A flavonol derivative containing an acylhydrazine active fragment and its application

Abstract

This invention discloses a flavonol derivative containing an acylhydrazine active fragment and its application. The derivative has good antibacterial effects against rice sheath blight, cucumber anthracnose, strawberry gray mold, wheat scab, apple rot, apple spot, apple rot and tomato early blight. It can be used to control plant fungal diseases, and the raw materials for synthesis are low cost and the synthesis method is simple.

Description

Technical Field

[0001] This invention relates to the field of pesticides, and more specifically to a flavonol derivative containing an acylhydrazine active fragment and its application. Background Technology

[0002] The control and suppression of plant pathogens is an important area of ​​pesticide research. Chemical control remains the primary method for preventing the spread and outbreaks of plant pathogenic fungi in agriculture, and the widespread use of fungicides has effectively controlled most plant pathogens. However, with the continuous expansion of fungicide use, plant pathogens have developed resistance to traditional fungicides. At the same time, the high toxicity of existing fungicides to non-target organisms and their serious environmental pollution have greatly limited their application in production. Therefore, the development of novel fungicides that are highly efficient, specific to target organisms, and environmentally friendly is of great importance and significance for ensuring increased and stable agricultural yields and food security.

[0003] Flavonol skeletons are widely found in natural products and bioactive molecules, with the highest concentrations in the flowers and leaves of dicotyledonous plants. These structures are extensively used in drug development. The physiological activities of flavonoids mainly include antitumor, antioxidant, anti-inflammatory, antiviral, antithrombotic, and vasodilatory effects.

[0004] Flavonoids possess broad-spectrum bactericidal effects, and their effectiveness against pathogenic fungi has also been initially demonstrated. However, the current efficacy of flavonoids against pathogenic fungi is limited. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the first objective of the present invention is to provide a class of flavonol derivatives containing acylhydrazine active fragments.

[0006] A second object of the present invention is to provide uses for the above-mentioned derivatives. The flavonol derivatives of the present invention containing hydrazide active fragments exhibit highly efficient and broad-spectrum activity against plant pathogenic fungi.

[0007] The technical solution adopted by this invention to solve its technical problem is:

[0008] In a first aspect, the present invention provides a flavonol derivative having an acylhydrazine-containing active fragment as shown in general formula (I), or a pharmaceutically acceptable salt, solvate, optical isomer, or polymorph thereof:

[0009]

[0010] R1 is selected from hydrogen atom or alkoxy group; R2 is selected from halogen, halogen-substituted C1-C3 alkyl, C1-C6 alkyl, or alkoxy group.

[0011] In the specific implementation scheme, R1 is selected from hydrogen atom and methoxy group; R2 is selected from halogen, trifluoromethyl, methyl, methoxy group and tert-butyl group.

[0012] In a specific implementation scheme, R1 is selected from hydrogen atom, methoxy, ethoxy or propoxy; R2 is selected from halogen, fluorine-substituted methyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy or tert-butyl.

[0013] In a specific implementation scheme, R1 is selected from hydrogen atom or methoxy group; R2 is selected from fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxy, or tert-butyl.

[0014] In the specific implementation plan, R1 is selected from hydrogen atoms and methoxy groups; R 2 It is selected from 4-methyl, 2-methyl, 2-fluoro, 2-trifluoromethyl, 2,4-difluoro, 2-chloro, 3-chloro, 2,4-dichloro, 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, 4-methoxy, 3-methoxy, or 4-tert-butyl.

[0015] In specific embodiments, the present invention also protects the following flavonol derivatives containing hydrazide active fragments, or pharmaceutically acceptable salts, solvates, optical isomers, or polymorphs thereof:

[0016]

[0017]

[0018]

[0019]

[0020]

[0021] In a second aspect, the present invention provides a method for preparing a flavonol derivative containing an acylhydrazine active fragment as shown in formula (I), or a pharmaceutically acceptable salt, solvate, optical isomer, or polymorph thereof, wherein a substituted flavonol carboxylic acid (II) and a substituted phenylhydrazine react at room temperature in the presence of triethylamine (Et3N), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (TBTU), and dichloromethane (DCM) to generate the flavonol derivative (I) containing an acylhydrazine active fragment:

[0022]

[0023] Among the above structural formulas:

[0024] Both R1 and R2 have the definitions of the corresponding groups as described above.

[0025] Thirdly, the present invention provides the use of flavonol derivatives containing hydrazide active fragments of formula (I), or pharmaceutically acceptable salts, solvates, optical isomers or polymorphs thereof, in the prevention and control of plant fungal diseases.

[0026] This invention reveals that these derivatives exhibit significant inhibitory activity against plant pathogenic fungi and can be applied to inhibit plant pathogenic fungi and prevent plant fungal diseases.

[0027] Fourthly, the present invention provides the use of flavonol derivatives containing hydrazide active fragments of formula (I), or pharmaceutically acceptable salts, solvates, optical isomers or polymorphs thereof, in the preparation of reagents for the prevention and control of plant fungal diseases.

[0028] In specific implementation schemes, the fungi are rice sheath blight fungus, cucumber anthracnose fungus, tomato early blight fungus, wheat scab fungus, apple spot fungus, apple rot fungus, and / or strawberry gray mold fungus, etc.

[0029] In the specific implementation plan, the fungal diseases are rice sheath blight, cucumber anthracnose, tomato early blight, wheat scab, apple spot, apple rot, and / or strawberry gray mold, etc.

[0030] In a specific implementation plan, the plants are rice, cucumber, tomato, wheat, apple, strawberry, etc.

[0031] Fifthly, the present invention provides a reagent containing a flavonol derivative of formula (I) with an acylhydrazine active fragment as described above, or a pharmaceutically acceptable salt, solvate, optical isomer or polymorph thereof.

[0032] In a specific implementation plan, the reagent dosage form is selected from any one of emulsifiable concentrates, suspensions, wettable powders, powders, granules, aqueous solutions, poison baits, mother liquors, and mother powders.

[0033] Sixthly, the present invention provides the application of the reagents described above in the prevention and control of plant fungal diseases.

[0034] In specific implementation schemes, the fungi are rice sheath blight fungus, cucumber anthracnose fungus, tomato early blight fungus, wheat scab fungus, apple spot fungus, apple rot fungus, and / or strawberry gray mold fungus, etc.

[0035] In specific implementation plans, the fungal diseases include rice sheath blight, cucumber anthracnose, tomato early blight, wheat scab, apple spot, apple rot fungus, and / or strawberry gray mold, etc.

[0036] In a specific implementation plan, the plants are rice, cucumber, tomato, wheat, apple, strawberry, etc.

