Benzopyridinone ethenylpyrimidines, processes for their preparation and medical uses thereof

Abstract

The present application relates to benzopyridone ethenyl pyrimidine compounds, and a preparation method and medical application thereof, and belongs to the technical field of chemical synthesis, and the benzopyridone ethenyl pyrimidine compounds are shown as general formula I, the compounds have good inhibitory activity on one or more of gram-positive bacteria, gram-negative bacteria and fungi, can be used for preparing antibacterial and / or antifungal drugs, and have no obvious drug resistance, can provide more efficient and safe candidate drugs for clinical anti-infection treatment, and help to solve the increasingly serious microbial drug resistance, stubborn pathogenic microorganisms and new emerging harmful microorganisms and other clinical treatment problems.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to benzopyridone ethylene pyrimidine compounds, their preparation methods, and pharmaceutical applications. Background Technology

[0002] Pyrimidine rings are an important class of six-membered nitrogen-containing heterocycles. Their unique structure allows them to interact with biomolecules through various non-covalent bonds, giving them broad application potential in medicinal chemistry. Particularly in antimicrobial applications, many pyrimidine-based antimicrobial drugs are already widely used clinically. They inhibit enzyme function and lead to bacterial death by forming supramolecular enzyme complexes through supramolecular interactions with enzymes in microorganisms. Therefore, the development of novel pyrimidine ring-based drugs shows great application value in the antibacterial field, especially their hybridization with some clinical drug skeletons.

[0003] Benzopyridone-based quinolone antibiotics are an important class of first-line antibacterial drugs, making significant contributions to protecting public health. To date, four generations of quinolone drugs have been successfully developed and marketed. However, due to widespread clinical use and even abuse, bacterial resistance to these drugs has increased significantly, leading to decreased clinical efficacy. Structural modification of the benzopyridone skeleton to develop new antibacterial drugs is an important method for addressing the increasingly serious problem of drug resistance. Many studies have reported that the combination of azole heterocyclic compounds and benzopyridone exhibits good antimicrobial activity, while studies on the combination of pyrimidines are less common. In this study, an olefinic fragment was used at the C-7 position of benzopyridone to conjugate aromatic pyrimidine compounds, resulting in a novel framework structure of benzopyridone ethylene pyrimidine molecules. The introduction of the conjugated structure helps improve the affinity of the compound for DNA, enzymes, or other receptors in vivo through various non-covalent interactions with the target site, thereby enhancing antibacterial activity. Simultaneously, the construction of the new molecule structure may lead to the discovery of new antibacterial mechanisms, potentially overcoming severe bacterial resistance. Summary of the Invention

[0004] In view of this, one objective of the present invention is to provide benzopyridone ethylene pyrimidine compounds and their pharmaceutically acceptable salts; a second objective is to provide a method for preparing benzopyridone ethylene pyrimidine compounds and their pharmaceutically acceptable salts; and a third objective is to provide the application of benzopyridone ethylene pyrimidine compounds and their pharmaceutically acceptable salts in the preparation of antibacterial and / or antifungal drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial therapy and helping to solve increasingly serious clinical treatment problems such as drug resistance, stubborn pathogenic microorganisms, and newly emerging harmful microorganisms.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] 1. Benzopyridone ethylene pyrimidine compounds and their pharmaceutically acceptable salts, with structures shown in general formula I:

[0007]

[0008] In the formula,

[0009] n is an integer between 0 and 18;

[0010] R 1 It can be hydrogen, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl, hydroxyl, cyano, ester, carboxyl, phenyl, substituted phenyl or heteroaryl;

[0011] R 2 It can be hydrogen, amino, amine, cyano, nitro, halogen, alkyl, alkoxy, or alkyl mercapto.

[0012] Preferred:

[0013] n can be any one of 0, 1, 2, 3, 4, 5, 8, 12 or 16;

[0014] R 1 It is any one of hydrogen, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl;

[0015] R 2 It can be any one of amino, amine, methoxy, or methyl mercapto.

