A formononetin derivative containing benzylpiperidine and its preparation method and application

Abstract

The present invention discloses a benzylpiperidine-containing formononetin derivative, a preparation method, and an application thereof, belonging to the technical field of pesticide synthesis. The present invention introduces a benzylpiperidine group with excellent activity into the structure of formononetin to synthesize a series of formononetin derivatives containing benzylpiperidine. Testing of the inhibitory activity of the synthesized formononetin derivatives containing benzylpiperidine against plant pathogenic bacteria reveals that the synthesized formononetin derivatives containing benzylpiperidine can effectively inhibit plant pathogenic bacteria, particularly Xanthomonas.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticide synthesis, and particularly relates to a formononetin derivative containing benzylpiperidine, a preparation method and an application thereof. Background Art

[0002] Bacterial plant diseases cause severe reductions in crop yield and quality. Examples include rice bacterial blight caused by Xanthomonas oryzae, citrus canker caused by Xanthomonas citri, mango angular leaf spot caused by Xanthomonas mangoes, and strawberry angular leaf spot caused by Xanthomonas fragariae. These pathogens pose challenges and obstacles to agricultural production worldwide due to their rapid reproduction, strong transmission, and susceptibility to drug resistance. Pesticides are key to controlling these diseases. Currently, chemically synthesized antimicrobial agents are primarily used to reduce and control the severity of these diseases. However, long-term, irrational use not only leads to drug resistance in pathogens but also negatively impacts human health and the environment. A sustainable strategy to combat these diseases is to identify and alternate new antimicrobial agents with low toxicity, good environmental compatibility, and unique mechanisms of action.

[0003] Botanical green pesticides offer advantages such as high efficiency, low toxicity, high selectivity, and resistance to pests and diseases. With environmental protection gaining increasing attention, they have attracted widespread attention in the global pesticide industry, providing opportunities and a vast market for their development. Therefore, identifying antibacterial active ingredients from plants and modifying and transforming them into effective precursors for innovative pesticides is a key approach to developing botanical green pesticides.

[0004] Formononetin (FMN, 7-hydroxy-4'-methoxyisoflavonoid) is a member of the isoflavone family and is widely found in leguminous plants such as Astragalus, Glycyrrhiza, Pueraria, and Tripterygium wilfordii. Modern pharmacological studies have shown that formononetin not only exhibits antibacterial, antitumor, antilipid, antiarrhythmic, and antilipid peroxidation properties, but also improves atherosclerosis, scavenges oxygen free radicals, and inhibits vascular smooth muscle cell proliferation. In 2008, Yang et al. synthesized 17 novel formononetin derivatives and screened their antibacterial activity. The results showed that some of these compounds exhibited excellent antibacterial activity against Bacillus subtilis, with a minimum inhibitory concentration (MIC) of 0.78 μg / mL. In 2016, Zhang et al. reported a structurally modified formononetin compound that exhibited potent inhibitory activity against Helicobacter pylori, demonstrating high clinical value and providing a new therapeutic option for H. pylori. In 2019, Yang et al. reported a series of formononetin derivatives with anti-breast cancer effects. The experimental results showed that the synthesized compounds had inhibitory activity against breast cancer cells SUM159 and MCF-7, with the optimal IC50 being 0.36μM, and can be used to treat breast cancer. In 2020, Besbas et al. extracted a formononetin glycoside from Solanum nigrum and studied its biological activity. The results showed that the analogue had good antioxidant, anti-hemolytic, and anti-inflammatory activities. A large number of literature surveys found that research on formononetin and its derivatives mainly focused on the medical field, and their clinical application had significant efficacy, but there were few applications and reports on formononetin and its derivatives in the pesticide field.

[0005] Piperidine is a nitrogen-containing heterocyclic ring commonly found in natural alkaloids. It not only possesses a broad spectrum of biological activities, including antibacterial, antiviral, anticancer, and antioxidant activities, but also offers advantages such as good selectivity, high activity, and low toxicity. Examples include the broad-spectrum anticonvulsant piperine, the antimalarial active ingredient febrifugine, the immunosuppressant rapamycin, and the antibiotic cycloheximide. In the pharmaceutical and pesticide fields, piperidine is an important pharmacophore, and its derivatives possess a wide range of pharmacological activities, including antibacterial, anti-inflammatory, antiviral, anticancer, antimalarial, and antipsychotic activities. This makes piperidine a highly favored scaffold in drug synthesis, and piperidine-containing molecular building blocks are frequently used in the synthesis of small drug molecules. Benzylpiperidine is an important intermediate compound commonly used in organic synthesis. It can act as a catalyst, ligand, or raw material in various chemical reactions, such as carbonylation, diazotization, and Michael addition.

[0006] In summary, there has been no research on the introduction of benzylpiperidine into the structure of formononetin to synthesize formononetin derivatives containing benzylpiperidine, nor has there been any research on the agricultural activity of formononetin derivatives containing benzylpiperidine. Summary of the Invention

[0007] The present invention aims to provide a formononetin derivative containing benzylpiperidine and its preparation method and application. The provided formononetin derivative containing benzylpiperidine can be used to inhibit plant pathogenic bacteria, especially Xanthomonas.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] One of the technical solutions of the present invention is to provide a formononetin derivative containing benzylpiperidine, the structure of which is shown in the following formula:

[0010]

[0011] In the above formula, n is an integer from 2 to 6, and R is independently selected from H, one or more halogens, one or more nitro groups, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, one or more C1-C6 alkoxy groups, or one or more C1-C6 substituted alkoxy groups.

[0012] Preferably, the halogen is F, Cl or Br.

[0013] The second technical solution of the present invention is to provide a method for preparing the formononetin derivative containing benzylpiperidine, comprising the following steps:

[0014] (1) Using formononetin and dibromoalkane as raw materials, heat the reaction in a solvent under alkaline conditions. After the reaction is completed, ice water is added to precipitate the product, which is then filtered and the residue is cleaned to obtain intermediate a.

[0015] The structural formula of the dibromoalkane is: , where n is an integer from 2 to 6;

[0016] The structural formula of the intermediate a is: , where n is an integer from 2 to 6;

[0017] (2) Using intermediate a and 1-boc-4-methylaminopiperidine as raw materials and potassium carbonate as catalyst, heating reaction is carried out in a solvent to obtain intermediate b;

[0018] The structural formula of the intermediate b is: , where n is an integer from 2 to 6;

[0019] (3) Using intermediate b as the starting material, remove the boc protection to obtain intermediate c;

[0020] The structural formula of the intermediate c is: , where n is an integer from 2 to 6;

[0021] (4) Using intermediate c and substituted benzyl chloride as raw materials and potassium carbonate as catalyst, the formononetin derivative containing benzylpiperidine is prepared under heating and reflux;

[0022] The structural formula of the substituted benzyl chloride is: , wherein R is independently selected from H, one or more halogens, one or more nitro groups, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, one or more C1-C6 alkoxy groups, or one or more C1-C6 substituted alkoxy groups.

[0023] Preferably, the molar ratio of formononetin to dibromoalkane in step (1) is 11.0:(54.8-109.6); the temperature of the heating reaction is 80°C and the time is 4-10 hours; the alkaline condition is provided by anhydrous potassium carbonate; and the impurity removal step comprises: washing the filter residue with water and petroleum ether in sequence, then beating, standing, filtering, and completing the washing.

[0024] More preferably, the molar ratio of formononetin to anhydrous potassium carbonate in step (1) is 11.0:32.9; and the solution used for pulping is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1.

[0025] Preferably, the molar ratio of the intermediate a, 1-boc-4-methylaminopiperidine and potassium carbonate in step (2) is 3.9:(3.9-7.7):(11.6-38.5); the temperature of the heating reaction is 80° C., and the time is 4-10 h; and a purification step is further included after the heating reaction.

[0026] More preferably, the purification step specifically comprises: filtering the reaction system after the heating reaction, evaporating the filtrate to dryness, and performing column chromatography to complete purification; wherein the eluent used for the column chromatography is ethyl acetate.

[0027] Preferably, the step of removing the boc protection in step (3) comprises: dissolving the intermediate b in methanol, heating to 40-80°C, adding dropwise a 15-37% HCl solution by mass, reacting for 1-4 h, and removing the boc protection.

[0028] Preferably, the step (3) further includes a separation step after the removal of the BOC protection. The separation step is specifically as follows: after the removal of the BOC protection, the reaction system is poured into ice water, the system is adjusted to 8-9 using a 5 wt % NaHCO 3 solution, and then extracted with dichloromethane. The extract is evaporated to dryness to obtain intermediate b.

[0029] Preferably, in step (4), the molar ratio of the intermediate c, substituted benzyl chloride and potassium carbonate is 1.2:(1.2-1.4):(2.4-3.6); and the heating reflux time is 1-2 h.

[0030] Preferably, the step (4) further includes a purification step after the heating and reflux, and the purification step specifically includes: pouring the reaction system after heating and reflux into water, extracting with dichloromethane, evaporating the extract to dryness, and performing column chromatography to complete purification; wherein the eluent used for column chromatography is a mixture of dichloromethane and methanol in a volume ratio of 40:1.

[0031] The third technical solution of the present invention is to provide an application of the above-mentioned formononetin derivative containing benzylpiperidine in the preparation of drugs for inhibiting plant pathogenic bacteria.

[0032] Preferably, the plant pathogenic bacteria include one or more of X. oryzae var. oryzae, Xoo; X. citrus canker, Xac; Xcm. mango bacterial angular leaf spot fungus; Xf. strawberry angular leaf spot fungus; Psa. actinidia var. solanacearum; Pcb. potato soft rot fungus; Ac. melon fruit spot fungus; and Ps. tomato bacterial wilt fungus.

[0033] The beneficial technical effects of the present invention are as follows:

[0034] The present invention provides a benzylpiperidine-containing formononetin derivative, a preparation method and an application thereof. The present invention introduces a benzylpiperidine group with excellent activity into the structure of formononetin, and synthesizes a series of formononetin derivatives containing benzylpiperidine. By testing the inhibitory activity of the synthesized formononetin derivatives containing benzylpiperidine on plant pathogenic bacteria, it is found that the synthesized formononetin derivatives containing benzylpiperidine can effectively inhibit plant pathogenic bacteria, especially Xanthomonas. DETAILED DESCRIPTION

[0035] Various exemplary embodiments of the present invention are now described in detail. This detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terms used in the present invention are only for describing specific embodiments and are not intended to limit the present invention.

[0036] In addition, for numerical ranges in the present invention, it is understood that each intervening value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between any stated value or stated range, and any other stated value or intervening value in the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention.

[0038] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0039] One of the technical objectives of the present invention is to provide a formononetin derivative containing benzylpiperidine, the structure of which is shown in the following formula:

[0040]

[0041] In the above formula, n is an integer from 2 to 6, and R is independently selected from H, one or more halogens, one or more nitro groups, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, one or more C1-C6 alkoxy groups, or one or more C1-C6 substituted alkoxy groups.

[0042] Preferably, the halogen is F, Cl or Br.

