Quinazolinone-triazene compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of synthesis of novel compounds, and discloses a quinazolinone-triazene compound and a preparation method and application thereof.A triazene group based on dimethylamine, diethylamine, diisopropylamine, morpholine ring or 4-methylpiperidine ring is introduced to a quinazolinone parent through a diazotization reaction, and the quinazolinone-triazene compound is obtained. The quinazolinone-triazene compound with a brand new structure is designed and synthesized, the synthesis route is short, the preparation method is simple, the raw materials are easy to obtain, the cost is low, and the yield is high. The compounds have certain inhibitory activity on gram-positive bacteria, gram-negative bacteria and fungi (including clinical drug-resistant bacteria), can be used for preparing antibacterial or antifungal drugs, and can also be used for DNA intercalating agents, bactericides and antitumor drugs. The preparation raw materials are high in commercialization degree, cheap and easy to obtain, the preparation route is short, and the method is simple.

Description

Technical Field

[0001] The invention belongs to the technical field of new compound synthesis, and specifically relates to a quinazolinone-triazene compound and a preparation method and application thereof. Background Art

[0002] Quinazolinone compounds are one of the important components of various natural products and heterocyclic compounds with important pharmacological activities. They have attracted widespread attention from chemists because of their important pharmaceutical and physiological activities such as antibacterial, anticancer, anti-inflammatory, and vasodilatory activities. Quinazolinone has a unique condensed aromatic structure and is easy to interact with enzymes, DNA, proteins, etc. in the body through various non-covalent bonding forces such as hydrogen bonding, π-π stacking, electrostatic and hydrophobic interactions, thus showing a variety of biological activities, especially in the field of medicinal chemistry, showing broad application prospects. Quinazolinone compounds have attracted much attention due to their outstanding ability to not produce drug-resistant bacteria, showing great development value. In recent years, quinazolinone has received widespread attention in medicinal chemistry, especially in the field of antibacterial, and a lot of work has been devoted to the development of quinazolinone derivatives with medical value. Therefore, exploratory research on quinazolinone is conducive to the development of candidate drug molecules with a wider antimicrobial spectrum, stronger activity, and less toxic side effects.

[0003] Triazene compounds are an important class of DNA alkylating agents with extremely strong anti-cancer activity and low toxicity. Currently, there are two clinical drugs, temozolomide and dacarbazine, used to treat malignant tumors. However, the application of triazene structures in the antibacterial field is still relatively lacking and has great potential for exploration.

[0004] The present invention is the first to introduce a triazene group based on dimethylamine, diethylamine, diisopropylamine, morpholine ring or 4-methylpiperidine ring into a quinazolinone matrix through a diazotization reaction, and to design and synthesize a class of quinazolinone-triazene compounds with a completely new structure, in order to obtain antibacterial molecules with better activity, and to explore the antibacterial activity of these compounds. Summary of the invention

[0005] In view of this, one of the objects of the present invention is to provide a class of quinazolinone-triazene compounds, a second object is to provide a method for preparing the quinazolinone-triazene compounds; and a third object is to provide an application of the quinazolinone-triazene compounds.

[0006] To achieve the above-mentioned purpose, the present invention provides the following technical solutions:

[0007] A quinazolinone-triazene compound, the general structural formula of the quinazolinone-triazene compound is as follows:

[0008]

[0009] Wherein, R1 and R2 are one of H, halogen, nitro, amino, hydroxyl, thiol, sulfonyl, carbonyl, aryl, alkoxy, alkyl or CF3, and the R3-N-R4 is one of NH-containing aromatic compound, NH-containing aliphatic chain or NH-containing aliphatic ring.

[0010] Preferably, R1 and R2 are one of H, halogen, alkoxy, alkyl or CF3, and R3-N-R4 is one of NH-containing aliphatic chain or NH-containing aliphatic ring.

[0011] More preferably, R1 and R2 are one of H, halogen or CF3, and R3-N-R4 is one of dimethylamine, diethylamine, diisopropylamine, morpholine ring or 4-methylpiperidine ring.

[0012] Most preferably, the quinazolinone-triazene compound is any one of the following compounds:

[0013]

[0014]

[0015]

[0016] The second object of the present invention is to provide a method for preparing a quinazolinone-triazene compound, comprising the following steps:

[0017] a. Preparation of intermediate II: Using R1 and R2 substituted anthranilic acid as the starting material, condensation with acetic acid formamidine in an organic solvent to obtain compound II, i.e., quinazolinone mother ring, whose structural formula is:

[0018]

[0019] R1 and R2 are one of H, halogen, nitro, amino, hydroxyl, thiol, sulfonyl, carbonyl, aryl, alkoxy, alkyl or CF3;

[0020] b. Preparation of intermediate III: Using quinazolinone as the starting material, reacting with 4-nitrobenzyl bromide in an organic solvent to obtain intermediate III, i.e., compound 3-(4-nitrobenzyl)quinazolinone, the structural formula of which is:

[0021]

[0022] c. Preparation of intermediate IV: 3-(4-nitrobenzyl)quinazolinone is used as a starting material, and reacted with sodium dithionite and sodium carbonate in a solvent to obtain intermediate IV, i.e., compound 3-(4-aminobenzyl)quinazolinone, whose structural formula is:

[0023]

[0024] d. Preparation of quinazolinone-triazene compounds: 3-(4-aminobenzyl)quinazolinone is used as a starting material, and sodium nitrite is reacted in concentrated hydrochloric acid to generate the hydrochloride of compound V, which is then dropped into an aqueous solution containing an NH compound and sodium carbonate to obtain a quinazolinone-triazene compound. The structural formula of compound V is:

[0025]

[0026] The NH-containing compound is any one of dimethylamine, diethylamine, diisopropylamine, morpholine ring or 4-methylpiperidine ring.

[0027] The third object of the present invention is to provide the use of quinazolinone-triazene compounds in the preparation of antibacterial or antifungal drugs.

[0028] Preferably, the bacteria are any one or more of Staphylococcus aureus standard bacteria 25923 and 29213, Pseudomonas aeruginosa standard bacteria 27853, Escherichia coli standard bacteria 25922, Enterococcus faecalis and Acinetobacter baumannii; the fungi are any one or more of Candida albicans standard bacteria 90023, Candida parapsilosis standard bacteria 22019, Candida tropicalis and Aspergillus fumigatus.

[0029] Preferably, the quinazolinone-triazene compound is used as a DNA intercalator.

[0030] Preferably, the quinazolinone-triazene compound is used as an effective fungicide.

[0031] Preferably, the Schiff base imidazobenzothiazole compounds and pharmaceutically acceptable salts thereof are used as effective anti-tumor drugs.