[0037] Beneficial effects

[0038] Compared with the prior art, this invention has significant advantages: It introduces hydrazide fragments, which are excellent active groups, into the structure of flavonols, and designs and synthesizes a series of flavonol derivatives (I) containing hydrazide active fragments. These compounds have novel structures. When applied to the resistance of plant pathogenic fungi, these compounds exhibit outstanding inhibitory activity against plant pathogenic fungi, demonstrating significant progress in this technical solution. Some of these compounds show inhibitory activity against rice sheath blight, strawberry gray mold, tomato early blight, and apple rot fungus exceeding that of the control agents carbendazim and cyprodinil, demonstrating significant application value. Detailed Implementation

[0039] The essential features of this invention are embodied in the following embodiments, but these should not be construed as limiting the invention in any way. Reagents or instruments used, unless otherwise specified, are considered to be conventional products that can be purchased commercially.

[0040] Preparation Examples

[0041] Example 1: Synthesis of 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)-N'-phenylacetylhydrazine (I1)

[0042] 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid (II-1) (2.0 mmol), triethylamine (2.0 mmol), and O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (2.4 mmol) were added to an 18 mL test tube, followed by dichloromethane (5.0 mL) and phenylhydrazine (2.0 mmol). The mixture was stirred at room temperature for 12 hours, after which the reaction was stopped. 20 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 10 mL), washed with saturated brine (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The mixture was then purified by silica gel column chromatography to obtain compound 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)-N'-phenylacetylhydrazine (I1).

[0043]

[0044] Example 2: Synthesis of N'-(4-fluorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I2) was the same as in Example 1, except that phenylhydrazine was replaced with 4-fluorophenylhydrazine.

[0045] Example 3: Synthesis of N'-(4-chlorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I3) was the same as in Example 1, except that phenylhydrazine was replaced with 4-chlorophenylhydrazine.

[0046] Example 4: Synthesis of N'-(4-methylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I4) was the same as in Example 1, except that phenylhydrazine was replaced with 4-methylphenylhydrazine.

[0047] Example 5: Synthesis of N'-(2-methylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I5) was the same as in Example 1, except that phenylhydrazine was replaced with 2-methylphenylhydrazine.

[0048] Example 6 Synthesis of N'-(2-fluorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I6) The synthesis was otherwise the same as in Example 1, except that phenylhydrazine was replaced with 2-fluorophenylhydrazine.

[0049] Example 7 Synthesis of N'-(2-trifluoromethylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I7)

[0050] The rest is the same as in Example 1, except that phenylhydrazine is replaced with 2-trifluoromethylphenylhydrazine.

[0051] Example 8 Synthesis of N'-(4-methoxyphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I8)

[0052] The rest is the same as in Example 1, except that phenylhydrazine is replaced with 4-methoxyphenylhydrazine.

[0053] Example 9 Synthesis of N'-(4-tert-butylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I9)

[0054] The rest is the same as in Example 1, except that phenylhydrazine is replaced with 4-tert-butylphenylhydrazine.

[0055] Example 10 Synthesis of N'-(2,4-difluorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I10)

[0056] The rest is the same as in Example 1, except that phenylhydrazine is replaced with 2,4-difluorophenylhydrazine.

[0057] Example 11 Synthesis of N'-(4-trifluoromethylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I11)

[0058] The rest is the same as in Example 1, except that phenylhydrazine is replaced with 4-trifluoromethylphenylhydrazine.

[0059] Example 12: Synthesis of N'-(3-chlorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I12) was the same as in Example 1, except that phenylhydrazine was replaced with 3-chlorophenylhydrazine.

[0060] Example 13: Synthesis of N'-(2-chlorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I13) was the same as in Example 1, except that phenylhydrazine was replaced with 2-chlorophenylhydrazine.

[0061] Example 14 Synthesis of N'-(2,4-dichlorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I14)

[0062] The rest is the same as in Example 1, except that phenylhydrazine is replaced with 2,4-dichlorophenylhydrazine.

[0063] Example 15 Synthesis of N'-(3-methoxyphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I15)

[0064] The rest is the same as in Example 1, except that phenylhydrazine is replaced with 3-methoxyphenylhydrazine.

[0065] Example 16 The synthesis of N'-(4-bromophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I16) is the same as in Example 1, except that phenylhydrazine is replaced with 4-bromophenylhydrazine.

[0066] Example 17 Synthesis of 2-((2-(2-methoxyphenyl)-4-oxo-4H-benzopyran-3-yl)oxy)-N'-phenylacetylhydrazine (I17)

[0067] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid.

[0068] Example 18 Synthesis of N'-(4-methoxyphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I18)

[0069] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 4-methoxyphenylhydrazine.

[0070] Example 19 Synthesis of N'-(4-fluorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I19)

[0071] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 4-fluorophenylhydrazine.

[0072] Example 20 Synthesis of N'-(2,4-difluorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I20)

[0073] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 2,4-difluorophenylhydrazine.

[0074] Example 21 Synthesis of N'-(4-methylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I21)

[0075] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 4-methylphenylhydrazine.

[0076] Example 22 Synthesis of N'-(4-tert-butylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I22)

[0077] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 4-tert-butylphenylhydrazine.

[0078] Example 23 Synthesis of N'-(2-chlorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I23)

[0079] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 2-chlorophenylhydrazine.

[0080] Example 24 Synthesis of N'-(4-chlorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I24)

[0081] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 4-chlorophenylhydrazine.

[0082] Example 25 Synthesis of N'-(4-trifluoromethylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I25)

[0083] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 4-trifluoromethylphenylhydrazine.

[0084] Example 26 Synthesis of N'-(2-methylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I26)

[0085] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 2-methylphenylhydrazine.

[0086] Example 27 Synthesis of N'-(2-fluorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I27)

[0087] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 2-fluorophenylhydrazine.

[0088] Example 28 Synthesis of N'-(3-chlorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I28)

[0089] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 3-chlorophenylhydrazine.

[0090] Example 29 Synthesis of N'-(2,4-dichlorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I29)

[0091] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 2,4-dichlorophenylhydrazine.

[0092] Example 30 Synthesis of N'-(2-trifluoromethylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I30)

[0093] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 2-trifluoromethylphenylhydrazine.

[0094] Example 31 Synthesis of N'-(3-methoxyphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I31)

[0095] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 3-methoxyphenylhydrazine.

[0096] Example 32 Synthesis of N'-(4-bromophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I32)

[0097] The rest is the same as in Example 1, except that 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetic acid is replaced with 2-((4-oxo-2-(2-methoxyphenyl)-4H-benzopyran-3-yl)oxy)acetic acid, and phenylhydrazine is replaced with 4-bromophenylhydrazine.