[0043] The second technical purpose of the present invention is to provide a method for preparing the above-mentioned formononetin derivative containing benzylpiperidine, the steps comprising:

[0044] (1) Using formononetin and dibromoalkane as raw materials, heat the reaction at 80°C in an alkaline solvent for 4-10 hours. After the reaction is complete, the reaction system is dispersed with ice water, filtered, washed, and slurried to obtain intermediate a.

[0045] The reaction formula is as follows:

[0046]

[0047] In some embodiments, the solvent is ethanol; after the reaction is completed, the reaction solution is dispersed with ice water to precipitate solids; after the precipitated solids, filtration and washing steps are further performed; the washing is performed with water and petroleum ether respectively; the slurrying is performed with petroleum ether / ethyl acetate = 3:1 (v / v);

[0048] Wherein, the molar ratio of the formononetin to the dibromoalkane is 11.0:(54.8-109.6); the molar ratio of the formononetin to anhydrous potassium carbonate is 11.0:32.9;

[0049] (2) Intermediate a and 1-boc-4-methylaminopiperidine were used as raw materials and potassium carbonate was used as catalyst to react in acetonitrile solvent at 80°C for 8-10 hours to prepare intermediate b;

[0050] The reaction formula is as follows:

[0051]

[0052] In some embodiments, after the reaction is completed, the process further comprises filtration, vacuum rotary evaporation, and column chromatography; the filtration is to remove insoluble matter; the column chromatography uses pure ethyl acetate as an eluent;

[0053] Wherein, the molar ratio of the intermediate a, 1-boc-4-methylaminopiperidine and potassium carbonate is 3.9:(3.9-7.7):(11.6-38.5);

[0054] (3) Using intermediate b as raw material and methanol as solvent, add 15-37 wt.% HCl solution dropwise at a temperature of 40-80 °C for 1-4 h to remove the boc protection, then pour the reaction system into ice water and adjust the system to alkaline with NaHCO3 aqueous solution to prepare intermediate c;

[0055] The reaction formula is as follows:

[0056]

[0057] In some embodiments, the concentration of the NaHCO3 aqueous solution is 5 wt.%; the alkaline pH value is 8-9; after adjusting to alkalinity, the process further comprises extraction and vacuum rotary evaporation; the extraction is performed using dichloromethane;

[0058] (4) Using intermediate c and substituted benzyl chloride as raw materials and potassium carbonate as catalyst, a benzylpiperidine-containing formononetin derivative was prepared by refluxing in a solvent;

[0059] The reaction formula is as follows:

[0060]

[0061] In some embodiments, the solvent is acetonitrile; the reflux reaction time is 1 to 2 hours; after the reaction is completed, the reaction system is dispersed in water, and then extracted, dried, vacuum rotary evaporation, and column chromatography are performed, and the column chromatography eluent is a mixture of dichloromethane and methanol in a volume ratio of 40:1.

[0062] The molar ratio of the intermediate c, substituted benzyl chloride and potassium carbonate is 1.2:(1.2-1.4):(2.4-3.6).

[0063] The third technical purpose of the present invention is to provide an application of the above-mentioned formononetin derivative containing benzylpiperidine in the preparation of drugs for inhibiting plant pathogenic bacteria.

[0064] To achieve the above technical objectives, the present invention provides the following embodiments.

[0065] Example 1

[0066] 7-(3-((1-benzylpiperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number H1), the steps are as follows:

[0067] (1) Synthesis of 7-(3-bromopropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one: Formononetin (3.0 g, 11.0 mmol), anhydrous potassium carbonate (4.5 g, 32.9 mmol), and 80 mL of ethanol were added to a 250 mL three-necked flask and heated to 80°C with stirring for 0.5 h. Dibromopropane (5.6 mL, 54.8 mmol) was then slowly added and allowed to react for 6 h. After the reaction was completed, the flask was dispersed with 500 mL of ice water to precipitate a large amount of solid. The solid was filtered, washed several times with water and petroleum ether, and dried. The resulting white solid was then slurried with 60 mL of a solvent of petroleum ether / ethyl acetate = 3:1, v / v, overnight and filtered to obtain a white solid with a yield of 85.6%.

[0068] (2) Synthesis of tert-butyl-4-((3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)propyl)(methyl)amino)piperidine-1-carboxylate: 1-boc-4-methylaminopiperidine (1.65 g, 7.71 mmol) and anhydrous K2CO3 (5.33 g, 38.54 mmol) were added to 250 mL of acetonitrile solution and stirred at room temperature for 0.5 h. Then, 7-(3-bromopropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (1.5 g, 3.85 mmol) was added to the system and the temperature was raised to 80°C for 8 h. After the reaction was completed, the mixture was filtered and the filter cake was washed with dichloromethane. The filtrate was collected and evaporated under reduced pressure. The product was then purified by column chromatography using pure ethyl acetate to obtain a white solid with a yield of 64.3%.

[0069] (3) Preparation of 3-(4-methoxyphenyl)-7-(3-(methyl(piperidin-4-yl)amino)propoxy)-4H-chromen-4-one: The product in step (2) was dissolved in 50 mL of methanol in a 100 mL single-necked flask, and 6 mL of 15 wt.% aqueous hydrochloric acid solution was added dropwise. The mixture was refluxed at 60°C for 2 h. After the reaction was completed, a large amount of solvent was removed by vacuum evaporation, and the system was dispersed in 100 mL of water. The pH value was then adjusted to 8-9 with 5 wt.% NaHCO3 solution, and the mixture was extracted with dichloromethane. The organic phase was collected and the solvent was removed by vacuum evaporation to obtain an oily product with a yield of 87.3%.

[0070] (4) Synthesis of 7-(3-((1-benzylpiperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one: 3-(4-methoxyphenyl)-7-(3-(methyl(piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (0.5 g, 1.18 mmol), anhydrous K2CO3 (0.33 g, 2.37 mmol), and 20 mL of acetonitrile were added to a 50 mL round-bottom flask. The mixture was heated to reflux and stirred for 0.5 h. Benzyl chloride (170 μL, 1.42 mmol) was slowly added dropwise and the reaction was continued for 2 h. After the reaction was completed, the system was dispersed into a 100 mL flask. The product was added to 1 mL of water and extracted three times with dichloromethane. The organic phase was collected and dried over anhydrous Na2SO4. The crude product was evaporated under reduced pressure and then purified by column chromatography (dichloromethane:methanol = 40:1, v / v) to obtain the target compound in a yield of 57%.

[0071] Example 2

[0072] Synthesis of 7-(3-((1-(4-chlorobenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H2) was prepared by the same steps as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-chlorobenzyl chloride. Yield: 44%.

[0073] Example 3

[0074] The synthesis of 7-(3-((1-(3-chlorobenzyl)piperidin-4-yl)(methyl 1)amino)propoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number H3) was carried out in the same manner as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-chlorobenzyl chloride. Yield: 43%.

[0075] Example 4

[0076] The synthesis of 7-(3-((1-(2-chlorobenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H4) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-chlorobenzyl chloride. Yield: 58%.

[0077] Example 5

[0078] The synthesis of 7-(3-((1-(4-fluorobenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H5) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-fluorobenzyl chloride. Yield: 50%.

[0079] Example 6

[0080] The synthesis of 7-(3-((1-(3-fluorobenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H6) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-fluorobenzyl chloride. Yield: 66%.

[0081] Example 7

[0082] Synthesis of 7-(3-((1-(2-fluorobenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H7) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-fluorobenzyl chloride. Yield: 51%

[0083] Example 8

[0084] The synthesis of 7-(3-((1-(4-bromobenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H8) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-bromobenzyl chloride. Yield: 47%.

[0085] Example 9

[0086] The synthesis of 7-(3-((1-(2-bromobenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H9) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-bromobenzyl chloride. Yield: 60%.

[0087] Example 10

[0088] The synthesis of 3-(4-methoxyphenyl)-7-(3-(methyl(1-(4-methylbenzyl)piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (Compound No. H10) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-methylbenzyl chloride. Yield: 54%.

[0089] Example 11

[0090] The synthesis of 3-(4-methoxyphenyl)-7-(3-(methyl(1-(3-methylbenzyl)piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (Compound No. H11) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-methylbenzyl chloride. Yield: 50%.

[0091] Example 12

[0092] The synthesis of 3-(4-methoxyphenyl)-7-(3-(methyl(1-(2-methylbenzyl)piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (Compound No. H12) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-methylbenzyl chloride. Yield: 54%.

[0093] Example 13

[0094] The synthesis of 7-(3-((1-(4-methoxybenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H13) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-methoxybenzyl chloride. Yield: 48%.

[0095] Example 14

[0096] The synthesis of 7-(3-((1-(3-methoxybenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H14) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-methoxybenzyl chloride. Yield: 58%.

[0097] Example 15

[0098] The synthesis of 3-(4-methoxyphenyl)-7-(3-(methyl(1-(4-nitrobenzyl)piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (Compound No. H15) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-nitrobenzyl chloride. Yield: 75%.

[0099] Example 16

[0100] The synthesis of 3-(4-methoxyphenyl)-7-(3-(methyl(1-(3-nitrobenzyl)piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (Compound No. H16) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (5) was replaced with an equimolar amount of 3-nitrobenzyl chloride. Yield: 62%.

[0101] Example 17

[0102] The synthesis of 3-(4-methoxyphenyl)-7-(3-(methyl(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (Compound No. H17) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-trifluoromethylbenzyl chloride. Yield: 58%.

[0103] Example 18

[0104] The synthesis of 3-(4-methoxyphenyl)-7-(3-(methyl(1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (Compound No. H18) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-nitrobenzyl chloride. Yield: 32%.

[0105] Example 19

[0106] The synthesis of 7-(3-((1-(2,4-dichlorobenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H19) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2,4-dichlorobenzyl chloride. Yield: 58%.

[0107] Example 20

[0108] The synthesis of 7-(3-((1-(3,4-dimethylbenzyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H20) was carried out using the same procedures as in Example 1, except that the benzyl chloride in step (5) was replaced with an equimolar amount of 3,4-dimethylbenzyl chloride. Yield: 38%.

[0109] Example 21

[0110] The synthesis of 7-(4-((1-benzylpiperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number H21) was performed as follows:

[0111] (1) Synthesis of 7-(4-bromobutoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one: The same as step 1 of Example 1, except that 1,3-dibromopropane was replaced with an equimolar amount of 1,4-dibromobutane.

[0112] (2) Synthesis of tert-butyl 4-((4-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)butyl)(methyl)amino)piperidine-1-carboxylate: The same as step 2 of Example 1, except that 7-(3-bromopropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one was replaced with an equal molar amount of 7-(4-bromobutoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one.

[0113] (3) Preparation of 3-(4-methoxyphenyl)-7-(4-(methyl(piperidin-4-yl)amino)butoxy)-4H-chromen-4-one: The same as step 3 of Example 1, except that tert-butyl-4-((3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)propyl)(methyl)amino)piperidine-1-carboxylate was replaced with an equimolar amount of tert-butyl 4-((4-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)butyl)(methyl)amino)piperidine-1-carboxylate.

