Formononetin derivative containing piperidine-4-carbohydrazide as well as preparation method and application of formononetin derivative

Abstract

The invention discloses a formononetin derivative containing piperidine-4-carbohydrazide as well as a preparation method and application of the formononetin derivative, and belongs to the technical field of pesticide synthesis. According to the invention, a piperidine-4-carbohydrazide group with excellent activity is introduced into the structure of formononetin, a series of formononetin derivatives of piperidine-4-carbohydrazide are synthesized, and the activity of the synthesized formononetin derivatives containing piperidine-4-carbohydrazide in inhibiting plant pathogens is tested. It is found that the formononetin derivative of piperidine-4-carbohydrazide synthesized by the invention can effectively inhibit plant pathogenic fungi, especially rhizoctonia solani.

Description

Technical Field

[0001] This invention belongs to the field of pesticide synthesis technology, specifically relating to a strychnine derivative containing piperidine-4-carbonylhydrazide, its preparation method and application. Background Technology

[0002] Plant diseases, especially those caused by fungi and bacteria, are a major threat to global agricultural production, leading to reduced crop yields and quality. For a long time, chemically synthesized pesticides have played a central role in plant disease control. However, the long-term, large-scale use of these drugs has caused serious problems, including the development of pathogen resistance, damage to non-target organisms (such as pollinating insects), and the threat of pesticide residues to the environment and food safety. Therefore, developing novel, highly efficient, low-toxicity, and environmentally friendly green pesticides has become a research hotspot in agricultural science and plant protection.

[0003] Plant-derived green pesticides have become an important direction in modern agricultural scientific research due to their environmentally friendly characteristics. These pesticides typically possess multiple advantages, including high bioavailability, low mammalian toxicity, high selectivity, and low likelihood of inducing resistance. With the increasing global demand for ecological environmental protection and the increasingly stringent pesticide residue limits, the development of plant-derived pesticides has received widespread attention in the international pesticide field, creating favorable development opportunities and broad market prospects. Currently, discovering lead compounds from plants and optimizing their structures has become an important strategy for innovative pesticide research and development. For example, successful cases such as pyrethroids isolated from pyrethrum and azadirachtin extracted from neem are examples of how structural modification of natural active ingredients significantly improves their stability and bioactivity. Modern medicinal chemistry research shows that rational structural modification of natural products can retain their environmental compatibility advantages while improving their physicochemical properties and efficacy. Therefore, systematically screening active ingredients from plant resources and optimizing their structures using modern synthetic chemistry techniques has become an effective approach to developing novel plant-derived pesticides. This research direction not only meets the needs of sustainable agricultural development, but also provides a scientifically feasible solution to the problems of chemical pesticide resistance and environmental pressure.

[0004] Arganicin is a typical isoflavone compound widely found in legumes and various clover species, including red clover, astragalus, and sophora japonica. Studies have shown that arganicin possesses various biological activities, including anti-inflammatory, anticancer, and antitumor effects. Previous research has primarily focused on the biological characteristics of arganicin and its potential contribution as a pharmacological compound in testing for certain diseases. In 2012, Ren et al. designed and synthesized a series of nitrogen mustard-containing arganicin derivatives; most of these compounds exhibited stronger cytotoxicity than the anticancer drug chlorambucil, with some showing significant inhibitory activity against SH-SY5Y.50 The value is 2.08 μ M, superior to phenylalanine nitrogen mustard (IC50) 50 =5.5 μ In 2017, Zhang et al. synthesized a class of podophyllin derivatives containing aminodithiocarbamates. Some compounds showed inhibitory effects on various tumor cell lines, including EC-109, MGC-803, and PC-3. Compared to the natural product podophyllin, compound 5 exhibited approximately 28-fold increased anti-prostate cancer activity. In 2019, Yang et al. designed and synthesized three compounds containing podophyllotoxin and podophyllin, and evaluated their anticancer efficacy. Pharmacological results showed that the IC50 of some compounds was determined in the A549 lung tumor cell line. 50 The value is 0.753 μ In 2021, Zuo et al. designed and synthesized a series of isoflavone derivatives with a substituted benzyloxy group at the 4-position. Using an isolated rat mesenteric artery ring model, they evaluated the vasodilatory capacity of these compounds using a linear electromyography system. Some compounds showed significant vasodilatory effects in rat mesenteric artery rings that contracted due to potassium ions, and also had a hypotensive effect on spontaneously hypertensive rats (SHR).

[0005] Piperidine is a nitrogen-containing heterocyclic compound and an important pharmacophore and superior heterocyclic structure in the field of drug discovery. Piperidine and its derivatives exhibit a variety of biological activities, such as antibacterial, anti-inflammatory, antihypertensive, anticonvulsant, antimalarial, antiviral, and anticancer properties. Due to its unique structure and superior biological activities, its study is of great significance. Acylhydrazides, as important nitrogen-containing structures, have been widely used as precursors or intermediates in the synthesis of many organic molecules due to their multifunctionality and broad biological activities. Related studies have shown that acylhydrazides possess a variety of biological activities, such as antifungal, herbicidal, insecticidal, anticancer, and anti-inflammatory activities.

[0006] In summary, no studies have been found on the synthesis of strychnine derivatives containing piperidine-4-carbonylhydrazine by introducing piperidine-4-carbonylhydrazine into the strychnine structure, nor have any studies on the use of strychnine derivatives containing piperidine-4-carbonylhydrazine in agricultural activity research been conducted. Summary of the Invention

[0007] The purpose of this invention is to provide a piperidine-4-carbonylhydrazine-containing argentin derivative, its preparation method, and its application. The provided argentin derivative containing piperidine-4-carbonylhydrazine can be used to inhibit plant pathogenic fungi, especially rice sheath blight pathogen.

[0008] To achieve the above objectives, the present invention provides the following technical solution: One of the technical solutions of this invention is to provide a strychnosine derivative containing piperidine-4-carbonylhydrazine, the structure of which is shown in the following formula:

[0009] In the above formula, R is independently selected from one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, and one or more C1-C6 substituted alkoxy groups.

[0010] Preferably, the halogen is F, Cl, or Br.

[0011] The R is an independent halogen of one or more: R = 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 3,4-di-F, 3,5-di-F, 3,4-di-Cl; the alkyl group: R = 4-CH3, 4-CH2CH3, 4-CN; the substituted alkyl group: R = 3-CF3, 4-CF3; the substituted alkoxy group: R = 4-OCF3.

[0012] The second technical solution of the present invention provides a method for preparing the above-mentioned piperidine-4-carbonylhydrazine-containing strychnosine derivative, the steps of which include: (1) Using substituted phenylhydrazine and 1-Boc-4-piperidinecarboxylic acid as raw materials, HATU and DIPEA were added as catalysts, and the reaction was carried out at room temperature. After the reaction was completed, the product was poured into water to precipitate, filtered, and intermediate a was obtained; the structural formula of intermediate a is: ; (2) Using intermediate a as a raw material, the BOC protection was removed under acidic conditions. After the reaction was completed, the mixture was concentrated under reduced pressure and recrystallized to obtain intermediate b. The structural formula of intermediate b is: ; (3) Using gentianin and epoxybromopropane as raw materials, the reaction is carried out in a solvent under alkaline conditions. After the reaction is completed, ice water is added to precipitate the product. The product is filtered, and the residue is cleaned of impurities to obtain intermediate c. The structural formula of the intermediate c is: ; (4) Using intermediates b and c as raw materials and potassium carbonate as catalyst, the reaction was carried out in a solvent and then purified to obtain a strychnine derivative containing piperidine-4-carbonylhydrazine. The structural formula of the substituted phenylhydrazine is: R is independently selected from one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, and one or more C1-C6 substituted alkoxy groups.

[0013] Preferably, the molar ratio of the substituted phenylhydrazine, 1-Boc-4-piperidinecarboxylic acid, HATU and DIPEA in step (1) is 1:(1~2):(1~2):(1~3); and the reaction time at room temperature is 10~12 h.

