CN117285510A - Benzopyridone vinyl pyrimidine compound, and preparation method and medical application thereof - Google Patents

Abstract

The present invention relates to benzopyridonevinypyrimidine compounds and their preparation methods and pharmaceutical applications. It belongs to the field of chemical synthesis technology. The benzopyridonevinypyrimidine compound is shown in the general formula I. This type of compound is effective against gram-positive bacteria and leather. One or more species of blue-negative bacteria and fungi have good inhibitory activity and can be used to prepare antibacterial and/or antifungal drugs without obvious drug resistance, which can provide more efficient and effective methods for clinical anti-infection treatment. Safe drug candidates can help solve clinical treatment problems such as increasingly serious microbial drug resistance, stubborn pathogenic microorganisms, and emerging harmful microorganisms.

Description

Benzopyridone vinyl pyrimidine compound and its preparation method and medical application

Technical Field

The invention belongs to the technical field of chemical synthesis, and specifically relates to benzopyridone vinyl pyrimidine compounds and preparation methods and medical applications thereof.

Background Art

The pyrimidine ring is an important class of six-membered nitrogen-containing heterocyclic rings. Its unique structure enables it to bind to biological molecules through a variety of non-covalent bonding interactions, and has a wide range of application potential in the field of medicinal chemistry. In particular, in the field of antimicrobial drugs, many pyrimidine-based antimicrobial drugs have been widely used in clinical practice; they can inhibit the function of enzymes and cause bacterial death by forming supramolecular interactions with enzymes in microorganisms. Therefore, the development of new structural drugs based on pyrimidine rings has great application value in the field of antibacterial drugs, especially hybridization with some clinical drug skeletons.

Benzopyridone-based quinolone antibiotics are an important first-line antibiotic that has made important contributions to protecting people's lives and health. So far, four generations of quinolone drugs have been successfully developed and marketed. However, due to the widespread use and even abuse in clinical practice, bacterial resistance to this type of drug has increased significantly, resulting in a decrease in clinical efficacy. Structural modification based on the parent structure of the benzopyridone skeleton to develop new antibacterial drugs is an important method to solve the increasingly serious problem of drug resistance. Many studies have reported that the combination of azole heterocyclic compounds and benzopyridone shows good antimicrobial activity, while there are fewer studies on the combination of pyrimidines with it. In this study, the benzopyridone vinyl pyrimidine molecule with a new framework structure was obtained by using an ene cyanide fragment at the C-7 position of benzopyridone. The introduction of the conjugated structure helps to improve the affinity of the compound with DNA, enzymes or other receptors in the body through a variety of non-covalent bond forces to interact with the target and enhance the antibacterial activity; at the same time, the construction of new structural molecules may lead to the discovery of new antibacterial mechanisms, which is expected to overcome serious bacterial resistance.

Summary of the invention

In view of this, one of the objects of the present invention is to provide benzopyridone vinyl pyrimidine compounds and pharmaceutically acceptable salts thereof; a second object is to provide a method for preparing benzopyridone vinyl pyrimidine compounds and pharmaceutically acceptable salts thereof; a third object is to provide the use of benzopyridone vinyl pyrimidine compounds and pharmaceutically acceptable salts thereof in the preparation of antibacterial and/or antifungal drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial treatment, and helping to solve clinical treatment problems such as increasingly serious drug resistance, stubborn pathogenic microorganisms and newly emerging harmful microorganisms.

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

1. Benzopyridone vinyl pyrimidine compounds and pharmaceutically acceptable salts thereof, the structure of which is shown in the general formula I:

In the formula,

n is an integer from 0 to 18;

^R1 is hydrogen, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl, hydroxyl, cyano, ester, carboxyl, phenyl, substituted phenyl or heteroaryl;

^R2 is hydrogen, amino, amine, cyano, nitro, halogen, alkyl, alkoxy or alkylthiol.

Preferred:

n is any one of 0, 1, 2, 3, 4, 5, 8, 12 or 16;

^R1 is any one of hydrogen, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl;

^R2 is any one of amino, amine, methoxy or methylmercapto.

Preferably, it is any one of the following compounds:

Preferably, the pharmaceutically acceptable salt is hydrochloride, bromate, iodide, sulfate, nitrate, trifluoroacetate or acetate.

2. A method for preparing the benzopyridone vinyl pyrimidine compound and its pharmaceutically acceptable salt, the method being as follows:

a. Adding the compound represented by the general formula II to ethanol, adding various pyrimidine aldehyde compounds and then reflux reacting under the action of a base to obtain the benzopyridone vinyl pyrimidine compound represented by the general formula I;

in:

n is 0, 1, 2, 3, 4, 5, 8, 12 or 16;

^R1 is hydrogen, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl.

b. Preparation of pharmaceutically acceptable salts of benzopyridone vinyl pyrimidine compounds of general formula I: dissolve the benzopyridone vinyl pyrimidine compounds of general formula I in an organic solvent, add a pharmaceutically acceptable acid and react until no precipitate is generated to obtain pharmaceutically acceptable salts of the benzopyridone vinyl pyrimidine compounds of general formula I.

Preferably,

In step a, the base is one of dimethylamine, diethylamine, N-ethylethanolamine, diethanolamine, pyrrolidine, piperidine, morpholine or sodium acetate, the molar ratio of intermediate II, pyrimidine aldehyde compound and base is 1:1-1.5:0.2-1.2, and the reaction is specifically carried out at 60-90° C. for 8-24 hours with ethanol as solvent;

In step b, the organic solvent is at least one of chloroform, acetone, acetonitrile, ether, tetrahydrofuran, dioxane or N,N-dimethylformamide; and the pharmaceutically acceptable acid is hydrochloric acid or sulfuric acid.

