Quinazolone enone azole compounds, their preparation methods and applications

Abstract

The present invention relates to a quinazolone enoneazole compound, its preparation method and application. As shown in general formula I, this kind of compound has certain inhibitory activity against one or more of Gram-positive bacteria and Gram-negative bacteria, can be used for preparing antibacterial drugs, and has no obvious drug resistance. Moreover, the preparation raw materials are simple, cheap and easily available, which has important significance for the application in the aspect of anti-infection.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, relates to quinazolinone enone azole compounds, and also relates to a preparation method and application of the compounds. Background Art

[0002] Pathogen infections threaten human health, and antibiotics have always been the main treatment for pathogenic microbial infections. However, over the past few decades, excessive and inappropriate exposure to antibiotics has led to the offset of bacterial antibiotic pressure and the development of drug resistance, making the effectiveness of clinical drugs increasingly limited. A global survey showed that 4.95 million people died from diseases caused by bacterial antimicrobial resistance (AMR) in 2019, which means that the number of deaths caused by drug resistance exceeded that of HIV / AIDS or malaria. In addition, a large amount of literature shows that current drugs with a single target are easily inactivated against multidrug-resistant pathogens due to target failure caused by bacterial gene mutations. There is no doubt that there is an urgent need to identify new antibacterial drugs with novel structures and multiple targets to deal with infections from multidrug-resistant bacteria.

[0003] Quinazolinone alkaloids, as the core structure of traditional Chinese medicine ingredients such as febrifugine, evodiamine and tryptamine, have great potential for biological activity. Quinazolinone has a unique structural feature of the benzopyrimidinone skeleton and is considered to be an important new antimicrobial chemical structural framework. The synthesis, structural modification and biomedical potential of its derivatives have naturally attracted great attention. In particular, quinazolinone has a structure similar to the widely used clinical antibacterial drug quinolone and has been widely studied in the antimicrobial field. The combination of quinazolinone and many azoles such as thiazole, oxadiazole, pyrazole and imidazole shows excellent antibacterial activity. Therefore, the combination of quinazolinone and azole compounds has infinite potential in the antibacterial field.

[0004] As nitrogen-containing heterocyclic compounds with electron-rich aromatic structures, azole compounds have received extensive attention in drug design and development, and have been widely used in agrochemicals, medicine and other fields. The unique structure of azole compounds makes it easy for them to bind to multiple targets in organisms through a variety of weak interactions such as hydrogen bonds, coordination, ion dipole, hydrophobic interaction, van der Waals force, etc., and show significant biological activity.

[0005] As an important class of structures, ethylene ketones have the excellent characteristics of easy synthesis and multiple modification sites. In addition, ethylene ketones can not only act as bridging groups to promote the increase of conjugated systems, thereby inserting DNA to prevent bacterial DNA replication, but also regulate biological activity by attaching different aromatic rings on both sides of ethylene ketones. Therefore, ethylene ketone fragments with this unique polar functional group are widely used as a framework for drug design. A large number of literature studies have shown that ethylene ketones in some conjugates play an important role in the activity of the molecule, and the biological activity will disappear if the ethylene ketone group is removed. .

[0006] Based on our work in the field of quinazolinone and azole antimicrobial drugs, we inserted ethylene ketone between quinazolinone and azole to construct quinazolinone enone azole structural compounds, hoping to develop new antibacterial molecules to solve the increasingly serious global problem of drug resistance. Summary of the invention

[0007] In view of this, one of the purposes of the present invention is to provide a quinazolinone ketone azole compound and a pharmaceutically acceptable salt thereof; the second purpose of the present invention is to provide a method for preparing a quinazolinone ketone azole compound and a pharmaceutically acceptable salt thereof; the third purpose of the present invention is to provide the use of the quinazolinone ketone azole compound and a pharmaceutically acceptable salt thereof in the preparation of antibacterial drugs. The fourth purpose of the present invention is to provide the quinazolinone ketone azole compound and a pharmaceutically acceptable salt thereof and a preparation of the pharmaceutically acceptable salt thereof. Thereby, more efficient and safe candidate drugs are provided for clinical antimicrobial treatment, which helps to solve the increasingly serious clinical treatment problems such as drug resistance, stubborn pathogenic microorganisms and newly emerging harmful microorganisms.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] 1. Quinazolinone ketone azole compounds and pharmaceutically acceptable salts thereof, the structure of which is shown in the general formula I:

[0010]

[0011] In the formula,

[0012] It is an imidazole ring and a substituted imidazole ring, a thiazole ring and a substituted thiazole ring, an indole ring and a substituted indole ring, a benzimidazole ring and a substituted benzimidazole ring, a benzofuran ring or a benzothiophene ring.

[0013] X, Y, Z, W are C, CH, NH, N, O or S atoms;

[0014] Preferably, it is any one of the following compounds:

[0015]

[0016]

[0017]

[0018] 2. A method for preparing a quinazolinone enone azole compound, the method being as follows:

[0019] a. Preparation of intermediate II1-6: Using anthranilic acid or anthranilamide compound and pyruvic acid as starting materials, intermediate II1-6 is obtained by cyclization reaction;

[0020]

[0021] b. Preparation of intermediate III: Different types of halogenated compounds react with 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde to obtain intermediate III;

[0022]

[0023] in:

[0024] R 1 is hydrogen, alkyl, cyano, alkoxy, alkenyl, alkynyl, aryl, hydroxyalkyl, carboxyl, ester, acyl or heterocyclic; and n is an integer of 0-15.

[0025] c. Preparation of quinazolinone enone azole compounds of general formula I-1 to 13: Intermediates II 1 to 6 undergo condensation reaction with aldehydes under the action of a base to obtain quinazolinone enone azole compounds of general formula I-1 to 13.

[0026] d. Preparation of quinazolinone enone azole compounds of general formula I-14-40: Intermediates II 1-6 undergo condensation reaction with intermediates III under the action of a base to obtain quinazolinone enone azole compounds of general formula I14-40.

[0027] Preferably,

[0028] In step a, the molar ratio of o-aminobenzamide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1-hydroxybenzotriazole monohydrate is 1:1.2-2:1.2-2. After reacting at room temperature for 6-8 hours, the obtained solid is reacted in a 0.5M sodium hydroxide aqueous solution for 30 minutes to obtain intermediate II-1;

[0029] In step b, the molar ratio of the intermediate II 1-6 to the aldehyde is 1:1.2; the base is piperidine; the condensation reaction is specifically carried out using ethanol as a solvent at 80-100° C. for 5 hours;

[0030] In step c, the molar ratio of the intermediate II 1-6 to the intermediate III is 1:1.2; the base is or sodium hydroxide aqueous solution; the condensation reaction is specifically carried out using ethanol as solvent at room temperature or 80-100° C. for 5-8 hours;

[0031] In step d, the molar ratio of the 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde, the halogenated compound and potassium carbonate is 1:1.5-2:1.5-2, and the reaction is specifically carried out at 80-100° C. for 4-10 hours using acetonitrile as solvent;

[0032] 3. Use of the quinazolinone ketone azole compound and its pharmaceutically acceptable salt in the preparation of antibacterial drugs.

[0033] Preferably, the bacteria are one or more of methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922 or Acinetobacter baumannii.

[0034] 4. A preparation containing the quinazolinone ketone azole compound and its pharmaceutically acceptable salt.

[0035] Preferably, the preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.

[0036] The beneficial effects of the present invention are as follows: the present invention provides quinazolone enone azole compounds and preparation methods and applications thereof. The present invention utilizes the principle of drug design splicing, introduces an enone fragment at the C-2 position of quinazolone to bridge quinazolone and azole compounds, and modifies 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde compounds in different ways, thereby designing and synthesizing a series of novel quinazolone enone azole compounds. These compounds are found to be effective against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, and Enterococcus faecium) through in vitro antimicrobial activity testing. Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) have certain inhibitory activity and can be used to prepare antibacterial drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial treatment, 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 ketone azole compounds of the present invention can also be used to prepare the active site trigger of PBP2a. DETAILED DESCRIPTION

[0037] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0038] Example 1, preparation of intermediate II:

[0039]

[0040] The preparation was carried out according to the method described in reference “Rasapalli, S.; Murphy, ZF; Sammeta, VR; Golen, JA; Weig, AW; Melander, RJ; Melander, C.; Macha, P.; Vasudev, M C Synthesis and biofilm inhibition studies of 2-(2-amino-6-arylpyrimidin-4-yl)quinazolin-4(3H)-ones. Bioorg. Med. Chem. Lett. 2020, 30, 127550.”

[0041] Example 2, Preparation of Intermediate III:

[0042]

[0043] 2-Butyl-5-chloro-1H-imidazole-4-carboxaldehyde (7 mmol), potassium carbonate (14 mmol), halogenated compound (11 mmol) and acetonitrile (20 mL) were added to a 100 mL round-bottom flask and stirred at 80° C. for 4-10 hours. The mixture was filtered and the solvent was distilled off under reduced pressure to obtain a crude product which was purified by silica gel column chromatography to obtain compound III.