[0016] Preferably, it is any one of the following compounds:

[0017]

[0018] Preferably, the pharmaceutically acceptable salt is a hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate, or acetate.

[0019] 2. The method for preparing the benzopyridone ethylene pyrimidine compound and its pharmaceutically acceptable salt, wherein the method is as follows:

[0020] a. Add the compound shown in general formula II to ethanol, add various pyrimidine aldehydes, and then reflux under the action of alkali to obtain the benzopyridone ethylene pyrimidine compound shown in general formula I.

[0021]

[0022] in:

[0023] n can be 0, 1, 2, 3, 4, 5, 8, 12 or 16;

[0024] R 1 It can be hydrogen, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl.

[0025] b. Preparation of pharmaceutically acceptable salts of benzopyridone ethylene pyrimidine compounds represented by general formula I: Dissolve the benzopyridone ethylene pyrimidine compound represented by general formula I in an organic solvent, add a pharmaceutically acceptable acid and react until no precipitate is formed, thus obtaining pharmaceutically acceptable salts of the benzopyridone ethylene pyrimidine compound represented by formula I.

[0026] Preferably,

[0027] 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 to 1.5:0.2 to 1.2. Specifically, the reaction is carried out in ethanol as solvent at 60-90°C for 8 to 24 hours.

[0028] 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.

[0029] 3. The use of the benzopyridone vinylpyrimidine compounds and their pharmaceutically acceptable salts in the preparation of antibacterial and / or antifungal drugs.

[0030] 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, and Pseudomonas aeruginosa ATCC. 9027, any one or more of 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.

[0031] 4. Preparations containing the aforementioned benzopyridone ethylene pyrimidine compounds and their pharmaceutically acceptable salts.

[0032] Preferably, the preparation is one of the following: tablets, capsules, granules, injections, powder for injection, eye drops, liniments, suppositories, ointments, or aerosols.

[0033] The beneficial effects of this invention are as follows: This invention provides benzopyridone ethylene pyrimidine compounds, their preparation methods, and applications. Utilizing the principle of drug design and synthesis, this invention hybridizes pyrimidine compounds at the C-7 position of benzopyridone via a cyanoethylene fragment, designing and synthesizing a series of benzopyridone ethylene pyrimidine compounds. These compounds, after in vitro antimicrobial activity testing, were 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) and 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) all exhibit certain inhibitory activities. These can be used to prepare antibacterial and / or antifungal drugs, and they do not show significant drug resistance. This provides more highly effective and safe candidate drugs for clinical antimicrobial therapy, helping to address increasingly serious clinical treatment problems such as drug resistance, persistent pathogenic microorganisms, and emerging harmful microorganisms.

[0034] Other advantages, objectives, and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination, or may be learned from practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Detailed Implementation

[0035] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0036] Example 1: Preparation of Intermediate II

[0037]

[0038] Intermediate II was prepared by the method described in the references "[1] Kamal, A.; Deviah, V.; Reddy, KL; Kumar, MS Synthesis and biological activity of fluoroquinolone-pyrrolo[2,1-c][1,4]benzodiazepine conjugates. Bioorg. Med. Chem. 2005, 13, 2021-2029. [2] Valery, NC; Nataliya, NM; Fedor, VA; Svetlana, KK; Emiliya, VN; Marina, AE; Mikhail, IK; Marionella, AK Synthesis and antimycobacterial evaluation of new(2-oxo-2H-chromen-3-yl)substituted fluoroquinolones. J. Fluorine Chem. 2018, 208, 15-23."

[0039] Example 2, Preparation of compound I-1-1:

[0040]

[0041] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 104 mg of yellow solid I-1-1, yield: 75.4%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0042] Example 3, Preparation of compound I-1-2:

[0043]

[0044] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 102 mg of yellow solid I-1-2, yield: 74.8%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0045] Example 4, Preparation of compound I-1-3:

[0046]

[0047] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 116 mg of yellow solid I-1-3, yield: 76.8%, melting point: >300 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) δ14.81(s,1H),9.07(s,1H),8.89(s,2H),8.17(d,J=6.0Hz,1H),8.12(d,J=10.5H z,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.

