CN110963996B - Indanazolol compound containing acetophenone substituent, preparation method and medical application thereof - Google Patents

Abstract

The present invention relates to an isatinazole alcohol compound containing acetophenone substituent, a preparation method and medical application thereof. Gram-negative bacteria and fungi have certain inhibitory activities, and can be used to prepare antibacterial and/or antifungal drugs. The preparation materials are simple, cheap and easy to obtain, and the synthesis route is short, which is of great significance in the application of anti-infection.

Description

Isatinazole alcohol compound containing acetophenone substituent and its preparation method and medicine application

technical field

The invention belongs to the field of chemical synthesis, relates to an isatinazole alcohol compound containing acetophenone substituent, and also relates to a preparation method and medical application of the compound.

Background technique

Microbial infections have become the greatest threat to human health. To date, a large number of antibiotics and synthetic drugs have been used to treat microbial infections. However, the over-reliance on these antimicrobial drugs has led to the emergence of some multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and vancomycin-resistant Enterococcus faecium, thus making many traditional of antibiotics and synthetic drugs are ineffective. Therefore, the development of antibacterial drugs with new structures has become very urgent, especially the development of some antibacterial drugs with high efficiency, low toxicity and low drug resistance has attracted extensive attention.

Isatin is a well-known pharmaceutical agent and is widely present in the brain, nerve endings and other fluidic sites of humans and animals as a biomodulator. The versatility of the molecular structure of isatin makes it an ideal substrate for structural modification and derivatization, and it can be used by non-covalent bonding forces (hydrogen bonding, metal ion coordination, ion-dipole interactions, π-π stacking, hydrophobic-hydrophobic interaction, and van der Waals forces) combined with various active targets such as enzymes and receptors in the organism to exhibit a wide range of biological activities, such as antibacterial, antifungal, anticancer, antidepressant, Antispasmodic, anti-HIV, anti-inflammatory, etc. The isatin derivative oxindole has been widely used in the synthesis of drug molecules. For example, the drugs SU-5416 and SU-11248 containing oxindole fragments approved by the U.S. Food and Drug Administration have been used to treat the gastrointestinal tract. tumor and advanced renal cancer. In addition, thiazolin and thiazolinone generated by isatin cyclization can increase their antibacterial activity. With the advent of many drugs containing isatin structural fragments, the synthesis of isatin-like drug molecules and their biological activity research have increasingly become a hot spot in the field of pharmaceutical research and development. , expect to obtain isatin drugs with good pharmacokinetic properties, low toxicity and side effects and high biological activity.

The oxazole fragment is an important pharmacodynamic fragment that widely exists in biologically active molecules. In recent years, many oxazoles have been successfully developed and widely used in clinical practice. For example, the triazole alcohols, fluconazole and voriconazole, as first-line drugs for the treatment of fungal infections, have very good curative effects in the treatment of Candida albicans and neococcus-negative infections. Nitroimidazole azole alcohols such as metronidazole, secnidazole and ornidazole have been used for many years to treat infectious diseases caused by anaerobic bacteria. The research and development of oxazole antibacterial drugs has attracted extensive attention. In addition, the unique aromatic nitrogen heterocyclic structure of the azole ring enables the azole derivatives to rapidly and efficiently interact with biological macromolecules such as proteins, enzymes and receptors in the organism and exert good biological activity. Azole compounds have the advantages of high cure rate, good pharmacokinetic properties, high activity and low toxicity in the treatment of infectious diseases. As a hydrogen bond donor, the hydroxyl group can interact with active molecules in the organism through hydrogen bonding to improve the biological activity of drug molecules. New compounds have received extensive attention. Therefore, the use of oxazole fragments to modify the molecular structure of isatin in order to obtain high-efficiency and low-toxicity antibacterial drugs has aroused our research interest.

SUMMARY OF THE INVENTION

In view of this, the object of the present invention is to provide a kind of isatinazole alcohol compounds and pharmaceutically acceptable salts thereof; the second purpose of the present invention is to provide a preparation method of isatinazole alcohol compounds and pharmaceutically acceptable salts thereof; the present invention The third purpose of the present invention is to provide a preparation containing the isatinazole alcohol compounds; the fourth purpose of the present invention is to provide the isatinazole alcohol compounds and their pharmaceutically acceptable salts in the preparation of antibacterial and/or antifungal compounds. application in medicine.

To achieve the above object, the present invention provides the following technical solutions:

1. Isatinazole alcohol compounds containing acetophenone substituents and their pharmaceutically acceptable salts, the structures are shown in general formulas III and IV:

In the formula, R ¹ is hydrogen, alkyl; R ² is hydrogen, nitro; R ³ is hydrogen, nitro; R ⁵ is hydrogen, halogen, alkyl.

Preferably, R ¹ is hydrogen, methyl; R ² is hydrogen, nitro; R ³ is hydrogen, nitro; R ⁵ is hydrogen, chlorine, methyl.

Preferably, it is any one of the following compounds:

More preferably, the isatinazole alcohol compounds are III-1, III-2, III-3, III-4, III-5, III-6, IV-1, IV-2, IV-3, IV -4, IV-6.

2. The preparation method of the described isatinazole alcohol compounds containing acetophenone substituents and pharmaceutically acceptable salts thereof,

a. the preparation of the pharmaceutically acceptable salt of the isatin azole alcohol compound shown in the general formula I: the azole compound is dissolved in an organic solvent, and under the action of a base, it is separated from the isatin epoxide shown in the general formula VI. The cyclic reaction is to obtain the pharmaceutically acceptable salt of the isatinazole alcohol compound shown in the general formula I;

b. the preparation of the pharmaceutically acceptable salt of the isatinazole alcohol compounds containing acetophenone substituent shown in general formula III: the compound shown in general formula I is dissolved in an organic solvent, a carbonyl compound is added, and under the action of a base Condensation reaction occurs to obtain the pharmaceutically acceptable salt of the isatinazole alcohol compound containing acetophenone substituent shown in general formula III;

c. Preparation of pharmaceutically acceptable salts of isatinazole alcohol compounds containing acetophenone substituents shown in general formula IV: the compound shown in general formula III undergoes dehydration under the catalysis of acid to obtain the preparation shown in general formula IV Pharmaceutically acceptable salts of isatinazole alcohols containing acetophenone substituents.

Preferably, in step a, the temperature of the ring-opening reaction is 60°C; the reaction time is 12h; the base is potassium carbonate; the ratio of the amount of isatin to potassium carbonate is 1.25:1;

In step b, the base used in the aldol condensation reaction is diethylamine; the reaction is carried out at 18-25° C.; after the reaction, the crude product can be obtained directly by distillation under reduced pressure;

In step c, the acid used in the dehydration reaction is a mixed acid of glacial acetic acid and hydrochloric acid; the volume ratio of hydrochloric acid to glacial acetic acid is 1:3; the reaction is carried out under reflux; after the reaction, sodium bicarbonate is needed to neutralize.

3. A preparation containing said isatinazole alcohol compound containing an acetophenone substituent and a pharmaceutically acceptable salt thereof.

Preferably, the preparations are tablets, capsules, powders, granules, drop pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols or transdermal patch.

4. Use of the acetophenone-substituted isatinazole compounds and their pharmaceutically acceptable salts in the preparation of antibacterial and/or antifungal drugs.

Preferably, the bacteria is any one of Methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii one or more species; the fungi are any one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus, and Candida parapsilosis.

The beneficial effects of the present invention are as follows: the present invention utilizes the principle of drug design and splicing, firstly introduces oxadiazole fragments on indole, and designs and synthesizes a series of isatin oxadiazoles compounds containing acetophenone substituents with novel structures. In vitro antimicrobial activity test found that it was resistant to Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), Gram-negative bacteria ( Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023 and Candida parapsilosis ATCC20019) have certain inhibitory activity and can be used to prepare antibacterial and/or antifungal drugs, thereby providing more efficient and safe drug candidates for clinical antimicrobial therapy, which will help It aims to solve clinical treatment problems such as increasingly serious drug resistance, stubborn pathogenic microorganisms, and emerging harmful microorganisms.

Detailed ways

The preferred embodiments of the present invention will be described in detail below.

In the present invention, isatin derivative VI refers to "Mehra N V, Hopper M, Patel N, Hall D, Wrischnik L A, Land K M, Kumar V. Design and synthesis of β-amino alcohol based β-lactam-isatin chimeras and preliminary analysis of in vitro activity against the protozoal pathogen Trichomonas vaginalis. Med. Chem. Commun., 2013, 4, 1018–1024.”.