3. Use of the benzopyridone vinyl pyrimidine compounds and pharmaceutically acceptable salts thereof in the preparation of antibacterial and/or antifungal drugs.

Preferably, the bacteria are methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC (B) 26001, Staphylococcus aureus CMCC (B) 26003, Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027, Pseudomonas aeruginosa CMCC (B) 10104 or Acinetobacter baumannii; the fungus is any one or more of Candida albicans, Candida albicans ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 22019.

4. A preparation containing the benzopyridone vinyl pyrimidine compound and its pharmaceutically acceptable salt.

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

The beneficial effects of the present invention are as follows: the present invention provides a benzopyridone vinyl pyrimidine compound and a preparation method and application thereof. The present invention utilizes the principle of drug design splicing to hybridize a pyrimidine compound at the C-7 position of benzopyridone through a cyanide vinyl fragment, and designs and synthesizes a series of benzopyridone vinyl pyrimidine compounds. The compounds are tested for in vitro antimicrobial activity and found to be effective against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC (B) 26001, Staphylococcus aureus CMCC (B) 26003), Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC The present invention discloses a novel novel novel antibacterial and antifungal drug having certain inhibitory activity against a variety of bacteria (such as Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC15442, Pseudomonas aeruginosa ATCC 9027, Pseudomonas aeruginosa CMCC(B)10104, Acinetobacter baumannii) and fungi (Candida albicans, Candida albicans ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC22019), and can be used to prepare antibacterial and/or antifungal drugs without obvious drug resistance, providing more efficient and safe candidate drugs for clinical antibacterial treatment, and helping to solve the increasingly serious clinical treatment problems such as drug resistance, stubborn pathogenic microorganisms and newly emerging harmful microorganisms.

Other advantages, objectives and features of the present invention will be described in the following description to some extent, and to some extent, will be obvious to those skilled in the art based on the following examination and study, or can be taught from the practice of the present invention. The objectives and other advantages of the present invention can be realized and obtained through the following description.

DETAILED DESCRIPTION

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.

Example 1. Preparation of Intermediate II

References "[1]Kamal, A.; Devaiah, V.; Reddy, K.L.; Kumar, M.S.Synthesis and biological activity of fluoroquinolone-pyrrolo[2,1-c][1,4]benzodiazepineconjugates.Bioorg.Med.Chem. 2005,13,2021-2029. [2] Valery, N.C.; Nataliya, N.M.; Fedor, V.A.; Svetlana, K.K.; Emiliya, V.N.; Marina, A.E.; Mikhail, I.K.; Marionella, A.K. Synthesis and antimycobacterial evaluation of new(2) -oxo-2H-chromen-3-yl)substituted fluoroquinolones.J.Fluorine Chem.2018,208,15-23." The intermediate II was prepared by the method described.

Example 2, Preparation of Compound I-1-1:

Intermediate II-1 (100 mg, 0.36 mmol), 2-amino-5-pyrimidinecarboxaldehyde (49 mg, 0.40 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78° C. for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 104 mg of yellow solid I-1-1, with a yield of 75.4%, and a melting point of >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.90(s,1H),9.12(s,1H),8.90(s,2H),8.23(d,J＝6.2Hz,1H),8.17(d,J＝10.6Hz,1H),7.81(s,1H),7.69(s,2H),4.68(m,2H),1.46(t,J＝7.0Hz,3H)ppm.

Example 3, Preparation of Compound I-1-2:

Intermediate II-2 (100 mg, 0.35 mmol), 2-amino-5-pyrimidinecarboxaldehyde (47 mg, 0.38 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78° C. for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 102 mg of yellow solid I-1-2, with a yield of 74.8%, and a melting point of >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.83(s, 1H), 9.10(s, 1H), 8.90(s, 2H), 8.21(d, J＝6.3Hz, 1H), 8.15(d, J＝10.6Hz, 1H), 7.78(s, 1H), 7.68(s, 2H), 4.62(t, J＝7.2Hz, 2H), 1.89(m, 2H), 0.93(t, J＝7.3Hz, 3H)ppm.

Example 4, Preparation of Compound I-1-3:

Intermediate II-3 (100 mg, 0.33 mmol), 2-amino-5-pyrimidinecarboxaldehyde (45 mg, 0.36 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78° C. for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 116 mg of yellow solid I-1-3, yield: 76.8%, melting point: >300°C; ¹ H NMR (600 MHz, 25°C, DMSO-d ₆ )δ14.81(s, 1H), 9.07(s, 1H), 8.89(s, 2H), 8.17(d, J＝6.0Hz, 1H), 8.12(d, J＝10.5Hz, 1H), 7.79(s, 1H), 7.64(s, 2H), 4.64(t, J＝7.3Hz, 2H), 1.84(m, 2H), 1.37(m, 2H), 0.94(t, J＝7.4Hz, 3H)ppm.

Example 5, Preparation of Compound I-1-4:

Intermediate II-4 (100 mg, 0.32 mmol), 2-amino-5-pyrimidinecarboxaldehyde (43 mg, 0.35 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78° C. for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 115 mg of yellow solid I-1-4, with a yield of 87.1%, and a melting point of 293.5-295.0°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.83(s,1H),9.08(s,1H),8.89(s,2H),8.17(d,J＝6.2Hz,1H),8.11(d,J＝10.6Hz,1H),7.79(s,1H),7.70(s,2H),4.64(t,J＝7.3Hz,2H),1.85(m,2H),1.34(m,4H),0.90–0.85(m,3H)ppm.

Example 6, Preparation of Compound I-1-5:

Intermediate II-5 (100 mg, 0.28 mmol), 2-amino-5-pyrimidinecarboxaldehyde (38 mg, 0.31 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78° C. for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 83 mg of yellow solid I-1-5, with a yield of 64.3%, and a melting point of 256.1-258.2°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.84(s,1H),9.07(s,1H),8.89(s,2H),8.14(m,2H),7.79(s,1H),7.69(s,2H),4.63(t,J＝7.4Hz,2H),1.84(m,2H),1.35–1.21(m,10H),0.82(t,J＝6.7Hz,3H)ppm.

