Coumarin compounds containing 7-N / O acetylhydrazine and preparation method and application thereof

Abstract

The present invention discloses 7- N / O Coumarin compounds of acetylhydrazine and their preparation method and application. N / O The preparation method of the coumarin compound of acetylhydrazine is simple to operate, does not involve precious metals in the reaction, and has high reaction efficiency. N / O New coumarin compounds of acetylhydrazine have good fungicidal activity, 7- N / O The novel coumarin compounds of acetylhydrazine exhibited high efficiency and / or broad spectrum antibacterial activity. N / O New coumarin compounds of acetylhydrazine have good herbicidal activity and can be effectively used to control pathogenic fungi of crops and common field weeds.

Description

Technical Field

[0001] The present invention belongs to the technical field of compounds, and in particular relates to a coumarin compound containing 7-N / O acetic hydrazide, a preparation method and an application thereof. Background Art

[0002] Coumarin compounds, as secondary metabolites of phenylpropanoids synthesized by plants, possess excellent environmental compatibility, unique physiological activities, and strong structural plasticity. In the agricultural sector, coumarins exhibit antifungal, antibacterial, antiviral, and herbicidal activities, attracting widespread attention from pesticide developers.

[0003] As an important nitrogen-containing structure, the hydrazide unit is widely present in compounds with antifungal, insecticidal, and herbicide activities. Compared to the more common amide backbone, the hydrazide backbone possesses greater flexibility and can more effectively bind to active enzymes in organisms. Therefore, the development of 7-N / O acetylhydrazide compounds based on the natural coumarin backbone is of great significance and extremely important value.

[0004] Currently, new coumarin compounds of 7-N / O acetylohydrazide, their synthesis routes, and antibacterial and herbicidal activities have not been reported. Summary of the Invention

[0005] Purpose of the invention: The technical problem to be solved by the present invention is to adopt a strategy of splicing substructures of active units, use ethyl bromoacetate as a connecting bridge, introduce a phenylhydrazide fragment into the coumarin skeleton, and construct a series of new coumarin compounds of 7-N / O acetylhydrazide with antibacterial and antifungal activities as well as herbicidal activities.

[0006] The technical problem that the present invention also aims to solve is to provide a preparation method for a series of novel coumarin compounds of 7-N / O acetic hydrazide.

[0007] The technical problem that the present invention also aims to solve is to provide the use of coumarin compounds of 7-N / O acetylhydrazine in the preparation of products for inhibiting or killing pathogens.

[0008] The final technical problem to be solved by the present invention is to provide a series of new coumarin compounds of 7-N / O acetylhydrazine for use in weed control.

[0009] Technical solution: In order to solve the above technical problems, the first aspect of the present invention provides a coumarin compound of 7-N / O acetylhydrazine, the structure of which is shown in Formula III:

[0010]

[0011] wherein R1 is selected from Me, Et, Pr or CF3; R2 is selected from H or Cl; R3 is selected from H or Me; R′ is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-CH3O, 3-CH3O, 4-CH3O, 3,4-diCH3, 2,3-diCl, 2,4-diCl, 2,5-diCl, 2,6-diCl, 3,4-diCl, 3,5-diCl, 2,3,6-trCl, 2,4,6-trCl, 2,4-diF, and 3,4-diF; and preferably, R′ is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 4-Br, 4-CH3O, 3,4-diCH3 or 2,4,6-trCl; and X is selected from N or O.

[0012] Wherein, the structure of the compound is shown in Formula I:

[0013]

[0014] wherein R1 is selected from Me, Et, Pr, and CF3; R′ is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-CH3O, 3-CH3O, 4-CH3O, 3,4-diCH3, 2,3-diCl, 2,4-diCl, 2,5-diCl, 2,6-diCl, 3,4-diCl, 3,5-diCl, 2,3,6-trCl, 2,4,6-trCl, 2,4-diF, and 3,4-diF; preferably, R′ is selected from 2-F, 3-F, 4-F, 2-Cl, 4-Cl, and 4-CF3;

[0015] Wherein, the structure of the compound is shown in Formula II:

[0016]

[0017] R1 is selected from Me, CF3; R2 is selected from H, Cl; R3 is selected from H, Me; R′ is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-CH3O, 3-CH3O, 4-CH3O, 3,4-diCH3, 2,3-diCl, 2,4-diCl, 2,5-diCl, 2,6-diCl, 3,4-diCl, 3,5-diCl, 2,3,6-trCl, 2,4,6-trCl, 2,4-diF, 3,4-diF, and preferably, R′ is selected from 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 2-Br, 4-Br, 4-CH3O, 3,4-diCH3, 2,4,6-trCl.

[0018] A second aspect of the present invention provides a method for preparing a coumarin compound of 7-N-acetylhydrazine, comprising the following steps:

[0019] (1) Using 3-aminophenol as a raw material, EA, sodium bicarbonate and phenyl chloroformate were added in sequence to prepare N-(3-hydroxyphenyl)phenyl carbamate;

[0020] (2) N-(3-hydroxyphenyl)carbamic acid phenyl ester reacts with concentrated sulfuric acid solution, followed by addition of β-keto acid ester to prepare substituted coumarin amino acid phenyl ester;

[0021] (3) adding potassium hydroxide solution to the substituted coumarin amino acid phenyl ester, dissolving and stirring, and then heating and stirring to react to obtain the intermediate substituted 7-aminocoumarin;

[0022] (4) Adding acetonitrile solution to substituted 7-aminocoumarin, N,N-diisopropylethylamine (DIEA), and sodium iodide to dissolve them, and then adding ethyl bromoacetate dropwise in a reactor to react to prepare the intermediate ethyl 2-((2-azino-4-(substituted)-2H-coumarin-7-yl)amino)acetate;

[0023] (5) Dissolving the intermediate ethyl 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetate in ethanol, adding sodium hydroxide solution, stirring at room temperature, and monitoring the reaction progress by TLC. After the reaction is complete, adjusting the pH value of the aqueous phase to prepare the intermediate 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid;

[0024] (6) Acetonitrile solution was added to the intermediate 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid and substituted phenylhydrazine to fully dissolve them, and then O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate was added, followed by dropwise addition of triethylamine. The reaction was stirred at room temperature and the reaction progress was monitored by TLC to prepare a series of target compounds 7-N-acetylhydrazine coumarin.

[0025] Furthermore, the preparation method of the 7-N acetylhydrazine coumarin compound of the present invention specifically comprises:

[0026] Using 3-aminophenol (1) as a raw material, a 7-N-acetylhydrazine coumarin compound represented by formula I is obtained through protection reaction, cyclization reaction, deprotection reaction, substitution reaction, deprotection reaction, and condensation reaction, comprising the following steps:

[0027] Step (1): Add 3-aminophenol (1) to a flask, then add EA:H2O=2:1 as a solvent, sonicate for 1 minute to completely dissolve the raw materials, then add sodium bicarbonate and stir in an ice bath for 5 minutes, and slowly add phenyl chloroformate dropwise. Monitor the reaction process by TLC. Wait until the reaction is completed. Pour the reaction solution into a separatory funnel and let it stand for stratification. Collect the organic layer, wash it three times with water and saturated brine respectively, then concentrate the organic phase and dry it by rotary evaporation to obtain white solid N-(3-hydroxyphenyl)phenyl carbamate (2); wherein the molar ratio of 3-aminophenol (1) to phenyl chloroformate is 1:1.2.

[0028] Step (2): add N-(3-hydroxyphenyl)carbamic acid phenyl ester (2) to a round-bottom flask, pour anhydrous ethanol into a small beaker, and slowly pour concentrated sulfuric acid solution into the beaker containing anhydrous ethanol while stirring with a glass rod. After the diluted concentrated sulfuric acid ethanol solution is cooled, it is poured into the above-mentioned round-bottom flask and stirred for 15 minutes to fully dissolve the raw materials. Subsequently, β-keto ester is slowly added dropwise, and after the addition is complete, the reaction is stirred at room temperature for 4-6 hours. TLC monitors the reaction process. After the reaction is completed, the reaction solution is slowly poured into ice water, and a large amount of gray solid precipitates. After suction filtration, the filter cake is washed with a small amount of ethanol and dried to obtain a gray powder substituted coumarin amino acid phenyl ester (4); wherein the molar ratio of N-(3-hydroxyphenyl)carbamic acid phenyl ester (2) to β-keto ester is 1:1.

[0029] Step (3): Add substituted coumarin amino acid phenyl ester (4) to a round-bottom flask, then add 45% potassium hydroxide solution (w:w) to the round-bottom flask, dissolve and stir, then heat to 100°C and stir to react for about 1 hour. Monitor the reaction process by TLC until the reaction is complete. Pour the reaction solution into ice water, add concentrated hydrochloric acid dropwise to adjust the pH value to 1 to 2, then add ammonia water to adjust the pH value to 4 to 5. If a solid is generated, filter it with suction and recrystallize it from ethanol to obtain the intermediate substituted 7-aminocoumarin (5).

[0030] Step (4): add substituted 7-aminocoumarin (5), N,N-diisopropylethylamine (DIEA) and sodium iodide to a flask, add acetonitrile solution to dissolve it, stir magnetically for about 5 minutes, add ethyl bromoacetate dropwise to the reaction flask, adjust the heating device to 95°C, reflux for 24 hours, and monitor the reaction progress by TLC. When the reaction is complete, remove the heating device, pour the hot reaction solution into ice water while stirring, and let it stand overnight to obtain a large amount of gray-brown solid. The mixed solution is then filtered, and the upper solid is washed with a small amount of ethanol and dried to obtain the intermediate ethyl 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetate (6); wherein the molar ratio of substituted 7-aminocoumarin (5) to sodium iodide and ethyl bromoacetate is 1:1.2:1.2.

[0031] Step (5), the intermediate ethyl 2-((2-nitrogen-4-(substituted)-2H-coumarin-7-yl)amino)acetate (6) was added to a round-bottom flask, dissolved with ethanol, and magnetically stirred for about 15 minutes to fully dissolve it. A 10% sodium hydroxide solution was added to the reaction flask, stirred at room temperature for about 4 hours, and the reaction progress was monitored by TLC. After the reaction was complete, the ethanol solution was removed by distillation under reduced pressure, and the resulting residue was poured into a beaker, distilled water was added, and 15% dilute hydrochloric acid was taken to adjust the pH value of the aqueous phase to 2-3. A large amount of gray-brown solid precipitated. The mixed solution was filtered, and the upper solid was washed with a small amount of ethanol and dried to obtain the intermediate 2-((2-nitrogen-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid (7).

[0032] Step (6), the intermediate 2-((2-azino-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid (7) and substituted phenylhydrazine were added to a round-bottom flask, and acetonitrile solution was added to fully dissolve. O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) was weighed and added to a reaction flask, followed by dropwise addition of triethylamine, and stirred at room temperature for about 3 hours. The reaction progress was monitored by TLC. After the reaction was completed, if solid precipitated, it was filtered and the upper solid was washed with a small amount of dichloromethane. If no solid precipitated, it was extracted with ethyl acetate and the organic phases were combined. The solvent in the obtained organic phases was removed by vacuum concentration. The dry loading method was used for column chromatography purification, and petroleum ether / ethyl acetate system was used as eluent to obtain a series of target compounds 7-N-acetylhydrazine coumarin; wherein the molar ratio of substituted 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid (7) to substituted phenylhydrazine, TBTU, and triethylamine was 1:1:1:1.

[0033] A third aspect of the present invention provides a method for preparing a coumarin compound of 7-O acetylhydrazine, comprising the following steps:

[0034] (1) Using substituted meta-diphenol as a raw material, concentrated sulfuric acid ethanol solution and β-ketoester are sequentially added to react to prepare substituted 7-hydroxycoumarin;

[0035] (2) Adding acetonitrile solution to substituted 7-hydroxycoumarin, N,N-diisopropylethylamine (DIEA), and sodium iodide to dissolve them, and then adding ethyl bromoacetate dropwise in a reactor to react to prepare the intermediate ethyl 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetate;

[0036] (3) dissolving ethyl 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetate in ethanol, adding sodium hydroxide solution, stirring at room temperature, and monitoring the reaction progress by TLC. After the reaction is complete, adjusting the pH value of the aqueous phase to prepare the intermediate 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid;

[0037] (4) Acetonitrile solution was added to the intermediate 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid and substituted phenylhydrazine to fully dissolve them, and then O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate was added, followed by dropwise addition of triethylamine. The reaction was stirred at room temperature and the reaction progress was monitored by TLC to prepare a series of target compounds 7-O acetylhydrazine coumarin.

