4,8-epoxy-1,3-dioxolano[4,5-d]-1,2-diazepines and methods of preparation and use thereof

Abstract

The application discloses 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazole compounds and a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazole compounds, a preparation method thereof, and application thereof in preparation of antitumor drugs. The structural general formula of the 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazole compounds is as follows: wherein R1 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, benzyl, methoxy-substituted benzyl, halogen-substituted benzyl, phenyl, C1-C4 alkyl-substituted phenyl, hydroxyl-substituted alkyl, and ethoxycarbonylmethyl; and R2 is selected from hydrogen, C1-C4 alkyl, and benzyl. The 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazole compounds provided by the method have novel structures, many modifiable sites, mild reaction conditions, cheap and readily available raw materials, few steps, simple operation, good stereoselectivity, a simple synthesis method, and are suitable for industrialized production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazepine Compounds, their preparation methods, and their applications in the preparation of antitumor drugs. Background Technology

[0002] Azoxysaccharides are a class of sugar derivatives in which the oxygen atom on the sugar ring is replaced by a nitrogen atom, also known as iminosaccharides. In 1966, nojirimycin, a zoxysaccharide compound, was first isolated from Streptomyces and its structure was determined (Inouye S, Tsuruoka T, Niida T. Structure of nojirimycin, sugar antibiotic with nitrogen in the ring. J Antibiotics, Ser A, 1966, 19(6):288.). In 1967, Paulsen et al. synthesized the first artificially synthesized 1-deoxynojirimycin (Paulsen H, Sangster I, Heyns K. Monosaccharide mitstickstoffhaltigem Ring, XIII. Synthese und Reaktionen von Keto-piperidinosen. Chem Ber, 1967, 100(3):802.). Currently, numerous studies have shown that zoxysaccharide compounds possess significant biological activities such as antiviral infection, antitumor activity, and treatment of diabetes. For example, castanospermine, as a glucosidase inhibitor, can significantly inhibit tumor growth in nude mice, and its analogues can inhibit breast cancer cell proliferation and induce apoptosis without affecting normal cells (Pili R, Chang J, Partis RA, Mueller RA, Chrest FJ, Passaniti A. The alpha-glucosidase I inhibitor castanospermine altersendothelial cell glycosylation, prevents angiogenesis, and inhibits tumor growth. Cancer Res, 1995, 55(13):2920-2926.). Therefore, azasaccharide compounds and their derivatives have a promising future as therapeutic drugs for anti-tumor related diseases.

[0003] 1,3-Dioxolane[4,5-d]-1,2-diazazepine These compounds are a novel class of azasaccharides, and also a group of seven-membered heterocyclic compounds with diverse physiological activities. They possess high practical and academic value, and their synthesis involves inexpensive and readily available raw materials, high yields, and a low variety and content of impurities, indicating significant potential for future development. These compounds are structurally stable, easy to store, and not easily volatile, thus posing no major storage problems. 1,3-Dioxolanecyclo[4,5-d]-1,2-diaza Nitrogen-oxygen heterocyclic compounds are nitrile heterocyclic compounds containing both nitrogen and oxygen atoms. Due to their structural diversity, they exhibit a wide range of biological activities and have extensive applications in medicinal chemistry. Therefore, developing efficient and green synthetic methods for nitrile heterocyclic compounds has significant application value.

[0004] Cancer is a disease caused by genes. When the genes that regulate cell growth mutate or are damaged, the cells lose control and continue to proliferate and divide, resulting in tumors. Due to its unlimited proliferation, transformation and easy metastasis, it is clinically characterized by high recurrence and mortality rates. According to the latest global cancer burden data in 2020 (provided by IARC), there were 19.29 million new cancer cases worldwide in 2020. Therefore, cancer has become a medical problem that plagues the whole world.

[0005] With the development of society and science, cancer treatment methods have been continuously improved, evolving from toxic attacks on cells to targeted therapies against cancer cells. Molecular targeted therapy refers to the design and development of therapeutic drugs at the cellular and molecular level, targeting known carcinogenic sites. Once in the body, these drugs specifically bind to these carcinogenic sites, exerting a specific effect that kills tumor cells without affecting surrounding normal tissue cells. Common characteristics of molecularly targeted drugs include minimal impact on normal tissue cells, mild toxicity, and a slow onset of action. They inhibit the malignant biological behavior of tumor cells by specifically targeting one or more sites on the tumor cells. Summary of the Invention

[0006] This invention provides a 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxy compound of formula I. The invention relates to a class of compounds and their pharmaceutically acceptable salts, and provides methods for preparing said compounds and their application as small molecule inhibitors in the treatment and / or prevention of various malignant tumors such as non-small cell lung cancer, small cell lung cancer, colon cancer, breast cancer, melanoma, cervical cancer, liver cancer, and prostate cancer.

[0007]

[0008] R1 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, benzyl, methoxy-substituted benzyl, halogen-substituted benzyl, phenyl, C1-C4 alkyl-substituted phenyl, hydroxy-substituted alkyl, and ethoxycarbonylmethyl;

[0009] R2 is selected from hydrogen, C1-C4 alkyl, and benzyl.

