into a 500 mL flask and dissolve it in 50 mL of dichloromethane. Weigh ethyl m-aminobenzoate into a 100 mL beaker and dissolve it in 50 mL of dichloromethane. Add the ethyl m-aminobenzoate dropwise slowly using a constant pressure dropping funnel. After the addition is complete, weigh triethylamine (4.05 g, 40 mmol) into a 100 mL beaker and dissolve it in dichloromethane as in the previous step. Add the triethylamine dropwise slowly using 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-diaza (i.e., the product from step C of Example 1) (2.00 g, 10 mmol), added dropwise, reacted overnight at room temperature. TLC monitoring (DCM:EA = 10:1) showed the reaction was essentially complete. Separation by column chromatography (DCM:EA = 25:1) yielded 3.54 g of solid, yield 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-diaza Preparation of 5-formamide

[0109] Weigh (3aR,4R,8R,8aR)-N-[3-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza 5-Formamide (3.91 g, 10 mmol) was added to a 50 mL beaker, along with lithium hydroxide (0.718 g, 30 mmol) and 30 mL of water. 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 monitored by TLC until it was nearly complete. Insoluble matter was removed by filtration. The pH was adjusted to 3-4 with concentrated hydrochloric acid in an ice bath, resulting in the precipitation of a large amount of solid. This solid was filtered, dried, and yielded 1.90 g of a brown solid (yield 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-dioxolane[4,5-d]-1,2-diaza 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-diaza 5-Formamide (0.36 g, 1 mmol) was added to a 10 mL flask, along with EDCI (0.23 g, 1.2 mmol), HOBT (0.16 g, 1.2 mmol), 5 mL DMF, and 0.12 g TEA. After stirring for 30 min, benzylamine (0.12 g, 1.1 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction was monitored by TLC the next day and found to be almost complete. 50 mL of water was added, and the mixture was extracted three times with ethyl acetate, washed with water and then with saturated brine. The extract was dried, filtered, and subjected to column chromatography (PE:EA = 1:1) to give 0.3781 g of a white solid, yield 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-(naphthyl-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (MA02)

[0113] Following the preparation method of Example 12, benzylamine was replaced with 1-naphthylamine to obtain 0.2502 g of white solid, yield 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-diaza Preparation of 5-formamide (MA03)

[0115] Following the preparation method of Example 12, replacing benzylamine with p-toluidine yielded 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-diaza Preparation of 5-formamide (MA04)

[0117] Following 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℃; 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-diaza Preparation of 5-formamide (MA05)

[0119] Following 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-diaza Preparation of 5-formamide (MA06)

[0121] Following the preparation method of Example 12, 4-fluorobenzylamine was replaced with benzylamine to obtain 0.2642 g of white solid, with a yield of 56.15%; Mp: 207.5-208.6℃; 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-diaza Preparation of 5-formamide (MA07)

[0123] Following the preparation method of Example 12, benzylamine was replaced with 4-trifluoromethoxyaniline to obtain 0.2333 g of white solid, yield 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-diaza Preparation of 5-formamide (MA08)

[0125] Following 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-diaza Preparation of 5-formamide (MA09)

[0127] Following 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-diaza Preparation of 5-formamide (MB01)

[0129] Referring to the preparation method of Example 12, but replacing m-aminobenzoic acid with p-aminobenzoic acid in step G, and replacing (3aR,4R,8R,8aR)-N-[3-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxybenzoic acid in step H... -5-Formamide is replaced with (3aR,4R,8R,8aR)-N-[4-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza -5-Formamide, in step I, benzylamine was replaced with 4-trifluoromethoxyaniline to give 0.7144 g of white solid, yield 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-toluamide formyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (MB02)

[0131] Referring to the preparation method of Example 12, but replacing m-aminobenzoic acid with p-aminobenzoic acid in step G, and replacing (3aR,4R,8R,8aR)-N-[3-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxybenzoic acid in step H... -5-Formamide is replaced with (3aR,4R,8R,8aR)-N-[4-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza -5-Formamide, in step I, benzylamine was replaced with p-toluidine to give 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-diaza Preparation of 5-formamide (MB03)