[0048] Example 5, Preparation of compound I-1-4:

[0049]

[0050] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 115 mg of yellow solid I-1-4, yield: 87.1%, melting point: 293.5-295.0 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0051] Example 6, Preparation of compound I-1-5:

[0052]

[0053] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 83 mg of yellow solid I-1-5, yield: 64.3%, melting point: 256.1-258.2 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0054] Example 7, Preparation of compound I-1-6:

[0055]

[0056] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 83 mg of yellow solid I-1-6, yield: 74.2%, melting point: 266.8-268.2 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0057] Example 8, Preparation of compound I-1-7:

[0058]

[0059] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 82 mg of yellow solid I-1-7, yield: 67.8%, melting point: 249.5-250.3 °C. 1 H NMR(400MHz,25℃,DMSO-d6)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.

[0060] Example 9, Preparation of compound I-1-8:

[0061]

[0062] 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, the mixture was cooled to room temperature, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 96 mg of yellow solid I-1-8, yield: 70.6%, melting point: >300 °C. 1 H NMR(400MHz,25℃,DMSO-d6)δ14.81(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.

[0063] Example 10, Preparation of compound I-1-9:

[0064]

[0065] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 80 mg of yellow solid I-1-9, yield: 58.4%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0066] Example 11, Preparation of compound I-1-10:

[0067]

[0068] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 96 mg of yellow solid I-1-10, yield: 72.2%, melting point: 285.9-287.2 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) δ14.74(s,1H),9.04(s,1H),8.88(s,2H),8.12(d,J=10.6Hz,1H),8.05(d,J=5.9H z,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.

[0069] Example 12, Preparation of compound I-1-11:

[0070]

[0071] 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 was completed, the mixture was cooled to room temperature, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 43 mg of yellow solid I-1-11, yield: 63.2%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6+CF3COOH) δ9.02(s,1H),8.91(s,2H),8.54(d,J=5.7Hz,1H),8.02(d,J =10.3Hz,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.

[0072] Example 13, Preparation of compound I-1-12:

[0073]

[0074] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 113 mg of yellow solid I-1-12, yield 83.7%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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,1 H),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.

[0075] Example 14, Preparation of compound I-1-13:

[0076]

[0077] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 109 mg of yellow solid I-1-13, yield 82.0%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0078] Example 15, Preparation of compound I-1-14:

[0079]

[0080] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 74 mg of yellow solid I-1-14, yield 56.1%, melting point: 293.9-295.2 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0081] Example 16, Preparation of compound I-1-15:

[0082]

[0083] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 111 mg of yellow solid I-1-15, yield 76.6%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0084] Example 17, Preparation of compound I-1-16:

[0085]

[0086] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 108 mg of yellow solid I-1-16, yield 82.4%, melting point: >300 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) 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.

[0087] Example 18, Preparation of compound I-1-17:

[0088]

[0089] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 90 mg of yellow solid I-1-17, yield 68.6%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0090] Example 19, Preparation of compound I-1-18:

[0091]

[0092] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 98 mg of yellow solid I-1-18, yield 75.4%, melting point: >300 °C. 1 H NMR(400MHz,25℃,DMSO-d6)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.

[0093] Example 20, Preparation of compound I-1-19:

[0094]

[0095] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 112 mg of yellow solid I-1-19, yield 77.8%, melting point: 279.8-282.3 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0096] Example 21, Preparation of compound I-1-20:

[0097]

[0098] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 105 mg of yellow solid I-1-20, yield 80.8%, melting point: >300 °C. 1 H NMR(400MHz,25℃,DMSO-d6)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.

[0099] Example 22, Preparation of compound I-1-21:

[0100]

[0101] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 97 mg of yellow solid I-1-21, yield 75.8%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) δ14.68(s,1H),9.32(s,1H),8.84(s,2H),8.14(d,J=10.7H z,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.