[0010] Further, R1 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 4-methoxybenzyl, 2-fluorobenzyl, phenyl, 4-methylphenyl, 2-hydroxyethyl, and ethoxycarbonylmethyl;

[0011] R2 is selected from hydrogen, methyl, or benzyl.

[0012] Furthermore, the present invention preferably uses the following compounds:

[0013] (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0014] (3aR,4R,8R,8aR)-6-isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0015] (3aR,4R,8R,8aR)-6-tert-butyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0016] (3aR,4R,8R,8aR)-6-cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0017] (3aR,4R,8R,8aR)-6-cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0018] (3aR,4R,8R,8aR)-6-cyclohexyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0019] (3aR,4R,8R,8aR)-6-benzyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0020] (3aR,4R,8R,8aR)-6-(4-methoxybenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0021] (3aR,4R,8R,8aR)-6-(2-fluorobenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0022] (3aR,4R,8R,8aR)-2,2-dimethyl-6-phenylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0023] (3aR,4R,8R,8aR)-2,2-dimethyl-6-(4-methylphenyl)hexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0024] 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza] -6-yl]ethanol;

[0025] 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza] [-6-yl]ethyl acetate;

[0026] (3aR,4R,8R,8aR)-5-benzyl-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0027] (3aR,4R,8R,8aR)-6-benzyl-2,2,5-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0028] (3aS,4S,8S,8aS)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza- ;

[0029] (3aS,4S,8S,8aS)-6-ethyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza- ;

[0030] (3aS,4S,8S,8aS)-6-isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0031] (3aS,4S,8S,8aS)-6-cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza ;

[0032] (3aS,4S,8S,8aS)-6-cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza .

[0033] This invention also provides a method for preparing some compounds, comprising the following steps:

[0034]

[0035] R1 and R2 are the corresponding functional groups at the corresponding positions in compounds Q01-Q15 of this invention. X represents a halogen, specifically bromine or chlorine. D-ribose is used as the starting material for preparing compounds Q01-Q15, while L-ribose is used to prepare compounds Q16-Q20.

[0036] A pharmaceutical composition comprising 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxy as shown in Formula I. Class of compounds or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients.

[0037] The present invention also provides 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxy as shown in Formula I. The use of class of compounds or their pharmaceutically acceptable salts, or the above-described pharmaceutical compositions, in the preparation of antitumor drugs. The tumors include non-small cell lung cancer, colon cancer, breast cancer, melanoma, and ovarian cancer.

[0038] The beneficial effects of this invention are:

[0039] The present invention provides 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazepine The compounds exhibit novel structures, numerous modifiable sites, and require mild reaction conditions, readily available and inexpensive raw materials, involve few steps, are simple to operate, and possess good stereoselectivity. The synthetic method provided by this invention is simple and suitable for industrial production. The compounds of this invention exhibit varying degrees of tumor cell proliferation inhibitory activity against A549, HCT116, MCF7, and A375 tumor cell lines, providing more novel compounds for anti-tumor drugs. Detailed Implementation

[0040] The present invention will be further described in detail below with reference to specific embodiments. However, this should not be construed as limiting the scope of the above-described subject matter of the present invention to the following embodiments; all technologies implemented based on the content of the present invention fall within the scope of the present invention.

[0041] 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.

[0042] Example 1: (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q01)

[0043] Step A: Preparation of (3aR,6R,6aR)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolane-4-ol

[0044] 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 (TEA) 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%.

[0045] Step B: Preparation of [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d]-1,3-dioxolane-4-yl]methyl-p-methylbenzenesulfonate

[0046] 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%.

[0047] Step C: (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation

[0048] [(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 (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%. (c0.7,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; Found 201.12260.

[0049] Example 2: (3aR,4R,8R,8aR)-6-isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q02)

[0050] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with isopropylhydrazine hydrochloride to obtain 0.116 g of a white solid, with a yield of 50.6%. mp: 40.5–42.1. (c 0.5, CHCl3). 1 H NMR(400MHz, CDCl3) δ6.86(d,J=3.3Hz,1H),4.93–4.91(m,1H),4.73–4.69(m,1H),4.56–4.52(m,1H),4.28–4.23(m,1H),3 .52(hept,J=6.4Hz,1H),1.49–1.45(m,4H),1.37–1.35(m,1H),1.29(s,3H),1.18(d,J=3.6Hz,3H),1.16(d,J=3.7Hz,3H). 13 C NMR(101MHz, CDCl3)δ111.67,92.90,84.19,82.26,79.84,47.54,44.02,24.59,20.78,20.71.HRMS(ESI)m / z:Calcd for C 11 H 21 N₂O₃([M+H)) + )229.15467; Found 229.15453.

