A thiazolidine-2,4-dione derivative containing benzyl piperidine and preparation method and application thereof

Abstract

This invention discloses a benzylpiperidine-containing thiazoline-2,4-dione derivative, its preparation method, and its application, belonging to the field of pesticide synthesis and application technology. This invention synthesizes a series of benzylpiperidine-containing thiazoline-2,4-dione derivatives by combining the highly active benzylpiperidine group with a thiazoline-2,4-dione structure via flexible bonds. Through tests on the inhibitory activity of the synthesized benzylpiperidine-containing thiazoline-2,4-dione derivatives against plant pathogenic fungi, it was found that the benzylpiperidine-containing thiazoline-2,4-dione derivatives synthesized in this invention can effectively inhibit plant pathogenic fungi, especially rice sheath blight pathogen.

Description

Technical Field

[0001] This invention belongs to the field of pesticide synthesis technology, specifically relating to a thiazoline-2,4-dione derivative containing benzylpiperidine, its preparation method, and its application. Background Technology

[0002] Plant fungal diseases are crucial plant pathogenic stressors in agricultural production, posing a significant obstacle to sustainable agricultural development. Among various plant pathogens, Rhizoctonia solani, which causes rice sheath blight, is particularly prominent. Rhizoctonia solani Fungal diseases are considered one of the most destructive fungal pathogens in global rice cultivation. Typically, yield losses can reach 10%–30%. In the event of an outbreak, yield reductions can even exceed 50%, posing a serious threat to regional and global food security. Although various chemical fungicides are currently available for controlling plant fungal diseases, the problem of pathogenic fungi developing resistance to existing agents is becoming increasingly prominent. Therefore, developing next-generation fungicides with novel molecular structures, superior antifungal activity, environmental friendliness, and unique mechanisms of action has become a key focus of agrochemical research.

[0003] Piperidine heterocycles, due to their unique structural features, have become key frameworks for the design and synthesis of bioactive small molecules. In their molecular structure, the basic nitrogen atom exhibits significant protonation under physiological pH conditions. This property not only significantly improves the water solubility of piperidine-containing compounds but also enhances their membrane permeability, thereby significantly improving overall bioavailability. Based on these advantages, many piperidine-containing compounds have been developed into commercial drugs, with representative examples including efendil and donepezil.

[0004] Besides piperidine heterocycles, sulfur-containing heterocyclic compounds have demonstrated significant value as important structural units in pharmaceutical and agrochemical research. Among them, thiazolidinediones (TZDs) occupy a unique position in medicinal chemistry. For example, a novel coumarin-thiazolidinone hybrid molecule designed by Sumitra N. et al. exhibited potent antibacterial activity against Staphylococcus aureus (MIC = 0.5 μg / mL), and recent studies have further validated its inhibitory efficacy against Mycobacterium tuberculosis and Candida albicans. Although TZD derivatives have proven effective against various pathogens, there has been no evidence of synthesizing benzylpiperidine-containing thiazolidinedione derivatives by incorporating benzylpiperidine into the thiazolidinedione structure, nor has there been any evidence of using benzylpiperidine-containing thiazolidinedione derivatives in agrochemical activity studies. Summary of the Invention

[0005] The purpose of this invention is to provide a thiazoline-2,4-dione derivative containing benzylpiperidine, its preparation method, and its application. The provided thiazoline-2,4-dione derivative containing benzylpiperidine can be used to inhibit plant pathogenic fungi, especially rice sheath blight pathogen.

[0006] 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 thiazolidin-2,4-dione derivative containing benzylpiperidine, with the following structure: , 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.

[0007] The substituted alkyl group is trifluoromethyl, ether, carboxymethyl, cyano, benzyl or allyl; the substituted alkoxy group is trifluoromethoxy, benzyloxy or p-methoxybenzyloxy.

[0008] Preferably, the halogen is F, Cl, or Br.

[0009] The second technical solution of the present invention provides a method for preparing the above-mentioned thiazolidin-2,4-dione derivative containing benzylpiperidine, comprising the following steps: (1) Using thiazolidin-2,4-dione and dibromoalkane 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 a. The structural formula of the dibromoalkane is: , where n is an integer from 2 to 6; The structural formula of 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, intermediate b was prepared by heating in a solvent. The structural formula of intermediate b is: , where n is an integer from 2 to 6; (3) Using intermediate b as raw material, remove 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, potassium carbonate as catalyst, the thiazoline-2,4-dione derivative containing benzylpiperidine was prepared by heating under reflux. The structural formula of the substituted benzyl chloride is: 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.

[0010] Preferably, the molar ratio of thiazolidin-2,4-dione and dibromoalkane in step (1) is 1:3; the heating reaction temperature is 80°C and the time is 4~10h; the alkaline conditions are provided by anhydrous potassium carbonate; the impurity removal step includes: washing the filter residue with water and petroleum ether in sequence, then slurrying, letting it stand, filtering, and completing the washing.

[0011] More preferably, the molar ratio of thiazolidin-2,4-dione and anhydrous potassium carbonate in step (1) is 1:3; the solution used for pulping is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1.

[0012] Preferably, in step (2), the molar ratio of intermediate a, 1-boc-4-methylaminopiperidine and potassium carbonate is 3.9:(3.9~7.7):(11.6~38.5); the heating reaction is carried out at a temperature of 80°C for 4~10 h; and a purification step is included after the heating reaction.

[0013] More preferably, the purification step specifically includes: filtering the reaction system after heating, evaporating the filtrate to dryness, and performing column chromatography to complete the purification; wherein the eluent used for column chromatography is ethyl acetate.

[0014] Preferably, the step of removing BOC protection in step (3) includes: dissolving intermediate B in methanol, heating to 40~80℃, adding dropwise a 15~37% HCl solution, reacting for 1-4 h, and removing BOC protection.

[0015] Preferably, step (3) further includes a separation step after removing BOC protection. The separation step specifically involves: after removing BOC protection, the reaction system is poured into ice water, the system is adjusted to 8-9 using 5wt% NaHCO3 solution, and then extracted with dichloromethane. The extract is evaporated to dryness to obtain intermediate b.

[0016] Preferably, 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); and the heating reflux time is 1~2h.

[0017] Preferably, step (4) further includes a purification step after heating and reflux. 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 the purification; wherein the eluent used for column chromatography is a mixture of dichloromethane and methanol in a volume ratio of 40:1.

[0018] The third technical solution of the present invention provides the application of the above-mentioned thiazoline-2,4-dione derivative containing benzylpiperidine in the preparation of drugs for inhibiting plant pathogenic fungi.

[0019] Preferably, the plant pathogenic fungus includes *Rhizoctonia solani* (rice sheath blight fungus). Rhizoctonia solani ), Phytophthora capsici ( Phytophthora capsica ); Sclerotinia sclerotiorum ( Sclerotinia sclerotiorum ), wheat scab ( Fusarium graminearum ); Grape cavitation pathogen ( Botryosphaeria dothidea ) and kiwifruit stem spot pathogen ( Phomopsis sp ).

[0020] The beneficial technical effects of the present invention are as follows: This invention provides a benzylpiperidine-containing thiazoline-2,4-dione derivative, its preparation method, and its application. This invention synthesizes a series of benzylpiperidine-containing thiazoline-2,4-dione derivatives by combining a benzylpiperidine group with excellent activity and a thiazoline-2,4-dione with antibacterial activity via flexible bond splicing. Through testing the inhibitory activity of the synthesized benzylpiperidine-containing thiazoline-2,4-dione derivatives on plant pathogenic fungi, it was found that the benzylpiperidine-containing thiazoline-2,4-dione derivatives synthesized in this invention can effectively inhibit plant pathogenic fungi, especially rice sheath blight pathogen. Detailed Implementation

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] One of the technical objectives of this invention is to provide a thiazolidin-2,4-dione derivative containing benzylpiperidine, with the structure shown below: , 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.