[0102] Example 23, Preparation of compound I-1-22:

[0103]

[0104] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 102 mg of yellow solid I-1-22, yield 81.0%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0105] Example 24, Preparation of compound I-1-23:

[0106]

[0107] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 122 mg of yellow solid I-1-23, yield 87.8%, melting point: >300 °C. 1 H NMR(600MHz,25℃,DMSO-d6)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.

[0108] Example 25, Preparation of compound I-1-24:

[0109]

[0110] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 107 mg of yellow solid I-1-24, yield 84.3%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) δ14.80(s,1H),9.26(s,1H),8.85(s,2H),8.19(d,J=6.2Hz,1H),8.13(d,J=10.7H z,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.

[0111] Example 26, Preparation of compound I-1-25:

[0112]

[0113] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 108 mg of yellow solid I-1-25, yield 84.2%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0114] Example 27, Preparation of compound I-1-26:

[0115]

[0116] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 114 mg of yellow solid I-1-26, yield 89.1%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0117] Example 28, Preparation of compound I-1-27:

[0118]

[0119] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 106 mg of yellow solid I-1-27, yield 82.8%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0120] Example 29, Preparation of compound I-2-1:

[0121]

[0122] 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 was completed, the mixture was cooled to room temperature, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 65 mg of yellow solid I-2-1, yield 69.9%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6+CF3COOH) δ9.19(s,1H),8.73(s,2H),8.03(d,J=10.5Hz,1H),7.95(d,J= 5.9Hz,1H),7.50(s,1H),7.33(d,J=8.2Hz,2H),7.13(d,J=8.1Hz,2H),5.78(s,2H),3.11(s,6H)ppm.

[0123] Example 30, Preparation of compound I-2-2:

[0124]

[0125] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 61 mg of yellow solid I-2-2, yield 62.2%, melting point: 296.4-297.2 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) 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.

[0126] Example 31, Preparation of compound I-2-3:

[0127]

[0128] 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, the mixture was cooled to room temperature, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 78 mg of yellow solid I-2-3, yield 58.2%, melting point: 296.7-299.0 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) 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=7.8H z,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.

[0129] Example 32, Preparation of compound I-2-4:

[0130]

[0131] 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, the mixture was cooled to room temperature, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 63 mg of yellow solid I-2-4, yield 52.9%, melting point: 268.2-270.4 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) 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.

[0132] Example 33, Preparation of compound I-2-5:

[0133]

[0134] 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 was completed, the mixture was cooled to room temperature, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 68 mg of yellow solid I-2-5, yield 69.4%, melting point: >300 °C. 1 H NMR (400MHz, 25℃, DMSO-d6+CF3COOH) δ9.15(s,1H),8.76(s,2H),8.02(d,J=10.6Hz,1H),7.89(d,J=5.9Hz,1H),7 .47(s,1H),7.36(d,J=8.2Hz,2H),7.16(d,J=8.1Hz,2H),5.75(s,2H),3.52–3.48(m,4H),1.87–1.83(m,4H)ppm.

[0135] Example 34, Preparation of compound I-2-6:

[0136]

[0137] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 86 mg of yellow solid I-2-6, yield 64.2%, melting point: >300 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) 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.

[0138] Example 35, Preparation of compound I-2-7:

[0139]

[0140] 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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 84 mg of yellow solid I-2-7, yield 84.0%, melting point: >300 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) 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.

[0141] Example 36, Preparation of compound I-2-8:

[0142]

[0143] 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, and water (10 mL) was added with continuous stirring. The solid obtained by filtration was recrystallized to give 77 mg of white solid I-2-8, yield 59.2%, melting point: 266.9-268.2 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) 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.

[0144] Example 37, Preparation of compound I-2-9:

[0145]

[0146] Intermediate II-22 (70 mg, 0.17 mmol), 2-methylmercaptopyrimidine-5-carboxaldehyde (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, and water (10 mL) was added with continuous stirring. The solid obtained by filtration was recrystallized to give 50 mg of green solid I-2-9, with a yield of 53.2% and a melting point of 268.6-270.5 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) 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.