[0051] Example 3: (3aR,4R,8R,8aR)-6-tert-butyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q03)

[0052] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with tert-butylhydrazine hydrochloride to obtain 0.059 g of a pale yellow solid, with a yield of 24.2%. (c 0.5, CHCl3). 1H NMR(600MHz, CDCl3)δ4.90–4.83(m,1H),4.80–4.76(m,1H),4.70–4.67(m,1H),4.29–4.25(m,1H), 2.76(dd,J=11.1,2.4Hz,1H),2.54(dd,J=11.1,1.8Hz,1H),1.46(s,3H),1.35(s,3H),0.98(s,9H). 13 CNMR(101MHz,CDCl3)δ111.07,92.03,83.02,82.61,79.13,55.20,50.37,26.11,24.97,24.59.HRMS(ESI)m / z:Calcd for C 12 H 32 N₂O₃([M+H)) + )243.17032; Found 243.16968.

[0053] Example 4: (3aR,4R,8R,8aR)-6-cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q04)

[0054] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with cyclopropylhydrazine hydrochloride to obtain 0.140 g of a white solid, with a yield of 61.7%. mp: 98.7–99.6 °C. (c 0.5, CHCl3). 1 H NMR (400MHz, CDCl3) δ4.84–4.80(m,1H),4.80–4.78(m,1H),4.78–4.77(m,1H),4.34–4.20(m,1H),3.67(dd,J=12.0, 2.3Hz, 1H), 3.01 (tt, J=6.8, 3.6Hz, 1H), 2.46 (dd, J=12.0, 1.5Hz, 1H), 1.48 (s, 3H), 1.35 (s, 3H), 0.79–0.45 (m, 4H). 13 C NMR(101MHz, CDCl3)δ111.69,95.30,83.26,82.05,79.82,44.42,31.22,26.05,24.60,6.32,6.22.HRMS(ESI)m / z:Calcd forC 11 H 19 N₂O₃([M+H)) +)227.13902; Found 227.13887.

[0055] Example 5: (3aR,4R,8R,8aR)-6-cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q05)

[0056] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with cyclopentanehydrazine hydrochloride to obtain 0.142 g of a white solid, with a yield of 55.7%. mp: 100.4-101.4 °C. (c 0.25, CHCl3). 1 H NMR (400MHz, CDCl3) δ4.93–4.88(m,1H),4.85–4.74(m,2H),4.25–4.19(m,1H),3.83(p,J=7.8Hz,1 H),3.53(dd,J=12.3,2.3Hz,1H),2.49–2.22(m,1H),2.03–1.50(m,8H),1.48(s,3H),1.36(s,3H). 13 C NMR(101MHz, CDCl3)δ111.64,94.17,83.83,82.23,79.81,57.86,43.49,30.85,30.66,26.05,24.58,24.42,23.95.HRMS(ESI)m / z:Calcd for C 13 H 23 N₂O₃([M+H)) + )255.17032; Found255.17012.

[0057] Example 6: (3aR,4R,8R,8aR)-6-cyclohexyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q06)

[0058] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with cyclohexylhydrazine hydrochloride to obtain 0.084 g of a pale yellow solid, with a yield of 31.3%. (c 0.5, CHCl3). 1H NMR (400MHz, CDCl3) δ4.95–4.90(m,1H),4.89–4.83(m,1H),4.80–4.73(m,1H),4.22–4. 13(m,1H),3.39(dd,J=12.6,2.4Hz,1H),3.12(tt,J=10.4,3.7Hz,1H),2.30(dd,J=12.6 ,2.9Hz,0H),2.01–1.94(m,1H),1.89(dt,J=12.2,3.2Hz,1H),1.79–1.68(m,2H),1.58( dt,J=12.6,3.1Hz,1H),1.45(s,3H),1.33(s,3H),1.28–1.21(m,2H),1.17–1.02(m,3H). 13 C NMR(101MHz, CDCl3)δ111.60,92.40,84.21,82.32,79.84,55.24,44.17,30.49,26.04,25.82,24.84,24.59.HRMS(ESI)m / z:Calcd for C 14 H 25 N₂O₃([M+H)) + )269.18597; Found 269.18518.

[0059] Example 7: (3aR,4R,8R,8aR)-6-benzyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q07)

[0060] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with benzylhydrazine dihydrochloride to obtain 0.200 g of white solid, with a yield of 72.4%. mp: 107.5-109.1 °C. (c 0.7, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.38–7.27(m,5H),4.94(d,J=5.7Hz,1H),4.80(d,J=5.7Hz,1H),4.71(s,1H),4.27(t,J=2.1Hz,1H),4.23( d,J=13.1Hz,1H),4.05(d,J=13.1Hz,1H),3.61(dd,J=12.4,2.4Hz,1H),2.31(dt,J=12.4,1.5Hz,1H),1.50(s,3H),1.38(s,3H). 13C NMR(101MHz, CDCl3)δ137.13,129.22,128.57,127.52,111.62,94.86,83.65,81.93,79.94,54.20,43.01,26.05,24.59.HRMS(ESI)m / z:Calcd for C 15 H 21 N₂O₃([M+H)) + )277.15467; Found 277.15390.

