CN116410184A - Quinazolinone ketene azole compound, and preparation method and application thereof - Google Patents
Quinazolinone ketene azole compound, and preparation method and application thereof Download PDFInfo
- Publication number
- CN116410184A CN116410184A CN202310370401.5A CN202310370401A CN116410184A CN 116410184 A CN116410184 A CN 116410184A CN 202310370401 A CN202310370401 A CN 202310370401A CN 116410184 A CN116410184 A CN 116410184A
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- CN
- China
- Prior art keywords
- quinazolinone
- compound
- preparation
- imidazole
- ketene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000002360 preparation method Methods 0.000 title claims abstract description 91
- -1 Quinazolinone ketene azole compound Chemical class 0.000 title claims abstract description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 179
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 142
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 96
- 238000006243 chemical reaction Methods 0.000 claims description 72
- 239000000543 intermediate Substances 0.000 claims description 57
- 239000000843 powder Substances 0.000 claims description 47
- 239000002904 solvent Substances 0.000 claims description 47
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 16
- 241000191967 Staphylococcus aureus Species 0.000 claims description 15
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
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- JLVIHQCWASNXCK-UHFFFAOYSA-N 2-butyl-5-chloro-1h-imidazole-4-carbaldehyde Chemical compound CCCCC1=NC(C=O)=C(Cl)N1 JLVIHQCWASNXCK-UHFFFAOYSA-N 0.000 claims description 7
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
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- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention relates to a quinazolinone ketene azole compound, a preparation method and application thereof, which are shown in a general formula I, wherein the compound has certain inhibitory activity on one or more of gram-positive bacteria and gram-negative bacteria, can be used for preparing antibacterial medicines, has no obvious drug resistance, has simple preparation raw materials, is low in cost and is easy to obtain, and has important significance in the aspect of resisting infection.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a quinazolinone ketene azole compound, and a preparation method and application of the compound.
Background
Pathogen infection threatens human health, and antibiotics have been the main treatment means for pathogenic microorganism infection. However, over the last decades, excessive and improper exposure of antibiotics has led to the cancellation of bacterial antibiotic stress and the development of resistance, making clinical drugs increasingly limited in effectiveness. Global investigation showed 495 tens of thousands of people dying from bacterial resistance (AMR) caused disease in 2019, which means that the number of deaths caused by drug resistance exceeded HIV/AIDS or malaria. In addition, a large number of documents indicate that the current drugs with a single target point are easy to inactivate multi-drug resistant pathogens due to target point failure caused by bacterial gene mutation. There is no doubt an urgent need to identify novel antibacterial agents with novel structures and multi-targeting to cope with infections with multi-drug resistant bacteria.
The quinazolinone alkaloid has a large biological activity potential as a core structure of traditional Chinese medicine components such as dichroine, evodiamine, tryptamine and the like. The structural features of quinazolinone with a unique benzopyrimidinone backbone are considered an important new antimicrobial chemical structural framework, and the synthesis, structural modification and biomedical potential of its derivatives have naturally attracted great attention. In particular, quinazolinones have structures similar to the quinolones, which are widely used antibacterial agents in clinic, and have been widely studied in the field of antimicrobial. The combination of quinazolinone and a number of azoles such as thiazole, oxadiazole, pyrazole, imidazole, and the like exhibits excellent antibacterial activity. Therefore, the combination of quinazolinone and azole compounds has infinite potential in the antibacterial field.
As the nitrogen-containing heterocycle with the electron-rich aromatic structure, the azole compound is widely focused in the design and development of medicines and is widely applied to a plurality of fields of agricultural chemicals, medicines and the like. The unique structure of azole compounds makes them susceptible to binding to multiple targets in organisms through a variety of weak interactions such as hydrogen bonding, complexation, ion dipoles, hydrophobic interactions, van der waals forces, etc., exhibiting significant biological activity.
Ketene, an important class of structures, has the excellent properties of ease of synthesis and multiple modification sites. In addition, ketene can be used as bridging group to promote the increase of conjugated system, so that the inserted DNA can prevent the replication of bacterial DNA, and the biological activity can be regulated by attaching different aromatic rings on two sides of ketene. Ketene fragments having such unique polar functional groups are therefore widely used as frameworks for drug design. Numerous literature studies have shown that ketene in some conjugates has an important role in molecular activity, and that its biological activity is lost by removal of ketene. .
Based on the work foundation of the field of quinazolinone and azole antimicrobial, vinyl ketone is inserted between the quinazolinone and the azole to construct a quinazolinone ketene azole structural compound, and development of new antimicrobial molecules is expected to solve the increasingly serious problem of global drug resistance.
Disclosure of Invention
Accordingly, one of the objects of the present invention is to provide a quinazolinone ketene azole compound and pharmaceutically acceptable salts thereof; the second purpose of the invention is to provide a preparation method of quinazolinone ketene azole compounds and pharmaceutically acceptable salts thereof; the invention further aims to provide application of the quinazolinone ketene azole compound and pharmaceutically acceptable salts thereof in preparation of antibacterial drugs. The fourth object of the present invention is to provide a preparation of the quinazolinone ketene azole compound, its pharmaceutically acceptable salt and its pharmaceutically acceptable salt. Thereby providing more efficient and safe candidate medicines for clinical antimicrobial treatment and being beneficial to solving the clinical treatment problems of serious drug resistance, refractory pathogenic microorganisms, newly-appearing harmful microorganisms and the like.