[0147] Example 38, Preparation of compound I-2-10:

[0148]

[0149] Intermediate II-22 (100 mg, 0.25 mmol), 4-amino-2-methylthiopyrimidine-5-carboxaldehyde (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, and water (10 mL) was added with constant stirring. The solid obtained by filtration was recrystallized to give 114 mg of white solid I-2-10, yield 83.2%, melting point: 247.9-249.8 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) 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.

[0150] Example 39: In vitro antimicrobial activity of benzopyridone vinylpyrimidine compounds

[0151] The benzopyridone ethylene pyrimidine compounds prepared in Examples 2–38 were tested using the serial dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) to detect their effectiveness 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) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853 ... The minimum inhibitory concentrations (MICs) of the test compounds (Candida albicans, Candida albicans ATCC 9027, Candida albicans CMCC(B)10104, Acinetobacter baumannii) and fungi (Candida albicans, Candida albicans ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 22019) were determined by dissolving the test compounds in a small amount of dimethyl sulfoxide and then diluting them with culture medium to 512 μg / mL. After continuous dilution, the microorganisms were inoculated and cultured at 37°C for 24 hours. The culture plates were then shaken thoroughly on a shaker, and the MICs were measured at a wavelength of 600 nm and read visually. The results are shown in Tables 1-3.

[0152] Table 1. In vitro anti-Gram-positive bacteria activity (MIC, μg / mL) of benzopyridone ethylene pyrimidine compounds prepared in Examples 2-38

[0153]

[0154] As can be seen from Table 1, the benzopyridone ethylene pyrimidine compound I prepared in this invention showed good inhibitory effects on the tested Gram-positive bacteria. The benzyl-substituted compounds had relatively good inhibitory activity. In particular, the trifluoromethylbenzyl-substituted compound I-1-22 showed good inhibitory activity against a series of Staphylococcus aureus strains, with MIC values ​​of 0.25-0.5 μg / mL, which is far superior to the reference drug sulfadiazine and superior to the clinical drugs norfloxacin and ciprofloxacin.

[0155] Table 2. In vitro anti-Gram-negative bacterial activity (MIC, μg / mL) of the benzopyridone ethylene pyrimidine compounds prepared in Examples 2–38.

[0156]

[0157] As can be seen from Table 2, the benzopyridone ethylene pyrimidine compound I prepared in this invention showed a certain inhibitory effect on the tested Gram-negative bacteria. Most of the compounds with electron-withdrawing substituents on the benzene ring had good inhibitory activity, and many compounds showed better anti-Gram-negative bacterial activity than the reference drug.

[0158] Table 3. In vitro antifungal activity (MIC, μg / mL) of the benzopyridone vinylpyrimidine compounds prepared in Examples 2–38

[0159]

[0160]

[0161] As shown in Table 3, the benzopyridone ethylene pyrimidine compound I prepared in this invention exhibited certain inhibitory effects on the tested fungi. Most compounds in this series showed strong inhibitory activity against *Aspergillus fumigatus*, superior to the reference drug fluconazole. Compound I-1-27 showed good inhibitory activity against all five tested fungi, especially *Aspergillus fumigatus*, with a MIC value of 0.25 μg / mL, representing an inhibitory activity 1024 times that of fluconazole.

[0162] Example 40: Pharmaceutical Uses of Benzopyridone Ethylpyrimidine Compounds

[0163] Based on the above antimicrobial activity test results, the benzopyridone vinylpyrimidine compounds of the present invention exhibit good antibacterial and antifungal activity and can be formulated into antibacterial and antifungal drugs for clinical use. These drugs can be single-component formulations, for example, formulated from a single-structure benzopyridone vinylpyrimidine compound and pharmaceutically acceptable excipients; or they can be compound formulations, for example, formulated from a single-structure benzopyridone vinylpyrimidine compound and existing antibacterial and antifungal active ingredients (such as norfloxacin or fluconazole) and pharmaceutically acceptable excipients, or formulated from several benzopyridone vinylpyrimidine compounds with different structures and pharmaceutically acceptable excipients. The formulation types include, but are not limited to, tablets, capsules, powders, granules, drop pills, injections, powder for injection, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches, and various sustained-release, controlled-release, and nano-formulations.