[0044] Example 3, Preparation of Compound I-1:

[0045]

[0046] Add intermediate II-1 (26 mg, 0.27 mmol) to a 25 mL round-bottom flask, sodium hydroxide aqueous solution (30%, 0.2 mL) as a catalyst, ethanol (10 mL) as a solvent, stir at room temperature for 15 minutes, add compound 1H-imidazole-2-carboxaldehyde (26 mg, 0.27 mmol), continue to reflux at room temperature for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-1 (48 mg) was obtained with a yield of 68.6%. Yellow powder; melting point: 167–169°C; 1 H NMR (600 MHz, DMSO-d 6)δ12.51(s,1H,imidazole-NH),8.57(d,J=16.2Hz,1H,CH=CH-imidazole),8.23(d,J=7.8Hz,1H,quinazolone-5-H),7.96(t,J=7.5Hz,1H,quinazolinone-7-H),7.92(d, J=8.0Hz,1H,quinazolinone-8-H),7.80(m,3H,CH=CH-imidazole,imidazole-4-H,imidazole-5-H),7.71(t,J=7.4Hz,1H,quinazolinone-6-H)ppm.HRMS(ESI)calcd.for C 14 H 10 N 4 O 2 [M+H] + ,267.0877;found,267.0877.

[0047] Example 4, Preparation of Compound I-2:

[0048]

[0049] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at room temperature for 15 minutes, add compound 1H-imidazole-4-carboxaldehyde (26mg, 0.27mmol), continue to reflux at room temperature for 8 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-2 (45mg) was obtained with a yield of 63.6%. Yellow powder; melting point: 245-247℃; 1 H NMR (600 MHz, DMSO-d 6)δ12.24(s,1H,quinazolinone-NH),8.22(d,J=8.0Hz,1H,quinazolone-5-H),8.01(d,J=15.6Hz,1H,CH=CH-imidazole),7.95–7.91(m,3H,quinazolinone-7-H,quinazol inone-8-H, imidazole-2-H),7.86(d,J=15.6Hz,1H,CH=CH-imidazole),7.79(s,1H,imidazole-5-H),7.68(t,J=7.8Hz,1H,quinazolinone-6-H)ppm.HRMS(ESI)calcd.for C 14 H 10 N 4 O 2 [M+H] + ,267.0877;found,267.0878.

[0050] Example 5, Preparation of Compound I-3:

[0051]

[0052] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), piperidine (0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound 5-thiazolecarboxaldehyde (30mg, 0.27mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-3 (44mg) was obtained with a yield of 58.7%. Yellow powder; melting point: 187-189°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.41(s,1H,quinazolone-NH),9.33(s,1H,thiazole-2-H),8.49(s,1H,thiazole-4-H),8.27–8.15(m,2H,quinazolone-5-H,CH=CH-thiazole),7.94(m ,2H,quinazolinone-7-H,quinazolinone-8-H),7.82(d,J=15.8Hz,1H,CH=CH-thiazole),7.69(t,J=7.1Hz,1H,quinazolinone-6-H).HRMS(ESI)calcd.for C 14 H9 N 2 O 2 S[M+H] + ,248.0488;found,248.0494.

[0053] Example 6, Preparation of Compound I-4:

[0054]

[0055] Add intermediate II-1 (50 mg, 0.27 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80°C for 15 minutes, add compound 2-thiazolecarboxaldehyde (64 mg, 0.27 mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography until the end of the reaction. After column chromatography separation and drying, compound I-4 (38 mg) was obtained with a yield of 50.9%. Yellow powder; melting point: >300°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.46(s,1H,quinazolone-NH),8.30(d,J=15.9Hz,1H,CH=CH-thiazole),8.22(d,J=7 .8Hz,1H,quinazolone-5-H),8.13(d,1H,J=2.9Hz,thiazole-4-H),8.07(d,1H,J=3.0Hz, thiazole-5-H),8.01(d,J=15.9Hz,1H,CH=CH-thiazole),8.00–7.92(m,2H,quinazolone-7-H,quinazolone-8-H),7.69(t,1H,J=7.1Hz,quinazolone-6-H).HRMS(ESI)calcd.for C 14 H 9 N 2 O 2 S[M+H] + ,248.0488;found,248.0488.

[0056] Example 7, Preparation of Compound I-5:

[0057]

[0058] In a 25mL round-bottom flask, add intermediate II-2 (50mg, 0.24mmol), piperidine (0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound 2-thiazolecarboxaldehyde (27mg, 0.24mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-5 (34mg) was obtained with a yield of 46.7%. Yellow powder; melting point: 213-215°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.58(s,1H,quinazolone-NH),8.27(d,J=10.1Hz,1H,thiazole-4-H),8.25(d,J=11.1Hz,1H,quinazolone-5-H),8.13(d,J=3.0Hz,1H,CH=CH-thiazole),8.08(d,J=3. 0Hz,1H,CH=CH-thiazole),8.00(d,J=15.9Hz,1H,quinazolone-8-H),7.79(d,J=7.6Hz,1H,,thiazole-5-H),7.54(t,J=7.5Hz,1H,,thiazole-6-H).HRMS(ESI)calcd.for C 14 H 8 FN 3 O 2 S[M+H] + ,302.0394;found,302.0393.

[0059] Example 8, Preparation of Compound I-6:

[0060]

[0061] In a 25mL round-bottom flask, add intermediate II-3 (50mg, 0.22mmol), piperidine (0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound 2-thiazolecarboxaldehyde (26mg, 0.22mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-6 (26mg) was obtained with a yield of 36.4%. Yellow powder; melting point: 205-207°C; 1 H NMR (600 MHz, DMSO-d 6)δ12.64(s,1H,quinazolone-NH),8.24(d,J=15.9Hz,1H,thiazole-4-H),8.20(d,J=8.5Hz,1H,quinazolone-5-H),8.13(s,1H,CH=CH-thiazole),8.08(s ,1H,CH=CH-thiazole),8.06(s,1H,quinazolone-8-H),8.00(d,J=15.9Hz,1H,thiazole-5-H),7.71(d,J=8.5Hz,1H,thiazole-6-H).HRMS(ESI)calcd.for C 14 H 8 C1N 3 O 2 S[M+H] + ,318.0099;found,318.0097.

[0062] Example 9, Preparation of Compound I-7:

[0063]

[0064] In a 25mL round-bottom flask, add intermediate II-4 (50mg, 0.20mmol), piperidine (0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound 2-thiazolecarboxaldehyde (22mg, 0.20mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-7 (33mg) was obtained with a yield of 47.4%. Yellow powder; melting point: 273-275°C; 1 H NMR (600 MHz, DMSO-d 6 )δ8.22(d,J=15.9Hz,1H,thiazole-4-H),8.05(s,1H,quinazolone-7-H),7.96(s,1H,quinazolone-5-H),7.92(s, 1H,CH=CH-thiazole),7.81(s,1H,CH=CH-thiazole),7.76(d,J=16.1Hz,1H,thiazole-5-H).HRMS(ESI)calcd.for C 14 H 7 Cl 2 N 3 O 2 S[M+H] + ,351.9709;found,351.9692.

[0065] Example 10, Preparation of Compound I-8:

[0066]

[0067] Add intermediate II-5 (50 mg, 0.25 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80°C for 15 minutes, add compound 2-thiazolecarboxaldehyde (22 mg, 0.25 mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-8 (58 mg), with a yield of 39.4%. Yellow powder; melting point: 280-282°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.12(s,1H,quinazolone-NH),8.35(d,J=15.9Hz,1H,CH=CH-thiazole),8.21(s,1H,quinazolone-5-H),8.13(d,J=3.1Hz,1H,thiazole-4-H),8.06(d,J=3.0Hz,1H,t hiazole-5-H),8.01(d,J=15.9Hz,1H,CH=CH-thiazole),7.88(d,J=7.8Hz,1H,quinazolone-7-H),7.80(d,J=7.3Hz,1H,quinazolone-8-H),2.44(s,3H,quinazolone-CH) 3 ).HRMS(ESI)calcd.for C 15 H 11 N 3 O 2 S[M+H] + ,298.0645;found,298.0644.

[0068] Example 11, Preparation of Compound I-9:

[0069]

[0070] Add intermediate II-6 (50 mg, 0.25 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80°C for 15 minutes, add compound 2-thiazolecarboxaldehyde (22 mg, 0.25 mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-9 (50 mg), with a yield of 34.0%. Yellow powder; melting point: 207-209°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.36(s,1H,quinazolone-NH),8.29(d,J=15.9Hz,1H,CH=CH-thiazole),8.12(d,J=2.9Hz,1H,thiazole-4-H),8.06(d,J=2.8Hz,1H,thiazole-5-H),7.98(d,J=15.9Hz, 1H,CH=CH-thiazole),7.85(d,J=8.2Hz,1H,quinazolone-5-H),7.75(d,J=8.3Hz,1H,quinazolone-7-H),7.73–7.67(m,1H,quinazolone-6-H),2.45(s,3H,quinazolone-CH) 3 ).HRMS(ESI)calcd.for C 15 H 11 N 3 O 2 S[M+H] + ,298.0645;found,298.0646.

[0071] Example 12, Preparation of Compound I-10:

[0072]

[0073] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), piperidine (0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80℃ for 15 minutes, add compound 1H-benzo[d]imidazole-2-carboxaldehyde (39mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-10 (43mg) was obtained with a yield of 51.2%. Yellow powder; melting point: 218-220℃; 1 H NMR (600 MHz, DMSO-d 6)δ12.59(s,1H,benzimidazole-NH),8.84(d,J=16.3Hz,1H,CH=CH-benzimidazole),8.24(d,J=7.7Hz,1H, quinazolone-5-H),7.98(m,2H,quinazolinone-8-H,quinazolinone-7-H),7.91(d,J=16.3Hz,1H,CH=CH-b enzimidazole),7.85(m,2H,benzimidazole-4-H,benzimidazole-7-H),7.72(t,J=6.6Hz,1H,quinazolin one-6-H),7.55(dd,J=6.1,3.0Hz,2H,benzimidazole-5-H,benzimidazole-6-H)ppm.HRMS(ESI)calcd.for C 18 H 12 N 4 O 2 [M+H] + ,317.1033;found,317.1032.