In order to achieve the above purpose, the present invention provides the following technical solutions:
1. the quinazolinone ketene azole compound and pharmaceutically acceptable salts thereof have the structure shown in the general formula I:
in the method, in the process of the invention,
X, Y, Z, W is C, CH, NH, N, O or an S atom;
preferably, any one of the following compounds is used:
2. the preparation method of the quinazolinone ketene azole compound comprises the following steps:
a. preparation of intermediate II 1-6: taking anthranilic acid or an anthranilamide compound and pyruvic acid as starting materials, and performing cyclization reaction to obtain an intermediate II1-6;
b. preparation of intermediate III: different types of halogenated compounds react with 2-butyl-5-chloro-1H-imidazole-4-formaldehyde to obtain an intermediate III;
wherein:
R 1 is hydrogen, alkyl, cyano, alkoxy, alkenyl, alkynyl, aryl, hydroxyalkyl, carboxyl, ester, acyl, or heterocyclic; n is an integer of 0 to 15.
c. Preparation of quinazolinone ketene azole compounds shown in general formulas I-1-13: the intermediates II1-6 respectively react with aldehyde under the action of alkali to obtain the quinazolinone ketene azole compounds shown in the general formulas I-1-13.
d. Preparation of quinazolinone ketene azole compounds shown in general formulas I-14-40: and respectively carrying out condensation reaction on the intermediates II1-6 and the intermediate III under the action of alkali to obtain the quinazolinone ketene azole compounds shown in the general formulas I14-40.
Preferably, the method comprises the steps of,
in the step a, the mol ratio of the anthranilamide to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the 1-hydroxybenzotriazole monohydrate is 1:1.2-2:1.2-2, and after the reaction is carried out for 6-8 hours at room temperature, the obtained solid is reacted in a 0.5M sodium hydroxide aqueous solution for 30 minutes to obtain an intermediate II-1;
in the step b, the molar ratio of the intermediates II1-6 to the aldehyde is 1:1.2; the alkali is piperidine; the condensation reaction is carried out by taking ethanol as solvent, reacting for 5h at 80-100 ℃;
in the step c, the molar ratio of the intermediates II1 to 6 to the intermediate III is 1:1.2; the alkali is or sodium hydroxide aqueous solution; the condensation reaction is carried out by taking ethanol as solvent, reacting at room temperature or 80-100 ℃ for 5-8 h;
in the step d, the ratio of the 2-butyl-5-chloro-1H-imidazole-4-formaldehyde to the halogenated compound to the potassium carbonate is 1:1.5-2:1.5-2, and the reaction is specifically carried out by taking acetonitrile as a solvent and reacting for 4-10H at 80-100 ℃;
3. the application of the quinazolinone ketene azole compound and the pharmaceutically acceptable salt thereof in preparing antibacterial drugs.
Preferably, the bacteria are one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC29213, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922, or acinetobacter baumannii.
4. The preparation containing the quinazolinone ketene azole compound and pharmaceutically acceptable salts thereof.
Preferably, the preparation is one of tablets, capsules, granules, injection, powder injection, eye drops, liniments, suppositories, ointments or aerosols.
The invention has the beneficial effects that: the invention provides a quinazolinone ketene azole compound and a preparation method and application thereof, wherein the quinazolinone ketene azole compound is designed and synthesized by utilizing a drug design splicing principle and introducing ketene fragments to a C-2 position of quinazolinone to bridge the quinazolinone and the azole compound and carrying out different modifications on 2-butyl-5-chloro-1H-imidazole-4-formaldehyde compounds, and the compounds are designed and synthesized to form a series of novel quinazolinone ketene azole compounds, and the compounds are detected by in vitro antimicrobial activity to find out that the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC 29213), gram-negative bacteria (klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922 and acinetobacter baumannii), so that the compounds can be used for preparing antimicrobial drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial treatment, and solving the problems of serious and serious pathogenic bacteria, such as clinical and intractable microbial diseases. In addition, the quinazolinone ketene azole compound can be used for preparing an active site trigger of PBP2 a.
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Example 1, preparation of intermediate II:
reference "Rasapalli, s.; murphy, z.f.; samreta, v.r.; golen, j.a.; weig, a.w.; melander, r.j.; melander, c.; macha, P.; vasudev, M.C. Synthesis and biofilm inhibition studies of2- (2-amino-6-arylpyrimidin-4-yl) quinazolin-4 (3H) -one.Bioorg.Med.chem.Lett.2020, 30,127550.
Example 2, preparation of intermediate III:
in a 100mL round bottom flask was added 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde (7 mmol), potassium carbonate (14 mmol) and halogenated compound (11 mmol) and acetonitrile (20 mL) and stirred at 80℃for 4-10 hours. Filtering, distilling the solvent under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain the compound III.