Example 7, Preparation of Compound I-1-6:

Intermediate II-6 (100 mg, 0.24 mmol), 2-amino-5-pyrimidinecarboxaldehyde (33 mg, 0.27 mmol) and piperidine (4 mg, 0.04 mmol) were reacted in ethanol (8 mL) at 78° C. for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 83 mg of yellow solid I-1-6, with a yield of 74.2%, and a melting point of 266.8-268.2°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.87(s,1H),9.10(s,1H),8.89(s,2H),8.16(m,2H),7.80(s,1H),7.70(s,2H),4.64(t,J＝7.2Hz,2H),1.88–1.79(m,2H),1.25(m,18H),0.83(t,J＝6.6Hz,3H)ppm.

Example 8, Preparation of Compound I-1-7:

Intermediate II-7 (100 mg, 0.21 mmol), 2-amino-5-pyrimidinecarboxaldehyde (29 mg, 0.23 mmol) and piperidine (4 mg, 0.04 mmol) were reacted in ethanol (8 mL) at 78° C. for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 82 mg of yellow solid I-1-7, with a yield of 67.8%, and a melting point of 249.5-250.3°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.79(s,1H),9.08(s,1H),8.89(s,2H),8.15(m,2H),7.79(s,1H),7.67(s,2H),4.64(t,J＝7.2Hz,2H),1.83(m,2H),1.35–1.16(m,30H),0.84(t,J＝6.7Hz,3H)ppm.

Example 9, Preparation of Compound I-1-8:

Intermediate II-8 (100 mg, 0.35 mmol), 2-amino-5-pyrimidinecarboxaldehyde (47 mg, 0.38 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and water (10 mL) was added and stirred continuously. The solid obtained by suction filtration was recrystallized to obtain 96 mg of yellow solid I-1-8, with a yield of 70.6%, and a melting point of >300 ° C; ¹ H NMR (400 MHz, 25 ° C, DMSO-d ₆ ) δ 14.81 (s, 1H), 9.11 (s, 1H), 8.88 (s, 2H), 8.17-8.12 (m, 2H), 7.77 (s, 1H), 7.71 (s, 2H), 6.13 (m, 1H), 5.36-5.28 (m, 4H) ppm.

Example 10, Preparation of Compound I-1-9:

Intermediate II-9 (100 mg, 0.35 mmol), 2-amino-5-pyrimidinecarboxaldehyde (47 mg, 0.38 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 80 mg of yellow solid I-1-9, yield: 58.4%, melting point: >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.47(s,1H),9.22(s,1H),8.90(s,2H),8.25(d,J＝6.2Hz,1H),8.16(d,J＝10.6Hz,1H),7.80(s,1H),7.73(s,2H),5.57(d,J＝2.5Hz,2H),3.83(s,1H)ppm.

Example 11, Preparation of Compound I-1-10:

Intermediate II-10 (100 mg, 0.32 mmol), 2-amino-5-pyrimidinecarboxaldehyde (43 mg, 0.35 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 96 mg of yellow solid I-1-10, with a yield of 72.2%, and a melting point of 285.9-287.2°C; ¹ H NMR (600 MHz, 25°C, DMSO-d ₆ )δ14.74(s,1H),9.04(s,1H),8.88(s,2H),8.12(d,J＝10.6Hz,1H),8.05(d,J＝5.9Hz,1H),7.80(s,1H),7.62(s,2H),5.41(d,J＝6.8Hz,1H),5.23(d,J＝6.7Hz,2H),1.89(s,3H),1.77(s,3H)ppm.

Example 12, Preparation of Compound I-1-11:

Intermediate II-11 (50 mg, 0.17 mmol), 2-amino-5-pyrimidinecarboxaldehyde (24 mg, 0.19 mmol) and piperidine (3 mg, 0.03 mmol) were reacted in ethanol (8 mL) at 78° C. for 12 hours. After the reaction, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 43 mg of yellow solid I-1-11, with a yield of 63.2%, and a melting point of >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ +CF ₃ COOH) δ9.02 (s, 1H), 8.91 (s, 2H), 8.54 (d, J＝5.7 Hz, 1H), 8.02 (d, J＝10.3 Hz, 1H), 7.99–7.74 (bs, 2H), 7.67 (s, 1H), 3.82 (m, 1H), 1.28 (m, 2H), 1.11–1.04 (m, 2H) ppm.

Example 13, Preparation of Compound I-1-12:

Intermediate II-12 (100 mg, 0.33 mmol), 2-amino-5-pyrimidinecarboxaldehyde (45 mg, 0.37 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 113 mg of yellow solid I-1-12, with a yield of 83.7%, and a melting point of >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.86(s,1H),9.12(s,1H),8.90(s,2H),8.32(d,J＝6.2Hz,1H),8.15(d,J＝10.6Hz,1H),7.81(s,1H),7.69(s,2H),4.53(d,J＝7.3Hz,2H),1.53–1.46(m,1H),0.65–0.60(m,2H),0.55–0.51(m,2H)ppm.

Example 14, Preparation of Compound I-1-13:

Intermediate II-13 (100 mg, 0.32 mmol), 2-amino-5-pyrimidinecarboxaldehyde (43 mg, 0.35 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 109 mg of yellow solid I-1-13, with a yield of 82.0%, and a melting point of >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.86(s,1H),9.10(s,1H),8.90(s,2H),8.20(d,J＝6.2Hz,1H),8.13(d,J＝10.5Hz,1H),7.77(s,1H),7.70(s,2H),4.70(d,J＝7.4Hz,2H),2.90(m,1H),2.00–1.92(m,2H),1.91–1.82(m,4H)ppm.