[0098] Compounds I2-I32 were synthesized sequentially according to the method in Example 1. The structures of the synthesized flavonol derivatives (I1-I32) containing the hydrazide active fragment were confirmed by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The physicochemical parameters and spectral data of the target compounds are shown below:

[0099] 2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)-N'-phenylacetylhydrazine (I1): white solid, yield 91.5%, melting point 184.8-185.2℃; 1 H NMR (500MHz, CDCl3) δ10.32 (s, 1H), 8.30 (dd, J = 8.0, 1.7Hz, 1H), 8.05 (m, 2H), 7.76 (m, 1 H),7.63–7.56(m,4H),7.48(m,1H),7.26–7.20(m,1H),7.03–6.85(m,3H),4.43(s,2H); 13 C NMR (125MHz, CDCl3) δ175.5,168.5,157.0,155.5,147.9,141.1,134.3,131.6,130.0,12 9.1,129.0,128.5,126.0,125.4,123.7,121.1,118.2,113.9,72.8; HRMS(ESI)m / z[M+H] + Calcd.For C 23 H 19 N2O4:387.1345, Found:387.1342.

[0100] N'-(4-fluorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I2): white solid, yield 93.2%, melting point 188.7-190.1℃; 1H NMR(500MHz, CDCl3)δ10.39(s,1H),8.30(dd,J=8.1,1.7Hz,1H),8.07–8.00(m,2 H),7.76(m,1H),7.63–7.56(m,4H),7.48(m,1H),6.98–6.89(m,4H),4.41(s,2H); 13 C NMR (125MHz, CDCl3) δ175.5, 168.6, 157.9 (d, J = 238.5Hz), 157.0, 155.5, 144.0 (d, J = 1.25Hz), 141.1, 134. 3,131.6,129.9,129.1,128.5,125.9,125.4,123.6,118.2,115.6(d,J=22.6Hz),115.3(d,J=7.8Hz),72.8; 19 F NMR(470MHz, CDCl3)δ-123.6; HRMS(ESI)m / z[M+H] + Calcd.For C 23 H 17 FN2O4:405.1251,Found:405.1247.

[0101] 3-Amino-6-(4-methoxyphenyl)-5-phenylpyrazine-2-carboxynitrile (I3): yellow solid, yield 64%, melting point 204-205℃; 1 H NMR (400MHz, CDCl3) δ7.46–7.39(m,2H),7.38–7.35(m,1H),7.34–7.29(m,2H),7.28–7.23(m,2H),6.80(d,J=8.8Hz,2H),5.27(s,2H),3.80(s,3H). 13 C NMR (100MHz, CDCl3)δ

[0102] 159.7,154.2,153.7,144.3,137.6,130.6,129.7,129.6,129.5,128.3,115.6,113.7,110.5,55.2; HRMS(ESI-TOF)m / z:[M+H] + calcd for C 18 H 15 N4O 303.1240, found 303.1246.

[0103] N'-(4-methylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I4): white solid, yield 95.3%, melting point 192.0-192.9℃; 1 H NMR(500MHz, CDCl3)δ10.25(s,1H),8.29(dd,J=8.0,1.7Hz,1H),8.10–7.98(m,2H),7.75(m,1H),7.63– 7.55(m,4H),7.49–7.43(m,1H),7.04(d,J=8.1Hz,2H),6.86(d,J=8.4Hz,2H),4.42(s,2H),2.26(s,3H). 13 C NMR (125MHz, CDCl3)δ

[0104] 175.4,168.4,156.9,155.4,145.5,141.0,134.2,131.6,130.5,130.0,129.6,1 29.0,128.4,126.0,125.3,123.6,118.2,114.1,72.7,20.6.HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 21 N2O4:401.1501, Found:401.1500.

[0105] N'-(2-methylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I5): white solid, yield 88.6%, melting point 189.2-189.7℃; 1 H NMR (500MHz, CDCl3) δ10.34(s,1H),8.29(dd,J=8.0,1.7Hz,1H),8.05(dd,J=6.7,3.0Hz,2H),7.76(m,1H),7.62–7.56(m,4H) ,7.50–7.45(m,1H),7.13(m,1H),7.08(d,J=7.3Hz,1H),6.99(dd,J=8.0,1.2Hz,1H),6.84(m,1H),4.44(s,2H),2.29(s,3H); 13C NMR (125MHz, CDCl3) δ175.5,168.1,157.0,155.5,145.6,141.1,134.3,131.6,130.3,130.0,129. 1,128.5,126.9,126.0,125.3,123.6,123.3,120.8,118.2,112.4,72.8,17.1; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 21 N2O4:401.1501, Found:401.1499.

[0106] N'-(2-fluorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I6): white solid, yield 82.6%, melting point 179.8-180.5℃; 1 H NMR(500MHz, CDCl3)δ10.38(s,1H),8.29(dd,J=8.0,1.7Hz,1H),8.08–8.02(m,2H),7.76(m,1 H),7.64–7.55(m,4H),7.48(m,1H),7.10–6.97(m,3H),6.83(m,1H),6.33(s,1H),4.42(s,2H); 13 C NMR (125MHz, CDCl3) δ175.5,168.6,157.0,155.5,151.5(d,J=240.8Hz),141.1,136.0(d,J=10.7Hz),134.3,131.6,129.9,129 .1,128.5,125.9,125.4,124.4(d,J=3.6Hz),123.6,120.9(d,J=7.0Hz),118.2,115.0(d,J=18.0Hz),114.7(d,J=1.3Hz),72.8; 19 F NMR(470MHz, CDCl3)δ-133.7; HRMS(ESI)m / z[M+H] + Calcd.For C 23 H 18 FN2O4:405.1251,Found:405.1247.

[0107] N'-(2-trifluoromethylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I7): white solid, yield 86.5%, melting point 159.1-159.9℃;1 H NMR(500MHz, CDCl3)δ10.43(s,1H),8.29(dd,J=8.0,1.6Hz,1H),8.07–8.04(m,2H),7.79–7.75(m,1H),7.63–7.58(m ,4H),7.53–7.46(m,2H),7.45–7.40(m,1H),7.19(d,J=8.3Hz,1H),6.94(t,J=7.6Hz,1H),6.67(s,1H),4.44(s,2H); 13 C NMR (125MHz, CDCl3) δ175.59,168.57,157.10,155.48,152.92(d,J=3.1Hz),145.56,141.14,134.37,133.08,131.7,129 .92,129.08,128.47,126.5(q,J=5.0Hz),125.93,125.44,123.58,119.93,118.24,114.79(d,J=30.5Hz),113.62,72.86; 19 FNMR(470MHz, CDCl3)δ-61.5; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 18 F3N2O4:455.1219,Found:455.1216.