[0032] The beneficial effects of the present invention are as follows: the present invention introduces a triazene group based on dimethylamine, diethylamine, diisopropylamine, morpholine ring or 4-methylpiperidine ring into a quinazolinone matrix through a diazotization reaction, and designs and synthesizes a class of quinazolinone-triazene compounds with a completely new structure, namely, compounds shown in general formula I. The synthetic route is short, the preparation method is simple, the raw materials are easily available, the cost is low, and the yield is high. The results of in vitro antimicrobial activity test show that the synthesized Schiff base imidazobenzothiazole compounds of the present invention exhibit certain inhibitory effects on Gram-positive bacteria, Gram-negative bacteria and fungi (including drug-resistant bacteria). More importantly, the antibacterial activity of some compounds on Gram-positive bacteria and Gram-negative bacteria is comparable to or even stronger than that of the clinical drug norfloxacin; the antibacterial activity of some compounds on fungi is comparable to or even stronger than that of fluconazole. Therefore, the compounds can be made into single or compound antibacterial or antifungal drugs in various dosage forms for clinical use, thereby providing more efficient and safe candidate drug molecules for clinical antimicrobial treatment, and helping to solve the increasingly serious clinical treatment problems such as drug resistance, stubborn pathogenic microorganisms and newly emerging harmful microorganisms. In addition, the quinazolinone-triazene compounds synthesized by the present invention can also be used to prepare DNA intercalators, bactericides and antitumor preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 UV absorption spectrum of quinazolinone-triazene compound I-3e titrated against calf thymus DNA

[0034] Figure 2 The bactericidal rate effect diagram of quinazolinone-triazene compound I-4d as a bactericide DETAILED DESCRIPTION

[0035] In order to make the objectives, technical solutions and beneficial effects of the present invention more clear, preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0036] Example 1. Preparation of Quinazolinone-Triazene Compound I-1a

[0037]

[0038] In a 100 mL round-bottom flask, 2-amino-4-fluorobenzoic acid (3.10 g, 20 mmol, 1 eq) and formamidine acetate (2.27 g, 22 mmol, 1.2 eq) were dissolved in ethylene glycol methyl ether (50 mL), stirred and refluxed at 130 ° C for 18 h, and the reaction was monitored by TLC. After cooling to room temperature, the solvent was removed by rotary evaporation, extracted with dichloromethane, washed three times with 1% ammonia water, washed with saturated brine, and dried to obtain 2.74 g of brown-grey solid, i.e., intermediate II-1, with a yield of 83.47%.

[0039]

[0040] In a 100 mL round-bottom flask, intermediate II-1 (0.82 g, 5 mmol, 1 eq), 4-nitrobenzyl bromide (1.62 g, 7.5 mmol, 1.5 eq) and potassium carbonate (1.04 g, 7.5 mmol, 1.5 eq) were added. The mixture was refluxed in an oil bath at 60 °C in acetone (50 mL) for 5 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature, the solvent was removed by rotary evaporation, and the mixture was extracted with dichloromethane. The mixture was concentrated, separated and purified by column chromatography (ethyl acetate: petroleum ether 1:3), and dried to obtain 1.44 g of a light grey product, namely intermediate III-1, with a yield of 96.23%.

[0041]

[0042] Add intermediate III-1 (1.50 g, 5 mmol, 1 eq) and water (30 mL) into a 250 mL round-bottom flask, stir and suspend, slowly drop an aqueous solution (40 mL) of sodium dithionite (8.72 g, 50 mmol, 10 eq) and sodium carbonate (5.30 g, 50 mmol, 10 eq), stir at 70 ° C for 2 h, monitor the reaction by TLC, cool to room temperature, filter, and wash with saturated brine to obtain 1.14 g of white solid, namely intermediate IV-1, with a yield of 84.76%.

[0043]

[0044] Add intermediate IV-1 (1.35 g, 5 mmol, 1 eq) into a 25 mL eggplant-shaped flask, dissolve with concentrated hydrochloric acid (36%, 1 mL), dilute with 2 mL of water, then add dropwise a solution of sodium nitrite (0.69 g, 10 mmol, 2 eq) in water (3 mL), stir in an ice bath (0-5°C) for 30 min, monitor the completion of the reaction by TLC, and obtain a hydrochloride solution of intermediate V-1, which is light brown.

[0045]

[0046] To a 50 mL eggplant-shaped bottle, add 40% aqueous dimethylamine solution (1.13 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep in an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-1 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. Wash the crude product with saturated brine, concentrate, and column chromatography (dichloromethane) to obtain 1.12 g of brown solid, i.e., compound I-1a, with a yield of 68.92%.

[0047] Compound I-1a: brown powder; 1H-NMR (500MHz, CDCl3): δ8.26(s,1H,N=CH),8.03(s,1H,Ar-H),7.32(d,J=7.2Hz,2H,Ar-H),7.25(t,J=9 .4Hz,3H,Ar-H),7.15(d,J=7.2Hz,1H,Ar-H),5.09(s,2H,N-CH2-Ar),3.25(s,6H,N-CH3); m / z: 325.1339.

[0048] Example 2: Preparation of Quinazolinone-Triazene Compound I-1b

[0049]

[0050] To a 50 mL eggplant-shaped flask, diethylamine (0.73 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) were added. The mixture was kept in an ice bath (0-5°C) and the hydrochloride solution of the intermediate V-1 obtained in the previous step was dripped dropwise into the flask while stirring. The reaction was allowed to proceed for 1 h. After the reaction was completed as monitored by TLC, the mixture was filtered at low temperature. The crude product was washed with saturated brine, concentrated, and subjected to column chromatography (dichloromethane) to obtain 1.06 g of a brown solid, i.e., compound I-1b, with a yield of 60.22%.

[0051] Compound I-1b: brown powder; 1 H-NMR (500MHz, CDCl3): δ8.26(dd,J=8.9,6.1Hz,1H,N=CH),8.02(s,1H,Ar-H),7.31(d,J=8.4Hz,2H,Ar-H),7.29-7.20(m,3H,Ar-H),7.13 (td,J=8.6,2.5Hz,1H,Ar-H),5.08(s,2H,N-CH2-Ar),3.67(q,J=7.2Hz,4H,N-CH2-CH3),1.17(t,J=6.4Hz,6H,N-CH2-CH3); m / z: 353.1652.

[0052] Example 3. Preparation of Quinazolinone-Triazene Compound I-1c

[0053]

[0054] To a 50 mL eggplant-shaped flask, diisopropylamine (1.01 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) were added. The mixture was kept in an ice bath (0-5°C) and the hydrochloride solution of the intermediate V-1 obtained in the previous step was dripped dropwise into the flask while stirring. The reaction was allowed to proceed for 1 h. After the reaction was completed as monitored by TLC, the mixture was filtered at low temperature. The crude product was washed with saturated brine and concentrated and subjected to column chromatography (dichloromethane) to obtain 1.33 g of a dark pink solid, i.e., compound I-1c, with a yield of 69.81%.

[0055] Compound I-1c: dark pink powder; 1 H-NMR (500MHz, CDCl3): δ8.26(dd,J=8.9,6.1Hz,1H,N=CH),8.04(s,1H,Ar-H),7.32(d,J=8.4Hz,2H,Ar-H),7.29-7.26(m,1H,Ar-H),7.24(d,J =8.3Hz,2H,Ar-H),7.14(td,J=8.5,2.5Hz,1H,Ar-H),5.09(s,2H,N-CH2-Ar),3.61(d,2H,N-CH-CH3),1.21(s,12H,N-CH-CH3); m / z: 381.1965.

[0056] Example 4. Preparation of Quinazolinone-Triazene Compound I-1d

[0057]

[0058] To a 50 mL eggplant-shaped flask, add morpholine (0.87 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep in an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-1 obtained in the previous step into the flask dropwise while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. Wash the crude product with saturated brine, concentrate, and column chromatography (dichloromethane) to obtain 1.51 g of a dark yellow solid, i.e., compound I-1d, with a yield of 82.29%.

[0059] Compound I-1d: dark yellow powder; 1H-NMR (500MHz, CDCl3): δ8.24(d,J=8.3Hz,1H,N=CH),8.08(s,1H,Ar-H),7.62(d,J=2.3Hz,1H,Ar-H),7.39-7.30(m ,3H,Ar-H),7.27(d,J=8.3Hz,2H,Ar-H),5.14(s,2H,N-CH2-Ar),3.74(d,J=9.0,8H,N-CH2-CH2-CH); m / z: 367.1445.