Preparation of isatin derivatives shown in VII-VIII: Reference "Chouhan M, Senwar KR, Sharma R, Grover V, Nair V A. Regiospecific epoxide opening: a facile approach for the synthesis of 3-hydroxy-3-aminomethylindolin-2- one derivative. Green Chem., 2011, 13, 2553–2560. Senwar KR, Sharma P, Reddy TS, Jeengar MK, Nayak VL, Naidu VG M, Kamal A, Shankaraiah N. Spirooxindole-derived morpholine-fused-1,2 ,3-triazoles: Design, synthesis, cytotoxicity and apoptosis inducing studies. Eur. J. Med. Chem., 2015, 102, 413–424.”; Definition of R ⁶ in general formulas VII to VIII hydrogen, alkyl, alkenyl, benzene base, substituted phenyl. Wherein, R ^{6 in VIII-1 is hydrogen, R 6} in VIII-2 is vinyl, R ⁶ in VIII-3 is phenyl, R ⁶ in VIII-4 is p-fluorophenyl, and R ⁶ in VIII- ⁵ is p-Chlorophenyl, R ⁶ in VIII-6 is 2,4-dichlorophenyl.

In the following examples, room temperature refers to the condition that the temperature is 18-25°C.

Example 1. Preparation of compound I-1

2-methyl-5-nitroimidazole (1.90 g, 15 mmol) and potassium carbonate (1.65 g, 12 mmol) were added to a 50 mL round-bottomed flask, and 20 mL of acetonitrile was used as solvent for stirring at 60° C. for 1 hour, and isatin derivatives were added. Compound VI (2.03 g, 10 mmol), continued to stir the reaction at 60° C., followed by thin layer chromatography until the end of the reaction. Acetonitrile was distilled off under reduced pressure, extracted with water and chloroform, and then concentrated, recrystallized, and dried to obtain compound I-1 (2.47 g), yield 74.8%; yellow solid; melting point: 235-237°C. ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 8.30 (s, 1H, Im-H-4), 7.68 (t, J=7.8Hz, 1H, isatin-H-6), 7.57 (d ,J=6.5Hz,1H,isatin-H-4),7.27(d,J=8.0Hz,1H,isatin-H-7),7.14(t,J=7.5Hz,1H,isatin-H-5) , 5.56 (d, J=4.8Hz, 1H, -OH), 4.20-4.16 (m, 1H, CH _1a -Im), 4.10-4.06 (m, 1H, OHCH), 4.03 (dd, J=13.6, 9.1 Hz, 1H, CH _1b -Im), 3.75 (dd, J=5.8, 1.6 Hz, 2H, NCH ₂ ), 2.38 (s, 3H, CH ₃ -Im).

Embodiment 2, the preparation of compound I-2

4-Nitroimidazole (1.69 g, 15 mmol) and potassium carbonate (1.65 g, 12 mmol) were added to a 50 mL round-bottomed flask, and 20 mL of acetonitrile was used as a solvent for stirring at 60° C. for 1 hour, and isatin derivative VI (2.03 g) was added. , 10 mmol), continued to stir the reaction at 60 °C, followed by thin layer chromatography until the end of the reaction. Acetonitrile was distilled off under reduced pressure, extracted with water and chloroform, and concentrated, recrystallized, and dried to obtain compound I-2 (2.50 g), yield 64.8%; yellow solid; melting point: 221-223°C. ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 8.35 (s, 1H, Im-H-5), 7.81 (s, 1H, Im-H-2), 7.67 (t, J=7.8 Hz ,1H,isatin-H-6),7.57(d,J=8.3Hz,1H,isatin-H-4),7.23(d,J=8.0Hz,1H,isatin-H-7),7.14(t, J=7.5Hz,1H,isatin-H-5),5.62(s,1H,-OH),4.31-4.26(m,1H,CH _1a -Im),4.09(t,J=8.5Hz,2H,CH _1b - Im, OHCH), 3.71 (d, J=4.8 Hz, 2H, NCH ₂ ).

Example 3. Preparation of compound II-1

In a 50mL round-bottomed flask, add hydroxylamine hydrochloride (0.04g, 0.60mmol) dissolved in 5mL ethanol, and a catalytic amount of hydrochloric acid, and then slowly dropwise add 5mL ethanol solution of I-1 (0.20g, 0.60mmol) at room temperature, The reaction was stirred at reflux and followed by thin layer chromatography until completion of the reaction. The ethanol was distilled off under reduced pressure, diluted with water, filtered, recrystallized, and dried to obtain compound II-1 (0.17 g), yield 81.3%; yellow solid; melting point: >250°C. ¹ H NMR (600 MHz, CDCl ₃ , ppm): δ 13.39 (s, 1H, -NOH), 8.33 (s, 1H, Im-H-4), 8.00 (d, J=8.3 Hz, 1H, isatin- H-4),7.44(t,J=7.2Hz,1H,isatin-H-6),7.21(d,J=7.9Hz,1H,isatin-H-7),7.09(t,J=7.3Hz, 1H,isatin-H-5),5.53(d,J=5.5Hz,1H,-OH),4.17(dd,J=14.0,2.6Hz,1H,CH _1a -Im),4.10-4.05(m,1H , OHCH),), 3.99(dd, J=9.0Hz, 13.8Hz, 1H, CH _1b -Im), 3.79(dd, J=13.1, 6.3Hz, 2H, NCH ₂ ), 2.38(s, 3H, CH ₃ -Im).

Example 4. Preparation of compound II-2

A 50 mL round-bottomed flask was added with hydrazine hydrate (0.04 mL, 0.90 mmol) dissolved in 5 mL of ethanol, and a catalytic amount of hydrochloric acid, and then 5 mL of ethanol solution of I-1 (0.30 g, 0.90 mmol) was slowly added dropwise at room temperature, The reaction was stirred at reflux and followed by thin layer chromatography until completion of the reaction. The ethanol was distilled off under reduced pressure, diluted with water, filtered, recrystallized, and dried to obtain compound II-2 (0.21 g), yield 67.7%; red solid; melting point: >250°C. ¹ H NMR (600 MHz, CDCl ₃ , ppm): δ 8.90 (s, 2H, NNH ₂ ), 8.33 (s, 1H, Im-H-4), 7.97 (d, J=7.5 Hz, 1H, isatin- H-4),7.30(t,J=7.7Hz,1H,isatin-H-6),7.17(d,J=8.0Hz,1H,isatin-H-7),7.04(t,J=7.5Hz, 1H,isatin-H-5),5.48(d,J=5.7Hz,1H,-OH),4.15(dd,J=14.1,2.6Hz,1H,CH _1a -Im),4.09-4.05(m,1H , OHCH), 3.96 (dd, J=14.1, 8.9 Hz, 1H, CH _1b -Im), 3.79 (d, J=6.0 Hz, 2H, NCH ₂ ), 2.35 (s, 3H, CH ₃ -Im).

Example 5. Preparation of compound II-3

In a 50mL round-bottomed flask, add phenylhydrazine (0.12mL, 1.21mmol) dissolved in 5mL of ethanol, and a catalytic amount of hydrochloric acid, then slowly dropwise add 5mL of ethanol solution of I-1 (0.30g, 0.90mmol) at room temperature, The reaction was stirred at reflux and followed by thin layer chromatography until completion of the reaction. Ethanol was distilled off under reduced pressure, diluted with water, and then filtered, recrystallized, and dried to obtain compound II-3 (0.28 g), yield 73.6%; yellow solid; melting point: >250°C. ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 12.69 (s, 1H, =NNHAr), 8.32 (s, 1H, Im-H-4), 7.61 (d, J=7.4Hz, 1H, isatin-H-4), 7.46(d, J=7.8Hz, 2H, Ar-H), 7.39(t, J=7.9Hz, 2H, Ar-H), 7.34(t, J=7.7Hz, 1H, isatin-H-6),7.26(d,J=7.9Hz,1H,isatin-H-7),7.13(t,J=7.5Hz,1H,isatin-H-5),7.06(t,J=7.3 Hz, 1H, Ar-H), 5.56 (d, J=4.8Hz, 1H, -OH), 4.21 (dd, J=14.1, 2.8Hz, 1H, CH _1a -Im), 4.16-4.10 (m, 1H , OHCH), 4.03 (dd, J=14.1, 8.9 Hz, 1H, CH _1b -Im), 3.90-3.83 (m, 2H, NCH ₂ ), 2.38 (s, 3H, CH ₃ -Im).