[0133] Referring to the preparation method of Example 12, but replacing m-aminobenzoic acid with p-aminobenzoic acid in step G, and replacing (3aR,4R,8R,8aR)-N-[3-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxybenzoic acid in step H... -5-Formamide is replaced with (3aR,4R,8R,8aR)-N-[4-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza -5-Formamide, in step I, benzylamine was replaced with 4-fluoroaniline to give 0.4478 g of white solid, yield 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-(naphthyl-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (MB04)

[0135] Referring to the preparation method of Example 12, but replacing m-aminobenzoic acid with p-aminobenzoic acid in step G, and replacing (3aR,4R,8R,8aR)-N-[3-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxybenzoic acid in step H... -5-Formamide is replaced with (3aR,4R,8R,8aR)-N-[4-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza -5-Formamide, in step I, benzylamine was replaced with 1-naphthylamine to give 0.5299 g of white solid, yield 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-diaza Preparation of 5-formamide (MB05)

[0137] Referring to the preparation method of Example 12, but replacing m-aminobenzoic acid with p-aminobenzoic acid in step G, and replacing (3aR,4R,8R,8aR)-N-[3-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxybenzoic acid in step H... -5-Formamide is replaced with (3aR,4R,8R,8aR)-N-[4-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza -5-Formamide, in step I, benzylamine was replaced with 4-trifluoromethylaniline to give 0.36 g of white solid, yield 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-diaza Preparation of 5-formamide (MB06)

[0139] Referring to the preparation method of Example 12, but replacing m-aminobenzoic acid with p-aminobenzoic acid in step G, and replacing (3aR,4R,8R,8aR)-N-[3-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxybenzoic acid in step H... -5-Formamide is replaced with (3aR,4R,8R,8aR)-N-[4-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza -5-Formamide, in step I, benzylamine was replaced with 3-chloro-4-fluoroaniline to give 0.3822 g of white solid, yield 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-diaza Preparation of 5-formamide (MB07)

[0141] Referring to the preparation method of Example 12, but replacing m-aminobenzoic acid with p-aminobenzoic acid in step G, and replacing (3aR,4R,8R,8aR)-N-[3-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxybenzoic acid in step H... -5-Formamide is replaced with (3aR,4R,8R,8aR)-N-[4-(ethoxyformyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza -5-Formamide, in step I, benzylamine was replaced with 3-trifluoromethylaniline to give 0.2730 g of white solid, yield 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-diaza Preparation of 5-formamide (MC01)

[0143] Weigh triphosgene (0.20 g, 0.67 mmol) and dichloromethane into a flask, slowly add a dichloromethane solution of 4-aminodiphenyl ether (CAS: 139-59-3) (0.37 g, 2.0 mmol), then slowly add a dichloromethane solution of triethylamine (0.40 mL, 4.0 mmol), followed by slowly adding (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza (Example 1, Step C product) A solution of (0.20 g, 1.0 mmol) in dichloromethane was stirred overnight at room temperature. After most of the dichloromethane was distilled off under reduced pressure, 0.2137 g of a white solid was obtained by column chromatography (DCM:EA = 20:1), yield 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-toluenethio)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (MCO2)

[0145] Following the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-(p-toluenethio)aniline (CAS: 22865-52-7) to obtain 0.4415 g of white solid, yield 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-tolueneamino)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (MCO3)