[0061] Example 8: (3aR,4R,8R,8aR)-6-(4-methoxybenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q08)

[0062] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with 4-methoxybenzylhydrazine hydrochloride to obtain 0.232 g of white solid, with a yield of 75.5%. mp: 58.9-61.6 °C. (c 0.5, CHCl3). 1 H NMR(400MHz, CDCl3)δ7.26(d,J=8.7Hz,3H),6.86(d,J=8.7Hz,2H),4.95–4.88(m,1H),4.83–4.78(m,1H),4.70–4.68(m,1H),4.29–4.24(m,1H),4 .17(d,J=12.8Hz,1H),3.98(d,J=12.9Hz,1H),3.79(s,3H),3.62(dd,J=1 2.4, 2.4Hz, 1H), 2.34 (dd, J = 12.4, 3.0Hz, 1H), 1.47 (s, 3H), 1.36 (s, 3H). 13 C NMR (101MHz, CDCl3) δ159.10,130.46,129.67,114.02,111.69,94.69,83.66,81.97,79.94,55.28,53.52,43.05,26.02,24.55.HRMS(ESI)m / z:Calcd for C 16 H 23 N₂O₄([M+H)) + )307.16523; Found 307.16498.

[0063] Example 9: (3aR,4R,8R,8aR)-6-(2-fluorobenzyl)-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q09)

[0064] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with 2-fluorobenzylhydrazine hydrochloride to obtain 0.115 g of white solid, with a yield of 38.9%. (c 0.25, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.42–7.34(m,1H),7.30–7.22(m,2H),7.15–7.07(m,1H),7 .04(ddd,J=9.7,8.2,1.2Hz,1H),4.97–4.90(m,1H),4.83–4.78(m,1H),4.75–4.6 8(m,1H),4.36(d,J=13.3Hz,1H),4.30–4.27(m,1H),4.02(d,J=13.3Hz,1H),3.68 (dd,J=12.7,2.4Hz,1H),2.39(dd,J=12.7,2.9Hz,1H),1.48(s,3H),1.36(s,3H). 13 C NMR (101MHz, CDCl3) δ161.63 (d, J = 246.0Hz), 136.11, 131.39 (d, J = 5.0Hz), 129.20 (d, J = 8.0Hz), 124.13 (d, J = 4.0Hz), 11 5.47(d,J=22.0Hz),111.85,95.15,83.65,81.85,79.97,47.64(d,J=2.0Hz),43.17,26.01,24.59.HRMS(ESI)m / z:Calcd for C 15 H 20 FN2O3([M+H)) + )295.14525; Found295.14471.

[0065] Example 10: (3aR,4R,8R,8aR)-2,2-dimethyl-6-phenylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q10)

[0066] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with phenylhydrazine hydrochloride to obtain 0.013 g of orange-red solid, with a yield of 5.0%. (c 0.25, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.19–7.14(m,2H),6.94–6.88(m,2H),6.79(tt,J=7.3,1.2Hz,1H),4.97–4.89(m,1H),4.80–4.72(m,1H) ,4.68–4.62(m,1H),4.38–4.31(m,1H),3.40(dd,J=11.5,3.2Hz,0H),2.96(dd,J=11.5,2.1Hz,1H),1.41(s,3H),1.23(s,3H). 13 C NMR(101MHz, CDCl3)δ149.34,129.05,120.39,113.64,111.74,91.48,82.70,82.50,78.24,51.62,26.01,24.54.HRMS(ESI)m / z:Calcd for C 14 H 19 N₂O₃([M+H)) + )263.13902; Found 263.13828.

[0067] Example 11: (3aR,4R,8R,8aR)-2,2-dimethyl-6-(4-methylphenyl)hexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q11)

[0068] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with 4-methylphenylhydrazine hydrochloride to obtain 0.016 g of yellow solid, with a yield of 5.8%. (c 0.32, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.26(d,J=8.7Hz,3H),6.86(d,J=8.7Hz,2H),4.95–4.88(m,1H),4.83–4.78(m,1H),4.29–4.24(m,1H),4.17(d,J= 12.8Hz,1H),3.98(d,J=12.9Hz,1H),3.79(s,4H),3.62(dd,J=12.4,2.4Hz,1H),2.34(dd,J=12.4,3.0Hz,1H),1.47(s,3H),1.36(s,3H). 13C NMR(101MHz, CDCl3)δ147.18,129.90,129.52,113.89,111.69,91.52,82.75,82.56,78.30,52.13,26.02,24.55,20.38.HRMS(ESI)m / z:Calcd for C 15 H 21 N₂O₃([M+H)) + )277.15467; Found277.15448.

[0069] Example 12: 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza] Preparation of 6-yl]ethanol (Q12)

[0070] Following the preparation method of Example 1, methylhydrazine sulfate in step C was replaced with 2-hydroxyethylhydrazine to obtain 0.088 g of white solid, with a yield of 38.2%. mp: 69.3–71.5 °C. (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ4.88(d,J=5.7Hz,1H),4.75(d,J=5.7Hz,1H),4.62(s,1H),4.21(s,1H),3.75(dt,J=7.9,3.9Hz,2H),3.54(dd,J=13 .6,2.6Hz,1H),3.41(ddd,J=13.4,7.0,3.3Hz,1H),2.68(ddd,J=13.4,5.4,3.3Hz,1H),2.35(d,J=13.6Hz,1H),1.47(s,3H),1.36(s,3H). 13 C NMR(101MHz, CDCl3)δ112.28,96.28,83.41,81.39,79.53,61.78,51.94,42.81,25.97,24.65.HRMS(ESI)m / z:Calcd for C 10 H 19 N₂O₄([M+H)) + )231.13393; Found 231.13290.