[0038] Wherein, the molar ratio of the 3-aminophenol to phenyl chloroformate is 1:1-3; preferably, the molar ratio of the N-(3-hydroxyphenyl)phenyl carbamate to β-ketoester is 1:0.8-3; preferably, the molar ratio of the substituted 7-aminocoumarin to sodium iodide and ethyl bromoacetate is 1:1-3:1-3; preferably, the molar ratio of the substituted 2-((2-azino-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid to substituted phenylhydrazine, TBTU, and triethylamine is 1: 1~2.5:1~2.5:1~2.5; preferably, the molar ratio of the substituted meta-diphenol to β-ketoester is 1:0.8~3; preferably, the molar ratio of the substituted 7-hydroxycoumarin to sodium iodide and ethyl bromoacetate is 1:1~3:1~3; preferably, the molar ratio of the 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid to substituted phenylhydrazine, TBTU and triethylamine is 1:1~2.5:1~2.5:1~2.5.

[0039] Furthermore, the preparation method of the coumarin compound of 7-O acetylhydrazine specifically includes:

[0040] Using substituted meta-diphenol (9) as a raw material, a 7-O-acetylhydrazine coumarin compound shown in formula II is obtained through cyclization reaction, substitution reaction, deprotection reaction, and condensation reaction, comprising the following steps:

[0041] Step (1): add the substituted meta-diphenol (9) to a round-bottom flask, pour anhydrous ethanol into a small beaker, and slowly pour the concentrated sulfuric acid solution into the beaker containing anhydrous ethanol while stirring with a glass rod. After the diluted concentrated sulfuric acid ethanol solution cools, pour it into the above-mentioned round-bottom flask and stir for 15 minutes to fully dissolve the raw materials. Then slowly add β-ketoester dropwise, and after the addition is complete, stir at room temperature and react for 4-6 hours. TLC monitors the reaction process. After the reaction is completed, slowly pour the reaction solution into ice water, and a large amount of gray solid precipitates. After suction filtration, wash the filter cake with a small amount of ethanol and dry it to obtain the substituted 7-hydroxycoumarin (10); wherein the molar ratio of the substituted meta-diphenol (9) to the β-ketoester is 1:1.

[0042] Step (2): substituted 7-hydroxycoumarin (10), N,N-diisopropylethylamine (DIEA) and sodium iodide are added to a flask, acetonitrile solution is added to dissolve it, magnetic stirring is carried out for about 5 minutes, ethyl bromoacetate is added dropwise to the reaction flask, the heating device is adjusted to 95°C, reflux reaction is carried out for 24 hours, and the reaction progress is detected by TLC. When the reaction is complete, the heating device is removed, and the reaction solution is poured into ice water while stirring while hot, and allowed to stand overnight to obtain a large amount of solid. The mixed solution is then filtered, and the upper solid is washed with a small amount of ethanol and dried to obtain the intermediate ethyl 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetate (11); wherein the molar ratio of substituted 7-hydroxycoumarin (10) to sodium iodide and ethyl bromoacetate is 1:1.2:1.2.

[0043] Step (3), the intermediate ethyl 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetate (11) was added to a round-bottom flask, dissolved with ethanol, and magnetically stirred for about 15 minutes to fully dissolve it. A 10% sodium hydroxide solution was added to the reaction flask, stirred at room temperature for about 4 hours, and the reaction progress was monitored by TLC. After the reaction was complete, the ethanol solution was distilled off under reduced pressure, and the resulting residue was poured into a beaker, distilled water was added, and 15% dilute hydrochloric acid was taken to adjust the pH value of the aqueous phase to 2-3. A large amount of solid precipitated, and the mixed solution was filtered, the upper solid was washed with a small amount of ethanol, and dried to obtain the intermediate 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid (12).

[0044] Step (4), the intermediate 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid (12) and substituted phenylhydrazine were added to a round-bottom flask, and acetonitrile solution was added to fully dissolve. O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) was weighed and added to a reaction flask, followed by dropwise addition of triethylamine, and stirred at room temperature for about 3 hours. The reaction progress was monitored by TLC. After the reaction was completed, if solid precipitated, it was filtered and the upper solid was washed with a small amount of dichloromethane. If no solid precipitated, it was extracted with ethyl acetate and the organic phases were combined. The solvent in the obtained organic phases was removed by vacuum concentration. The dry loading method was used for column chromatography purification, and petroleum ether / ethyl acetate system was used as eluent to obtain a series of target compounds 7-O acetylhydrazine coumarin; wherein the molar ratio of 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid (12) to substituted phenylhydrazine, TBTU, and triethylamine was 1:1:1:1.

[0045] The method for preparing the coumarin compounds of 7-N / O acetylhydrazine of the present invention also includes purification of the target compound. There are no special requirements for the purification method. Those skilled in the art can adopt various conventional purification methods, for example, extraction with an extractant, drying with a desiccant, and impurity removal by column chromatography and the like to obtain a high-purity target compound.

[0046] The fourth aspect of the present invention provides the use of the coumarin compound of 7-N / O acetylhydrazine in the preparation of a product for inhibiting or killing pathogens.

[0047] The pathogens include but are not limited to crop pathogenic fungi, and the crop pathogenic fungi include but are not limited to one or more of rice sheath blight (Rhizoctonia solani), strawberry gray mold (Botrytis cinerea), wheat head blight (Fusarium graminearum), tomato early blight (Altemaria solani), cucumber anthracnose (Colletotrichum orbiculare) or apple leaf spot (Alternaria alternata).

[0048] The fifth aspect of the present invention provides the use of the coumarin compound of 7-N / O acetylhydrazine in weed control. Preferably, the weed control includes but is not limited to the removal of weeds in the field.

[0049] The field weeds include but are not limited to one or more of barnyard grass (Echinochloa crus-galli), crabgrass (Digitaria sanguinalis (L.) Scop.), velvetleaf (Abutilon theophrasti Medicus) or amaranth (Amaranthus retroflexus L.).

[0050] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0051] 1. The present invention uses various unsubstituted 3-aminophenols, various substituted β-ketoesters, ethyl bromoacetate, and various substituted or unsubstituted phenylhydrazines as starting materials to obtain novel coumarin compounds of 7-N-acetylhydrazine through a simple six-step reaction. The preparation method of the novel coumarin compounds of 7-N-acetylhydrazine of the present invention is simple to operate, does not require precious metals in the reaction, and is highly efficient.

[0052] 2. The present invention uses various substituted or unsubstituted m-diphenols, various substituted β-ketoesters, ethyl bromoacetate, and various substituted or unsubstituted phenylhydrazines as starting materials to produce novel coumarin compounds of 7-O-acetohydrazide through a simple four-step reaction. The preparation method of the novel coumarin compounds of 7-O-acetohydrazide of the present invention is simple to operate, does not involve the use of precious metals in the reaction, and is highly efficient.

[0053] 3. The novel coumarin compounds of 7-N / O acetohydrazide of the present invention have excellent fungicidal activity and exhibit high efficiency and / or broad-spectrum antibacterial activity. The novel coumarin compounds of 7-N / O acetohydrazide of the present invention have excellent herbicidal activity and can be effectively used to control pathogenic fungi of crops and common field weeds. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 The graph shows the control effect of compounds 43, 22 and acifluorfen on Amaranthus retroflexus after treatment for 14 days at 100 μg / mL;

[0055] Figure 2 The graph shows the control effect of compounds 43, 22 and acifluorfen on velvetleaf after treatment for 14 days at 100 μg / mL;

[0056] Figure 3 The graph shows the control effect of compounds 43, 22 and clethodim on barnyardgrass at 100 μg / mL for 14 days;

[0057] Figure 4 The graph shows the control effect of compounds 43, 22 and clethodim on crabgrass at 100 μg / mL for 14 days. DETAILED DESCRIPTION

[0058] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0059] The technical solution of the present invention is described in detail through examples. In the examples, unless otherwise specified, all raw materials used were purchased from commercial sources (Table 1), all of which were analytically pure and free of expiration, moisture absorption, or deterioration. The room temperature was 25°C.

[0060] Table 1. List of main reagents

[0061]

[0062]

[0063] Me represents a methyl group, Et represents an ethyl group, and Pr represents a propyl group.

[0064] Example 1 Preparation of Novel Coumarin Compounds of 7-N-Acetylhydrazine

[0065]

[0066] Wherein, R1 is selected from Me, Et, Pr, CF3; R′ is selected from 2-F, 3-F, 4-F, 2-Cl, 4-Cl, 4-CF3.

[0067] The specific steps are as follows:

[0068] 1. Protection reaction: 6.5 g of 3-aminophenol (1) was added to a 250 mL two-necked flask, followed by 100 mL of ethyl acetate (EA) and 50 mL of water. The mixture was ultrasonicated for 1 min to completely dissolve the raw materials. 5 g (60 mmol) of sodium bicarbonate was then added and stirred in an ice bath for 5 min. 9.4 g (60 mmol) of phenyl chloroformate was slowly added dropwise. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was poured into a separatory funnel and allowed to stand for stratification. The organic layer was collected and washed three times with water and saturated brine. The organic phase was then concentrated and dried by rotary evaporation to obtain N-(3-hydroxyphenyl)phenylcarbamate (2) as a white solid.

[0069] 2. Cyclization reaction: 8.35 g (50 mmol) of N-(3-hydroxyphenyl)carbamic acid phenyl ester (2) was added to a round-bottom flask, 6 mL of anhydrous ethanol was poured into a small beaker, and 14 mL of concentrated sulfuric acid solution was slowly poured into the beaker containing anhydrous ethanol while stirring with a glass rod. After the diluted concentrated sulfuric acid ethanol solution was cooled, it was poured into the round-bottom flask and stirred for 15 minutes to fully dissolve the raw materials. Subsequently, 50 mmol of β-keto acid ester (3) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4-6 hours. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was slowly poured into 200 mL of ice water. A large amount of gray solid precipitated. After filtration, the filter cake was washed with a small amount of ethanol and dried to obtain a gray powder of substituted coumarin amino acid phenyl ester (4).

[0070] 3. Deprotection reaction: Add substituted coumarin amino acid phenyl ester (4) to a 50 mL round-bottom flask, then add 10 mL of 45% potassium hydroxide solution (w:w) to the flask, dissolve and stir, then heat to 100°C and stir for about 1 hour. Monitor the reaction process by TLC. After the reaction is complete, pour the reaction solution into ice water, add concentrated hydrochloric acid dropwise to adjust the pH to 1 to 2, and then add ammonia water to adjust the pH to 4 to 5. If a solid is generated, filter it and recrystallize it from ethanol to obtain the intermediate substituted 7-aminocoumarin (5).

[0071] 4. Substitution reaction: 7-aminocoumarin (5) (10 mmol), N,N-diisopropylethylamine (DIEA) (10 mmol) and 1.8 g (12 mmol) of sodium iodide were added to a flask, 20 mL of acetonitrile solution was added to dissolve the mixture, and the mixture was stirred magnetically for 5 min. 12 mmol of ethyl bromoacetate was added dropwise to the reaction flask. The heating device was adjusted to 95°C and the mixture was refluxed for 24 hours. The reaction progress was monitored by TLC. After the reaction was complete, the heating device was removed and the reaction solution was poured into 100 mL of ice water while stirring while hot. The mixture was allowed to stand overnight to obtain a large amount of gray-brown solid. The mixture was then filtered, and the upper solid was washed with a small amount of ethanol and dried to obtain the intermediate ethyl 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetate (6).

[0072] 5. Deprotection reaction: The intermediate ethyl 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetate (6) was added to a 250 mL round-bottom flask, dissolved with 100 mL of ethanol, and fully dissolved by magnetic stirring for 15 min. 15 mL of 10% sodium hydroxide solution was added to the reaction flask, stirred at room temperature for about 4 h, and the reaction progress was monitored by TLC. After the reaction was complete, the ethanol solution was removed by vacuum distillation, and the resulting residue was poured into a beaker. 20 mL of distilled water was added, and 15% dilute hydrochloric acid was taken to adjust the pH value of the aqueous phase to 2-3. A large amount of gray-brown solid precipitated. The mixed solution was filtered, and the upper solid was washed with a small amount of ethanol and dried to obtain the intermediate 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid (7).