[0014] Preferably, the step of removing Boc protection in step (2) includes: dissolving intermediate a in acetonitrile, heating to 50~80℃, adding trifluoroacetic acid dropwise at a molar ratio of 1:5~10, heating under reflux for 2~5 h to remove Boc protection.

[0015] More preferably, step (2) further includes a separation step after removing Boc protection. The separation step specifically involves adding acetonitrile to the reaction system multiple times after removing Boc protection, concentrating under reduced pressure to remove excess trifluoroacetic acid, and finally adding ethanol for recrystallization.

[0016] Preferably, the molar ratio of gentianin, epichlorohydrin and potassium carbonate in step (3) is 1:(1~4):(1~4); and the reaction time at room temperature is 10~12 h.

[0017] Preferably, the molar ratio of intermediate b, intermediate c and K2CO3 in step (4) is 1:(1~2):(2~4), and the heating reflux time is 3~6h.

[0018] Preferably, the purification step in step (4) specifically involves: pouring the reaction system after heating and reflux into ice water to precipitate the product, filtering, collecting the filter residue, and purifying it by silica gel column chromatography (dichloromethane:methanol = 15:1, v / v).

[0019] The third technical solution of the present invention provides the application of the above-mentioned piperidine-4-carbonylhydrazine-containing strychnosine derivative in the preparation of drugs for inhibiting plant pathogenic fungi.

[0020] Preferably, the plant pathogenic fungi include rice sheath blight fungus (Rs), pepper phytophthora (Pc), rapeseed sclerotinia sclerotiorum (Ss), kiwifruit stem spot fungus (Ps), grape bud fungus (Bd), Fusarium oxysporum (Fo), wheat scab (Fg), anthracnose fungus (Cg), cucumber wilt fungus (Foc), and Chinese cabbage black spot fungus (Ab).

[0021] The beneficial technical effects of the present invention are as follows: This invention provides a piperidine-4-carbonylhydrazine-containing basididin derivative, its preparation method, and its application. This invention introduces a piperidine-4-carbonylhydrazine group with excellent activity into the structure of basididin, synthesizing a series of basididin derivatives containing piperidine-4-carbonylhydrazine. Through testing the inhibitory activity of the synthesized basididin derivatives containing piperidine-4-carbonylhydrazine against plant pathogenic fungi, it was found that the basididin derivatives containing piperidine-4-carbonylhydrazine synthesized in this invention can effectively inhibit plant pathogenic fungi, especially rice sheath blight pathogen. Detailed Implementation

[0022] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0023] Furthermore, regarding the numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0024] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this invention.

[0025] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0026] One of the technical objectives of this invention is to provide a strychnosine derivative containing piperidine-4-carbonylhydrazine, with the structure shown in the following formula:

[0027] In the above formula, R is independently selected from one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, and one or more C1-C6 substituted alkoxy groups.

[0028] Preferably, the halogen is F, Cl, or Br.

[0029] The second technical objective of this invention is to provide a method for preparing the above-mentioned piperidine-4-carbonylhydrazine-containing strychnosine derivative, the steps of which include: (1) Using substituted phenylhydrazine and 1-Boc-4-piperidinic acid as raw materials and DMF as solvent, the reaction was carried out overnight at room temperature under the action of catalysts HATU and DIPEA. The reaction solution was poured into water, and the precipitated solid was filtered and dried to obtain intermediate a; The reaction formula is as follows:

[0030] The molar ratio of the substituted phenylhydrazine, 1-Boc-4-piperidinecarboxylic acid, HATU and DIPEA is 1:(1~2):(1~2):(1~2).

[0031] (2) Using intermediate a as raw material and acetonitrile as solvent, trifluoroacetic acid was added dropwise under the condition of heating to 50~80 ℃ and reacted for 2~5 h to remove Boc protection. The solvent was removed by vacuum distillation and the intermediate b was obtained by recrystallization from ethanol.

[0032] The reaction formula is as follows:

[0033] The molar ratio of intermediate a to trifluoroacetic acid is 1:(5~10).

[0034] (3) Using strychnosine as raw material and DMF as solvent, the mixture was stirred at room temperature for 30 min and then epoxybromopropane was added. The reaction was carried out at room temperature for 12-24 h. After the reaction was completed, the solid was precipitated in ice water, filtered, and dried to obtain intermediate a; The reaction formula is as follows:

[0035] The molar ratio of the argentin, potassium carbonate, and epibromopropane is 1:(1~4):(1~4).

[0036] (4) Using intermediates b and c as raw materials and potassium carbonate as a catalyst, a strychnosine derivative containing piperidine-4-carbonylhydrazine was prepared by reflux in a solvent. The reaction formula is as follows:

[0037] In some embodiments, the solvent is isopropanol; the reflux reaction time is 3-6 h; after the reaction is completed, the reaction system is dispersed in ice water to precipitate solids, which are then filtered, dried, and then subjected to column chromatography, with the column chromatography eluent being a mixture of dichloromethane and methanol in a volume ratio of 15:1.

[0038] The molar ratio of intermediate 1, intermediate c and potassium carbonate is 1:(1~2):(1~3).

[0039] The third technical objective of this invention is to provide the application of the above-mentioned piperidine-4-carbonylhydrazine-containing argentin derivative in the preparation of drugs for inhibiting plant pathogenic fungi.

[0040] To achieve the above-mentioned technical objectives, the present invention provides the following embodiments.

[0041] Example 1 N-(2-Fluorophenyl)-1-(2-hydroxy-3-(3-(4-methoxyphenyl)-4-oxo-4-) H -chromene-7-yloxy)propyl)piperidine-4-formylhydrazide (compound number X1), the steps are as follows: (1) Synthesis of tert-butyl-4-(2-(2-fluorophenyl)hydrazine-1-carboxylyl)piperidine-1-carboxylic acid ester: 1-Boc-4-piperidinecarboxylic acid (1.0 g, 5.23 mmol) and HATU (2.39 g, 6.28 mmol) dissolved in DMF were added to a 100 mL round-bottom flask, and DIPEA (1.09 mL, 6.28 mmol) was added dropwise. After stirring for 30 minutes, 2-fluorophenylhydrazine (0.99 g, 7.85 mmol) was added and the reaction was allowed to proceed overnight. After the reaction was completed, the mixture was dispersed in 500 mL of ice water, and a large amount of solid precipitated. The solid was filtered, washed several times with water, and dried to obtain a brown solid with a yield of 87.6%.

[0042] (2) Synthesis of N'-(2-fluorophenyl)piperidine-4-carboxylhydrazide: The product from step (1) (1.55 g, 4.59 mmol) was dissolved in 50 mL of acetonitrile in a 100 mL round-bottom flask, and trifluoroacetic acid (2.05 mL, 27.56 mmol) was added dropwise. The mixture was heated under reflux for 3 hours. The solvent was removed by vacuum distillation, and the product was recrystallized from ethanol to give a brown solid with a yield of 78.3%.

[0043] (3) 3-(4-methoxyphenyl)-7-(ethylene oxide-2-ylmethoxy)-4 H Preparation of 4-chromone: Arganin (5 g, 18.64 mmol) and anhydrous potassium carbonate (7.73 g, 55.91 mmol) were dissolved in 130 mL of ethanol in a 250 mL single-necked flask. After stirring at room temperature for 30 minutes, epichlorohydrin (3.06 mL, 37.28 mmol) was added, and the reaction was allowed to proceed for 24 h at room temperature. After the reaction was complete, the system was dispersed in 800 mL of water, precipitating a large amount of solid. The solid was filtered, washed several times with water, and dried to obtain a white solid with a yield of 92.3%.