[0114] (4) Synthesis of 7-(4-((1-benzylpiperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one: 7-(4-((1-benzylpiperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (0.5 g, 1.5 mmol) and anhydrous K2CO3 (0.32 g, 2.29 mmol) were added to 20 mL of acetonitrile solution in a 50 mL round-bottom flask. The mixture was heated to reflux and stirred for 30 min. Benzyl chloride (165 μL, 1.37 mmol) was slowly added dropwise and the reaction was continued for 2 h. After the reaction was completed, the system was dispersed in a 100 mL flask. The product was added to 1 mL of water and extracted with dichloromethane three times. The organic phase was collected and dried over anhydrous Na2SO4. The crude product was evaporated under reduced pressure and then purified by column chromatography (dichloromethane:methanol = 40:1, v / v) to obtain the target compound in a yield of 45%.

[0115] Example 22

[0116] The synthesis of 7-(4-((1-(4-chlorobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H22) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-chlorobenzyl chloride. Yield: 68%.

[0117] Example 23

[0118] The synthesis of 7-(4-((1-(3-chlorobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H23) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-chlorobenzyl chloride. Yield: 41%.

[0119] Example 24

[0120] The synthesis of 7-(4-((1-(2-chlorobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H24) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-chlorobenzyl chloride. Yield: 44%.

[0121] Example 25

[0122] The synthesis of 7-(4-((1-(4-fluorobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H25) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-fluorobenzyl chloride. Yield: 61%.

[0123] Example 26

[0124] The synthesis of 7-(4-((1-(3-fluorobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H26) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-fluorobenzyl chloride. Yield: 77%.

[0125] Example 27

[0126] The synthesis of 7-(4-((1-(2-fluorobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H27) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-fluorobenzyl chloride. Yield: 38%.

[0127] Example 28

[0128] The synthesis of 7-(4-((1-(4-bromobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H28) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-bromobenzyl chloride. Yield: 41%.

[0129] Example 29

[0130] The synthesis of 7-(4-((1-(3-bromobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H29) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equal molar amount of 3-bromobenzyl chloride. Yield: 43%.

[0131] Example 30

[0132] The synthesis of 3-(4-methoxyphenyl)-7-(4-(methyl(1-(4-methylbenzyl)piperidin-4-yl)amino)butoxy)-4H-chromen-4-one (Compound No. H30) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-methylbenzyl chloride. Yield: 58%.

[0133] Example 31

[0134] The synthesis of 3-(4-methoxyphenyl)-7-(4-(methyl(1-(3-methylbenzyl)piperidin-4-yl)amino)butoxy)-4H-chromen-4-one (Compound No. H31) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-methylbenzyl chloride. Yield: 56%.

[0135] Example 32

[0136] The synthesis of 3-(4-methoxyphenyl)-7-(4-(methyl(1-(3-methylbenzyl)piperidin-4-yl)amino)butoxy)-4H-chromen-4-one (Compound No. H32) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-methylbenzyl chloride. Yield: 57%.

[0137] Example 33

[0138] The synthesis of 7-(4-((1-(4-methoxybenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H33) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-methoxybenzyl chloride. Yield: 62%.

[0139] Example 34

[0140] The synthesis of 7-(4-((1-(3-methoxybenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H34) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-methoxybenzyl chloride. Yield: 53%.

[0141] Example 35

[0142] The synthesis of 7-(4-((1-(4-nitrobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H35) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-nitrobenzyl chloride. Yield: 32%.

[0143] Example 36

[0144] The synthesis of 7-(4-((1-(3-nitrobenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H36) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-nitrobenzyl chloride. Yield: 47%.

[0145] Example 37

[0146] The synthesis of 7-(4-((1-(4-trifluoromethylbenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H37) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 4-trifluoromethylbenzyl chloride. Yield: 63%.

[0147] Example 38

[0148] The synthesis of 7-(4-((1-(3-trifluoromethylbenzyl)piperidin-4-yl)(methyl)amino)butoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H38) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3-trifluoromethylbenzyl chloride. Yield: 42%.

[0149] Example 39

[0150] The synthesis of 7-(4-((1-(2,4-dichlorobenzyl)piperidin-4-yl)(methyl)amino)butoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H39) was carried out using the same procedures as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2,4-dichlorobenzyl chloride. Yield: 42%.

[0151] Example 40

[0152] The synthesis of 7-(4-((1-(3,4-dimethylbenzyl)piperidin-4-yl)(methyl)amino)butoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (Compound No. H40) was carried out in the same manner as in Example 21, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 3,4-dimethylbenzyl chloride. Yield: 53%.

[0153] The physicochemical properties and mass spectrometry data of the formononetin derivatives containing benzylpiperidine synthesized in Examples 1 to 40 are shown in Table 1. The H NMR spectrum ( 1 H NMR) and carbon spectroscopy ( 13 C NMR) data are shown in Table 2.

[0154] Table 1 Physicochemical properties of target compounds and their mass spectrometry analysis data

[0155] Compound Yield (%) Traits Melting point (℃) HRMS, m / z (calcd.) H1 57% White solid 73-74 <![CDATA[513.27478(513.27441)[M+H] + ]]> H2 44% White solid 70-71 <![CDATA[547.23581(547.23529)[M+H] + ]]> H3 43% White solid 91-92 <![CDATA[547.23581(547.23529)[M+H] + ]]> H4 58% White solid 74-75 <![CDATA[547.23581(547.23535)[M+H] + ]]> H5 50% White solid 99-100 <![CDATA[531.26536(531.26477)[M+H] + ]]> H6 66% White solid 67-69 <![CDATA[531.26536(531.26489)[M+H] + ]]> H7 51% White solid 63-64 <![CDATA[531.26536(531.26489)[M+H] + ]]> H8 47% White solid 67-68 <![CDATA[591.18530(591.18481)[M+H] + ]]> H9 60% White solid 89-91 <![CDATA[591.18530(591.18475)[M+H] + ]]> H10 54% White solid 66-67 <![CDATA[527.29043(527.29010)[M+H] + ]]> H11 50% White solid 91-93 <![CDATA[527.29043(527.28992)[M+H] + ]]> H12 54% White solid 74-76 <![CDATA[527.29043(527.29010)[M+H] + ]]> H13 48% White solid 68-69 <![CDATA[543.28535(543.28497)[M+H] + ]]> H14 58% White solid 64-65 <![CDATA[543.28535(543.28491)[M+H] + ]]> H15 75% White solid 62-63 <![CDATA[558.25986(558.25958)[M+H] + ]]> H16 62% White solid 77-79 <![CDATA[558.25986(558.25958)[M+H] + ]]> H17 58% White solid 69-71 <![CDATA[581.26217(581.26178)[M+H] + ]]> H18 32% White solid 70-71 <![CDATA[581.26217(581.26172)[M+H] + ]]> H19 58% White solid 64-65 <![CDATA[581.19684(581.19635)[M+H] + <!-- 11 -->]]> H20 38% White solid 50-51 <![CDATA[541.30608(541.30591)[M+H] + ]]> H21 45% White solid 84-85 527.29043(527.28992)[M+H]+ H22 68% White solid 95-96 561.25146(561.25098)[M+H]+ H23 41% White solid 84-85 561.25146(561.25098)[M+H]+ H24 44% White solid 98-99 561.25146(561.25073)[M+H]+ H25 61% White solid 83-84 545.28101(545.28052)[M+H]+ H26 77% White solid 75-76 545.28101(545.28052)[M+H]+ H27 38% White solid 89-90 545.28101(545.28058)[M+H]+ H28 41% White solid 109-110 605.20095(605.20038)[M+H]+ H29 43% White solid 77-78 605.20095(605.20032)[M+H]+ H30 58% White solid 95-96 541.30608(541.30646)[M+H]+ H31 56% White solid 92-94 541.30608(541.30566)[M+H]+ H32 57% White solid 82-84 541.30608(541.30573)[M+H]+ H33 62% White solid 87-88 557.30100(557.30011)[M+H]+ H34 53% White solid 71-72 557.30100(557.30060)[M+H]+ H35 32% White solid 97-99 572.27551(572.27490)[M+H]+ H36 47% White solid 80-82 572.27551(572.27502)[M+H]+ H37 63% White solid 86-88 595.27782(595.27728)[M+H]+ H38 42% White solid 80-82 595.27782(595.27728)[M+H]+ H39 43% White solid 109-111 595.21249(595.21179)[M+H]+ H40 51% White solid 101-103 555.32173(555.32141)[M+H]+