Example 15, Preparation of Compound I-1-14:

Intermediate II-14 (100 mg, 0.30 mmol), 2-amino-5-pyrimidinecarboxaldehyde (41 mg, 0.34 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 74 mg of yellow solid I-1-14 with a yield of 56.1%. The melting point was 293.9-295.2°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.85(s,1H),9.11(s,1H),8.90(s,2H),8.23(d,J＝6.2Hz,1H),8.15(d,J＝10.7Hz,1H),7.78(s,1H),7.70(s,2H),4.62(d,J＝7.6Hz,2H),2.44(m,1H),1.71–1.61(m,4H),1.50(m,2H),1.30(m,2H)ppm.

Example 16, Preparation of Compound I-1-15:

Intermediate II-15 (100 mg, 0.29 mmol), 2-amino-5-pyrimidinecarboxaldehyde (40 mg, 0.32 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 111 mg of yellow solid I-1-15 with a yield of 76.6%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.76(s,1H),9.01(s,1H),8.89(s,2H),8.18(d,J＝6.1Hz,1H),8.13(d,J＝10.7Hz,1H),7.77(s,1H),7.71(s,2H),4.51(d,J＝7.3Hz,2H),1.90(s,1H),1.60(m,6H),1.17–1.09(m,4H)ppm.

Example 17, Preparation of Compound I-1-16:

Intermediate II-16 (100 mg, 0.30 mmol), 2-amino-5-pyrimidinecarboxaldehyde (40 mg, 0.33 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78° C. for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 108 mg of yellow solid I-1-16, with a yield of 82.4%, and a melting point of >300°C; ¹ H NMR (600 MHz, 25°C, DMSO-d ₆ )δ14.78(s, 1H), 9.30(s, 1H), 8.83(s, 2H), 8.49(d, J＝4.8Hz, 1H), 8.12(t, J＝8.0Hz, 2H), 7.87(t, J＝7.8Hz, 1H), 7.70(s, 2H), 7.64(d, J＝7.9Hz, 1H), 7.62(s, 1H), 7.35(t, J＝6.2Hz, 1H), 6.05(s, 2H)ppm.

Example 18, Preparation of Compound I-1-17:

Intermediate II-17 (100 mg, 0.29 mmol), 2-amino-5-pyrimidinecarboxaldehyde (40 mg, 0.32 mmol) and piperidine (6 mg, 0.07 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 90 mg of yellow solid I-1-17, with a yield of 68.6%, and a melting point of >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.78(s,1H),9.31(s,1H),8.83(s,2H),8.15–8.10(m,2H),7.72(s,2H),7.60(s,1H),7.38(s,5H),5.94(s,2H)ppm.

Example 19, Preparation of Compound I-1-18:

Intermediate II-18 (100 mg, 0.28 mmol), 2-amino-5-pyrimidinecarboxaldehyde (38 mg, 0.31 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78° C. for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and the mixture was stirred continuously. The solid obtained by filtration was recrystallized to obtain 98 mg of yellow solid I-1-18 with a yield of 75.4%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.72(s,1H),9.27(s,1H),8.84(s,2H),8.17–8.10(m,2H),7.72(s,2H),7.67(s,1H),7.40(m,2H),7.32–7.26(m,1H),7.21(t,J＝7.5Hz,1H),6.01(s,2H)ppm.

Example 20, Preparation of Compound I-1-19:

Intermediate II-19 (100 mg, 0.28 mmol), 2-amino-5-pyrimidinecarboxaldehyde (38 mg, 0.31 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78° C. for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 112 mg of yellow solid I-1-19 with a yield of 77.8%. The melting point was 279.8-282.3°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.75(s,1H),9.32(s,1H),8.83(s,2H),8.14(d,J＝10.8Hz,1H),8.06(d,J＝6.3Hz,1H),7.73(s,2H),7.59(s,1H),7.46–7.41(m,1H),7.33–7.28(m,1H),7.19(m,2H),5.94(s,2H)ppm.

Example 21, Preparation of Compound I-1-20:

Intermediate II-20 (100 mg, 0.28 mmol), 2-amino-5-pyrimidinecarboxaldehyde (38 mg, 0.31 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78° C. for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and the mixture was stirred continuously. The solid obtained by filtration was recrystallized to obtain 105 mg of yellow solid I-1-20 with a yield of 80.8%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.77(s,1H),9.31(s,1H),8.85(s,2H),8.17–8.10(m,2H),7.72(s,2H),7.63(s,1H),7.46(m,2H),7.22(t,J＝8.8Hz,2H),5.91(s,2H)ppm.

Example 22, Preparation of Compound I-1-21:

Intermediate II-21 (100 mg, 0.27 mmol), 2-amino-5-pyrimidinecarboxaldehyde (37 mg, 0.30 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and the mixture was stirred continuously. The solid obtained by filtration was recrystallized to obtain 97 mg of yellow solid I-1-21 with a yield of 75.8%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.68(s,1H),9.32(s,1H),8.84(s,2H),8.14(d,J＝10.7Hz,1H),8.07(d,J＝6.2Hz,1H),7.72(s,2H),7.61(s,1H),7.43(m,4H),5.93(s,2H)ppm.

Example 23, Preparation of Compound I-1-22:

Intermediate II-22 (100 mg, 0.25 mmol), 2-amino-5-pyrimidinecarboxaldehyde (33 mg, 0.27 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and the mixture was stirred continuously. The solid obtained by filtration was recrystallized to obtain 102 mg of yellow solid I-1-22 with a yield of 81.0%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.75(s,1H),9.37(s,1H),8.82(s,2H),8.16(d,J＝10.7Hz,1H),8.03(d,J＝6.1Hz,1H),7.78–7.71(m,4H),7.58(m,3H),6.05(s,2H)ppm.