Example 3 preparation of Compound I-1:
to a 25mL round bottom flask was added intermediate II-1 (26 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as a catalyst, ethanol (10 mL) as a solvent, stirring at room temperature for 15 minutes, and compound 1H-imidazole-2-carbaldehyde (26 mg,0.27 mmol) was added, and the reflux reaction was continued at room temperature for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-1 (48 mg) with a yield of 68.6%. Yellow powder; melting point: 167-169 ℃; 1 H NMR(600MHz,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.
example 4 preparation of Compound I-2:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at room temperature for 15 min, added compound 1H-imidazole-4-carbaldehyde (26 mg,0.27 mmol), and the reflux reaction was continued at room temperature for 8H, monitored by thin layer chromatographyThe reaction was followed to completion. Separating by column chromatography, and drying to obtain compound I-2 (45 mg) with a yield of 63.6%. Yellow powder; melting point: 245-247 ℃; 1 H NMR(600MHz,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,quinazolinone-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.
example 5 preparation of Compound I-3:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring for 15 min at 80℃and compound 5-thiazolecarboxaldehyde (30 mg,0.27 mmol) was added and the reflux reaction was continued for 10h at 80℃and monitored by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-3 (44 mg) with 58.7% yield. Yellow powder; melting point: 187-189 ℃; 1 H NMR(600MHz,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 H 9 N 2 O 2 S[M+H] + ,248.0488；found,248.0494.
example 6 preparation of Compound I-4:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), piperidine (0.2 mL)The catalyst, ethanol (10 mL) as solvent, was stirred at 80deg.C for 15 min, 2-thiazolecarboxaldehyde (64 mg,0.27 mmol) was added and the reflux reaction was continued at 80deg.C for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-4 (38 mg) with a yield of 50.9%. Yellow powder; melting point: > 300 ℃; 1 H NMR(600MHz,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.
example 7 preparation of Compound I-5:
in a 25mL round bottom flask was added intermediate II-2 (50 mg,0.24 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring for 15 min at 80℃and compound 2-thiazolecarboxaldehyde (27 mg,0.24 mmol) was added and the reflux reaction was continued for 10h at 80℃and monitored by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-5 (34 mg) with 46.7% yield. Yellow powder; melting point: 213-215 ℃; 1 H NMR(600MHz,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.
example 8 preparation of Compound I-6:
in a 25mL round bottom flask was added intermediate II-3 (50 mg,0.22 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring for 15 min at 80℃and compound 2-thiazolecarboxaldehyde (26 mg,0.22 mmol) was added and the reflux reaction was continued for 10h at 80℃and monitored by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-6 (26 mg) with a yield of 36.4%. Yellow powder; melting point: 205-207 ℃; 1 H NMR(600MHz,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 ClN 3 O 2 S[M+H] + ,318.0099；found,318.0097.
example 9 preparation of Compound I-7:
in a 25mL round bottom flask was added intermediate II-4 (50 mg,0.20 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring for 15 min at 80℃and compound 2-thiazolecarboxaldehyde (22 mg,0.20 mmol) was added and the reflux reaction was continued for 10h at 80℃and monitored by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-7 (33 mg) with a yield of 47.4%. Yellow powder; melting point: 273-275 ℃; 1 H NMR(600MHz,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.
example 10 preparation of Compound I-8:
in a 25mL round bottom flask was added intermediate II-5 (50 mg,0.25 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring for 15 min at 80℃and compound 2-thiazolecarboxaldehyde (22 mg,0.25 mmol) was added and the reflux reaction was continued for 10h at 80℃and monitored by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-8 (58 mg) with 39.4% yield. Yellow powder; melting point: 280-282 ℃; 1 H NMR(600MHz,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,thiazole-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.
example 11 preparation of Compound I-9:
in a 25mL round bottom flask was added intermediate II-6 (50 mg,0.25 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring for 15 min at 80℃and compound 2-thiazolecarboxaldehyde (22 mg,0.25 mmol) was added and the reflux reaction was continued for 10h at 80℃and monitored by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-9 (50 mg) with 34.0% yield. Yellow powder; melting point: 207-209 ℃; 1 H NMR(600MHz,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.
example 12 preparation of Compound I-10:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80deg.C for 15 min, and Compound 1H-benzo [ d ] was added]Imidazole-2-carbaldehyde (39 mg,0.27 mmol) was continuously refluxed at 80℃for 10 hours, and monitored and tracked by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-10 (43 mg) with a yield of 51.2%. Yellow powder; melting point: 218-220 ℃; 1 H NMR(600MHz,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-benzimidazole),7.85(m,2H,benzimidazole-4-H,benzimidazole-7-H),7.72(t,J＝6.6Hz,1H,quinazolinone-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.
example 13 preparation of Compound I-11:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80deg.C, benzothiophene-3-carbaldehyde (43 mg,0.27 mmol) was added, reflux reaction was continued for 10h at 80deg.C, and TLC was monitored and followed to completion. Separating by column chromatography, and drying to obtain compound I-11 (5)4 mg), yield 61.2%. Yellow powder; melting point: 196-198 ℃; 1 H NMR(600MHz,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,benzothiophene-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.