[0073] 6. Condensation reaction: 3.00 mmol of the intermediate 2-((2-azino-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid (7) and 3.00 mmol of substituted phenylhydrazine (8) were added to a 50 mL round-bottom flask and fully dissolved with 25 mL of acetonitrile solution. 3.00 mmol of O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) was weighed and added to a reaction flask, followed by the dropwise addition of 6.00 mmol of triethylamine. The reaction was stirred at room temperature for 3 h and the reaction progress was monitored by TLC. After the reaction, if solid precipitated, it was filtered and the upper solid layer was washed with a small amount of dichloromethane. If no solid precipitated, it was extracted with ethyl acetate, and the organic phases were combined and the solvent removed by vacuum concentration. The organic phases were then purified by column chromatography using a dry loading method with a petroleum ether / ethyl acetate system as the eluent to obtain a series of target compounds, 7-N-acetylhydrazine coumarin 1-12. The substituent groups of each compound are shown in Table 2. The 7-N-acetylhydrazine coumarin compounds represented by Formula I are shown in Table 2.

[0074] Table 2. 7-N-acetylhydrazine coumarin compounds

[0075]

[0076] The structural characterization data of the target compounds 7-N-acetylhydrazine coumarin 1 to 12 are as follows:

[0077] Compound 1: N'-(4-fluorophenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)amino)acetylhydrazide:

[0078] White solid, yield: 47.5%, mp: 163.5-164.5℃, 1H NMR (400MHz, DMSO-d6) δ9.93(d,J=3.0Hz,1H),7.74(d,J=2.9Hz,1H),7.47(d,J=8.7Hz,1H),6.98(t,J=6.2Hz,1H),6.94(t,J=8.9Hz,2H),6.7 3(d,J=4.6Hz,1H),6.71(d,J=4.6Hz,1H),6.68(dd,J=8.8,2.2Hz,1H),6.45(d,J=2.3Hz,1H),5.96(s,1H),3.90(d,J=6.2Hz,2H),2.33(s,3H). 13 C NMR (125MHz, DMSO-d6) δ170.01,161.25,155.95,154.32,152.62,146.28,127.90,126.41,125.08,115.58 (d,J=22.5Hz),114.00(d,J=8.5Hz),110.01(d,J=29.0Hz),108.50,97.47.45.05,18.55.HR-MS(ESI):m / z calcd for C 18 H 17 FN3O3([M+H] + )342.1248,Found342.1254.

[0079] Compound 2: 2-((4-ethyl-2-oxo-2H-coumarin-7-yl)amino)-N′-(3-fluorophenyl)acetohydrazide:

[0080] White solid, yield: 65.8%, mp: 161.8-162.5℃, 1 H NMR (500MHz, DMSO-d6) δ9.93(d,J=3.6Hz,1H),8.06(s,1H),7.47(dd,J=8.8,4.2Hz,1H),7.06(dt,J=12.3,6.0Hz,1H),6.97(d,J=5.2Hz,1H),6.69–6 .61(m,1H),6.54–6.47(m,1H),6.46–6.33(m,3H),5.89(d,J=4.0Hz,1H),3 .90(t,J=5.2Hz,2H),2.67(dt,J=11.6,6.0Hz,2H),1.15(t,J=7.2Hz,3H). 13C NMR (125MHz, DMSO-d6) δ170.12, 164.69, 162.78, 161.52, 159.20, 156.15, 152.44, 151.97 (d, J = 10.0Hz), 130.72 (d, J = 10.0Hz), 125. 96,111.32,108.92(d,J=31.0Hz),106.69,105.10(d,J=21.0Hz),99.23(d,J=25.0Hz),97.73,45.08,24.55,13.11.HR-MS(ESI):m / z calcd for C 19 H 19 FN3O3([M+H] + )356.1405,Found 356.1414.

[0081] Compound 3: 2-((4-ethyl-2-oxo-2H-coumarin-7-yl)amino)-N'-(4-fluorophenyl)acetylhydrazide:

[0082] White solid, yield: 44.8%, mp: 162.7-163.5℃, 1 H NMR (400 MHz, DMSO-d6) 1 H NMR (400MHz, DMSO-d6) δ9.94(d,J=3.0Hz,1H),7.76(d,J=2.9Hz,1H),7.52(d,J=8.8Hz,1H),7.00(t,J=6.4Hz,1H),6.95(t,J=8.8Hz,2H),6.73(dd,J= 8.9,4.5Hz,2H),6.68(dd,J=8.8,2.3Hz,1H),6.46(d,J=2.3Hz,1H),5.94( s, 1H), 3.91 (d, J = 6.2Hz, 2H), 2.73 (q, J = 7.5Hz, 2H), 1.21 (t, J = 7.4Hz, 3H). 13 C NMR (125MHz, DMSO-d6) δ169.98,161.52,159.30,157.29,156.13,155.43,152.50,146.32,126.01,115 .58(d,J=22.5Hz),113.97(d,J=7.5Hz),108.97,106.64,97.66,45.01,24.55,13.16.HR-MS(ESI):m / z calcd forC 19 H 19 FN3O3([M+H] +)356.1405,Found 356.1415.

[0083] Compound 4: N'-(2-chlorophenyl)-2-((4-ethyl-2-oxo-2H-coumarin-7-yl)amino)acetylhydrazide:

[0084] White solid, yield: 48.4%, mp: 163.4-164.1℃, 1 H NMR(500MHz,DMSO-d6)δ10.15–10.03(m,1H),7.50(d,J=8.8Hz,2H),7.26(d, J=7.8Hz,1H),7.09(t,J=7.7Hz,1H),7.02(t,J=6.2Hz,1H),6.81(d,J=8.0Hz ,1H),6.75–6.71(m,1H),6.71–6.68(m,1H),6.49(d,J=2.2Hz,1H),5.92(s,1 H), 3.96 (d, J = 6.1Hz, 2H), 2.70 (q, J = 10.6, 8.9Hz, 2H), 1.19 (t, J = 7.2Hz, 3H). 13 C NMR(125MHz,DMSO-d6)δ170.01,161.53,159.24,156.15,152.47,145.12,129.69,128.11,125.9 5,120.07,117.72,113.55,111.39,109.02,106.67,97.74,45.04,24.56,13.14.HR-MS(ESI):m / z calcd for C 19 H 19 ClN3O3([M+H] + )372.1109,Found372.1105.

[0085] Compound 5: N'-(4-chlorophenyl)-2-((4-ethyl-2-oxo-2H-coumarin-7-yl)amino)acetylhydrazide:

[0086] White solid, yield: 51.5%, mp: 163.9-164.6℃, 1H NMR (400MHz, DMSO-d6) δ9.96(d,J=2.3Hz,1H),7.97(s,1H),7.52(d,J=8.8Hz,1H),7.13(d,J=8.9Hz,2H),7.00(t,J=6.2Hz,1H),6.77–6.68( m,2H),6.67(dd,J=8.8,2.3Hz,1H),6.46(d,J=2.3Hz,1H),5.93(s,1H),3.92(d,J=6.1Hz,2H),2.72(q,J=7.5Hz,2H),1.20(t,J=7.4Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ169.53,161.02,158.81,155.65,152.00,148.27,128.45,125.54,1 21.86,113.76,110.82,108.51,106.18,97.19,44.51,24.07,12.68.HR-MS(ESI):m / zcalcd for C 19 H 19 ClN3O3([M+H] + )372.1109,Found 372.1111.

[0087] Compound 6: N'-(2-fluorophenyl)-2-((2-oxo-4-propyl-2H-coumarin-7-yl)amino)acetylhydrazide:

[0088] White solid, yield: 49.5%, mp: 165.9-166.6℃, 1 H NMR(500MHz,DMSO-d6)δ9.98(s,1H),7.73(s,1H),7.52(dd,J=8.9,2.6Hz,1H),7.11–6.99(m,2H),6.92(t,J=7.7Hz,1H),6.79(t,J=8.5Hz,1H),6. 74–6.65(m,2H),6.46(s,1H),5.92(s,1H),3.92(d,J=5.8Hz,2H),2.66(t ,J=7.5Hz,2H),1.61(td,J=14.5,6.9Hz,2H),0.95(td,J=7.4,2.6Hz,3H). 13CNMR(126MHz,DMSO-d6)δ169.54,160.86,157.30,155.79,152.02,149.20,136.83,125.69,124.38,118.73, 114.87(d,J=17.6Hz),113.69,110.88,108.59,107.10,97.21,44.49,32.89,21.65,13.75.HR-MS(ESI):m / z calcd for C 20 H 21 FN3O3([M+H] + )370.1561,Found370.1564.

[0089] Compound 7: N'-(4-fluorophenyl)-2-((2-oxo-4-propyl-2H-coumarin-7-yl)amino)acetylhydrazide:

[0090] White solid, yield: 39.8%, mp: 164.8-165.6℃, 1 H NMR (500MHz, DMSO-d6) δ9.96(d,J=4.6Hz,1H),7.78(s,1H),7.51(t,1H),7.02(d,J=5.8Hz,1H),6.96–6.91(m,2H),6.76–6.71(m,2H),6.70–6. 65(m,1H),6.46(d,J=2.8Hz,1H),5.92(d,J=4.1Hz,1H),3.92(s,2H),2.65(q,J=7.8,6.8Hz,2H),1.60(h,J=7.0Hz,2H),0.95(d,J=6.9Hz,3H). 13 C NMR(126MHz, DMSO-d6)δ169.51,160.89,157.30,155.89(d,J=233.5Hz),155.79,152.02,145.85,125.70,115.09 (d,J=22.3Hz),113.51(d,J=7.8Hz),110.85,108.60,107.11,97.22,44.55,32.90,21.64,13.74.HR-MS(ESI):m / z calcd for C 20 H 21 FN3O3([M+H] + )370.1561,Found 370.1563.

[0091] Compound 8: 2-((2-oxo-4-propyl-2H-coumarin-7-yl)amino)-N'-(4-(trifluoromethyl)phenyl)acetylhydrazide:

[0092] White solid, yield: 40.0%, mp: 165.4-166.0℃, 1 H NMR (500MHz, DMSO-d6) δ10.10(s,1H),8.46(s,1H),7.52(d,J=8.5Hz,1H),7.42(d,J=7.5Hz,2H),7.04(s,1H),6.84(d,J=7.5Hz,2H),6.69(d, J=8.9Hz,1H),6.49(s,1H),5.92(d,J=2.9Hz,1H),3.97(d,J=3.3Hz,2H),2.80–2.57(m,2H),1.61(q,J=7.3,6.8Hz,2H),0.95(t,J=7.1Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ169.71,160.89,157.27,155.81,152.47,152.02,126.12,125.73,123.98(q,J=63.1Hz ),118.39(q,J=32.0Hz),111.64,110.83,108.69,107.20,97.34,44.59,32.93,21.66,13.71.HR-MS(ESI):m / z calcd for C 21 H 21 F3N3O3([M+H] + )420.1530,Found 420.1540.

[0093] Compound 9: N'-(4-chlorophenyl)-2-((2-oxo-4-propyl-2H-coumarin-7-yl)amino)acetylhydrazide:

[0094] White solid, yield: 33.0%, mp: 164.1-165.0℃, 1H NMR(500MHz,DMSO-d6)δ9.98(d,J=3.2Hz,1H),7.98(t,J=7.0Hz,1H),7.59–7.49 (m,1H),7.47–7.37(m,1H),7.19–7.06(m,2H),6.73(dd,J=9.1,3.2Hz,2H),6.68( dt,J=9.1,3.0Hz,1H),6.46(d,J=3.0Hz,1H),5.93(d,J=4.5Hz,1H),3.92(s,2H) ,2.66(q,J=6.9,5.8Hz,2H),1.61(dq,J=14.4,7.4Hz,2H),0.96(t,J=7.2Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ169.57,160.90,157.34,155.78,152.02,148.29,128.46,125.75,1 21.90,119.21,113.79,108.63,107.14,97.26,44.57,32.92,21.67,13.76.HR-MS(ESI):m / z calcd for C 20 H 21 ClN3O3([M+H] + )386.1266,Found386.1265.