[0044] (4) N-(2-fluorophenyl)-1-(2-hydroxy-3-(3-(4-methoxyphenyl)-4-oxo-4) HSynthesis of N'-(2-fluorophenyl)piperidin-4-carboxyhydrazide (0.99 g, 4.16 mmol), anhydrous K2CO3 (1.15 g, 8.32 mmol), and 50 mL of isopropanol were added to a 100 mL round-bottom flask. After stirring under reflux for 0.5 h, 3-(4-methoxyphenyl)-7-(ethylene oxide-2-ylmethoxy)-4H-chromene-4-one (0.90 g, 2.77 mmol) was added and reacted for 6 h. After the reaction was completed, the system was dispersed in 500 mL of water, and a large amount of solid precipitated. The solid was filtered, washed several times with water, dried, and the crude product was obtained. The target compound (dichloromethane:methanol = 15:1, v / v) was then obtained by column chromatography with a yield of 21%.

[0045] Example 2: N-(3-fluorophenyl)-1-(2-hydroxy-3-(3-(4-methoxyphenyl)-4-oxo-4-) H Synthesis of 2-fluorophenylhydrazine (X2) was performed as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 3-fluorophenylhydrazine. Yield: 37%.

[0046] Example 3: N-(4-fluorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-fluorophenylhydrazine (compound number X3) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-fluorophenylhydrazine. Yield: 43%.

[0047] Example 4: N-(3,4-difluorophenyl)-1-(2-hydroxy-3-(3-(4-methoxyphenyl)-4-oxo-4-) H -chromene-7-yloxy)propyl)piperidine-4-carboxylhydrazine (compound number X4), the procedure is the same as in Example 1, except that the 2-fluorophenylhydrazine in step (1) is replaced with an equimolar amount of 3,4-difluorophenylhydrazine. Yield: 42%.

[0048] Example 5: N-(3,5-difluorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-fluorophenylhydrazine (compound number X5) was performed in the same manner as in Example 1, except that the 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 3,5-difluorophenylhydrazine. Yield: 38%.

[0049] Example 6: N-(2-chloro-4-fluorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-chloro-4-fluorophenylhydrazine (compound number X6) was performed in the same manner as in Example 1, except that the 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 2-chloro-4-fluorophenylhydrazine. Yield: 31%.

[0050] Example 7: N-(3-chloro-4-fluorophenyl)-1-(2-hydroxy-3-(3-(4-methoxyphenyl)-4-oxo-4-) H The synthesis of (-chromene-7-yloxy)propyl)piperidine-4-formylhydrazine (compound number X7) was performed according to the same procedure as in Example 1, except that the 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 3-chloro-4-fluorophenylhydrazine. Yield: 37% Example 8: N'-(4-bromo-2-fluorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-chlorophenylhydrazine (X8) was performed as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-bromo-2-fluorophenylhydrazine. Yield: 52%.

[0051] Example 9: 1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-(3-(trifluoromethyl)phenyl)piperidine-4-carboxylhydrazine (compound number X9) was performed in the same manner as in Example 1, except that the 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 3-trifluoromethylphenylhydrazine. Yield: 35%.

[0052] Example 10: 1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylhydrazine (compound number X10), the steps were the same as in Example 1, except that the 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-trifluoromethylphenylhydrazine. Yield: 39%.

[0053] Example 11: 1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) HSynthesis of 2-(4-(trifluoromethoxy)phenyl)piperidine-4-carboxylhydrazine (compound number X11) was performed in the same manner as in Example 1, except that the 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-trifluoromethoxyphenylhydrazine. Yield: 26%.

[0054] Example 12: N-(2-chlorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-chlorophenylhydrazine (compound number X12) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 2-chlorophenylhydrazine. Yield: 35%.

[0055] Example 13: N-(3-chlorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-chlorophenylhydrazine (compound number X13) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 3-chlorophenylhydrazine. Yield: 24%.

[0056] Example 14: N-(4-chlorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-fluorophenylhydrazine (compound number X14) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-chlorophenylhydrazine. Yield: 48%.

[0057] Example 15: N-(3,4-dichlorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-fluorophenylhydrazine (compound number X15) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 3,4-dichlorophenylhydrazine. Yield: 37%.

[0058] Example 16: N-(3,5-dichlorophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-fluorophenylhydrazine (compound number X16) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 3,5-dichlorophenylhydrazine. Yield: 35%.

[0059] Example 17: N-(2-bromophenyl)-1-(2-hydroxy-3-(3-(4-methoxyphenyl)-4-oxo-4- H Synthesis of 2-fluorophenylhydrazine (X17) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 2-bromophenylhydrazine. Yield: 29%.

[0060] Example 18: N-(3-bromophenyl)-1-(2-hydroxy-3-(3-(4-methoxyphenyl)-4-oxo-4- H Synthesis of 2-fluorophenylhydrazine (X18) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 3-bromophenylhydrazine. Yield: 41%.

[0061] Example 19: N-(4-bromophenyl)-1-(2-hydroxy-3-(3-(4-methoxyphenyl)-4-oxo-4- H Synthesis of 2-fluorophenylhydrazine (X19)-(xylen-7-yloxy)propyl)piperidine-4-carboxylhydrazine (compound number X19) was performed in the same manner as in Example 1, except that the 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-bromophenylhydrazine. Yield: 45%.

[0062] Example 20: 1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-chlorophenylhydrazine (compound number X20) was performed in the same manner as in Example 1, except that the 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-methylphenylhydrazine. Yield: 25%.

[0063] Example 21: N-(4-ethylphenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-chlorophenylhydrazine (compound number X21) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-ethylphenylhydrazine. Yield: 34%.

[0064] Example 22: N-(4-cyanophenyl)-1-(2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4) H Synthesis of 2-fluorophenylhydrazine (compound number X22) was performed in the same manner as in Example 1, except that 2-fluorophenylhydrazine in step (1) was replaced with an equimolar amount of 4-cyanophenylhydrazine. Yield: 46%.

[0065] The physicochemical properties and mass spectrometry data of the piperidine-4-carbazide-containing genistein derivatives synthesized in Examples 1-22 are shown in Table 1. (1H NMR spectroscopy data are not included.) 1 H NMR and carbon spectroscopy 13 The C NMR data are shown in Table 2.