[0108] N'-(4-methoxyphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I8): white solid, yield 90.2%, melting point 157.7-158.2℃; 1 H NMR (500MHz, CDCl3) δ10.25 (s, 1H), 8.28 (d, J = 8.1Hz, 1H), 8.02 (m, 2H), 7.73 (m, 1H), 7.62– 7.53(m,4H),7.45(m,1H),6.95–6.89(m,2H),6.85–6.76(m,2H),4.41(s,2H),3.74(s,3H); 13 C NMR (125MHz, CDCl3) δ175.4,168.4,156.9,155.4,154.5,141.5,141.0,134.2,131.5,130. 0,129.0,128.4,125.9,125.3,123.6,118.1,115.7,114.5,72.6,55.6; HRMS(ESI)m / z[M+H]+ Calcd.For C 24 H 21 N2O5: 417.1450, Found: 417.1447.

[0109] N'-(4-tert-butylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I9): white solid, yield 96.0%, melting point 149.0-149.8℃; 1 H NMR(500MHz, CDCl3)δ10.23(s,1H),8.28(dd,J=8.2,1.6Hz,1H),8.03(m,2H),7.74(m,1H),7.60–7.5 4(m,4H),7.48–7.43(m,1H),7.25(d,J=8.5Hz,2H),6.88(d,J=8.5Hz,2H),4.41(s,2H),1.27(s,9H); 13 C NMR (125MHz, CDCl3) δ175.4,168.3,156.9,155.4,145.4,143.9,141.0,134.2,131.6,130.0,1 29.0,128.4,126.0,125.9,125.3,123.6,118.2,113.6,72.7,34.0,31.4; HRMS(ESI)m / z[M+H] + Calcd.For C 27 H 27 N2O4: 443.1971, Found: 443.1969.

[0110] N'-(2,4-difluorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I10): yellow solid, yield 83.7%, melting point 203.8-204.6℃; 1 H NMR (500MHz, CDCl3) δ10.42 (s, 1H), 8.29 (d, J = 8.0Hz, 1H), 8.05–8.02 (m, 2H), 7.76 (m, 1H), 7.63–7.55(m,4H),7.48(m,1H),7.02(m,1H),6.86–6.73(m,2H),6.26(s,1H),4.40(s,2H); 13C NMR (125MHz, CDCl3) δ175.6,168.8,157.1,156.8(dd,J=241.1,11.0Hz),155.5,151.4(dd,J=242.5,11.3Hz),141.1,134.4,132.5(dd,J=10.8,3.2H z),131.7,129.9,129.1,128.5,125.9,125.4,123.6,118.2,115.5(dd,J= 9.1, 3.5Hz), 110.9 (dd, J = 22.0, 3.5Hz), 103.8 (dd, J = 26.7, 22.3Hz), 72.8; 19 F NMR(470MHz, CDCl3)δ-120.8,129.4; HRMS(ESI)m / z[M+H] + Calcd.ForC 23 H 17 F2N2O4:423.1156,Found:423.1154.

[0111] N'-(4-trifluoromethylphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I11): white solid, yield 78.1%, melting point 221.7-222.4℃; 1 H NMR (500MHz, DMSO-d6) δ10.22(s,1H),8.46(s,1H),8.25–8.13(m,3H),7.86(t,J=7.8Hz,1H),7.79(d,J=8.5Hz, 1H),7.61(t,J=3.7Hz,3H),7.53(t,J=7.8Hz,1H),7.44(d,J=8.3Hz,2H),6.85(s,1H),6.84(s,1H),4.74(s,2H). 13 C NMR(125MHz,DMSO-d6)δ173.9,167.8,155.1,154.8,152.3,139.3,134.4,131.1,130.3,128.7,128.712 6.1(q,J=3.8Hz),125.3,125.1(q,J=268.8Hz),125.0,123.4,118.5,118.3(d,J=31.8Hz),111.5,69.7. 19 F NMR(470MHz,DMSO-d6)δ-59.2; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 18F3N2O4:455.1219,Found:455.1216.

[0112] N'-(3-chlorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I12): white solid, yield 86.1%, melting point 160.5-161.1℃; 1 H NMR(500MHz, CDCl3)δ10.41(s,1H),8.29(dd,J=8.1,1.7Hz,1H),8.09–7.99(m,2H),7.76(m,1H),7.62–7.56(m,4H),7.47( m,1H),7.13(t,J=8.0Hz,1H),6.92(t,J=2.1Hz,1H),6.85(dd,J=7.9,2.0Hz,1H),6.80(dd,J=8.2,2.2Hz,1H),4.42(s,2H); 13 C NMR (125MHz, CDCl3) δ175.5,168.8,157.0,155.4,149.2,141.1,134.9,134.3,131.7,130.1,12 9.9,129.1,128.4,126.0,125.4,123.6,121.0,118.2,113.7,112.0,72.8; HRMS(ESI)m / z[M+H] + Calcd.For C 23 H 18 ClN2O4:421.0955,Found:421.0952.

[0113] N'-(2-chlorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I13): white solid, yield 90.8%, melting point 196.3-197.0℃; 1 H NMR(500MHz, CDCl3)δ10.40(s,1H),8.29(dd,J=8.0,1.7Hz,1H),8.08–8.02(m,2H),7.76(m,1H),7.63–7.56(m,4H),7.47(td,J=7.5,1.1H z,1H),7.30–7.25(m,1H),7.16(td,J=7.8,1.5Hz,1H),7.04(dd,J=8.1,1.6Hz,1H),6.82(td,J=7.7,1.6Hz,1H),6.54(s,1H),4.43(s,2H); 13C NMR (125MHz, CDCl3) δ175.5,168.5,157.0,155.5,143.8,141.1,134.3,131.6,129.9,129.3,12 9.1,128.5,127.6,125.9,125.4,123.6,121.1,119.5,118.2,113.7,72.9; HRMS(ESI)m / z[M+H] + Calcd.ForC 23 H 18 ClN2O4:421.0955,Found:421.0952.