[0164] 1. Preparation of Compound I-1-22 tablets

[0165] Prescription: 10g of compound I-1-22, 50g of corn starch, 187g of lactose, 3.0g of magnesium stearate, and an appropriate amount of 70% ethanol solution, to make 1000 tablets.

[0166] Preparation: Dry corn starch at 105℃ for 5 hours for later use; mix compound I-1-22 with lactose and corn starch evenly, prepare a soft mass with 70% ethanol solution, sieve to make wet granules, add magnesium stearate, compress into tablets to obtain the product; each tablet weighs 250mg and contains 10mg of active ingredient.

[0167] 2. Preparation of Compound I-1-22 Capsules

[0168] 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, talc (100 mesh) 2.0g, sweetener 1.25g, orange flavoring 0.25g, coloring as needed, water as needed, to make 1000 capsules.

[0169] Preparation: The prescribed amount of compound I-1-22 is micronized and pulverized into an extremely fine powder, then mixed with the prescribed amounts of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talc, sweetener, orange flavoring and coloring. The mixture is then softened with water, granulated through a 12–14 mesh sieve, dried at 40–50℃, sieved and granulated, and filled into empty capsules to obtain the product. Each capsule weighs 50 mg and contains 25 mg of active ingredient.

[0170] 3. Preparation of Compound I-1-22 Granules

[0171] Prescription: Compound I-1-22 26g, dextrin 120g, sucrose 280g.

[0172] Preparation method: Mix compound I-1-22, dextrin and sucrose evenly, wet granulate, dry at 60℃, and package to obtain the final product.

[0173] 4. Preparation of Compound I-2-4 Injection

[0174] Prescription: Compound I-2-4 10g, propylene glycol 500mL, water for injection 500mL, to prepare a total of 1000mL.

[0175] Preparation: Weigh compound I-2-4, add propylene glycol and water for injection, 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, then filter with microporous membranes with pore sizes of 0.45μm and 0.22μm in sequence, and finally fill into 10mL ampoules and sterilize with flowing steam at 100℃ for 45 minutes to obtain the product.

[0176] 5. Preparation of Compound I-1-22 Powder for Injection

[0177] Preparation method: The intermediate I-1-22 aseptic powder is dispensed under aseptic conditions to obtain the product.

[0178] 6. Preparation of Compound I-2-4 Eye Drops

[0179] Prescription: Compound I-2-4 3.78g, sodium chloride 0.9g, boric acid buffer solution as needed, distilled water to 1000mL.

[0180] Preparation: 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 well, filter through a microporous membrane, fill into containers, seal, and sterilize with flowing steam at 100°C for 1 hour to obtain the final product.

[0181] 7. Preparation of Compound I-1-22 Liniment

[0182] Prescription: Compound I-1-22 4g, potassium soap 7.5g, camphor 5g, distilled water to 100mL.

[0183] Preparation: Dissolve camphor in a 95% (v / v) ethanol solution and set aside; liquefy potassium soap by heating and set aside; weigh compound I-1-22, add potassium soap solution and camphor ethanol solution while stirring continuously, then gradually add distilled water, and after complete emulsification, add distilled water to the total volume to obtain the final product.

[0184] 8. Preparation of Compound I-1-22 Suppositories

[0185] Prescription: Compound I-1-22 4g, gelatin 14g, glycerin 70g, distilled water added to 100mL, to make 100 pieces.

[0186] Preparation: Weigh gelatin and glycerin, add distilled water to 100mL, heat in a water bath at 60℃ until melted into a paste, add compound I-1-22, stir well, pour into a vaginal suppository mold when it is almost solidified, cool and solidify to obtain the product.

[0187] 9. Preparation of compound I-1-22 ointment

[0188] Prescription: Compound I-1-22 0.5–2g, cetyl alcohol 6–8g, white petrolatum 8–10g, liquid paraffin 8–19g, monoglyceride 2–5g, polyoxyethylene (40) stearate 2–5g, glycerin 5–10g, ethylparaben 0.1g, distilled water to 100g.