[0026] Preferably, the halogen is F, Cl, or Br.

[0027] The second technical objective of this invention is to provide a method for preparing the above-mentioned thiazolidin-2,4-dione derivative containing benzylpiperidine, the steps of which include: (1) Using thiazoline-2,4-dione and dibromoalkane as raw materials, the reaction was carried out in a solvent under alkaline conditions at 80°C for 4-10 hours. After the reaction was completed, the reaction system was dispersed with ice water, and then filtered, washed and pulped to obtain intermediate a. The reaction formula is as follows: , In some embodiments, the solvent is acetonitrile; after the reaction is completed, the reaction solution is further dispersed with ice water to precipitate solids; after the solids are precipitated, the reaction solution is further filtered and washed; the washing is performed with water and petroleum ether respectively; the pulping is performed with petroleum ether / ethyl acetate = 3:1 (v / v); The molar ratio of the thiazolidin-2,4-dione to the dibromoalkane is 1:3; the molar ratio of the anhydrous potassium carbonate of the thiazolidin-2,4-dione is 1:3. (2) Using intermediate a and 1-boc-4-methylaminopiperidine as raw materials and potassium carbonate as catalyst, intermediate b was prepared by reacting in acetonitrile solvent at 80°C for 8-10 h. The reaction formula is as follows: , In some embodiments, the reaction is further performed by filtration, rotary evaporation under reduced pressure, and column chromatography; the filtration is to remove insoluble substances; and the column chromatography uses pure ethyl acetate as the eluent. The molar ratio of intermediate a, 1-boc-4-methylaminopiperidine, and potassium carbonate is 3.9:(3.9~7.7):(11.6~38.5). (3) Using intermediate b as raw material and methanol as solvent, add HCl solution with a concentration of 15-37wt.% dropwise under the condition of heating to 40-80 ℃ and react for 1-4 h to remove boc protection. Then pour the reaction system into ice water and adjust the system to alkaline with NaHCO3 aqueous solution to prepare intermediate c. The reaction formula is as follows: , In some embodiments, the NaHCO3 aqueous solution for saturation solution The alkaline pH value is 8-9; after adjusting to alkalinity, the process further includes extraction and vacuum rotary evaporation; the extraction is performed using dichloromethane. (4) Using intermediate c and substituted benzyl chloride as raw materials and potassium carbonate as catalyst, thiazoline-2,4-dione derivatives containing benzylpiperidine were prepared by reflux in a solvent. The reaction formula is as follows: , In some embodiments, the solvent is acetonitrile; the reflux reaction time is 1-2 hours; after the reaction is completed, the reaction system is dispersed in water, and then extracted, dried, subjected to vacuum rotary evaporation, and column chromatography, wherein the column chromatography eluent is a mixture of dichloromethane and methanol in a volume ratio of 40:1.

[0028] The molar ratio of intermediate c, substituted benzyl chloride, and potassium carbonate is 1.2:(1.2~1.4):(2.4~3.6).

[0029] The third technical objective of this invention is to provide an application of the above-mentioned thiazoline-2,4-dione derivative containing benzylpiperidine in the preparation of drugs for inhibiting plant pathogenic bacteria.

[0030] To achieve the above-mentioned technical objectives, the present invention provides the following embodiments.

[0031] Example 1

[0032] (Z)-3-(3-((1-benzylpiperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)benzyl)thiazolidin-2,4-dione (compound number D1), the steps are as follows: (1) Synthesis of intermediate a: (Z)-3-(3-bromopropyl)-5-(4-(trifluoromethoxy)phenylimino)thiazoline-2,4-dione: Thiazolidine-2,4-dione (3.0 g, 10.37 mmol), anhydrous potassium carbonate (4.3 g, 31.1 mmol), and 60 mL of acetonitrile were added to a 250 mL three-necked flask and heated to 60 °C. After stirring for 0.5 h, dibromopropane (31.1 mmol) was slowly added and reacted for 6 h. 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 petroleum ether, dried, and then the resulting white solid was slurried overnight with 60 mL of petroleum ether / ethyl acetate (3:1, v / v). The mixture was filtered to obtain a white solid with a yield of 81.4%.

[0033] (2) Intermediate b: Synthesis of tert-butyl(Z)-4-((3-(2,4-dioxo-5-(4-(trifluoromethoxy)phenylimino)thiazolidin-3-yl)propyl)(methyl)amino)piperidine-1-carboxylic acid ester: 1-boc-4-methylaminopiperidine (3.13 mL, 14.63 mmol) and anhydrous K2CO3 (3.03 g, 21.94 mmol) were added to 250 mL of acetonitrile solution. After stirring at room temperature for 0.5 h, intermediate b was added to the system, and the temperature was raised to 81 °C for 12 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with dichloromethane, the filtrate was collected and rotary evaporated under reduced pressure, and then column chromatography with pure ethyl acetate was performed to obtain a white solid with a yield of 71.3%.

[0034] (3) Synthesis of intermediate c: (Z)-3-(3-(methyl(piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenylmethylene)thiazolidin-2,4-dione: 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.% hydrochloric acid aqueous solution was added dropwise. The mixture was refluxed at 60 °C for 2 h. After the reaction was complete, a large amount of solvent was evaporated under reduced pressure, and the system was dispersed in 100 mL of water. The pH was then adjusted to 8-9 with 5 wt.% NaHCO3 solution. The mixture was extracted with dichloromethane, and the organic phase was collected. The organic phase was removed by rotary evaporation under reduced pressure. Synthesis of (Z)-3-(3-((1-benzylpiperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolidin-2,4-dione (D1): The product from step (3), 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 reacted for 2 h. After the reaction was complete, the system was dispersed in 100 mL of water. Extracted three times with dichloromethane in mL of water, the organic phase was collected, dried with anhydrous Na2SO4, and the crude product was obtained by rotary evaporation under reduced pressure. The target compound was then obtained by column chromatography (dichloromethane:methanol = 40:1, v / v), with a yield of 72%.

[0035] Example 2

[0036] Synthesis of (Z)-3-(3-(methyl(1-(2-methylphenyl)piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenyldicyclopentyl)thiazolyl-2,4-dione (compound number D2), following the same procedure as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-methylbenzyl chloride. Yield: 69%.

[0037] Example 3

[0038] Synthesis of (Z)-3-(3-((1-(2-bromobenzyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolidin-2,4-dione (compound number D3), following the same procedure as in Example 1, except that the benzyl chloride in step (4) was replaced with an equimolar amount of 2-bromobenzyl chloride. Yield: 65%.

[0039] Example 4

[0040] Synthesis of (Z)-2-((4-((3-(2,4-dioxo-5-(4-(trifluoromethoxy)phenylmethylene)thiazolidin-3-yl)propyl)(methyl)amino)piperidin-1-yl)methyl)benzonitrile (compound number D4), the steps were the same as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 2-cyanobenzyl chloride. Yield: 57%.

[0041] Example 5

[0042] Synthesis of (Z)-3-(3-((1-(2-fluorobenzyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)dicyclopentadiazolidine-2,4-dione (compound number D5), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 2-fluorobenzyl chloride. Yield: 64%.