Example 24, Preparation of Compound I-1-23:

Intermediate II-23 (100 mg, 0.25 mmol), 2-amino-5-pyrimidinecarboxaldehyde (33 mg, 0.27 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 122 mg of yellow solid I-1-23, with a yield of 87.8%, and a melting point of >300°C; ¹ H NMR (600 MHz, 25°C, DMSO-d ₆ )δ14.76(s,1H),9.26(s,1H),8.84(s,2H),8.14–8.11(m,2H),7.71(s,2H),7.62(s,1H),7.28(d,J＝7.9Hz,2H),7.19(d,J＝7.9Hz,2H),5.86(s,2H),2.27(s,3H)ppm.

Example 25, Preparation of Compound I-1-24:

Intermediate II-24 (100 mg, 0.27 mmol), 2-amino-5-pyrimidinecarboxaldehyde (37 mg, 0.30 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and the mixture was stirred continuously. The solid obtained by filtration was recrystallized to obtain 107 mg of yellow solid I-1-24 with a yield of 84.3%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.80(s,1H),9.26(s,1H),8.85(s,2H),8.19(d,J＝6.2Hz,1H),8.13(d,J＝10.7Hz,1H),7.73(s,2H),7.64(s,1H),7.36(d,J＝8.7Hz,2H),6.95(d,J＝8.7Hz,2H),5.84(s,2H),3.73(s,3H)ppm.

Example 26, Preparation of Compound I-1-25:

Intermediate II-25 (100 mg, 0.27 mmol), 2-amino-5-pyrimidinecarboxaldehyde (37 mg, 0.30 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and the mixture was stirred continuously. The solid obtained by filtration was recrystallized to obtain 108 mg of yellow solid I-1-25 with a yield of 84.2%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.70(s,1H),9.26(s,1H),8.85(s,2H),8.15(d,J＝10.7Hz,1H),8.10(d,J＝6.2Hz,1H),7.72(s,2H),7.68(s,1H),7.48(m,1H),7.39–7.33(m,1H),7.10(m,1H),5.97(s,2H)ppm.

Example 27, Preparation of Compound I-1-26:

Intermediate II-26 (100 mg, 0.27 mmol), 2-amino-5-pyrimidinecarboxaldehyde (37 mg, 0.30 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 114 mg of yellow solid I-1-26, with a yield of 89.1%, and a melting point of >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ9.16(s,1H),8.84(s,2H),8.11(d,J＝10.8Hz,1H),8.03(d,J＝6.2Hz,1H),7.71(s,2H),7.65(s,1H),7.37–7.26(m,3H),5.94(s,2H)ppm.

Example 28, Preparation of Compound I-1-27:

Intermediate II-27 (100 mg, 0.27 mmol), 2-amino-5-pyrimidinecarboxaldehyde (37 mg, 0.30 mmol) and piperidine (5 mg, 0.06 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and the mixture was stirred continuously. The solid obtained by filtration was recrystallized to obtain 106 mg of yellow solid I-1-27 with a yield of 82.8%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.62(s, 1H), 9.26(s, 1H), 8.87(s, 2H), 8.13(d, J＝10.7Hz, 1H), 8.07(d, J＝6.1Hz, 1H), 7.75(s, 2H), 7.72(s, 1H), 7.54(t, J＝6.6Hz, 1H), 7.22(t, J＝8.5Hz, 2H), 6.04(s, 2H)ppm.

Example 29, Preparation of Compound I-2-1:

Intermediate II-22 (70 mg, 0.17 mmol), 2-chloro-5-pyrimidinecarboxaldehyde (27 mg, 0.19 mmol) and dimethylamine (10 mg, 0.21 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 65 mg of yellow solid I-2-1, with a yield of 69.9%, and a melting point of >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ +CF ₃ COOH) δ9.19 (s, 1H), 8.73 (s, 2H), 8.03 (d, J＝10.5 Hz, 1H), 7.95 (d, J＝5.9 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J＝8.2 Hz, 2H), 7.13 (d, J＝8.1 Hz, 2H), 5.78 (s, 2H), 3.11 (s, 6H) ppm.

Example 30, Preparation of Compound I-2-2:

Intermediate II-22 (70 mg, 0.17 mmol), 2-chloro-5-pyrimidinecarboxaldehyde (27 mg, 0.19 mmol) and diethylamine (15 mg, 0.21 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 61 mg of yellow solid I-2-2 with a yield of 62.2%. The melting point was 296.4-297.2°C; ¹ H NMR (600 MHz, 25°C, DMSO-d ₆ )δ14.69(s,1H),9.36(s,1H),8.89(s,2H),8.13(d,J＝10.6Hz,1H),8.02(d,J＝6.0Hz,1H),7.75(d,J＝7.9Hz,2H),7.61(s,1H),7.58(d,J＝8.0Hz,2H),6.05(s,2H),3.68(m,4H),1.17(t,J＝7.0Hz,6H)ppm.

Example 31, Preparation of Compound I-2-3:

Intermediate II-22 (80 mg, 0.20 mmol), 2-chloro-5-pyrimidinecarboxaldehyde (31 mg, 0.22 mmol) and N-ethylethanolamine (35 mg, 0.40 mmol) were reacted in ethanol (8 mL) at 78 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and water (10 mL) was added and stirred continuously. The solid obtained by filtration was recrystallized to obtain 78 mg of yellow solid I-2-3, with a yield of 58.2%, melting point: 296.7-299.0 ° C; ¹ H NMR (600 MHz, 25 ° C, DMSO-d ₆ )δ14.72(s,1H),9.36(s,1H),8.89(s,2H),8.14(d,J＝10.7Hz,1H),8.03(d,J＝5.9Hz,1H),7.75(d,J＝7.8Hz,2H),7.63(s,1H),7.58(d,J＝7.8Hz,2H),6. 06(s,2H),4.80(t,J＝5.3Hz,1H),3.73(m,4H),3.63(m,2H),1.17(t,J＝7.0Hz,3H)ppm.