example 14 preparation of Compound I-12:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80deg.C, and the compound benzofuran-3-carbaldehyde 37mg,0.27 mmol) was added and the reflux reaction was continued at 80deg.C for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-12 (32 mg) with a yield of 38.1%. Yellow powder; melting point: 205-207 ℃; 1 H NMR(600MHz,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,quinazolone-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,1H,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.
example 15 preparation of Compound I-13:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring for 15 min at 80℃and compound 1H-indole-3-carbaldehyde (39 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10H, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-13 (26 mg) with a yield of 31.0%. Yellow powder; melting point: 234-236 ℃; 1 H NMR(600MHz,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.
example 16 preparation of Compound I-14:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), piperidine (0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80℃and 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde (30 mg,0.32 mmol) as compound was added and the reflux reaction was continued for 10H at 80℃and monitored by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-14 (101 mg) with a yield of 53.4%. Yellow powder; melting point: 123-125 ℃; 1 H NMR(600MHz,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),7.89–7.85(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 ClN 4 O 2 [M+H] + ,357.1113；found,357.1112.
example 17 preparation of Compound I-15:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-1 (57 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-15 (38 mg) with a yield of 37.2%. Yellow powder; melting point: 194-196 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ12.33(s,1H,quinazolinone-NH),8.21(d,J＝7.8Hz,1H,quinazolinone-5-H),8.16(d,J＝16.1Hz,1H,CH＝CH-imidazole),7.92(t,J＝7.5Hz,1H,quinazolinone-7-H),7.88(d,J＝7.7Hz,1H,quinazolinone-8-H),7.73(d,J＝16.1Hz,1H,CH＝CH-imidazole),7.67(t,J＝7.4Hz,1H,quinazolinone-6-H),4.22–4.17(m,2H,CH 2 CH 3 ),2.74[t,J＝7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.67(p,J＝7.6Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.38[q,J＝7.4Hz,2H,(CH 2 ) 2 CH 2 CH 3 ],1.30(t,J＝7.2Hz,3H,CH 2 CH 3 ),0.93[t,J＝7.4Hz,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.
example 18 preparation of Compound I-16:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-2 (60 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-16 (93 mg) with a yield of 87.7%. Yellow powder; melting point: 216-218 ℃; 1 H NMR(600MHz,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 ClN 4 O 2 [M+Na] + ,399.1582；found,399.1580.
example 19 preparation of Compound I-17:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-3 (64 mg,0.27 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-17 (88 mg) with a yield of 80.2%. Yellow powder; melting point: 171-173 ℃; 1 H NMR(600MHz,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 ClN 4 O 2 [M+H] + ,435.1558；found,435.1557.
example 20 preparation of Compound I-18:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-4 (68 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-18 (82 mg) with a yield of 72.3%. Yellow powder; melting point: 178-180 ℃; 1 H NMR(600MHz,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.
example 21 preparation of Compound I-19:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80℃and Compound III-5 (72 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-19 (99 mg) with a yield of 84.5%. Yellow powder; melting point: 175-177 ℃; 1 H NMR(600MHz,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 ,(CH 2 ) 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.for C 24 H 29 ClN 4 O 2 [M+H] + ,447.2052；found,447.2051.
example 22 preparation of Compound I-20:
in a 25mL round bottom flask was added intermediate II-11 (50 mg,0.27 mmoll), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80℃and III-6 (80 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-20 (80 mg) with a yield of 64.2%. Yellow powder; melting point: 159-161 ℃; 1 H NMR(600MHz,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 CH 3 ,(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 ClN 4 O 2 [M+H] + ,469.2365；found,469.2365.
example 23 preparation of Compound I-21:
in a 25mL round bottom flask was added intermediate II-11 (50 mg,0.27 mmmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 minutes, compound III-7 (87 mg,0.27 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-21 (98 mg) with a yield of 71.5%. Yellow powder; melting point: 135-137 ℃; 1 H NMR(600MHz,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 CH 3 ],2.72[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 ) 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＝7.3Hz,3H,(CH 2 ) 3 CH 3 ],0.80[t,J＝6.9Hz,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.
example 24 preparation of Compound I-22:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmoll), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80℃and Compound III-8 (61 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by TLC until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-22 (84 mg) with yield of 78.9%. Yellow powder; melting point: 205-207 ℃; 1 H NMR(600MHz,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＝7.6Hz,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 ClN 4 O 3 [M+H] + ,401.1375；found,401.1375.
example 25 preparation of Compound I-23:
in a 25mL round bottom flask was added intermediate II-11 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-9 (73 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-23 (86 mg) with 73.0% yield. Yellow powder; melting point: 209-211 ℃; 1 H NMR(600MHz,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,quinazolinone-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＝7.6Hz,2H,CH 2 (CH 2 ) 2 CH 3 ],1.61(p,J＝7.6Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.36[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 ClN 4 O 4 [M+Na] + ,437.0987；found,437.0990.
example 26 preparation of Compound I-24:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-10 (68 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-24 (41 mg) with a yield of 36.3%. Yellow powder; melting point: 151-153 ℃; 1 H NMR(600MHz,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,quinazolinone-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,(CH 2 ) 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 ClN 4 O 2 [M+H] + ,425.1739；found,425.1738.