[0060] Example 5. Preparation of Quinazolinone-Triazene Compound I-1e

[0061]

[0062] To a 50 mL eggplant-shaped bottle, add 4-methylpiperidine (0.99 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5 ° C), and drip the hydrochloride solution of the intermediate V-1 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature, wash the crude product with saturated brine, and obtain 1.07 g of dark yellow solid, i.e., compound I-1e, after concentration and column chromatography (dichloromethane). The yield is 56.46%.

[0063] Compound I-1e: dark yellow solid; 1 H-NMR (500MHz, CDCl3): δ8.17(d,J=8.2Hz,1H,N=CH),8.07(s,1H,Ar-H),7.61(d,J=1.6Hz,1H,Ar-H),7.36(dd ,J=8.6,2.0Hz,1H,Ar-H),7.32(d,J=7.9Hz,2H,Ar-H),7.24(d,J=8.5Hz,2H,Ar-H),5.09(s,2H,N-CH2-Ar),4.4 0(s,2H,N-CH2-CH2-CH),3.00(s,2H,N-CH2-CH2-CH),1.70(d,J=13.6Hz,2H,N-CH2-CH2-CH),1.64-1.57(m,1H, CH2-CH-CH3), 1.21 (dd, J=12.2, 4.3Hz, 2H, N-CH2-CH2-CH), 0.92 (d, J=6.6Hz, 3H, CH2-CH-CH3); m / z: 379.1808.

[0064] Example 6. Preparation of Quinazolinone-Triazene Compound I-2a

[0065]

[0066] In a 100 mL round-bottom flask, 2-amino-4-chlorobenzoic acid (3.43 g, 20 mmol, 1 eq) and formamidine acetate (2.27 g, 22 mmol, 1.2 eq) were dissolved in ethylene glycol methyl ether (50 mL), stirred and refluxed at 130 ° C for 18 h, and the reaction was monitored by TLC. After cooling to room temperature, the solvent was removed by rotary evaporation, extracted with dichloromethane, washed three times with 1% ammonia water, washed with saturated brine, and dried to obtain 2.98 g of brown-grey solid, namely intermediate II-2, with a yield of 82.54%.

[0067]

[0068] In a 100 mL round-bottom flask, add intermediate II-2 (0.90 g, 5 mmol, 1 eq), 4-nitrobenzyl bromide (1.62 g, 7.5 mmol, 1.5 eq) and potassium carbonate (1.04 g, 7.5 mmol, 1.5 eq), reflux in acetone (50 mL) at 60 ° C oil bath for 5 h, monitor the reaction by TLC, cool to room temperature, remove the solvent by rotary evaporation, extract with dichloromethane, concentrate, separate and purify by column chromatography (ethyl acetate: petroleum ether 1:3), and dry to obtain 1.59 g of light gray product, namely intermediate III-2, with a yield of 94.92%.

[0069]

[0070] Add intermediate III-2 (1.57 g, 5 mmol, 1 eq) and water (30 mL) into a 250 mL round-bottom flask, stir and suspend, slowly dropwise add an aqueous solution (40 mL) of sodium dithionite (8.72 g, 50 mmol, 10 eq) and sodium carbonate (5.30 g, 50 mmol, 10 eq), stir at 70 ° C for 2 h, monitor the reaction by TLC, cool to room temperature, filter, and wash with saturated brine to obtain 1.08 g of white solid, namely intermediate IV-2, with a yield of 75.26%.

[0071]

[0072] Add intermediate IV-2 (1.35 g, 5 mmol, 1 eq) into a 25 mL eggplant-shaped flask, dissolve with concentrated hydrochloric acid (36%, 1 mL), dilute with 2 mL of water, then add dropwise a solution of sodium nitrite (0.69 g, 10 mmol, 2 eq) in water (3 mL), stir in an ice bath (0-5°C) for 30 min, monitor the completion of the reaction by TLC, and obtain a hydrochloride solution of intermediate V-2, which is brown-yellow.

[0073]

[0074] To a 50 mL eggplant-shaped bottle, add 40% aqueous dimethylamine solution (1.13 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep in an ice bath (0-5°C), and drip the hydrochloride solution of the intermediate V-2 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. The crude product is washed with saturated brine, concentrated, and subjected to column chromatography (dichloromethane) to obtain 1.17 g of a brown solid, i.e., compound I-2a, with a yield of 68.62%.

[0075] Compound I-2a: brown powder; 1 H-NMR (500MHz, CDCl3): δ8.29(s,1H,N=CH),8.12(s,1H,Ar-H),7.30(dd,J=6.9Hz,2H,Ar-H),7.25(t,J=9 .4Hz,3H,Ar-H),7.03(d,J=7.2Hz,1H,Ar-H),5.09(s,2H,N-CH2-Ar),3.22(s,6H,N-CH3); m / z: 341.1043.

[0076] Example 7. Preparation of Quinazolinone-Triazene Compound I-2b

[0077]

[0078] To a 50 mL eggplant-shaped flask, diethylamine (0.73 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) were added. The mixture was kept in an ice bath (0-5°C) and the hydrochloride solution of the intermediate V-2 obtained in the previous step was dripped dropwise into the flask while stirring. The reaction was allowed to proceed for 1 h. After the reaction was completed as monitored by TLC, the mixture was filtered at low temperature. The crude product was washed with saturated brine, concentrated, and subjected to column chromatography (dichloromethane) to obtain 1.30 g of a brown solid, i.e., compound I-2b, with a yield of 70.46%.

[0079] Compound I-2b: brown solid; 1 H-NMR (500MHz, CDCl3): δ8.26 (d, J=8.3Hz, 1H, N=CH), 8.05 (s, 1H, Ar-H), 7.31 (d, J=8.4Hz, 2H, Ar-H), 7.29-7.20 (m, 3H, Ar-H), 7.13(s,1H,Ar-H),5.09(s,2H,N-CH2-Ar),3.54(q,J=7.2Hz,4H,N-CH2-CH3),1.17(t,J=6.4Hz,6H,N-CH2-CH3); m / z: 369.1356.

[0080] Example 8. Preparation of Quinazolinone-Triazene Compound I-2c

[0081]

[0082] To a 50 mL eggplant-shaped flask, diisopropylamine (1.01 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) were added. The mixture was kept in an ice bath (0-5°C) and the hydrochloride solution of the intermediate V-2 obtained in the previous step was dripped dropwise into the flask while stirring. The reaction was allowed to proceed for 1 h. After the reaction was completed as monitored by TLC, the mixture was filtered at low temperature. The crude product was washed with saturated brine, concentrated, and subjected to column chromatography (dichloromethane) to obtain 1.01 g of a dark pink solid, i.e., compound I-2c, with a yield of 50.88%.

[0083] Compound I-2c: dark pink powder; 1 H-NMR (500MHz, CDCl3): δ8.26(dd,J=8.7,6.1Hz,1H,N=CH),8.04(s,1H,Ar-H),7.32(d,J=8.2Hz,2H,Ar-H),7.29-7.26(m,1H,Ar-H),7.24 (d,J=8.3Hz,2H,Ar-H),7.14(d,J=8.1,1H,Ar-H),5.09(s,2H,N-CH2-Ar),3.55(d,2H,N-CH-CH3),1.20(s,12H,N-CH-CH3); m / z: 397.1669.

[0084] Example 9. Preparation of Quinazolinone-Triazene Compound I-2d

[0085]

[0086] To a 50 mL eggplant-shaped flask, add morpholine (0.87 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep in an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-2 obtained in the previous step into the flask dropwise while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. Wash the crude product with saturated brine, concentrate, and column chromatography (dichloromethane) to obtain 1.22 g of a light yellow solid, i.e., compound I-2d, with a yield of 63.71%.