[0074] Example 13, Preparation of Compound I-11:

[0075]

[0076] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), piperidine (0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound benzothiophene-3-carboxaldehyde (43mg, 0.27mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-11 (54mg) was obtained with a yield of 61.2%. Yellow powder; melting point: 196-198°C; 1 H NMR (600 MHz, DMSO-d 6)δ12.42(s,1H,quinazolone-NH),8.71(s,1H,benzothiophene-2-H),8.23(m,4H,CH=CH-benzothiophene,quinazolone-5-H,CH=CH-benzothiophene,benzothiophene-4-H),8.13(d,J=8.0Hz,1H,benzothio phene-7-H),7.95(m,2H,quinazolone-7-H,quinazolone-8-H),7.69(m,1H,quinazolone-6-H),7.59(t ,J=7.5Hz,1H,benzothiophene-6-H),7.52(t,J=7.5Hz,1H,benzothiophene-5-H).HRMS(ESI)calcd.for C 19 H 12 N 2 O 2 S[M+H] + ,333.0692;found,333.0693.

[0077] Example 14, Preparation of Compound I-12:

[0078]

[0079] Add intermediate II-1 (50 mg, 0.27 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80°C for 15 minutes, add compound benzofuran-3-carboxaldehyde (37 mg, 0.27 mmol), continue reflux reaction at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-12 (32 mg), with a yield of 38.1%. Yellow powder; melting point: 205-207°C; 1 H NMR (600 MHz, DMSO-d 6)δ12.42(s,1H,quinazolone-NH),8.78(s,1H,benzofuran-2-H),8.26–8.18(m,2H,CH=CH-benzofuran,qui nazolone-5-H),8.13–8.07(m,2H,CH=CH-benzofuran,benzofuran-4-H),8.00(d,J=8.0Hz,1H,benzofuran- 7-H),7.96(t,J=7.4Hz,1H,quinazolone-7-H),7.76(d,J=7.7Hz,1H,quinazolone-8-H),7.70(t,J=7.4Hz,1 H,quinazolone-6-H),7.54-7.49(m,2H,benzothiophene-6-H,benzothiophene-5-H).HRMS(ESI)calcd.for C 19 H 12 N 2 O 3 [M+Na] + ,339.0740;found,339.0744.

[0080] Example 15, Preparation of Compound I-13:

[0081]

[0082] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), piperidine (0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound 1H-indole-3-carboxaldehyde (39mg, 0.27mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-13 (26mg) was obtained with a yield of 31.0%. Yellow powder; melting point: 234-236°C; 1 H NMR (600 MHz, DMSO-d 6)δ12.16(s,2H,indole-NH,quinazolone-NH),8.28–8.21(m,3H,quinazolone-5-H,CH=CH-indole,indole-2-H),8.05–8.00(m,2H,quinazolone-7-H,CH=CH-indole),7.98(d, J=8.0Hz,1H,indole-4-H),7.94(m,1H,quinazolone-8-H),7.67(t,J=7.4Hz,1H,quinazolone-6-H),7.55(d,J=7.8Hz,1H,indole-7-H),7.32(m,2H,indole-5-H,indole-6-H). 1 HRMS(ESI)calcd.for C 19 H 13 N 3 O 2 [M+H] + ,316.1081;found,316.1074.

[0083] Example 16, Preparation of Compound I-14:

[0084]

[0085] Add intermediate II-1 (50 mg, 0.27 mmol) and piperidine (0.2 mL) as catalyst and ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80 ° C for 15 minutes, add compound 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde (30 mg, 0.32 mmol), continue to reflux at 80 ° C for 10 hours, and monitor and track the reaction by thin layer chromatography until the end of the reaction. After column chromatography separation and drying, compound I-14 (101 mg) was obtained with a yield of 53.4%. Yellow powder; melting point: 123-125 ° C; 1 H NMR (600 MHz, DMSO-d 6)δ13.13(s,1H,imidazole-NH),12.28(s,1H,quinazolone-NH),8.22(d,J=7.6Hz,1H,quinazolone-5-H),7.93(d,J=8.1Hz,1H,quinazolone-7-H),7.89–7.8 5(m,2H,CH=CH-imidazole,quinazolinone-8-H),7.68(t,J=7.3Hz,1H,quinazolone-6-H),7.62(d,J=15.9Hz,1H,CH=CH-imidazole),2.69[t,J=7.5Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.68(p,J=7.5Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.34[q,J=7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],0.92[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 18 H 17 C1N 4 O 2 [M+H] + ,357.1113;found,357.1112.

[0086] Example 17, Preparation of Compound I-15:

[0087]

[0088] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as catalyst, ethanol (10mL) as solvent, stir at 80℃ for 15 minutes, add compound III-1 (57mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-15 (38mg), with a yield of 37.2%. Yellow powder; melting point: 194-196℃; 11H NMR (600 MHz, DMSO-d 6 ) δ 12.33 (s, 1H, quinazolinone-NH), 8.21 (d, J = 7.8 Hz, 1H, quinazolinone-5-H), 8.16 (d, J = 16.1 Hz, 1H, CH=CH-imidazole), 7.92 (t, J = 7.5 Hz, 1H, quinazolinone-7-H), 7.88 (d, J = 7.7 Hz, 1H, quinazolinone-8-H), 7.73 (d, J = 16.1 Hz, 1H, CH=CH-imidazole), 7.67 (t, J = 7.4 Hz, 1H, quinazolinone-6-H), 4.22–4.17 (m, 2H, CH 2 CH 3 ), 2.74 [t, J = 7.6 Hz, 2H, CH 2 (CH 2 ) 2 CH 3 , 1.67 (p, J = 7.6 Hz, 2H, CH 2 CH 2 CH 2 CH 3 ), 1.38 [q, J = 7.4 Hz, 2H, (CH 2 ) 2 CH 2 CH 3 , 1.30 (t, J = 7.2 Hz, 3H, CH 2 CH 3 ), 0.93 [t, J = 7.4 Hz, 3H, (CH 2 ) 3 CH 3 ppm. HRMS (ESI) calcd. for C 20 H 21 ClN 4 O 2 [M + H] + , 385.1426; found, 385.1426.

[0089] Example 18. Preparation of Compound I-16:

[0090]

[0091] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as catalyst, ethanol (10mL) as solvent, stir at 80℃ for 15 minutes, add compound III-2 (60mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-16 (93mg), with a yield of 87.7%. Yellow powder; melting point: 216-218℃; 1 H NMR (600 MHz, DMSO-d 6 )δ12.31(s,1H,quinazolone-NH),8.21(d,J=7.7Hz,1H,quinazolone-5-H),8.10(d,J=16.2Hz,1H,CH=CH-imidazole),7.93(t,J=7.2Hz,1H,quinazolinone-7 -H),7.85(d,J=8.0Hz,1H,quinazolinone-8-H),7.73(d,J=16.2Hz,1H,CH=CH-imidazole),7.68(t,J=7.4Hz,1H,quinazolinone-6-H),4.12(t,J=7.4Hz,2H,CH 2 CH 2 CH 3 ),2.74[t,J=7.5Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.69(m,4H,CH 2 CH 2 CH 2 CH 3 ,CH 2 CH 2 CH 3 ),1.38[m,2H,(CH 2 ) 2 CH 2 CH 3 ],0.97t,J=7.3Hz,3H,CH 2 CH 2 CH 3 ),0.92[t,J=7.3Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 21 H 23 C1N4 O 2 [M+Na] + ,399.1582;found,399.1580.

[0092] Example 19, Preparation of Compound I-17:

[0093]

[0094] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as catalyst, ethanol (10mL) as solvent, stir at 80℃ for 15 minutes, add compound III-3 (64mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-17 (88mg), with a yield of 80.2%. Yellow powder; melting point: 171-173℃; 1 H NMR (600 MHz, DMSO-d 6 )δ12.32(s,1H,quinazolone-NH),8.21(d,J=7.8Hz,1H,quinazolone-5-H),8.10(d,J=16.2Hz,1H,CH=CH-imidazole),7.93(t,J=7.6Hz,1H,quinazolinone-7- H),7.84(d,J=8.0Hz,1H,quinazolinone-8-H),7.72(d,J=16.2Hz,1H,CH=CH-imidazole),7.68(t,J=7.5Hz,1H,quinazolinone-6-H),4.14[t,J=7.6Hz,2H.N-CH 2 (CH 2 ) 2 CH 3 ],2.73[t,J=7.6Hz,2H,imidazole-2-CH 2 (CH 2 ) 2 CH 3 ],1.67(q,J=7.6Hz,4H,imidazole-2-CH 2 CH 2 CH 2 CH 3 ,N-CH 2 CH 2 CH 2 CH 3),1.44–1.36[m,4H,imidazole-2-(CH 2 ) 2 CH 2 CH 3 ,N-(CH 2 ) 2 CH 2 CH 3 ],0.96[t,J=7.3Hz,3H,imidazole-2-(CH 2 ) 3 CH 3 ],0.93[t,J=7.3Hz,3H,N-(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 22 H 25 C1N 4 O 2 [M+H] + ,435.1558;found,435.1557.