Example 6. Preparation of compound II-4

In a 50mL round-bottom flask, 2,4-dinitrophenylhydrazine (0.18mL, 0.90mmol) dissolved in 5mL ethanol, and a catalytic amount of hydrochloric acid were added, and then I-1 (0.30g, 0.90g was slowly added dropwise at room temperature) mmol) in 5 mL of ethanol, the reaction was stirred under reflux, followed by thin layer chromatography until the end of the reaction. The ethanol was distilled off under reduced pressure, diluted with water, filtered, recrystallized, and dried to obtain compound II-4 (0.32 g), yield 69.5%; yellow solid; melting point: >250°C. ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 14.44 (s, 1H, N-NH), 8.89 (d, J=2.5 Hz, 1H, Ar-H), 8.51 (dd, J=9.5 ,2.5Hz,1H,Ar-H),8.31(d,J=10.6Hz,2H,Im-H-4,Ar-H),7.70(d,J=7.5Hz,1H,isatin-H-4) ,7.47(t,J=7.8Hz,1H,isatin-H-6),7.30(d,J=7.9Hz,1H,isatin-H-7),7.17(t,J=7.5Hz,1H,isatin- H-5),5.57(s,1H,-OH),4.22(dd,J=13.9,2.3Hz,1H,CH _1a -Im),4.15-4.11(m,1H,OHCH),4.06(dd,J =13.9, 9.2 Hz, 1H, CH _1b -Im), 3.91-3.83 (m, 2H, NCH ₂ ), 2.39 (s, 3H, CH ₃ -Im).

Example 7. Preparation of compound II-5

In a 50 mL round-bottomed flask, add thiosemicarbazide (0.082 g, 0.90 mmol) dissolved in 5 mL of ethanol, and a catalytic amount of hydrochloric acid, and then slowly dropwise add a 5 mL ethanol solution of I-1 (0.30 g, 0.90 mmol) at room temperature , the reaction was stirred under reflux, followed by thin layer chromatography until the end of the reaction. The ethanol was distilled off under reduced pressure, diluted with water, and then filtered, recrystallized, and dried to obtain compound II-5 (0.25 g), yield 69.4%; red solid; melting point: >250°C. ¹ H NMR (600 MHz, CDCl ₃ , ppm): δ 12.41 (s, 1H, =NNHCSNH ₂ ), 9.07 (s, 1H, =NNHCSNH _1a ), 8.73 (s, 1H, =NNHCSNH _1b ), 8.30 (s ,1H,Im-H-4),7.72(d,J=7.3Hz,1H,isatin-H-4),7.44(t,J=7.4Hz,1H,isatin-H-6),7.27(d, J=7.8Hz,1H,isatin-H-7),7.16(t,J=7.4Hz,1H,isatin-H-5),5.56(d,J=4.6Hz,1H,-OH),4.19(d , J=13.7Hz, 1H, CH _1a -Im), 4.14-4.07 (m, 1H, OHCH), 4.03 (dd, J=13.5, 9.6Hz, 1H, CH _1b -Im), 3.88-3.79 (m, 2H, NCH2), 2.37 (s, 3H, _{CH3 -} Im).

Example 8. Preparation of compound II-6

Compound II-5 (0.20 g, 0.49 mmol) and 40% chloroacetaldehyde aqueous solution (0.05 g, 0.73 mmol) were added to a 50 mL round-bottomed flask, 20 mL of ethanol was used as a solvent, a catalytic amount of triethylamine was added at room temperature, and the mixture was refluxed. The reaction was stirred for 2 to 3 hours, followed by thin layer chromatography to complete the reaction. The ethanol was distilled off under reduced pressure, diluted with water, filtered, recrystallized, and dried to obtain compound II-6 (0.17 g), yield 64.5%; yellow solid; melting point: >250°C. ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 13.18 (s, 1H, = NNHCSNH ₂ ), 8.32 (s, 1H, Im-H-4), 7.58 (d, J=7.2 Hz, 1H ,isatin-H-4),7.46-7.40(m,2H,isatin-H-6,thiazole-H-4),7.29(d,J=7.8Hz,1H,isatin-H-7),7.22(s ,1H,thiazole-H-5),7.16(t,J＝7.2Hz,1H,isatin-H-5),5.57(d,J＝4.9Hz,1H,-OH),4.20(d,J＝14.0 Hz, 1H, CH _1a -Im), 4.15-4.10 (m, 1H, OHCH), 4.05 (d, J=13.8Hz, 1H, CH _1b -Im), 3.87-3.80 (m, 2H, NCH ₂ ), 2.38 (s, 3H, _CH3 -Im).

Example 9. Preparation of compound II-7

In a 50mL round-bottomed flask, add hydroxylamine hydrochloride (0.054g, 0.79mmol) dissolved in 5mL of ethanol, and a catalytic amount of hydrochloric acid, and then slowly dropwise add 5mL of ethanolic solution of I-2 (0.25g, 0.79mmol) at room temperature, The reaction was stirred at reflux and followed by thin layer chromatography until completion of the reaction. The ethanol was distilled off under reduced pressure, diluted with water, filtered, recrystallized and dried to obtain compound II-7 (0.21 g), yield 80.7%; brown solid; melting point: >250°C. ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 13.36 (s, 1H, -NOH), 8.38 (s, 1H, Im-H-5), 8.00 (d, J=7.4Hz, 1H, isatin-H-4),7.83(s,1H,Im-H-2),7.44(t,J=8.2Hz,1H,isatin-H-6),7.17(d,J=7.9Hz,1H,isatin -H-7),7.09(t,J=7.5Hz,1H,isatin-H-5),5.56(s,1H,-OH),4.28(dd,J=13.2,2.0Hz,1H,CH _1a - Im), 4.13-4.06 (m, 1H, OHCH), 4.04 (dd, J=13.3, 8.7 Hz, 1H, CH _1a -Im), 3.75 (d, J=5.7 Hz, 2H, NCH ₂ ).

Example 10. Preparation of compound II-8

A 50 mL round-bottomed flask was added with hydrazine hydrate (0.039 mL, 0.79 mmol) dissolved in 5 mL of ethanol, and a catalytic amount of hydrochloric acid, and then 5 mL of ethanol solution of I-2 (0.25 g, 0.79 mmol) was slowly added dropwise at room temperature, The reaction was stirred at reflux and followed by thin layer chromatography until completion of the reaction. The ethanol was distilled off under reduced pressure, diluted with water, and then filtered, recrystallized, and dried to obtain compound II-8 (0.17 g), yield 65.3%; brown solid; melting point: >250°C; ¹ H NMR (600MHz) , DMSO-d ₆ , ppm): δ 8.91 (s, 2H, NNH ₂ ), 8.39 (s, 1H, Im-H-5), 7.97 (d, J=7.5Hz, 1H, isatin-H-4 ),7.83(s,1H,Im-H-2),7.30(t,J=7.7Hz,1H,isatin-H-6),7.14(d,J=7.9Hz,1H,isatin-H-7) ,7.05(t,J=7.5Hz,1H,isatin-H-5),5.51(d,J=5.6Hz,1H,-OH),4.24(dd,J=13.6,2.3Hz,1H,CH _1a - Im), 4.10-4.05 (m, 1H, OHCH), 4.01 (dd, J=13.6, 8.6 Hz, 1H, CH _1b -Im), 3.79-3.72 (m, 2H, NCH ₂ ).

Example 11. Preparation of compound II-9

In a 50mL round-bottomed flask, add phenylhydrazine (0.07mL, 0.63mmol) dissolved in 5mL of ethanol, and a catalytic amount of hydrochloric acid, and then slowly dropwise add 5mL of ethanol solution of I-2 (0.20g, 0.63mmol) at room temperature, The reaction was stirred at reflux and followed by thin layer chromatography until completion of the reaction. The ethanol was distilled off under reduced pressure, diluted with water, and then filtered, recrystallized, and dried to obtain compound II-9 (0.20 g), yield 80.0%; yellow solid; melting point: >250°C; ¹ H NMR (600 MHz) , DMSO-d ₆ , ppm): δ12.68 (s, 1H, =NNHAr), 8.39 (s, 1H, Im-H-5), 7.85 (s, 1H, Im-H-2), 7.61 (d ,J=7.4Hz,1H,isatin-H-4),7.46(d,J=7.7Hz,2H,Ar-H),7.39(t,J=7.9Hz,2H,Ar-H),7.34(t ,J=8.2Hz,1H,isatin-H-6),7.22(d,J=7.9Hz,1H,isatin-H-7),7.13(t,J=7.6Hz,1H,isatin-H-5) ,7.06(t,J=7.3Hz,1H,Ar-H),5.62(d,J=5.4Hz,1H,-OH),4.31(dd,J=13.6,2.6Hz,1H,CH _1a -Im) , 4.18-4.13 (m, 1H, OHCH), 4.08 (dd, J=13.7, 8.5 Hz, 1H, CH _1b -Im), 3.83 (d, J=5.9 Hz, 2H, NCH ₂ ).