[0087] Compound I-2d: pale yellow powder; 1H-NMR (500MHz, CDCl3): δ8.18(d,J=8.6Hz,1H,N=CH),8.03(s,1H,Ar-H),7.62(d,J=1.7Hz,1H,Ar-H),7.42-7.31(m,3H, Ar-H), 7.27 (d, J=8.3Hz, 2H, Ar-H), 5.10 (s, 2H, N-CH2-Ar), 3.74 (dt, J=9.3, 4.4Hz, 8H, N-CH2-CH2-CH); m / z: 383.1149.

[0088] Example 10. Preparation of Quinazolinone-Triazene Compound I-2e

[0089]

[0090] To a 50 mL eggplant-shaped bottle, add 4-methylpiperidine (0.99 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5 ° C). While stirring, drip the hydrochloride solution of the intermediate V-2 obtained in the previous step into the bottle drop by drop. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. The crude product is washed with saturated brine, concentrated, and column chromatography (dichloromethane) to obtain 1.39 g of a light yellow solid, i.e., compound I-2e, with a yield of 70.37%.

[0091] Compound I-2e: pale yellow powder; 1 H-NMR (500MHz, CDCl3): δ8.17(d,J=8.6Hz,1H,N=CH),8.02(s,1H,Ar-H),7.61(d,J=1.9Hz,1H,Ar-H),7.37(dd ,J=8.6,2.0Hz,1H,Ar-H),7.33(d,J=8.4Hz,2H,Ar-H),7.24(d,J=8.4Hz,2H,Ar-H),5.08(s,2H,N-CH2-Ar),4.4 0(s,2H,N-CH2-CH2-CH),3.00(s,2H,N-CH2-CH2-CH),1.70(d,J=13.6Hz,2H,N-CH2-CH2-CH),1.64-1.57(m,1H, CH2-CH-CH3), 1.21 (dd, J=12.2, 4.3Hz, 2H, N-CH2-CH2-CH), 0.92 (d, J=6.6Hz, 3H, CH2-CH-CH3); m / z: 395.1513.

[0092] Example 11. Preparation of Quinazolinone-Triazene Compound I-3a

[0093]

[0094] In a 100 mL round-bottom flask, 2-amino-4-bromobenzoic acid (4.32 g, 20 mmol, 1 eq) and acetic acid formamidine (2.27 g, 22 mmol, 1.2 eq) were dissolved in ethylene glycol methyl ether (50 mL), stirred and refluxed at 130 ° C for 18 h, and the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature and the solvent was removed by rotary evaporation. The mixture was extracted with dichloromethane, washed with ammonia water (1%) for 3 times, washed with saturated brine, and dried to obtain 2.63 g of brown-grey solid, i.e., intermediate II-3, with a yield of 58.44%.

[0095]

[0096] In a 100 mL round-bottom flask, add intermediate II-3 (1.13 g, 5 mmol, 1 eq), 4-nitrobenzyl bromide (1.62 g, 7.5 mmol, 1.5 eq) and potassium carbonate (1.04 g, 7.5 mmol, 1.5 eq), reflux in acetone (50 mL) at 60 ° C oil bath for 5 h, monitor the reaction by TLC, cool to room temperature, remove the solvent by rotary evaporation, extract with dichloromethane, concentrate, separate and purify by column chromatography (ethyl acetate: petroleum ether 1:3), and dry to obtain 1.66 g of light gray product, namely intermediate III-3, with a yield of 92.22%.

[0097]

[0098] Add intermediate III-2 (1.80 g, 5 mmol, 1 eq) and water (30 mL) into a 250 mL round-bottom flask, stir and suspend, slowly drop an aqueous solution (40 mL) of sodium dithionite (8.72 g, 50 mmol, 10 eq) and sodium carbonate (5.30 g, 50 mmol, 10 eq), stir at 70 ° C for 2 h, monitor the reaction by TLC, cool to room temperature, filter, wash with saturated brine to obtain 1.11 g of white solid, i.e., intermediate IV-3, with a yield of 67.27%.

[0099]

[0100] Add intermediate IV-3 (1.65 g, 5 mmol, 1 eq) into a 25 mL eggplant-shaped flask, dissolve with concentrated hydrochloric acid (36%, 1 mL), dilute with 2 mL of water, then add dropwise a solution of sodium nitrite (0.69 g, 10 mmol, 2 eq) in water (3 mL), stir in an ice bath (0-5°C) for 30 min, monitor the completion of the reaction by TLC, and obtain a hydrochloride solution of intermediate V-3, which is light brown.

[0101]

[0102] To a 50 mL eggplant-shaped bottle, add 40% aqueous dimethylamine solution (1.13 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-3 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. Wash the crude product with saturated brine, concentrate, and column chromatography (dichloromethane) to obtain 0.97 g of a white solid, i.e., compound I-3a, with a yield of 50.38%.

[0103] Compound I-3a: white powder; 1 H-NMR (500MHz, CDCl3): δ8.19(s,1H,N=CH),8.06(s,1H,Ar-H),7.29(d,J=7.2Hz,2H,Ar-H),7.24(t,J=9 .4Hz,3H,Ar-H),7.14(d,J=7.2Hz,1H,Ar-H),5.08(s,2H,N-CH2-Ar),3.33(s,6H,N-CH3); m / z: 385.0538.

[0104] Example 12: Preparation of Quinazolinone-Triazene Compound I-3b

[0105]

[0106] Add diethylamine (0.73 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) to a 50 mL eggplant-shaped flask, keep an ice bath (0-5°C), and drip the hydrochloride solution of the intermediate V-3 obtained in the previous step into the flask drop by drop while stirring. React for 1 h. After the reaction is completed by TLC monitoring, filter at low temperature, wash the crude product with saturated brine, and obtain 1.21 g of brown solid after concentration and column chromatography (dichloromethane), i.e., compound I-3b, with a yield of 58.60%.

[0107] Compound I-3b: brown powder; 1 H-NMR (500MHz, CDCl3): δ8.23(s,1H,N=CH),8.05(s,1H,Ar-H),7.31(d,J=8.4Hz,2H,Ar-H),7.29-7.20(m,3H,Ar-H),7.13 (s,1H,Ar-H),5.09(s,2H,N-CH2-Ar),3.54(q,J=7.2Hz,4H,N-CH2-CH3),1.17(t,J=6.4Hz,6H,N-CH2-CH3); m / z: 413.0851.

[0108] Example 13. Preparation of Quinazolinone-Triazene Compound I-3c

[0109]

[0110] Add diisopropylamine (1.01 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) to a 50 mL eggplant-shaped bottle, keep an ice bath (0-5°C), and drip the hydrochloride solution of the intermediate V-3 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature, wash the crude product with saturated brine, and obtain 1.41 g of dark pink solid, i.e., compound I-3c, after concentration and column chromatography (dichloromethane). The yield is 63.95%.

[0111] Compound I-3c: dark pink powder; 1 H-NMR (500MHz, CDCl3): δ8.25 (d, J = 7.9, 1H, N = CH), 8.09 (s, 1H, Ar-H), 7.32 (d, J = 8.4Hz, 2H, Ar-H), 7.33-7.27 (m, 1H, Ar-H), 7.24 (d, J = 6. 7Hz,2H,Ar-H),7.08(td,J=8.1,2.0Hz,1H,Ar-H),5.09(s,2H,N-CH2-Ar),3.61(d,2H,N-CH-CH3),1.21(s,12H,N-CH-CH3); m / z: 441.1164.