Example 32, Preparation of Compound I-2-4:

Intermediate II-22 (70 mg, 0.17 mmol), 2-chloro-5-pyrimidinecarboxaldehyde (27 mg, 0.19 mmol) and diethanolamine (36 mg, 0.34 mmol) were reacted in ethanol (8 mL) at 78 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and water (10 mL) was added and stirred continuously. The solid obtained by suction filtration was recrystallized to obtain 63 mg of yellow solid I-2-4, with a yield of 52.9%, melting point: 268.2-270.4 ° C; ¹ H NMR (600 MHz, 25 ° C, DMSO-d ₆ )δ14.73(s,1H),9.37(s,1H),8.90(s,2H),8.14(d,J＝10.7Hz,1H),8.04(d,J＝6.1Hz,1H),7.75(d,J＝8.1Hz,2H),7.67(s,1H),7.59(d,J＝8.0Hz,2H),6. 07(s,2H),4.85(s,2H),3.79(t,J＝6.2Hz,4H),3.64(d,J＝6.3Hz,4H)ppm.

Example 33, Preparation of Compound I-2-5:

Intermediate II-22 (70 mg, 0.17 mmol), 2-chloro-5-pyrimidinecarboxaldehyde (27 mg, 0.19 mmol) and tetrahydropyrrole (18 mg, 0.21 mmol) were reacted in ethanol (8 mL) at 78°C for 8 hours. After the reaction, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 68 mg of yellow solid I-2-5 with a yield of 69.4%. The melting point was >300°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ +CF ₃ COOH) δ9.15 (s, 1H), 8.76 (s, 2H), 8.02 (d, J＝10.6 Hz, 1H), 7.89 (d, J＝5.9 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J＝8.2 Hz, 2H), 7.16 (d, J＝8.1 Hz, 2H), 5.75 (s, 2H), 3.52–3.48 (m, 4H), 1.87–1.83 (m, 4H) ppm.

Example 34, Preparation of Compound I-2-6:

Intermediate II-22 (100 mg, 0.25 mmol), 2-chloro-5-pyrimidinecarboxaldehyde (39 mg, 0.27 mmol) and piperidine (25 mg, 0.30 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 86 mg of yellow solid I-2-6, with a yield of 64.2%, and a melting point of >300°C; ¹ H NMR (600 MHz, 25°C, DMSO-d ₆ )δ14.71(s, 1H), 9.37(s, 1H), 8.86(s, 2H), 8.11(d, J＝10.6Hz, 1H), 8.01(d, J＝6.0Hz, 1H), 7.75(d, J＝8.0Hz, 2H), 7.59(d, J＝8.1Hz, 3H), 6.06(s, 2H), 3.87(t, J＝5.5Hz, 4H), 1.67(m, 2H), 1.56(m, 4H)ppm.

Example 35, Preparation of Compound I-2-7:

Intermediate II-22 (70 mg, 0.17 mmol), 2-chloro-5-pyrimidinecarboxaldehyde (27 mg, 0.19 mmol) and morpholine (18 mg, 0.21 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 84 mg of yellow solid I-2-7 with a yield of 84.0%. The melting point was >300°C; ¹ HNMR (600 MHz, 25°C, DMSO-d ₆ )δ14.72(s, 1H), 9.37(s, 1H), 8.91(s, 2H), 8.14(d, J＝10.7Hz, 1H), 8.03(d, J＝6.1Hz, 1H), 7.75(d, J＝8.1Hz, 2H), 7.65(s, 1H), 7.58(d, J＝8.1Hz, 2H), 6.06(s, 2H), 3.86(t, J＝4.8Hz, 4H), 3.71–3.68(m, 4H)ppm.

Example 36, Preparation of Compound I-2-8:

Intermediate II-22 (100 mg, 0.25 mmol), 2-methoxy-5-pyrimidinecarboxaldehyde (38 mg, 0.27 mmol) and sodium acetate (8 mg, 0.10 mmol) were reacted in ethanol (8 mL) at 78°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 77 mg of white solid I-2-8 with a yield of 59.2%. The melting point was 266.9-268.2°C; ¹ H NMR (400 MHz, 25°C, DMSO-d ₆ )δ14.66(s,1H),9.38(s,1H),9.12(s,2H),8.20(d,J＝10.6Hz,1H),8.13(d,J＝6.2Hz,1H),7.89(s,1H),7.75(d,J＝8.1Hz,2H),7.59(d,J＝8.1Hz,2H),6.07(s,2H),4.03(s,3H)ppm.

Example 37, Preparation of Compound I-2-9:

Intermediate II-22 (70 mg, 0.17 mmol), 2-methylthiopyrimidine-5-carbaldehyde (29 mg, 0.19 mmol) and sodium acetate (7 mg, 0.09 mmol) were reacted in ethanol (8 mL) at 78°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 50 mg of green solid I-2-9 with a yield of 53.2%. The melting point was 268.6-270.5°C; ¹ H NMR (600 MHz, 25°C, DMSO-d ₆ )δ14.67(s,1H),9.36(s,1H),9.09(s,2H),8.19(d,J＝10.7Hz,1H),8.13(d,J＝5.9Hz,1H),7.90(s,1H),7.74(d,J＝8.1Hz,2H),7.58(d,J＝8.1Hz,2H),6.06(s,2H),2.60(s,3H)ppm.