Example 12. Preparation of compound II-10

2,4-dinitrophenylhydrazine (0.12 g, 0.63 mmol) dissolved in 5 mL of ethanol, and a catalytic amount of hydrochloric acid were added to a 50 mL round-bottomed flask, and then 1-2 (0.20 g, 0.63 mmol) was slowly added dropwise at room temperature. mmol) in 5 mL of ethanol, the reaction was stirred under reflux, followed by thin layer chromatography until the end of the reaction. Ethanol was distilled off under reduced pressure, diluted with water, and then filtered, recrystallized, and dried to obtain compound II-10 (0.23 g), yield 73.4%; orange solid; melting point: >250°C; ¹ H NMR ( 600MHz, DMSO-d ₆ , ppm): δ14.40 (s, 1H, N-NH), 8.87 (d, J=2.6Hz, 1H, Ar-H), 8.50 (dd, J=9.5, 2.5Hz, 1H, Ar-H), 8.37 (d, J=1.2Hz, 1H, Im-H-5), 8.29 (d, J=9.5Hz, 1H, Ar-H), 7.83 (d, J=1.2Hz, 1H,Im-H-2),7.67(d,J=7.3Hz,1H,isatin-H-4),7.45(t,J=7.7Hz,1H,isatin-H-6),7.24(d,J =7.9Hz,1H,isatin-H-7),7.16(t,J=7.5Hz,1H,isatin-H-5),5.63(s,1H,-OH),4.32(d,J=11.3Hz, 1H, _CH1a -Im), 4.16-4.13 (m, 1H, OHCH), 4.12-4.08 (m, 1H, _CH1b -Im), 3.82 (d, J=5.8 Hz, 2H, NCH2 ₎ .

Example 13. Preparation of compound II-11

A 50 mL round-bottomed flask was added with thiosemicarbazide (0.057 g, 0.63 mmol) dissolved in 5 mL of ethanol, and a catalytic amount of hydrochloric acid, and then 5 mL of ethanol solution of I-2 (0.20 g, 0.63 mmol) was slowly added dropwise at room temperature , the reaction was stirred under reflux, followed by thin layer chromatography until the end of the reaction. The ethanol was distilled off under reduced pressure, diluted with water, and then filtered, recrystallized, and dried to obtain compound II-11 (0.17 g), yield 69.1%; yellow solid; melting point: >250°C; ¹ H NMR (600MHz) , DMSO-d ₆ , ppm): δ 12.40 (s, 1H, = NNHCSNH ₂ ), 9.08 (s, 1H, = NNHCSNH _1a ), 8.74 (s, 1H, = NNHCSNH _1b ), 8.37 (s, 1H, Im-H-5),7.82(s,1H,Im-H-2),7.72(d,J=7.4Hz,1H,isatin-H-4),7.44(t,J=7.7Hz,1H,isatin -H-6),7.23(d,J=8.0Hz,1H,isatin-H-7),7.16(t,J=7.5Hz,1H,isatin-H-5),5.61(d,J=5.2Hz ,1H,-OH),4.29(dd,J=11.4,1.8Hz,1H,CH _1a -Im),4.14-4.11(m,1H,OHCH),4.07(dd,J=13.2,8.4Hz,1H, CH _1b -Im), 3.79 (d, J=5.7 Hz, 2H, NCH ₂ ).

Example 14. Preparation of compound III-1

In a 50 mL round-bottomed flask, compound I-1 (0.50 g, 1.51 mmol) and 4-chloroacetophenone (0.19 mL, 1,51 mmol) were added, 10 mL of methanol was used as a solvent, and diethylamine (0.15 mL, 1.51 mmol) was added at room temperature. mmol), reacted at room temperature, followed by thin-layer chromatography to the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, dried and other post-processing to obtain compound III-1 (0.55g), yield 75.3%; white Solid; melting point: 231-233°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.30 (s, 1H, Im-H-4), 7.92 (d, J=8.6 Hz, 2H, Ar -H),7.56(d,J=8.5Hz,2H,Ar-H),7.37(d,J=7.4Hz,1H,isatin-H-4),7.28(t,J=8.1Hz,1H,isatin -H-6),7.17(d,J=7.9Hz,1H,isatin-H-7),6.97(t,J=7.6Hz,1H,isatin-H-5),6.18(s,1H,-OH ), 5.60 (d, J=4.8Hz, 1H, -OH), 4.24-4.19 (m, 1H, CH _1a -Im), 4.15-4.08 (m, 3H, CH _1b -Im, OHCH, C(OH) CH _1a CO), 3.86-3.76 (m, 2H, NCH ₂ ), 3.69 (d, J=17.7 Hz, 1H, C(OH)CH _1b CO), 2.37 (s, 3H, CH ₃ ).

Example 15. Preparation of compound III-2

In a 50 mL round-bottomed flask, compound I-1 (0.50 g, 1.51 mmol) and 4-methylacetophenone (0.20 mL, 1,51 mmol) were added, 10 mL of methanol was used as a solvent, and diethylamine (0.15 mL, 1.51mmol), reacted at room temperature, followed by thin-layer chromatography to the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, dried and other post-processing to obtain compound III-2 (0.48g), yield 68.5%; White solid; melting point: 179-181°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.34 (s, 1H, Im-H-4), 7.83 (d, J=8.1 Hz, 2H, Ar-H),7.38(d,J=7.1Hz,1H,isatin-H-4),7.31(d,J=8.0Hz,2H,Ar-H),7.28(t,J=8.1Hz,1H, isatin-H-6),7.18(d,J=7.9Hz,1H,isatin-H-7),6.96(t,J=7.5Hz,1H,isatin-H-5),6.17(s,1H,- OH), 5.64 (d, J=3.5Hz, 1H, -OH), 4.22 (d, J=17.8Hz, CH _1a -Im), 4.14-4.08 (m, 2H, CH _1b -Im, OHCH), 3.84 -3.77 (m, 2H, NCH ₂ ), 3.68 (d, J=17.8Hz, 1H, C(OH)CH _1a CO), 3.17 (d, J=5.2 Hz, 1H, C(OH)CH _1b CO) , 2.38 (s, 3H, _CH3 ), 2.36 (s, 3H, Ar- _CH3 ).

Example 16. Preparation of compound III-3

In a 50 mL round-bottomed flask, compound I-1 (0.50 g, 1.51 mmol) and acetophenone (0.17 mL, 1.51 mmol) were added, 10 mL of methanol was used as a solvent, and diethylamine (0.15 mL, 1.51 mmol) was added at room temperature, The reaction was carried out at room temperature, followed by thin-layer chromatography to the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain compound III-3 (0.51 g), yield 74.8%; white solid; melting point : 207-209°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): 8.33 (s, 1H, Im H-4), 7.93 (d, J=7.5 Hz, 2H, Ar-H), 7.65 ( t,J=7.3Hz,1H,Ar-H),7.51(t,J=7.6Hz,2H,ArH),7.39(d,J=7.1Hz,1H,isatin-H-4),7.28(t, J=7.7Hz,1H,isatin-H-6),7.19(d,J=7.8Hz,1H,isatin-H-7),6.97(t,J=7.5Hz,1H,isatin-H-5), 6.19(s,1H,-OH),5.64(d,J=3.9Hz,1H,-OH),4.25(d,J=17.9Hz,1H,CH _1a -Im),4.15-4.10(m,3H, CH _1b -Im, OHCH, NCH _1a ), 3.83-3.79 (m, 1H, NCH _1b ), 3.72 (d, J=17.8Hz, 1H, C(OH)CH _1a CO), 3.48-3.41 (m, 1H , C(OH)CH _1b CO), 2.38 (d, J=5.8 Hz, 3H, CH ₃ ).

Example 17. Preparation of compound III-4

Compound I-2 (0.50 g, 1.58 mmol) and 4-chloroacetophenone (0.20 mL, 1,58 mmol) were added to a 50 mL round-bottomed flask, 10 mL of methanol was used as a solvent, and diethylamine (0.16 mL, 1.58 mmol) was added at room temperature. mmol), reacted at room temperature, followed by thin-layer chromatography to the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, dried and other post-processing to obtain compound III-4 (0.52g), yield 70.2%; white solid; melting point: 235-237°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.35 (s, 1H, Im-H-5), 7.93 (d, J=8.6 Hz, 2H, Ar -H),7.81(s,1H,Im-H-2),7.57(d,J=8.6Hz,2H,Ar-H),7.38(d,J=6.9Hz,1H,isatin-H-4) ,7.28(t,J＝7.2Hz,1H,isatin-H-6),7.14(d,J＝7.9Hz,1H,isatin-H-7),6.97(t,J＝7.4Hz,1H,isatin- H-5), 6.19(s, 1H, -OH), 5.65(d, J=4.6Hz, 1H, -OH), 4.24-4.19(m, 2H, CH ₂ -Im), 4.13-4.07(m, 2H, NCH ₂ ), 3.76-3.73 (m, 1H, OHCH), 3.68 (d, J=17.7Hz, 1H, C(OH)CH _1a CO), 3.17 (d, J=5.2Hz, 1H, C( OH)CH _1b CO).