[0156] Table 2 NMR spectrum data of target compounds

[0157] Compound <![CDATA[ 1 H NMR and 13 C NMR (TMS as internal standard) H1 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91(s, 1H), 7.53 – 7.46 (m, 2H), 7.31 (d, J = 6.2 Hz, 4H),7.24 (dd, J = 6.1, 2.8 Hz, 1H), 6.97 (dd, J = 8.9, 2.4 Hz,3H), 6.84 (d, J = 2.3 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H),3.84 (s, 3H), 3.49 (s, 2H), 3.02 – 2.83 (m, 2H), 2.65 (t, J= 7.0 Hz, 2H), 2.41 (tt, J = 11.6, 3.8 Hz, 1H), 2.30 (s,3H), 2.05 – 1.88 (m, 4H), 1.76 – 1.68 (m, 2H), 1.60 (qd, J= 12.2, 3.8 Hz, 2H); 13 C NMR (125 MHz, CDCl3)δ 175.88,163.36, 159.45, 157.88, 152.02, 138.10, 130.09, 129.19,128.15, 127.63, 126.99, 124.74, 124.19, 118.18, 114.86,113.87, 100.46, 66.63, 63.00, 61.35, 55.29, 53.16, 49.72,37.86, 27.55, 27.22. <!-- 12 -->]]> H2 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.91(s, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.28 – 7.29 (m, 4H),6, 2.96 (dd 6.83 (d, J = 2.2 Hz, 1H),4.10 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.44 (s, 2H), 2.91(d, J = 11.6 Hz, 2H), 2, J, 4.71 (H0, J = Hz). 11.3 Hz, 1H), 2.35 (s, 3H), 2.04 (q, J = 6.5 Hz, 2H),1.96 (t, J = 11.2 Hz, 2H), 1.76 (d, J = 12.0 Hz, 2H), 1, 6 = 61(tt, 2H); 13 C NMR (125 MHz, CDCl3) δ175.83, 163.22, 159.44, 157.84, 152.02, 136.58, 132.68,130.35, 130.06, 1738.29, [124.13, 118.23,114.78, 113.86, 100.47, 66.47, 62.07, 61.44, 55.28, 52.94,49.86, 37.64, 27.83]] H3 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.48 (m, 2H), 7.31 (s, 1H), 7.23 (d, J = 6.1Hz, 2H), 7.17 (dd, J = 6.3, 1.9 Hz, 1H), 6.99 – 6.95 (m,3H), 6.84 (d, J = 2.3 Hz, 1H), 4.11 (t, J = 6.1 Hz, 2H),3.84 (s, 3H), 3.45 (s, 2H), 2.91 (d, J = 11.7 Hz, 2H), 2.67(t, J = 7.0 Hz, 2H), 2.43 (t, J = 11.3 Hz, 1H), 2.32 (s,3H), 2.02 – 1.93 (m, 4H), 1.73 (d, J = 12.0 Hz, 2H), 1.64 –1.56 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 175.86, 163.32,159.45, 157.87, 152.02, 140.56, 134.04, 130.08, 129.41,128.94, 127.64, 127.12, 127.10, 124.75, 124.18, 118.21,114.84, 113.87, 100.47, 66.59, 62.35, 61.38, 55.30, 53.17,49.77, 37.82, 27.54, 27.15.]]> H4 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.48 (m, 2H), 7.46 (dd, J = 7.6, 1.4 Hz, 1H),7.33 (dd, J = 7.8, 1.2 Hz, 1H), 7.22 (dd, J = 7.5, 1.2 Hz,1H), 7.18 (dd, J = 7.6, 1.7 Hz, 1H), 6.99 – 6.96 (m, 3H),6.85 (d, J = 2.3 Hz, 1H), 4.11 (t, J = 6.1 Hz, 2H), 3.84(s, 3H), 3.60 (s, 2H), 2.97 (d, J = 11.7 Hz, 2H), 2.68 (t,J = 7.0 Hz, 2H), 2.44 (d, J = 11.5 Hz, 1H), 2.32 (s, 3H),2.08 (t, J = 10.9 Hz, 2H), 2.03 – 1.98 (m, 2H), 1.74 (d, J= 12.0 Hz, 2H), 1.63 (td, J = 12.0, 3.4 Hz, 2H); 13 C NMR (125MHz, CDCl3) δ 175.87, 163.34, 159.45, 157.88, 152.02,136.05, 134.12, 130.55, 130.09, 129.33, 128.00, 127.65,126.56, 124.76, 124.19, 118.21, 114.86, 113.88, 100.47,66.63, 61.38, 59.08, 55.31, 53.31, 49.80, 37.86, 27.67,27.17. <!-- 13 -->]]> H5 <![CDATA[ 1 H NMR (500 MHz, CDCl3)δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.50 – 7.47 (m, 2H), 7.24 (dd, J = 7.1, 4.2 Hz, 2H),7.00 – 6.95 (m, 5H), 6.83 (d, J = 2.3 Hz, 1H), 4.10 (t, J =6.1 Hz, 2H), 3.83 (s, 3H), 3.43 (s, 2H), 2.90 (d, J = 11.7Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H), 2.41 (dt, J = 7.9, 4.3Hz, 1H), 2.30 (s, 3H), 2.00 – 1.92 (m, 4H), 1.72 (d, J =12.5 Hz, 2H), 1.61 – 1.55 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ175.85, 163.34, 161.89 (d, J = 244.7 Hz), 159.46, 157.87,152.01, 133.88, 130.56 (d, J = 7.6 Hz), 130.08, 127.63,124.75, 124.17, 118.21, 115.01, 114.83, 113.88, 100.48,66.61, 62.15, 61.37, 55.29, 53.06, 49.77, 37.81, 27.55,27.17; 19 F NMR (470 MHz, CDCl3) δ -115.78.]]> H6 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.50 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 7.9 Hz, 1H),7.07 – 7.03 (m, 2H), 6.98 (q, J = 3.5, 2.9 Hz, 2H), 6.96 –6.91 (m, 2H), 6.85 (d, J = 2.2 Hz, 1H), 4.11 (t, J = 6.2Hz, 2H), 3.84 (s, 3H), 3.46 (s, 2H), 2.91 (d, J = 11.6 Hz,2H), 2.64 (t, J = 7.0 Hz, 2H), 2.39 (ddd, J = 11.5, 8.0,3.8 Hz, 1H), 2.30 (s, 3H), 1.98 (d, J = 6.6 Hz, 2H), 1.94(d, J = 10.0 Hz, 2H), 1.71 (d, J = 12.2 Hz, 2H), 1.60 (td,J = 12.0, 3.4 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.88,163.41, 162.86 (d, J = 245.2 Hz), 159.48, 157.90, 152.02,141.27 (d, J = 7.0 Hz), 130.10, 129.52 (d, J = 8.2 Hz),127.66, 124.78, 124.46 (d, J = 2.3 Hz), 124.22, 118.22,115.66 (d, J = 21.1 Hz), 114.86, 113.90, 113.79 (d, J =21.2 Hz), 100.50, 66.68, 62.43, 61.33, 55.31, 53.28, 49.74,37.91, 27.71, 27.33. 19 F NMR (470 MHz, CDCl3) δ -113.70. <!-- 14 -->]]> H7 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.48 (m, 2H), 7.35 (td, J = 7.5, 1.6 Hz, 1H),7.23 (qd, J = 5.6, 3.6 Hz, 1H), 7.10 (td, J = 7.5, 1.0 Hz,1H), 7.04 – 7.00 (m, 1H), 6.96 (d, J = 8.8 Hz, 3H), 6.84(d, J = 2.3 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.83 (s,3H), 3.57 (s, 2H), 2.96 (d, J = 11.7 Hz, 2H), 2.65 (t, J =7.0 Hz, 2H), 2.40 (dt, J = 7.8, 4.3 Hz, 1H), 2.30 (s, 3H),2.04 (d, J = 10.2 Hz, 2H), 2.00 – 1.97 (m, 2H), 1.73 (d, J= 12.5 Hz, 2H), 1.61 (td, J = 12.0, 3.4 Hz, 2H). 13 C NMR(125MHz, CDCl3) δ 175.86, 163.35, 161.31 (d, J = 245.8 Hz),159.46, 157.88, 152.01, 131.60 (d, J = 4.4 Hz), 130.08,128.72 (d, J = 8.2 Hz), 127.63, 124.75, 124.57 (d, J = 14.6Hz), 124.20, 123.78 (d, J = 3.3 Hz), 118.21, 115.17 (d, J =22.3 Hz), 114.85, 113.88, 100.47, 66.61, 61.25, 55.29,55.12, 52.90, 49.74, 37.83, 27.55, 27.18. 19 F NMR (470 MHz,CDCl3) δ -117.65.]]> H8 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.48 (m, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.17(d, J = 8.3 Hz, 2H), 6.97 (dd, J = 8.9, 2.7 Hz, 3H), 6.84(d, J = 2.3 Hz, 1H), 4.10 (t, J = 6.2 Hz, 2H), 3.84 (s,3H), 3.42 (s, 2H), 2.89 (d, J = 11.7 Hz, 2H), 2.65 (t, J =7.0 Hz, 2H), 2.39 (dt, J = 7.9, 3.6 Hz, 1H), 2.30 (s, 3H),1.99 (d, J = 6.5 Hz, 2H), 1.95 – 1.91 (m, 2H), 1.71 (d, J =12.4 Hz, 2H), 1.61 – 1.55 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ175.85, 163.36, 159.47, 157.88, 152.01, 137.41, 131.22,130.72, 130.08, 127.64, 124.76, 124.19, 120.71, 118.21,114.82, 113.88, 100.49, 66.63, 62.25, 61.32, 55.30, 53.16,49.74, 37.84, 27.63, 27.23. <!-- 15 -->]]> H9 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.52 – 7.48 (m, 2H), 7.47 (s, 1H), 7.37 (d, J = 7.8Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.7 Hz,1H), 6.99 – 6.95 (m, 3H), 6.84 (d, J = 2.3 Hz, 1H), 4.11(t, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.44 (s, 2H), 2.90 (d, J= 11.6 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.41 (td, J =7.9, 4.1 Hz, 1H), 2.31 (s, 3H), 2.01 – 1.93 (m, 4H), 1.72(d, J = 12.1 Hz, 2H), 1.60 (td, J = 12.0, 3.5 Hz, 2H). 13 CNMR (125 MHz, CDCl3) δ 175.85, 163.37, 159.48, 157.89,152.01, 140.94, 131.85, 130.09, 130.04, 129.72, 127.66,127.57, 124.77, 124.21, 122.36, 118.23, 114.84, 113.90,100.51, 66.64, 62.32, 61.36, 55.30, 53.21, 49.76, 37.85,27.63, 27.24.]]> H10 <h2 style=";text-align:left;direction:ltr"><![CDATA[ <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.47 (m, 2H), 7.19 (d, J = 7.9 Hz, 2H), 7.12(d, J = 7.8 Hz, 2H), 6.96 (dd, J = 8.8, 1.6 Hz, 3H), 6.84(d, J = 2.3 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.84 (s,3H), 3.47 (s, 2H), 2.95 (d, J = 11.7 Hz, 2H), 2.67 (t, J =7.0 Hz, 2H), 2.43 (dq, J = 7.9, 3.9, 3.5 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H), 1.98 (dd, J = 18.5, 9.1 Hz, 4H), 1.74 (d, J = 12.0 Hz, 2H), 1.63 (tt, J = 11.9, 6.1 Hz, 2H).<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> CNMR (125 MHz, CDCl3) δ 175.85, 163.33, 159.48, 157.88,152.02, 136.73, 134.59, 130.08, 129.23, 128.86, 127.65,124.76, ]]><h2 style=";text-align:left;direction:ltr"> H11 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.48 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 7.12(s, 1H), 7.08 (dd, J = 12.5, 7.5 Hz, 2H), 6.97 (dd, J =8.9, 2.4 Hz, 3H), 6.84 (d, J = 2.3 Hz, 1H), 4.11 (t, J =6.1 Hz, 2H), 3.84 (s, 3H), 3.46 (s, 2H), 2.95 (d, J = 11.8Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H), 2.43 (td, J = 7.8, 3.9Hz, 1H), 2.34 (s, 3H), 2.31 (s, 3H), 2.02 – 1.94 (m, 4H),1.73 (d, J = 12.0 Hz, 2H), 1.66 – 1.58 (m, 2H). 13 C NMR (125MHz, CDCl3) δ 175.85, 163.35, 159.47, 157.88, 152.01,137.84, 137.78, 130.08, 129.93, 128.02, 127.79, 127.64,126.30, 124.76, 124.20, 118.23, 114.83, 113.89, 100.50,66.62, 62.99, 61.41, 55.29, 53.16, 49.77, 37.82, 27.48,27.17, 21.36. <!-- 16 -->]]> H12 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.50 (d, J = 8.8 Hz, 2H), 7.26 – 7.23 (m, 1H), 7.14(d, J = 5.3 Hz, 3H), 6.99 – 6.95 (m, 3H), 6.85 (d, J = 2.3Hz, 1H), 4.11 (t, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.42 (s,2H), 2.93 (d, J = 11.6 Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H),2.44 – 2.40 (m, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 2.03 –1.95 (m, 4H), 1.72 (d, J = 12.2 Hz, 2H), 1.61 – 1.53 (m,2H). 13 C NMR (125 MHz, CDCl3) δ 175.85, 163.36, 159.47,157.88, 152.01, 137.33, 136.74, 130.15, 130.08, 129.58,127.65, 126.86, 125.43, 124.76, 124.21, 118.23, 114.84,113.89, 100.51, 66.68, 61.57, 60.62, 55.29, 53.35, 49.83,37.84, 27.79, 27.17, 19.23.]]> H13 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.50 – 7.47 (m, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.96(dd, J = 8.9, 2.1 Hz, 3H), 6.85 – 6.83 (m, 3H), 4.10 (t, J= 6.1 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.44 (s, 2H),2.94 (d, J = 11.6 Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H), 2.41(td, J = 9.6, 7.9, 5.7 Hz, 1H), 2.30 (s, 3H), 1.97 (dd, J =15.1, 8.5 Hz, 4H), 1.72 (d, J = 12.0 Hz, 2H), 1.65 – 1.57(m, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.83, 163.34, 159.45,158.66, 157.87, 152.00, 130.42, 130.07, 129.75, 127.62,124.73, 124.19, 118.20, 114.82, 113.87, 113.48, 100.48,66.60, 62.26, 61.32, 55.28, 55.19, 52.91, 49.73, 37.82,27.44, 27.17.]]