[0114] N'-(2,4-dichlorophenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I14): white solid, yield 76.5%, melting point 232.5-234.2℃; 1 H NMR (500MHz, DMSO-d6) δ10.23(s,1H),8.17(m,,3H),7.87(m,1H),7.80(d,J=8.4Hz,1H),7.70(d,J=1.8Hz,1H),7.61(dt,J= 5.8,2.9Hz,3H),7.57–7.52(m,1H),7.41(d,J=2.3Hz,1H),7.17(dd,J=8.7,2.4Hz,1H),6.81(d,J=8.8Hz,1H),4.73(s,2H); 13 C NMR (125MHz, DMSO-d6) δ173.9,167.8,155.2,154.8,143.8,139.3,134.4,131.2,130.3,128. 7,128.5,127.6,125.4,125.1,123.4,122.0,118.6,117.7,114.0,69.7; HRMS(ESI)m / z[M+H] + Calcd.For C 23 H 17 Cl2N2O4:455.0565,Found:455.0562.

[0115] N'-(3-methoxyphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I15): yellow solid, yield 89.5%, melting point 162.5-163.2℃; 1H NMR(500MHz, CDCl3)δ10.27(s,1H),8.29(dd,J=8.1,1.7Hz,1H),8.11–8.00(m,2H),7.81–7.74(m,1H),7.6 0–7.55(m,4H),7.46(d,J=1.1Hz,1H),7.11(t,J=7.6Hz,1H),6.84–6.63(m,3H),4.43(s,2H),2.28(s,3H); 13 CNMR (125MHz, CDCl3) δ175.4,168.4,156.8,155.4,147.8,141.0,138.9,134.2,131.6,130.0,129. 0,128.9,128.4,125.9,125.3,123.6,122.0,118.2,114.5,111.0,72.7,21.5; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 21 N2O5: 417.1450, Found: 417.1447.

[0116] N'-(3-methoxyphenyl)-2-((4-oxo-2-phenyl-4H-benzopyran-3-yl)oxy)acetylhydrazine (I16): white solid, yield 93.8%, melting point 205.2-206.3℃; 1 H NMR(500MHz,DMSO-d6)δ10.10(d,J=2.1Hz,1H),8.22–8.11(m,3H),8.01(d,J=2.6Hz,1H),7.91–7.81(m ,1H),7.79(d,J=8.3Hz,1H),7.64–7.49(m,4H),7.29–7.24(m,2H),6.69(d,J=8.8Hz,2H),4.71(s,2H); 13 CNMR(125MHz,DMSO-d6)δ173.9,167.7,155.1,154.8,148.5,139.3,134.4,131.3,131.1, 130.3,128.7,128.7,125.3,125.0,123.4,118.5,114.2,109.3,69.7; HRMS(ESI)m / z[M+H] + Calcd.For C 23 H 18 BrN2O4:465.0450,Found:465.0449.

[0117] 2-((2-(2-methoxyphenyl)-4-oxo-4H-benzopyran-3-yl)oxy)-N'-phenylacetylhydrazine (I17): yellow solid, yield 92.6%, melting point 135.6-136.5℃; 1 H NMR(500MHz, CDCl3)δ9.73(s,1H),8.31(dd,J=8.1,1.7Hz,1H),7.72(m,1H),7.60–7.47(m,3H),7.45(td,J=7.6,7.1,1.1Hz,1H),7 .20(dd,J=8.6,7.3Hz,2H),7.13(t,J=7.5Hz,1H),7.08(d,J=8.4Hz,1H),6.93–6.80(m,3H),6.13(s,1H),4.43(s,2H),3.86(s,3H); 13 C NMR (125MHz, CDCl3) δ175.0,168.7,157.1,156.9,155.9,147.8,141.6,133.9,132.7,130.5,129. 0,125.9,125.1,124.0,121.0,120.8,119.1,118.3,113.7,111.6,72.6,55.8; HRMS(ESI)m / z[M+H] + Calcd.ForC 24 H 21 N2O5: 417.1450, Found: 417.1447.

[0118] N'-(4-methoxyphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I18): yellow solid, yield 90.5%, melting point 152.4-152.9℃; 1 H NMR(500MHz, CDCl3)δ9.69(s,1H),8.30(dd,J=8.0,1.6Hz,1H),7.71(m,1H),7.57–7.48(m,3H),7.47–7.42(m,1H),7.1 2(td,J=7.4,1.0Hz,1H),7.07(d,J=8.4Hz,1H),6.85–6.75(m,4H),6.03(s,1H),4.42(s,2H),3.85(s,3H),3.74(s,3H); 13C NMR (125MHz, CDCl3) δ175.0,168.6,157.1,156.8,155.9,154.5,141.6,141.5,133.9,132.7,130.5,1 25.9,125.0,124.0,120.8,119.1,118.3,115.6,114.4,111.5,72.6,55.7,55.6; HRMS(ESI)m / z[M+H] + Calcd.For C 25 H 23 N2O6:447.1556, Found:447.1557.

[0119] N'-(4-fluorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I19): white solid, yield 80.7%, melting point 127.7-128.8℃; 1 H NMR (500MHz, CDCl3) δ9.84 (s, 1H), 8.30 (d, J = 8.0Hz, 1H), 7.72 (t, J = 7.9Hz, 1H), 7.53 (dt, J = 18.9, 8.3Hz, 3H), 7.46 (t, J = 7.7Hz, 1H), 7.13 (t,J=6.7Hz,1H),7.08(d,J=9.3Hz,1H),6.89(dt,J=8.7,4.5Hz,2H),6.81(dt,J=8.9,3.1Hz,2H),6.12(s,1H),4.40(s,2H),3.86(s,3H); 13 C NMR (125MHz, CDCl3) δ175.1,168.9,157.8(d,J=238.4Hz),157.1,157.0,155.9,144.0(d,J=2.2Hz),141.6,134.0,1 32.7,130.5,125.9,125.1,124.0,120.8,119.1,118.3,115.5(d,J=22.6Hz),115.1(d,J=7.8Hz),111.6,72.7,55.8; 19 FNMR(470MHz, CDCl3)δ-123.7; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 20 FN2O5:435.1356,Found:435.1352.

[0120] N'-(2,4-difluorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I20): white solid, yield 83.8%, melting point 170.3-171.1℃; 1 H NMR(500MHz, CDCl3)δ9.92(s,1H),8.31(dd,J=8.0,1.7Hz,1H),7.76–7.68(m,1H),7.59–7.44(m,4H),7.14(t,J=7.5Hz ,1H),7.08(d,J=7.6Hz,1H),6.94–6.88(m,1H),6.82–6.77(m,1H),6.74(m,1H),6.16(s,1H),4.38(s,2H),3.87(s,3H); 13 C NMR(125MHz,CDCl3)δ175.2,169.0,157.1,157.1,156.8(dd,J=240.0,11.3Hz) ,155.9,151.0(dd,J=244.2,11.8Hz),141.7,134.0,132.8,132.4(dd,J=10.8,3 .1Hz),130.5,125.9,125.1,123.9,120.8,119.0,118.3,115.4(dd,J=9.1,3.7 Hz), 111.6, 110.8 (dd, J=22.0, 3.6Hz), 103.7 (dd, J=26.7, 22.2Hz), 72.8, 55.8; 19 FNMR(470MHz, CDCl3)δ-121.3,129.0; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 19 F2N2O5:453.1262,Found:453.1260.