[0071] Example 13: 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza] Preparation of ethyl 6-yl]ethyl acetate (Q13)

[0072] Following the preparation method of Example 1, the methylhydrazine sulfate in step C was replaced with ethyl hydrazine hydrochloride to obtain 0.118 g of white solid, with a yield of 43.5%. (c 0.25, CHCl3). 1 H NMR (400MHz, CDCl3) δ5.02–4.95(m,1H),4.82–4.76(m,1H),4.69–4.62(m,1H),4.24–4.14(m,3H),4.04(d,J=16.9Hz,1H) ,3.53(d,J=2.4Hz,1H),3.51–3.46(m,1H),2.37(dd,J=12.7,2.9Hz,0H),1.46(s,3H),1.35(s,3H),1.27(t,J=7.1Hz,3H). 13 C NMR(101MHz, CDCl3)δ170.52,111.85,96.04,83.43,81.69,79.91,60.94,51.09,42.57,26.02,24.59,14.14.HRMS(ESI)m / z:Calcd for C 12 H 21 N₂O₅([M+H)) + )273.14450; Found 273.14429.

[0073] Example 14: (3aR,4R,8R,8aR)-5-benzyl-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q14)

[0074] Following the preparation method of Example 1, (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxy ... (Q01).

[0075] Weigh (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza (1.00 g, 5.0 mmol) was placed in a flask, dissolved in pyridine, and benzyl bromide (1.71 g, 10.0 mmol) was slowly added dropwise with stirring. The reaction mixture was stirred at room temperature for 3 h. The reaction solution was diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate for 2 h. After most of the ethyl acetate was evaporated under reduced pressure, the mixture was separated by column chromatography (PE:EA = 8:1) to give 1.37 g of white solid, yield 94.6%. mp: 125.8-127.9 °C. (c 0.7, CHCl3). 1 H NMR (600MHz, CDCl3) δ7.35 (dd, J=7.8, 1.4Hz, 2H), 7.32–7.27 (m, 2H), 7.25–7. 21(m,1H),4.86–4.80(m,1H),4.76–4.71(m,1H),4.56–4.45(m,1H),4.30–4.2 4(m,1H),4.05(d,J=12.1Hz,1H),3.91(d,J=12.1Hz,1H),3.16(dd,J=11.7,2. 1Hz,1H),2.50(s,3H),2.29(dd,J=11.7,1.9Hz,1H),1.42(s,3H),1.32(s,3H). 13 C NMR (101MHz, CDCl3) δ137.44,129.49,128.40,127.16,111.17,93.19,83.62,82.92,79.45,50.24,42.77,42.10,26.04,24.49.HRMS(ESI)m / z:Calcd for C 16 H 23 N₂O₃([M+H)) + )291.17032; Found 291.16962.

[0076] Example 15: (3aR,4R,8R,8aR)-6-benzyl-2,2,5-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q15)

[0077] Following the preparation method of Example 7, (3aR,4R,8R,8aR)-6-benzyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazamethoxy ... (Q07).

[0078] Using compound Q07 and dimethyl sulfate, and following the preparation method in Example 14, 0.165 g of a pale yellow powdery solid was obtained, with a yield of 67.3%. (c 0.3, CHCl3). 1 H NMR (600MHz, CDCl3) δ7.37–7.32(m,2H),7.32–7.27(m,2H),7.25–7.21(m,1 H),4.86–4.80(m,1H),4.76–4.72(m,1H),4.53–4.48(m,1H),4.29–4.25(m, 1H),4.05(d,J=12.1Hz,1H),3.91(d,J=12.1Hz,1H),3.16(dd,J=11.7,2.1H z,1H),2.50(s,3H),2.29(dd,J=11.7,3.0Hz,0H),1.42(s,3H),1.32(s,3H). 13 CNMR(101MHz, CDCl3)δ137.44,129.49,128.40,127.16,111.17,93.19,83.61,82.92,79.45,50.23,42.77,42.10,26.04,24.49.HRMS(ESI)m / z:Calcd for C 16 H 23 N₂O₃([M+H)) + )291.17032; Found291.16937.

[0079] Example 16: (3aS,4S,8S,8aS)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q16)

[0080] Step A: Preparation of (3aS,6S,6aS)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-ol

[0081] Weigh 5.0 g (33.3 mmol) of L-ribose into a flask, add 25 mL of acetone, and slowly add 0.25 mL of sulfuric acid dropwise under ice bath conditions. Remove the ice bath, stir the reaction mixture at room temperature for 1.5 h, and then add triethylamine to neutralize the reaction solution to neutral. After distilling off most of the acetone under reduced pressure, separate the product by column chromatography (PE:EA = 2:1) to obtain 5.37 g of a pale yellow viscous liquid, with a yield of 84.8%.