[0147] Referring to the preparation method of Example 28, 4-aminodiphenyl ether was replaced with N 1 -(p-Tolyl)phenyl-1,4-diamine (CAS: 33227-76-8) gave 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-diaza 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 was completed, the mixture was poured into 50 mL of water and extracted three times with ethyl acetate. The organic phases were combined, and the organic layer was washed with brine. The mixture was then dried over anhydrous MgSO₄, and the solvent was removed under reduced pressure to obtain 1.90 g of a pale yellow oily substance of 4-(methylthio)-4'-nitrodiphenyl ether, with a yield of 72.7%. The obtained pale yellow oily substance of 4-(methylthio)-4'-nitrodiphenyl ether (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 the reaction was refluxed for 12 h. After distilling off the ethanol under reduced pressure, a pale yellow solid was obtained, which was separated by column chromatography (PE:EA = 8:1) to give 1.20 g of 4-[4-(methylthio)phenoxy]aniline, a pale yellow solid, 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] Following 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 white solid, yield 51.23%; MP: 142.2-143.1℃; 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-(naphthyl-2-yloxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (MC05)

[0153] Following 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 white solid, yield 62.47%; MP: 168.6-169.1℃; 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-diaza Preparation of 5-formamide (MC06)

[0155] Following 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 white solid, yield 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-diaza Preparation of 5-formamide (MC07)

[0157] Following 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, with a yield of 80.20%; MS: 216.3 ([M+H)). + ).

[0158] Following the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-[4-(methoxy)phenoxy]aniline to obtain 0.1513 g of white solid, yield 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-diaza Preparation of 5-formamide (MC08)

[0160] Following 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 white solid, yield 89.85%; MP: 128.8-129.9℃; 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-diaza Preparation of 5-formamide (MC09)

[0162] Following the method for preparing 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, with a yield of 65.44%; MS: 258.3 ([M+H)). + ).

[0163] Following the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-(2-methoxy-4-propylphenoxy)aniline to obtain 0.2066 g of white solid, yield 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-(naphthyl-1-yloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of 5-formamide (MC10)

[0165] Following 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-(naphth-1-yloxy)aniline as a white solid, with a yield of 56.82%. MS: 236.3 ([M+H) + ).

[0166] Following the preparation method of Example 28, 4-aminodiphenyl ether was replaced with 4-(naphthyl-1-yloxy)aniline to obtain 0.2942 g of white solid, yield 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 resuscitation

[0175] Cryopreservation tubes containing A549 non-small cell lung cancer cells, A375 melanoma cells, MCF-7 human breast cancer cells, and Calu-3 human lung adenocarcinoma cells were removed from the liquid nitrogen tank and thawed by shaking in a 37.0°C water bath. The thawed cryopreservation solution was transferred to 15mL centrifuge tubes containing culture medium, centrifuged at 1050rpm for 3min, the supernatant was discarded, and 1mL of complete culture medium was added to resuspend the cells. The cells were then seeded into 75mL culture flasks pre-filled with warm complete culture medium. After shaking the culture flasks to ensure even distribution of cells, they were incubated in a 37.0°C, 5% CO2 incubator. Cell morphology and growth were observed periodically.

[0176] Step B: Cell passage

[0177] When the cells in the culture flask reach 80%-90% confluence, discard the culture medium, add 3 mL of 0.25% trypsin solution, and incubate at 37.0℃ for 2 min. Add 6 mL of culture medium to stop the digestion, repeatedly pipetting the cells from the flask wall to transfer them to a 15 mL centrifuge tube. Centrifuge at 1050 rpm for 3 min, discard the supernatant, and resuspend the cells in complete culture medium containing 10% fetal bovine serum to prepare a single-cell suspension. Mix thoroughly and count the cells. (Prepare 100 μL 2-5 * 10^10 cells / mL) 3 Inoculate one well per 96-well culture plate, filling the edge wells with sterile PBS to avoid edge effects. Incubate at 37.0℃ and 5% CO2 for 24 hours.