[0121] N'-(4-methylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I21): white solid, yield 90.2%, melting point 186.9-187.6℃; 1H NMR (500MHz, CDCl3) δ9.66 (s, 1H), 8.31 (d, J = 8.0Hz, 1H), 7.71 (t, J = 7.9Hz, 1H), 7.53 (dt, J = 19.0, 7.1Hz, 3H), 7.45 (t, J = 7.3Hz, 1H), 7.13 (t,J=7.4Hz,1H),7.08(d,J=8.5Hz,1H),7.01(d,J=7.9Hz,2H),6.76(d,J=7.8Hz,2H),6.05(s,1H),4.43(s,2H),3.86(s,3H),2.25(s,3H); 13 C NMR (125MHz, CDCl3) δ175.0,168.6,157.1,156.8,155.9,145.5,141.5,133.9,132.7,130.5,130.4,129.5, 125.9,125.0,124.0,120.8,119.1,118.3,113.9,111.5,72.6,55.8,20.5.HRMS(ESI)m / z[M+H]+Calcd.For C 25 H 23 N2O5: 431.1607, Found: 431.1603.

[0122] N'-(4-tert-butylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I22): white solid, yield 85.7%, melting point 142.3-143.5℃; 1 H NMR(500MHz, CDCl3)δ9.70(s,1H),8.31(d,J=8.0Hz,1H),7.72(t,J=8.6Hz,1H),7.58–7.49(m,3H),7.48–7.44(m,1H),7.27–7.21 (m,2H),7.13(t,J=7.5Hz,1H),7.08(d,J=8.4Hz,1H),6.80(d,J=8.6Hz,2H),6.07(s,1H),4.43(s,2H),3.86(s,3H),1.27(s,9H); 13C NMR (125MHz, CDCl3) δ175.0,168.6,157.1,156.8,155.9,145.3,143.8,141.6,133.9,132.7,130.5,125.9,12 5.9,125.1,124.0,120.8,119.2,118.3,113.6,111.6,72.6,55.8,34.0,31.4; HRMS(ESI)m / z[M+H]+Calcd.For C28H29N2O5:473.2076,Found:473.2074.

[0123] N'-(2-chlorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I23): white solid, yield 83.8%, melting point 162.7-164.2℃; 1 H NMR(500MHz, CDCl3)δ9.85(s,1H),8.29(dd,J=8.0,1.7Hz,1H),7.71(m,1H),7.52(m,3H),7.45(t,J=7.6Hz,1H),7.24(dd,J=7.4,1.7Hz, 1H),7.16–7.10(m,2H),7.07(d,J=8.5Hz,1H),6.90(d,J=8.1Hz,1H),6.84–6.75(m,1H),6.43(d,J=3.8Hz,1H),4.41(s,2H),3.86(s,3H); 13 C NMR (125MHz, CDCl3) δ175.1,168.8,157.1,157.0,155.9,143.7,141.7,134.0,132.8,130.5,129.3,127. 6,125.9,125.1,123.9,121.1,120.8,119.4,119.1,118.3,113.6,111.6,72.8,55.8; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 20 N2O5:451.1061, Found:451.1057.

[0124] N'-(4-chlorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I24): white solid, yield 80.1%, melting point 145.0-145.6℃; 1H NMR (500MHz, CDCl3) δ9.87 (s, 1H), 8.30 (d, J = 8.0Hz, 1H), 7.72 (m, 1H), 7.60–7.49 (m, 3H), 7.46 (t,J=7.3Hz,1H),7.17–7.07(m,4H),6.80–6.76(m,2H),6.14(s,1H),4.40(s,2H),3.86(s,3H). 13 C NMR (125MHz, CDCl3) δ175.2,169.0,157.1,157.0,155.9,146.5,141.7,134.0,132.8,130.5,128. 9,125.9,125.7,125.2,123.9,120.8,119.1,118.4,115.0,111.6,72.7,55.8.HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 20 N2O5:451.1061, Found:451.1057.

[0125] N'-(4-trifluoromethylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I25): white solid, yield 83.7%, melting point 182.6-183.8℃; 1 H NMR (500MHz, DMSO-d6) δ9.94(s,1H),8.39(s,1H),8.19(d,J=8.0Hz,1H),7.84(t,J=7.9Hz,1H),7.69(d,J=8.5Hz,1H),7.64–7. 52(m,3H),7.44(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,1H),7.14(t,J=7.5Hz,1H),6.79(d,J=8.4Hz,2H),4.63(s,2H),3.83(s,3H); 13 C NMR (125MHz, DMSO-d6) δ173.6,167.9,156.9,155.7,155.2,152.3,140.1,134.3,132.4,130.7,126.1(q,J=3.8Hz) ,125.3,125.1,125.0(q,J=268.8Hz),123.6,120.4,119.2,118.5,118.2(d,J=31.9Hz),111.9,111.5,70.2,55.8. 19F NMR(470MHz,DMSO-d6)δ-59.2; HRMS(ESI)m / z[M+H] + Calcd.ForC 25 H 20 F3N2O5:485.1324,Found:485.1320.

[0126] N'-(2-methylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I26): white solid, yield 77.3%, melting point 179.3-180.6℃; 1 H NMR(500MHz, CDCl3)δ9.76(s,1H),8.31(dd,J=8.0,1.7Hz,1H),7.72(m,1H),7.60–7.49(m,3H),7.45(m,1H) ,7.14(td,J=7.5,1.0Hz,1H),7.11–7.04(m,3H),6.86–6.80(m,2H),4.45(s,2H),3.86(s,3H),2.26(s,3H); 13 C NMR (125MHz, CDCl3) δ175.1,168.4,157.1,156.9,155.9,145.5,141.6,133.9,132.7,130.5,130.3,126.8,1 25.9,125.1,124.0,123.2,120.8,120.7,119.1,118.3,112.3,111.6,72.7,55.8,17.0; HRMS(ESI)m / z[M+H] + Calcd.For C 25 H 20 F3N2O5:431.1607,Found:431.1610.