Example 38, Preparation of Compound I-2-10:

Intermediate II-22 (100 mg, 0.25 mmol), 4-amino-2-methylthiopyrimidine-5-carbaldehyde (46 mg, 0.27 mmol) and piperidine (25 mg, 0.30 mmol) were reacted in ethanol (8 mL) at 78°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added and stirred continuously, and the solid obtained by filtration was recrystallized to obtain 114 mg of white solid I-2-10, with a yield of 83.2%, melting point: 247.9-249.8°C; ¹ H NMR (600 MHz, 25°C, DMSO-d ₆ )δ9.37(s,1H),9.06(s,1H),8.25–8.22(m,3H),7.73(d,J＝8.1Hz,2H),7.54(d,J＝8.0Hz,2H),6.03(s,2H),2.62(s,3H)ppm.

Example 39: In vitro antimicrobial activity of benzopyridone vinyl pyrimidine compounds

The doubling dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) was used to detect the effects of the benzopyridone vinyl pyrimidine compounds prepared in Examples 2 to 38 on Gram-positive bacteria (methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC (B) 26001, Staphylococcus aureus CMCC (B) 26003), Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC The minimum inhibitory concentration (MIC) of the test compound was dissolved in a small amount of dimethyl sulfoxide, and then diluted to 512 μg/mL with culture medium. After serial dilution, the microorganisms were inoculated and cultured at 37°C for 24 hours. The culture plate was placed on an oscillator and shaken thoroughly. The MIC was measured at a wavelength of 600 nm and read by naked eyes. The results are shown in Tables 1-3.

Table 1. In vitro anti-Gram-positive bacterial activity (MIC, μg/mL) of the benzopyridone vinyl pyrimidine compounds prepared in Examples 2 to 38

As can be seen from Table 1, the benzopyridone vinyl pyrimidine compound I prepared in the present invention exhibits a good inhibitory effect on the tested Gram-positive bacteria, and the benzyl-substituted compounds have relatively good inhibitory activity, especially the trifluoromethylbenzyl-substituted compound I-1-22 exhibits good inhibitory activity against a series of Staphylococcus aureus strains, with an MIC value of 0.25 to 0.5 μg/mL, which is much better than the reference drug sulfadiazine, and better than the clinical drugs norfloxacin and ciprofloxacin.

Table 2. In vitro anti-Gram-negative bacterial activity (MIC, μg/mL) of the benzopyridone vinyl pyrimidine compounds prepared in Examples 2 to 38

As can be seen from Table 2, the benzopyridone vinyl pyrimidine compound I prepared in the present invention exhibits a certain inhibitory effect on the tested Gram-negative bacteria, most of the compounds having electron-withdrawing substituents on the benzene ring have good inhibitory activity, and many compounds exhibit better anti-Gram-negative bacteria activity than the reference drugs.

Table 3. In vitro antifungal activity (MIC, μg/mL) of the benzopyridone vinyl pyrimidine compounds prepared in Examples 2 to 38

As can be seen from Table 3, the benzopyridone vinyl pyrimidine compound I prepared in the present invention exhibits a certain inhibitory effect on the tested fungi. Most compounds in this series have strong inhibitory activity against Aspergillus fumigatus, which is better than the reference drug fluconazole. Compound I-1-27 exhibits good inhibitory activity against the five tested fungi, especially against Aspergillus fumigatus, with a MIC value of 0.25 μg/mL, and the inhibitory activity is 1024 times that of fluconazole.

Example 40: Pharmaceutical Use of Benzopyridone Vinyl Pyrimidine Compounds

According to the above-mentioned antimicrobial activity test results, the benzopyridone vinyl pyrimidine compounds of the present invention have good antibacterial and antifungal activities, and can be made into antibacterial and antifungal drugs for clinical use. These drugs can be either single-prescription preparations, such as being made of a benzopyridone vinyl pyrimidine compound of a structure and a pharmaceutically acceptable adjuvant; or compound preparations, such as being made of a benzopyridone vinyl pyrimidine compound of a structure and existing antibacterial and antifungal active ingredients (such as norfloxacin or fluconazole, etc.) and pharmaceutically acceptable adjuvants, or being made of several benzopyridone vinyl pyrimidine compounds of different structures and pharmaceutically acceptable adjuvants. 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.

1. Preparation of Compound I-1-22 Tablets

Prescription: Compound I-1-22 10g, corn starch 50g, lactose 187g, magnesium stearate 3.0g, an appropriate amount of 70% by volume ethanol solution, a total of 1000 tablets.

Preparation method: Dry corn starch at 105°C for 5 hours for later use; mix compound I-1-22 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.

2. Preparation of compound I-1-22 capsules

Prescription: Compound I-1-22 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.

Preparation method: The prescribed amount of compound I-1-22 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.

3. Preparation of Compound I-1-22 Granules

Prescription: Compound I-1-22 26g, dextrin 120g, sucrose 280g.

Preparation method: Mix compound I-1-22, dextrin and sucrose evenly, granulate by wet method, dry at 60°C, and package to obtain the product.

4. Preparation of Compound I-2-4 Injection

Prescription: Compound I-2-4 10 g, propylene glycol 500 mL, water for injection 500 mL, a total of 1000 mL.

Preparation method: Weigh compound I-2-4, 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 in a 10mL ampoule, and sterilize with circulating steam at 100℃ for 45 minutes.

5. Preparation of Compound I-1-22 Powder Injection

Preparation method: The intermediate I-1-22 sterile powder is packaged under aseptic conditions to obtain the product.

6. Preparation of compound I-2-4 eye drops

Prescription: 3.78 g of compound I-2-4, 0.9 g of sodium chloride, appropriate amount of boric acid buffer solution, and distilled water added to 1000 mL.

Preparation method: Weigh compound I-2-4 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.

7. Preparation of Compound I-1-22 Ointment

Prescription: Compound I-1-22 4g, potassium soap 7.5g, camphor 5g, distilled water added to 100mL.

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-1-22, 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.