[0178] Step C: Cytotoxicity and Proliferation Inhibition

[0179] After 24 hours of incubation in the 96-well culture plates, the culture medium was discarded, and 200 μL of complete culture medium containing the samples was replaced for another 72 hours. Three to five concentration gradients were set up for each sample group, with three replicates for each concentration. 20 μL of MTT solution (5 mg / mL, prepared with PBS, pH 7.4) was added to each well, and incubation continued for 4 hours. 150 μL of DMSO was added to each well, and the plates were shaken for 3 minutes to fully dissolve the crystals. The absorbance of each well was measured at 490 nm, 570 nm, or 630 nm using a microplate reader, and the results were recorded. The cell drug response (concentration required to achieve 50% maximum cellular effect, EC50) was also recorded. 50 The experimental data were obtained by calculation using the software GraphPad Prism 8.0.1.

[0180]

[0181]

[0182] Among the target compounds mentioned above, all compounds exhibited varying degrees of inhibitory activity against tumor cell proliferation in A549, A375, MCF-7, and Calu-3 cell lines. YA01, YA03, YA07, YA10, MA01, MA06, and MC06 showed significant inhibitory activity against A549 cell line, while YA03 and YA08 showed significant inhibitory activity against Calu-3 cell line. Their EC50 values ​​were... 50 All were below 10 μM.

[0183] Formulation Examples

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

[0185] Example 40: Tablet Formulation

[0186] The active compound is 25-1000 mg, starch is 45 mg, microcrystalline cellulose is 35 mg, polyvinylpyrrolidone (10% aqueous solution) is 4 mL, sodium carboxymethyl cellulose is 4.5 mg, magnesium stearate is 0.5 mg, and talc is 1 mg.

[0187] Example 18: Suspension Formulation

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

[0189] Example 19: Aerosol Formulation

[0190] 0.25 mg of active compound, 25-75 mL of ethanol, and 70 mg of propellant 22 (dichlorofluoromethane).

[0191] Example 20: Suppository Formulation

[0192] 250 mg of active compound and 2000 mL of saturated fatty acid glycerides.

[0193] Example 21: Injectable Formulation

[0194] 50 mg of the active compound, 1000 mL of isotonic salt solution.

[0195] Example 22: Ointment Formulation

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

[0197] Example 23: Ointment Formulation

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

[0199] Example 24: Water-in-oil cream formulation

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

[0201] Example 25: Water-in-oil cream formulation

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

[0203] Example 26: Oil-in-water cream formulation

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

[0205] Example 27: Lotion Formulation

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

[0207] Example 28: Formulation of a suspension for injection

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

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

[0210] The active compound was 0.1% w / w, sorbitan trioleate was 0.7% w / w, trichlorofluoromethane was 24.8% w / w, dichlorotetrafluoroethane was 24.8% w / w, and dichlorodifluoromethane was 49.6% w / w.

[0211] Example 30: Formulation of atomizing solution

[0212] Add 7 mg of the active compound and 5 mg of propylene glycol to water to a final volume of 10 g.

[0213] Example 31: Powder Formulation for Inhalation

[0214] Fill a capsule with a mixture of the following ingredients: 0.1 mg of micronized active compound and 20 mg of lactose. Inhale the powder using an inhalation device.

[0215] Example 32: Powder Formulation for Inhalation

[0216] The spherical powder is packed into a multi-dose powder inhaler, with each dose containing 0.1 mg of micronized active compound.

[0217] Example 33: Powder Formulation for Inhalation

[0218] The spheroidized powder is loaded into a multi-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, acetylated 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, defoamer MMS 0.1 mg.

[0221] Example 35: Capsule Formulation of Vaccines

[0222] Active compound 2.0 mg, small sugar globules 305 mg, Aquocoat ECD 30 5.0 mg, acetylsalicylic acid tributyl ester 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] Add 2 mg of active compound, 25 mg of sodium carboxymethyl cellulose, 0.5 mg of disodium EDTA, 0.8 mg of methylparaben, 0.2 mg of propylparaben, 7 mg of sodium chloride, 1.8 mg of citric acid, and 0.01 mg of Tween-80 to pure water to 1 mL.