[0066] Table 1. Physicochemical properties and mass spectrometry data of the target compounds compound Yield (%) Properties Melting point (°C) HRMS, m / z (calcd.) X1 21% White solid 84-86 562.23479(562.23389)[M+H]+ X2 44% White solid 205-206 562.23479(562.23413)[M+H]+ X3 43% White solid 236-237 560.21914(560.22089)[M+H]+ X4 42% White solid 219-220 580.22537(580.22424)[M+H]+ X5 31% White solid 228-229 580.22537(580.22473)[M+H]+ X6 38% White solid 175-176 580.22537(580.22424)[M+H]+ X7 37% White solid 203-205 596.19582(596.196476)[M+H]+ X8 47% White solid 180-181 638.12965(638.13196)[M+H]+ X9 60% White solid 233-234 621.23160(621.23065)[M+H]+ X10 39% White solid 215-217 527.29043(527.28992)[M+H]+ X11 26% White solid 228-229 628.22561(628.22534)[M+H]+ X12 35% White solid 218-219 578.20524(578.20380)[M+H]+ X13 24% White solid 228-229 578.20524(578.20428)[M+H]+ X14 48% White solid 218-219 578.20524(578.20435)[M+H]+ X15 37% White solid 213-214 612.16627(612.16571)[M+H]+ X16 35% White solid 236-237 612.16627(612.16577)[M+H]+ X17 29% White solid 197-198 622.15472(622.15533)[M+H]+ X18 41% White solid 232-233 622.15472(622.15375)[M+H]+ X19 45% White solid 218-219 622.15472(622.15466)[M+H]+ X20 25% White solid 177-179 558.25986(558.25867)[M+H]+ X21 34% White solid 94-95 572.27551(572.27441)[M+H]+ X22 46% White solid 226-228 569.23946(569.23926)[M+H]+ Table 2. NMR spectral data of the target compound compound <![CDATA[ 1 H NMR and 13 C NMR (TMS as internal standard)<!-- 8 --> ]]> X1 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.66(d, J = 2.5 Hz, 1H), 8.36 - 8.35(m, 1H), 7.99 (d, J = 9.0 Hz, 1H),7.56 (s, 1H), 7.49 - 7.46 (m, 2H),7.14 - 7.13 (m, 1H), 7.06 - 6.99(m, 2H), 6.96 - 6.92 (m, 3H), 6.69- 6.63 (m, 2H), 4.94 (d, J = 4.5Hz, 1H), 4.11 (dd, J = 10.0, 3.0Hz, 1H), 4.01 - 3.96 (m, 2H), 3.74(s, 3H), 2.91 (dd, J = 32.0, 11.0Hz, 2H), 2.41 (dd, J = 13.0, 6.0Hz, 1H), 2.34 (dd, J = 13.0, 6.0Hz, 1H), 2.21 - 2.15 (m, 1H), 2.03- 1.96 (m, 2H), 1.66 - 1.59 (m,4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.16, 174.88, 163.76, 159.51,157.93, 153.98, 150.63 (d, 1 J C-F =237.3 Hz), 137.55 (d, 2 J C-F = 10.5Hz), 130.60, 127.46, 125.04,125.02, 124.23 (d, 3 J C-F = 90.3Hz), 119.03 (d, 3 J C-F = 6.6 Hz),118.03, 115.63, 115.33 (d, 2 J C-F =17.8 Hz), 114.12, 113.76, 101.62,72.53, 66.93, 61.62, 55.66, 54.13,53.95, 40.63, 29.03. 19 F NMR (470MHz, DMSO- d 6) δ -133.11. <!-- 9 -->]]> X2 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.65(d, J = 2.5 Hz, 1H), 8.36 (s, 1H),7.99 - 7.97 (m, 2H), 7.49 - 7.46(m, 2H), 7.14 (d, J = 2.5 Hz, 1H),7.11 - 7.09 (m, 1H), 7.05 (dd, J =9.0, 2.5 Hz, 1H), 6.96 - 6.93 (m,2H), 6.47 - 6.45 (m, 1H), 6.43 -6.39 (m, 1H), 6.34 (dt, J = 11.5,2.0 Hz, 1H), 5.03 - 4.85 (m, 1H),4.11 (dd, J = 10.0, 3.0 Hz, 1H),4.01 - 3.95 (m, 2H), 3.74 (s, 3H),2.91 (dd, J = 31.0, 11.5 Hz, 2H),2.41 (dd, J = 13.0, 6.5 Hz, 1H),2.34 (dd, J = 13.0, 6.5 Hz, 1H),2.17 (td, J = 12.5, 4.0 Hz, 1H),2.03 - 1.96 (m, 2H), 1.68 - 1.53(m, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.16, 174.91, 163.77, 163.69 (d, 1 J C-F = 238.8 Hz), 159.51, 157.93,153.98, 152.34, 152.25, 130.83 (d, 3 J C-F = 9.9 Hz), 130.60, 127.46,124.59, 123.87, 118.03, 115.63,114.12, 108.54, 104.90 (d, 2 J C-F =21.3 Hz), 101.62, 98.90 (d, 2 J C-F =25.5 Hz), 72.54, 66.93, 61.62,55.65, 54.12, 53.94, 29.03. 19 F NMR(470 MHz, DMSO- d 6) δ -113.14. <!-- 10 -->]]> X3 <![CDATA[ 1 HNMR (500 MHz, DMSO- d 6) δ 9.61 (d, J = 3.0 Hz, 1H), 8.36 (s, 1H),7.99 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.50 - 7.46 (m,2H), 7.14 (d, J = 2.5 Hz, 1H),7.05 (dd, J = 9.0, 2.5 Hz, 1H),6.97 - 6.90 (m, 4H), 6.64 - 6.61(m, 2H), 4.94 (s, 1H), 4.11 (dd, J = 10.0, 3.0 Hz, 1H), 4.01 - 3.95(m, 2H), 3.74 (s, 3H), 2.91 (dd, J = 32.0, 11.0 Hz, 2H), 2.41 (dd, J = 13.0, 6.5 Hz, 1H), 2.34 (dd, J =13.0, 6.0 Hz, 1H), 2.18 - 2.12(m,1H), 2.03 - 1.95(m, 2H), 1.66 -1.57 (m, 4H). 13 C NMR (125 MHz,DMSO- d 6) δ 174.68, 174.39, 163.29,159.03, 157.45, 155.77 (d, 1 J C-F =276.6 Hz), 153.51, 146.12, 130.13,126.98, 124.11, 123.39, 117.55,115.21 (d, 3 J C-F = 12.3 Hz),115.08, 113.65, 113.19 (d, 2 J C-F =7.6 Hz), 101.14, 72.06, 66.45,61.14, 55.18, 53.66, 53.48, 40.15,28.57. 19 F NMR (470 MHz, DMSO- d 6) δ-119.63.<!-- 11 --> ]]> X4 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.66(d, J = 3.0 Hz, 1H), 8.36 (s, 1H),7.99 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 3.0 Hz, 1H), 7.49 - 7.46 (m,2H), 7.16 - 7.11 (m, 2H), 7.05(dd, J = 9.0, 2.5 Hz, 1H), 6.97 -6.94 (m, 2H), 6.56 - 6.52 (m, 1H),6.44 - 6.41 (m, 1H), 4.94 (s, 1H),4.11 (dd, J = 9.5, 3.0 Hz, 1H),4.01 - 3.94 (m, 2H), 3.74 (s, 3H),2.91 (dd, J = 32.0, 11.0 Hz, 2H),2.41 (dd, J = 12.5, 6.0 Hz, 1H),2.34 (dd, J = 13.0, 6.5 Hz, 1H),2.19 - 2.13 (m, 1H), 2.02 - 1.95(m, 2H), 1.68 - 1.56 (m, 4H). 13 CNMR (125 MHz, DMSO- d 6) δ 175.16,174.97, 163.77, 159.51, 157.93,153.99, 149.32 (d, 3 J C-F = 13.5Hz), 147.63 (d, 3 J C-F = 7.8 Hz),142.13, 130.60, 127.46, 124.59,123.87, 118.03, 117.87, 115.63,114.12, 108.15, 101.62, 100.97 (d, 2 J C-F = 20.7 Hz), 72.53, 66.93,61.60, 55.66, 54.11, 53.93, 40.57,28.99. 19 F NMR (470 MHz, DMSO- d 6) δ -138.28, -152.40. <!-- 12 -->]]> X5 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.70(d, J = 2.5 Hz, 1H), 8.36 (s, 1H),8.27 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.49 - 7.46 (m,2H), 7.14 (d, J = 2.5 Hz, 1H),7.05 (dd, J = 9.0, 2.5 Hz, 1H),6.97 - 6.94 (m, 2H), 6.39 - 6.35(m, 1H), 6.22 (dd, J = 10.0, 2.5Hz, 2H), 4.94 (d, J = 4.5 Hz, 1H),4.11 (dd, J = 9.5, 3.0 Hz, 1H),4.01 - 3.95 (m, 2H), 3.74 (s, 3H),2.91 (dd, J = 32.0, 11.0 Hz, 2H),2.41 (dd, J = 13.0, 6.5 Hz, 1H),2.34 (dd, J = 13.0, 6.0 Hz, 1H),2.20 - 2.14 (m, 1H), 2.03 - 1.96(m, 2H), 1.69 - 1.55 (m, 4H). 13 CNMR (125 MHz, DMSO- d 6) δ 175.16,174.95, 164.75 (d, 1 J C-F = 16.0Hz), 163.77, 162.83 (d, 1 J C-F =16.1 Hz), 159.51, 157.93, 153.98,153.16 (t, 3 J C-F = 13.0 Hz),130.60, 127.46, 124.59, 123.87,118.03, 115.64, 114.13, 101.62,95.08 (d, 2 J C-F = 28.4 Hz), 93.34(t, 2 J C-F = 26.3 Hz), 72.53, 66.93,61.60, 55.66, 54.09, 53.91,28.98. 19 F NMR (470 MHz, DMSO- d 6) δ -110.18. <!-- 13 -->]]> X6 <![CDATA[ 1 HNMR (500 MHz, DMSO- d 6) δ 9.81 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H),8.03 (d, J = 8.5 Hz, 1H), 7.54 -7.50 (m, 2H), 7.34 (d, J = 2.5 Hz,1H), 7.28 (dd, J = 8.5, 3.0 Hz,1H), 7.18 (d, J = 2.5 Hz, 1H),7.10 (dd, J = 9.0, 2.5 Hz, 1H),7.04 (td, J = 8.5, 2.5 Hz, 1H),7.01 - 6.98 (m, 2H), 6.70 (q, J =5.5 Hz, 1H), 4.98 (d, J = 4.5 Hz,1H), 4.15 (dd, J = 10.0, 3.0 Hz,1H), 4.05 - 3.99 (m, 2H), 3.79 (s,3H), 2.95 (dd, J = 32.5, 11.5 Hz,2H), 2.46 (dd, J = 12.5, 6.0 Hz,1H), 2.38 (dd, J = 12.7, 6.0 Hz,1H), 2.25 - 2.19(m, 1H), 2.08 -2.00 (m, 2H), 1.73 - 1.60 (m, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.16, 174.83, 163.77, 159.51,157.94, 155.42 (d, 1 J C-F = 235.6Hz), 154.00, 142.30, 130.61,127.47, 124.59, 123.87, 118.04,117.71 (d, 3 J C-F = 10.4 Hz), 116.70(d, 3 J C-F = 25.6 Hz), 115.64,115.05 (d, 2 J C-F = 21.8 Hz),114.13, 113.89 (d, 2 J C-F = 8.1 Hz),101.63, 72.53, 66.93, 61.60,55.66, 54.10, 53.92, 40.60,28.98. 