[0095] Compound 10: N'-(3-fluorophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)amino)acetylhydrazide:

[0096] White solid, yield: 35.0%, mp: 167.5-168.2℃, 1 H NMR (400MHz, DMSO-d6) δ9.98(d,J=2.4Hz,1H),8.10(d,J=2.4Hz,1H),7.41(q,J=7.2,6.0Hz,3H),7.12(q,J= 7.6Hz,1H),6.79(dd,J=9.2,2.4Hz,1H),6.62–6.50(m,3H),6.43(d,J=13.6Hz,2H),4.00(d,J=13.2Hz,1H). 13C NMR (125MHz, DMSO-d6) δ169.71, 164.71, 162.79, 159.85, 157.11, 153.50, 151.95 (d, J = 10.5Hz), 140.71 (q, J = 31.5Hz), 130.73 (d, J = 9.5 Hz),127.81,125.84,110.12,108.75(d,J=16.5Hz),105.11(d,J=21.5Hz),102.86,99.22(d,J=25.5Hz),98.00,44.81.HR-MS(ESI):m / z calcd for C 18 H 14 F4N3O3([M+H] + )396.0966,Found396.0961.

[0097] Compound 11: N'-(4-fluorophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)amino)acetylhydrazide:

[0098] White solid, yield: 44.0%, mp: 167.8-168.4℃, 1 H NMR(500MHz,DMSO-d6)δ9.99(s,1H),7.80(s,1H),7.46–7.33(m,2H),6.95(t,J=8.4H z,2H),6.75(dt,J=9.3,6.0Hz,3H),6.57(s,1H),6.49(s,1H),3.97(d,J=6.0Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ173.15,169.17,159.43,156.89,156.65,155.03,153.05,145.81,140.25(q,J=32.0Hz),125.36, 122.01(q,J=275.2Hz),115.14(d,J=22.2Hz),113.55(d,J=7.6Hz),108.21(d,J=5.2Hz),102.37,44.33.HR-MS(ESI):m / z calcd for C 18 H 14 F4N3O3([M+H] + )396.0966,Found396.0967.

[0099] Compound 12: N′-(4-chlorophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)amino)acetylhydrazide:

[0100] White solid, yield: 50.8%, mp: 169.1-170.0℃, 1 H NMR (500MHz, DMSO-d6) δ10.00(s,1H),8.00(s,1H),7.40(s,2H),7.14(d,J=8.3Hz,2H),6.84–6.67(m,3H),6.54(d,J=27.3Hz,2H),3.98(s,2H). 13 C NMR (126MHz, DMSO-d6) δ169.14, 159.39, 156.62, 153.02, 148.22, 140.21 (q, J = 31.8Hz), 128.47, 125.37 ,121.99(q,J=276.1Hz),121.92,113.76,109.65,108.24,102.36,97.47,44.27.HR-MS(ESI):m / zcalcd for C 18 H 14 ClF3N3O3([M+H] + )411.0670,Found 411.0675.

[0101] Example 2 Preparation of Novel Coumarin Compounds of 7-O-Acetylhydrazine

[0102]

[0103] wherein R1 is selected from Me, CF3; R2 is selected from H, Cl; R3 is selected from H, Me; R 、 Selected from 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 2-Br, 4-Br, 4-CH3O, 3,4-diCH3, 2,4,6-trCl.

[0104] 1. Cyclization reaction: 50 mmol of substituted or unsubstituted resorcinol (9) was added to a round-bottom flask. 6 mL of anhydrous ethanol was poured into a small beaker. 14 mL of concentrated sulfuric acid solution was slowly poured into the beaker containing anhydrous ethanol and stirred with a glass rod. After the diluted concentrated sulfuric acid ethanol solution cooled, it was poured into a 100 mL round-bottom flask and stirred for 15 minutes to fully dissolve the raw materials. Subsequently, 50 mmol of β-ketoester (3) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4-6 hours. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was slowly poured into 200 mL of ice water. A large amount of gray solid precipitated. After filtration, the filter cake was washed with a small amount of ethanol and dried to obtain the substituted 7-hydroxycoumarin (10).

[0105] 2. Substitution reaction: 10 mmol of substituted 7-hydroxycoumarin (10), 10 mmol of N,N-diisopropylethylamine (DIEA) and 1.8 g (12 mmol) of sodium iodide were added to a 50 mL flask, 20 mL of acetonitrile solution was added to dissolve the mixture, and magnetic stirring was performed for about 5 minutes. 12 mmol of ethyl bromoacetate was added dropwise to the reaction flask. The heating device was adjusted to 95°C and refluxed for 24 hours. The reaction progress was monitored by TLC. When the reaction was complete, the heating device was removed and the reaction solution was poured into ice water while stirring while hot and allowed to stand overnight to obtain a large amount of solid. The mixed solution was then filtered, and the upper solid was washed with a small amount of ethanol and dried to obtain the intermediate ethyl 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetate (11).

[0106] 3. Deprotection reaction: The intermediate ethyl 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetate (11) was added to a 250 mL round-bottom flask, dissolved with 100 mL of ethanol, and magnetically stirred for about 15 min to fully dissolve it. 15 mL of 10% sodium hydroxide solution was added to the reaction flask, stirred at room temperature for about 4 h, and the reaction progress was monitored by TLC. After the reaction was complete, the ethanol solution was removed by vacuum distillation, and the resulting residue was poured into a 50 mL beaker, 20 mL of distilled water was added, and 15% dilute hydrochloric acid was used to adjust the pH value of the aqueous phase to 2-3. A large amount of solid precipitated. The mixed solution was filtered, and the upper solid was washed with a small amount of ethanol and dried to obtain the intermediate 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid (12).

[0107] 4. Condensation reaction: 3.00 mmol of the intermediate 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid (12) and 3.00 mmol of the substituted phenylhydrazine (8) were added to a 50 mL round-bottom flask and fully dissolved in 25 mL of acetonitrile solution. O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) was weighed and added to the reaction flask, followed by dropwise addition of 6.00 mmol of triethylamine. The mixture was stirred at room temperature for about 3 h and the reaction progress was monitored by TLC. After the reaction was completed, if solid precipitated, it was filtered and the upper solid was washed with a small amount of dichloromethane. If no solid precipitated, it was extracted with ethyl acetate and the organic phases were combined. The solvent in the obtained organic phases was removed by vacuum concentration. The mixture was purified by column chromatography using a dry loading method and a petroleum ether / ethyl acetate system as the eluent to obtain a series of target compounds 7-O-acetylhydrazine coumarin 13-53. The substituent groups of each compound are shown in Table 3. The 7-O acetylhydrazide coumarin shown in Formula II is shown in Table 3.

[0108] Table 3. 7-O Acetylhydrazide Coumarin

[0109]

[0110]

[0111] The structural characterization data of the target compounds 7-O acetylhydrazide coumarin 13-53 are as follows:

[0112] Compound 13: N′-(2-fluorophenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0113] White solid, yield: 67.8%, mp: 131.3-131.7℃, 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 7.78 (s, 1H), 7.73 (d, J = 8.8Hz, 1H), 7.11-7.01 (m, 3H) ,6.96(t,J=7.7Hz,1H),6.79(dd,J=12.3,4.5Hz,1H),6.25(s,1H),4.83(s,2H),2.41(s,3H). 13 C NMR (126MHz, DMSO-d6) δ167.40,160.89,160.35,154.6,153.63,136.79,126.67,124.64,119. 12,113.90,113.79,112.84,111.61,101.78,66.56,45.65,18.33,8.64.HR-MS(ESI):m / zcalcd for C 18 H 15 FN2O4([M+H] + )343.1089,found 343.1092.

[0114] Compound 14: N'-(3-fluorophenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0115] White solid, yield: 64.1%, mp: 159.1-160.1℃, 1 H NMR (400MHz, DMSO-d6) δ10.06(d,J=3.3Hz,1H),7.73(d,J=8.8Hz,1H),7.51(d,J=3.3Hz,1H), 7.05(dd,J=8.8,2.5Hz,1H),7.01(d,J=2.4Hz,1H),6.71(dd,J=21.1,9.1Hz,4H),4.77(s,2H). 13C NMR (100MHz, DMSO-d6) δ167.32, δ163.30 (d, J = 241.1Hz), 160.81, 160.22, 154.63, 153.52, 151.42 (d, J = 10.5Hz), 130.39 (d, J = 9.8 Hz),126.65,113.79,112.77,111.60,108.44,104.78(d,J=21.4Hz),101.76,98.83(d,J=25.7Hz),66.50,18.30.HR-MS(ESI):m / z calcd forC 18 H 15 FN2O4([M+H] + )343.1089,found 343.1092.

[0116] Compound 15: N′-(4-fluorophenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0117] White solid, yield: 84.1%, mp: 119.0-119.8℃, 1 H NMR (400MHz, DMSO-d6) δ10.12(d,J=2.9Hz,1H),7.82(d,J=2.8Hz,1H),7.74(d,J=8.8Hz,1H),7.06(dd,J=8.8,2.5Hz,1H), 7.02(d,J=2.4Hz,1H),6.97(t,J=8.9Hz,2H),6.76-6.68(m,2H),6.26(d,J=1.1Hz,1H),4.80(s,2H),2.42(d,J=0.9Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ167.35,160.88,160.39,155.21,154.68,153.69,145.79,126 .70,115.44,115.26,113.80,112.81,111.65,101.79,66.59,18.34.HR-MS(ESI):m / z calcd for C 18 H 15 FN2O4([M+H] + )343.1089,found343.1089.

[0118] Compound 16: N′-(2-chlorophenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0119] White solid, yield: 81.6%, mp: 145.9-146.7℃, 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),7.74(d,J=8.7Hz,1H),7.57(d,J=1.2Hz,1H),7.28(dt,J=13.7,6.8H z,1H),7.13(t,J=7.7Hz,1H),7.09-7.03(m,2H),6.83-6.68(m,2H),6.25(s,1H),4.83(s,2H),2.42(s,3H). 13 C NMR(126MHz,DMSO-d6)δ167.72,161.13,160.76,154.97,154.06,144.85,129.71,128.20,127 .03,120.27,117.76,114.20,113.49,113.22,111.94,102.12,66.85,18.66.HR-MS(ESI):m / z calcd for C 18 H 15 ClN2O4([M+H] + )359.0793,found 359.0795.

[0120] Compound 17: N′-(3-chlorophenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0121] White solid, yield: 79.5%, mp: 133.7-134.4℃, 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.14(d,J=2.1Hz,1H),7.74(d,J=8.8Hz,1H),7.13(t,J=8.0Hz,1 H),7.09-7.01(m,2H),6.73-6.64(m,2H),6.61(t,J=1.9Hz,1H),6.25(s,1H),4.84(s,2H),2.41(s,3H). 13C NMR(126MHz,DMSO-d6)δ167.56,160.84,160.43,154.74,153.72,150.85,133.79,130.60,126 .81,118.39,114.01,112.92,111.73,111.59,111.29,101.84,66.63,18.40.HR-MS(ESI):m / z calcd for C 18 H 15 ClN2O4([M+H] + )359.0793,found359.0796.

[0122] Compound 18: N'-(2-bromophenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0123] White solid, yield: 76.2%, mp: 142.4-142.7℃, 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),7.74(d,J=8.7Hz,1H),7.45(dd,J=7.9,1.2Hz,1H),7.34(s,1H),7.17(t,J =7.7Hz,1H),7.12-7.02(m,2H),6.78(d,J=8.2Hz,1H),6.73-6.67(m,1H),6.26(s,1H),4.83(s,2H),2.42(s,3H). 13 C NMR(126MHz,DMSO-d6)δ167.36,160.86,160.40,154.71,153.70,145.57,132.61,128.51,126.74,1 20.64,113.91,113.50,112.92,111.69,107.22,101.87,66.61,18.39(d,J=1.3Hz).HR-MS(ESI):m / z calcd for C 18 H 15 BrN2O4([M+H] + )403.0288,found 403.0291.

[0124] Compound 19: N'-(4-bromophenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0125] White solid, yield: 80.7%, mp: 145.5-146.3℃,1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.05(d,J=1.9Hz,1H),7.73(d,J=8.7Hz,1H),7.27(d,J=8.8Hz,2H),7.0 5(dd,J=8.8,2.4Hz,1H),7.02(d,J=2.3Hz,1H),6.69(d,J=8.8Hz,2H),6.25(s,1H),4.81(s,2H),2.41(s,3H). 13 C NMR(126MHz,DMSO-d6)δ167.50,160.87,160.47,154.70,153.70,148.66,131.58,126 .73,114.59,113.91,112.85,111.70,109.87,101.83,66.60,18.42.HR-MS(ESI):m / z calcd for C 18 H 15 BrN2O4([M+H] + )403.0288,found 403.0291.