[0112] Example 14. Preparation of Quinazolinone-Triazene Compound I-3d

[0113]

[0114] To a 50 mL eggplant-shaped flask, add morpholine (0.87 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep in an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-3 obtained in the previous step into the flask dropwise while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. Wash the crude product with saturated brine, concentrate, and column chromatography (dichloromethane) to obtain 1.19 g of a white solid, i.e., compound I-3d, with a yield of 55.74%.

[0115] Compound I-3d: white powder; 1H-NMR (500MHz, CDCl3): δ8.09(d,J=8.5Hz,1H,N=CH),8.02(s,1H,Ar-H),7.80(d,J=1.8Hz,1H,Ar-H),7.53(dd,J=8.5,1.8Hz,1H),7.35(d, J=8.4Hz,2H,Ar-H),7.26(d,J=8.4Hz,2H,Ar-H),5.09(s,2H,N-CH2-Ar),3.74(ddd,J=10.8,9.3,4.3Hz,8H,N-CH2-CH2-O); m / z: 427.0644.

[0116] Example 15. Preparation of Quinazolinone-Triazene Compound I-3e

[0117]

[0118] To a 50 mL eggplant-shaped bottle, add 4-methylpiperidine (0.99 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5 ° C). While stirring, drip the hydrochloride solution of the intermediate V-3 obtained in the previous step into the bottle drop by drop. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. The crude product is washed with saturated brine, concentrated, and column chromatography (dichloromethane) to obtain 1.38 g of a light yellow solid, i.e., compound I-3e, with a yield of 62.87%.

[0119] Compound I-3e: pale yellow powder; 1 H-NMR (500MHz, CDCl3): δ8.10(d,J=8.5Hz,1H,N=CH),8.02(s,1H,Ar-H),7.80(d,J=1.8Hz,1H,Ar-H),7.53( dd,J=8.5,1.9Hz,1H,Ar-H),7.33(d,J=8.4Hz,2H,Ar-H),7.24(d,J=8.5Hz,2H,Ar-H),5.09(s,2H,N-CH2-Ar) ,4.41(s,2H,N-CH2-CH2-CH),3.00(s,2H,N-CH2-CH2-CH),1.74-1.67(m,2H,N-CH2-CH2-CH),1.58(s,1H,CH2 -CH-CH3), 1.22 (dd, J=12.0, 4.5Hz, 2H, N-CH2-CH2-CH), 0.92 (d, J=6.6Hz, 3H, CH2-CH-CH3).; m / z: 439.1008.

[0120] Example 16. Preparation of Quinazolinone-Triazene Compound I-4a

[0121]

[0122] In a 100 mL round-bottom flask, 2-amino-4,5-difluorobenzoic acid (3.46 g, 20 mmol, 1 eq) and acetic acid formamidine (2.27 g, 22 mmol, 1.2 eq) were dissolved in ethylene glycol methyl ether (50 mL), stirred and refluxed at 130 ° C for 18 h, and the reaction was monitored by TLC. After cooling to room temperature, the solvent was removed by rotary evaporation, extracted with dichloromethane, washed with ammonia water (1%) for 3 times, washed with saturated brine, and dried to obtain 2.88 g of brown-grey solid, i.e., intermediate II-4, with a yield of 79.12%.

[0123]

[0124] In a 100 mL round-bottom flask, add intermediate II-4 (0.91 g, 5 mmol, 1 eq), 4-nitrobenzyl bromide (1.62 g, 7.5 mmol, 1.5 eq) and potassium carbonate (1.04 g, 7.5 mmol, 1.5 eq), reflux in acetone (50 mL) at 60 ° C in an oil bath for 5 h, monitor the reaction by TLC, cool to room temperature, remove the solvent by rotary evaporation, extract with dichloromethane, concentrate, separate and purify by column chromatography (ethyl acetate: petroleum ether 1:3), and dry to obtain 1.53 g of light gray product, namely intermediate III-4, with a yield of 96.45%.

[0125]

[0126] Add intermediate III-4 (1.59 g, 5 mmol, 1 eq) and water (30 mL) into a 250 mL round-bottom flask, stir and suspend, slowly dropwise add an aqueous solution (40 mL) of sodium dithionite (8.72 g, 50 mmol, 10 eq) and sodium carbonate (5.30 g, 50 mmol, 10 eq), stir at 70 ° C for 2 h, monitor the reaction by TLC, cool to room temperature, filter, and wash with saturated brine to obtain 1.19 g of white solid, namely intermediate IV-4, with a yield of 88.48%.

[0127]

[0128] Add intermediate IV-4 (1.35 g, 5 mmol, 1 eq) into a 25 mL eggplant-shaped flask, dissolve with concentrated hydrochloric acid (36%, 1 mL), dilute with 2 mL of water, then add dropwise a solution of sodium nitrite (0.69 g, 10 mmol, 2 eq) in water (3 mL), stir in an ice bath (0-5°C) for 30 min, monitor the completion of the reaction by TLC, and obtain a hydrochloride solution of intermediate V-4, which is light brown.

[0129]

[0130] To a 50 mL eggplant-shaped bottle, add 40% aqueous dimethylamine solution (1.13 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-4 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed by TLC monitoring, filter at low temperature. The crude product is washed with saturated brine, concentrated, and subjected to column chromatography (dichloromethane) to obtain 1.06 g of a white solid, i.e., compound I-4a, with a yield of 61.81%.

[0131] Compound I-4a: white powder; 1 H-NMR (500MHz, CDCl3): δ8.05 (t, J=4.1Hz, 2H, Ar-H), 7.41 (dd, J=11.1, 7.4Hz, 1H, Ar-H), 7.35 (d, J=7. 9Hz, 2H, Ar-H), 7.26 (d, J = 7.8Hz, 2H, Ar-H), 5.09 (s, 2H, N-CH2-Ar), 3.25 (s, 6H, N-CH3); m / z: 343.1245.

[0132] Example 17: Preparation of Quinazolinone-Triazene Compound I-4b

[0133]

[0134] Add diethylamine (0.73 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) to a 50 mL eggplant-shaped flask, keep an ice bath (0-5°C), and drip the hydrochloride solution of the intermediate V-4 obtained in the previous step into the flask drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature, wash the crude product with saturated brine, and obtain 1.24 g of a light yellow solid after concentration and column chromatography (dichloromethane), i.e., compound I-4b, with a yield of 66.85%.

[0135] Compound I-4b: pale yellow powder; 1 H-NMR (500MHz, CDCl3): δ8.26(s,1H,N=CH),7.31(d,J=8.4Hz,2H,Ar-H),7.30-7.20(m,3H,Ar-H),7.13(s,1H,Ar -H), 5.09 (s, 2H, N-CH2-Ar), 3.45 (q, J=7.2Hz, 4H, N-CH2-CH3), 1.22 (t, J=6.4Hz, 6H, N-CH2-CH3); m / z: 371.1558.

[0136] Example 18. Preparation of Quinazolinone-Triazene Compound I-4c

[0137]

[0138] Add diisopropylamine (1.01 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) to a 50 mL eggplant-shaped bottle, keep an ice bath (0-5°C), and drip the hydrochloride solution of the intermediate V-4 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature, wash the crude product with saturated brine, and obtain 1.35 g of dark pink solid, i.e., compound I-4c, after concentration and column chromatography (dichloromethane). The yield is 67.67%.