[0127] N'-(2-fluorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I27): white solid, yield 78.2%, melting point 181.9-182.8℃; 1H NMR(500MHz, CDCl3)δ9.82(s,1H),8.31(dd,J=8.1,1.7Hz,1H),7.77–7.69(m,1H),7.59–7.49(m,2H),7.46(t,J=7.6Hz,1H),7.13(t,J=7.5 Hz,1H),7.08(d,J=8.4Hz,1H),6.99(dd,J=11.3,7.7Hz,2H),6.96–6.91(m,1H),6.86–6.77(m,1H),6.25(s,1H),4.42(s,2H),3.86(s,3H); 13 C NMR (125MHz, CDCl3) δ175.1,168.8,157.1,157.0,155.9,151.4(d,J=240.8Hz),141.7,135.9(d,J=10.1Hz),134.0,132.7,130.5,125 .9,125.1,124.4(d,J=3.6Hz),124.0,120.8(d,J=8.2Hz),119.1,118.3,115.0(d,J=18.1Hz),114.7(d,J=1.3Hz),111.6,72.8,55.8; 19 F NMR(470MHz, CDCl3)δ-113.6; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 20 FN2O5:435.1356,Found:435.1352.

[0128] N'-(3-chlorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I28): white solid, yield 83.9%, melting point 171.6-172.1℃; 1 H NMR(500MHz, CDCl3)δ9.86(s,1H),8.31(dd,J=8.1,1.6Hz,1H),7.75–7.69(m,1H),7.59–7.49(m,3H), 7.48–7.44(m,1H),7.17–7.06(m,2H),6.85–6.81(m,2H),6.75–6.70(m,1H),4.41(s,2H),3.87(s,3H); 13C NMR (125MHz, CDCl3) δ175.1,169.0,157.1,157.0,155.9,149.2,141.6,134.8,134.0,132.8,130.5,130. 1,125.9,125.1,124.0,120.9,120.8,119.1,118.3,113.6,112.0,111.6,72.7,55.8; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 20 ClN2O5:451.1061,Found:451.1058.

[0129] N'-(2,4-dichlorophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I29): white solid, yield 83.0%, melting point 172.0-172.9℃; 1 H NMR(500MHz, CDCl3)δ10.00(s,1H),8.30(dd,J=8.1,1.7Hz,1H),7.73(m,J=8.7,7.0,1.7Hz,1H),7.59–7.43(m ,4H),7.27(d,J=2.3Hz,1H),7.18–7.06(m,3H),6.86(d,J=8.7Hz,1H),6.39(s,1H),4.39(s,2H),3.87(s,3H); 13 C NMR (125MHz, CDCl3) δ175.2,168.9,157.2,157.2,155.9,142.6,141.8,134.1,132.8,130.5,128.9,127. 7,125.9,125.2,125.2,123.9,120.8,119.8,119.0,118.4,114.5,111.6,72.9,55.8; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 19 Cl2N2O5:485.0671,Found:485.0667.

[0130] N'-(2-trifluoromethylphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I30): yellow solid, yield 88.2%, melting point 119.5-119.8℃; 1H NMR (500MHz, CDCl3) δ9.88(d,J=3.9Hz,1H),8.31(dd,J=8.1,1.7Hz,1H),7.78–7.68(m,1H),7.60–7.42(m,5H),7.38(t,J=7. 9Hz,1H),7.14(t,J=7.5Hz,1H),7.07(dd,J=15.3,8.3Hz,2H),6.92(t,J=7.6Hz,1H),6.57(s,1H),4.44(s,2H),3.87(s,3H); 13 C NMR (125MHz, CDCl3) δ175.2,168.9,157.1(d,J=6.6Hz),155.9,145.5,141.7,134.0,133.0,132.8,130.5,126.4(q,J=5 .3Hz),125.2,124.0,122.4(q,J=271.3Hz),120.8,119.9,119.1,118.4,114.8(q,J=30.7Hz),113.6,111.6,72.8,55.8; 19 F NMR(470MHz, CDCl3)δ-61.7; HRMS(ESI)m / z[M+H] + Calcd.ForC 25 H 20 F3N2O5:485.1324,Found:485.1320.

[0131] N'-(3-methoxyphenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I31): white solid, yield 96.9%, melting point 151.3-151.9℃; 1 H NMR(500MHz, CDCl3)δ9.73(s,1H),8.31(dd,J=8.1,2.0Hz,1H),7.72(td,J=8.3,2.1Hz,1H),7.58–7.49(m,3H),7.49– 7.42(m,1H),7.16–7.04(m,3H),6.70(d,J=7.4Hz,2H),6.65(d,J=8.8Hz,1H),4.43(s,2H),3.86(s,3H),2.27(s,3H).; 13C NMR (125MHz, CDCl3) δ175.0,168.7,157.1,156.8,155.9,147.8,141.6,138.8,133.9,132.7,130.5,128.9,1 25.9,125.1,124.0,121.9,120.8,119.1,118.3,114.4,111.5,110.8,72.6,55.7,21.5; HRMS(ESI)m / z[M+H] + Calcd.ForC 25 H 23 N2O6:447.1556, Found:447.1557.

[0132] N'-(4-bromophenyl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-benzo-3-yl)oxy)acetylhydrazine (I32): white solid, yield 91.1%, melting point 167.3-168.9℃; 1 H NMR(500MHz, CDCl3)δ9.87(s,1H),8.30(dd,J=8.0,1.7Hz,1H),7.72(m,1H),7.60–7.41(m,4H),7.32–7.2 3(m,2H),7.18–7.09(m,1H),7.08(dd,J=8.4,0.9Hz,1H),6.73(d,J=8.8Hz,2H),4.40(s,2H),3.86(s,3H); 13 CNMR (125MHz, CDCl3)δ

[0133] 175.1,169.0,157.1,157.0,155.9,147.0,141.7,134.0,132.8,131.8,130.5,125.9,1 25.2,123.9,120.8,119.1,118.4,115.4,113.0,111.6,72.7,55.8; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 20 BrN2O5:495.0556,Found:495.0556.

[0134] Application Examples

[0135] Example 33: Bactericidal activity of a flavonol derivative I1-I32 containing an acylhydrazine active fragment of formula (I) of the present invention.

[0136] The bioactivity of a flavonol derivative I1-I32 containing an acylhydrazine active fragment against seven tested plant pathogens—Alternaria solani (early blight of tomato), Gibberella zeae (wheat scab), Rhizoctoriza solani (rice sheath blight), Alternaria mali (apple spot), Botrytiscinerea (strawberry gray mold), Valsa mali (apple rot), and Colletotrichum orbiculare (cucumber anthracnose)—was determined using a mycelial growth method. The specific operational steps are as follows:

[0137] 1. Weigh 15 mg of the original drug and dissolve it in 0.6 mL of LDM to prepare a stock solution;

[0138] 2. Take 0.1 mL of the stock solution and add it to 50 mL of sterile potato dextrose agar medium (PDA medium). Shake well to obtain a drug-containing medium of 50 mg / L.