[0043] Example 6

[0044] Synthesis of (Z)-3-(3-(methyl(1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenyldicyclopentyl)thiazolyl-2,4-dione) (compound number D6), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 2-trifluoromethylbenzyl chloride. Yield: 60%.

[0045] Example 7

[0046] Synthesis of (Z)-3-(3-((1-(3-chlorobenzyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolidin-2,4-dione (compound number D7), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 3-chlorobenzyl chloride. Yield: 48% Example 8

[0047] Synthesis of (Z)-3-(3-(methyl(1-(3-methylphenyl)piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenyldicyclopentane)thiazolyl-2,4-dione (compound number D8), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 3-methylbenzyl chloride. Yield: 62%.

[0048] Example 9

[0049] Synthesis of (Z)-3-(3-((1-(3-fluorobenzyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolidin-2,4-dione (compound number D9), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 3-fluorobenzyl chloride. Yield: 44%.

[0050] Example 10

[0051] Synthesis of (Z)-3-(3-((1-(3-bromobenzyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolidin-2,4-dione (compound number D10), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 3-bromobenzyl chloride. Yield: 51%.

[0052] Example 11

[0053] Synthesis of (Z)-3-(3-((1-(3-methoxyphenyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolidin-2,4-dione (compound number D11), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 3-methoxybenzyl chloride. Yield: 44%.

[0054] Example 12

[0055] Synthesis of (Z)-3-(3-(methyl(1-(3-(trifluoromethyl)phenyl)piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenyldicyclopentyl)thiazolidin-2,4-dione (compound number D12), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 3-trifluoromethylbenzyl chloride. Yield: 43%.

[0056] Example 13

[0057] Synthesis of (Z)-3-(3-(methyl(1-(3-(trifluoromethoxy)phenyl)piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenyldione)-2,4-thiazolidinedione) (compound number D13), the procedure was the same as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 3-trifluoromethoxybenzyl chloride. Yield: 61%.

[0058] Example 14

[0059] Synthesis of (Z)-3-(3-((1-(4-chlorophenyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)dicyclopentadiazolidine-2,4-dione (compound number D14), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 4-chlorobenzyl chloride. Yield: 62%.

[0060] Example 15

[0061] Synthesis of (Z)-3-(3-((1-(4-fluorobenzyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)dicyclopentadiazolidine-2,4-dione (compound number D15), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 4-fluorochloride. Yield: 54%.

[0062] Example 16

[0063] Synthesis of (Z)-3-(3-((1-(4-bromophenyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolidin-2,4-dione (compound number D16), following the same procedure as in Example 1, except that benzyl chloride in step (5) was replaced with an equimolar amount of 4-bromobenzyl chloride. Yield: 63%.

[0064] Example 17

[0065] Synthesis of (Z)-3-(3-(methyl(1-(4-methylphenyl)piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl disubstituted)thiazolidin-2,4-dione (compound number D17), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 4-methylbenzyl chloride. Yield: 53%.

[0066] Example 18

[0067] Synthesis of (Z)-3-(3-(methyl(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl dibon)thiazolyl-2,4-dione (compound number D18), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 4-trifluoromethoxybenzyl chloride. Yield: 56%.

[0068] Example 19

[0069] Synthesis of (Z)-3-(3-(methyl(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl dibon)thiazolidin-2,4-dione (compound number D19), following the same procedure as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 4-trifluoromethylbenzyl chloride. Yield: 46%.

[0070] Example 20

[0071] Synthesis of (Z)-3-(3-((1-(4-(tert-butyl)phenyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolyl-2,4-dione (compound number D20), following the same procedure as in Example 1, except that benzyl chloride in step (5) was replaced with an equimolar amount of 4-tert-butylbenzyl chloride. Yield: 47%.

[0072] Example 21

[0073] Synthesis of (Z)-3-(3-((1-(2,6-dimethylphenyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)diallyl)thiazolyl-2,4-dione (compound number D21), following the same procedure as in Example 1, except that benzyl chloride in step (5) was replaced with an equimolar amount of 2,6-dimethylbenzyl chloride. Yield: 54%.

[0074] Example 22

[0075] Synthesis of (Z)-3-(3-((1-(2,6-dichlorophenyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)phenyl)dicyclopentadiazolidine-2,4-dione (compound number D22), following the same procedure as in Example 1, except that benzyl chloride in step (5) was replaced with an equimolar amount of 2,6-dichlorobenzyl chloride. Yield: 59%.

[0076] Example 23

[0077] Synthesis of (Z)-3-(3-((1-(3,5-dibromobenzyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)benzylidene)thiazolyl-2,4-dione (compound number D23), following the same procedure as in Example 1, except that benzyl chloride in step (5) was replaced with an equimolar amount of 3,5-dibromobenzyl chloride. Yield: 47%.

[0078] Example 24

[0079] Synthesis of (Z)-3-(3-((1-(3,5-dimethoxybenzyl)piperidin-4-yl)(methyl)amino)propyl)-5-(4-(trifluoromethoxy)benzylmethyl)thiazolyl-2,4-dione (compound number D24), following the same procedure as in Example 1, except that benzyl chloride in step (5) was replaced with an equimolar amount of 3,5-dimethoxybenzyl chloride. Yield: 61%.

[0080] The physicochemical properties and mass spectrometry data of the thiazoline-2,4-dione derivatives containing benzylpiperidine synthesized in Examples 1-24 are shown in Table 1. (1H NMR spectroscopy data are also provided.) 1 H NMR and carbon spectroscopy (H NMR) 13 The C NMR data are shown in Table 2.