> H14 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.47 (m, 2H), 7.22 (t, J = 8.1 Hz, 1H), 6.99 –6.95 (m, 3H), 6.88 (d, J = 7.3 Hz, 2H), 6.84 (d, J = 2.3Hz, 1H), 6.81 – 6.78 (m, 1H), 4.11 (t, J = 6.1 Hz, 2H),3.83 (s, 3H), 3.80 (s, 3H), 3.47 (s, 2H), 2.95 (d, J = 11.7Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H), 2.42 (dd, J = 15.3, 7.4Hz, 1H), 2.31 (s, 3H), 2.02 – 1.94 (m, 4H), 1.73 (d, J =12.0 Hz, 2H), 1.65 – 1.57 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ175.85, 163.34, 159.51, 159.47, 157.88, 152.01, 139.76,130.08, 129.10, 127.64, 124.75, 124.20, 121.44, 118.22,114.83, 114.62, 113.88, 112.33, 100.50, 66.62, 62.86,61.37, 55.29, 55.17, 53.12, 49.78, 37.82, 27.54, 27.15. <!-- 17 -->]]> H15 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 8.17 (d,J = 1.9 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.91 (s, 1H),7.50 (d, J = 3.0 Hz, 2H), 7.48 (d, J = 3.0 Hz, 2H), 6.99 –6.95 (m, 3H), 6.84 (d, J = 2.3 Hz, 1H), 4.11 (t, J = 6.1Hz, 2H), 3.83 (s, 3H), 3.55 (s, 2H), 2.88 (d, J = 11.6 Hz,2H), 2.65 (t, J = 7.0 Hz, 2H), 2.40 (ddd, J = 11.5, 7.8,3.7 Hz, 1H), 2.30 (s, 3H), 2.02 – 1.97 (m, 4H), 1.72 (d, J= 12.2 Hz, 2H), 1.60 (tt, J = 12.0, 6.1 Hz, 2H). 13 C NMR (125MHz, CDCl3) δ 175.84, 163.38, 159.48, 157.88, 152.00,147.00, 146.70, 130.07, 129.35, 127.65, 124.77, 124.17,123.45, 118.22, 114.80, 113.89, 100.51, 66.63, 62.13,61.18, 55.30, 53.41, 49.75, 37.86, 27.76, 27.27.]]> H16 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.20 – 8.17 (m, 2H), 8.09 (dd, J =8.2, 1.4 Hz, 1H), 7.90 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H),7.50 – 7.45 (m, 3H), 6.99 – 6.95 (m, 3H), 6.84 (d, J = 2.3Hz, 1H), 4.11 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.55 (s,2H), 2.89 (d, J = 11.6 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H),2.39 (ddt, J = 11.4, 7.4, 3.6 Hz, 1H), 2.30 (s, 3H), 1.98(dd, J = 13.2, 6.5 Hz, 4H), 1.72 (d, J = 12.1 Hz, 2H), 1.60(tt, J = 11.9, 6.1 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ175.84, 163.39, 159.47, 157.88, 152.00, 148.25, 141.05,134.92, 130.07, 129.06, 127.63, 124.75, 124.19, 123.61,122.08, 118.20, 114.83, 113.88, 100.50, 66.63, 62.01,61.23, 55.29, 53.31, 49.71, 37.89, 27.71, 27.31.]]> H17 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.56 (d, J = 8.1 Hz, 2H), 7.51 – 7.48 (m, 2H), 7.42(d, J = 8.0 Hz, 2H), 6.99 – 6.95 (m, 3H), 6.84 (d, J = 2.3Hz, 1H), 4.11 (t, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.52 (s,2H), 2.90 (d, J = 11.7 Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H),2.41 (dq, J = 11.5, 3.7 Hz, 1H), 2.30 (s, 3H), 2.01 – 1.95(m, 4H), 1.72 (d, J = 12.2 Hz, 2H), 1.63 – 1.56 (m, 2H). 13 CNMR (125 MHz, CDCl3) δ 175.85, 163.37, 159.48, 157.88,152.00, 142.77, 130.08, 129.15 (q, J = 32.4 Hz), 129.10,127.65, 124.21 (d, J = 271.8 Hz), 125.08 (q, J = 3.9 Hz),124.77, 123.13, 118.22, 114.82, 113.89, 100.51, 66.64,62.43, 61.30, 55.29, 53.30, 49.77, 37.84, 27.69, 27.25. 19 FNMR (470 MHz, CDCl3) δ -62.20. <!-- 18 -->]]> H18 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.57 (s, 1H), 7.50 (t, J = 2.4 Hz, 2H), 7.48 (d, J =2.1 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 6.98 – 6.95 (m, 3H),6.84 (d, J = 2.3 Hz, 1H), 4.11 (t, J = 6.1 Hz, 2H), 3.83(s, 3H), 3.52 (s, 2H), 2.91 (d, J = 11.7 Hz, 2H), 2.69 (t,J = 7.0 Hz, 2H), 2.49 – 2.43 (m, 1H), 2.34 (s, 3H), 2.03 –1.96 (m, 4H), 1.75 (d, J = 12.1 Hz, 2H), 1.62 (tt, J =12.0, 6.1 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.85, 163.35,159.50, 157.90, 152.01, 139.63, 132.23, 130.48 (d, J = 32.0Hz), 130.09, 128.60, 127.69, 125.52 (d, J = 4.2 Hz),124.79, 124.21, 124.19 (d, J = 272.1 Hz), 123.84 (d, J =3.7 Hz), 118.24, 114.81, 113.90, 100.52, 68.40, 62.40,61.15, 55.30, 53.24, 53.11, 37.63, 27.56, 26.86, 24.05. 19 FNMR (470 MHz, CDCl3) δ -62.31.]]> H19 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.51 – 7.48 (m, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.34(d, J = 2.1 Hz, 1H), 7.21 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 –6.95 (m, 3H), 6.84 (d, J = 2.3 Hz, 1H), 4.11 (t, J = 6.2Hz, 2H), 3.83 (s, 3H), 3.53 (s, 2H), 2.92 (d, J = 11.7 Hz,2H), 2.66 (t, J = 7.0 Hz, 2H), 2.45 – 2.40 (m, 1H), 2.31(s, 3H), 2.09 – 2.04 (m, 2H), 2.02 – 1.97 (m, 2H), 1.73 (d,J = 12.2 Hz, 2H), 1.63 – 1.56 (m, 2H). 13 C NMR (125 MHz,CDCl3) δ 175.83, 163.37, 159.49, 157.89, 152.00, 134.92,134.63, 132.87, 131.29, 130.08, 129.04, 127.66, 126.87,124.78, 124.20, 118.24, 114.81, 113.90, 100.53, 66.65,61.31, 58.54, 55.29, 53.31, 49.80, 37.85, 27.78, 27.22.]]> H20 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.48 (m, 2H), 7.07 (d, J = 6.9 Hz, 2H), 7.01(d, J = 9.2 Hz, 1H), 6.96 (dd, J = 9.0, 2.4 Hz, 3H), 6.84(d, J = 2.3 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.84 (s,3H), 3.46 (s, 2H), 2.98 (d, J = 11.7 Hz, 2H), 2.68 (t, J =7.1 Hz, 2H), 2.48 (d, J = 11.5 Hz, 1H), 2.32 (s, 3H), 2.24(s, 3H), 2.24 (s, 3H), 2.00 (dd, J = 12.1, 4.8 Hz, 4H),1.74 (d, J = 13.1 Hz, 2H), 1.68 – 1.63 (m, 2H). 13 C NMR (125MHz, CDCl3) δ 175.85, 163.34, 159.48, 157.88, 152.01,136.35, 135.39, 130.62, 130.08, 129.39, 127.65, 126.80,126.36, 124.77, 124.21, 118.24, 114.83, 113.89, 100.51,66.60, 62.63, 61.32, 55.29, 52.98, 49.77, 37.75, 27.34,27.10, 19.71, 19.39. <!-- 19 -->]]> H21 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.1 Hz, 1H), 7.90 (s,1H), 7.49 (d, J = 5.6 Hz, 2H), 7.31 (s, 4H), 7.26 (s, 1H),6.97 (s, 3H), 6.82 (s, 1H), 4.07 (s, 2H), 3.83 (s, 3H),3.51 (s, 2H), 2.98 (d, J = 9.7 Hz, 2H), 2.62 (s, 2H), 2.56(s, 1H), 2.36 (s, 3H), 2.00 (t, J = 10.8 Hz, 2H), 1.81 (dd,J = 31.5, 19.9 Hz, 6H), 1.70 – 1.63 (m, 2H). 13 C NMR (125MHz, CDCl3) δ 175.81, 163.22, 159.45, 157.85, 152.00,137.83, 130.06, 129.14, 128.18, 127.65, 127.08, 124.73,124.15, 118.22, 114.77, 113.86, 100.47, 68.21, 62.81,61.31, 55.27, 53.01, 52.87, 37.36, 27.12, 26.75, 23.60.]]> H22 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.50 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H),7.23 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.7 Hz, 3H), 6.83(d, J = 2.2 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.84 (s,3H), 3.44 (s, 2H), 2.91 (d, J = 11.6 Hz, 2H), 2.55 – 2.50(m, 2H), 2.43 – 2.36 (m, 1H), 2.28 (s, 3H), 1.93 (d, J =11.4 Hz, 2H), 1.87 – 1.82 (m, 2H), 1.71 (d, J = 12.5 Hz,2H), 1.68 – 1.54 (m, 4H). 13 C NMR (125 MHz, CDCl3) δ 175.86,163.36, 159.49, 157.90, 152.01, 136.96, 132.59, 130.34,130.10, 128.28, 127.68, 124.78, 124.20, 118.22, 114.82,113.90, 100.50, 68.43, 62.23, 61.09, 55.31, 53.24, 53.12,37.71, 27.63, 26.87, 24.18.]]> H23 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.49 (d, J = 8.7 Hz, 2H), 7.31 (s, 1H), 7.23 (d, J =6.2 Hz, 2H), 7.20 – 7.16 (m, 1H), 6.96 (dd, J = 8.9, 2.1Hz, 3H), 6.83 (d, J = 2.2 Hz, 1H), 4.07 (t, J = 6.3 Hz,2H), 3.84 (s, 3H), 3.45 (s, 2H), 2.95 – 2.90 (m, 2H), 2.61– 2.56 (m, 2H), 2.49 (t, J = 11.7 Hz, 1H), 2.33 (s, 3H),1.97 (t, J = 10.9 Hz, 2H), 1.88 – 1.83 (m, 2H), 1.76 (d, J= 12.1 Hz, 2H), 1.70 (dd, J = 14.7, 7.1 Hz, 2H), 1.66 –1.58 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.84, 163.29,159.47, 157.88, 152.02, 140.57, 134.06, 130.09, 129.42,128.92, 127.68, 127.14, 127.07, 124.77, 124.18, 118.23,114.80, 113.89, 100.49, 68.32, 62.30, 61.22, 55.30, 53.12,53.08, 37.54, 27.40, 26.82, 23.90. <!-- 20 -->]]> H24 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.49 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 6.4 Hz, 1H),7.36 – 7.31 (m, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.18 (td, J= 7.7, 1.5 Hz, 1H), 6.97 (d, J = 8.7 Hz, 3H), 6.83 (d, J =2.3 Hz, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.60(s, 2H), 2.98 (d, J = 11.6 Hz, 2H), 2.60 – 2.55 (m, 2H),2.48 (d, J = 11.4 Hz, 1H), 2.33 (s, 3H), 2.09 (t, J = 11.0Hz, 2H), 1.88 – 1.83 (m, 2H), 1.77 (d, J = 12.0 Hz, 2H),1.74 – 1.68 (m, 2H), 1.64 (td, J = 12.2, 3.5 Hz, 2H). 13 C NMR(125 MHz, CDCl3) δ 175.85, 163.31, 159.48, 157.89, 152.02,136.07, 134.14, 130.55, 130.09, 129.34, 128.01, 127.69,126.56, 124.77, 124.20, 118.23, 114.81, 113.89, 100.50,68.35, 61.21, 59.07, 55.30, 53.27, 53.10, 37.60, 27.57,26.84, 23.94.]]> H25 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.50 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 7.3 Hz, 2H),7.01 – 6.95 (m, 5H), 6.83 (d, J = 2.2 Hz, 1H), 4.07 (t, J =6.4 Hz, 2H), 3.84 (s, 3H), 3.45 (s, 2H), 2.92 (d, J = 11.6Hz, 2H), 2.56 – 2.51 (m, 2H), 2.43 (s, 1H), 2.29 (s, 3H),1.94 (t, J = 11.1 Hz, 2H), 1.87 – 1.82 (m, 2H), 1.73 (d, J= 11.9 Hz, 2H), 1.70 – 1.64 (m, 2H), 1.60 (td, J = 12.0,3.3 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.86, 163.35,161.91 (d, J = 244.9 Hz), 159.49, 157.90, 152.01, 134.01(d, J = 3.8 Hz), 130.54 (d, J = 7.9 Hz), 130.10, 127.69,124.79, 124.20, 118.23, 115.02, 114.84 (d, J = 3.0 Hz),113.91, 100.50, 68.40, 62.18, 61.17, 55.31, 53.14, 53.11,37.66, 27.55, 26.87, 24.09. 19 F NMR (470 MHz, CDCl3) δ -115.86. <!-- 21 -->]]> H26 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.8 Hz, 1H), 7.90 (s,1H), 7.49 (d, J = 8.2 Hz, 2H), 7.25 (s, 1H), 7.05 (s, 2H),7.00 – 6.91 (m, 4H), 6.83 (s, 1H), 4.07 (d, J = 5.5 Hz,2H), 3.83 (s, 3H), 3.47 (s, 2H), 2.93 (d, J = 9.7 Hz, 2H),2.55 (s, 2H), 2.44 (s, 1H), 2.30 (s, 3H), 1.97 (t, J = 10.7Hz, 2H), 1.85 (s, 2H), 1.67 (ddd, J = 40.3, 25.8, 10.2 Hz,6H). 13 C NMR (125 MHz, CDCl3) δ 175.83, 163.34, 162.87 (d, J= 245.1 Hz), 159.49, 157.89, 152.00, 141.27 (d, J = 7.0Hz), 130.08, 129.52 (d, J = 8.1 Hz), 127.67, 124.77, 124.42(d, J = 3.1 Hz), 124.21, 118.23, 115.61 (d, J = 21.4 Hz),114.80, 113.80 (d, J = 23.8 Hz), 100.51, 62.36, 61.15,55.29, 53.21, 53.09, 37.62, 27.56, 26.84, 24.05. 19 F NMR (470MHz, CDCl3) δ -113.68.]]> H27 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.51 – 7.46 (m, 2H), 7.35 (td, J = 7.5, 1.5 Hz, 1H),7.25 – 7.21 (m, 1H), 7.10 (td, J = 7.4, 0.9 Hz, 1H), 7.04 –7.00 (m, 1H), 6.97 – 6.93 (m, 3H), 6.81 (d, J = 2.3 Hz,1H), 4.06 (t, J = 5.9 Hz, 2H), 3.83 (s, 3H), 3.59 (s, 2H),3.00 (d, J = 11.8 Hz, 2H), 2.73 – 2.68 (m, 2H), 2.64 (d, J= 11.5 Hz, 1H), 2.42 (s, 3H), 2.07 (t, J = 11.2 Hz, 2H),1.89 – 1.80 (m, 6H), 1.72 – 1.64 (m, 2H) 13 C NMR (125 MHz,CDCl3) δ 175.82, 163.14, 161.28 (d, J = 246.1 Hz), 159.46,157.84, 152.03, 131.57 (d, J = 4.4 Hz), 130.07, 130.06,128.91 (d, J = 8.2 Hz), 127.68, 124.75, 124.14, 123.86 (d,J = 3.4 Hz), 118.27, 115.22 (d, J = 22.2 Hz), 114.75,113.87, 100.48, 68.07, 61.41, 55.28, 54.92, 52.99, 52.41,37.14, 26.87, 26.68, 23.20. 