[0126] Compound 20: N′-(4-methoxyphenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0127] White solid, yield: 87.6%, mp: 158.0-158.7℃, 1 H NMR (400MHz, DMSO-d6) δ10.07(d,J=3.3Hz,1H),7.74(d,J=8.8Hz,1H),7.51(d,J=3.3Hz,1H),7.06(dd,J=8.8,2.5Hz,1H),7 .02(d,J=2.4Hz,1H),6.71(dd,J=21.1,9.1Hz,4H),6.26(d,J=1.1Hz,1H),4.78(s,2H),3.65(s,3H),2.42(d,J=0.9Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ167.91,161.18,161.12,154.96,154.38,153.47,143.24,127 .13,114.77,114.61,114.27,113.37,111.90,102.07,66.85,18.72.HR-MS(ESI):m / z calcd for C 19 H 18N2O5([M+H] + )355.1289,found355.1289.

[0128] Compound 21: N'-(3,4-dimethylphenyl)-2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0129] White solid, yield: 77.3%, mp: 127.5-128.1℃, 1 H NMR (400MHz, DMSO-d6) δ10.03(d,J=3.0Hz,1H),7.73(d,J=8.7Hz,1H),7.57(d,J=3.0Hz,1H),7.06(dd,J=8.8,2.4Hz,1H) ,7.02(d,J=2.4Hz,1H),6.87(d,J=8.8Hz,1H),6.47(d,J=5.8Hz,2H),6.25(s,1H),4.79(s,2H),2.41(s,3H),2.07(s,6H). 13 C NMR (126MHz, DMSO-d6) δ167.32,160.88,160.30,154.70,153.54,147.25,136.37,129.80,126.65,1 26.37,114.02,112.89,111.64,110.28,101.76,66.59,19.76,18.63,18.30.HR-MS(ESI):m / zcalcd for C 20 H 20 N2O4([M+H] + )353.1496,found 353.1499.

[0130] Compound 22: 2-((4-methyl-2-oxo-2H-coumarin-7-yl)oxy)-N′-(2,4,6-trichlorophenyl)acetohydrazide:

[0131] White solid, yield: 74.3%, mp: 148.4-148.5℃, 1 H NMR (400MHz, DMSO-d6) δ10.39(d,J=1.3Hz,1H),7.69(d,J=8.8Hz,1H),7.49(s,2H),7.45(d,J=1.2Hz,1H),7 .00(dd,J=8.8,2.5Hz,1H),6.95(d,J=2.4Hz,1H),6.23(d,J=0.9Hz,1H),4.70(s,2H),2.40(d,J=0.6Hz,3H).13 C NMR(126MHz,DMSO-d6)δ166.77,160.89,160.31,154.66,153.62,140.79,128.68,126 .63,125.36,124.47,113.79,112.78,111.61,101.66,65.82,18.34.HR-MS(ESI):m / z calcd for C 18 H 13 Cl3N2O4([M+H] + )427.0013,found 427.0018.

[0132] Compound 23: N'-(2-fluorophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0133] White solid, yield: 67.8%, mp: 168.4-168.9℃, 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),7.78(s,1H),7.68(d,J=7.6Hz,1H),7.21-7.14(m,2H),7.06(dd,J=12.6,3 .5Hz,1H),6.97(t,J=7.5Hz,1H),6.91(s,1H),6.81(t,J=8.0Hz,1H),6.73(dd,J=11.9,6.9Hz,1H),4.86(s,2H). 13 C NMR(100MHz,DMSO-d6)δ167.17(s),161.67(s),158.92(s),155.81(s),151.57(s) ),149.19(s),139.62(q,J=31.5Hz),136.72(d,J=10.7Hz),126.13(s),124.67(d, J=3.2Hz),121.90(d,J=275.2Hz),119.18(d,J=6.6Hz),115.10(d,J=17.7Hz),11 4.08(s),113.89(s),107.15(s),102.77(s),66.64(s).HR-MS(ESI):m / zcalcdfor C 18 H 12 F4N2O4([M+H] + )397.0806,found 397.0803.

[0134] Compound 24: N′-(3-fluorophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0135] White solid, yield: 69.6%, mp: 165.1-165.7℃, 67.8%, 1 H NMR (400MHz, DMSO-d6) δ10.15(d,J=2.2Hz,1H),8.13(d,J=1.7Hz,1H),7.68(d,J=7.4Hz,1H),7.20–7.09(m,3H), 6.90(s,1H),6.55(dd,J=8.2,1.4Hz,1H),6.48(td,J=8.3,2.0Hz,1H),6.41(dt,J=11.7,2.2Hz,1H),4.88(s,2H). 13 C NMR(126MHz,DMSO-d6)δ167.35,163.49(d,J=240.5Hz),161.73,159.00,155.8 7,151.49(d,J=10.4Hz),139.79(q,J=31.3Hz),130.62(d,J=10.0Hz),126.26,1 21.96(d,J=275.5Hz),114.15,113.86(d,J=5.6Hz),108.66(d,J=2.1Hz),107. 25,105.10(d,J=21.3Hz),102.86,99.02(d,J=25.9Hz),66.72.HR-MS(ESI):m / z calcd for C 18 H 12 F4N2O4([M+H] + )397.0806,found 397.0804.

[0136] Compound 25: N′-(4-fluorophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0137] White solid, yield: 64.1%, mp: 189.2-189.8℃, 1H NMR (400MHz, DMSO-d6) δ10.14(d,J=2.5Hz,1H),7.83(d,J=2.6Hz,1H),7.67(d,J=8.5Hz,1H),7.16(d d,J=12.8,2.3Hz,2H),6.98(t,J=8.8Hz,2H),6.89(s,1H),6.75(dd,J=8.8,4.6Hz,2H),4.85(s,2H). 13 C NMR(100MHz,DMSO-d6)δ167.06,161.64,158.88,157.28,155.78,154.95,145.74,139.56(d,J=32.1Hz ),126.09,115.31(d,J=22.3Hz),114.00,113.71(d,J=7.5Hz),107.09,102.71,66.64.HR-MS(ESI):m / z calcd for C 18 H 12 F4N2O4([M+H] + )397.0806,found397.0809.

[0138] Compound 26: N′-(2-chlorophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0139] White solid, yield: 66.7%, mp: 190.1-190.6℃, 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),7.68(d,J=7.2Hz,1H),7.57(s,1H),7.29(dd,J=7.9,1.3 Hz,1H),7.17(ddd,J=16.6,10.1,4.8Hz,3H),6.91(s,1H),6.83-6.72(m,2H),4.88(s,2H).13C NMR (100MHz, DMSO-d6) δ167.21, 161.70, 158.96, 155.85, 144.61, 139.71 (d, J = 30.7Hz), 129.45, 127. 95,126.17,123.30,120.60,119.99,117.51,114.13,113.27,107.18,102.83,66.69.HR-MS(ESI):m / z calcd for C 18 H 12 ClF3N2O4([M+H] +)413.0511,found413.0513.

[0140] Compound 27: N′-(3-chlorophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0141] White solid, yield: 74.1%, mp: 199.5-199.9℃, 1 H NMR (400MHz, DMSO-d6) δ10.17(d,J=2.1Hz,1H),8.15(d,J=2.1Hz,1H),7.68(d,J=7.9Hz,1 H),7.22-7.09(m,3H),6.89(s,1H),6.74-6.67(m,2H),6.62(t,J=1.9Hz,1H),4.89(s,2H). 13 C NMR(100MHz,DMSO-d6)δ167.13,160.16(d,J=279.5Hz),158.77,155.74,150.76,139.55(d,J=32.2Hz),133.65,130 .46,126.08,120.46,118.23,114.01,113.79(d,J=5.9Hz),111.46,111.17,107.12,102.67,66.62.HR-MS(ESI):m / z calcd for C 18 H 12 ClF3N2O4([M+H] + )413.0511,found413.0513.

[0142] Compound 28: N′-(2-bromophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0143] White solid, yield: 76.5%, mp: 196.7-197.2℃, 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.68(d,J=8.8Hz,1H),7.45(dd,J=7.9,1.3Hz,1H),7.34(d,J=1.6Hz, 1H),7.21-7.15(m,3H),6.91(s,1H),6.80(dd,J=8.1,1.2Hz,1H),6.71(td,J=7.7,1.4Hz,1H),4.88(s,2H). 13C NMR (126MHz, DMSO-d6) δ171.19,167.19,161.70,158.97,155.84,145.57,139.7(q,J=31.5Hz),132.6 3,128.55,126.19,123.02,120.70,114.13,113.55,107.25,107.18,102.84,66.66.HR-MS(ESI):m / z calcd for C 18 H 12 BrF3N2O4([M+H] + )457.0005,found457.0008.

[0144] Compound 29: N'-(4-bromophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0145] White solid, yield: 80.2%, mp: 190.6-191.4℃, 1 H NMR (400MHz, DMSO-d6) δ10.16(d,J=2.4Hz,1H),8.05(d,J=2.3Hz,1H),7.68(dd,J=8.6,1.3Hz,1H), 7.28(d,J=8.8Hz,2H),7.16(dt,J=8.9,2.4Hz,2H),6.90(s,1H),6.70(d,J=8.8Hz,2H),4.86(s,2H). 13 C NMR(100MHz,DMSO-d6)δ167.35,161.89,159.14,156.05,148.86,139.67(q,J=32.0Hz),131.77, 126.38,122.16(d,J=276.0Hz),114.74,114.27,109.97,107.39,103.00,66.89.HR-MS(ESI):m / z calcd for C 18 H 12 BrF3N2O4([M+H] + )457.0005,found 457.0001.

[0146] Compound 30: N'-(4-cyanophenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0147] White solid, yield: 70.9%, mp: 167.5-168.4℃, 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.72(s,1H),7.69(d,J=7.3Hz,1H),7.55(d,J=8.6Hz,2H) ,7.19(d,J=2.4Hz,1H),7.16(d,J=9.1Hz,1H),6.91(s,1H),6.80(d,J=8.8Hz,2H),4.90(s,2H). 13 C NMR(100MHz,DMSO-d6)δ167.34,161.64,159.02,155.86,152.86,139.69(q,J=32.0Hz),133.69, 126.27,123.33,120.60,120.31,114.07,112.12,107.27,102.81,99.43,66.64.HR-MS(ESI):m / z calcd for C 19 H 12 F3N3O4([M+H] + )404.0853,found404.0851.

[0148] Compound 31: N'-(4-methoxyphenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0149] White solid, yield: 80.0%, mp: 193.2-193.9℃, 1 H NMR (400MHz, DMSO-d6) δ10.08(d,J=3.3Hz,1H),7.67(d,J=7.3Hz,1H),7.51(d,J=3.3Hz ,1H),7.18-7.13(m,2H),6.90(s,1H),6.72(q,J=9.1Hz,4H),4.83(s,2H),3.65(s,3H). 13 C NMR (100MHz, DMSO-d6) δ166.80,161.62,158.78,155.72,152.87,142.96,139.64(q,J=32.0H z),126.01,114.68,114.26,113.98,113.93,107.01,102.65,66.62,55.33.HR-MS(ESI):m / z calcd forC 19 H 15 F3N2O5([M+H] + )409.1005,found 409.1008

[0150] Compound 32: N'-(3,4-dimethylphenyl)-2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0151] White solid, yield: 64.1%, mp: 201.5-201.9℃, 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),7.68(d,J=8.2Hz,1H),7.57(s,1H),7.16(d, J=7.7Hz,2H),6.94-6.83(m,2H),6.47(d,J=8.6Hz,2H),4.84(s,2H),2.08(s,6H). 13 C NMR (126MHz, DMSO-d6) δ166.96,161.70,158.87,155.79,147.20,139.62(q,J=31.5Hz),136.37,129.81,127 .44,126.40,126.12,123.00,114.09,113.98,110.28,107.11,102.71,66.65,19.79,18.64.HR-MS(ESI):m / z calcd for C 20 H 17 F3N2O4([M+H] + )407.1213, found 407.1211. Compound 33: 2-((2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N'-(2,4,6-trichlorophenyl)acetohydrazide:

[0152] White solid, yield: 50.5%, mp: 164.1-164.4℃, 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),7.60(d,J=4.2Hz,1H),7.46(d,J=0.8Hz,2H),7.41(s,1H),7.06(s,2H),6.85(s,1H),4.70(s,2H). 13C NMR(100MHz,DMSO-d6)δ166.60,161.69,158.89,155.78,140.78,139.62(q,J=31.5Hz),128.69,12 6.03,125.44,124.54,113.99,113.78(d,J=4.8Hz),107.07,102.63,65.92,45.91.HR-MS(ESI):m / z calcd for C 18 H9Cl4F3N2O4([M+H] + )516.9314,found 516.9310.