[0095] Example 20, Preparation of Compound I-18:

[0096]

[0097] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound III-4 (68mg, 0.27mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-18 (82mg) was obtained with a yield of 72.3%. Yellow powder; melting point: 178-180°C; 1 H NMR (600 MHz, DMSO-d 6)δ12.27(s,1H,quinazolone-NH),8.21(d,J=7.7Hz,1H,quinazolone-5-H),8.09(d,J=16.2Hz,1H,CH=CH-imidazole),7.92(t,J=7.3Hz,1H,quinazolinone-7-H),7.84(d,J=8.0Hz,1H,quinazolinone-8-H),7.72(d,J=16.2Hz,1H,CH=CH-imidazole),7.67(t,J=7.4Hz,1H,quinazolinone-6-H),4.13[t,J=7.6Hz,2H,CH 2 (CH 2 ) 3 CH 3 ],2.73[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.67[m,4H,CH 2 CH 2 CH 2 CH 3 ,CH 2 CH 2 (CH 2 ) 2 CH 3 ],1.38[m,6H,(CH 2 ) 2 CH 2 CH 3 ,(CH 2 ) 2 CH 2 CH 2 CH 3 ,(CH 2 ) 3 CH 2 CH 3 ],0.92[t,J=7.3Hz,3H,(CH 2 ) 3 CH 3 ],0.88[t,J=6.6Hz,3H,(CH 2 ) 4 CH 3 ]ppm.HRMS(ESI)calcd.for C 23 H 27 ClN 4 O 2 [M+H] +,427.1895;found,427.1895.

[0098] Example 21, Preparation of Compound I-19:

[0099]

[0100] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as catalyst, ethanol (10mL) as solvent, stir at 80℃ for 15 minutes, add compound III-5 (72mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-19 (99mg), with a yield of 84.5%. Yellow powder; melting point: 175-177℃; 1 H NMR (600 MHz, DMSO-d 6 )δ12.32(s,1H,quinazolone-NH),8.21(d,J=7.8Hz,1H,quinazolone-5-H),8.09(d,J=16.2Hz,1H,CH=CH-imidazole),7.92(t,J=7.4Hz,1H,quinazolinone-7 -H),7.84(d,J=8.0Hz,1H,quinazolinone-8-H),7.72(d,J=16.2Hz,1H,CH=CH-imidazole),7.68(t,J=7.4Hz,1H,quinazolinone-6-H),4.14[t,J=7.5Hz,2H,CH 2 (CH 2 ) 4 CH 3 ],2.73[t,J=7.5Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.67[m,4H,CH 2 CH 2 CH 2 CH 3 ,CH 2 CH 2 (CH 2 ) 3 CH 3 ],1.38[m,4H,(CH 2 ) 2 CH 2 CH 3 ,(CH2 ) 2 CH 2 CH 3 ],1.30[m,4H,(CH 2 ) 3 CH 2 CH 2 CH 3 ,(CH 2 ) 4 CH 2 CH 3 ],0.92[t,J=7.3Hz,3H,(CH 2 ) 3 CH 3 ],0.85[t,J=6.7Hz,3H,(CH 2 ) 5 CH 3 ]ppm.HRMS(ESI)calcd.forC 24 H 29 C1N 4 O 2 [M+H] + ,447.2052;found,447.2051.

[0101] Example 22, Preparation of Compound I-20:

[0102]

[0103] In a 25mL round-bottom flask, add intermediate II-11 (50mg, 0.27mmoll), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add III-6 (80mg, 0.27mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-20 (80mg) was obtained with a yield of 64.2%. Yellow powder; melting point: 159-161°C; 1 H NMR (600 MHz, DMSO-d 6)δ12.25(s,1H,quinazolone-NH),8.21(d,J=7.6Hz,1H,quinazolone-5-H),8.07(d,J=16.2Hz,1H,CH=CH-imidazole),7.91(t,J=7.2Hz,1H,quinazolinone-7-H),7.83(d,J=7.9Hz,1H,quinazolinone-8-H),7.72(d,J=16.2Hz,1H,CH=CH-imidazole),7.67(t,J=7.2Hz,1H,quinazolinone-6-H),4.13[t,J=7.3Hz,2H,CH 2 (CH 2 ) 6 CH 3 ],2.72[t,J=7.5Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.71–1.62[m,4H,CH 2 CH 2 CH 2 CH 3 ,CH 2 CH 2 (CH 2 ) 5 CH 3 ],1.41–1.34[m,4H,(CH 2 ) 2 CH 2 CH 3 ,(CH 2 ) 2 CH 2 (CH 2 ) 4 CH 3 ],1.30[q,J=7.2Hz,2H,(CH 2 ) 3 CH 2 (CH 2 ) 3 CH 3 ],1.27–1.18[m,6H,(CH 2 ) 4 CH 2 (CH 2 ) 2 CH 3 ,(CH 2 ) 6 CH 2 CH3 ,(CH 2 ) 5 CH 2 CH 2 CH 3 ],0.92[t,J=7.3Hz,3H,(CH 2 ) 3 CH 3 ],0.81[t,J=6.4Hz,3H,(CH 2 ) 7 CH 3 ]ppm.HRMS(ESI)calcd.for C 26 H 33 C1N 4 O 2 [M+H] + ,469.2365;found,469.2365.

[0104] Example 23, Preparation of Compound I-21:

[0105]

[0106] Add intermediate II-11 (50 mg, 0.27 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80 ° C for 15 minutes, add compound III-7 (87 mg, 0.27 mmol), continue to reflux at 80 ° C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-21 (98 mg) was obtained with a yield of 71.5%. Yellow powder; melting point: 135-137 ° C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.26(s,1H,quinazolone-NH),8.21(d,J=7.8Hz,1H,quinazolone-5-H),8.07(d,J=16.2Hz,1H,CH=CH-imidazole),7.91(t,J=7.4Hz,1H,quinazolinone-7 -H),7.83(d,J=8.0Hz,1H,quinazolinone-8-H),7.73(d,J=16.2Hz,1H,CH=CH-imidazole),7.67(t,J=7.4Hz,1H,quinazolinone-6-H),4.13[t,J=7.5Hz,2H,CH 2 (CH 2 ) 8 CH3 , 2.72 [t, J = 7.6 Hz, 2H, CH 2 (CH 2 ) 2 CH 3 , 1.67 [m, 4H, CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 (CH 2 ) 7 CH 3 , 1.42–1.34 [m, 4H, (CH 2 ) 2 CH 2 CH 3 , (CH 2 ) 2 CH 2 (CH 2 ) 6 CH 3 , 1.30 [m, 2H, (CH 2 ) 3 CH 2 (CH 2 ) 5 CH 3 , 1.27–1.12 [m, 10H, (CH 2 ) 4 (CH 2 ) 5 CH 3 , 0.92 [t, J = 7.3 Hz, 3H, (CH 2 ) 3 CH 3 , 0.80 [t, J = 6.9 Hz, 3H, (CH 2 ) 9 CH 3 ppm. HRMS (ESI) calcd. for C 28 H 37 ClN 4 O 2 [M + H] + , 497.2678; found, 497.2679.

[0107] Example 24. Preparation of Compound I-22:

[0108]

[0109] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmoll), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound III-8 (61mg, 0.27mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-22 (84mg) was obtained with a yield of 78.9%. Yellow powder; melting point: 205-207°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.33(s,1H,quinazolone-NH),8.21(d,J=7.8Hz,1H,quinazolone-5-H),8.18(d,J=16.1Hz,1H,CH=CH-imidazole),7.93(t,J=7.6Hz,1H,quinazolinone-7- H),7.89(d,J=8.0Hz,1H,quinazolinone-8-H),7.81(d,J=16.1Hz,1H,CH=CH-imidazole),7.68(t,J=7.4Hz,1H,quinazolinone-6-H),4.22(t,J=4.8Hz,2H,N-CH 2 -CH 2 -OH), 3.69–3.62 (m, 2H, N-CH 2 -CH 2 -OH), 2.76[t, J = 7.6 Hz, 2H, CH 2 (CH 2 ) 2 CH 3 ],1.68(p,J=7.6Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.39[m,2H,(CH 2 ) 2 CH 2 CH 3 ],0.92[t,J=7.3Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 20 H 21 C1N 4 O 3 [M+H] +,401.1375;found,401.1375.

[0110] Example 25, Preparation of Compound I-23:

[0111]

[0112] In a 25mL round-bottom flask, add intermediate II-11 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as catalyst, ethanol (10mL) as solvent, stir at 80℃ for 15 minutes, add compound III-9 (73mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-23 (86mg), with a yield of 73.0%. Yellow powder; melting point: 209-211℃; 1 H NMR (600 MHz, DMSO-d 6 )δ12.33(s,1H,quinazolone-NH),8.21(d,J=7.8Hz,1H,quinazolone-5-H),8.13(d,J=16.1Hz,1H,CH=CH-imidazole),7.92(t,J=7.5Hz,1H,quinazolinon e-7-H),7.89(d,J=7.9Hz,1H,quinazolinone-8-H),7.68(d,J=7.7Hz,1H,quinazolinone-6-H),7.64(d,J=16.1Hz,1H,CH=CH-imidazole),5.07(s,2H,N-CH 2 -COOH), 2.70[t, J = 7.6 Hz, 2H, CH 2 (CH 2 ) 2 CH 3 ],1.61(p,J=7.6Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.36[m,2H,(CH 2 ) 2 CH 2 CH 3 ],0.90[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 20 H 19 C1N4 O 4 [M+Na] + ,437.0987;found,437.0990.