19 F NMR (470 MHz, CDCl3) δ -117.63. <!-- 22 -->]]> H28 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.51 – 7.48 (m, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.18(d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.6 Hz, 3H), 6.82 (d, J =2.3 Hz, 1H), 4.06 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.42(s, 2H), 2.90 (dd, J = 11.8, 3.5 Hz, 2H), 2.53 – 2.49 (m,2H), 2.40 (td, J = 7.9, 4.0 Hz, 1H), 2.27 (s, 3H), 1.97 –1.91 (m, 2H), 1.86 – 1.81 (m, 2H), 1.71 (d, J = 12.5 Hz,2H), 1.67 – 1.63 (m, 2H), 1.61 – 1.55 (m, 2H). 13 C NMR (125MHz, CDCl3) δ 175.84, 163.35, 159.46, 157.87, 151.99,137.50, 131.21, 130.70, 130.08, 127.66, 124.75, 124.18,120.68, 118.19, 114.81, 113.88, 100.47, 68.41, 62.26,61.04, 55.29, 53.23, 53.10, 37.70, 27.62, 26.86, 24.17.]]> H29 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.50 – 7.46 (m, 3H), 7.37 (d, J = 7.7 Hz, 1H), 7.22(d, J = 7.6 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.96 (d, J =8.5 Hz, 3H), 6.82 (d, J = 1.9 Hz, 1H), 4.07 (t, J = 6.1 Hz,2H), 3.83 (s, 3H), 3.44 (s, 2H), 2.93 (d, J = 11.5 Hz, 2H),2.66 – 2.60 (m, 2H), 2.56 (t, J = 11.6 Hz, 1H), 2.37 (s,3H), 1.98 (t, J = 11.3 Hz, 2H), 1.86 (dd, J = 13.9, 7.0 Hz,2H), 1.80 (s, 2H), 1.77 (s, 2H), 1.64 (tt, J = 11.8, 6.1Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.81, 163.22, 159.47,157.86, 152.01, 140.75, 131.80, 130.10, 130.07, 129.75,127.67, 127.53, 124.75, 124.16, 122.37, 118.25, 114.77,113.88, 100.50, 68.21, 62.15, 61.35, 55.28, 53.03, 52.92,37.34, 27.18, 26.76, 23.57.]]> H30 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.50 – 7.47 (m, 2H), 7.19 (d, J = 7.9 Hz, 2H), 7.12(d, J = 7.8 Hz, 2H), 6.97 – 6.93 (m, 3H), 6.82 (d, J = 2.3Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.49 (s,2H), 2.99 (d, J = 11.8 Hz, 2H), 2.69 – 2.65 (m, 2H), 2.62(d, J = 11.6 Hz, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 2.01 (t,J = 11.4 Hz, 2H), 1.86 (d, J = 5.4 Hz, 2H), 1.84 (s, 2H),1.80 (d, J = 6.8 Hz, 2H), 1.73 – 1.66 (m, 2H). 13 C NMR (125MHz, CDCl3) δ 175.81, 163.17, 159.46, 157.85, 152.02,136.91, 134.14, 130.06, 129.22, 128.92, 127.67, 124.75,124.15, 118.26, 114.76, 113.87, 100.49, 68.12, 62.34,61.34, 55.27, 52.97, 52.54, 37.19, 26.79, 26.70, 23.30,21.07. <!-- 23 -->]]> H31 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.49 (d, J = 8.6 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H),7.09 (dd, J = 18.7, 9.0 Hz, 3H), 6.97 – 6.93 (m, 3H), 6.82(d, J = 2.1 Hz, 1H), 4.07 (t, J = 5.6 Hz, 2H), 3.83 (s,3H), 3.49 (s, 2H), 3.00 (d, J = 11.5 Hz, 2H), 2.74 – 2.64(m, 3H), 2.43 (s, 3H), 2.34 (s, 3H), 2.02 (t, J = 11.4 Hz,2H), 1.90 – 1.80 (m, 6H), 1.76 – 1.68 (m, 2H). 13 C NMR (125MHz, CDCl3) δ 175.80, 163.14, 159.47, 157.85, 152.02,137.88, 137.26, 130.06, 129.92, 128.11, 127.99, 127.68,126.29, 124.76, 124.15, 118.28, 114.74, 113.87, 100.50,68.07, 62.64, 61.48, 55.28, 52.97, 52.60, 37.10, 26.72,26.69, 23.16, 21.34.]]> H32 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 1H), 7.90 (s,1H), 7.49 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 5.6 Hz, 1H),7.15 (s, 3H), 6.96 (d, J = 7.8 Hz, 3H), 6.82 (s, 1H), 4.07(s, 2H), 3.83 (s, 3H), 3.43 (s, 2H), 2.95 (d, J = 10.3 Hz,2H), 2.64 (s, 2H), 2.58 (s, 1H), 2.36 (d, J = 15.1 Hz, 6H),2.00 (t, J = 11.2 Hz, 2H), 1.83 (dd, J = 24.1, 8.9 Hz, 6H),1.61 (d, J = 11.0 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.81,163.22, 159.46, 157.85, 152.01, 137.31, 136.48, 130.18,130.06, 129.58, 127.65, 126.94, 125.44, 124.74, 124.16,118.23, 114.77, 113.87, 100.49, 68.21, 61.57, 60.48, 55.27,53.04, 37.34, 27.33, 26.75, 23.50, 19.20.]]> H33 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.50 – 7.47 (m, 2H), 7.23 (d, J = 8.5 Hz, 2H), 6.97 –6.93 (m, 3H), 6.85 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 2.3Hz, 1H), 4.06 (t, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.79 (s,3H), 3.50 (s, 2H), 3.01 (d, J = 11.6 Hz, 2H), 2.71 (d, J =7.0 Hz, 3H), 2.43 (s, 3H), 2.08 – 2.01 (m, 2H), 1.92 – 1.82(m, 6H), 1.74 (q, J = 11.7 Hz, 2H). 13 C NMR (125 MHz, CDCl3)δ 175.82, 163.12, 159.47, 158.93, 157.85, 152.04, 130.57,127.68, 124.76, 124.14, 118.28, 114.75, 113.87, 113.64,100.50, 68.04, 61.82, 61.30, 55.28, 55.21, 52.95, 52.23,37.08, 26.66, 26.50, 23.09. <!-- 24 -->]]> H34 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.51 – 7.46 (m, 2H), 7.22 (t, J = 8.0 Hz, 1H), 6.98 –6.94 (m, 3H), 6.88 (d, J = 6.7 Hz, 2H), 6.83 – 6.77 (m,2H), 4.07 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H),3.48 (s, 2H), 2.98 (d, J = 11.7 Hz, 2H), 2.70 – 2.62 (m,2H), 2.59 (s, 1H), 2.38 (s, 3H), 2.00 (t, J = 11.3 Hz, 2H),1.85 (td, J = 13.5, 12.6, 6.5 Hz, 4H), 1.80 – 1.73 (m, 2H),1.68 (tt, J = 11.9, 5.9 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ175.81, 163.20, 159.54, 159.46, 157.85, 152.02, 139.46,130.07, 129.15, 127.67, 124.75, 124.16, 121.40, 118.25,114.77, 114.60, 113.87, 112.43, 100.49, 68.17, 62.66,61.36, 55.28, 55.17, 53.01, 52.80, 37.30, 27.05, 26.74,23.46.]]> H35 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 8.17 –8.13 (m, 2H), 7.90 (s, 1H), 7.49 (d, J = 8.7 Hz, 4H), 6.96(dd, J = 8.8, 1.9 Hz, 3H), 6.82 (d, J = 2.3 Hz, 1H), 4.07(t, J = 6.3 Hz, 2H), 3.83 (s, 3H), 3.56 (s, 2H), 2.90 (d, J= 11.6 Hz, 2H), 2.59 – 2.55 (m, 2H), 2.47 (t, J = 11.4 Hz,1H), 2.32 (s, 3H), 2.01 (td, J = 12.0, 2.0 Hz, 2H), 1.88 –1.83 (m, 2H), 1.77 (d, J = 12.1 Hz, 2H), 1.73 – 1.68 (m,2H), 1.65 – 1.58 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.83,163.30, 159.48, 157.87, 152.00, 147.00, 146.64, 130.07,129.33, 127.67, 124.77, 124.15, 123.46, 118.22, 114.78,113.89, 100.49, 68.34, 62.07, 61.01, 55.29, 53.32, 53.11,37.55, 27.56, 26.82, 23.93.]]> H36 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.8 Hz, 2H), 8.10 (d,J = 8.1 Hz, 1H), 7.90 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H),7.48 (dd, J = 8.1, 4.9 Hz, 3H), 6.96 (d, J = 8.7 Hz, 3H),6.82 (d, J = 2.2 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.83(s, 3H), 3.56 (s, 2H), 2.91 (dt, J = 11.7, 3.2 Hz, 2H),2.55 (t, J = 7.4 Hz, 2H), 2.45 (td, J = 7.9, 3.9 Hz, 1H),2.30 (s, 3H), 2.01 (t, J = 11.8 Hz, 2H), 1.88 – 1.82 (m,2H), 1.75 (d, J = 12.0 Hz, 2H), 1.70 – 1.65 (m, 2H), 1.60(td, J = 12.1, 3.4 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ175.83, 163.32, 159.46, 157.87, 152.00, 148.25, 141.03,134.91, 130.07, 129.07, 127.65, 124.74, 124.17, 123.59,122.08, 118.20, 114.80, 113.87, 100.48, 68.38, 61.97,61.02, 55.28, 53.27, 53.08, 37.64, 27.56, 26.84, 24.07. <!-- 25 -->]]> H37 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.56 (d, J = 8.1 Hz, 2H), 7.51 – 7.48 (m, 2H), 7.43(d, J = 8.0 Hz, 2H), 6.98 – 6.95 (m, 3H), 6.83 (d, J = 2.3Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.52 (s,2H), 2.91 (d, J = 11.6 Hz, 2H), 2.57 – 2.53 (m, 2H), 2.47 –2.42 (m, 1H), 2.30 (s, 3H), 2.01 – 1.95 (m, 2H), 1.88 –1.82 (m, 2H), 1.74 (d, J = 12.2 Hz, 2H), 1.70 – 1.66 (m,2H), 1.64 – 1.57 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.85,163.33, 159.48, 157.89, 152.01, 142.75, 130.08, 129.16 (d,J = 32.1 Hz), 129.09, 127.67 (d, J = 0.3 Hz), 125.09 (q, J= 3.7 Hz), 124.77, 124.21 (d, J = 272.0 Hz), 124.18,118.22, 114.81, 113.90, 113.89, 113.87, 100.49, 68.38,62.40, 61.08, 55.29, 53.28, 53.12, 37.62, 27.57, 26.85,24.04. 19 F NMR (470 MHz, CDCl3) δ -62.22.]]> H38 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.57 (s, 1H), 7.50 (dd, J = 8.7, 2.7 Hz, 4H), 7.44 –7.40 (m, 1H), 6.96 (d, J = 8.6 Hz, 3H), 6.83 (d, J = 2.2Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.52 (s,2H), 2.92 (d, J = 11.6 Hz, 2H), 2.58 – 2.53 (m, 2H), 2.44(d, J = 11.6 Hz, 1H), 2.31 (s, 3H), 1.98 (t, J = 11.0 Hz,2H), 1.88 – 1.83 (m, 2H), 1.75 (d, J = 12.2 Hz, 2H), 1.71 –1.66 (m, 2H), 1.64 – 1.58 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ175.85, 163.35, 159.50, 157.90, 152.01, 139.63, 132.23,130.48 (d, J = 32.1 Hz), 130.09, 128.60, 127.69, 125.52 (q,J = 3.7 Hz), 124.79, 124.21, 124.20 (d, J = 272.4 Hz),123.82 (d, J = 4.0 Hz), 118.24, 114.81, 113.90, 100.52,68.40, 62.40, 61.15, 55.30, 53.24, 53.11, 37.63, 27.56,26.86, 24.05. 19 F NMR (470 MHz, CDCl3) δ -62.31. <!-- 26 -->]]> H39 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.49 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.3 Hz, 1H),7.35 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.3, 2.0 Hz, 1H),6.96 (d, J = 8.6 Hz, 3H), 6.82 (d, J = 2.2 Hz, 1H), 4.07(t, J = 6.3 Hz, 2H), 3.83 (s, 3H), 3.54 (s, 2H), 2.93 (d, J= 11.7 Hz, 2H), 2.60 – 2.55 (m, 2H), 2.48 (t, J = 11.7 Hz,1H), 2.32 (s, 3H), 2.08 (t, J = 11.0 Hz, 2H), 1.88 – 1.82(m, 2H), 1.77 (d, J = 12.1 Hz, 2H), 1.72 – 1.67 (m, 2H),1.64 – 1.57 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.82,163.31, 159.49, 157.88, 152.00, 134.87, 134.63, 132.89,131.29, 130.07, 129.04, 127.68, 126.87, 124.77, 124.19,118.24, 114.78, 113.89, 100.51, 68.35, 61.13, 58.50, 55.29,53.23, 53.11, 37.57, 27.61, 26.83, 23.91.]]> H40 <![CDATA[ 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s,1H), 7.51 – 7.47 (m, 2H), 7.08 (d, J = 5.0 Hz, 2H), 7.03(d, J = 7.8 Hz, 1H), 6.97 – 6.93 (m, 3H), 6.82 (d, J = 2.3Hz, 1H), 4.07 (t, J = 5.7 Hz, 2H), 3.83 (s, 3H), 3.49 (s,2H), 3.02 (d, J = 11.8 Hz, 2H), 2.74 – 2.67 (m, 3H), 2.43(s, 3H), 2.25 (s, 3H), 2.24 (s, 3H), 2.04 (t, J = 11.5 Hz,2H), 1.91 – 1.82 (m, 6H), 1.74 (dt, J = 11.7, 5.8 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 175.81, 163.14, 159.49, 157.86,152.03, 136.50, 135.74, 130.64, 130.08, 129.50, 127.70,126.82, 124.78, 124.16, 118.31, 114.74, 113.89, 100.52,68.06, 62.27, 61.40, 55.29, 52.96, 52.40, 37.08, 26.68,26.54, 23.11, 19.71, 19.40.]]>