19 F NMR (470 MHz, DMSO- d 6) δ -124.85. <!-- 14 -->]]> X7 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.67(d, J = 3.0 Hz, 1H), 8.36 (s, 1H),7.99 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 3.0 Hz, 1H), 7.49 - 7.46 (m,2H), 7.16 - 7.11 (m, 2H), 7.05(dd, J = 9.0, 2.5 Hz, 1H), 6.97 -6.93 (m, 2H), 6.70 (dd, J = 6.5,3.0 Hz, 1H), 6.61 - 6.58 (m, 1H),4.94 (s, 1H), 4.11 (dd, J = 10.0,3.0 Hz, 1H), 4.01 - 3.96 (m, 2H),3.74 (s, 3H), 2.91 (dd, J = 32.5,11.0 Hz, 2H), 2.41 (dd, J = 13.0,6.0 Hz, 1H), 2.34 (dd, J = 13.0,6.0 Hz, 1H), 2.19 - 2.16 (m, 1H),1.99 (td, J = 11.5, 8.5 Hz, 2H),1.67 - 1.55 (m, 4H). 13 C NMR (125MHz, DMSO- d 6) δ 175.16, 174.97,163.77, 159.51, 157.93, 153.98,151.01 (d, 1 J C-F = 234.5 Hz),147.53, 130.60, 127.46, 124.59,123.87, 119.81 (d, 2 J C-F = 18.3Hz), 118.03, 117.45 (d, 3 J C-F =21.9 Hz), 115.63, 114.13, 113.25,112.40, 101.62, 72.54, 66.93,61.60, 55.66, 54.10, 53.92, 40.57,28.99. 19 F NMR (470 MHz, DMSO- d 6) δ -130.54. <!-- 15 -->]]> X8 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.69(d, J = 2.5 Hz, 1H), 8.37 (s, 1H),7.99 (d, J = 9.0 Hz, 1H), 7.79 (s,1H), 7.49 – 7.46 (m, 2H), 7.31(dd, J = 11.5, 2.5 Hz, 1H), 7.15 –7.11 (m, 2H), 7.05 (dd, J = 9.0,2.5 Hz, 1H), 6.96 – 6.94 (m, 2H),6.60 (t, J = 9.0 Hz, 1H), 4.94 (d, J = 4.5 Hz, 1H), 4.11 (dd, J =10.0, 3.0 Hz, 1H), 4.01 – 3.95 (m,2H), 3.74 (s, 3H), 2.91 (dd, J =33.0, 12.0 Hz, 2H), 2.41 (dd, J =12.5, 6.0 Hz, 1H), 2.34 (dd, J =13.0, 6.0 Hz, 1H), 2.19 – 2.12 (m,1H), 2.03 – 1.93 (m, 2H), 1.68 –1.55 (m, 4H). 13 C NMR (125 MHz,DMSO- d 6) δ 175.16, 174.88, 163.77,159.51, 157.94, 154.01, 150.30 (d, 1 J C-F = 242.9 Hz), 137.24 (d, 2 J C-F = 10.6 Hz), 130.61, 127.90,127.47, 124.59, 123.87, 118.52 (d, 2 J C-F = 21.1 Hz), 118.03, 115.65,115.15, 114.13, 108.44 (d, 3 J C-F =8.3 Hz), 101.63, 72.53, 66.93,61.60, 55.67, 54.10, 53.91,28.99. 19 F NMR (470 MHz, DMSO- d 6) δ -129.79. <!-- 16 -->]]> X9 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.73(d, J = 2.5 Hz, 1H), 8.36 (s, 1H),8.14 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.49 - 7.46 (m,2H), 7.30 (t, J = 8.0 Hz, 1H),7.14 (d, J = 2.5 Hz, 1H), 7.05(dd, J = 9.0, 2.5 Hz, 1H), 6.97 -6.94 (m, 3H), 6.88 (dd, J = 12.5,2.0 Hz, 2H), 4.94 (d, J = 4.5 Hz,1H), 4.11 (dd, J = 10.0, 3.0 Hz,1H), 4.01 - 3.74 (m, 3H), 3.74 (s,3H), 2.91 (dd, J = 32.5, 11.5 Hz,2H), 2.42 (dd, J = 13.0, 6.0 Hz,1H), 2.34 (dd, J = 13.0, 6.5 Hz,1H), 2.21 - 2.17 (m, 1H), 2.04 -1.96 (m, 2H), 1.68 - 1.57 (m, 4H). 13 C NMR (126 MHz, DMSO- d 6) δ 175.16, 174.98, 163.77, 159.51,157.94, 153.99, 150.69, 130.60,130.40, 130.10 (d, 2 J C-F = 30.9Hz), 127.46, 124.59, 123.87,118.03, 116.10, 115.64, 114.94 (d, 3 J C-F = 1.6 Hz), 114.13, 108.22 (d, 3 J C-F = 1.6 Hz), 101.62, 72.54,66.93, 61.60, 55.66, 54.08, 53.90,28.98. 19 F NMR (470 MHz, DMSO- d 6) δ -61.31. <!-- 17 -->]]> X10 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.78(d, J = 2.0 Hz, 1H), 8.41 (s, 1H),8.36 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.54 - 7.51 (m,2H), 7.45 (d, J = 8.0 Hz, 2H),7.18 (d, J = 2.5 Hz, 1H), 7.10(dd, J =9.0, 2.5 Hz, 1H), 7.01 -6.98 (m, 2H), 6.76 (d, J = 8.0 Hz,2H), 4.98 (s, 1H), 4.16 (dd, J =10.0, 3.0 Hz, 1H), 4.05 - 3.99 (m,2H), 3.78 (s, 3H), 2.96 (dd, J =32.0, 11.5 Hz, 2H), 2.46 (dd, J =13,0, 6.0 Hz, 1H), 2.38 (dd, J =13.0, 6.5 Hz, 1H), 2.26 - 2.20 (m,1H), 2.08 - 2.01 (m, 2H), 1.74 -1.61 (m, 4H). 13 C NMR (125 MHz,DMSO- d 6) δ 175.16, 174.93, 163.77,159.51, 157.94, 153.99, 153.16,130.60, 127.47, 126.71, 124.49,124.23 (d, 2 J C-F = 89.8 Hz), 118.55(d, 4 J C-F = 31.8 Hz), 118.04,115.63, 114.13, 111.83, 101.63,72.53, 66.94, 61.60, 55.65, 54.11,53.93, 40.60, 29.03. 19 F NMR (470MHz, DMSO-D6) δ -59.01. <!-- 18 -->]]> X11 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.66(d, J = 3.0 Hz, 1H), 8.36 (s, 1H),7.99 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.49 - 7.49 (m,2H), 7.13 (d, J = 2.5 Hz, 1H),7.09 - 7.04 (m, 3H), 6.96 - 6.93(m, 2H), 6.69 - 6.65 (m, 2H), 4.94(d, J = 4.5 Hz, 1H), 4.11 (dd, J =9.5, 2.5 Hz, 1H), 4.01 - 3.94 (m,2H), 3.74 (s, 3H), 2.91 (dd, J =32.5, 11.0 Hz, 2H), 2.41 (dd, J =13.0, 6.5 Hz, 1H), 2.34 (dd, J =13.0, 6.0 Hz, 1H), 2.19 - 2.14 (m,1H), 2.03 - 1.96 (m, 2H), 1.65 -1.56 (m, 4H). 13 C NMR (125 MHz,DMSO- d 6) δ 175.16, 174.95, 163.76,159.50, 157.93, 153.98, 149.29,140.74, 130.60, 127.46, 124.59,123.87, 122.46, 120.81 (d, 1 J C-F =221.4 Hz), 118.03, 115.62, 114.12,113.11, 101.61, 72.52, 66.93,61.61, 55.65, 54.12, 53.95,29.04. 19 F NMR (470 MHz, DMSO- d 6) δ -57.20. <!-- 19 -->]]> X12 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.81(d, J = 2.5 Hz, 1H), 8.40 (s, 1H),8.03 (d, J = 9.0 Hz, 1H), 7.53 -7.51 (m, 2H), 7.39 (d, J = 2.0 Hz,1H), 7.27 (dd, J = 8.0, 1.5 Hz,1H), 7.18 (d, J = 2.5 Hz, 1H),7.16 - 7.12 (m, 1H), 7.09 (dd, J =9.0, 2.5 Hz, 1H), 7.01 - 6.98 (m,2H), 6.74 - 6.70 (m, 2H), 4.99 (d, J = 4.5 Hz, 1H), 4.18 - 4.14 (m,1H), 4.05 - 3.99 (m, 2H), 3.78 (s,3H), 2.96 (dd, J = 32.5, 11.5 Hz,2H), 2.46 (dd, J = 13.0, 6.5 Hz,1H), 2.39 (dd, J = 12.5, 6.0 Hz,1H), 2.27 - 2.20 (m, 1H), 2.08 -2.01 (m, 2H), 1.75 - 1.61 (m, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.15, 174.77, 163.76, 159.50,157.93, 153.98, 145.33, 130.60,129.65, 128.28, 127.46, 124.59,123.86, 119.88, 118.03, 117.66,115.63, 114.12, 113.14, 101.62,72.53, 66.93, 61.62, 55.66, 54.12,53.95, 40.63, 29.01. <!-- 20 -->]]> X13 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.65(d, J = 2.5 Hz, 1H), 8.36 (s, 1H),8.00 - 7.97 (m, 2H), 7.49 - 7.46(m, 2H), 7.14 (d, J = 2.5 Hz, 1H),7.10 - 7.04 (m, 2H), 6.97 - 6.94(m, 2H), 6.66 - 6.64 (m, 1H), 6.60(t, J = 2.0 Hz, 1H), 6.57 - 6.56(m, 1H), 4.94 (s, 1H), 4.11 (dd, J = 10.0, 3.0 Hz, 1H), 4.01 - 3.96(m, 2H), 3.74 (s, 3H), 2.95 - 2.87(m, 2H), 2.41 (dd, J = 13.0, 6.0Hz, 1H), 2.34 (dd, J = 13.0, 6.5Hz, 1H), 2.20 - 2.15 (m, 1H), 2.01-1.97 (m, 2H), 1.65 - 1.56 (m,4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.16, 174.91, 163.77, 159.51,157.94, 153.99, 151.65, 133.95,130.92, 130.61, 127.46, 124.59,123.87, 118.29, 118.03, 115.64,114.13, 111.76, 111.15, 101.63,72.54, 66.93, 61.60, 55.66, 54.11,53.92, 40.58, 29.04, 29.01. <!-- 21 -->]]> X14 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.68(d, J = 2.5 Hz, 1H), 8.40 (s, 1H),8.03 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 3.0 Hz, 1H), 7.53 - 7.50 (m,2H), 7.18 (d, J = 2.0 Hz, 1H),7.16 - 7.14 (m, 2H), 7.09 (dd, J =9.0, 2.5 Hz, 1H), 7.01 - 6.98 (m,2H), 6.68 - 6.66 (m, 2H), 4.99 (d,J = 4.0 Hz, 1H), 4.15 (dd, J =10.0, 3.0 Hz, 1H), 4.05 - 3.99 (m,2H), 3.78 (s, 3H), 2.95 (dd, J =33.0, 11.5 Hz, 2H), 2.45 (dd, J =13.0, 6.5 Hz, 1H), 2.38 (dd, J =13.0, 6.0 Hz, 1H), 2.23 - 2.16 (m,1H), 2.07 - 1.99 (m, 2H), 1.72 -1.59 (m, 4H). 13 C NMR (125 MHz,DMSO- d 6) δ 175.16, 174.89, 163.76,159.50, 157.93, 153.99, 149.02,130.60, 129.00, 127.46, 124.58,123.87, 122.12, 118.02, 115.64,114.12, 113.99, 101.61, 72.53,66.92, 61.61, 55.65, 54.13, 53.94,40.61, 29.04. <!