[0081] Table 1. Physicochemical properties and mass spectrometry analysis data of the target compounds compound Yield (%) Properties Molecular formula HRMS, m / z (calcd.) D1 72% White solid <![CDATA[C 27 H 31 F3N3O3S]]> <![CDATA[534.20327( 534.20142)[M+H] + ]]> D2 69% White solid <![CDATA[C 28 H 33 F3N3O3S]]> <![CDATA[548.21892(548.21692)[M+H] + ]]> D3 65% White solid <![CDATA[C 27 H 30 F3N3O3SBr]]> <![CDATA[612.11379(612.11133)[M+H] + ]]> D4 57% White solid <![CDATA[C 28 H 30 F3N4O3S]]> <![CDATA[559.19852(559.19641)[M+H] + ]]> D5 64% White solid <![CDATA[C 27 H 30 F4N3O3S]]> <![CDATA[552.19385(552.19147)[M+H] + <!-- 8 -->]]> D6 60% White solid <![CDATA[C 28 H 30 F6N3O3S]]> <![CDATA[602.19066(602.18829)[M+H] + ]]> D7 48% White solid <![CDATA[C 27 H 30 F3ClN3O3S]]> <![CDATA[568.16430(568.16217)[M+H] + ]]> D8 62% White solid <![CDATA[C 28 H 33 F3N3O3S]]> <![CDATA[548.21892(548.21686)[M+H] + ]]> D9 44% White solid <![CDATA[C 27 H 30 F4N3O3S]]> <![CDATA[552.19385(552.19220)[M+H] + ]]> D10 51% White solid <![CDATA[C 27 H 30 F3BrN3O3S]]> <![CDATA[612.11379(612.11139)[M+H] + ]]> D11 44% White solid <![CDATA[C 28 H 33 F3N3O4S]]> <![CDATA[564.21384(564.21167)[M+H] + ]]> D12 43% White solid <![CDATA[C 28 H 30 F6N3O3S]]> <![CDATA[602.19066(602.18848.)[M+H] + ]]> D13 61% White solid <![CDATA[C 28 H 30 F6N3O4S]]> <![CDATA[618.18557( 618.18341)[M+H] + ]]> D14 62% White solid <![CDATA[C 27 H 30 F3ClN3O3S]]> <![CDATA[568.16430( 568.16199)[M+H] + ]]> D15 54% White solid <![CDATA[C 27 H 30 F4N3O3S]]> <![CDATA[552.19385(552.19177)[M+H] + ]]> D16 63% White solid <![CDATA[C 27 H 30 F3BrN3O3S]]> <![CDATA[612.11379(612.11151)[M+H] + ]]> D17 53% White solid <![CDATA[C 28 H 33 F3N3O3S]]> <![CDATA[548.21892(548.21704)[M+H] + ]]> D18 56% White solid <![CDATA[C 28 H 30 F6N3O4S]]> <![CDATA[618.18557(618.18341)[M+H] + ]]> D19 46% White solid <![CDATA[C 28 H 30 F6N3O3S]]> <![CDATA[602.19066(602.18823)[M+H] + ]]> D20 47% White solid <![CDATA[C 31 H 39 F3N3O3S]]> <![CDATA[590.26587(590.26361)[M+H] + ]]> D21 54% White solid <![CDATA[C 29 H 35 F3N3O3S]]> 562.23457(562.23254)[M+H]+ D22 59% White solid <![CDATA[C 27 H 29 F3Cl2N3O3S]]> 602.12533(602.12299)[M+H]+ D23 47% White solid <![CDATA[C 27 H 29 F3Br2N3O3S]]> 690.02430(690.02155)[M+H]+ D24 61% White solid <![CDATA[C 29 H 35 F3N3O5S]]> 594.22440(594.22211)[M+H]+ Table 2. NMR spectral data of the target compound compound <![CDATA[ 1 H NMR, 13 C NMR and 19 F NMR (TMS as internal standard) D1 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.83 (s, 1H), 7.52 (d, J = 7.8 Hz,2H), 7.32 – 7.22 (m, 7H), 3.78 (t, J = 7.2 Hz, 2H), 3.54 (s, 2H), 2.98(d, J = 10.8 Hz, 2H), 2.54 (t, J =7.2 Hz, 2H), 2.47 – 2.42 (m, 1H),2.24 (s, 3H), 2.03 (t, J = 11.4 Hz,2H), 1.84 (p, J = 7.2 Hz, 2H), 1.71(d, J = 12.6 Hz, 2H), 1.64 (td, J =12.0, 3.6 Hz, 2H). 13 C NMR(150MHz, Chloroform- d ) δ 167.4, 166.1,150.2, 137.0, 131.8, 131.7, 131.6,129.4, 128.3, 127.3, 122.4, 121.3,120.2 (q, J = 258.6 Hz), 62.7,60.9, 52.8, 51.0, 40.4, 37.0,27.0, 25.3. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5. <!-- 9 -->]]> D2 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.54 (d, J = 8.4 Hz,2H), 7.31 (d, J = 8.6 Hz, 2H), 7.28(d, J = 6.7 Hz, 1H), 7.19 – 7.13(m, J = 2.8, 2.3 Hz, 3H), 3.81 (t, J = 7.2 Hz, 2H), 3.48 (s, 2H), 2.97(d, J = 11.2 Hz, 2H), 2.62 (t, J =7.2 Hz, 2H), 2.55 (s, 1H), 2.34(s, 3H), 2.32 (s, 3H), 2.05 (t, J =11.7 Hz, 2H), 1.93 (t, J = 7.2 Hz,2H), 1.77 (d, J = 12.3 Hz, 2H),1.67 – 1.60 (m, 2H). 13 C NMR(150MHz, Chloroform- d ) δ 167.4, 166.1,150.2, 137.4, 131.9, 131.7, 130.3,129.8, 127.2, 125.6, 122.3, 121.3,120.2 (q, J = 258.7 Hz), 61.3,60.2, 52.9, 51.0, 40.3, 36.8,27.0, 25.1, 19.3. 19 F NMR(470 MHz,DMSO- d 6) δ -57.5.]]> D3 <![CDATA[ 1 H NMR(500 MHz, Chloroform- d ) δ7.82 (s, 1H), 7.52 – 7.43 (m, 4H),7.30 – 7.23 (m, 3H), 7.06 (td, J =7.7, 2.0 Hz, 1H), 3.79 (t, J = 7.2Hz, 2H), 3.54 (s, 2H), 2.93 (d, J =7.5 Hz, 2H), 2.51 (t, J = 7.0 Hz,2H), 2.40 – 2.33 (m, 1H), 2.21 (s,3H), 2.08 – 2.03 (m, 2H), 1.82 (p, J = 7.0 Hz, 2H), 1.68 – 1.63 (m,2H), 1.60 – 1.51 (m, 2H). 13 C NMR(150 MHz, Chloroform- d ) δ 167.4,166.1, 150.2, 142.7, 132.8, 132.5,131.8, 131.7, 131.7, 129.9, 127.4,122.4, 121.3, 120.2 (q, J = 258.7Hz), 117.8, 112.8, 61.1, 60.3,53.1, 51.0, 40.5, 37.0, 36.4,29.6, 27.4, 25.4. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5. <!-- 10 -->]]> D4 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.62 (d, J = 7.8 Hz,1H), 7.54 (d, J = 6.0 Hz, 4H), 7.34(dd, J = 8.4, 3.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 3.80 (t, J = 7.2Hz, 2H), 3.66 (s, 2H), 2.91 (d, J =7.8 Hz, 2H), 2.56 (t, J = 7.2 Hz,2H), 2.45 (s, 1H), 2.26 (s, 3H),2.09 (t, J = 12.0 Hz, 2H), 1.88 –1.84 (m, 2H), 1.71 (d, J = 12.6 Hz,2H), 1.61 – 1.55 (m, 2H). 13 C NMR(150 MHz, Chloroform- d ) δ 167.4,166.1, 150.2, 142.7, 132.8, 132.5,131.8, 131.7, 131.7, 129.9, 127.4,122.4, 121.3, 120.2 (q, J = 258.7Hz), 117.8, 112.8, 61.1, 60.3,53.1, 51.0, 40.5, 37.0, 36.4,29.6, 27.4, 25.4. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5. <!-- 11 -->]]> D5 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.84 (s, 1H), 7.53 (d, J = 8.4 Hz,2H), 7.36 (t, J = 6.6 Hz, 1H), 7.31(d, J = 8.4 Hz, 2H), 7.24 – 7.22(m, 1H), 7.10 (t, J = 7.2 Hz, 1H),7.01 (t, J = 9.0 Hz, 1H), 3.79 (t, J = 7.2 Hz, 2H), 3.59 (s, 2H), 2.97(d, J = 11.4 Hz, 2H), 2.53 (t, J =7.2 Hz, 2H), 2.40 (t, J = 11.4 Hz,1H), 2.24 (s, 3H), 2.05 (t, J =11.4 Hz, 2H), 1.84 (t, J = 7.2 Hz,2H), 1.69 (d, J = 12.0 Hz, 2H),1.60 (t, J = 12.0 Hz, 2H). 13 C NMR(150 MHz, Chloroform- d ) δ 167.4,166.1, 161.3 (d, J = 246.2 Hz),150.2, 131.7, 131.6, 128.8 (d, J =8.0 Hz), 124.4, 123.8 (q, J = 3.4Hz), 122.5, 121.3, 120.3(q, J =258.8 Hz), 115.2 (d, J = 22.3 Hz),61.0, 55.0, 52.8, 51.0, 40.5,37.0, 29.6, 27.2, 25.4. 19 F NMR(470 MHz, Chloroform- d ) d -57.5, -117.6.<!-- 12 --> ]]> D6 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.86 (s, 1H), 7.79 (d, J = 7.8 Hz,1H), 7.60 (dd, J = 7.9, 1.2 Hz,1H), 7.54 (d, J = 8.4 Hz, 2H), 7.50(t, J = 7.8 Hz, 1H), 7.31 (d, J =9.0 Hz, 3H), 3.81 (t, J = 7.8 Hz,2H), 3.62 (s, 2H), 2.90 (d, J =10.8 Hz, 2H), 2.58 (t, J = 7.2 Hz,2H), 2.44 (t, J = 11.4 Hz, 1H),2.28 (s, 3H), 2.05 (t, J = 11.4 Hz,2H), 1.87 (p, J = 7.2 Hz, 2H), 1.71(d, J = 12.6 Hz, 2H), 1.63 – 1.56(m, 2H). 13 C NMR(150 MHz,CHLOROFORM- D ) δ 167.5, 166.1,150.2, 138.1, 131.8, 131.7, 131.7,130.1, 128.4, 128.2, 126.6, 125.59(d, J = 5.8 Hz), 125.3, 122.4,121.3, 120.28 (q, J = 258.8 Hz),61.2, 58.0, 53.3, 51.1, 40.5,37.1, 27.5, 25.4. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5.]]