[0082] Step B: Preparation of [(3aS,4S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-yl]methyl-p-methylbenzenesulfonate

[0083] The synthesis of (3aS,6S,6aS)-6-hydroxymethyl-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-ol (5.37 g, 28.2 mmol) was weighed and placed in a flask. Pyridine was added to dissolve the solid. A pyridine solution of p-toluenesulfonyl chloride (5.38 g, 28.2 mmol) was slowly added under ice bath conditions. The mixture was stirred overnight at room temperature. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate for 2 h. After most of the ethyl acetate was evaporated under reduced pressure, the solid was separated by column chromatography (PE:EA = 4:1) to obtain 6.22 g of white solid, with a yield of 64.0%.

[0084] Step C: (3aS,4S,8S,8aS)-2,2,6-trimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation

[0085] [(3aS,4S,6aS)-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), and triethylamine (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, column chromatography (PE:EA = 2:1) was performed to give 0.110 g of a colorless waxy solid, yield 55.0%. (c 0.7, CHCl3). 1 HNMR(600MHz, CDCl3)δ4.88–4.85(m,1H),4.85–4.82(m,1H),4.78–4.74(m,1H),4.29–4.24(m,1H), 2.72(dd,J=11.3,2.2Hz,1H),2.36(dd,J=11.3,2.0Hz,1H),2.32(s,3H),1.46(s,3H),1.34(s,3H). 13 C NMR(101MHz, CDCl3)δ111.39,91.48,82.77,82.72,78.74,59.98,46.26,26.02,24.52.HRMS(ESI)m / z:Calcd for C9H 17 N₂O([M+H)) +)3 201.12337; Found201.12262.

[0086] Example 17: (3aS,4S,8S,8aS)-6-ethyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q17)

[0087] Referring to the preparation method of Example 16, methylhydrazine sulfate in step C was replaced with ethylhydrazine hydrochloride to obtain 0.111 g of white solid, yield 52.0%. mp: 127.5–129.1 °C. (c 0.52, CHCl3). 1 H NMR (400MHz, CDCl3) δ4.89–4.86(m,1H),4.80–4.76(m,1H),4.70–4.67(m,1H),4.22–4.16(m,1H),3.51(dd,J=12.7,2.4Hz,1H),3.03 (dq,J=12.4,7.2Hz,1H),2.92(dq,J=12.2,7.3Hz,1H),2.33(dd,J=12.7,2.8Hz,1H),1.47(s,4H),1.36(s,3H),1.07(t,J=7.2Hz,3H). 13 C NMR(101MHz, CDCl3)δ111.81,94.82,83.66,81.87,79.89,44.40,43.11,26.03,24.62,12.51.HRMS(ESI)m / z:Calcd for C 10 H 19 N₂O₃([M+H)) + )215.13902; Found 215.13892.

[0088] Example 18: (3aS,4S,8S,8aS)-6-isopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q18)

[0089] Referring to the preparation method of Example 16, methylhydrazine sulfate in step C was replaced with isopropylhydrazine hydrochloride to obtain 0.122 g of white solid, with a yield of 53.3%. mp: 40.9–41.9 °C. (c 0.25, CHCl3). 1H NMR (400MHz, CDCl3) δ4.91 (s, 1H), 4.87 (d, J = 5.7Hz, 1H), 4.77 (d, J = 5.7Hz, 1H), 4.19 (t, J = 1.7Hz, 1H), 3.51 (dq, J = 12.8, 6. 5Hz,1H),3.42(dd,J=12.6,2.4Hz,1H),2.32(dt,J=12.6,1.3Hz,1H),1.47(s,3H),1.35(s,3H),1.09(dd,J=6.2,4.7Hz,6H). 13 C NMR(101MHz, CDCl3)δ111.66,92.90,84.20,82.26,79.83,47.53,44.02,26.04,24.59,20.79,20.72.HRMS(ESI)m / z:Calcd for C 11 H 21 N₂O₃([M+H)) + )229.15467; Found 229.15450.

[0090] Example 19: (3aS,4S,8S,8aS)-6-cyclopropyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q19)

[0091] Referring to the preparation method of Example 16, methylhydrazine sulfate in step C was replaced with cyclopropylhydrazine hydrochloride to obtain 0.118 g of white solid, with a yield of 52.2%. mp: 99.0–99.4 °C. (c 0.5, CHCl3). 1 H NMR (400MHz, CDCl3) δ4.84–4.81(m,1H),4.81–4.78(m,1H),4.78–4.76(m,1H),4.33–4.22(m,1H),3.67(dd,J=12.0, 2.3Hz, 1H), 3.01 (tt, J=6.6, 3.6Hz, 1H), 2.46 (dd, J=12.0, 3.1Hz, 1H), 1.48 (s, 3H), 1.35 (s, 3H), 0.66–0.40 (m, 4H). 13 C NMR(101MHz, CDCl3)δ111.70,95.30,83.26,82.05,79.83,44.42,31.23,26.05,24.60,6.32,6.22.HRMS(ESI)m / z:Calcd forC 11 H19 N₂O₃([M+H)) + )227.13902; Found 227.13896.