-- 22 -->]]> X15 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.75(d, J = 2.5 Hz, 1H), 8.40 (s, 1H),8.15 (d, J = 2.5 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.53 - 7.50 (m,2H), 7.34 (d, J = 8.5 Hz, 1H),7.18 (d, J = 2.5 Hz, 1H), 7.09(dd, J = 9.0, 2.5 Hz, 1H), 7.01 -6.98 (m, 2H), 6.80 (d, J = 2.5 Hz,1H), 6.65 (dd, J = 9.0, 3.0 Hz,1H), 4.98 (s, 1H), 4.15 (dd, J =9.5, 3.0 Hz, 1H), 4.08 - 4.00 (m,2H), 3.78 (s, 3H), 2.95 (dd, J =32.0, 11.5 Hz, 2H), 2.45 (dd, J =12.5, 6.0 Hz, 1H), 2.38 (dd, J =13.0, 6.0 Hz, 1H), 2.24 - 2.18 (m,1H), 2.07 - 2.00 (m, 2H), 1.72 -1.62 (m, 4H). 13 C NMR (125 MHz,DMSO- d 6) δ 175.16, 174.95, 163.76,159.51, 157.93, 153.98, 150.27,131.68, 131.12, 130.60, 127.46,124.59, 123.87, 119.63, 118.03,115.63, 114.13, 113.41, 112.86,101.62, 72.53, 66.93, 61.59,55.66, 54.08, 53.90, 40.55, 28.99.<!-- 23 -->]]> X16 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.77(d, J = 2.0 Hz, 1H), 8.40 (s, 1H),8.31 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.53 - 7.50 (m,2H), 7.18 (d, J = 2.5 Hz, 1H),7.09 (dd, J = 9.0, 2.5 Hz, 1H),7.01 - 6.98 (m, 2H), 6.80 (t, J =2.0 Hz, 1H), 6.61 (d, J = 2.0 Hz,2H), 4.98 (s, 1H), 4.15 (dd, J =10.0, 3.0 Hz, 1H), 4.05 - 3.99 (m,2H), 3.78 (s, 3H), 2.95 (dd, J =32.5, 11.5 Hz, 2H), 2.45 (dd, J =13.0, 6.5 Hz, 1H), 2.38 (dd, J =12.5, 6.0 Hz, 1H), 2.25 - 2.19 (m,1H), 2.04 (td, J = 13.0, 10.0 Hz,2H), 1.72 - 1.62 (m, 4H). 13 C NMR(125 MHz, DMSO- d 6) δ 175.16,174.97, 163.76, 159.50, 157.93,153.98, 152.47, 134.89, 130.60,127.46, 124.59, 123.87, 118.03,117.58, 115.64, 114.13, 110.58,101.62, 72.54, 66.93, 61.59,55.66, 54.07, 53.89, 28.97. <!-- 24 -->]]> X17 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.83(d, J = 2.5 Hz, 1H), 8.34 (s, 1H),7.98 (d, J = 9.0 Hz, 1H), 7.49 -7.46 (m, 2H), 7.39 (dd, J = 7.5,1.0 Hz, 1H), 7.16 - 7.10 (m, 3H),7.04 (dd, J = 9.0, 2.0 Hz, 1H),6.96 - 6.93 (m, 2H), 6.68 - 6.62(m, 2H), 4.96 (s, 1H), 4.12 - 4.09(m, 1H), 4.01 - 3.95 (m, 2H), 3.74(s, 3H), 2.92 (dd, J = 32.5, 11.5Hz, 2H), 2.42 (dd, J = 13.0, 6.0Hz, 1H), 2.35 (dd, J = 12.5, 6.0Hz, 1H), 2.23 - 2.18 (m, 1H), 2.04- 1.97 (m, 2H), 1.71 - 1.60 (m,4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.15, 174.74, 163.74, 159.50,157.91, 153.94, 146.29, 132.84,130.59, 128.88, 127.45, 124.59,123.86, 120.65, 118.04, 115.61,114.11, 113.47, 107.56, 101.59,72.52, 66.93, 61.62, 55.65, 54.10,53.95, 40.63, 29.00. <!-- 25 -->]]> X18 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.65(d, J = 3.0 Hz, 1H), 8.36 (s, 1H),7.99 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.49 - 7.46 (m,2H), 7.14 (d, J = 2.5 Hz, 1H),7.06 - 7.01 (m, 2H), 6.96 - 6.93(m, 2H), 6.79 - 6.77 (m, 1H), 6.75(t, J = 2.0 Hz, 1H), 6.61 (dd, J =8.0, 1.0 Hz, 1H), 4.94 (d, J = 3.5Hz, 1H), 4.11 (dd, J = 10.0, 3.0Hz, 1H), 4.01 - 3.96 (m, 2H), 3.74(s, 3H), 2.91 (dd, J = 32.0, 11.0Hz, 2H), 2.41 (dd, J = 13.0, 6.5Hz, 1H), 2.34 (dd, J = 12.5, 6.0Hz, 1H), 2.20 - 2.14 (m, 1H), 2.04- 1.96 (m, 2H), 1.64 - 1.58 (m,4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.16, 174.91, 163.77, 159.50,157.93, 153.98, 151.77, 131.25,130.60, 127.46, 124.59, 123.87,122.56, 121.18, 118.03, 115.64,114.67, 114.13, 111.50, 101.62,72.54, 66.93, 61.61, 55.66, 54.10,53.92, 40.58, 29.03. <!-- 26 -->]]> X19 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.68(d, J = 3.0 Hz, 1H), 8.40 (s, 1H),8.03 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 3.0 Hz, 1H), 7.53 - 7.50 (m,2H), 7.28 - 7.25 (m, 2H), 7.18 (d, J = 2.5 Hz, 1H), 7.09 (dd, J =9.0, 2.5 Hz, 1H), 7.01 - 6.98 (m,2H), 6.63 - 6.61 (m, 2H), 4.98 (s,1H), 4.15 (dd, J = 9.5, 3.0 Hz,1H), 4.05 - 3.99 (m, 2H), 3.78 (s,3H), 2.95 (dd, J = 32.5, 11.5 Hz,2H), 2.45 (dd, J = 13.0, 6.5 Hz,1H), 2.38 (dd, J = 13.0, 6.5 Hz,1H), 2.22 - 2.17 (m, 1H), 2.06 -1.99 (m, 2H), 1.71 - 1.59 (m, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.16, 174.87, 163.76, 159.51,157.93, 153.98, 149.43, 131.83,130.60, 127.46, 124.59, 123.87,118.03, 115.63, 114.52, 114.13,109.62, 101.62, 72.53, 66.93,61.61, 55.66, 54.12, 53.94, 40.61,29.04, 29.02. <!-- 27 -->]]> X20 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.60(d, J = 3.5 Hz, 1H), 8.40 (s, 1H),8.03 (d, J = 9.0 Hz, 1H), 7.53 -7.51 (m, 3H), 7.18 (d, J = 2.5 Hz,1H), 7.09 (dd, J = 9.0, 2.5 Hz,1H), 7.01 - 6.98 (m, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.5Hz, 2H), 5.00 (s, 1H), 4.17 - 4.14(m, 1H), 4.05 - 4.02 (m, 2H), 3.78(s, 3H), 2.95 (dd, J = 33.0, 11.0Hz, 2H), 2.45 (s, 1H), 2.40 (s,1H), 2.22 - 2.18 (m, 1H), 2.15 (s,3H), 2.04 (d, J = 10.0 Hz, 2H),1.68 - 1.62 (m, 4H). 13 C NMR (126MHz, DMSO- d 6) δ 175.16, 174.74,163.76, 159.50, 157.93, 154.00,147.79, 130.61, 129.61, 127.46,124.58, 123.86, 118.03, 115.65,114.12, 112.76, 101.61, 72.52,66.87, 61.59, 55.66, 54.13, 53.96,29.03, 20.66. <!-- 28 -->]]> X21 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.57(d, J = 3.5 Hz, 1H), 8.36 (s, 1H),7.99 (d, J = 9.0 Hz, 1H), 7.49 -7.47 (m, 3H), 7.14 (d, J = 2.5 Hz,1H), 7.05 (dd, J = 9.0, 2.5 Hz,1H), 6.96 - 6.90 (m, 4H), 6.57 -6.55 (m, 2H), 4.97 (s, 1H), 4.12 -4.09 (m, 1H), 4.01 - 3.96 (m, 2H),3.74 (s, 3H), 2.92 (dd, J = 32.5,9.5 Hz, 2H), 2.41 (q, J = 7.5 Hz,4H), 2.18 - 2.14 (m, 1H), 2.01 (d, J = 17.0 Hz, 2H), 1.64 - 1.58 (m,4H), 1.06 (t, J = 7.5 Hz, 3H). 13 CNMR (125 MHz, DMSO- d 6) δ 175.16,174.74, 163.75, 159.51, 157.93,153.99, 148.02, 134.20, 130.60,128.44, 127.47, 124.59, 123.87,118.04, 115.64, 114.13, 112.75,101.62, 72.50, 66.83, 61.56,55.66, 53.95, 28.99, 27.91, 16.63. <!-- 29 -->]]> X22 <![CDATA[ 1 H NMR (500 MHz, DMSO- d 6) δ 9.82(s, 1H), 8.61 (s, 1H), 8.40 (s,1H), 8.03 (d, J = 8.5Hz, 1H), 7.55- 7.51 (m, 4H), 7.18 (d, J = 2.5Hz, 1H), 7.09 (dd, J = 9.0, 2.5Hz, 1H), 7.01 - 6.98 (m, 2H), 6.72- 6.69 (m, 2H), 4.98 (d, J = 4.5Hz, 1H), 4.15 (dd, J = 9.5, 3.0Hz, 1H), 4.05 - 3.99 (m, 2H), 3.78(s, 3H), 2.95 (dd, J = 32.0, 11.0Hz, 2H), 2.46 (dd, J = 13.0, 6.0Hz, 1H), 2.38 (dd, J = 12.5, 6.0Hz, 1H), 2.25 - 2.20 (m, 1H), 2.25- 2.00 (m, 2H), 1.74 - 1.63 (m,4H). 13 C NMR (125 MHz, DMSO- d 6) δ 175.16, 174.91, 163.76, 159.51,157.93, 153.98, 153.54, 133.93,130.60, 127.46, 124.59, 123.87,120.62, 118.03, 115.63, 114.13,112.04, 101.62, 99.21, 72.53,66.94, 61.59, 55.66, 54.09, 53.91,29.02.]]> Experimental Example 1 Anti-plant pathogenic fungal activity test Test method: The mycelial growth rate method was used to evaluate the in vitro activity of 10 plant pathogenic fungi (Rs of rice sheath blight, Pc of pepper phytophthora, Ss of rapeseed sclerotinia, Ps of kiwifruit stem spot fungus, Bd of grape bud blight fungus, Fo of Fusarium oxysporum, Fg of wheat scab, Cg of anthracnose fungus, Foc of cucumber wilt, and Ab of Chinese cabbage black spot fungus). The commercial fungicide azoxystrobin and the parent fungus gentianin were used as positive controls. The specific steps are as follows: (1) Preparation steps of culture medium: First, weigh 40.0 g potato dextrose agar (PDA), add an appropriate amount of distilled water, heat to boiling, and finally adjust the volume to 1000 mL. Measure 20.0 mL of culture medium with a graduated cylinder, then dispense it into 50 mL Erlenmeyer flasks, autoclave at 120 ℃ for 20 min, and set aside for later use.