example 27 preparation of Compound I-25:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-11 (64 mg,0.27 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-25 (83 mg) with 76.0% yield. Yellow powder; melting point: 185-187 ℃; 1 H NMR(600MHz,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 2 CH 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 ClN 4 O 2 [M+H] + ,411.1582；found,411.1584.
example 28 preparation of Compound I-26:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-12 (68 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-26 (92 mg) with a yield of 81.5%. Yellow powder; melting point: 180-182 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ12.35(s,1H,quinazolone-NH),8.21(d,J＝7.7Hz,1H,quinazolone-5-H),8.12(d,J＝16.1Hz,1H,CH＝CH-imidazole),7.93(t,J＝7.3Hz,1H,quinazolinone-7-H),7.86(d,J＝7.8Hz,1H,quinazolinone-8-H),7.76(d,J＝16.0Hz,1H,CH＝CH-imidazole),7.68(t,J＝7.1Hz,1H,quinazolinone-6-H),4.22(d,J＝6.4Hz,2H,N-CH 2 -cyclobutyl),2.74[t,J＝7.2Hz,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＝7.1Hz,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.
example 29 preparation of Compound I-27:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-13 (71 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10h, followed by thin layer chromatography monitoring to completion. Separating by column chromatography, and drying to obtain compound I-27 (75 mg) with a yield of 64.3%. Yellow powder; melting point: 174-176 ℃; . 1 H NMR(600MHz,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 ClN 4 O 2 [M+H] + ,439.1895；found,439.1894.
Example 30 preparation of Compound I-28:
adding the intermediate II-1 into a 25mL round bottom flask50mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring at 80deg.C for 15 min, adding compound III-14 (75 mg,0.27 mmol), and continuing reflux reaction at 80deg.C for 10 hr, and monitoring and tracking by thin layer chromatography until the reaction is completed. Separating by column chromatography, and drying to obtain compound I-28 (80 mg) with a yield of 66.5%. Yellow powder; melting point: 181-183 ℃; 1 H NMR(600MHz,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 ClN 4 O 2 [M+H] + ,453.2052；found,453.2050.
example 31 preparation of Compound I-29:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80℃and Compound III-15 (86 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by TLC until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-29 (103 mg) with a yield of 84.1%. Yellow powder; melting point: 199-201 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ12.26(s,1H,quinazolone-NH),8.19(d,J＝7.0Hz,1H,quinazolone-5-H),8.07(d,J＝16.0Hz,1H,CH＝CH-imidazole),7.92(t,J＝7.6Hz,1H,quinazolinone-7-H),7.81(d,J＝7.2Hz,1H,quinazolinone-8-H),7.68-7.63(m,2H,CH＝CH-imidazole,quinazolinone-6-H),7.19(d,J＝6.1Hz,2H,Ph-2,6-H),6.98(d,J＝6.2Hz,2H,Ph-3,5-H),5.45(s,2H,CH 2 -Ar),2.74[t,J＝7.5Hz,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＝7.3Hz,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.
example 32 preparation of Compound I-30:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80℃and Compound III-16 (83 mg,0.27 mmol) was added and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-30 (109 mg) with yield of 85.2%. Yellow powder; melting point: 191-193 ℃; 1 H NMR(600MHz,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,1H,CH＝CH-imidazole),7.91(t,J＝7.7Hz,1H,quinazolinone-7-H),7.80(d,J＝8.0Hz,1H,quinazolinone-8-H),7.66(t,J＝7.4Hz,1H,quinazolinone-6-H),7.61(d,J＝16.1Hz,1H,CH＝CH-imidazole),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.
example 33 preparation of Compound I-31:
in a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-17 (78 mg,0.27 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-31 (91 mg) with 73.7% yield. Yellow powder; melting point: 184-186 ℃; 1 H NMR(600MHz,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 ClFN 4 O 2 [M+H] + ,465.1488；found,465.1488.
example 34 preparation of Compound I-32:
into a 25mL round bottom flask was added intermediate II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%,0.2 mL) as a catalyst, ethanol (10 mL) as a solvent, stirring at 80℃for 15 minutes, adding compound III-18 (86 mg,0.27 mmol), and continuing the reflux reaction at 80℃for 10 hours, and monitoring and tracking by thin layer chromatography until the reaction is finished. Separating by column chromatography, and drying to obtain compound I-32 (111 mg) with a yield of 84.9%. Yellow powder; melting point: 213-215 ℃; 1 H NMR(600MHz,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,quinazolone-5-H),8.05(d,J＝16.1Hz,1H,CH＝CH-imidazole),7.91(t,J＝8.2Hz,1H,quinazolinone-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 ClN 5 O 4 [M+Na] + ,514.1253；found,514.1248
example 35 preparation of Compound I-33:
in a 25mL round bottom flask was added compound II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-19 (83 mg,0.27 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-33 (108 mg) with yield of 85.0%. Yellow powder; melting point: 191-193 ℃; 1 H NMR(600MHz,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,1H),7.67(t,J＝7.5Hz,1H,Ar-2-H),7.62(d,J＝16.1Hz,1H,CH＝CH-imidazole),7.47(d,J＝8.4Hz,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,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 Cl 2 N 4 O 2 [M+H] + ,481.1193；found,481.1193.