[0153] Compound 34: 2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N′-(2-fluorophenyl)acetohydrazide:

[0154] White solid, yield: 67.6%, mp: 145.1-145.4℃, 1 H NMR(400MHz,DMSO-d6)δ10.11(s,1H),7.82(s,1H),7.65(s,1H),7.34(s,1H),7.09-7.04(m ,1H),7.02-6.97(m,2H),6.89(t,J=8.0Hz,1H),6.74(dd,J=11.9,6.7Hz,1H),5.02(s,2H). 13 C NMR(100MHz,DMSO-d6)δ166.97(s),158.76(s),157.16(s),154.53(s),151.82 (s),149.44(s),138.89(q,J=31.1Hz),136.83(d,J=10.6Hz),125.24(s),124.9 4(d,J=3.1Hz),121.84(d,J=276.0Hz),119.64(d,J=6.8Hz),119.28(s),115.3 8(d,J=17.7Hz),114.18(s),107.73(s),103.31(s),67.26(s).HR-MS(ESI):m / z calcd for C 18 H 11 ClF4N2O4([M+H] + )431.0416,found431.0420.

[0155] Compound 35: 2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N′-(3-fluorophenyl)acetohydrazide:

[0156] White solid, yield: 70.5%, mp: 155.9-156.3℃, 1 H NMR(400MHz,DMSO-d6)δ10.09(d,J=1.9Hz,1H),8.17(s,1H),7.66(s,1H),7.37(s,1H),7.15 (dd,J=15.1,8.1Hz,1H),7.00(s,1H),6.62-6.56(m,1H),6.49(t,J=8.5Hz,2H),5.02(s,2H). 13 C NMR (126MHz, DMSO-d6) δ166.70,164.40,162.49,158.45,156.98,154.35,151.37(d,J=10.5Hz),138.60(q,J=32.76Hz),130.54(d,J=11.6H z),125.00,119.05,115.24,108.55(d,J=2.7Hz),107.49,105.04(d,J=21.6Hz),103.12,98.97(d,J=26.0Hz),67.15.HR-MS(ESI):m / zcalcd for C 18 H 11 ClF4N2O4([M+H] + )431.0416,found 431.0418.

[0157] Compound 36: 2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N'-(4-fluorophenyl)acetohydrazide:

[0158] White solid, yield: 56.7%, mp: 152.3-152.9℃, 1 H NMR (400MHz, DMSO-d6) δ10.07(d,J=2.7Hz,1H),7.85(d,J=2.6Hz,1H),7.65(s, 1H),7.34(s,1H),6.99(dd,J=11.5,6.2Hz,3H),6.81-6.73(m,2H),4.99(s,2H). 13C NMR (126MHz, DMSO-d6) δ167.06, 161.64, 158.87, 157.04, 155.77, 155.19, 145.72 (d, J = 2.0Hz), 139.56 (q, J = 31.5 Hz),126.09,115.31(d,J=22.5Hz),114.00,113.71(d,J=7.7Hz),107.09,102.70,99.67,66.64.HR-MS(ESI):m / z calcd for C 18 H 11 ClF4N2O4([M+H] + )431.0416,found431.0419.

[0159] Compound 37: 2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N′-(2-chlorophenyl)acetohydrazide:

[0160] White solid, yield: 73.4%, mp: 112.7-113.5℃, 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),7.66(d,J=1.2Hz,1H),7.60(s,1H),7.35(s,1H),7.31-7.26(m,1H),7.1 6(dd,J=11.3,4.1Hz,1H),7.00(s,1H),6.89(dd,J=8.2,1.2Hz,1H),6.76(dd,J=7.8,1.4Hz,1H),5.03(s,2H). 13 C NMR (126MHz, DMSO-d6) δ170.40(s), 166.50(s), 158.36(s), 157.57(d, J=62. 7Hz),156.89(s),154.26(s),145.44(s),144.66(s),138.42(d,J=33.1Hz),1 32.49(d,J=13.2Hz),128.40(d,J=33.7Hz),124.79(d,J=17.0Hz),122.68(s ),120.50(s),118.88(s),107.41(s),107.07(s),66.98(s).HR-MS(ESI):m / z calcd for C 18 H 11 Cl2F3N2O4([M+H] + )447.0121,found 447.0127.

[0161] Compound 38: 2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N'-(3-chlorophenyl)acetohydrazide:

[0162] White solid, yield: 76.9%, mp: 136.1-136.6℃, 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),7.66(d,J=1.3Hz,1H),7.60(s,1H),7.36(s,1H),7.29(dt,J=9.4,2.8H z,1H),7.21-7.10(m,1H),7.00(s,1H),6.89(dd,J=8.2,1.3Hz,1H),6.77(td,J=7.8,1.4Hz,1H),5.03(s,2H). 13 C NMR (126MHz, DMSO-d6) δ166.89, 158.75, 157.25, 154.63, 144.83, 144.03, 138.78 (q, J = 32.76Hz), 129.69, 128.19, 125. 19(dd,J=4.7,2.0Hz),121.95(d,J=279.0Hz),120.19,119.25,117.69,113.50,107.82,103.50,67.37.HR-MS(ESI):m / z calcdfor C 18 H 11 Cl2F3N2O4([M+H] + )447.0121,found 447.0118.

[0163] Compound 39: N'-(2-bromophenyl)-2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0164] White solid, yield: 64.3%, mp: 153.3-154.2℃, 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),7.66(s,1H),7.45(d,J=7.8Hz,1H),7.36(d,J=4.8Hz,2H) ,7.20(t,J=7.6Hz,1H),7.00(s,1H),6.88(d,J=8.1Hz,1H),6.71(dd,J=7.5Hz,1H),5.03(s,2H). 13C NMR (100MHz, DMSO-d6) δ 166.47, 158.33, 156.87, 154.24, 145.42, 144.64, 138.42 (d, J = 33.4Hz), 132. 48,128.38,124.78,120.50,118.87,115.22,113.41,107.40,107.07,103.12,66.98.HR-MS(ESI):m / z calcd for C 18 H 11 BrClF3N2O4([M+H] + )492.9595,found492.9596.

[0165] Compound 40: N′-(4-bromophenyl)-2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0166] White solid, yield: 75.2%, mp: 188.4-189.1℃, 1 H NMR(400MHz,DMSO-d6)δ10.09(d,J=2.1Hz,1H),8.08(s,1H),7.66(s,1H),7.34(s ,1H),7.30(s,1H),7.28(s,1H),7.01(s,1H),6.73(d,J=8.8Hz,2H),5.00(s,2H). 13 C NMR (126MHz, DMSO-d6) δ166.51,158.34,156.87,154.24,148.46,147.63,138.40(d,J=29.3Hz),131.57,131.31(d ,J=1.0Hz),124.82(d,J=10.0Hz),121.59(d,J=274.1Hz),118.87,114.37,109.70,107.40,67.01.HR-MS(ESI):m / z calcd for C 18 H 11 BrClF3N2O4([M+H] + )492.9595,found 492.9599.

[0167] Compound 41: 2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N'-(4-cyanophenyl)acetohydrazide:

[0168] White solid, yield: 67.7%, mp: 169.1-170.0℃,1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),7.65(d,J=8.4Hz,2H),7.49(d,J=8.7Hz,3H),7.25(s,1H),7.00(s,1H),4.90(s,2H). 13 C NMR(126MHz,DMSO-d6)δ166.78,158.52,156.94,154.35,152.77,138.56(d,J=32.4Hz),133.63, 128.71,125.00,124.74,120.24,119.00,112.08,107.57,103.10,99.44,67.01.HR-MS(ESI):m / z calcd for C 19 H 11 ClF3N3O4([M+H] + )438.0463,found 438.0467.

[0169] Compound 42: 2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N'-(3,4-dimethylphenyl)acetohydrazide:

[0170] White solid, yield: 76.5%, mp: 158.4-158.9℃, 1 H NMR (400MHz, DMSO-d6) δ9.98(d,J=2.8Hz,1H),7.66(s,1H),7.61(d,J=2.7Hz,1H),7.33(s,1H),7.00(d,J=5 .4Hz,1H),6.89(d,J=8.0Hz,1H),6.54(s,1H),6.51(d,J=8.0Hz,1H),4.98(s,2H),2.11(s,3H),2.08(s,3H). 13 C NMR (126MHz, DMSO-d6) δ166.91,158.83,157.23,154.56,147.28,146.39,139.05(q,J=31.5Hz),136.93,13 0.23,127.14,125.32,119.47,115.32,114.37,110.68,107.74,103.20,67.43,20.08,18.92.HR-MS(ESI)cd for C 20 H 16 ClF3N2O4([M+H] +)441.0824,found 441.0826.

[0171] Compound 43: 2-((6-chloro-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N'-(2,4,6-trichlorophenyl)acetohydrazide:

[0172] White solid, yield: 70.0%, mp: 189.7-190.2℃, 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),7.64(d,J=5.7Hz,2H),7.49(s,2H),7.24(s,1H),6.99(s,1H),4.90(s,2H). 13 C NMR(126MHz,DMSO-d6)δ166.12,158.46,157.49,156.87,154.30,140.73,138.60(q,J=32.76Hz),128 .70,125.94(q,J=277.2Hz),125.85,125.68,124.76,118.96,107.48,103.03,66.40.HR-MS(ESI):m / z calcd for C 18 H9Cl4F3N2O4([M+H] + )516.9314,found516.9310.

[0173] Compound 44: N′-(2-fluorophenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0174] White solid, yield: 77.6%, mp: 179.6-180.2℃, 1 H NMR (400MHz, DMSO-d6) δ10.08(d,J=1.6Hz,1H),7.78(s,1H),7.58(d,J=8.2Hz,1H),7.16-7.04(m,2H),6.97(t ,J=7.5Hz,1H),6.89(s,1H),6.86-6.79(m,1H),6.75(ddd,J=15.3,10.1,4.4Hz,1H),4.90(s,2H),2.31(s,3H). 13C NMR (126MHz, DMSO-d6) δ171.27,167.29,159.41,155.91(d,J=740.6Hz),151.28,149.38,139.81(q,J=31.5Hz),136.73,136.65,124.58(d, J=3.3Hz),123.14,119.07(d,J=6.6Hz),115.02(d,J=17.4Hz),114.43,113.88(d,J=3.3Hz),109.44,107.20,66.90,8.44.HR-MS(ESI):m / z calcd for C 19 H 14 F4N2O4([M+H] + )411.0963,found 411.0961.

[0175] Compound 45: N'-(3-fluorophenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0176] White solid, yield: 54.1%, mp: 150.4-150.7℃, 1 H NMR (400MHz, DMSO-d6) δ10.06(d,J=2.2Hz,1H),8.13(d,J=1.5Hz,1H),7.58(d,J=8.2Hz,1H),7.17- 7.09(m,2H),6.90(s,1H),6.55(dd,J=8.2,1.4Hz,1H),6.51-6.38(m,2H),4.91(s,2H),2.31(s,3H). 13 C NMR(126MHz,DMSO-d6)δ168.02,164.59,162.66,159.56,159.45,153.17,151.40(d,J=9.3Hz),14 0.33(dd,J=34.4,27.4Hz),123.48,120.97,114.88,107.54,100.00,67.02,8.99.HR-MS(ESI):m / z calcd for C 19 H 14 F4N2O4([M+H] + )411.0963,found 411.0961.