Example 18. Preparation of compound III-5

In a 50 mL round-bottomed flask, compound I-2 (0.50 g, 1.58 mmol) and 4-methylacetophenone (0.21 mL, 1,58 mmol) were added, 10 mL of methanol was used as a solvent, and diethylamine (0.16 mL, 1.58mmol), reacted at room temperature, followed by thin-layer chromatography to the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, dried and other post-processing to obtain compound III-5 (0.46g), yield 64.7%; White solid; melting point: 229-231°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.35 (s, 1H, Im-H-5), 7.81 (d, J=8.3 Hz, 3H, Im H-2,Ar-H),7.38(d,J=7.2Hz,1H,isatin-H-4),7.31(d,J=8.0Hz,2H,Ar-H),7.28(t,J= 7.8Hz,1H,isatin-H-6),7.14(d,J=7.9Hz,1H,isatin-H-7),6.96(t,J=7.4Hz,1H,isatin-H-5),6.15( s, 1H, -OH), 5.65 (d, J=4.2Hz, 1H, -OH), 4.24-4.17 (m, 2H, CH ₂ -Im), 4.13-4.07 (m, 2H, NCH ₂ ), 3.79 -3.73(m,1H,OHCH),3.66(d,J=17.7Hz,1H,C(OH) _CH1aCO ),3.17(d,J=5.2Hz,1H,C(OH) _CH1bCO ), 2.36 (s, 3H, _ArCH3 ).

Example 19. Preparation of compound III-6

In a 50mL round-bottom flask, compound I-2 (0.50g, 1.58mmol) and acetophenone (0.18mL, 1,58mmol) were added, 10mL methanol was used as a solvent, and diethylamine (0.16mL, 1.58mmol) was added at room temperature, The reaction was carried out at room temperature, followed by thin-layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain compound III-6 (0.53 g), yield 77.9%; white solid; melting point : 225-227°C; ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 8.36 (s, 1H, Im-H-5), 7.92 (d, J=7.5Hz, 2H, Ar-H) , 7.81(s, 1H, Im-H-2), 7.64(t, J=7.4Hz, 1H, Ar-H), 7.51(t, J=7.7Hz, 2H, Ar-H), 7.39(d, J=7.2Hz,1H,isatin-H-4),7.28(t,J=7.6Hz,1H,isatin-H-6),7.15(d,J=7.9Hz,1H,isatin-H-7), 6.97(t,J=7.4Hz,1H,isatin-H-5),6.18(s,1H,-OH),5.66(d,J=4.3Hz,1H,-OH),4.27-4.20(m,2H , CH ₂ -Im), 4.12 (d, J=8.5Hz, 2H, NCH ₂ ), 3.79-3.75 (m, 1H, OHCH), 3.70 (d, J=17.8 Hz, 1H, C(OH)CH _1a CO), 3.18 (d, J=5.3 Hz, 1H, C(OH)CH _1b CO).

Example 20. Preparation of compound IV-1

Compound III-1 (0.24 g, 0.50 mmol) was added to a 50 mL round-bottomed flask, 10 mL of ethanol was used as a solvent, 37% hydrochloric acid (0.25 mL) and glacial acetic acid (0.75 mL) were added at room temperature, and the temperature was controlled at 120 ° C to react, thin layer Chromatography was followed up to the end of the reaction, and saturated sodium bicarbonate solution was added for neutralization, and then post-processing such as concentration, extraction, column chromatography separation, recrystallization, and drying was performed to obtain compound IV-1 (0.22 g), with a yield of 92.1%; orange Color solid; melting point: 211-213°C; ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 8.35 (s, 1H, Im-H-4), 8.10 (d, J=8.2Hz, 2H, Ar-H),8.03(d,J=7.6Hz,1H,isatin-H-4),7.78(s,1H,CHalkene),7.68(d,J=7.4Hz,2H,Ar-H),7.45( t,J=7.6Hz,1H,isatin-H-6),7.21(d,J=7.9Hz,1H,isatin-H-7),7.04(t,J=7.6Hz,1H,isatin-H-5 ), 5.57 (s, 1H, -OH), 4.20 (d, J=15.9Hz, 1H, CH _1a -Im), 4.16-4.07 (br m, 1H, OHCH), 4.03 (dd, J=13.9, 9.0 Hz, 1H, CH _1b -Im), 3.85-3.80 (m, 2H, NCH ₂ ), 2.39 (s, 3H, CH ₃ ).

Example 21. Preparation of compound IV-2

Compound III-2 (0.23 g, 0.50 mmol) was added to a 50 mL round-bottomed flask, 10 mL of ethanol was used as a solvent, 37% hydrochloric acid (0.25 mL) and glacial acetic acid (0.75 mL) were added at room temperature, and the temperature was controlled at 120 ° C to react, thin layer Chromatography was followed up to the end of the reaction, and saturated sodium bicarbonate solution was added for neutralization, and then through post-processing such as concentration, extraction, column chromatography separation, recrystallization, drying, etc., compound IV-2 (0.20 g) was obtained with a yield of 91.5%; Color solid; melting point: 216-218°C; ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 8.35 (s, 1H, Im-H-4), 7.99-7.95 (m, 3H, Ar-H ,isatin-H-4),7.78(s,1H,CHalkene),7.42(d,J=7.6Hz,3H,Ar-H,isatin-H-6),7.21(d,J=7.9Hz,1H, isatin-H-7), 7.02(t, J=7.6Hz, 1H, isatin-H-5), 5.57(s, 1H, -OH), 4.20(d, J=13.8Hz, 1H, CH _1a -Im ), 4.15-4.08(m, 1H, OHCH), 4.03(dd, J=13.9, 9.0Hz, 1H, CH _1b -Im), 3.86-3.79(m, 2H, NCH ₂ ), 2.42(s, 3H, Ar- _CH3 ), 2.39 (s, 3H, _CH3 ).

Example 22. Preparation of compound IV-3

Compound III-3 (0.23 g, 0.50 mmol) was added to a 50 mL round-bottomed flask, 10 mL of ethanol was used as a solvent, 37% hydrochloric acid (0.25 mL) and glacial acetic acid (0.75 mL) were added at room temperature, and the temperature was controlled at 120 ° C to react, thin layer Chromatography was followed up to the end of the reaction, and saturated sodium bicarbonate solution was added for neutralization, and after post-processing such as concentration, extraction, column chromatography separation, recrystallization, drying, etc., compound IV-3 (0.20 g) was obtained with a yield of 93.5%; Color solid; melting point: 173-175°C; ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 8.35 (s, 1H, Im-H-4), 8.08 (d, J=7.4Hz, 2H, Ar-H),7.99(d,J=7.6Hz,1H,Ar-H),7.81(s,1H,CHalkene),7.74(t,J=7.4Hz,1H,isatin-H-4),7.62( t,J=7.7Hz,2H,Ar-H),7.44(t,J=7.7Hz,1H,isatin-H-6),7.21(d,J=7.9Hz,1H,isatin-H-7), 7.03(t,J=7.6Hz,1H,isatin-H-5),5.57(d,J=5.5Hz,1H,-OH),4.20(d,J=13.9Hz,1H,CH _1a -Im), 4.16-4.10 (m, 1H, OHCH), 4.03 (dd, J=14.0, 9.0Hz, 1H, CH _1b -Im), 3.85-3.80 (d, J=28.6Hz, 2H, NCH ₂ ), 2.41 (d , J=18.1 Hz, 3H, CH ₃ ).

Example 23. Preparation of compound IV-4

Compound III-4 (0.24 g, 0.50 mmol) was added to a 50 mL round-bottomed flask, 10 mL of ethanol was used as a solvent, 37% hydrochloric acid (0.25 mL) and glacial acetic acid (0.75 mL) were added at room temperature, and the temperature was controlled at 120 ° C to react, thin layer Chromatography was followed up to the end of the reaction, and saturated sodium bicarbonate solution was added for neutralization, and after concentration, extraction, column chromatography separation, recrystallization, drying and other post-processing to obtain compound IV-4 (0.21g), the yield was 91.5%; orange Color solid; melting point: 131-133°C; ¹ H NMR (600MHz, DMSO-d ₆ , ppm): δ 8.40 (s, 1H, Im-H-5), 8.10 (d, J=8.5Hz, 2H, Ar-H),8.02(d,J=7.6Hz,1H,isatin-H-4),7.85(s,1H,CHalkene),7.78(s,1H,Im-H-2),7.68(d,J =8.5Hz,2H,Ar-H),7.44(t,J=7.7Hz,1H,isatin-H-6),7.19(d,J=7.9Hz,1H,isatin-H-7),7.03(t ,J=7.6Hz,1H,isatin-H-5),4.94(s,1H,-OH),4.31(d,J=14.7Hz,1H,CH _1a -Im),4.14-4.06(m,2H, NCH2 ₎ , 3.79 (d, J=5.6 Hz, 2H, _CH1b -Im, OHCH).