example 36 preparation of Compound I-34:
in a 25mL round bottom flask was added compound II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-20 (92 mg,0.27 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-34 (103 mg) with 75.2% yield. Yellow powder; melting point: 182-184 ℃; 1 H NMR(600MHz,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＝8.1Hz,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.
example 37 preparation of Compound I-35:
in a 25mL round bottom flask was added compound II-1 (50 mg,0.27 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-21 (83 mg,0.27 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-35 (83 mg) with a yield of 64.9%. Yellow powder; melting point: 202-204 ℃; 1 H NMR(600MHz,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.for C 25 H 22 Cl 2 N 4 O 2 [M+H] + ,481.1193；found,481.1194.
example 38 preparation of Compound I-36:
a25 mL round bottom flask was charged with Compound II-2 (50 mg,0.24 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent,stirring was carried out at 80℃for 15 minutes, compound III-14 (69 mg,0.24 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-36 (47 mg) with a yield of 53.4%. Yellow powder; melting point: 180-182 ℃; 1 H NMR(600MHz,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＝16.2Hz,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 ClFN 4 O 2 [M+H] + ,471.1958；found,471.1960.
example 39 preparation of Compound I-37:
in a 25mL round bottom flask was added compound II-3 (50 mg,0.22 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred at 80℃for 15 min, compound III-14 (64 mg,0.22 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-37 (47 mg) with a yield of 42.9%. Yellow powder; melting point: 209-211 ℃; 1 H NMR(600MHz,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.
example 40 preparation of Compound I-38:
in a 25mL round bottom flask was added compound II-4 (50 mg,0.2 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80℃and compound III-14 (55 mg,0.2 mmol) was added and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-38 (78 mg) with 76.9% yield. Yellow powder; melting point: 200-202 ℃; 1 H NMR(600MHz,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.
example 41 preparation of Compound I-39:
in a 25mL round bottom flask was added compound II-5 (50 mg,0.25 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirring at 80℃for 15 min, compound III-14 (70 mg,0.25 mmol) was added, and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-39 (62 mg) with a yield of 53.7%. Yellow powder; melting point: 209-211 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ12.26(s,1H,quinazolinone-NH),8.10(d,J＝16.3Hz,1H,CH＝CH-imidazole),8.02(s,1H,quinazolinone-5-H),7.75(s,2H,quinazolinone-7,8-H),7.71(d,J＝16.1Hz,1H,CH＝CH-imidazole),4.02(d,J＝7.1Hz,2H,N-CH 2 -cyclohexane),2.72[t,J＝7.6Hz,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＝7.3Hz,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＝7.3Hz,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.
example 42 preparation of Compound I-40:
in a 25mL round bottom flask was added compound II-6 (50 mg,0.25 mmol), aqueous sodium hydroxide (30%, 0.2 mL) as catalyst, ethanol (10 mL) as solvent, stirred for 15 min at 80℃and compound III-14 (64 mg,0.25 mmol) was added and the reflux reaction was continued at 80℃for 10 hours, followed by monitoring by thin layer chromatography until the reaction was completed. Separating by column chromatography, and drying to obtain compound I-40 (68 mg) with 58.9% yield. Yellow powder; melting point: 214-216 ℃; 1 H NMR(600MHz,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 CH 3 ]ppm.HRMS(ESI)calcd.for C 26 H 31 ClN 4 O 2 [M+H] + ,467.2208；found,467.2208.
example 43 in vitro antimicrobial Activity of quinazolinone ketene azoles:
the test compounds were dissolved in a small amount of dimethyl sulfoxide by a 96-well microdilution method conforming to the clinical laboratory standards (Clinical and Laboratory Standards Institute, CLSI) established by the national committee of america, the quinazolinone-azoles prepared in examples 3 to 42 were examined for Minimum Inhibitory Concentrations (MIC) of gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC 29213), gram-negative bacteria (klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922, acinetobacter baumannii), diluted with water to prepare a solution with a concentration of 1.28mg/mL, then the solution was diluted with a culture solution to 128 μg/mL, cultured at 35 ℃ for 24 to 72 hours, and after shaking the culture plate sufficiently on an oscillator, MIC was measured at a wavelength nm, and the results are shown in tables 1 to 2.
Table 1, in vitro anti-gram-positive bacterial Activity data (MIC, μg/mL) of quinazolinone and ketene azoles prepared in examples 3-42
Table 2, in vitro anti-gram-negative bacterial Activity data (MIC, μg/mL) of quinazolinone and ketene azoles prepared in examples 3-42
As can be seen from Table 1, the compound of the present invention showed a certain inhibitory effect on the gram-positive bacteria tested, and in particular, the compound I-4 showed excellent inhibitory activity against MRSA, staphylococcus aureus 29213 and enterococcus faecalis tested, with MIC values of 0.5, 4, 1 and 2. Mu.g/mL, respectively. Compounds I-7 and I-9 have good inhibitory activity against enterococcus faecalis and MIC value of 1 μg/mL. The inhibition activity of the reference drug norfloxacin on the tested MRSA, staphylococcus aureus 25923, staphylococcus aureus 29213 and enterococcus faecalis is obviously superior to that of the reference drug norfloxacin (MIC values are 8, 4, 2, 4 and 2 mug/mL respectively). Some compounds have antibacterial activity comparable to, or even stronger than, the reference drug norfloxacin.