[0139] Compound I-4c: dark pink powder; 1 H-NMR (500MHz, CDCl3): δ8.26 (dd, J=8.9, 6.1Hz, 1H, N=CH), 7.32 (d, J=8.4Hz, 2H, Ar-H), 7.29-7.26 (m, 1H, Ar-H), 7.24 (d, J=8.3Hz, 2 H, Ar-H), 7.14 (td, J = 8.5, 2.5 Hz, 1H, Ar-H), 5.09 (s, 2H, N-CH2-Ar), 3.61 (d, 2H, N-CH-CH3), 1.21 (s, 12H, N-CH-CH3); m / z: 399.1871.

[0140] Example 19. Preparation of Quinazolinone-Triazene Compound I-4d

[0141]

[0142] To a 50 mL eggplant-shaped flask, add morpholine (0.87 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-4 obtained in the previous step into the flask dropwise while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. Wash the crude product with saturated brine, concentrate, and column chromatography (dichloromethane) to obtain 1.08 g of a light yellow solid, i.e., compound I-4d, with a yield of 56.10%.

[0143] Compound I-4d: pale yellow powder; 1H-NMR (500MHz, CDCl3): δ8.01(t,J=4.3Hz,2H,Ar-H),7.40(dd,J=10.5,7.1Hz,1H,Ar-H),7.35(d,J=8.3Hz,2H,Ar-H),7.26(d, J=8.3Hz,2H,Ar-H),5.09(s,2H,N-CH2-Ar),3.83-3.73(m,4H,N-CH2-CH2-O),3.74-3.66(m,4H,N-CH2-CH2-O); m / z: 385.1350.

[0144] Example 20: Preparation of Quinazolinone-Triazene Compound I-4e

[0145]

[0146] To a 50 mL eggplant-shaped bottle, add 4-methylpiperidine (0.99 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5 ° C). While stirring, drip the hydrochloride solution of the intermediate V-4 obtained in the previous step into the bottle drop by drop. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. The crude product is washed with saturated brine, concentrated, and column chromatography (dichloromethane) to obtain 1.46 g of a light yellow solid, i.e., compound I-4e, with a yield of 73.55%.

[0147] Compound I-4e: pale yellow powder; 1 H-NMR (500MHz, CDCl3): δ8.06-7.95(m,2H,Ar-H),7.40(dd,J=10.5,7.1Hz,1H,N= CH),7.33(d,J=8.4Hz,2H,Ar-H),7.24(d,J=8.4Hz,2H,Ar-H),5.08(s,2H,N-CH2-A r),4.41(s,2H,N-CH2-CH2-CH),3.01(s,2H,N-CH2-CH2-CH),1.61(tdd,J=10.7,7 .2,3.4Hz,1H,N-CH2-CH2-CH),0.92(d,J=6.5Hz,3H,CH2-CH-CH3); m / z: 397.1714.

[0148] Example 21. Preparation of Quinazolinone-Triazene Compound I-5a

[0149]

[0150] In a 100 mL round-bottom flask, 2-amino-4-trifluoromethylbenzoic acid (4.10 g, 20 mmol, 1 eq) and acetic acid formamidine (2.27 g, 22 mmol, 1.2 eq) were dissolved in ethylene glycol methyl ether (50 mL), stirred and refluxed at 130 ° C for 18 h, and the reaction was monitored by TLC. After cooling to room temperature, the solvent was removed by rotary evaporation, extracted with dichloromethane, washed with ammonia water (1%) 3 times, washed with saturated brine, and dried to obtain 3.65 g of brown-grey solid, i.e., intermediate II-5, with a yield of 80.04%.

[0151]

[0152] In a 100 mL round-bottom flask, add intermediate II-5 (1.14 g, 5 mmol, 1 eq), 4-nitrobenzyl bromide (1.62 g, 7.5 mmol, 1.5 eq) and potassium carbonate (1.04 g, 7.5 mmol, 1.5 eq), reflux in acetone (50 mL) at 60 ° C oil bath for 5 h, monitor the reaction by TLC, cool to room temperature, remove the solvent by rotary evaporation, extract with dichloromethane, concentrate, separate and purify by column chromatography (ethyl acetate: petroleum ether 1:3), and dry to obtain 1.68 g of light gray product, namely intermediate III-5, with a yield of 96.28%.

[0153]

[0154] Add intermediate III-5 (1.75 g, 5 mmol, 1 eq) and water (30 mL) into a 250 mL round-bottom flask, stir and suspend, slowly dropwise add an aqueous solution (40 mL) of sodium dithionite (8.72 g, 50 mmol, 10 eq) and sodium carbonate (5.30 g, 50 mmol, 10 eq), stir at 70 ° C for 2 h, monitor the reaction by TLC, cool to room temperature, filter, wash with saturated brine to obtain 1.30 g of white solid, i.e., intermediate IV-5, with a yield of 81.50%.

[0155]

[0156] Add intermediate IV-5 (1.60 g, 5 mmol, 1 eq) into a 25 mL eggplant-shaped flask, dissolve with concentrated hydrochloric acid (36%, 1 mL), dilute with 2 mL of water, then add dropwise a solution of sodium nitrite (0.69 g, 10 mmol, 2 eq) in water (3 mL), stir in an ice bath (0-5°C) for 30 min, monitor the completion of the reaction by TLC, and obtain a hydrochloride solution of intermediate V-5, which is light brown.

[0157]

[0158] To a 50 mL eggplant-shaped bottle, add 40% aqueous dimethylamine solution (1.13 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-5 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed by TLC monitoring, filter at low temperature. Wash the crude product with saturated brine, concentrate, and column chromatography (dichloromethane) to obtain 1.13 g of a white solid, i.e., compound I-5a, with a yield of 66.27%.

[0159] Compound I-5a: white powder; 1 H-NMR (500MHz, CDCl3): δ8.36(d,J=8.3Hz,1H,N=CH),8.08(s,1H,Ar-H),7.88(s,1H,Ar-H),7.63(dd,J=8.2,1.6Hz,1H,Ar -H),7.33(d,J=8.5Hz,2H,Ar-H),7.22(d,J=8.5Hz,2H,Ar-H),5.06(s,2H,N-CH2-Ar),3.27(s,6H,N-CH3); m / z: 375.1307.

[0160] Example 22: Preparation of Quinazolinone-Triazene Compound I-5b

[0161]

[0162] Add diethylamine (0.73 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) to a 50 mL eggplant-shaped flask, keep an ice bath (0-5°C), and drip the hydrochloride solution of the intermediate V-5 obtained in the previous step into the flask drop by drop while stirring. React for 1 h. After the reaction is completed by TLC monitoring, filter at low temperature, wash the crude product with saturated brine, and obtain 1.10 g of brown solid after concentration and column chromatography (dichloromethane), i.e., compound I-5b, with a yield of 54.59%.

[0163] Compound I-5b: brown powder; 1 H-NMR (500MHz, CDCl3): δ8.18(s,1H,N=CH),8.02(s,1H,Ar-H),7.31(d,J=8.4Hz,2H,Ar-H),7.24(m,3H,Ar-H),7.11(s, 1H, Ar-H), 5.09 (s, 2H, N-CH2-Ar), 3.44 (q, J=7.2Hz, 4H, N-CH2-CH3), 1.10 (t, J=6.4Hz, 6H, N-CH2-CH3); m / z: 403.1620.

[0164] Example 23. Preparation of Quinazolinone-Triazene Compound I-5c

[0165]

[0166] Add diisopropylamine (1.01 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL) to a 50 mL eggplant-shaped bottle, keep an ice bath (0-5°C), and drip the hydrochloride solution of the intermediate V-5 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature, wash the crude product with saturated brine, and obtain 1.52 g of light yellow solid after concentration and column chromatography (dichloromethane), i.e., compound I-5c, with a yield of 70.53%.