> D7 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.54 (d, J = 9.0 Hz,2H), 7.32 (dd, J = 8.4, 4.8 Hz,4H), 7.14 (d, J = 7.8 Hz, 2H), 3.80(t, J = 7.2 Hz, 2H), 3.47 (s, 2H),2.90 (d, J = 12.0 Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H), 2.41 – 2.36 (m,1H), 2.23 (s, 3H), 1.96 (t, J =11.4 Hz, 1H), 1.84 (p, J = 7.2 Hz,2H), 1.68 (d, J = 11.4 Hz, 2H),1.60 – 1.53 (m, 2H). 13 C NMR(150MHz, Chloroform- d ) δ 167.4, 166.2,150.2, 148.2, 137.2, 131.8, 131.7,131.7, 130.3, 122.5, 121.3, 121.1,120.7, 119.6, 119.4, 62.1, 61.1,53.2, 51.1, 40.6, 37.1, 27.4,25.6. 19 F NMR(470 MHz, Chloroform- d ) δ -57.6, -57.7. <!-- 13 -->]]> D8 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.81 (s, 1H), 7.50 (d, J = 8.4 Hz,2H), 7.28 (d, J = 8.4 Hz, 2H), 7.17(t, J = 7.2 Hz, 1H), 7.11 (s, 1H),7.08 (d, J = 7.4 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 3.77 (t, J = 7.4Hz, 2H), 3.48 (s, 2H), 2.96 (d, J =11.4 Hz, 2H), 2.52 (t, J = 7.3 Hz,2H), 2.43 – 2.38 (m, 1H), 2.31 (s,3H), 2.22 (s, 3H), 2.00 (t, J =11.7 Hz, 2H), 1.84 – 1.80 (m, 2H),1.69 (d, J = 12.0 Hz, 2H), 1.62 (t, J = 10.2 Hz, 1H). 13 C NMR(150 MHz,Chloroform- d ) δ 167.2, 166.0,150.0, 137.7, 136.9, 131.6, 130.1,129.8, 128.1, 127.8, 127.7, 126.5,126.2, 122.3, 121.1, 121.0, 120.0(q, J = 231.9 Hz), 62.6, 60.8,53.0, 52.7, 50.9, 40.4, 36.9,26.9, 25.3, 21.2. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5. <!-- 14 -->]]> D9 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.83 (s, 1H), 7.52 (d, J = 8.4 Hz,2H), 7.30 (d, J = 8.4 Hz, 2H), 7.26– 7.22 (m, 1H), 7.04 (t, J = 7.8Hz, 2H), 6.92 (t, J = 8.4 Hz, 1H),3.79 (t, J = 7.2 Hz, 2H), 3.47 (s,2H), 2.91 (d, J = 11.4 Hz, 2H),2.56 (d, J = 6.9 Hz, 2H), 2.43 (d, J = 11.4 Hz, 1H), 2.26 (s, 3H),1.97 (t, J = 11.4 Hz, 2H), 1.86 (t, J = 7.2 Hz, 2H), 1.70 (d, J = 12.0Hz, 2H), 1.60 (t, J = 12.0 Hz, 2H). 13 C NMR(150 MHz, Chloroform- d ) δ167.4, 166.0, 162.8 (d, J = 245.5Hz), 150.1, 140.8 (d, J = 6.8 Hz),131.6, 129.5, 129.4, 124.5 (q, J =25.2 Hz), 122.4, 121.2, 121.1,119.34, 115.8, 115.6, 115.5,114.0, 113.8, 113.7, 62.2, 61.1,52.9, 51.0, 40.4, 36.9, 27.2,25.3. 19 F NMR (470 MHz, Chloroform- d ) δ -57.6, -113.6. <!-- 15 -->]]> D10 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.84 (s, 1H), 7.53 (d, J = 8.4 Hz,2H), 7.46 (s, 1H), 7.36 (d, J = 7.2Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H),7.22 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 3.80 (t, J = 7.3Hz, 2H), 3.44 (s, 2H), 2.90 (d, J =12.0 Hz, 2H), 2.55 (t, J = 7.2 Hz,2H), 2.42 (t, J = 12.0 Hz, 1H),2.26 (s, 3H), 1.96 (t, J = 11.4 Hz,2H), 1.85 (p, J = 7.2 Hz, 2H), 1.69(d, J = 12.0 Hz, 2H), 1.58 (qd, J =11.9, 3.9 Hz, 2H). 13 C NMR(150MHz, Chloroform- d ) δ 167.4, 166.1,150.2, 140.7, 131.8, 131.7, 131.7,131.6, 130.1, 129.73, 127.6,122.4, 122.4, 121.7, 120.24 (q, J =258.8 Hz), 62.2, 61.1, 53.1, 51.0,40.5, 37.0, 29.6, 27.3, 25.4. 19 FNMR (470 MHz, Chloroform- d ) δ -57.5. <!-- 16 -->]]> D11 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.84 (s, 1H), 7.53 (d, J = 9.0 Hz,2H), 7.31 (d, J = 9.0 Hz, 2H), 7.21(t, J = 7.8 Hz, 1H), 6.90 – 6.86(m, 2H), 6.81 – 6.77 (m, 1H), 3.81– 3.78 (m, 5H), 3.49 (s, 2H), 2.96– 2.94 (m, 2H), 2.53 (t, J = 7.2Hz, 2H), 2.41 – 2.37 (m, 1H), 2.23(s, 3H), 1.99 (t, J = 11.4 Hz, 2H),1.83 (p, J = 7.2 Hz, 2H), 1.69 (d, J = 12.0 Hz, 2H), 1.64 – 1.57 (m,2H). 13 C NMR(150 MHz, Chloroform- d ) δ 167.4, 166.1, 159.5, 150.2,139.4, 132.4, 131.7, 131.7, 131.6,129.1, 122.5, 121.5, 121.3, 120.2(d, J = 258.8 Hz), 114.6, 112.5,62.7, 60.9, 55.1, 53.1, 51.0,40.5, 37.0, 29.6, 29.3, 27.2,25.5. 19 F NMR(470 MHz, Chloroform- d ) δ -57.5. <!-- 17 -->]]> D12 <![CDATA[ 1 H NMR (600 MHz, Chloroform- d ) δ7.84 (s, 1H), 7.56 (s, 1H), 7.53(d, J = 9.0 Hz, 2H), 7.49 (d, J =7.8 Hz, 2H), 7.41 (t, J = 7.8 Hz,1H), 7.30 (d, J = 8.4 Hz, 2H), 3.80(t, J = 7.2 Hz, 2H), 3.51 (s, 2H),2.89 (d, J = 10.8 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.43 – 2.38 (m,1H), 2.24 (s, 3H), 1.97 (t, J =12.0, 2.4 Hz, 2H), 1.84 (p, J = 7.2Hz, 2H), 1.69 (d, J = 12.0 Hz, 2H),1.61 – 1.54 (m, 2H). 13 C NMR(150MHz, Chloroform- d ) δ 167.4, 166.1,150.2, 139.6, 132.3, 131.7, 131.6,130.4 (q, J = 32.1 Hz), 128.6,125.5 (d, J = 4.1 Hz), 124.2 (q, J =272.6 Hz), 125.1, 123.8 (d, J = 4.1Hz), 122.5, 121.3, 120.3 (q, J =258.7 Hz), 62.4, 61.1, 53.2, 51.0,40.5, 37.0, 27.4, 25.5. 19 F NMR(470 MHz, Chloroform- d ) δ -57.6, -62.3. <!-- 18 -->]]> D13 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.84 (s,1H), 7.53 (d, J = 9.0 Hz,2H), 7.34 – 7.27 (m, 3H), 7.22 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.09(d, J = 9.0 Hz, 1H), 3.80 (t, J =7.2 Hz, 2H), 3.48 (s, 2H), 2.90(d, J = 11.4 Hz, 2H), 2.55 (t, J =7.2 Hz, 2H), 2.43 – 2.39 (m, 1H),2.25 (s, 3H), 1.96 (t, J = 10.4 Hz,2H), 1.85 (p, J = 7.2 Hz, 2H), 1.69(d, J = 12.0 Hz, 2H), 1.68 – 1.54(m, 2H). 13 C NMR(150 MHz,Chloroform- d ) δ 167.4, 166.1,150.2, 149.2, 141.0, 131.7, 131.6,129.4, 127.2, 122.5, 121.3, 120.3(q, J = 232.6 Hz), 119.4, 119.3,62.2, 61.1, 58.3, 53.4, 53.1,51.0, 40.5, 37.0, 36.4, 27.4,25.5, 18.4. 19 F NMR (470 MHz,Chloroform- d ) δ -57.6.]]> D14 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.86 (s, 1H), 7.54 (d, J = 8.4 Hz,2H), 7.32 (d, J = 8.3 Hz, 2H), 7.28(d, J = 7.9 Hz, 2H), 7.24 (d, J =8.1 Hz, 2H), 3.80 (t, J = 7.2 Hz,2H), 3.45 (s, 2H), 2.92 – 2.89 (m,2H), 2.54 (t, J = 7.2 Hz, 2H), 2.42– 2.34 (m, 1H), 2.24 (s, 3H), 1.96(t, J = 11.4 Hz, 2H), 1.85 (p, J =7.2 Hz, 2H), 1.69 (d, J = 11.4 Hz,2H), 1.61 – 1.54 (m, 2H). 13 C NMR(150 MHz, Chloroform- d ) δ 167.4,166.1, 162.5, 150.2, 136.7, 132.6,131.7, 131.6, 130.4, 128.3, 122.5,121.3, 120.26 (q, J = 258.9 Hz),62.1, 61.0, 53.1, 53.0, 51.0,40.6, 37.1, 36.5, 31.4, 29.7,27.4, 25.5. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5. <!-- 19 -->]]> D15 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.84 (s, 1H), 7.53 (d, J = 9.0 Hz,2H), 7.31 (d, J = 8.4 Hz, 2H), 7.28– 7.22 (m, 2H), 6.98 (t, J = 8.4Hz, 2H), 3.79 (t, J = 7.2 Hz, 2H),3.43 (s, 2H), 2.90 (d, J = 12.0 Hz,2H), 2.51 (t, J = 7.2 Hz, 2H), 2.38– 2.33 (m, 1H), 2.22 (s, 3H), 1.93(t, J = 10.4 Hz, 2H), 1.82 (p, J =7.1 Hz, 2H), 1.67 (d, J = 12.6 Hz,2H), 1.58 – 1.54 (m, 2H). 13 C NMR(150 MHz, Chloroform- d ) δ 167.4,166.1, 161.9 (d, J = 244.7 Hz),150.2, 134.0, 131.7, 131.7, 131.7,130.6 (d, J = 7.8 Hz), 122.5,121.3, 120.3 (d, J = 258.8 Hz),114.9 (d, J = 21.1 Hz), 62.2, 61.1,53.1, 51.0, 40.6, 37.1, 27.4,25.6. 19 F NMR(470 MHz, Chloroform- d ) δ -57.6, -115.9.]]