[0113] Example 26, Preparation of Compound I-24:

[0114]

[0115] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80℃ for 15 minutes, add compound III-10 (68mg, 0.27mmmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-24 (41mg) was obtained with a yield of 36.3%. Yellow powder; melting point: 151–153℃; 1 H NMR (600 MHz, DMSO-d 6 )δ12.31(s,1H,quinazolone-NH),8.21(d,J=7.8Hz,1H,quinazolone-5-H),8.12(d,J=16.1Hz,1H,CH=CH-imidazole),7.92(t,J=7.6Hz,1H,quinazole olinone-7-H),7.86(d,J=8.1Hz,1H,quinazolinone-8-H),7.71–7.65(m,2H,CH=CH-imidazole,quinazolinone-6-H),5.12[t,J=6.4Hz,1H,CH=C(CH 3 ) 2 ],4.79(d,J=5.9Hz,2H,N-CH 2 ),2.73[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.87[s,3H,CH=C(CH 3 ) 2 ],1.72[s,3H,CH=C(CH 3 ) 2 ]1.65(p,J=7.7Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.37[h,J=7.3Hz,2H,(CH2 ) 2 CH 2 CH 3 ],0.91[t,J=7.3Hz,3H,(CH 2 ) 3 CH 3 ]ppm. 1 HRMS(ESI)calcd.for C 23 H 25 C1N 4 O 2 [M+H] + ,425.1739;found,425.1738.

[0116] Example 27, Preparation of Compound I-25:

[0117]

[0118] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80℃ for 15 minutes, add compound III-11 (64mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-25 (83mg) was obtained with a yield of 76.0%. Yellow powder; melting point: 185-187℃; 1 H NMR (600 MHz, DMSO-d 6 )δ12.34(s,1H,quinazolone-NH),8.23–8.17(m,2H,quinazolone-5-H,CH=CH-imidazole),7.93(t,J=7.4Hz,1H,quinazolinone-7-H),7.87(d,J= 8.0Hz,1H,quinazolinone-8-H),7.79(d,J=16.1Hz,1H,CH=CH-imidazole),7.68(t,J=7.4Hz,1H,quinazolinone-6-H),4.10(d,J=6.7Hz,2H,N-CH 2 -cyclopropyl),2.73[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.68(p,J=7.6Hz,2H,CH 2 CH 2CH 2 CH 3 ),1.39[q,J=7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],1.10(m,1H,cyclopropyl-1-CH),0.92[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ],0.57(m,2H,cyclopropyl-1-CH a ,cyclopropyl-2-CH a ),0.42(m,2H,cyclopropyl-1-CH b ,cyclopropyl-2-CH b )ppm.HRMS(ESI)calcd.for C 22 H 23 C1N 4 O 2 [M+H] + ,411.1582;found,411.1584.

[0119] Example 28, Preparation of Compound I-26:

[0120]

[0121] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80℃ for 15 minutes, add compound III-12 (68mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-26 (92mg) was obtained with a yield of 81.5%. Yellow powder; melting point: 180–182℃; 1 H NMR (600 MHz, DMSO-d 6) δ 12.35 (s, 1H, quinazolone - NH), 8.21 (d, J = 7.7 Hz, 1H, quinazolone - 5 - H), 8.12 (d, J = 16.1 Hz, 1H, CH=CH - imidazole), 7.93 (t, J = 7.3 Hz, 1H, quinazolinone - 7 - H), 7.86 (d, J = 7.8 Hz, 1H, quinazolinone - 8 - H), 7.76 (d, J = 16.0 Hz, 1H, CH=CH - imidazole), 7.68 (t, J = 7.1 Hz, 1H, quinazolinone - 6 - H), 4.22 (d, J = 6.4 Hz, 2H, N - CH 2 - cyclobutyl), 2.74 [t, J = 7.2 Hz, 2H, CH 2 (CH 2 ) 2 CH 3 , 2.62 (m, 1H, cyclobutyl - 1 - CH), 2.02–1.93 (m, 2H, cyclobutyl - 3 - CH 2 ), 1.81 (m, 4H, cyclobutyl - 2,4 - CH 2 ), 1.68 (m, 2H, CH 2 CH 2 CH 2 CH 3 ), 1.44–1.32 [m, 2H, (CH 2 ) 2 CH 2 CH 3 , 0.92 [t, J = 7.1 Hz, 3H, (CH 2 ) 3 CH 3 ppm. HRMS (ESI) calcd. for C 23 H 26 ClN 4 O 2 [M + H] + , 425.1739; found, 425.1739.

[0122] Example 29. Preparation of Compound I - 27:

[0123]

[0124] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as catalyst, ethanol (10mL) as solvent, stir at 80℃ for 15 minutes, add compound III-13 (71mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-27 (75mg), with a yield of 64.3%. Yellow powder; melting point: 174-176℃;. 1 H NMR (600 MHz, DMSO-d 6 )δ12.34(s,1H,quinazolone-NH),8.21(d,J=7.3Hz,1H,quinazolone-5-H),8.13(d,J=16.1Hz,1H,CH=CH-imidazole),7.93(t,J=6.6Hz,1H,quinazolinone-7- H),7.85(d,J=7.6Hz,1H,quinazolinone-8-H),7.76(d,J=16.1Hz,1H,CH=CH-imidazole),7.67(d,J=6.6Hz,1H,quinazolinone-6-H),4.13(d,J=6.6Hz,2H,N-CH 2 -cyclopentyl),2.73[t,J=6.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],2.19(m,1H,cyclopentyl-1-CH),1.69(m,6H,CH 2 CH 2 CH 2 CH 3 ,cyclopentyl-1-CH a ,cyclopentyl-2-CH a, cyclopentyl-3-CH a ,cyclopentyl-4-CH a ,cyclopentyl-5-CH a ),1.53(m,2H,cyclopentyl-2-CH b ,cyclopentyl-5-CH b ),1.39[m,2H,(CH 2 ) 2 CH 2 CH 3],1.33–1.20(m,2H,cyclopentyl-3-CH b ,cyclopentyl-4-CH b ),0.92[t,J=6.4Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 24 H 27 C1N 4 O 2 [M+H] + ,439.1895;found,439.1894.

[0125] Example 30, Preparation of Compound I-28:

[0126]

[0127] Add intermediate II-1 (50 mg, 0.27 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80 ° C for 15 minutes, add compound III-14 (75 mg, 0.27 mmol), continue to reflux at 80 ° C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-28 (80 mg) was obtained with a yield of 66.5%. Yellow powder; melting point: 181-183 ° C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.34(s,1H,quinazolinone-NH),8.22(d,J=8.6Hz,1H,quinazolinone-5-H),8.10(d,J=16.2Hz,1H,CH=CH-imidazole),7.94(t,J=7.6Hz,1H,quinazolinone-7 -H),7.84(d,J=8.0Hz,1H,1H,quinazolinone-8-H)),7.73(d,J=16.2Hz,1H,CH=CH-imidazole),7.69(t,J=7.3Hz,1H,quinazolinone-6-H),4.02(d,J=7.2Hz,2H,CH 2 -cyclohexane),2.72[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3],1.72–1.57(m,8H,cyclohexane-2,3,4,5,6H,cyclohexane-1H,CH 2 CH 2 CH 2 CH 3 ),1.38[m,2H,,(CH 2 ) 2 CH 2 CH 3 ],1.18–1.05(m,5H,cyclohexane-2,3,4,5,6H),0.92[t,J=7.3Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 25 H 29 C1N 4 O 2 [M+H] + ,453.2052;found,453.2050.

[0128] Example 31, Preparation of Compound I-29:

[0129]

[0130] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80°C for 15 minutes, add compound III-15 (86mg, 0.27mmol), continue to reflux at 80°C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-29 (103mg) was obtained with a yield of 84.1%. Yellow powder; melting point: 199–201°C; 1 H NMR (600 MHz, DMSO-d 6) δ 12.26 (s, 1H, quinazolone-NH), 8.19 (d, J = 7.0 Hz, 1H, quinazolone-5-H), 8.07 (d, J = 16.0 Hz, 1H, CH=CH-imidazole), 7.92 (t, J = 7.6 Hz, 1H, quinazolinone-7-H), 7.81 (d, J = 7.2 Hz, 1H, quinazolinone-8-H), 7.68 - 7.63 (m, 2H, CH=CH-imidazole, quinazolinone-6-H), 7.19 (d, J = 6.1 Hz, 2H, Ph-2,6-H), 6.98 (d, J = 6.2 Hz, 2H, Ph-3,5-H), 5.45 (s, 2H, CH 2 -Ar), 2.74 [t, J = 7.5 Hz, 2H, CH 2 (CH 2 ) 2 CH 3 , 2.27 (s, 3H, Ph-CH 3 ), 1.64 - 1.59 (m, 2H, CH 2 CH 2 CH 2 CH 3 ), 1.36 - 1.31 [m, 2H, (CH 2 ) 2 CH 2 CH 3 , 0.86 [t, J = 7.3 Hz, 3H, (CH 2 ) 3 CH 3 ppm. HRMS(ESI) calcd. for C 26 H 25 ClN 4 O 2 [M + H] + , 461.1739; found, 461.1740.