8. Preparation of Compound I-1-22 Suppositories

Prescription: Compound I-1-22 4g, gelatin 14g, glycerin 70g, distilled water added to 100mL, a total of 100 tablets.

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-1-22, stir evenly, pour into a vaginal suppository mold when it is almost solidified, cool and solidify to obtain.

9. Preparation of compound I-1-22 ointment

Prescription: Compound I-1-22 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.

Preparation method: Heat hexadecanol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate until completely dissolved, then mix 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-1-22 after emulsification, stir and cool to obtain.

10. Preparation of aerosol of compound I-1-22

Prescription: Compound I-1-22 2.5 g, Span20 3 g, talcum powder (100 mesh) 4 g, trichlorofluoromethane added to appropriate amount.

Preparation method: Dry compound I-1-22, Span20 and talcum powder in a vacuum drying oven for several hours, cool to room temperature in a dryer, grind into fine powder with a jet mill, mix according to the prescribed amount, pour into a sealed container, add trichloromonofluoromethane to the specified amount, and obtain.

In summary, the present invention provides benzopyridone vinyl pyrimidine compounds and pharmaceutically acceptable salts thereof. The present invention utilizes the principle of drug design splicing. Unlike the traditional quinolone antibacterial drugs that use aliphatic heterocyclic modification at the C-7 position, the present invention uses aromatic pyrimidine at the C-7 position of benzopyridone for reconstruction, and introduces alkyl, alkenyl, alkynyl, aryl or heterocyclic groups at the N-1 position of benzopyridone to adjust the physicochemical properties and affinity with the target. A series of benzopyridone vinyl pyrimidine compounds and pharmaceutically acceptable salts thereof are designed and synthesized. These compounds are found to be effective against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 1260 ... The present invention has certain inhibitory activity against gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027, Pseudomonas aeruginosa CMCC (B) 10104, Acinetobacter baumannii) and fungi (Candida albicans, Candida albicans ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 22019), and can be used to prepare antibacterial and antifungal drugs, provide more efficient and safe candidate drugs for clinical antibacterial treatment, and help solve the increasingly serious clinical treatment problems such as drug resistance, stubborn pathogenic microorganisms and newly emerging harmful microorganisms.

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 (10)

1. Benzopyridone vinylpyrimidine compounds and pharmaceutically acceptable salts thereof, characterized in that the structure is as shown in general formula I: In the formula, n is an integer from 0 to 18; R ¹ is hydrogen, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl, hydroxyl, cyano, ester, carboxyl, phenyl, substituted phenyl or heteroaryl; R ² is hydrogen, amino, amine, cyano, nitro, halogen, alkyl, alkoxy or alkylmercapto. 2. benzopyridone vinylpyrimidine compounds and pharmaceutically acceptable salts thereof as claimed in claim 1, characterized in that n is any of 0, 1, 2, 3, 4, 5, 8, 12 or 16 A sort of; R ¹ is any one of hydrogen, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl; R ² is any one of amino group, amine group, methoxy group or methylmercapto group. 3. The benzopyridonevinyrimidine compound and its pharmaceutically acceptable salt as claimed in claim 1, which is any one of the following compounds: 4. benzopyridone vinylpyrimidine compounds and pharmaceutically acceptable salts thereof as claimed in claim 1, characterized in that the pharmaceutically acceptable salts are hydrochlorides, bromates, iodates, sulfates, Nitrate, trifluoroacetate or acetate. 5. The preparation method of benzopyridonevinyrimidine compounds and pharmaceutically acceptable salts thereof according to any one of claims 1 to 4, characterized in that the method is as follows: a. Add the compound represented by the general formula II to ethanol, add various pyrimidine aldehyde compounds, and then perform a reflux reaction under the action of a base to prepare the benzopyridinone vinylpyrimidine compound represented by the general formula I; in: n is 0, 1, 2, 3, 4, 5, 8, 12 or 16; R ¹ is hydrogen, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl. b. Preparation of pharmaceutically acceptable salts of benzopyridone vinylpyrimidine compounds represented by the general formula I: Dissolve the benzopyridone vinylpyrimidine compounds represented by the general formula I in an organic solvent, and add a pharmaceutically acceptable acid The reaction is carried out until no precipitate is formed, thereby obtaining the pharmaceutically acceptable salt of the benzopyridone vinylpyrimidine compound shown in I. 6. The method of claim 5, characterized in that, In step a, the base is one of dimethylamine, diethylamine, N-ethylethanolamine, diethanolamine, pyrrolidine, piperidine, morpholine or sodium acetate, intermediate II, pyrimidine aldehyde compounds and The ratio of the amount of alkali substances is 1:1~1.5:0.2~1.2. The reaction specifically uses ethanol as the solvent and reacts at 60-90°C for 8 to 24 hours; In step b, the organic solvent is at least one of chloroform, acetone, acetonitrile, diethyl ether, tetrahydrofuran, dioxane or N,N-dimethylformamide; the pharmaceutically acceptable acid is hydrochloric acid or sulfuric acid. 7. Use of the benzopyridonevinyrimidine compounds and pharmaceutically acceptable salts thereof according to any one of claims 1 to 4 in the preparation of antibacterial and/or antifungal drugs. 8. The application according to claim 7, wherein the bacteria are methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC (B) 26001, Staphylococcus aureus CMCC (B) 26003, Klebsiella pneumoniae pneumoniae, E. coli, E. coli ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027, Pseudomonas aeruginosa CMCC (B )10104 or any one or more of Acinetobacter baumannii; the fungus is Candida albicans, Candida albicans ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 22019 any one or more. 9. A preparation containing the benzopyridone vinylpyrimidine compound and its pharmaceutically acceptable salt according to any one of claims 1 to 4. 10. The preparation according to claim 9, wherein the preparation is in the form of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols. A sort of.