[0158] Test Example 1

[0159] Anti-plant pathogenic bacteria activity test

[0160] Test method:

[0161] In vitro activity was evaluated using a turbidometric method against four Xanthomonas species (Xoo, X. oryzae; Xac, X. citri; Xcm, X. mango; X. fragariae) and four non-Xanthomonas species (Psa, Psa, Pcb, Ac, Ac, Ps. solanacearum). The commercial pesticides thiabendazole and zinc thiazide were used as positive controls. The specific steps are as follows:

[0162] (1) The eight plant pathogenic bacteria were evenly spread on NA solid culture medium and cultured in a constant temperature bacterial incubator at 28°C until single colonies were grown. An appropriate amount of central single colonies were selected and placed in NB liquid culture medium. The culture was continued in a constant temperature shaker at 28°C and 180 r / min until the logarithmic growth phase (OD 595 =0.6-0.8).

[0163] (2) Prepare 5 mL of 100 µg / mL drug-containing NB culture medium in a test tube for the sample and control. Add 1% DMSO to the test tube for the control. Take 200 µL from each test tube and measure its OD value, which is the OD value of the sterile culture medium. 595 Then, 40 μL of the test bacteria was added to each test tube and cultured in a constant temperature shaker at 28 °C and 180 rpm for 12-48 h. When the turbidity value was between 0.6 and 0.8, the OD value of each test tube was measured. 595 The inhibition rate of the tested compounds was calculated according to the following formula. The results are shown in Table 3.

[0164] (3) Correction of OD 595 Value = OD of culture medium containing bacteria 595 Value - sterile culture medium OD 595 value

[0165] Inhibition rate (%) = (corrected control culture medium bacterial solution OD 595 - Correction of OD of drug-containing culture medium 595 ) / corrected OD value of bacterial suspension in control culture medium × 100%.

[0166] (4) The results of the bioactivity test against plant pathogenic fungi are shown in Table 3.