[0092] Example 20: (3aS,4S,8S,8aS)-6-cyclopentyl-2,2-dimethylhexahydro-4H-4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza Preparation of (Q20)

[0093] Referring to the preparation method of Example 16, methylhydrazine sulfate in step C was replaced with cyclopentylhydrazine hydrochloride to obtain 0.160 g of white solid, with a yield of 63.0%. (c 0.5, CHCl3). 1 H NMR (400MHz, CDCl3) δ4.92–4.88(m,1H),4.84–4.75(m,2H),4.24–4.20(m,1H),3.90–3.76(m,1H),3.5 3(dd,J=12.3,2.3Hz,1H),2.35(dd,J=12.3,2.9Hz,0H),1.93–1.57(m,8H),1.48(s,4H),1.36(s,3H). 13 CNMR(101MHz, CDCl3)δ111.64,94.17,83.82,82.23,79.81,57.86,43.49,30.84,30.65,26.05,24.58,24.41,23.95.HRMS(ESI)m / z:Calcd for C 13 H 23 N₂O₃([M+H)) + )255.17032; Found 255.17018.

[0094] 4,8-Epoxy-1,3-dioxolane[4,5-d]-1,2-diazazepine List of compounds in the examples of compound-like compounds

[0095]

[0096]

[0097]

[0098] Pharmacological Examples

[0099] Example 21: Inhibitory activity of the test compound on the proliferation of non-small cell lung cancer A549, colon cancer HCT116, breast cancer MCF7, and melanoma A375 cells.

[0100] (1) Experimental materials

[0101] Non-small cell lung cancer cells A549, colon cancer cells HCT116, breast cancer cells MCF7, and melanoma cells A375 were seeded in 96-well plates at densities of 5000, 4000, 5000, and 4000 cells / well, respectively, with 100 μL per well, and used after 24 h.

[0102] The target compound was dissolved in DMSO and diluted with culture medium to prepare six different concentrations: 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM. The solutions were stored at -20°C until use. The final concentration of DMSO in the culture medium was less than 0.1%.

[0103] MTT: Dissolve in PBS to a concentration of 2 mg / mL and store at -20°C.

[0104] (2) Experimental methods

[0105] The antitumor proliferation activity of A549, HCT116, MCF7, and A375 cells was evaluated using the MTT assay. A549, HCT116, MCF7, and A375 cell lines were cultured in DMEM medium containing 10% fetal bovine serum (FBS). When cells reached 80-90% confluence, they were confluent and passaged for no more than 20 generations, then allowed to acclimatize for 24 hours before further treatment. These cells were then placed in 96-well plates and cultured at 37°C with 5% CO2 until complete cell adhesion. After 24 hours, different concentrations of the invention's representative compound were added. After another 24 hours of culture, MTT (2 mg / mL) was added, and the cells were cultured for another 4 hours. The culture medium was removed, the crystals were dissolved in DMSO, and the absorbance was measured at 570 nm using a Thermo Multiskan GO (Thermo Fisher Scientific, USA). Based on the formula: Cell growth inhibition rate = (1 - OD value of drug group / OD value of control group) × 100%, calculate the cell growth inhibition rate at the corresponding concentration. Plot a logarithmic curve of different concentrations of the test compound and its cell inhibition rate, and calculate the corresponding IC50 of the test compound. 50 Values ​​were determined according to the methods described above for representative compounds of the present invention.

[0106]

[0107]

[0108] Among the target compounds mentioned above, all compounds exhibited varying degrees of inhibitory activity against tumor cell proliferation in A549, HCT116, MCF7, and A375 tumor cell lines. Q14 and Q16 showed significant inhibitory activity against the A549 cell line, with IC50 values ​​exceeding 100%. 50 All values ​​were below 20 μM. Q10 showed significant inhibitory activity against the proliferation of HCT116 cell line, with an IC50 concentration of [missing value]. 50 At close to 10 μM, Q07 exhibits significant inhibitory activity against the proliferation of A375 cell line, with an IC50 value of [missing information]. 50 All were below 20 μM.

[0109] Formulation Examples

[0110] 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 described in the following examples refer to the target compounds prepared in the above examples.

[0111] Example 22: Tablet Formulation

[0112] 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.

[0113] Example 23: Suspension Formulation

[0114] 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.

[0115] Example 24: Aerosol Formulation

[0116] 0.25 mg of active compound, 25-75 mL of ethanol, and 70 mg of propellant 22 (dichlorofluoromethane).

[0117] Example 25: Suppository Formulation

[0118] 250 mg of active compound and 2000 mL of saturated fatty acid glycerides.

[0119] Example 26: Injectable Formulation

[0120] 50 mg of the active compound, 1000 mL of isotonic salt solution.

[0121] Example 27: Ointment Formulation

[0122] 0.025g of micronized active compound, 10g of liquid paraffin, and soft white wax to a total of 100g.