[0177] Compound 46: N'-(4-fluorophenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0178] White solid, yield: 70.2%, mp: 193.3-194.2℃, 1 H NMR (400MHz, DMSO-d6) δ10.04(d,J=19.4Hz,1H),7.79(d,J=19.4Hz,1H),7.56(d,J=11.1Hz,1H),7 .12-7.05(m,1H),6.97-6.83(m,3H),6.70(s,2H),4.86(d,J=21.6Hz,2H),2.28(d,J=21.8Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ167.33,159.48,158.94,157.09,155.23,153.01,145.75(d,J=1.8Hz),139.92(dd,J=62.7,32 .3Hz),123.2,115.31(d,J=22.3Hz),114.48,113.77(d,J=7.6Hz),109.45,107.23,66.94,8.77.HR-MS(ESI):m / zcalcd for C 19 H 14 F4N2O4([M+H] + )411.0963,found 411.0962.

[0179] Compound 47: N'-(2-chlorophenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0180] White solid, yield: 65.4%, mp: 157.9-158.4℃, 1 H NMR (400MHz, DMSO-d6) δ10.17 (s, 1H), 7.62-7.53 (m, 2H), 7.29 (d, J = 7.2Hz, 1H), 7.13(t,J=8.3Hz,2H),6.89(s,1H),6.83-6.73(m,2H),4.91(s,2H),2.31(s,3H). 13C NMR(126MHz,DMSO-d6)δ167.32,159.97,159.45,158.95,153.01,145.54,139.90(q,J=31.9Hz),132.58, 128.56,123.20,123.08,120.66,114.50,113.54,109.50,107.28,107.22,66.92,8.52.HR-MS(ESI):m / z calcd forC 19 H 14 ClF3N2O4([M+H] + )427.0667,found 427.0664.

[0181] Compound 48: N′-(3-chlorophenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0182] White solid, yield: 67.9%, mp: 154.8-155.2℃, 1 H NMR (400MHz, DMSO-d6) δ10.09(d,J=1.7Hz,1H),8.14(d,J=1.7Hz,1H),7.56(t,J=13.8Hz,1H),7 .13(t,J=8.0Hz,2H),6.88(s,1H),6.69(ddd,J=16.2,8.5,1.6Hz,3H),4.91(s,2H),2.31(s,3H). 13 C NMR (126MHz, DMSO-d6) δ167.46,159.42,158.92,153.05,150.83,139.99(q,J=31.5Hz),133.79,130.56,123.2 8,120.88,118.39,114.55,113.55(d,J=7.3Hz),111.60,111.32,109.32,107.30,66.97,8.50.HR-MS(ESI):m / z calcd for C 19 H 14 ClF3N2O4([M+H] + )427.0667,found 427.0670.

[0183] Compound 49: N′-(2-bromophenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0184] White solid, yield: 74.2%, mp: 149.9-150.4℃, 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),7.58(d,J=7.9Hz,1H),7.45(dd,J=7.9,1.3Hz,1H),7.32(s,1H),7.16(d d,J=15.6,8.2Hz,2H),6.90(s,1H),6.81-6.76(m,1H),6.71(td,J=7.7,1.4Hz,1H),4.91(s,2H),2.32(s,3H). 13 C NMR (126MHz, DMSO-d6) δ167.60,159.74,159.23,153.30,145.82,140.19(q,J=32.2Hz),132.87,128.78,123.51(d ,J=2.6Hz),123.36,120.95,114.79,113.84,109.86,107.56,107.51,100.00,67.22,8.80.HR-MS(ESI):m / zcalcd forC 19 H 14 BrF3N2O4([M+H] + )471.0162,found 471.0163.

[0185] Compound 50: N'-(2-bromophenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0186] White solid, yield: 80.0%, mp: 143.9-144.2℃, 1 H NMR (400MHz, DMSO-d6) δ10.08(d,J=2.3Hz,1H),8.04(d,J=2.2Hz,1H),7.58(d,J=7.9Hz,1H),7.27(d ,J=8.8Hz,2H),7.11(d,J=9.1Hz,1H),6.89(s,1H),6.68(d,J=8.9Hz,2H),4.89(s,2H),2.30(s,3H). 13CNMR(126MHz,DMSO-d6)δ167.19,159.35,158.79,152.93,148.54,139.76(q,J=31.5Hz),131 .39,123.13,122.99,114.40,114.36,109.59,109.33,107.15,66.83,8.62.HR-MS(ESI):m / z calcd for C 19 H 14 BrF3N2O4([M+H] + )471.0162,found 471.0158.

[0187] Compound 51: N'-(4-methoxyphenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0188] White solid, yield: 79.1%, mp: 187.5-187.1℃, 1 H NMR (400MHz, DMSO-d6) δ9.99(d,J=3.3Hz,1H),7.58(d,J=7.5Hz,1H),7.51(d,J=3.2Hz,1H),7.11(d,J=9 .1Hz,1H),6.89(s,1H),6.71(dd,J=23.3,9.0Hz,4H),4.86(s,2H),3.66(s,3H),2.32(d,J=10.9Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ167.22(s),159.53(s),159.02(s),153.02(s),143.03(s),140.44(q,J=32.3Hz),123.2 6(s),114.54(s),114.39(s),114.09(s),109.53(s),107.30(s),67.03(s),55.47(s),8.54(s).HR-MS(ESI):m / z calcd for C 20 H 17 F3N2O5([M+H] + )423.1162,found 423.1160.

[0189] Compound 52: N'-(3,4-dimethylphenyl)-2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)acetylhydrazide:

[0190] White solid, yield: 72.1%, mp: 180.8-181.3℃, 1 H NMR(400MHz, DMSO-d6)δ9.97(d,J=3.0Hz,1H),7.61-7.53(m,2H),7.12(d,J=9.1Hz,1H), 6.91-6.83(m,2H),6.50-6.42(m,2H),4.87(s,2H),2.31(s,3H),2.10(t,J=10.4Hz,6H). 13 C NMR (126MHz, DMSO-d6) δ171.39,167.19,159.50,158.96,153.04,147.22,136.37,129.81,126.4 2,123.20,114.52,113.99,110.34,109.40,107.26,67.00,19.80,18.65,8.77.HR-MS(ESI):m / z calcd forC 21 H 19 F3N2O4([M+H] + )421.1370, found 421.1367.

[0191] Compound 53: 2-((8-methyl-2-oxo-4-(trifluoromethyl)-2H-coumarin-7-yl)oxy)-N′-(2,4,6-trichlorophenyl)acetohydrazide:

[0192] White solid, yield: 80.1%, mp: 190.4-191.0℃, 1 H NMR (400MHz, DMSO-d6) δ10.38(d,J=1.9Hz,1H),7.51(s,2H),7.43(d,J=1.9Hz,1H),7.05(d,J=9.1Hz,1H),6.88(s,1H),4.78(s,2H),2.26(s,2H). 13 C NMR(126MHz,DMSO-d6)δ167.08,159.73,159.23,153.30,141.11,140.18(q,J=32.2Hz),128.98,125.8 5,124.96,123.37,114.67,113.90(d,J=6.4Hz),109.71,107.51,100.02,66.50,8.74.HR-MS(ESI):m / z calcd for C 19 H 12 Cl3F3N2O4([M+H] +)494.9888found 494.9892.

[0193] Example 3 Antibacterial activity detection of target compound

[0194] Six common agricultural plant pathogenic fungi, Botrytis cinerea (strawberry gray mold), Altemaria solani (tomato early blight), Rhizoctonia solani (rice sheath blight), Fusarium graminearum (wheat head blight), Colletotrichum orbiculare (cucumber anthracnose), and Alternaria alternata (apple leaf spot), were used as experimental targets. A mycelial growth rate assay was used to screen the target compounds for their antifungal activity. Commonly used commercial antifungals for controlling these crop diseases, along with commercial antifungals with some structural similarity to the target compounds, carbendazim, boscalid, and osthole, were selected as control agents.

[0195] Experiment: Petri dishes (Haimen Chuangxin Consumables Co., Ltd.), high-pressure sterilizer (TOMY SX-700), electric constant temperature biochemical incubator (Shanghai Jinghong Experimental Equipment Co., Ltd.), Eppendrof pipette, double-sided clean bench (Suzhou Purification Equipment Co., Ltd.), hole punch, turbidity meter, etc.

[0196] Experimental methods:

[0197] (I) Preliminary screening of the antifungal activity of 53 target compounds using the mycelial growth rate method

[0198] Preparation of potato dextrose agar (PDA) medium: Peel the potatoes, weigh 200 g, slice them, and put them into 1000 mL of water and cook for about 30 minutes. At this time, the potatoes are cooked but not into a paste. Filter them through two layers of gauze into a measuring cylinder, remove the residue, add water to 1000 mL, add 18 g of agar to the filtrate, cook until melted, add 20 g of glucose, stir evenly, and divide into Erlenmeyer flasks. Sterilize at 121°C and 1 MPa for 20 minutes.

[0199] Preparation of drug-containing culture medium: Accurately weigh 25 mg of the test compound (53 target compounds, commercial drugs carbendazim (purchased from Maclean, CAS No.: 10605-21-7), boscalid (purchased from Maclean, CAS No.: 188425-85-6), and osthole (purchased from Maclean, CAS No.: 484-12-8)) and dissolve in 1 mL of DMSO to prepare a 25 mg / mL drug solution. Pipette 0.1 mL of this solution into 50 mL of sterile PDA medium (final DMSO concentration approximately 0.2%) and shake thoroughly to prepare a drug-containing culture medium with a concentration of 50 μg / mL. Pour this medium evenly into three sterile culture dishes with a diameter of 9 cm. A medium prepared by adding an equal amount of DMSO (0.1 mL) serves as a blank control.

[0200] EC 50 Toxicity assay: Set a concentration gradient based on the initial screening activity test data, weigh 10 mg of the test compound, dissolve it in DMSO, and then dilute it into 5 concentrations (10 μg / mL, 5 μg / mL, 2.5 μg / mL, 1.25 μg / mL, 0.625 μg / mL). Prepare drug-containing plates, inoculate and culture the bacteria, and calculate the inhibition rate at each concentration. The linear equation and EC can be obtained using the statistical software DPS. 50 Values ​​and confidence intervals.

[0201] A medication group and a blank group were set up, and the treatment method and the amount of solvent added were the same as those of the medication group. The specific experimental data are shown in Table 4.

[0202] Inoculation and Activity Assay: Preserved strains of Botrytis cinerea, Altemaria solani, Rhizoctonia solani, Fusarium graminearum, Colletotrichum orbiculare, and Alternaria alternata (donated by the College of Plant Protection, Nanjing Agricultural University) were removed from a 4°C refrigerator and activated twice in fresh, sterile PDA medium before use. A microbial cake was prepared by punching holes at the edge of a normally growing colony using a borer (0.5 cm inner diameter). This cake was then inoculated with an inoculating needle onto the center of a drug-containing medium plate or a blank medium plate (mycelium facing upward) and incubated in an incubator at 25°C. When the colonies on the blank culture medium grow to about 2 / 3 of the plate diameter (i.e., the colony diameter is 6.5 cm), measure the colony diameter. Each colony diameter is measured twice using the cross-hatch method, and the average value (unit: cm) is calculated. Each treatment is replicated three times. The growth inhibition rate after drug treatment is calculated as follows:

[0203] Inhibition rate (%) = (blank group colony diameter - drug group colony diameter) / (blank group colony diameter - 0.5) × 100%

[0204] Table 4. Preliminary screening results of the antifungal activity of the target compounds [inhibition rate η (%)] (test concentration 50 μg / mL)

[0205]

[0206]

[0207] Table 4 shows the results of the antibacterial test on common agricultural fungi, from which the following conclusions can be drawn:

[0208] 1. 7-N / O acetylhydrazine coumarin compounds showed certain antifungal activity against common agricultural fungi, with some inhibition effects reaching 100%. Moreover, the inhibitory activity against some fungi was significantly higher than that of commercial pesticides (carbendazim, boscalid, and osthole).

[0209] 2. The mycelium growth rate method was used to determine that compounds 1-53 had significant inhibitory activity against rice sheath blight, apple spot pathogen, tomato early blight pathogen, cucumber anthracnose pathogen and strawberry gray mold pathogen. The inhibition rate of most compounds against rice sheath blight exceeded 80% at 50 μg / mL.

[0210] 3. Overall, when the substituent on the benzene ring of the hydrazine part is a halogen atom, it has a better antibacterial effect on rice sheath blight, apple spot pathogen, tomato early blight pathogen, cucumber anthracnose pathogen and strawberry gray mold pathogen.

[0211] 4. By comparing the activity results of Formula I and Formula II, the compound after N is replaced by O still has high antibacterial activity and the synthesis cost is reduced.