[0067] (2) Antifungal activity test procedure: Weigh 10 mg of the compound and dissolve it in 1 mL of DMSO. Add the solution to the sterilized culture medium to make the final concentration 100 mg / mL. μ g / mL, shake thoroughly to mix. Pour the mixed PDA medium from each bottle evenly into three petri dishes (60 mm in diameter) and allow to cool. Using a sterile inoculation needle, inoculate the center of each cooled petri dish with a 5 mm diameter mycelial cake, then seal with sealing film to effectively prevent the intrusion of external contaminants. PDA medium containing the same concentration of DMSO was used as a blank control in this experiment. After several days of incubation at 28 ℃, when the diameter (D) of the blank control group reached the range of 4.5-5.0 mm, the mycelial diameter was determined using the cross-sectional method. Each test compound was tested in triplicate, and the fungal inhibition rate was calculated according to formula (3-2): Inhibition rate I% = (CT) / (C-5) × 100 (3-2) C: Mycelial growth diameter in blank control (unit: mm) T: Diameter of mycelial growth after treatment with the chemical (unit: mm) (3) The results of the bioactivity test against plant pathogenic fungi are shown in Table 3.

[0068] Table 3. In vitro antifungal activity of X1-X22 (100 μL / mL) μ g / mL)

[0069] As can be seen from Table 3, all target compounds are at 100 μ At a concentration of g / mL, all compounds exhibited inhibitory activity against 10 plant fungi. Among them, compounds X1-X4, X6, X13, and X16 showed 100% inhibition of Rs, superior to azoxystrobin (75.5%) and gentiopicrin (52.0%). Compounds X1, X3-X7, X13, and X18 showed 100% inhibition of Fo, superior to azoxystrobin (51.5%) and gentiopicrin (25.4%). Compounds X1-X4 and X13 showed 100% inhibition of Cg, superior to azoxystrobin (66.8%) and gentiopicrin (10.8%). Overall, most compounds showed inhibitory activity against... Rs The inhibition rates of all compounds reached over 90% and were superior to those of the control drug. Therefore, the target compounds have specific inhibitory activity against rice sheath blight pathogen.