[0123] Example 28: Ointment Formulation

[0124] 0.025g of active compound, 5g of propylene glycol, 5g of sorbitan sesquioleate, 10g of liquid paraffin, and soft white wax to 100g.

[0125] Example 29: Water-in-oil cream formulation

[0126] 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.

[0127] Example 30: Water-in-oil cream formulation

[0128] 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.

[0129] Example 31: Oil-in-water cream formulation

[0130] 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.

[0131] Example 32: Lotion Formulation

[0132] 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.

[0133] Example 33: Formulation of a suspension for injection

[0134] 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.

[0135] Example 34: Aerosol Formulation for Oral and Nasal Inhalation

[0136] 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.

[0137] Example 35: Formulation of atomizing solution

[0138] Add 7 mg of the active compound and 5 mg of propylene glycol to water to a final volume of 10 g.

[0139] Example 36: Powder Formulation for Inhalation

[0140] 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.

[0141] Example 37: Powder Formulation for Inhalation

[0142] The spherical powder is packed into a multi-dose powder inhaler, with each dose containing 0.1 mg of micronized active compound.

[0143] Example 38: Powder Formulation for Inhalation

[0144] 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.

[0145] Example 39: Capsule Formulation

[0146] 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.

[0147] Example 40: Capsule Formulation of Vaccine

[0148] 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 NE30D 12.6 mg, Eudragit S100 12.6 mg, talc 0.16 mg.

[0149] Example 41: Enema Formulation

[0150] 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.

[0151] Example 42: Formulation containing liposomes

[0152] A. Preparation of the drip formulation

[0153] 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. The solution was then subjected to reduced pressure, thereby forming a lipid film on the surface of the glass tube. An aqueous solution (0.9% NaCl) was added to this 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 extremely small vesicles to 2 μm.

[0154] B. Preparation of inhalation formulations

[0155] 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.

[0156] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any other way. Any person skilled in the art may make changes or modifications to the above-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 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazonium compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that, The structure of Formula I is as follows: ； R1 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, benzyl, methoxy-substituted benzyl, halogen-substituted benzyl, phenyl, C1-C4 alkyl-substituted phenyl, 2-hydroxyethyl, and ethoxycarbonylmethyl. R2 is selected from hydrogen, C1-C4 alkyl, and benzyl.

2. The 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazonium compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, In Formula I, R1 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 4-methoxybenzyl, 2-fluorobenzyl, phenyl, 4-methylphenyl, and ethoxycarbonylmethyl; R2 is selected from hydrogen, methyl, and benzyl.

3. The 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazonium compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, It is any one of the following compounds: Q01: (3aR,4R,8R,8aR)-2,2,6-trimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q02: (3aR,4R,8R,8aR)-6-isopropyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q03: (3aR,4R,8R,8aR)-6-tert-butyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q04: (3aR,4R,8R,8aR)-6-cyclopropyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q05: (3aR,4R,8R,8aR)-6-cyclopentyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q06: (3aR,4R,8R,8aR)-6-cyclohexyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q07: (3aR,4R,8R,8aR)-6-benzyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q08: (3aR,4R,8R,8aR)-6-(4-methoxybenzyl)-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q09: (3aR,4R,8R,8aR)-6-(2-fluorobenzyl)-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q10: (3aR,4R,8R,8aR)-2,2-dimethyl-6-phenylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q11: (3aR,4R,8R,8aR)-2,2-dimethyl-6-(4-methylphenyl)hexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q12: 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6] H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-6-yl]ethanol; Q13: 2-[(3aR,4R,8R,8aR)-2,2-dimethylhexahydro-6] H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diaza-6-yl]ethyl acetate; Q14: (3aR,4R,8R,8aR)-5-benzyl-2,2,6-trimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q15: (3aR,4R,8R,8aR)-6-benzyl-2,2,5-trimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q16: (3aS,4S,8S,8aS)-2,2,6-trimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q17: (3aS,4S,8S,8aS)-6-ethyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q18: (3aS,4S,8S,8aS)-6-isopropyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q19: (3aS,4S,8S,8aS)-6-cyclopropyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazo; Q20: (3aS,4S,8S,8aS)-6-cyclopentyl-2,2-dimethylhexahydro-4 H -4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazoline.

4. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any one of the 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazonium compounds or pharmaceutically acceptable salts thereof as active ingredients, and a pharmaceutically acceptable carrier or diluent.

5. The use of the 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazonium compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3 in the preparation of an antitumor drug.

6. The use of the pharmaceutical composition according to claim 4 in the preparation of an antitumor drug.

7. The application according to claim 6, characterized in that, The tumors mentioned are selected from lung cancer, colon cancer, melanoma, and breast cancer.

8. The method for preparing the 4,8-epoxy-1,3-dioxolane[4,5-d]-1,2-diazazonium compound or a pharmaceutically acceptable salt thereof as described in claim 3, characterized in that, The preparation route includes: ； Wherein R1 and R2 are the corresponding groups at the corresponding positions of compounds Q01-Q15 according to claim 3; X represents bromine or chlorine; when preparing compounds Q16-Q20, the starting material D-ribose is replaced with L-ribose.

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