As can be seen from Table 2, the compounds of the present invention showed a certain inhibition effect on the gram-negative bacteria tested, in particular, the compound I-4 had excellent inhibitory activity on Klebsiella pneumoniae, E.coli 25922, P.aeruginosa and P.aeruginosa 27853 tested, and MIC values were 2, 0.5, 4 and 2. Mu.g/mL, respectively. The compound I-36 has good inhibitory activity on tested Klebsiella pneumoniae, escherichia coli 25922, pseudomonas aeruginosa and pseudomonas aeruginosa 27853, and MIC values are 4, 8, 1, 4 and 2 mug/mL respectively. The inhibition activity of the norfloxacin on the tested klebsiella pneumoniae, escherichia coli 25922, pseudomonas aeruginosa 27853 and acinetobacter baumannii (MIC values are respectively 4, 8, 4 and 2 mug/mL) are obviously superior to that of the reference medicament norfloxacin. Some compounds have antibacterial activity comparable to, or even stronger than, the reference drug norfloxacin.
Example 44 pharmaceutical use of quinazolinone ketene azole compound:
according to the detection result of the antimicrobial activity, the quinazolinone ketene azole compound provided by the invention has better antibacterial activity, and can be prepared into antibacterial medicines for clinical use. The medicines can be single preparations, for example, the medicines are prepared from quinazolinone ketene azole compounds with a structure and pharmaceutically acceptable auxiliary materials; the compound preparation can also be a compound preparation, for example, the compound preparation is prepared from quinazolinone ketene azole compounds with one structure and the existing antibacterial active ingredients (such as sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or the compound preparation is prepared from a plurality of quinazolinone ketene azole compounds with different structures and pharmaceutically acceptable auxiliary materials. The preparation type comprises dosage forms such as tablets, capsules, powder, granules, dripping pills, injection, powder injection, solution, suspension, emulsion, suppository, ointment, gel, film, aerosol, transdermal absorption patch and the like, and various slow release, controlled release preparations and nano preparations.
1. Preparation of Compound I-4 tablets
Prescription: 1000 tablets are prepared from 10g of compound I-4, 50g of corn starch, 187g of lactose, 3.0g of magnesium stearate and a proper amount of ethanol solution with the volume percentage concentration of 70%.
The preparation method comprises the following steps: drying corn starch at 105 ℃ for 5 hours for later use; uniformly mixing the compound I-4 with lactose and corn starch, preparing a soft material by using 70% ethanol solution, sieving to prepare wet granules, adding magnesium stearate, and tabletting to obtain the compound; each tablet weighs 250mg, and the content of active ingredients is 10mg.
2. Preparation of Compound I-7 Capsule
Prescription: compound I-7.25 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2.0g, sweetener 1.25g, orange essence 0.25g, pigment proper amount and water proper amount, and is prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound I-7 of the prescription amount, pulverizing into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment of the prescription amount, making soft mass with water, granulating with 12-14 mesh sieve, drying at 40-50deg.C, sieving, granulating, and encapsulating; each tablet weighs 50mg, and the active ingredient content is 25mg.
3. Preparation of Compound I-10 granules
Prescription: compound I-10 26g, dextrin 120g, sucrose 280g.
The preparation method comprises the following steps: mixing compound I-10, dextrin and sucrose, granulating by wet method, drying at 60deg.C, and packaging.
4. Preparation of Compound I-15 injection
Prescription: compound I-15 g, propylene glycol 500mL, water for injection 500mL, and total 1000mL.
The preparation method comprises the following steps: weighing compound I-15, adding propylene glycol and injection water, stirring for dissolving, adding 1g of active carbon, fully stirring, standing for 15 minutes, filtering and decarbonizing by using a 5 mu m titanium rod, finely filtering by sequentially using a microporous filter membrane with the pore diameter of 0.45 mu m and 0.22 mu m, finally filling and sealing in a 10mL ampoule, and sterilizing by flowing steam at 100 ℃ for 45 minutes to obtain the compound.
5. Preparation of compound I-18 powder injection
The preparation method comprises the following steps: packaging the intermediate I-8 sterile powder under sterile condition.
6. Preparation of Compound I-20 eye drops
Prescription: compound I-20.78 g, sodium chloride 0.9g, appropriate amount of boric acid buffer solution, distilled water was added to 1000mL.
The preparation method comprises the following steps: weighing compound I-20 and sodium chloride, adding into 500mL distilled water, regulating pH to 6.5 with boric acid buffer solution after dissolution, adding distilled water to 1000mL, stirring, filtering with microporous membrane, packaging, sealing, and sterilizing with 100deg.C circulating steam for 1 hr.
7. Preparation of compound I-16 liniment
Prescription: compound I-16 g, potassium soap 7.5g, camphor 5g, distilled water to 100mL.
The preparation method comprises the following steps: dissolving camphor with 95% ethanol solution for standby; heating and liquefying potassium soap for later use, weighing compound I-16, adding potassium soap solution and camphol ethanol solution under continuous stirring, gradually adding distilled water, emulsifying completely, and adding distilled water to full volume.