> D16 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.84 (s, 1H), 7.53 (d, J = 8.4 Hz,2H), 7.41 (d, J = 8.0 Hz, 2H), 7.31(d, J = 8.4 Hz, 2H), 7.17 (d, J =7.8 Hz, 2H), 3.79 (t, J = 7.2 Hz,2H), 3.42 (s, 2H), 2.89 (d, J =10.8 Hz, 2H), 2.51 (t, J = 7.2 Hz,2H), 2.39 – 2.33 (m, 1H), 2.22 (s,3H), 1.93 (d, J = 11.4 Hz, 2H),1.82 (p, J = 7.2 Hz, 2H), 1.67 (d, J = 12.0 Hz, 2H), 1.58 – 1.52 (m,2H). 13 C NMR(150 MHz, Chloroform- d ) δ 166.4, 165.1, 149.2, 136.4,130.7, 130.6, 130.2, 129.7, 121.5,120.3, 120.1, 119.7, 118.4, 116.7,61.2, 60.0, 52.2, 50.0, 39.6,36.1, 26.4, 24.6. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5. <!-- 20 -->]]> D17 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.54 (d, J = 8.4 Hz,2H), 7.31 (d, J = 8.4 Hz, 2H), 7.19(d, J = 7.2 Hz, 2H), 7.12 (d, J =7.8 Hz, 2H), 3.79 (t, J = 7.2 Hz,2H), 3.48 (d, J = 4.8 Hz, 2H), 2.97– 2.94 (m, 2H), 2.52 (t, J = 7.2Hz, 2H), 2.40 – 2.35 (m, 1H), 2.33(s, 3H), 2.22 (s, 3H), 1.96 (d, J =12.0 Hz, 2H), 1.83 (t, J = 7.2 Hz,2H), 1.68 (d, J = 12.6 Hz, 2H),1.61 (t, J = 12.0 Hz, 2H). 13 C NMR(150 MHz, Chloroform- d ) δ 167.4,166.1, 150.2, 136.8, 131.7, 131.7,129.5, 129.2, 129.0, 128.7, 122.5,121.3, 121.1, 121.0, 119.40, 62.6,60.9, 53.1, 52.8, 51.0, 40.6,37.1, 29.7, 27.2, 25.5, 21.1. 19 FNMR(470 MHz, Chloroform- d ) δ -57.5.]]> D18 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.54 (d, J = 9.0 Hz,2H), 7.33 – 7.29 (m, 3H), 7.23 (d, J = 6.0 Hz, 2H), 7.18 (dd, J = 6.0,2.4 Hz, 1H), 3.80 (t, J = 7.2 Hz,2H), 3.46 (s, 2H), 2.92 (d, J =11.4 Hz, 2H), 2.57 (t, J = 7.2 Hz,2H), 2.45 (s, 1H), 2.27 (s, 3H),1.98 (t, J = 11.4 Hz, 2H), 1.86 (p, J = 7.1 Hz, 2H), 1.71 (d, J = 12.0Hz, 2H), 1.63 – 1.56 (m, 2H). 13 CNMR (150 MHz, Chloroform- d ) δ167.4, 166.1, 150.2, 140.3, 134.1,131.8, 131.7, 131.7, 129.5, 129.0,127.2, 127.1, 122.4, 121.3, δ120.3 (q, J = 259.0 Hz), 62.2,61.1, 53.1, 51.1, 40.5, 37.0,27.2, 25.4. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5. <!-- 21 -->]]> D19 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.57 – 7.51 (m, 4H),7.42 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 3.80 (t, J = 7.2Hz, 2H), 3.52 (s, 2H), 2.90 (d, J =11.4 Hz, 2H), 2.57 (t, J = 7.2 Hz,2H), 2.44 (s, 1H), 2.27 (s, 3H),1.98 (t, J = 11.4 Hz, 2H), 1.86 (t, J = 7.2 Hz, 2H), 1.71 (d, J = 12.0Hz, 2H), 1.60 (t, J = 10.2 Hz, 2H). 13 C NMR(150 MHz, Chloroform- d ) δ167.4, 166.1, 150.2, 142.5, 131.8,131.7, 131.6, 129.1, 125.1, 123.3,122.4, 121.3, 120.25 (q, J = 258.8Hz), 62.3, 61.1, 53.1, 51.03,40.4, 37.0, 29.6, 27.3, 25.4,22.6, 14.1. 19 F NMR(470 MHz,Chloroform- d ) δ -57.6, -62.2.]]> D20 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.54 (d, J = 9.0 Hz,2H), 7.32 (t, J = 8.4 Hz, 4H), 7.23(d, J = 7.8 Hz, 2H), 3.79 (t, J =7.2 Hz, 2H), 3.48 (s, 2H), 2.96(d, J = 11.4 Hz, 2H), 2.52 (t, J =7.2 Hz, 2H), 2.41 – 2.36 (m, 1H),2.22 (s, 3H), 1.99 – 1.95 (m, 2H),1.83 (p, J = 7.2 Hz, 2H), 1.68 (d, J = 12.0 Hz, 2H), 1.63 – 1.59 (m,2H), 1.31 (s, 9H). 13 C NMR(150 MHz,Chloroform- d ) δ 167.4, 166.1,150.2, 150.0, 131.7, 131.7, 129.0,125.1, 122.5, 121.3, 121.1, 119.4,62.5, 61.0, 53.1, 51.1, 40.6,37.1, 34.4, 31.3, 27.2, 25.6. 19 FNMR(470 MHz, Chloroform- d ) δ -57.5. <!-- 22 -->]]> D21 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.54 (d, J = 7.8 Hz,2H), 7.31 (d, J = 8.4 Hz, 2H), 7.05(t, J = 7.2 Hz, 1H), 6.99 (d, J =7.2 Hz, 2H), 3.80 (t, J = 7.2 Hz,2H), 3.42 (s, 2H), 2.85 (d, J =10.8K Hz, 2H), 2.53 (t, J = 7.2 Hz,2H), 2.42 – 2.38 (m, 1H), 2.37 (s,6H), 2.23 (s, 3H), 2.03 (t, J =11.4 Hz, 2H), 1.85 (t, J = 7.2 Hz,2H), 1.66 (d, J = 12.0 Hz, 2H),1.49 – 1.41 (m, 2H). 13 C NMR(150MHz, Chloroform- d ) δ 167.4, 166.1,150.2, 138.1, 135.2, 131.7, 131.6,128.0, 126.7, 122.5, 121.3, 61.4,56.0, 52.9, 51.0, 45.2, 40.6,37.1, 29.6, 27.7, 25.4, 20.1. 19 FNMR(470 MHz, Chloroform- d ) δ -57.5]]> D22 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.54 (d, J = 9.0 Hz,2H), 7.32 (d, J = 8.4 Hz, 2H), 7.29(s, 1H), 7.28 (s, 1H), 7.13 (t, J =7.8 Hz, 1H), 3.80 (t, J = 7.2 Hz,2H), 3.70 (s, 2H), 2.96 (t, J = 4.8Hz, 2H), 2.89 (s, 1H), 2.55 (t, J =7.1 Hz, 2H), 2.43 (t, J = 11.6 Hz,1H), 2.24 (s, 3H), 2.22 – 2.18 (m,2H), 1.86 (t, J = 7.2 Hz, 2H), 1.67(d, J = 12.0 Hz, 2H), 1.51 (td, J =12.0, 3.6 Hz, 2H). 13 C NMR(150MHz, Chloroform- d ) δ 167.4, 166.1,150.2, 136.9, 134.6, 131.8, 131.7,131.7, 128.7, 128.3, 122.5, 121.3,120.3 (q, J = 258.7 Hz), 61.3,56.3, 53.2, 51.0, 40.5, 37.0,29.7, 27.3, 25.3. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5. <!-- 23 -->]]> D23 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.53 (d, J = 8.4 Hz,3H), 7.39 (s, 2H), 7.31 (d, J = 8.4Hz, 2H), 3.80 (t, J = 7.2 Hz, 2H),3.39 (s, 2H), 2.87 (d, J = 11.4 Hz,2H), 2.54 (t, J = 7.2 Hz, 2H), 2.39(t, J = 7.2 Hz, 1H), 2.24 (s, 3H),1.95 (t, J = 11.4 Hz, 2H), 1.84 (p, J = 7.2 Hz, 2H), 1.68 (d, J = 11.4Hz, 2H), 1.56 (qd, J = 12.0, 3.7Hz, 2H). 13 C NMR(150 MHz,Chloroform- d ) δ 167.4, 166.1,150.2, 142.9, 132.5, 131.7, 131.6,130.5, 122.7, 122.5, 121.3, 120.2(q, J = 259.9 Hz), 61.7, 61.0,53.2, 51.0, 40.5, 37.0, 29.6,27.4, 25.5. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5.]]> D24 <![CDATA[ 1 H NMR(600 MHz, Chloroform- d ) δ7.85 (s, 1H), 7.54 (d, J = 8.4 Hz,2H), 7.31 (d, J = 8.4 Hz, 2H), 6.55(s, 2H), 6.37 (s, 1H), 3.81 (d, J =7.2 Hz, 2H), 3.79 (s, 6H), 3.54(s, 2H), 3.03 (d, J = 10.8 Hz, 2H),2.59 (t, J = 7.2 Hz, 2H), 2.51 (s,1H), 2.28 (s, 3H), 2.10 (s, 2H),1.89 (t, J = 7.2 Hz, 2H), 1.77 (s,2H). 13 C NMR(126 MHz, Chloroform- d ) δ 167.4, 166.1, 160.7, 150.2,131.9, 131.7, 131.6, 122.3, 121.3,119.2, 107.2, 99.4, 62.5, 55.3,52.6, 51.0, 40.3, 36.9, 29.6,26.6, 25.1. 19 F NMR(470 MHz,Chloroform- d ) δ -57.5.]]> Experimental Example 1 Anti-plant pathogenic fungal activity test This study evaluated 24 synthetic thiazolidinedione-2,4-dione derivatives using the mycelial growth rate method to investigate their inhibitory activity against six plant pathogenic fungi. Two commercially available antifungal agents were used as positive controls: Az (produced by Yancheng Limin Agricultural Chemicals Co., Ltd.) and Fl (purchased from the Platinum-Strontium-Titanium platform). The specific implementation steps are as follows: Preparation steps of the culture medium: When preparing potato dextrose agar (PDA) medium, first weigh 40.1 g of PDA medium, then place it in 1000 mL of deionized water and heat to boiling until completely dissolved. Next, while still hot, quickly measure 20 mL of the medium and carefully pour it into a 50 mL Erlenmeyer flask. To ensure airtightness while maintaining permeability, use a breathable sealing film to tightly seal the flask opening. Finally, place the Erlenmeyer flask in an autoclave and set the temperature to 121℃ for 20 minutes for thorough sterilization, ready for subsequent use.