[0212] For compounds with an inhibition rate of more than 70% in the initial in vitro activity screening, the EC values ​​against the test pathogens were further determined at a concentration gradient of 10, 5, 2.5, 1.25, and 0.625 μg / mL. 50 The data were calculated using the DPS data processing system, EC 50 The values ​​are shown in Table 5-10.

[0213] Table 5. EC inhibition activity of some compounds against Rhizoctonia solani 50 (μg / mL) results

[0214]

[0215]

[0216] Table 6. Antifungal activity of some compounds against strawberry gray mold EC50 (μg / mL) results

[0217]

[0218] Table 7. Antifungal activity of some compounds against tomato early blight pathogen EC 50 (μg / mL) results

[0219]

[0220]

[0221] Table 8. Antifungal activity of some compounds against wheat scab pathogen EC 50 (μg / mL) results

[0222]

[0223] Table 9. Antibacterial activity of some compounds against cucumber anthracnose pathogen EC 50 (μg / mL) results

[0224]

[0225] Table 10. Antibacterial activity of some compounds against apple leaf spot pathogen EC 50 (μg / mL) results

[0226]

[0227]

[0228] Tables 5-10 show the test results for common agricultural fungi, from which we can draw the following conclusions:

[0229] 1. The introduction of electron-withdrawing groups at the R1 position of coumarin is beneficial to the improvement of the inhibitory activity of the compound against rice sheath blight. For example, the EC of compound 25 (R1 = CF3, R' = 4-F) against rice sheath blight is 50 The value was 0.36 μg / mL, compound 15 (R1=Me, R′=4-F; anti-R.solani EC 50 value = 1.06 μg / mL).

[0230] 2. The introduction of electron-withdrawing groups at the benzene ring of the hydrazide fragment is beneficial to the improvement of the inhibitory activity of the compound against rice sheath blight. For example, the EC of compound 23-29 (R1 = CF3, R' = 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 2-Br) against rice sheath blight is 50The values ​​were 0.49, 1.26, 0.36, 0.43, 0.60, and 0.40 μg / mL, respectively, which were superior to compound 31 (R1=CF3; R'=4-OMe anti-R.solani EC 50 value = 3.70 μg / mL).

[0231] Example 4 Detection of herbicidal activity of target compound

[0232] Four common field weeds—barnyard grass (Echinochloa crus-galli), crabgrass (Digitaria sanguinalis (L.) Scop.), velvetleaf (Abutilon theophrasti Medicus), and amaranthus retroflexus (Amaranthus retroflexus L.)—were selected for preliminary screening of target compounds for herbicidal activity using the small cup method. Clethodim and acifluorfen, commonly used commercial herbicides for controlling these weeds, were used as control agents.

[0233] Experimental methods:

[0234] The weed seeds for testing (including barnyard grass, crabgrass, velvet, and Amaranthus retroflexus) were evenly sown in small flower pots filled with culture soil. The culture soil ratio was matrix soil: black soil: foamed coconut brick = 1:1:1, and the flower pot size was 10 × 10 cm. 10 seeds of velvet were sown per pot, and 15 seeds were sown per pot for the other weeds. When the weeds grew to the 3-leaf stage, 5 weed seedlings with consistent growth were retained in each pot for standby use. The target compound to be tested, commercial herbicides clethodim and trifluorfen prepared by the present invention were dissolved in 0.1 mL of DMSO respectively and diluted to a concentration of 100 mg / L with a Tween-80 aqueous solution (0.1% v / v) for standby use. The weed seedlings for testing were placed on a conveyor belt (conveyor belt speed was 10 m / min) for application. A fan nozzle (DL-5) was used, the spray pressure was set to 0.4 MPa, the spray radiation range was 0.6 m, the flow rate was 0.54 L / min, the application liquid volume per hectare was 900 L, and the active ingredient dosage was 90 g / ha. A Tween-80 aqueous solution (0.1% v / v) was used for the blank control group. Each treatment was repeated twice. After the application, the test weeds were placed in a greenhouse for routine management and provided with natural light. After 14 days of cultivation, ineffective or poorly effective treatments were eliminated by visual inspection. The above-ground parts of the remaining treatment samples were cut and weighed for fresh weight to calculate the fresh weight control efficacy.

[0235] The calculation formula is as follows:

[0236]

[0237] Where: Cw is the fresh weight of control weeds; Pw is the fresh weight of treated weeds.

[0238] Table 11. Control efficacy of some target compounds at 100 μg / mL concentration against four weeds (90 g / ha)

[0239]

[0240]

[0241] From Table 11 and Figures 1 to 4 The test results of common field weeds can draw the following conclusions:

[0242] 1. At a concentration of 100 μg / mL, some compounds showed certain inhibitory activity against the dicotyledonous weeds Amaranthus retroflexus and Abelmoschus velvetleaf.

[0243] 2. Based on the control effect of the compounds on Amaranthus retroflexus, substituting halogen atoms on the benzene ring of the hydrazine moiety has a better control effect. Substituents on the coumarin ring have the least effect on activity.

[0244] 3. At a concentration of 100 μg / mL, the control efficacy of compound 22 on the dicotyledonous weeds Amaranthus retroflexus and Avicennia velvet was comparable to that of the control drug acifluorfen, both being 100%.

[0245] 4. At a concentration of 100 μg / mL, compound 43 had a better control effect on the monocotyledonous weed Digitaria tangutica than the control drug Clethodim, with a control effect of 100%.

Claims

1. 7-N / O acetylhydrazine coumarin compounds, the structure of the compound is shown in Formula III: ， in, R1 is selected from Me, Et, Pr or CF3; R2 is selected from H or Cl; R3 is selected from H or Me; R′ is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-CH3O, 3-CH3O, 4-CH3O, 3,4-diCH3, 2,3-diCl, 2,4-diCl, 2,5-diCl, 2,6-diCl, 3,4-diCl, 3,5-diCl, 2,3,6-trCl, 2,4-diF or 3,4-diF; X is selected from N or O.

2. The novel coumarin compound of 7-N / O acetylhydrazine according to claim 1, wherein the structure of the compound is as shown in Formula I: ， in, R1 is selected from Me, Et, Pr, CF3; R′ is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-CH3O, 3-CH3O, 4-CH3O, 3,4-diCH3, 2,3-diCl, 2,4-diCl, 2,5-diCl, 2,6-diCl, 3,4-diCl, 3,5-diCl, 2,3,6-trCl, 2,4,6-trCl, 2,4-diF, 3,4-diF or 4-CF3.

3. The novel coumarin compound of 7-N / O acetylhydrazine according to claim 2, wherein R' is selected from 2-F, 3-F, 4-F, 2-Cl, 4-Cl or 4-CF3.

4. The novel coumarin compound of 7-N / O acetylhydrazine according to claim 1, wherein the structure of the compound is shown in Formula II: , R1 is selected from Me, CF3; R2 is selected from H, Cl; R3 is selected from H, Me; R′ is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-CH3O, 3-CH3O, 4-CH3O, 3,4-diCH3, 2,3-diCl, 2,4-diCl, 2,5-diCl, 2,6-diCl, 3,4-diCl, 3,5-diCl, 2,3,6-trCl, 2,4-diF or 3,4-diF.

5. The novel coumarin compound of 7-N / O acetylhydrazide according to claim 4, wherein R′ is selected from 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 2-Br, 4-Br, 4-CH3O, and 3,4-diCH3.

6. The method for preparing the coumarin compound of 7-N / O acetylhydrazine according to claim 2, characterized in that: The method for preparing the coumarin compound of 7-N acetylhydrazine comprises the following steps: (1) Using 3-aminophenol as a raw material, ethyl acetate EA, sodium bicarbonate and phenyl chloroformate are added in sequence to prepare N-(3-hydroxyphenyl)phenyl carbamate; (2) N-(3-hydroxyphenyl)carbamic acid phenyl ester is added to concentrated sulfuric acid solution, followed by the addition of β-ketoester to prepare substituted coumarin amino acid phenyl ester; (3) adding potassium hydroxide solution to the substituted coumarin amino acid phenyl ester, dissolving and stirring, and then heating and stirring to react to obtain the intermediate substituted 7-aminocoumarin; (4) Adding acetonitrile solution to substituted 7-aminocoumarin, N,N-diisopropylethylamine (DIEA), and sodium iodide to dissolve them, and then adding ethyl bromoacetate dropwise in a reactor to react to prepare the intermediate ethyl 2-((2-azolo-4-(substituted)-2H-coumarin-7-yl)amino)acetate; (5) Dissolving the intermediate ethyl 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetate in ethanol, adding sodium hydroxide solution, stirring at room temperature, and monitoring the reaction progress by TLC. After the reaction is complete, adjusting the pH value of the aqueous phase to prepare the intermediate 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid; (6) Acetonitrile solution was added to the intermediate 2-((2-nitro-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid and substituted phenylhydrazine to fully dissolve them, and then O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate was added, followed by dropwise addition of triethylamine. The reaction was stirred at room temperature and the reaction progress was monitored by TLC to prepare a series of target compounds 7-N-acetylhydrazine coumarin.

7. The method for preparing the coumarin compound of 7-N / O acetylhydrazine according to claim 4, characterized in that: The method for preparing the coumarin compound of 7-O acetylhydrazine comprises the following steps: (1) Using substituted meta-diphenol as a raw material, concentrated sulfuric acid ethanol solution and β-ketoester are added in sequence to react and prepare substituted 7-hydroxycoumarin; (2) Adding acetonitrile solution to substituted 7-hydroxycoumarin, N,N-diisopropylethylamine (DIEA) and sodium iodide to dissolve them, and then adding ethyl bromoacetate dropwise in a reactor to react to prepare the intermediate ethyl 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetate; (3) dissolving ethyl 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetate in ethanol, adding sodium hydroxide solution, stirring at room temperature, and monitoring the reaction progress by TLC. After the reaction is complete, adjusting the pH value of the aqueous phase to prepare the intermediate 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid; (4) Acetonitrile solution was added to the intermediate 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid and substituted phenylhydrazine to fully dissolve them, and then O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate was added, followed by dropwise addition of triethylamine. The reaction was stirred at room temperature and the reaction progress was monitored by TLC to prepare a series of target compounds 7-O acetylhydrazine coumarin.

8. The preparation method according to claim 6, characterized in that The molar ratio of the 3-aminophenol to phenyl chloroformate is 1:1-3.

9. The preparation method according to claim 6, characterized in that The molar ratio of the N-(3-hydroxyphenyl)phenyl carbamate to the β-ketoester is 1:0.8-3; the molar ratio of the substituted 7-aminocoumarin to sodium iodide and ethyl bromoacetate is 1:1-3:1-3; the molar ratio of the 2-((2-azino-4-(substituted)-2H-coumarin-7-yl)amino)acetic acid to substituted phenylhydrazine, O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate and triethylamine is 1:1-2.5:1-2.5:1-2.

5.

10. The preparation method according to claim 7, characterized in that The molar ratio of the substituted meta-diphenol to the β-keto ester is 1:0.8-3; the molar ratio of the substituted 7-hydroxycoumarin to sodium iodide and ethyl bromoacetate is 1:1-3:1-3; the molar ratio of the 2-((2-oxo-4-(substituted)-2H-coumarin-7-yl)oxy)acetic acid to substituted phenylhydrazine, O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroboric acid and triethylamine is 1:1-2.5:1-2.5:1-2.

5.

11. Use of the coumarin compound of 7-N / O acetylhydrazine according to any one of claims 1 to 5 in the preparation of a product for inhibiting or killing pathogens, characterized in that: The pathogen is a crop pathogenic fungus, and the crop pathogenic fungus is one or more of rice sheath blight (Rhizoctonia solani), strawberry gray mold (Botrytis cinerea), wheat head blight (Fusarium graminearum), tomato early blight (Altemaria solani), cucumber anthracnose (Colletotrichum orbiculare) or apple spot (Alternaria alternata). 12.7-N / O acetylhydrazine coumarin compound for use in weed control, characterized in that: The weeds are one or more of barnyard grass (Echinochloa crus-galli), crabgrass (Digitaria sanguinalis (L.) Scop.), velvetleaf (Abutilontheophrasti Medicus) or amaranth (Amaranthus retroflexus L.); the structural formula of the coumarin compound of 7-N / O acetic hydrazide is: 。

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