8. Preparation of suppositories of Compound I-18
Prescription: compound I-18 g, gelatin 14g, glycerin 70g, distilled water 100mL, metric 100 pieces.
The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60deg.C to melt into paste, adding compound I-18, stirring, pouring into vaginal suppository mold when nearly solidifying, and cooling for solidification.
9. Preparation of Compound I-14 ointment
Prescription: 0.5-2g of compound I, 6-8g of hexadecanol, 8-10g of white vaseline, 8-19g of liquid paraffin, 2-5g of monoglyceride, 2-5g of polyoxyethylene (40) stearate, 5-10g of glycerol, 0.1g of ethylparaben and distilled water to 100g.
The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to dissolve completely, mixing, and keeping the temperature at 80deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85deg.C for dissolution, adding oil phase under stirring, emulsifying, adding compound I-14, stirring, and cooling.
10. Preparation of Compound I-19 aerosols
Prescription: compound I-19 2.5g,Span20 3g, talc (100 mesh) 4g, trichlorofluoromethane was added in an appropriate amount.
The preparation method comprises the following steps: drying compound I-19, span20 and talcum powder in vacuum drying oven for several hours, cooling to room temperature in a dryer, pulverizing into micropowder with jet mill, mixing according to prescription, filling into a sealed container, and adding trichloro-monofluoromethane to specified amount.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the present invention, which is intended to be covered by the claims of the present invention.
Claims (10)
1. The quinazolinone ketene azole compound and the pharmaceutically acceptable salt thereof are characterized in that the structure is shown as a general formula I:
in the method, in the process of the invention,
R 1 、R 2 、R 3 is hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl, amino, hydroxyl, cyano, carboxyl or nitro;
X, Y, Z, W is C, CH, NH, N, O or S atom.
2. The quinazolinone ketene azole compound and pharmaceutically acceptable salts thereof according to claim 1, wherein:
R 1 、R 2 、R 3 is hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl, amino, hydroxy, cyano, carboxylA group or nitro group;
X, Y, Z, W is C, CH, NH, N, O or S atom.
3. The quinazolinone oxazole compound and pharmaceutically acceptable salts thereof of claim 1 which is any of the following:
4. the quinazolinone ketene azole compound and pharmaceutically acceptable salts thereof according to claim 3, wherein: the pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.
5. A process for the preparation of quinazolinone and the pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 4, said process comprising:
a. preparation of intermediate II-1-6: taking anthranilic acid or an anthranilamide compound and pyruvic acid as starting materials, and obtaining an intermediate II-1-6 through cyclization reaction;
b. preparation of intermediate III: different types of halogenated compounds react with 2-butyl-5-chloro-1H-imidazole-4-formaldehyde to obtain an intermediate III;
wherein:
R 1 is hydrogen, alkyl, cyano, alkoxy, alkenyl, alkynyl, aryl, hydroxyalkyl, carboxyl, ester, acyl, or heterocyclic; n is an integer of 0 to 15.
c. Preparation of quinazolinone ketene azole compounds shown in general formulas I-1-13: the intermediates II1-6 respectively react with aldehyde under the action of alkali to obtain the quinazolinone ketene azole compounds shown in the general formulas I-1-13.
d. Preparation of quinazolinone ketene azole compounds shown in general formulas I-14-40: and respectively carrying out condensation reaction on the intermediates II1-6 and the intermediate III under the action of alkali to obtain the quinazolinone ketene azole compounds shown in the general formulas I14-40.
6. The method of claim 5, wherein;
in the step a, the mol ratio of the anthranilamide to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the 1-hydroxybenzotriazole monohydrate is 1:1.2-2:1.2-2, and after the reaction is carried out for 6-8 hours at room temperature, the obtained solid is reacted in a 0.5M sodium hydroxide aqueous solution for 30 minutes to obtain an intermediate II-1;
in the step b, the molar ratio of the intermediates II1-6 to the aldehyde is 1:1.2; the alkali is piperidine; the condensation reaction is carried out by taking ethanol as solvent, reacting for 5h at 80-100 ℃;
in the step c, the molar ratio of the intermediates II1 to 6 to the intermediate III is 1:1.2; the alkali is or sodium hydroxide aqueous solution; the condensation reaction is carried out by taking ethanol as solvent, reacting at room temperature or 80-100 ℃ for 5-8 h;
in the step d, the ratio of the 2-butyl-5-chloro-1H-imidazole-4-formaldehyde to the halogenated compound to the potassium carbonate is 1:1.5-2:1.5-2, and the reaction is specifically carried out by taking acetonitrile as a solvent at 80-100 ℃ for 4-10H.
7. Use of a quinazolinone ketene azole compound according to any of claims 1 to 4 and pharmaceutically acceptable salts thereof for the preparation of an antibacterial agent.
8. The use according to claim 7, characterized in that: the bacteria are one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC29213, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922 or acinetobacter baumannii.
9. A formulation comprising a quinazolinone ketene azole compound of any of claims 14 and pharmaceutically acceptable salts thereof.
10. The formulation of claim 9, wherein the formulation is one of a tablet, capsule, granule, injection, powder for injection, eye drop, liniment, suppository, ointment, or aerosol.
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