[0167] Table 3 In vitro antibacterial activity of H1-H40 (100 μg / mL)

[0168] Compds. Xoo Xac Xcm Xf Psa PCB Ac Ps H1 100 100 100 100 78.7±2.0 57.7±2.6 32.5±3.3 70.8±2.6 H2 100 100 100 100 76.6±3.5 69.9±0.5 73.0±1.1 72.9±3.9 H3 100 32.9±3.9 28.6±1.0 44.3±2.2 21.7±4.3 39.5±1.1 29.2±3.1 22.1±2.4 H4 100 55.7±1.0 57.0±1.4 41.7±2.8 34.2±3.6 40.9±2.2 31.8±2.4 32.8±2.5 H5 100 100 100 58.0±0.7 75.8±3.1 62.4±4.2 40.7±2.1 22.5±2.4 H6 100 100 100 100 61.8±1.4 43.8±3.5 46.2±2.6 37.0±1.0 H7 100 100 100 100 74.3±3.5 43.6±2.0 42.2±2.2 47.6±3.7 H8 100 100 100 100 69.2±2.2 53.1±4.7 66.7±2.8 52.1±1.0 H9 96.3±1.3 32.9±2.6 20.5±1.9 21.7±0.8 19.2±2.3 40.4±4.3 30.8±4.4 23.5±2.2 H10 100 100 100 100 69.9±1.9 62.3±3.1 66.5±4.1 64.1±2.5 H11 100 55.0±4.6 48.6±0.7 33.6±1.4 24.6±0.8 33.0±1.6 27.7±1.9 18.3±2.1 H12 100 64.8±1.3 47.3±2.5 31.1±3.9 32.8±2.2 31.2±4.3 35.1±4.6 14.7±0.9 H13 100 100 100 100 58.9±0.5 42.7±3.2 36.0±1.6 50.9±4.0 H14 100 100 100 100 67.9±4.0 64.2±4.3 49.5±1.9 50.8±1.0 H15 100 100 100 100 76.0±1.5 97.9±2.6 100 43.9±2.8 H16 100 100 94.8±4.8 46.3±4.1 67.4±0.5 83.2±2.6 58.5±3.3 38.3±3.2 H17 100 100 100 100 64.4±1.9 56.2±1.4 59±2.0 52.4±4.5 H18 100 100 63.5±3.9 100 41.6±1.4 35.3±2.1 34.1±4.3 46.6±2.4 H19 100 100 100 28.7±3.1 66.0±3.0 76.3±2.3 93.3±3.1 56.4±4.5 H20 100 100 100 100 86.7±3.6 65.5±4.0 87.2±3.5 79.1±3.1 H21 100 100 100 100 71.7±3.6 66.7±1.0 59.0±2.6 31.6±4.5 H22 98.7±1.2 38.7±2.2 29.3±3.2 41.2±3.9 37.6±2.0 42.3±4.9 41.5±3.9 19.1±0.6 H23 100 56.8±4.2 67.3±2.0 31.9±2.9 47.4±1.2 53.1±3.0 40.9±4.3 26.5±3.3 H24 100 57.6±4.4 52.5±1.1 37.2±4.6 41.6±0.6 50.2±2.8 37.2±1.5 22.1±2.2 H25 100 100 81.7±3.9 38.0±2.7 44.3±0.3 42.1±0.3 43.3±2.3 53.3±2.3 H26 100 100 97.9±0.8 100 68.9±4.3 59.4±6.9 51.0±3.6 54.1±1.6 H27 100 56.4±1.6 56.2±0.8 47.1±3.8 46.5±3.0 46.2±3.6 22.2±0.8 30.4±1.1 H28 85.7±1.0 40.4±1.7 12.6±0.8 21.5±4.2 39.1±1.2 43.4±4.9 40.4±1.3 15.0±2.9 H29 100 43.3±3.4 55.7±4.7 39.8±1.7 46.6±0.7 48.0±0.4 45.0±2.4 25.6±1.7 H30 100 77.8±2.3 81.9±2.2 58.3±4.4 57.6±1.4 42.9±1.4 41.6±1.6 44.2±0.9 H31 100 90.3±3.3 80.0±2.1 100 58.7±4.5 55.7±0.5 43.3±1.3 14.5±2.4 H32 100 58.0±2.4 51.9±2.8 45.3±2.7 41.4±4.0 56.5±3.5 40.2±2.1 15.2±0.9 H33 100 100 100 100 64.4±1.0 54.2±4.9 36.9±3.0 47.8±1.7 H34 100 100 100 100 79.4±0.2 62.7±0.9 53.6±0.5 50.9±3.8 H35 85.6±2.4 36.3±3.3 42.4±2.0 32.1±3.4 41.3±1.2 40.4±2.7 31.0±1.3 22.5±0.8 H36 100 46.0±4.8 44.5±1.1 54.9±0.7 43.0±3.5 59.4±3.2 37.7±1.2 21.2±2.7 H37 75.6±3.1 47.4±0.9 39.0±1.6 53.5±4.5 31.8±1.2 44.6±3.9 33.4±2.5 21.2±4.3 H38 100 62.1±4.6 76.0±2.9 53.7±1.5 51.2±1.6 49.3±3.9 55.9±0.7 29.8±1.1 H39 86.6±2.1 45.7±0.9 35.4±1.4 39.5±3.7 45.2±1.0 49.2±2.2 36.3±1.2 17.8±2.9 H40 100 65.7±3.8 86.1±2.8 100 37.1±4.6 54.0±3.3 38.0±2.3 31.8±2.0 FMN 31.2±3.3 44.6±3.1 32.9±2.8 45.8±0.2 24.8±2.9 21.9±3.4 39.4±4.3 38.9±3.8 TC 74.2±2.7 50.4±4.8 72.9±0.9 84.5±1.5 65.6±2.8 64.6±2.5 68.2±3.4 96.2±1.4 ZT 90.8±1.4 68.6±4.4 91.8±1.9 59.6±3.1 53.9±2.9 50.8±1.4 62.3±1.8 45.9±4.6

[0169] As shown in Table 3, all target compounds exhibited moderate inhibitory activity against eight plant bacteria at a concentration of 100 μg / mL. Among them, H1-H8, H10-H21, H23-H27, H29-H34, H36, H38, and H40 all exhibited 100% inhibition against Xoo, surpassing both thiophanate-methyl (74.2%) and zinc thiazole (90.8%). Compounds H1-H2, H5-H8, H10, H13-H21, H25-H26, and H33-H34 exhibited 100% inhibition against Xac, significantly surpassing both thiophanate-methyl (50.4%) and zinc thiazole (68.6%). Compounds H1-H2, H5-H8, H10, H13-H15, H17, H19-H21, and H33-H34 showed the most significant inhibitory activity against Xcm, achieving 100% inhibition, significantly outperforming thiophanate-methyl (72.9%) and zinc thiophanate-zinc (91.8%). Compounds H1-H2, H6-H8, H10, H13-H15, H17-H18, H20-H21, H26, H31, H33-H34, and H40 all exhibited 100% inhibition against Xf, exceeding thiophanate-methyl (84.5%) and zinc thiophanate-zinc (59.6%). Furthermore, some of these compounds exhibited significant antibacterial activity against four non-Xanthomonas species (Psa, Pcb, Ac, and Rs). In general, the target compounds showed significantly better inhibitory activity against four Xanthomonas species (Xoo, Xac, Xcm, Xf) than against four non-Xanthomonas species (Psa, Pcb, Ac, Rs). Therefore, the target compounds had specific inhibitory activity against Xanthomonas.

[0170] The above experimental activity data show that benzylpiperidine-containing formononetin derivatives have good inhibitory effects on plant pathogenic bacteria, especially Xanthomonas, and can be used as potential anti-plant pathogenic bacteria drugs with good application prospects.

[0171] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined by the claims of the present invention.

Claims

1. A formononetin derivative containing benzylpiperidine, characterized in that: The structure is shown below: In the above formula, n is an integer of 2 to 6, and R is independently selected from H, one or more halogens, one or more nitro groups, one or more C1-C6 alkyl groups, or one or more C1-C6 alkoxy groups.

2. A method for preparing the formononetin derivative containing benzylpiperidine according to claim 1, characterized in that the steps include: (1) Using formononetin and dibromoalkane as raw materials, heat the reaction in a solvent under alkaline conditions. After the reaction is completed, ice water is added to precipitate the product, which is then filtered and the residue is cleaned to obtain intermediate a. The structural formula of the dibromoalkane is: , where n is an integer from 2 to 6; The structural formula of the intermediate a is: , where n is an integer from 2 to 6; (2) Using intermediate a and 1-boc-4-methylaminopiperidine as raw materials and potassium carbonate as catalyst, heating reaction is carried out in a solvent to obtain intermediate b; The structural formula of the intermediate b is: , where n is an integer from 2 to 6; (3) Using intermediate b as the starting material, remove the boc protection to obtain intermediate c; The structural formula of the intermediate c is: , where n is an integer from 2 to 6; (4) Using intermediate c and substituted benzyl chloride as raw materials and potassium carbonate as catalyst, the formononetin derivative containing benzylpiperidine is prepared under heating and reflux; The structural formula of the substituted benzyl chloride is: , wherein R is independently selected from H, one or more halogens, one or more nitro groups, one or more C1-C6 alkyl groups, or one or more C1-C6 alkoxy groups.

3. The preparation method according to claim 2, characterized in that The molar ratio of formononetin to dibromoalkane in step (1) is 11.0:(54.8-109.6); the heating reaction temperature is 80° C. and the time is 4-10 hours; the alkaline condition is provided by anhydrous potassium carbonate; The impurity removal step includes: washing the filter residue with water and petroleum ether in sequence, then beating the filter residue, letting it stand, filtering, and completing the washing.

4. The preparation method according to claim 3, characterized in that The molar ratio of formononetin to anhydrous potassium carbonate in step (1) is 11.0:32.9; the solution used for pulping is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:

1.

5. The preparation method according to claim 2, characterized in that The molar ratio of the intermediate a, 1-boc-4-methylaminopiperidine and potassium carbonate in step (2) is 3.9:(3.9-7.7):(11.6-38.5); the temperature of the heating reaction is 80°C and the time is 4-10 hours; and a purification step is also included after the heating reaction.

6. The preparation method according to claim 2, characterized in that The step of removing the boc protection in step (3) comprises: dissolving the intermediate b in methanol, heating to 40-80°C, adding a 15-37% HCl solution dropwise, reacting for 1-4 hours, and removing the boc protection.

7. The preparation method according to claim 2, characterized in that After removing the BOC protection in step (3), a separation step is further included. The separation step is specifically as follows: after removing the BOC protection, the reaction system is poured into ice water, the system is adjusted to 8-9 using a 5 wt% NaHCO3 solution, and then extracted with dichloromethane. The extract is evaporated to dryness to obtain intermediate c.

8. The preparation method according to claim 2, characterized in that In step (4), the molar ratio of intermediate c, substituted benzyl chloride and potassium carbonate is 1.2:(1.2-1.4):(2.4-3.6); the heating reflux time is 1-2 h.

9. Use of the formononetin derivative containing benzylpiperidine according to claim 1 in the preparation of a drug for inhibiting plant pathogenic bacteria.

10. The use according to claim 9, characterized in that The plant pathogenic bacteria are selected from one or more of Xoo, Xac, Xcm, Xf., Psa. spp., Pcb, Ac, and Ps. spp.

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