[0131] Example 32. Preparation of Compound I-30:

[0132]

[0133] In a 25mL round-bottom flask, add intermediate II-1 (50mg, 0.27mmol), sodium hydroxide aqueous solution (30%, 0.2mL) as a catalyst, ethanol (10mL) as a solvent, stir at 80℃ for 15 minutes, add compound III-16 (83mg, 0.27mmol), continue to reflux at 80℃ for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-30 (109mg) was obtained with a yield of 85.2%. Yellow powder; melting point: 191–193℃; 1 H NMR (600 MHz, DMSO-d 6 )δ12.26(s,1H,quinazolone-NH),8.19(d,J=7.8Hz,1H,quinazolone-5-H),8.05(d,J=16.1Hz,1 H,CH=CH-imidazole),7.91(t,J=7.7Hz,1H,quinazolinone-7-H),7.80(d,J=8.0Hz,1H,quinazo linone-8-H),7.66(t,J=7.4Hz,1H,quinazolinone-6-H),7.61(d,J=16.1Hz,1H,CH=CH-imidazo le),7.46(d,J=8.4Hz,2H,Ph-3-H,Ph-5-H),7.12(d,J=8.3Hz,2H,Ph-2-H,Ph-6-H),5.52(s,2H,CH 2 -Ar),2.74[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.60(p,J=7.6Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.33[q,J=7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],0.86[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 25 H 22 Cl 2 N 4 O 2 [M+H] +,481.1193;found,481.1193.

[0134] Example 33, Preparation of Compound I-31:

[0135]

[0136] Add intermediate II-1 (50 mg, 0.27 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80 ° C for 15 minutes, add compound III-17 (78 mg, 0.27 mmol), continue to reflux at 80 ° C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. Separate by column chromatography and dry to obtain compound I-31 (91 mg) with a yield of 73.7%. Yellow powder; melting point: 184-186 ° C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.25(s,1H,quinazolone-NH),8.19(d,J=7.7Hz,1H,quinazolone-5-H),8.07(d,J=16.1Hz,1H,CH=CH-imidazole),7.92(t,J=7.2Hz,1H,quinazolinone-7-H),7.81(d,J=8 .0Hz,1H,quinazolinone-8-H),7.68–7.61(m,2H,CH=CH-imidazole,quinazolinone-6 -H),7.23(t,J=8.8Hz,2H,Ph-3,5-H),7.17–7.13(m,2H,Ph-2-H,Ph-6-H),5.51(s,2H,CH 2 -Ar),2.75[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.61(p,J=7.6Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.33[q,J=7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],0.86[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3]ppm.HRMS(ESI)calcd.for C 25 H 22 CIF 4 O 2 [M+H] + ,465.1488;found,465.1488.

[0137] Example 34, Preparation of Compound I-32:

[0138]

[0139] Add intermediate II-1 (50 mg, 0.27 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent to a 25 mL round-bottom flask, stir at 80 ° C for 15 minutes, add compound III-18 (86 mg, 0.27 mmol), continue to reflux at 80 ° C for 10 hours, and monitor and track the reaction by thin layer chromatography analysis until the end of the reaction. After column chromatography separation and drying, compound I-32 (111 mg) was obtained with a yield of 84.9%. Yellow powder; melting point: 213-215 ° C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.27(s,1H,quinazolone-NH),8.26(d,J=8.7Hz,2H,Ph-3,5-H),8.18(d,J=7.8Hz,1H,quin azolone-5-H),8.05(d,J=16.1Hz,1H,CH=CH-imidazole),7.91(t,J=8.2Hz,1H,quinazolinon e-7-H),7.79(d,J=8.1Hz,1H,quinazolinone-8-H),7.67(t,J=7.5Hz,1H,quinazolinone-6-H )),7.59(d,J=16.1Hz,1H,CH=CH-imidazole),7.36(d,J=8.6Hz,2H,Ph-2,6-H),5.73(s,2H,CH 2 -Ar),2.75[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.61(p,J=7.6Hz,3H,CH 2 CH 2 CH 2 CH 3 ),1.33[q,J=7.4Hz,2H,(CH 2 )2 CH 2 CH 3 ],0.85[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 25 H 22 C1N 5 O 4 [M+Na] + ,514.1253; found,514.1248

[0140] Example 35, Preparation of Compound I-33:

[0141]

[0142] Compound II-1 (50 mg, 0.27 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent were added to a 25 mL round-bottom flask, stirred at 80°C for 15 minutes, compound III-19 (83 mg, 0.27 mmol) was added, and the reaction was continued at 80°C for 10 hours under reflux, and the reaction was monitored and tracked by thin layer chromatography until the end of the reaction. After column chromatography separation and drying, compound I-33 (108 mg) was obtained with a yield of 85.0%. Yellow powder; melting point: 191–193°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.27(s,1H,quinazolone-NH),8.19(d,J=7.8Hz,1H,quinazolone-5-H),8.05(d,J=16. 1Hz,1H,CH=CH-imidazole),7.92(t,J=7.6Hz,1H,quinazolinone-7-H),7.80(d,J=8.1Hz,1 H),7.67(t,J=7.5Hz,1H,Ar-2-H),7.62(d,J=16.1Hz,1H,CH=CH-imidazole),7.47(d,J=8.4 Hz,2H,quinazolinone-6-H,Ar-4-H),7.12(d,J=8.3Hz,2H,Ar-5-H,Ar-6-H),5.53(s,2H,CH 2 -Ar),2.74[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.61(p,J=7.6Hz,2H,CH2 CH 2 CH 2 CH 3 ),1.33[q,J=7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],0.85[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 25 H 22 Cl 2 N 4 O 2 [M+H] + ,481.1193;found,481.1193.

[0143] Example 36, Preparation of Compound I-34:

[0144]

[0145] Compound II-1 (50 mg, 0.27 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent were added to a 25 mL round-bottom flask, stirred at 80°C for 15 minutes, compound III-20 (92 mg, 0.27 mmol) was added, and the reaction was continued at 80°C for 10 hours under reflux, and the reaction was monitored and tracked by thin layer chromatography until the end of the reaction. After column chromatography separation and drying, compound I-34 (103 mg) was obtained with a yield of 75.2%. Yellow powder; melting point: 182–184°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.27(s,1H,quinazolone-NH),8.19(d,J=7.6Hz,1H,quinazolone-5-H),8.04(d,J=16.1Hz,1H,CH=CH-imidazole),7.92(t,J=8.2Hz,1H,quinazolinone-7-H),7.81(d,J=8.1 Hz,1H,quinazolinone-8-H),7.69–7.62(m,2H,CH=CH-imidazole,Ph-3-H),7.39(t,J=9 .5Hz,1H,quinazolinone-6-H),7.08(m,1H,Ph-5-H),6.93(m,1H,Ph-6-H),5.53(s,2H,CH 2-Ar),2.76[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.60(q,J=7.6Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.34[q,J=7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],0.87[t,J=7.3Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 25 H 21 Cl 3 N 4 O 2 [M+H] + ,515.0803;found,515.0806.

[0146] Example 37, Preparation of Compound I-35:

[0147]

[0148] Compound II-1 (50 mg, 0.27 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent were added to a 25 mL round-bottom flask, stirred at 80°C for 15 minutes, compound III-21 (83 mg, 0.27 mmol) was added, and the reaction was continued at 80°C for 10 hours under reflux, and the reaction was monitored and tracked by thin layer chromatography until the end of the reaction. After column chromatography separation and drying, compound I-35 (83 mg) was obtained with a yield of 64.9%. Yellow powder; melting point: 202–204°C; 1 H NMR (600 MHz, DMSO-d 6)δ12.24(s,1H,quinazolone-NH),8.18(d,J=7.9,1H,quinazolone-5-H),7.95–7.87(m,2H,CH=CH-imidazole,quinazolinone-7-H),7.79(d,J=8.1Hz,1H,quinazolinone-8-H),7.66(t,J=7.6Hz,1H,Ar-3-H),7.63(d,J=7.9Hz,1H,quinazolinone-6-H),7.55(d,J=16.2Hz,1H,CH=CH-imidazole),7.37(d,J=7.7,1H,Ar-4-H),7.32(t,J=7.6Hz,1H,Ar-5-H),6.58(d,J=7.7Hz,1H,Ar-6-H),5.54(s,2H,CH 2 -Ar),2.73[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ,1.60(q,J=7.6Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.32[p,J=7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ,0.84[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ppm.HRMS(ESI)calcd.forC 25 H 22 Cl 2 N 4 O 2 [M+H] + ,481.1193;found,481.1194.