[0082] Antifungal activity test procedure: Add 100 μL (concentration 100%) to sterilized PDA medium. After thoroughly mixing the (µg / mL) drug solution, distribute the mixture evenly into three sterile culture dishes and allow it to cool before use.

[0083] Pre-activated fungal cultures were prepared into 5 mm diameter mycelial cakes using a punch, and these cakes were placed upside down in the center of cooled culture medium. PDA medium containing the same concentration of DMSO was used as a blank control. When the mycelium covered 3 / 4 of the culture dish, the diameter of the mycelium was measured using the cross-sectional method. Each test compound was tested in triplicate, and the fungal inhibition rate was calculated using formula (3-2). Inhibition rate (3-2) C: Mycelial growth diameter in blank control (unit: mm) T: Diameter of mycelial growth after treatment with the chemical (unit: mm) 5: Diameter of the mushroom cake (unit: mm).

[0084] EC 50 Determination of values: Based on the results of the preliminary screening test, compounds with inhibition rates superior to the control agent were selected to further investigate their activity against fungi with good inhibitory effects. Following the experimental method described in the preliminary screening, test concentration gradients of 25, 12.5, 6.25, 3.125, and 1.56 μg / mL were set up for testing. The growth of fungal hyphae at each concentration was recorded in detail. Subsequently, based on the collected data, the inhibition rate of fungal hyphae growth was calculated at each of the five different concentration gradients.