[0167] Compound I-5c: dark pink powder; 1 H-NMR (500MHz, CDCl3): (500MHz, CDCl3) δ8.29 (d, J = 8.3, 1H, N = CH), 8.06 (s, 1H, Ar-H), 7.33 (d, J = 7.7Hz, 2H, Ar-H), 7.28-7.25 (m, 1H, Ar-H), 7 .24(d,J=7.4Hz,2H,Ar-H),7.14(d,J=8.1,1H,Ar-H),5.09(s,2H,N-CH2-Ar),3.61(d,2H,N-CH-CH3),1.19(s,12H,N-CH-CH3); m / z: 431.1933.

[0168] Example 24. Preparation of Quinazolinone-Triazene Compound I-5d

[0169]

[0170] To a 50 mL eggplant-shaped flask, add morpholine (0.87 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL). Keep an ice bath (0-5°C) and drip the hydrochloride solution of the intermediate V-5 obtained in the previous step into the flask dropwise while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature. Wash the crude product with saturated brine, concentrate, and column chromatography (dichloromethane) to obtain 1.20 g of a light yellow solid, i.e., compound I-5d, with a yield of 57.56%.

[0171] Compound I-5d: pale yellow powder; 1H-NMR (500MHz, CDCl3): δ8.37(d,J=8.3Hz,1H,N=CH),8.10(s,1H,Ar-H),7.91(s,1H,Ar-H),7.64(d,J=8.3Hz,1H,Ar-H),7.36(d,J =8.3Hz, 2H, Ar-H), 7.28 (d, J = 8.3Hz, 2H, Ar-H), 5.13 (s, 2H, N-CH2-Ar), 3.74 (dt, J = 9.4, 4.3Hz, 8H, N-CH2-CH2-O); m / z: 417.1413.

[0172] Example 25. Preparation of Quinazolinone-Triazene Compound I-5e

[0173]

[0174] To a 50 mL eggplant-shaped bottle, add 4-methylpiperidine (0.99 g, 10 mmol, 2 eq), sodium carbonate (1.06 g, 10 mmol, 2 eq) and water (3 mL), keep an ice bath (0-5 ° C), and drip the hydrochloride solution of the intermediate V-5 obtained in the previous step into the bottle drop by drop while stirring. React for 1 h. After the reaction is completed as monitored by TLC, filter at low temperature, wash the crude product with saturated brine, and obtain 1.43 g of light yellow solid after concentration and column chromatography (dichloromethane), i.e., compound I-5e, with a yield of 66.67%.

[0175] Compound I-5e: pale yellow powder; 1 H-NMR (500MHz, CDCl3): δ8.36 (d, J = 8.3 Hz, 1H, N = CH), 8.08 (s, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.63 (dd, J = 8. 4,1.4Hz,1H,Ar-H),7.34(d,J=8.5Hz,2H,Ar-H),7.25(d,J=8.5Hz,2H,Ar-H),5.11(s,2H,N-CH2-Ar),4.40 (s,2H,N-CH2-CH2-CH),3.00(s,2H,N-CH2-CH2-CH),1.70(d,J=13.4Hz,2H,N-CH2-CH2-CH),1.64-1.57(m, 1H, N-CH2-CH2-CH), 1.27-1.17 (m, 2H, N-CH2-CH2-CH), 0.92 (d, J = 6.6Hz, 3H, CH2-CH-CH3).; m / z: 429.1776.

[0176] In vitro antimicrobial activity of quinazolinone-triazene compounds

[0177] The 96-well microdilution method of the Clinical and Laboratory Standards Institute of America (CLSI) was used to determine the minimum inhibitory concentration (MIC) of quinazolinone-triazene compound I against bacteria (Standard strains 25923 and 29213 for Staphylococcus aureus, Standard strains 27853 for Pseudomonas aeruginosa, Standard strains 25922 for Escherichia coli; Standard strains for clinically resistant Pseudomonas aeruginosa, Enterococcus faecalis and Acinetobacter baumannii) and fungi (Standard strains 90023 for Candida albicans, Standard strains 22019 for Candida parapsilosis; Clinically resistant Candida albicans, Candida tropicalis and Aspergillus fumigatus). The compound to be tested was dissolved in a small amount of dimethyl sulfoxide, diluted with water to make a solution with a concentration of 1.28 mg / mL, and then diluted with bacterial culture fluid to 1024 μg / mL, cultured at 37°C for 24 to 72 hours, and the culture plate was placed on an oscillator and fully stirred, and the MIC was measured at a wavelength of 490 nm. The results are shown in Table 1.

[0178] Table 1 In vitro antimicrobial activity of compounds I-1a to 5e (MIC / μg / mL)

[0179]

[0180]

[0181] As can be seen from Table 1, the quinazolinone-triazene compound I synthesized in the present invention exhibits a certain inhibitory effect on Gram-positive bacteria, Gram-negative bacteria and fungi (including drug-resistant bacteria). More importantly, the antibacterial activity of some compounds against Gram-positive bacteria and Gram-negative bacteria (including drug-resistant bacteria) is comparable to or even stronger than that of the clinical drug norfloxacin; the antibacterial activity of some compounds against fungi is comparable to or even stronger than that of fluconazole.

[0182] Application of Quinazolinone-Triazene Compounds in Pharmaceuticals

[0183] According to the above antimicrobial activity test results, the quinazolinone-triazene compounds synthesized by the present invention have good antibacterial and antifungal activities, and can be made into antibacterial or antifungal drugs for clinical use. The antibacterial or antifungal drugs can be either single-prescription preparations, such as those made from quinazolinone-triazene compounds of one structure and pharmaceutically acceptable excipients; or compound preparations, such as those made from quinazolinone-triazene compounds of one structure and existing antibacterial and antifungal active ingredients (such as norfloxacin, ciprofloxacin, sulfamethoxazole, fluconazole, fosfluconazole, itraconazole, etc.) and pharmaceutically acceptable excipients, or made from several quinazolinone-triazene compounds of different structures and pharmaceutically acceptable excipients. The preparation types include, but are not limited to, tablets, capsules, powders, granules, pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal absorption patches and other dosage forms, as well as various sustained-release, controlled-release preparations and nano preparations.

[0184] 1. Preparation of Tablet I

[0185] Raw materials: 10 g of compound I-1a, 187 g of lactose, 50 g of corn starch, 3.0 g of magnesium stearate, and 70% by volume ethanol solution.

[0186] Preparation process: Dry corn starch at 105°C for 5 hours for use, mix compound I-1a with lactose and corn starch, use 70% ethanol solution to make a soft material, sieve to make wet granules, dry, sieve the whole granules, add magnesium stearate, and press into tablets to obtain Tablet I; each tablet weighs 250 mg and has an active ingredient content of 10 mg.

[0187] 2. Preparation of Tablet II

[0188] Raw materials: compound I-2c 10 g, lactose 80 g, microcrystalline cellulose 5.0 g, magnesium stearate 5.0 g.

[0189] Preparation process: Compound I-2c is mixed evenly with lactose, microcrystalline cellulose and magnesium stearate, and tablets are obtained; each tablet weighs 0.5 g and contains 50 mg of active ingredient.

[0190] 3. Preparation of capsules

[0191] Raw materials: Compound I-2e 10 g, lactose 188 g, magnesium stearate 2.0 g, 70% volume percent ethanol solution.