[0149] Example 38. Preparation of Compound I-36:

[0150]

[0151] Compound II-2 (50 mg, 0.24 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent were added to a 25 mL round-bottom flask, stirred at 80°C for 15 minutes, compound III-14 (69 mg, 0.24 mmol) was added, and the reaction was continued at 80°C for 10 hours under reflux, and the reaction was monitored and tracked by thin layer chromatography until the end of the reaction. After column chromatography separation and drying, compound I-36 (47 mg) was obtained with a yield of 53.4%. Yellow powder; melting point: 180–182°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.46(s,1H,quinazolinone-NH),8.26(t,J=7.4Hz,1H,quinazolinone-5-H),8.05(d,J=16.2Hz,1H,CH=CH-imidazole),7.72(d,J=16.2H z,1H,CH=CH-imidazole),7.60(d,J=7.3Hz,1H,quinazolinone-8-H),7.54(t,J=7.4Hz,1H,quinazolinone-6-H),4.01(d,J=7.2Hz,2H,N-CH 2 -cyclohexane),2.72[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.72–1.60(m,6H,cyclohexyl-1-CH,cyclohexyl-2,4,6-CH a ,CH 2 CH 2 CH 2 CH 3 ),1.58(m,2H,cyclohexyl-3,5-CH a ),1.38[h,J=7.3Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],1.15(m,3H,cyclohexyl-3,4,5-CH b ),1.11–1.04(m,2H,cyclohexyl-2,6-CH b ),0.92[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3]ppm.HRMS(ESI)calcd.for C 25 H 28 CIF 4 O 2 [M+H] + ,471.1958;found,471.1960.

[0152] Example 39, Preparation of Compound I-37:

[0153]

[0154] Compound II-3 (50 mg, 0.22 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent were added to a 25 mL round-bottom flask, stirred at 80°C for 15 minutes, compound III-14 (64 mg, 0.22 mmol) was added, and the reaction was continued at 80°C for 10 hours under reflux, and the reaction was monitored and tracked by thin layer chromatography until the end of the reaction. After column chromatography separation and drying, compound I-37 (47 mg) was obtained with a yield of 42.9%. Yellow powder; melting point: 209–211°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.52(s,1H,quinazolinone-NH),8.19(d,J=8.5Hz,1H,quinazolinone-5-H),8.04(d,J=16.2Hz,1H,CH=CH-imidazole),7.88(s,1H, quinazolinone-8-H),7.73(d,J=16.3Hz,1H,CH=CH-imidazole),7.71(d,J=8.4Hz,1H,quinazolinone-6-H),4.01(d,J=7.2Hz,2H,N-CH 2 -cyclohexane),2.72[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.68(m,6H,cyclohexyl-1-CH,cyclohexyl-2,4,6-CH a ,CH 2 CH 2 CH 2 CH 3 ),1.58(m,2H,cyclohexyl-3,5-CH a ),1.38[h,J=7.4Hz,2H,(CH 2) 2 CH 2 CH 3 ],1.15(m,3H,cyclohexyl-3,4,5-CH b ),1.08(m,2H,cyclohexyl-2,6-CH b ),0.92[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 25 H 28 Cl 2 N 4 O 2 [M+H] + ,487.1662;found,487.1669.

[0155] Example 40, Preparation of Compound I-38:

[0156]

[0157] Compound II-4 (50 mg, 0.2 mmol) and sodium hydroxide aqueous solution (30%, 0.2 mL) were added to a 25 mL round-bottom flask as a catalyst and ethanol (10 ml) as a solvent. The mixture was stirred at 80 °C for 15 minutes, and compound III-14 (55 mg, 0.2 mmol) was added. The mixture was refluxed at 80 °C for 10 hours and monitored by thin layer chromatography until the reaction was completed. Compound I-38 (78 mg) was obtained by column chromatography and drying with a yield of 76.9%. Yellow powder; melting point: 200–202 °C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.82(s,1H,quinazolinone-NH),8.23(d,J=16.2Hz,1H,CH=CH-imidazole),8.16(s,1H,quinazolinone- 7-H),8.07(s,1H,quinazolinone-5-H),7.69(d,J=16.2Hz,1H,CH=CH-imidazole),4.00(d,J=7.3Hz,2H,N-CH 2 -cyclohexane),2.71[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3],1.70–1.57(m,6H,cyclohexyl-1-CH,cyclohexyl-2,4,6-CH a ,CH 2 CH 2 CH 2 CH 3 ),1.53(m,2H,yclohexyl-3,5-CH a ),1.38[h,J=7.2Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],1.13(m,3H,cyclohexyl-3,4,5-CH b ),1.08–1.02(m,2H,cyclohexyl-2,6-CH b ),0.92[t,J=7.4Hz,3H,(CH 2 ) 3 CH 3 ]ppm.HRMS(ESI)calcd.for C 25 H 28 Cl 3 N 4 O 2 [M+H] + ,521.1272;found,521.1271.

[0158] Example 41, Preparation of Compound I-39:

[0159]

[0160] Compound II-5 (50 mg, 0.25 mmol), sodium hydroxide aqueous solution (30%, 0.2 mL) as catalyst, ethanol (10 ml) as solvent were added to a 25 mL round-bottom flask, stirred at 80°C for 15 minutes, compound III-14 (70 mg, 0.25 mmol) was added, and the reaction was continued at 80°C for 10 hours under reflux, and the reaction was monitored and tracked by thin layer chromatography until the end of the reaction. After column chromatography separation and drying, compound I-39 (62 mg) was obtained with a yield of 53.7%. Yellow powder; melting point: 209–211°C; 1 H NMR (600 MHz, DMSO-d 6) δ 12.26 (s, 1H, quinazolinone-NH), 8.10 (d, J = 16.3 Hz, 1H, CH=CH-imidazole), 8.02 (s, 1H, quinazolinone-5-H), 7.75 (s, 2H, quinazolinone-7,8-H), 7.71 (d, J = 16.1 Hz, 1H, CH=CH-imidazole), 4.02 (d, J = 7.1 Hz, 2H, N-CH 2 -cyclohexane), 2.72 [t, J = 7.6 Hz, 2H, CH 2 (CH 2 ) 2 CH 3 , 2.39 (s, 1H, quinazolinone-6-CH 3 ), 1.68 (m, 6H, cyclohexyl-1-CH, cyclohexyl-2,4,6-CH a , CH 2 CH 2 CH 2 CH 3 ), 1.59 (m, 2H, cyclohexyl-3,5-CH a ), 1.38 [h, J = 7.3 Hz, 2H, (CH 2 ) 2 CH 2 CH 3 , 1.19–1.08 (m, 5H, cyclohexyl-2,3,4,5,6-CH b ), 0.92 [t, J = 7.3 Hz, 3H, (CH 2 ) 3 CH 3 ppm. HRMS (ESI) calcd. for C 26 H 31 ClN 4 O 2 [M + H] + , 467.2208; found, 467.2210.

[0161] Example 42. Preparation of Compound I-40:

[0162]

[0163] Compound II-6 (50 mg, 0.25 mmol) and sodium hydroxide aqueous solution (30%, 0.2 mL) were added to a 25 mL round-bottom flask as a catalyst and ethanol (10 ml) as a solvent. The mixture was stirred at 80°C for 15 minutes, and compound III-14 (64 mg, 0.25 mmol) was added. The reaction was continued at 80°C for 10 hours under reflux. The reaction was monitored and tracked by thin layer chromatography until the reaction was completed. Compound I-40 (68 mg) was obtained by column chromatography separation and drying, with a yield of 58.9%. Yellow powder; melting point: 214–216°C; 1 H NMR (600 MHz, DMSO-d 6 )δ12.32(s,1H,quinazolinone-NH),8.33(d,J=16.2Hz,1H,CH=CH-imidazole),8.04(d,J=7.9Hz,1H,quinazolinone-5-H),7.78(d,J=7.4Hz ,1H,quinazolinone-7-H),7.70(d,J=16.2Hz,1H,CH=CH-imidazole),7.55(t,J=7.6Hz,1H,quinazolinone-6-H),4.02(d,J=7.4Hz,2H,N-CH 2 -cyclohexane),2.72[t,J=7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],2.67(s,3H,quinazolinone-CH 3 ),1.64(m,6H,cyclohexyl-1-CH,cyclohexyl-2,4,6-CH a ,CH 2 CH 2 CH 2 CH 3 ),1.54(m,2H,cyclohexyl-3,5-CH a ),1.38[h,J=7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],1.13(m,3H,cyclohexyl-3,4,5-CH b ),1.06(m,2H,cyclohexyl-2,6-CH b ),0.92[t,J=7.4Hz,3H,(CH 2 ) 3 CH3 ]ppm.HRMS(ESI)calcd.for C 26 H 31 C1N 4 O 2 [M+H] + ,467.2208;found,467.2208.

[0164] Example 43, in vitro antimicrobial activity of quinazolinone ketone azole compounds:

[0165] The clinical trial standards (Clinical and Laboratory Standards) were followed. The minimum inhibitory concentration (MIC) of the quinazolinone ketone azole compounds prepared in Examples 3-42 against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) was examined by using a 96-well microdilution method of the CLSI Institute. The test compound was dissolved in a small amount of dimethyl sulfoxide, diluted with water to prepare a solution with a concentration of 1.28 mg / mL, and then diluted to 128 μg / mL with culture medium. The solution was cultured at 35°C for 24-72 hours, and the culture plate was fully shaken on an oscillator. The MIC was measured at a wavelength of 490 nm. The results are shown in Tables 1-2.