[0189] Preparation: Cetyl alcohol, white petrolatum, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate are heated and completely melted, then mixed and kept at 80°C to prepare the oil phase. Ethylparaben is added to glycerol and distilled water and heated to 85°C to dissolve. The oil phase is then added while stirring continuously. After emulsification, compound I-1-22 is added, stirred and cooled to obtain the final product.

[0190] 10. Preparation of Compound I-1-22 Aerosol

[0191] Prescription: Compound I-1-22 2.5g, Span20 3g, talc (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.

[0192] Preparation method: Place compound I-1-22, Span20 and talc powder in a vacuum drying oven and dry for several hours. Cool to room temperature in a desiccator and pulverize into fine powder using an air jet mill. Mix well according to the prescription amount, pour into a sealed container, and add trichlorofluoromethane to the specified amount to obtain the final product.

[0193] In summary, this invention provides benzopyridone ethylene pyrimidine compounds and their pharmaceutically acceptable salts. Utilizing the principle of drug design and synthesis, unlike traditional quinolone antibacterial drugs which use aliphatic heterocyclic modifications at the C-7 position, this study reconstitutes benzopyridone using aromatic pyrimidines at the C-7 position and introduces alkyl, alkenyl, alkynyl, aryl, or heterocyclic groups at the N-1 position of benzopyridone to regulate its physicochemical properties and affinity for the target. A series of benzopyridone ethylene pyrimidine compounds and their pharmaceutically acceptable salts were designed and synthesized. In vitro antimicrobial activity tests showed that these compounds were 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 ... 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 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) exhibit certain inhibitory activity. These can be used to prepare antibacterial and antifungal drugs, providing more efficient and safe candidate drugs for clinical antimicrobial therapy. This will help address increasingly serious clinical treatment problems such as drug resistance, persistent pathogenic microorganisms, and newly emerging harmful microorganisms.

[0194] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. Benzopyridone ethylene pyrimidine compounds and their pharmaceutically acceptable salts, characterized in that, The benzopyridone vinylpyrimidine compounds and their pharmaceutically acceptable salts are selected from I-1-1 to I-1-27 or I-2-1 to I-2-10:

2. The benzopyrone ethenylpyrimidine compound and pharmaceutically acceptable salt thereof according to claim 1, wherein The pharmaceutically acceptable salts are hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate, or acetate.

3. The use of the benzopyridone vinylpyrimidine compounds and their pharmaceutically acceptable salts as described in any one of claims 1 to 2 in the preparation of antibacterial or antifungal drugs.

4. The use according to claim 3, wherein the compound is ###0002### The bacteria are selected from Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, or Acinetobacter baumannii; the fungi are selected from Candida albicans, Candida tropicalis, Aspergillus fumigatus, or Candida parapsilosis ATCC 22019.

5. Use according to claim 4, characterized in that, The *Staphylococcus aureus* is methicillin-resistant *Staphylococcus aureus* N315, methicillin-resistant *Staphylococcus aureus* ATCC 43300, *Staphylococcus aureus* ATCC 25923, *Staphylococcus aureus* ATCC 29213, *Staphylococcus aureus* ATCC 12600, *Staphylococcus aureus* ATCC 6538, *Staphylococcus aureus* CMCC(B)26001, or *Staphylococcus aureus* CMCC(B)26003; the *Escherichia coli* is *Escherichia coli* ATCC25922; the *Pseudomonas aeruginosa* is *Pseudomonas aeruginosa* ATCC 27853, *Pseudomonas aeruginosa* ATCC 15442, *Pseudomonas aeruginosa* ATCC 9027, or *Pseudomonas aeruginosa* CMCC(B)10104; and the *Candida albicans* is *Candida albicans* ATCC90023.

6. Preparations containing the benzopyridone ethylene pyrimidine compound and its pharmaceutically acceptable salt as described in any one of claims 1 to 2.

7. The formulation of claim 6, wherein, The preparation is one of the following: tablets, capsules, granules, injections, powder for injection, eye drops, liniments, suppositories, ointments, or aerosols.

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