Example 24. Preparation of compound IV-5

Compound III-5 (0.23 g, 0.50 mmol) was added to a 50 mL round-bottomed flask, 10 mL of ethanol was used as a solvent, 37% hydrochloric acid (0.25 mL) and glacial acetic acid (0.75 mL) were added at room temperature, and the temperature was controlled at 120 ° C to react, thin layer Chromatography was followed up to the end of the reaction, and saturated sodium bicarbonate solution was added for neutralization, and then post-processing such as concentration, extraction, column chromatography separation, recrystallization, and drying was performed to obtain compound IV-5 (0.20 g), with a yield of 93.1%; orange Color solid; melting point: 117-119°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.40 (d, J=1.0 Hz, 1H, Im-H-5), 7.99 (d, J= 8.1Hz,2H,Ar-H),7.95(d,J=7.6Hz,1H,isatin-H-4),7.85(d,J=1.0Hz,1H,CHalkene),7.79(s,1H,Im- H-2),7.42(dd,J=7.1,4.9Hz,3H,Ar-H,isatin-H-6),7.19(d,J=7.9Hz,1H,isatin-H-7),7.02(t , J=7.6Hz,1H,isatin-H-5),4.76(brs,1H,-OH),4.30(d,J=14.9Hz,1H,CH _1a -Im),4.13-4.06(m,2H, NCH2 ₎ , 3.79 (d, J=5.7 Hz, 2H, _CH1b -Im, OHCH), 2.42 (s, 3H, Ar- _CH3 ).

Example 25. Preparation of compound IV-6

Compound III-6 (0.22 g, 0.50 mmol) was added to a 50 mL round-bottomed flask, 10 mL of ethanol was used as a solvent, 37% hydrochloric acid (0.25 mL) and glacial acetic acid (0.75 mL) were added at room temperature, and the temperature was controlled at 120 ° C to react, thin layer Chromatography was followed up to the end of the reaction, and saturated sodium bicarbonate solution was added for neutralization, and then post-processing such as concentration, extraction, column chromatography separation, recrystallization, and drying was performed to obtain compound IV-6 (0.19g), with a yield of 94.7%; orange Color solid; melting point: 99-101 °C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.40 (s, 1H, Im-H-5), 8.09 (d, J=7.2 Hz, 2H, Ar-H),7.98(d,J=7.6Hz,1H,isatin-H-4),7.85(s,1H,CHalkene),7.81(s,1H,Im-H-2),7.74(t,J =7.4Hz,1H,Ar-H),7.62(t,J=7.8Hz,2H,Ar-H),7.43(t,J=8.1Hz,1H,isatin-H-6),7.19(d,J =7.9Hz,1H,isatin-H-7),7.02(t,J=7.5Hz,1H,isatin-H-5),4.88(br s,1H,-OH),4.31(dd,J=13.2, 2.1 Hz, 1H, _CH1a -Im), 4.15-4.05 (m, 2H, _CH1b -Im, OHCH), 3.80 (d, J=5.7Hz, 2H, NCH2 ₎ .

Example 26. Preparation of compound V-1

The compound 2-methyl-5-nitroimidazole (0.95 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added to a 50 mL round-bottomed flask, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-1 (0.94 g, 5.0 mmol) was added, reacted under reflux, followed by thin layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain the compound. V-1 (1.12 g), yield 71.3%; white solid; melting point: 201-203°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 7.83 (s, 1H, Im-H-4) ,7.37(t,J＝7.7Hz,1H,isatin-H-6),7.10-7.04(m,2H,isatin-H-4,5),6.96(d,J＝6.9Hz,1H,isatin-H -7), 6.68 (s, 1H, -OH), 4.33 (q, J=14.5Hz, 2H, NCH ₂ ), 3.66 (dd, J=33.3, 14.1, 7.1 Hz, 2H, CH ₂ -Im), 2.07 (s, 3H, _CH3 -Im), 1.08 (t, J=7.2 Hz, _3H , _NCH2CH3 ).

Embodiment 27, the preparation of compound V-2

The compound 2-methyl-5-nitroimidazole (0.95 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added to a 50 mL round-bottomed flask, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-2 (1.0 g, 5.0 mmol) was added, reacted under reflux, followed by thin layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, dried and other post-processing to obtain the compound V-2 (1.24 g), yield 75.6%; white solid; melting point: 169-171°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 7.89 (s, 1H, Im-H-4) ,7.35(t,J＝7.7Hz,1H,isatin-H-6),7.06(t,J＝7.5Hz,1H,isatin-H-4),6.96(dd,J＝13.5,7.6Hz,2H, isatin-H-5,7), 6.76 (s, 1H, -OH), 5.81-5.75 (m, 1H, CH=CH ₂ ), 5.13-5.09 (m, 2H, CH=CH ₂ ), 4.40-4.33 (m, 2H, _CH2 -Im), 4.32-4.22 (m, 2H, NCH2), 2.07 (s, 3H, _{CH3 -} Im).

Example 28. Preparation of compound V-3

The compound 2-methyl-5-nitroimidazole (0.95 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added to a 50 mL round-bottomed flask, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-3 (1.25 g, 5.0 mmol) was added, reacted under reflux, followed by thin-layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain the compound. V-3 (1.51 g), 79.8% yield; white solid; melting point: 115-117°C; ¹ HNMR (600 MHz, DMSO-d ₆ , ppm): δ 7.85 (s, 1H, Im-H-4) ,7.29(t,J=7.8Hz,3H,isatin-H-6,Ar-H),7.25(d,J=7.1Hz,1H,isatin-H-4),7.21(d,J=7.6Hz, 2H,Ar-H),7.05(t,J=7.4Hz,1H,isatin-H-5),7.02(d,J=6.5Hz,1H,Ar-H),6.89(d,J=7.8Hz, 1H,isatin-H-7),6.86(d,J=4.0Hz,1H,-OH),4.87(s,2H,CH ₂ -Im),4.47-4.39(m,2H,NCH ₂ ),2.09( s, 3H, CH ₃ -Im).

Example 29. Preparation of compound V-4

The compound 2-methyl-5-nitroimidazole (0.95 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added to a 50 mL round-bottomed flask, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-4 (1.34 g, 5.0 mmol) was added, reacted under reflux, followed by thin-layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain the compound. V-4 (1.54 g), 77.7% yield; white solid; melting point: 228-230°C; ¹ HNMR (600 MHz, DMSO-d ₆ , ppm): δ 7.83 (s, 1H, Im-H-4) ,7.32-7.27(m,3H,isatin-H-6,Ar-H),7.12(t,J=8.9Hz,2H,Ar-H),7.06(t,J=7.3Hz,1H,isatin-H -5),7.01(d,J=7.3Hz,1H,isatin-H-4),6.93(d,J=7.8Hz,1H,isatin-H-7),6.83(s,1H,-OH), 4.85 (d, J=6.2Hz, 2H, _CH2 -Im), 4.41 (d, J=6.7Hz, 2H, NCH2), 2.09 (s, 3H, _{CH3 -} Im).

Embodiment 30, the preparation of compound V-5

The compound 2-methyl-5-nitroimidazole (0.95 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added to a 50 mL round-bottomed flask, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-5 (1.42 g, 5.0 mmol) was added, reacted under reflux, followed by thin layer chromatography to the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, dried and other post-processing to obtain the compound V-5 (1.79 g), 86.8% yield; white solid; melting point: 231-233°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 7.83 (s, 1H, Im-H-4) ,7.35(d,J＝8.5Hz,2H,Ar-H),7.31(t,J＝7.7Hz,1H,isatin-H-6),7.25(d,J＝8.4Hz,2H,Ar-H) ,7.06(t,J=7.4Hz,1H,isatin-H-5),7.02(d,J=7.3Hz,1H,isatin-H-4),6.91(d,J=7.9Hz,1H,isatin- H-7), 6.83(s, 1H, -OH), 4.86(s, 2H, NCH ₂ ), 4.45-4.39(m, 2H, CH ₂ -Im), 2.09(s, 3H, CH ₃ -Im) .