[0085] The results of the bioactivity test against plant pathogenic fungi are shown in Table 3.

[0086] Table 3. In vitro antifungal activity of D1–D24 (50 μg / mL)

[0087] As shown in Table 3, all target compounds exhibited inhibitory activity against the six plant fungi at a concentration of 50 μg / mL. Most compounds showed high inhibition rates (usually ≥90%) against Ss, Ps, Pc, Bd, and Rs, indicating that these compounds have broad-spectrum and potent antibacterial activity against these pathogens. The inhibition rate against Fg was relatively low (generally between 75% and 90%), but still higher than the positive control Az (50.0 ± 2.8%), indicating that the compounds had weaker activity against Fg, but were superior to the control drug.

[0088] Table 4. Pairs D1-D24 Sclerotinia sclerotiorum EC50 value determination

[0089] Table 5. Pairs D1-D24 Phomopsis sp EC50 value determination

[0090] Table 6. Pairs D1-D24 Phytophthora capsica EC50 value determination

[0091] Table 7. Pairs D1-D24 Botryosphaeria dothidea EC50 value determination

[0092] Table 8. Pairs D1-D24 Fusarium graminearum EC50 value determination

[0093] Table 9. Pairs D1-D24 Rhizoctonia solani EC50 value determination

[0094] Based on the preliminary screening results, the EC50 of 24 target compounds against 6 plant pathogens was further determined. 50 The values ​​(see Tables 4–9) were used to compare their fungicidal activities. The results showed that these active compounds possessed broad-spectrum activity, with several compounds exhibiting superior activity compared to Az. Compound D18, in particular, demonstrated excellent antifungal activity against Rs, with an EC50 value of [missing value]. 50 The concentration was 4.9 μg / mL.

[0095] The above experimental activity data show that the thiazoline-2,4-dione derivative containing benzylpiperidine has a good inhibitory effect on plant pathogenic fungi, especially rice sheath blight fungus (Rs), and can be used as a potential anti-plant pathogen drug with good application prospects.

[0096] 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 thiazoline-2,4-dione derivative containing benzylpiperidine, characterized in that: The structure is shown in the following formula: ， 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, and one or more C1-C6 substituted alkoxy groups.

2. The thiazolidin-2,4-dione derivative containing benzylpiperidine according to claim 1, characterized in that: The substituted alkyl group is trifluoromethyl, ether, carboxymethyl, cyano, benzyl or allyl; the substituted alkoxy group is trifluoromethoxy, benzyloxy or p-methoxybenzyloxy.

3. A method for preparing the thiazolidin-2,4-dione derivative containing benzylpiperidine as described in claim 1, characterized in that: step include: (1) Using thiazolidin-2,4-dione and dibromoalkane 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 a. The structural formula of the dibromoalkane is: ; The structural formula of intermediate a is: ; (2) Using intermediate a and 1-boc-4-methylaminopiperidine as raw materials, and alkali as catalyst, the reaction was carried out in a solvent by heating to obtain intermediate b; The structural formula of intermediate b is: ; (3) Using intermediate b as raw material, the boc protection is removed to obtain intermediate c; the structural formula of intermediate c is: ; (4) Using intermediate c and substituted benzyl chloride as raw materials, and potassium carbonate as a catalyst, the thiazoline-2,4-dione derivative containing benzylpiperidine was prepared by heating under reflux; the structural formula of the substituted benzyl chloride is: .

4. The preparation method according to claim 3, characterized in that: The molar ratio of thiazolidin-2,4-dione and dibromoalkane in step (1) is 1:3; the heating reaction temperature is 80°C and the time is 4~10h; the alkaline conditions are provided by anhydrous potassium carbonate; The impurity removal steps include: washing the filter residue sequentially with water and petroleum ether, then pulping, letting it stand, filtering, and completing the washing process.

5. The preparation method according to claim 4, characterized in that: The molar ratio of thiazolidin-2,4-dione and anhydrous potassium carbonate in step (1) is 1:3; the solution used for pulping is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:

1.

6. The preparation method according to claim 3, characterized in that: In step (2), the molar ratio of intermediate a, 1-boc-4-methylaminopiperidine and potassium carbonate is 3.9:(3.9~7.7):(11.6~38.5); the heating reaction is carried out at a temperature of 80°C for 4~10 h; and a purification step is also included after the heating reaction.

7. The preparation method according to claim 3, characterized in that: The step of removing BOC protection in step (3) includes: dissolving intermediate B in methanol, heating to 40-80℃, adding 15-37% HCl solution dropwise, reacting for 1-4 h to remove BOC protection; after removing BOC protection in step (3), a separation step is also included, which specifically involves: after removing BOC protection, pouring the reaction system into ice water, adjusting the system to 8-9 using saturated NaHCO3 solution, then extracting with dichloromethane, evaporating the extract to dryness to obtain intermediate B.

8. The preparation method according to claim 3, 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 and reflux time is 1~2h.

9. The use of the thiazoline-2,4-dione derivative containing benzylpiperidine as described in claim 1 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 mentioned are rice sheath blight fungus, pepper phytophthora fungus, rapeseed sclerotinia rot fungus, wheat scab fungus, grape bud blight fungus, and kiwifruit stem spot fungus.

Images