[0166] Table 1. In vitro anti-Gram-positive bacterial activity data (MIC, μg / mL) of quinazolinone ketone azole compounds prepared in Examples 3-42

[0167]

[0168] Table 2. In vitro anti-Gram-negative bacterial activity data (MIC, μg / mL) of quinazolinone ketone azole compounds prepared in Examples 3-42

[0169]

[0170] As can be seen from Table 1, the compounds of the present invention show a certain inhibitory effect on the tested Gram-positive bacteria. In particular, compound I-4 has good inhibitory activity on the tested MRSA, Staphylococcus aureus, Staphylococcus aureus 29213 and Enterococcus faecalis, with MIC values ​​of 0.5, 4, 1 and 2 μg / mL, respectively. Compounds I-7 and I-9 have good inhibitory activity on Enterococcus faecalis, with a MIC value of 1 μg / mL. It is significantly better than the inhibitory activity of the reference drug norfloxacin on the tested MRSA, Staphylococcus aureus, Staphylococcus aureus 25923, Staphylococcus aureus 29213 and Enterococcus faecalis (MIC values ​​are 8, 4, 2, 4 and 2 μg / mL, respectively). The antibacterial activity of some compounds is comparable to that of the reference drug norfloxacin, or even stronger.

[0171] As can be seen from Table 2, the compounds of the present invention show a certain inhibitory effect on the tested Gram-negative bacteria. In particular, compound I-4 has good inhibitory activity on the tested Klebsiella pneumoniae, Escherichia coli, Escherichia coli 25922, Pseudomonas aeruginosa and Pseudomonas aeruginosa 27853, and the MIC values ​​are 2, 2, 0.5, 4 and 2 μg / mL, respectively. Compound I-36 has good inhibitory activity on the tested Klebsiella pneumoniae, Escherichia coli, Escherichia coli 25922, Pseudomonas aeruginosa and Pseudomonas aeruginosa 27853, and the MIC values ​​are 4, 8, 1, 4, 2 μg / mL, respectively. It is significantly better than the inhibitory activity of the reference drug norfloxacin on the tested Klebsiella pneumoniae, Escherichia coli, Escherichia coli 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa 27853 and Acinetobacter baumannii (MIC values ​​are 4, 8, 8, 4, 4 and 2 μg / mL, respectively). The antibacterial activity of some compounds is comparable to or even stronger than that of the reference drug norfloxacin.

[0172] Example 44, pharmaceutical use of quinazolinone ketone azole compounds:

[0173] According to the above-mentioned antimicrobial activity test results, the quinazolinone ketone azole compounds of the present invention have good antibacterial activity and can be made into antibacterial drugs for clinical use. These drugs can be either single-prescription preparations, such as quinazolinone ketone azole compounds of a structure and pharmaceutically acceptable excipients; or compound preparations, such as quinazolinone ketone azole compounds of a structure and existing antibacterial active ingredients (such as sulfamethoxazole, fluconazole, phosphoconazole, itraconazole, etc.) and pharmaceutically acceptable excipients, or several quinazolinone ketone azole 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.

[0174] 1. Preparation of Compound I-4 Tablets

[0175] Prescription: Compound I-4 10 g, corn starch 50 g, lactose 187 g, magnesium stearate 3.0 g, and an appropriate amount of 70% by volume ethanol solution, making a total of 1000 tablets.

[0176] Preparation method: Dry corn starch at 105°C for 5 hours for later use; mix compound I-4 with lactose and corn starch evenly, use 70% ethanol solution to make a soft material, sieve to make wet granules, add magnesium stearate, and press into tablets; each tablet weighs 250 mg and contains 10 mg of active ingredient.

[0177] 2. Preparation of Compound I-7 Capsules

[0178] Prescription: Compound I-7 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low-substituted hydroxypropyl cellulose (100 mesh) 2.5g, talcum powder (100 mesh) 2.0g, sweetener 1.25g, orange flavor 0.25g, appropriate amount of pigment, appropriate amount of water, made into 1000 tablets.

[0179] Preparation method: The prescribed amount of compound I-7 is micronized and crushed into extremely fine powder, and then mixed with the prescribed amount of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweetener, orange flavor and pigment, and the mixture is made into a soft material with water, granulated with a 12-14 mesh sieve, dried at 40-50°C, sieved through the whole granules, and filled into empty capsules to obtain the product; each tablet weighs 50 mg and contains 25 mg of active ingredient.

[0180] 3. Preparation of Compound I-10 Granules

[0181] Prescription: Compound I-10 26g, dextrin 120g, sucrose 280g.

[0182] Preparation method: Compound I-10, dextrin and sucrose are mixed evenly, granulated by wet method, dried at 60°C, and packaged to obtain the product.

[0183] 4. Preparation of Compound I-15 Injection

[0184] Prescription: Compound I-15 10 g, propylene glycol 500 mL, water for injection 500 mL, a total of 1000 mL.

[0185] Preparation method: Weigh compound I-15, add propylene glycol and injection water, stir to dissolve, then add 1g of activated carbon, stir thoroughly and let stand for 15 minutes, filter with a 5μm titanium rod to remove carbon, and then filter with microporous filter membranes with pore sizes of 0.45μm and 0.22μm in turn, finally fill into a 10mL ampoule, and sterilize with circulating steam at 100℃ for 45 minutes.

[0186] 5. Preparation of Compound I-18 Powder Injection

[0187] Preparation method: The intermediate I-8 sterile powder is packaged under aseptic conditions to obtain the product.

[0188] 6. Preparation of compound I-20 eye drops

[0189] Prescription: Compound I-20 3.78 g, sodium chloride 0.9 g, appropriate amount of boric acid buffer solution, and distilled water added to 1000 mL.

[0190] Preparation method: Weigh compound I-20 and sodium chloride and add them to 500 mL of distilled water. After complete dissolution, adjust the pH to 6.5 with boric acid buffer solution, 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.

[0191] 7. Preparation of Compound I-16 Liniment

[0192] Prescription: Compound I-16 4g, potassium soap 7.5g, camphor 5g, distilled water added to 100mL.

[0193] Preparation method: Dissolve camphor in 95% ethanol solution by volume and set aside; heat potassium soap to liquefy it and set aside; weigh compound I-16, add potassium soap solution and camphor ethanol solution under constant stirring, and then gradually add distilled water. After complete emulsification, add distilled water to the full amount to obtain the compound.

[0194] 8. Preparation of Compound I-18 Suppositories

[0195] Prescription: Compound I-18 4g, gelatin 14g, glycerin 70g, distilled water added to 100mL, 100 metric tablets.

[0196] Preparation method: Weigh gelatin and glycerin, add distilled water to 100 mL, heat in a water bath at 60°C until it melts into a paste, add compound I-18, stir evenly, pour into a vaginal suppository mold when it is almost solidified, cool and solidify to obtain.

[0197] 9. Preparation of Compound I-14 Ointment

[0198] Prescription: Compound I-14 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, distilled water added to 100g.

[0199] Preparation method: Heat hexadecanol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate until completely dissolved, mix well, and keep warm at 80°C as the oil phase for later use; 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-14 after emulsification, stir and cool to obtain the product.

[0200] 10. Preparation of Compound I-19 Aerosol

[0201] Prescription: Compound I-19 2.5 g, Span 20 3 g, talcum powder (100 mesh) 4 g, trichlorofluoromethane added to appropriate amount.

[0202] Preparation method: Compound I-19, Span 20 and talcum powder are dried in a vacuum drying oven for several hours respectively, cooled to room temperature in a dryer, crushed into fine powder using a jet mill, mixed according to the prescribed amount, poured into a sealed container, and trichloromonofluoromethane is added to the prescribed amount to obtain the product.

[0203] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution, which should be included in the scope of the claims of the present invention.

Claims

1. Quinazolone enoneazole compounds and their pharmaceutically acceptable salts, characterized in that, the quinazolone enoneazole compounds and their pharmaceutically acceptable salts are selected from I-1 to I-40:

2. The quinazolone enoneazole compounds and their pharmaceutically acceptable salts according to claim 1, characterized in that, the pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.

3. The preparation method of the quinazolone enoneazole compounds and their pharmaceutically acceptable salts according to any one of claims 1 to 2, characterized in that, the preparation method is as follows: a. Preparation of intermediates II-1 to II-6: Using o-aminobenzoic acid or o-aminobenzamide compounds and pyruvic acid as starting materials, intermediates II-1 to II-6 are obtained through cyclization reaction; b. Preparation of intermediate III: Different types of halogenated compounds react with 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde to obtain intermediate III; Among them, n, R 1 correspond to the structures of the quinazolone enone azole compounds shown in I-15 to I-40 in claims 1-2; c. Preparation of the quinazolone enoneazole compounds shown in I-1 to I-13: Intermediates II-1 to II-6 respectively undergo condensation reactions with aldehydes under the action of a base to obtain the quinazolone enoneazole compounds shown in I-1 to I-13; d. Preparation of the quinazolone enoneazole compounds shown in I-14 to I-40: Intermediates II-1 to II-6 respectively undergo condensation reactions with 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde or intermediate III under the action of a base to obtain the quinazolone enoneazole compounds shown in I-14 to I-40.

4. The application of the quinazolone enoneazole compounds and their pharmaceutically acceptable salts according to any one of claims 1 to 2 in the preparation of antibacterial drugs.

5. The application according to claim 4, characterized in that, the bacteria are selected from one or more of Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa or Acinetobacter baumannii.

6. The application according to claim 5, characterized in that, the Staphylococcus aureus is methicillin-resistant Staphylococcus aureus, Staphylococcus aureus ATCC 25923 or Staphylococcus aureus ATCC 29213, the Escherichia coli is Escherichia coli ATCC 25922, and the Pseudomonas aeruginosa is Pseudomonas aeruginosa ATCC 27853.

7. A preparation containing the quinazolone enoneazole compounds and their pharmaceutically acceptable salts according to any one of claims 1 to 2.

8. The preparation according to claim 7, characterized in that, the preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.

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