Example 31. Preparation of compound V-6

The compound 2-methyl-5-nitroimidazole (0.95 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added to a 50 mL round-bottomed flask, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-6 (1.59 g, 5.0 mmol) was added, reacted under reflux, followed by thin-layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain the compound. V-6 (1.85 g), yield 82.9%; white solid; melting point: 118-120°C; ¹ HNMR (600 MHz, DMSO-d ₆ , ppm): δ 7.90 (s, 1H, Im-H-4) ,7.70(s,1H,Ar-H),7.32(dd,J=17.2,8.2Hz,2H,isatin-H-6,Ar-H),7.09(t,J=7.3Hz,1H,isatin-H -5),7.02(d,J=7.0Hz,1H,isatin-H-4),6.96(d,J=8.3Hz,1H,Ar-H),6.89(s,1H,-OH),6.86( d, J=7.8Hz, 1H, isatin-H-7), 4.91 (s, 2H, NCH ₂ ), 4.47-4.40 (m, 2H, CH ₂ -Im), 2.08 (s, 3H, CH ₃ -Im) ).

Example 32. Preparation of compound V-7

In a 50 mL round-bottomed flask, compound 4-nitroimidazole (0.84 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-1 (0.94 g, 5.0 mmol) was added, reacted under reflux, followed by thin layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain the compound. V-7 (1.18 g), 78.6% yield; white solid; melting point: 188-190°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 7.98 (s, 1H, Im-H-5 ),7.52(s,1H,Im-H-2),7.36(t,J=7.7Hz,1H,isatin-H-6),7.05(dd,J=8.5,5.8Hz,2H,isatin-H- 4,5),6.97(d,J=7.2Hz,1H,isatin-H-7),6.74(s,1H,-OH),4.44(q,J=13.9Hz,2H,NCH ₂ ),3.68( dd,J=14.1,7.1Hz,1H,CH _1a -Im),3.61(dd,J=14.1,7.1Hz,1H,CH _1b -Im),1.06(t,J=7.1Hz,3H,NCH ₂ CH ₃ ).

Example 33. Preparation of compound V-8

In a 50 mL round-bottomed flask, compound 4-nitroimidazole (0.84 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-2 (1.0 g, 5.0 mmol) was added, reacted under reflux, followed by thin layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, dried and other post-processing to obtain the compound V-8 (1.24 g), 78.9% yield; white solid; melting point: 180-182°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.02 (s, 1H, Im-H-5 ),7.55(s,1H,Im-H-2),7.34(t,J=7.8Hz,1H,isatin-H-6),7.05(d,J=7.5Hz,1H,isatin-H-4) , 6.96(d,J=8.4Hz,2H,isatin-H-5,7),6.80(s,1H,-OH),5.78-5.73(m,1H,CH= _CH2 ),5.11(dd,J =12.5, 10.5 Hz, 2H, CH= _CH2 ), 4.51-4.44 (m, 2H, _CH2 -Im), 4.31-4.21 (m, 2H, NCH2 ₎ .

Example 34. Preparation of compound V-9

In a 50 mL round-bottomed flask, compound 4-nitroimidazole (0.84 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-3 (1.25 g, 5.0 mmol) was added, reacted under reflux, followed by thin-layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain the compound. V-9 (1.60 g), 87.9% yield; white solid; melting point: 103-105°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.02 (s, 1H, Im-H-5 ),7.58(s,1H,Im-H-2),7.29-7.25(m,4H,isatin-H-6,Ar-H),7.21(d,J＝7.4Hz,2H,Ar-H), 7.05(t,J=7.4Hz,1H,isatin-H-5),7.01(d,J=7.3Hz,1H,isatin-H-4),6.90(s,1H,-OH),6.88(d, J = 7.9 Hz, 1H, isatin-H-7), 4.89-4.82 (m, 2H, NCH ₂ ), 4.57-4.49 (m, 2H, CH ₂ -Im).

Example 35. Preparation of compound V-10

In a 50 mL round-bottomed flask, compound 4-nitroimidazole (0.84 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-4 (1.34 g, 5.0 mmol) was added, reacted under reflux, followed by thin-layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain the compound. V-10 (1.39 g), 72.7% yield; white solid; melting point: 220-222°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.00 (d, J=1.3 Hz, 1H, Im-H-5), 7.57 (d, J=1.3Hz, 1H, Im-H-2), 7.31-7.28 (m, 3H, isatin-H-6, Ar-H), 7.11 (t, J= 8.9Hz,2H,Ar-H),7.05(d,J=7.4Hz,1H,isatin-H-4),7.00(d,J=7.3Hz,1H,Ar-H,isatin-H-5), 6.92(d, J=7.8Hz, 1H, Ar-H, isatin-H-7), 6.87(s, 1H, -OH), 4.84(s, 2H, CH ₂ -Im), 4.55-4.48(m, 2H, NCH ₂ ).

Example 36. Preparation of compound V-11

In a 50 mL round-bottomed flask, compound 4-nitroimidazole (0.84 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-5 (1.42 g, 5.0 mmol) was added, reacted under reflux, followed by thin layer chromatography to the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, dried and other post-processing to obtain the compound V-11 (1.69 g), 84.9% yield; white solid; melting point: 216-218°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.01 (s, 1H, Im-H-5 ),7.57(s,1H,Im-H-2),7.35(d,J=8.5Hz,2H,Ar-H),7.29(t,J=7.1Hz,1H,isatin-H-6),7.26 (d, J=8.5Hz, 2H, Ar-H), 7.06 (t, J=7.5Hz, 1H, isatin-H-5), 7.01 (d, J=7.2Hz, 1H, isatin-H-4) ,6.90(d,J=7.9Hz,1H,isatin-H-7),6.88(s,1H,-OH),4.85(s,2H,NCH ₂ ),4.56-4.49(m,2H,CH ₂ - Im).

Example 37. Preparation of compound V-12

In a 50 mL round-bottomed flask, compound 4-nitroimidazole (0.84 g, 7.5 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were added, and 15 mL of acetonitrile was used as a solvent, and the mixture was stirred at 60° C. for 1.5 h. After cooling to room temperature, compound VIII-6 (1.59 g, 5.0 mmol) was added, reacted under reflux, followed by thin-layer chromatography until the end of the reaction, and then concentrated, extracted, separated by column chromatography, recrystallized, and dried to obtain the compound. V-12 (1.57 g), 72.6% yield; white solid; melting point: 110-112°C; ¹ H NMR (600 MHz, DMSO-d ₆ , ppm): δ 8.05 (s, 1H, Im-H-5 ),7.69(d,J＝2.0Hz,1H,Ar-H),7.59(s,1H,Im-H-2),7.33-7.28(m,2H,isatin-H-6,Ar-H), 7.10(t,J=7.5Hz,1H,isatin-H-5),7.03(d,J=7.2Hz,1H,isatin-H-4),6.96(d,J=8.4Hz,1H,Ar-H ),6.94(s,1H,-OH),6.85(d,J=7.8Hz,1H,isatin-H-7),4.89(t,J=11.5Hz,2H,NCH ₂ ),4.53(q,J =14.0 Hz, 2H, _CH2 -Im).

Note: Im is imidazole, Ar is benzene ring.

Example 38. In vitro antimicrobial activity of isatinazole alcohol compounds

The 96-well microdilution method conforming to the Clinical and Laboratory Standards Institute (CLSI) established by the US National Committee was used to examine the effect of the isatinazole alcohol compounds prepared in Examples 1-37 on the resistance to Gram-positive bacteria (methicillin-resistant bacteria). Oxycillin Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa , Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis ATCC20019) minimum Inhibitory concentration (MIC), the compound to be tested was dissolved with a small amount of dimethyl sulfoxide, diluted with water to make a solution with a concentration of 1.28 mg/mL, and then diluted with culture medium to 128 μg/mL, and incubated at 35 °C for 24-72 hours, After the culture plate was fully shaken on a shaker, the MIC was measured at a wavelength of 490 nm. The results are shown in Table 1 and Table 2.

Table 1. In vitro antibacterial activity data (MIC, μg/mL) of isatinazole alcohol compounds I-1–V-12

It can be seen from Table 1 that the compounds I-1-V-12 prepared in Examples 1-37 of the present invention showed a certain inhibitory effect on the tested bacteria, and more importantly, the antibacterial activities of some compounds can be Comparable or even stronger than the reference drug norfloxacin.

Table 2. In vitro antifungal activity data of isatinazole alcohol compounds I-1–V-12 (MIC, μg/mL)

As can be seen from Table 2, the compounds I-1-V-12 prepared in Examples 1-37 of the present invention showed a certain inhibitory effect on the tested fungi, and more importantly, the antibacterial activities of some compounds can be Comparable or even stronger than the reference drug fluconazole.