[0070] The above experimental activity data show that the argentin derivative containing piperidine-4-carbonylhydrazine has a good inhibitory effect on plant pathogenic fungi, especially rice sheath blight fungus, and can be used as a potential anti-plant pathogen drug with good application prospects.

[0071] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A genistein derivative containing piperidine-4-carbonylhydrazine, characterized in that, The structure is shown in the following formula: ； In the above formula, R is independently selected from one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, and one or more C1-C6 substituted alkoxy groups.

2. The gentianin derivative containing piperidine-4-carbonylhydrazine according to claim 1, characterized in that, The R is an independent halogen of one or more: R = 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 3,4-di-F, 3,5-di-F, 3,4-di-Cl; the alkyl group: R = 4-CH3, 4-CH2CH3, 4-CN; the substituted alkyl group: R = 3-CF3, 4-CF3; the substituted alkoxy group: R = 4-OCF3.

3. A method for preparing the strychnosine derivative of piperidine-4-carbonylhydrazide according to claim 1 or 2, characterized in that the step... include: (1) Using substituted phenylhydrazine and 1-Boc-4-piperidinecarboxylic acid as raw materials, HATU and DIPEA were added as catalysts, and the reaction was carried out at room temperature. After the reaction was completed, the product was poured into water to precipitate, filtered, and intermediate a was obtained; the structural formula of intermediate a is: ; (2) Using intermediate a as raw material, BOC protection is removed under acidic conditions to obtain intermediate b; the structural formula of intermediate b is: ; (3) Using gentianin and epoxybromopropane as raw materials, the reaction is carried out in a solvent under alkaline conditions. After the reaction is completed, ice water is added to precipitate the product. The product is filtered, and the residue is cleaned of impurities to obtain intermediate c. The structural formula of the intermediate c is: ; (4) Using intermediates b and c as raw materials and potassium carbonate as catalyst, the reaction was carried out in a solvent and then purified to obtain a strychnine derivative containing piperidine-4-carbonylhydrazine. The structural formula of the substituted phenylhydrazine is: R is independently selected from one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, and one or more C1-C6 substituted alkoxy groups.

4. The preparation method according to claim 3, characterized in that, The molar ratio of the substituted phenylhydrazine, 1-Boc-4-piperidinecarboxylic acid, HATU and DIPEA in step (1) is 1:(1~2):(1~2):(1~3); the reaction time at room temperature is 10~12 h.

5. The preparation method according to claim 3, characterized in that, The step of removing Boc protection in step (2) includes: dissolving intermediate a in acetonitrile, heating to 50~80℃, adding trifluoroacetic acid dropwise at a molar ratio of 1:5~10, heating under reflux for 2~5h to remove Boc protection.

6. The preparation method according to claim 3, characterized in that, The molar ratio of gentianin, epichlorohydrin and potassium carbonate in step (3) is 1:(1~4):(1~4); the reaction time at room temperature is 10~12 h.

7. The preparation method according to claim 3, characterized in that, The molar ratio of intermediate b, intermediate c and K2CO3 in step (4) is 1:(1~2):(2~4), and the heating and reflux time is 3~6h.

8. The preparation method according to claim 3, characterized in that, The purification step described in step (4) is as follows: the reaction system after heating and reflux is poured into ice water to precipitate the product, filtered, the filter residue is collected, and purified by silica gel column chromatography (dichloromethane:methanol=15:1, v / v).

9. The use of the 4-carbon-piperidinylhydrazine derivative of claim 1 or 2 in the preparation of a drug for inhibiting plant pathogenic fungi.

10. The application according to claim 9, characterized in that, The plant pathogenic fungi include *Rs*, *Phytophthora*, *S.*, *S.*, *P.*, *S.*, *P.*, *P.*, *B.*, *B.*, *F.*, *F.*, *F.*, *C.*, *C.*, *F.*, *F.*, *F.*, *F.*, *F.*, *F.*, *F.*, *F.*, *F.*, and *F.*, *B.*, *B.*, and *B.*, *B.*, *B.*, and *B.*, *B.*, respectively.

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