[0139] 3. While the above-mentioned drug-containing culture medium is still hot, pour equal amounts into three sterile petri dishes with a diameter of 9 cm. After cooling and solidification, inoculate a 0.5 cm diameter mycelium cake in the center of the culture medium.

[0140] 4. Include a blank control without the test reagent, and replicate each treatment three times;

[0141] 5. Place the above-mentioned petri dishes in a constant temperature incubator at 25±1℃ and incubate in the dark until the colony diameter is about 7.0 to 7.5 cm. Then, measure the colony diameter and calculate the inhibition rate of each drug.

[0142] 6. The formula for calculating the inhibition rate of the compound against fungi is as follows: Inhibition rate = (Coronavirus diameter of blank control - Coronavirus diameter of test agent) ÷ (Coronavirus diameter of blank control - 5mm) × 100%.

[0143] The inhibitory activity of compounds I1-I32 against *Early Blight* of tomato, *Fusarium graminearum* of wheat, *Sheath blight* of rice, *Sclerotium lobata* of apple, *Gyromitra esculenta* of strawberry, *Fungiella esculenta* of apple, and *Anthracnose* of cucumber is shown in Table 1.

[0144] Table 1. Inhibition results of compounds I1-I32 against seven pathogens.

[0145]

[0146]

[0147]

[0148] a. The commercial fungicides carbendazim and cyazofamid were used as control fungicides.

[0149] Table 1 shows that target compound I exhibits antibacterial activity against all seven pathogens, particularly against *Rhizoctonia solani*, *Botrytis cinerea*, and *Anthracnose*. Nine compounds showed 100% inhibition against *Rhizoctonia solani*: I17, I19, I20, I23, I24, I25, I28, I31, and I32. Eight compounds showed inhibition rates exceeding 90% against *Botrytis cinerea*: I8, I18, I19, I20, I23, I24, I31, and I32. Six compounds showed inhibition rates exceeding 90% against *Aureobasidium perfringens*: I17, I19, I20, I23, I24, I31, and I32. 8, I19, I21, I24 and I32; the four compounds with inhibition rates exceeding 90% against early blight of tomato are I17, I19, I20 and I24; the compounds with inhibition rates exceeding 50% against Fusarium graminearum of wheat are I19, I24 and I32; the compound with inhibition rate exceeding 90% against apple spot disease is I19; the four compounds with inhibition rates exceeding 90% against anthracnose of cucumber are I8, I17, I18 and I19.

[0150] Analysis of the inhibition rate data obtained from the initial screening revealed that compounds with inhibition rates greater than 50% underwent further EC testing against the corresponding pathogens. 50 The specific methods for toxicity testing are as follows:

[0151] Weigh the test compound to prepare a stock solution, then gradually dilute it to prepare solutions of varying concentrations. Prepare drug-containing plates, using carbendazim as a control. Perform the remaining operations according to the initial activity screening method, calculating the inhibition rate at each concentration. Use DPS statistical software to determine the effective inhibition at intermediate concentrations (EC50). 50 ).

[0152] EC of some compounds 50 The results of the toxicity test are shown in Table 2:

[0153] Table 2 shows the EC values ​​of some compounds. 50 Toxicity test a

[0154]

[0155]

[0156]

[0157] a is repeated three times, and the average value is taken.

[0158] Table 2 shows that compounds I19, I20, I24, I27, I31, and I32 have EC50-like effects against rice sheath blight pathogens. 50 Less than 1 μg / mL, superior to the control drug cyazofamid; compound I24 showed an EC50 against strawberry gray mold.50 The concentrations were 0.87 μg / mL, superior to the control drug carbendazim; compounds I19, I20, I24, and I32 showed EC50 against early blight pathogens of tomato. 50 The effective concentrations were 4.88, 3.60, 1.71, and 3.25 μg / mL, respectively, which were superior to the control drug carbendazim. Compound I19 showed good antibacterial activity against all seven plant pathogens tested.

[0159] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, equivalent changes, and alterations made to the above embodiments without departing from the technical essence of the present invention shall fall within the scope of the present invention.

Claims

1. A flavonol derivative containing an acylhydrazine active fragment or a pharmaceutically acceptable salt thereof, as described below:

2. The method for preparing the flavonol derivative containing the hydrazide active fragment of claim 1, or a pharmaceutically acceptable salt thereof, is characterized in that, The method includes the following steps: In the presence of triethylamine, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid, and dichloromethane, a substituted flavonoid carboxylic acid (II) reacts with a substituted phenylhydrazine at room temperature to generate a flavonol derivative (I) containing an acylhydrazine active fragment:

3. The use of the flavonol derivative containing the hydrazide active fragment of claim 1 or a pharmaceutically acceptable salt thereof in the control of plant fungal diseases.

4. The use of the flavonol derivative containing the hydrazide active fragment of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a reagent for controlling plant fungal diseases.

5. The application according to claim 3 or 4, characterized in that, The fungi are rice sheath blight fungus, cucumber anthracnose fungus, tomato early blight fungus, wheat scab fungus, apple spot fungus, apple rot fungus and / or strawberry gray mold fungus.

6. The application according to claim 5, characterized in that, The fungal diseases mentioned are rice sheath blight, cucumber anthracnose, tomato early blight, wheat scab, apple spot, apple rot, and / or strawberry gray mold.

7. The application according to claim 5, characterized in that, The plants mentioned are rice, cucumber, tomato, wheat, apple, or strawberry.

8. A reagent comprising a flavonol derivative containing an acylhydrazine active fragment as described in claim 1, or a pharmaceutically acceptable salt thereof.

9. The reagent according to claim 8, characterized in that, The dosage form of the reagent is selected from any one of emulsifiable concentrate, suspension concentrate, wettable powder, powder, granule, aqueous solution, poison bait, mother liquor, and mother powder.

10. The use of the reagent according to claim 8 or 9 in the prevention and control of plant fungal diseases.

11. The application according to claim 10, characterized in that, The fungi are rice sheath blight fungus, cucumber anthracnose fungus, tomato early blight fungus, wheat scab fungus, apple spot fungus, apple rot fungus and / or strawberry gray mold fungus.

12. The application according to claim 10, characterized in that, The fungal diseases mentioned are rice sheath blight, cucumber anthracnose, tomato early blight, wheat scab, apple spot, apple rot, and / or strawberry gray mold.

13. The application according to claim 10, characterized in that, The plants mentioned are rice, cucumber, tomato, wheat, apple and / or strawberry.

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