Embodiment 39, the pharmaceutical use of isatinazole alcohol compounds

According to the above test results of antimicrobial activity, the isatinazole alcohol 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 preparations, for example, made from a structure of isatinazole alcohol compounds and pharmaceutically acceptable excipients; they can also be compound preparations, for example, made from a structure of isatinazole alcohol compounds and already It is made of antibacterial and antifungal active ingredients (such as norfloxacin, ciprofloxacin, sulfamethoxazole, fluconazole, fosfluconazole, itraconazole, etc.) and pharmaceutically acceptable excipients. Or it is made from several isatinazole alcohol compounds with different structures and pharmaceutically acceptable excipients. The formulation types include but are not limited to tablets, capsules, powders, granules, drop pills, injections, powders, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols dosage forms such as transdermal absorption patches, as well as various sustained-release, controlled-release preparations and nano-formulations.

1. Preparation of Compound I-1 Tablets

Recipe: Compound I-1 10g, lactose 187g, corn starch 50g, magnesium stearate 3.0g, an appropriate amount of an ethanol solution with a concentration of 70% by volume, and a total of 1000 tablets were made.

Preparation method: dry corn starch at 105°C for 5 hours for use; mix compound I-1 with lactose and corn starch uniformly, use 70% ethanol solution to make soft material, sieve to make wet granules, and then add magnesium stearate, Tablets are obtained; each tablet weighs 250 mg, and the active ingredient content is 10 mg.

2. Preparation of Compound II-2 Capsules

Prescription: compound II-2 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low-substituted hydroxypropyl cellulose (100 mesh) 2.5g, talc (100 mesh) 2g, 1.25g of sweetener, 0.25g of orange essence, appropriate amount of pigment, appropriate amount of water, make 1000 capsules.

Preparation method: After micronizing and pulverizing the compound II-2 in the prescription amount into a very fine powder, mix it with the prescription amount of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talc, sweetener, orange essence and Mix the pigments, make soft materials with water, granulate with a 12-14 mesh sieve, dry at 40-50°C, sieve and granulate, and put into empty capsules to obtain; each tablet weighs 50mg, and the active ingredient content is 25mg.

3. Preparation of Compound III-1 Granules

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

Preparation method: Compound III-1, dextrin and sucrose are mixed uniformly, granulated by wet method, dried at 60°C, and then packaged.

4. Preparation of Compound IV-2 Injection

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

Preparation method: Weigh compound IV-2, add propylene glycol and water for injection, stir to dissolve, then add 1 g of activated carbon, stir well and let stand for 15 minutes, filter and decarbonize with 5 μm titanium rod, and then use pore diameters of 0.45 μm and 0.22 μm in turn. The microporous membrane is finely filtered, and finally potted in 10mL ampoules, and sterilized by circulating steam at 100°C for 45 minutes.

5. Preparation of Compound V-1 Powder Injection

Preparation method: Compound V-1 aseptic powder is subpackaged under aseptic conditions and obtained.

6. Preparation of compound V-4 eye drops

Recipe: Compound V-4 3.78g, sodium chloride 0.9g, phenethyl alcohol 3g, an appropriate amount of boric acid buffer solution, distilled water was added to 1000mL.

Preparation method: Weigh compound V-4 and sodium chloride and add them to 500mL of distilled water, adjust the pH to 6.5 with boric acid buffer solution after complete dissolution, add distilled water to 1000mL, stir evenly, filter with microporous membrane, fill, seal, Sterilize with steam at 100°C for 1 hour.

7. Preparation of compound V-6 liniment

Prescription: Compound V-6 4g, potassium soap 7.5g, camphor 5g, distilled water to 100mL.

Preparation method: dissolving camphor with 95% ethanol solution by volume, for subsequent use; heating and liquefying potassium soap, for subsequent use, weighing compound V-6, adding potassium soap solution and camphor ethanol solution under constant stirring, and then gradually. Add distilled water, and then add distilled water to the full amount after emulsification is complete.

8. Preparation of compound V-8 suppository

Prescription: Compound V-8 4g, gelatin 14g, glycerin 70g, distilled water added to 100mL, 100 metric pieces.

Preparation method: Weigh gelatin and glycerin, add distilled water to 100mL, heat and melt in a water bath at 60°C, add compound V-8 when it becomes a paste, stir evenly, pour it into a vaginal suppository mold when it is nearly solidified, cool and solidify.

9. Preparation of compound V-9 ointment

Formulation: Compound V-9 0.5–2g, cetyl alcohol 6–8g, white petrolatum 8–10g, liquid paraffin 8–19g, monoglyceride 2–5g, polyoxyethylene (40) stearate 2–5g, Glycerol 5–10g, ethyl paraben 0.1g, distilled water to 100g.

Preparation method: heat cetyl alcohol, white petrolatum, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to dissolve completely, mix well, keep at 80°C, and use as oil phase for later use; Add glycerin and distilled water, heat to 85°C to dissolve, then add oil phase under constant stirring, add compound V-9 after emulsification, stir and cool to obtain.

10. Preparation of Compound V-11 and Fluconazole Compound Powder Injection

Prescription: Compound V-11 50g, fluconazole 50g, sodium benzoate 1g, a total of 100 bottles were made.

Preparation method: take the compound V-11, fluconazole and sodium benzoate of the recipe quantity, mix them evenly in a sterile state, and divide into 100 bottles to get the product.

11. Preparation of Compound II-4 Aerosol

Recipe: Compound II-4 2.5g, Span20 3g, talc (100 mesh) 4g, trichlorofluoromethane added to an appropriate amount.

Preparation method: put compound II-4, Span20 and talc respectively in a vacuum drying box to dry for several hours, cool to room temperature in a desiccator, pulverize into micropowder with a jet mill, then mix according to the recipe quantity, and pour into a closed container Inside, add trichloromonofluoromethane to the specified amount.

Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should Various changes may be made in details without departing from the scope of the invention as defined by the claims.

Claims (9)

1. the isatinazole alcohol compound or its pharmaceutically acceptable salt containing acetophenone substituent, it is characterized in that: structure is as shown in general formula III and IV:

In the formula, R ¹ is hydrogen, methyl; R ² is hydrogen, nitro; R ³ is hydrogen, nitro; R ⁵ is hydrogen, chlorine, methyl. 2. the isatinazole alcohol compound or its pharmaceutically acceptable salt containing acetophenone substituent according to claim 1, is characterized in that, is any one in following compound:

3. the preparation method of the isatinazole alcohol compound containing acetophenone substituent described in claim 1 or 2, is characterized in that: a. Preparation of isatin azole alcohol compounds shown in general formula I: the azole compound is dissolved in an organic solvent, and under the action of a base, a ring-opening reaction occurs with isatin epoxide shown in general formula VI to obtain Isatinazole alcohol compounds shown in general formula I;

b. preparation of the isatinazole alcohol compounds containing acetophenone substituent shown in general formula III: the compound shown in general formula I is dissolved in an organic solvent, a carbonyl compound is added, and a condensation reaction occurs under the action of a base to prepare Obtain the isatinazole alcohol compounds containing acetophenone substituent shown in general formula III; C. the preparation of the isatinazole alcohol compounds containing acetophenone substituent shown in general formula IV: the compound shown in general formula III is dehydrated under the catalysis of acid, namely the acetophenone-containing acetophenone shown in general formula IV is obtained. Substituted isatinazole alcohol compounds. 4. the preparation method of the isatinazole alcohol compounds containing acetophenone substituent according to claim 3, is characterized in that: In step a, the temperature of the ring-opening reaction is 60°C; the reaction time is 12h; the base is potassium carbonate; the ratio of the amount of isatin to potassium carbonate is 1.25:1; In step b, the base used in the aldol condensation reaction is diethylamine; the reaction is carried out at 18-25° C.; after the reaction, the crude product can be obtained directly by distillation under reduced pressure; In step c, the acid used in the dehydration reaction is a mixed acid of glacial acetic acid and hydrochloric acid; the volume ratio of hydrochloric acid to glacial acetic acid is 1:3; the reaction is carried out under reflux; after the reaction, sodium bicarbonate is needed to neutralize. 5. A preparation comprising the acetophenone-substituted isatinazole alcohol compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2. 6. preparation according to claim 5 is characterized in that: described preparation is tablet, capsule, powder, granule, drop pill, injection, solution, suspension, emulsion, suppository, ointment, gel Gel, film, aerosol or transdermal patch. 7. The preparation according to claim 6, wherein the preparation is a powder injection. 8. The application of the acetophenone substituent-containing isatinazole alcohol compound or its pharmaceutically acceptable salt according to claim 1 or 2 in the preparation of antibacterial and/or antifungal drugs. 9. application according to claim 8, is characterized in that, described bacterium is in Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii Any one or more of ; the fungus is any one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus, and Candida parapsilosis.