[0225] Example 37: Formulation containing liposomes

[0226] A. Preparation of the drip formulation

[0227] Dipalmitoyl lecithin (45 mg), dimyristoyl lecithin (7 mg), dipalmitoyl phosphatidylglycerol (1 mg), and the active compound (5 mg) were placed in a glass tube. All components were dissolved in chloroform, and most of the solvent was evaporated with N2. 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 phase inversion temperature higher than that of the lipid. The resulting suspension contained liposomes ranging in size from very small vesicles to 2 μm.

[0228] B. Preparation of inhalation formulations

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

[0230] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any other way. Any person skilled in the art may make changes or modifications to the disclosed technical content to create equivalent embodiments. Any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A 1,2-diaza-5-carboxamide compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of Formula I is as follows: ； 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 with the attached phenyl group, C1-C4 acyloxy, C1-C4 amide, C1-C4 alkylthio; R is one or more.

2. The 1,2-diaza-5-carboxamide compound or a pharmaceutically acceptable salt thereof according to claim 1, 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, propionyloxy, acetamido, and methylthio; R is one or more.

3. The 1,2-diaza-5-carboxamide compound or a pharmaceutically acceptable salt thereof according to claim 2, 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 with the attached phenyl group, naphthyl-2-yl with the attached phenyl group, 4-propionyloxy, 4-acetamido, 4-methylthio.

4. The 1,2-diaza-5-carboxamide compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that, The 1,2-diaza-5-carboxamide compound is any one of the following compounds: (3aR,4R,8R,8aR)-N-{4-{3-[4-(trifluoromethoxy)phenyl]ureoyl}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-{4-[3-(4-fluorophenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-{4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureoyl}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-{4-[3-(3-chloro-4-fluorophenyl)ureoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-{4-[3-(4-methoxyphenyl)ureoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-{4-[3-(3-trifluoromethylphenyl)ureoyl]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-{4-[3-(3-chlorophenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-{4-[3-(3-methylphenyl)ureo]phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-{4-{3-[3-(naphthyl-1-yl)]ureido}phenyl}-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (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-diaza-5-carboxamide; 4-{3-{4-[(3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carbamoyl]phenyl}ureoyl}phenylpropionate; (3aR,4R,8R,8aR)-N-[3-(benzylcarbamoyl)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-[3-(naphthyl-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-[4-(p-toluamide)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (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-diaza-5-carboxamide; (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-[4-(naphthyl-1-ylcarbamoyl)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-(4-phenoxyphenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-[4-(p-toluenethio)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-[4-(p-toluidine)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (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-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-[4-(naphthyl-2-yloxy)phenyl]-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (3aR,4R,8R,8aR)-N-(4-acetamidophenyl)-2,2,6-trimethylhexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (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-diaza-5-carboxamide; (3aR,4R,8R,8aR)-2,2,6-trimethyl-N-[4-(naphthyl-1-yloxy)phenyl]hexahydro-5H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-5-carboxamide.

5. A pharmaceutical composition, characterized in that, The active ingredient includes any one of the 1,2-diaza-5-carboxamide compounds or pharmaceutically acceptable salts thereof as claimed in any one of claims 1-4, and a pharmaceutically acceptable carrier or diluent.

6. The use of the 1,2-diaza-5-carboxamide compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4 in the preparation of an antitumor drug.

7. Use of the pharmaceutical composition according to claim 5 in the preparation of an antitumor drug.

8. The application according to claim 7, characterized in that, The tumors mentioned are selected from lung cancer, melanoma, breast cancer, and human lung adenocarcinoma cells.

9. A method for preparing the 1,2-diaza-5-carboxamide compound of claim 4 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: ； In synthetic route one, R is the corresponding group at the corresponding position of the compound described in claim 4; Synthesis Route 2: ； In synthetic route two, R represents the corresponding group at the corresponding position in the compound of claim 4; Synthesis Route 3: ； In synthetic route three, R represents the corresponding group at the corresponding position in the compound of claim 4; Synthesis Route 4: ； In synthetic route four, X and R are the corresponding groups at the corresponding positions of the compound described in claim 4.

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