[0192] Preparation process: Compound I-2e, lactose and magnesium stearate are mixed evenly, sieved, and filled into empty capsules to obtain; each capsule has a content weight of 200 mg and an active ingredient content of 10 mg.

[0193] 4. Preparation of granules

[0194] Raw materials: compound I-3b 126 g, dextrin 120 g, sucrose 280 g.

[0195] Preparation process: Compound I-3b, dextrin and sucrose are mixed evenly, granulated by wet method, dried at 60°C, and packaged to obtain the product.

[0196] 5. Preparation of injection

[0197] Raw materials: 10g of compound I-3d, 500mL of propylene glycol, 500mL of water for injection, a total of 1000mL. Preparation process: Weigh compound I-3d, add propylene glycol and water for injection, stir to dissolve, then add 1g of activated carbon, stir well and let stand for 15 minutes, filter with a 5μm titanium rod to remove carbon, and then finely filter with microporous filter membranes with pore sizes of 0.45μm and 0.22μm in turn, finally fill in a 10mL ampoule, and sterilize with circulating steam at 100℃ for 45 minutes to obtain.

[0198] 6. Preparation of powder injection

[0199] Preparation process: The sterile powder of compound I-4a is packaged under sterile conditions to obtain the compound I-4a.

[0200] 7. Preparation of eye drops

[0201] Raw materials: 3.78 g of compound I-4a, 0.9 g of sodium chloride, 3 g of phenylethanol, boric acid buffer solution, and distilled water.

[0202] Preparation process: Add compound I-4a and sodium chloride to 600 mL of distilled water, adjust the pH to 6.5 with boric acid buffer solution after complete dissolution, add phenylethanol, and then add distilled water to 1000 mL, stir evenly, filter with a microporous filter membrane, fill, seal, and sterilize with circulating steam at 100°C for 1 hour to obtain the product.

[0203] 8. Preparation of liniment

[0204] Raw materials: compound I-4c 4g, potassium soap 7.5g, camphor 5g, distilled water.

[0205] Preparation process: Dissolve camphor in 95% ethanol solution by volume and set aside; heat potassium soap to liquefy and set aside; weigh compound I-4c, add potassium soap solution and camphor ethanol solution under constant stirring, and then gradually add distilled water. After complete emulsification, add distilled water to 100 mL to obtain the compound.

[0206] 9. Preparation of suppositories

[0207] Raw materials: compound I-5b 4 g, gelatin 14 g, glycerol 70 g, distilled water.

[0208] Preparation process: Weigh gelatin and glycerin, add distilled water to 100 mL, heat in a water bath at 60°C to melt, add compound I-5b when it becomes a paste, stir evenly, pour into a vaginal suppository mold when it is almost solidified, cool and solidify to obtain.

[0209] 10. Preparation of ointment

[0210] Raw materials: compound I-5e 0.5-2g, hexadecanol 6-8g, white vaseline 8-10g, liquid paraffin 8-19g, monoglyceride 2-5g, polyoxyethylene (40) stearate 2-5g, glycerol 5-10g, ethylparaben 0.1g, and distilled water added to 100g.

[0211] Preparation process: Heat hexadecanol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate until completely melted and mix well, keep warm at 80°C and set aside as the oil phase; add ethyl paraben to glycerol and distilled water, heat to 85°C to dissolve, then add the oil phase under constant stirring, add compound I-5e after emulsification, stir and cool to obtain.

[0212] Quinazolinone-triazene compounds as DNA intercalators

[0213] The quinazolinone-triazene compound synthesized by the present invention can be effectively embedded in calf thymus DNA. The embedding effect is detected by ultraviolet absorption spectrum. Figure 1 .

[0214] Quinazolinone-triazene compounds as fungicides

[0215] The quinazolinone-triazene compounds synthesized by the present invention can kill bacteria quickly and effectively. Figure 2 .

[0216] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and do not constitute a limitation on the content of the present invention. Although the present invention has been exemplified in detail through the above embodiments, those skilled in the art can still make various changes in form and details according to the technical contents described in the Summary of the Invention and the Examples, without departing from the spirit and scope of the present invention as defined in the attached claims.

Claims

1. A quinazolinone-triazene compound, characterized in that: The general structural formula of the quinazolinone-triazene compound is as follows: Wherein, R1 and R2 are one of H, halogen, nitro, amino, hydroxyl, thiol, sulfonyl, carbonyl, aryl, alkoxy, alkyl or CF3, and the R3-N-R4 is one of NH-containing aromatic compound, NH-containing aliphatic chain or NH-containing aliphatic ring.

2. The quinazolinone-triazene compound according to claim 1, characterized in that The R1 and R2 are one of H, halogen, alkoxy, alkyl or CF3, and the R3-N-R4 is one of NH-containing aliphatic chain or NH-containing aliphatic ring.

3. The quinazolinone-triazene compound according to any one of claims 1 to 2, characterized in that: The R1 and R2 are one of H, halogen or CF3, and the R3-N-R4 is one of dimethylamine, diethylamine, diisopropylamine, morpholine ring or 4-methylpiperidine ring.

4. The quinazolinone-triazene compound according to any one of claims 1 to 3, characterized in that The quinazolinone-triazene compound is any one of the following compounds:

5. The quinazolinone-triazene compound according to any one of claims 1 to 4, characterized in that The preparation method of the quinazolinone-triazene compound comprises the following steps: a. Preparation of intermediate II: Using R1 and R2 substituted anthranilic acid as the starting material, condensation with acetic acid formamidine in an organic solvent to obtain compound II, i.e., quinazolinone mother ring, whose structural formula is: R1 and R2 are one of H, halogen, nitro, amino, hydroxyl, thiol, sulfonyl, carbonyl, aryl, alkoxy, alkyl or CF3; b. Preparation of intermediate III: Using quinazolinone as the starting material, reacting with 4-nitrobenzyl bromide in an organic solvent to obtain intermediate III, i.e., compound 3-(4-nitrobenzyl)quinazolinone, the structural formula of which is: c. Preparation of intermediate IV: 3-(4-nitrobenzyl)quinazolinone is used as a starting material, and reacted with sodium dithionite and sodium carbonate in a solvent to obtain intermediate IV, i.e., compound 3-(4-aminobenzyl)quinazolinone, whose structural formula is: d. Preparation of quinazolinone-triazene compounds: 3-(4-aminobenzyl)quinazolinone is used as a starting material, and sodium nitrite is reacted in concentrated hydrochloric acid to generate the hydrochloride of compound V, which is then dropped into an aqueous solution containing an NH compound and sodium carbonate to obtain a quinazolinone-triazene compound. The structural formula of compound V is: The NH-containing compound is any one of dimethylamine, diethylamine, diisopropylamine, morpholine ring or 4-methylpiperidine ring.

6. Use of the quinazolinone-triazene compound according to claim 1 in the preparation of antibacterial or antifungal drugs.

7. The use according to claim 6, characterized in that: The bacteria are any one or more of Staphylococcus aureus standard bacteria 25923 and 29213, Pseudomonas aeruginosa standard bacteria 27853, Escherichia coli standard bacteria 25922, Enterococcus faecalis and Acinetobacter baumannii; the fungi are any one or more of Candida albicans standard bacteria 90023, Candida parapsilosis standard bacteria 22019, Candida tropicalis and Aspergillus fumigatus.

8. Use of the quinazolinone-triazene compound according to claim 1 as a DNA intercalator.

9. Use of the quinazolinone-triazene compound according to claim 1 as an effective fungicide.

10. Use of the Schiff base imidazobenzothiazole compound and its pharmaceutically acceptable salt according to claim 1 as an effective anti-tumor drug.

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