Dithioacetal derivative containing sulfonyl piperazine unit as well as preparation method and application of dithioacetal derivative

Abstract

The invention relates to a dithioacetal derivative containing a sulfonyl piperazine unit as well as a preparation method and application of the dithioacetal derivative. The compound disclosed by the invention has excellent antiviral activity on tomato spotted wilt virus and the like, and can be used for medicines or medicaments for preventing and treating plant virus diseases such as tomato spotted wilt virus and the like. The structure and the preparation process are simple, and the production cost is low. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of chemical industry and pesticide, in particular to a dithioacetal derivative containing a sulfonylpiperazine unit and a preparation method thereof, and application of the dithioacetal derivative containing a sulfonylpiperazine unit in medicines for preventing and treating plant viruses such as tomato spotted wilt virus disease. Background Art

[0002] Tomato spotted wilt virus (TSWV) is a representative species of the genus Orthotospovirus in the family Tospoviridae of the order Bunyavirales. It is one of the top ten viruses that cause serious damage to agricultural production. It can infect more than 1,000 plant species from more than 80 families, including impatiens, lettuce, potato, chrysanthemum, celery, tobacco, soybean, pepper and tomato. It is a virus that seriously damages the yield and quality of economic crops such as tomatoes. It is mainly transmitted by western flower thrips and spreads in a cyclic proliferation mode. After the thrips are infected in the nymph stage, they can replicate themselves in the body in a cyclic proliferation mode and carry the virus for life. It was first discovered in Australia in 1915. It occurs all over the world, and the losses caused by viral diseases caused by TSWV exceed US$1 billion each year. TSWV is a tripartite single-stranded RNA (ssRNA) virus. The genome contains three types of RNA, namely small (S), medium (M) and large (L). The nonstructural protein NSs (52.4 KDa) encoded by S-RNA is related to gene silencing, and the nucleocapsid protein (N) (28.8 KDa) encoded by its complementary chain is a major structural protein that can assemble and convert genomic RNA into ribonucleoprotein complexes (RNPs). It is very important for TSWV infection and is closely related to the movement of the virus. M-RNA encodes the nonstructural protein NSm (33.6 KDa) and glycoprotein Gn-Gc (127.4 KDa). NSm has a significant effect on the cell-to-cell movement of TSWV. The RNA-dependent RNA polymerase (RdRp) (331.5 KDa) encoded by L-RNA is closely related to viral replication and transcription.

[0003] In 2017, Zhang Jian et al. (Zhang, J.; Zhao, L.; Zhu, C.; Wu, ZX; Zhang, GP; Gan, XH; Liu, DY; Pan, JK; Hu, DY; Song, BAFacile Synthesis of novel vanillin derivatives incorporating a bis(2-hydroxyethyl)dithioacetal moietyas antiviral agents[J]. J. Agric. Food Chem. 2017, 65, 4582-4588.) from the applicant's team reported a series of vanillin derivatives containing dithioacetals using vanillin as raw material. The results of biological activity assays showed that compound 6f exhibited the best therapeutic and protective activity against PVY and CMV, and its effective concentration EC 50 They were 217.6 mg / L, 205.7 mg / L and 206.3 mg / L, 186.2 mg / L respectively, which were better than ribavirin (848.0 mg / L, 808.1 mg / L and 858.2 mg / L, 766.5 mg / L respectively), fluorine and phosphorus (462.6 mg / L, 454.8 mg / L and 471.2 mg / L, 465.4 mg / L respectively) and ningnanmycin (440.5 mg / L, 425.3 mg / L and 426.1 mg / L, 405.3 mg / L respectively).

[0004] In 2018, Chen Jin et al. (Chen, J.; Shi, J.; Yu, L.; Liu, DY; Gan, XH; Song, BA; Hu, DY Design, synthesis, antiviral bioactivity, and defense mechanisms of novel dithioacetal derivatives bearing a strobilurin moiety [J]. J. Agric. Food Chem. 2018, 66, 5335-5345.) from the applicant's team reported that the dithioacetal compound C14 containing methoxyacrylate had a good inhibitory effect on PVY, CMV and TMV. The protective activity was 148.4, 113.2 and 214.6 mg / L, respectively, and the therapeutic activity EC 50The concentrations of ribavirin and viravir were 125.3, 108.9 and 181.7 mg / L, respectively, which were significantly higher than those of acyclovir (652.7, 665.4, 653.4 mg / L and 677.4, 690.3, 686.5 mg / L, respectively), chitosan oligosaccharide (547.3, 570.6, 507.9 mg / L and 553.4, 582.8, 513.8 mg / L, respectively), ningnanmycin (425.3, 513.3, 242.7 mg / L and 440.5, 549.1, 373.8 mg / L, respectively) and compound 6f (281.5, 244.3, 546.3 mg / L and 297.6, 259.6, 582.4 mg / L, respectively).

[0005] In 2018, Xie Dandan et al. (Xie, DD; Shi, J.; Zhang, AW; Lei, ZW; Zu, GC; Fu, Y.; Gan, XH; Yin, LM; Song, BA; Hu, DYSyntheses, antiviral

[0006] activities and induced resistance mechanisms of novel quinazolinederivatives containing a dithioacetal moiety[J].Bioorg.Chem.2018,80,433-443.) reported the anti-plant virus activity of quinazoline derivatives containing dithioacetals. Compound 4b had an anti-plant virus activity against cucumber mosaic virus (CMV, EC 50 248.6 mg / L) and potato virus Y (EC 50 350.5 mg / L) had a better protective effect, which was better than Ningnanmycin (357.7 mg / L and 493.7 mg / L respectively).

[0007] In 2019, Zhang Guoping et al. (Zhang Guoping, Wang Hua, Shi Wangming, Tian Dayu, Miao Tifang, Wei Zhenzhong. A naphthalene derivative containing dithioacetal and its preparation method, medicine and application. 2019, CN 109651216 A) reported that a naphthalene derivative containing dithioacetal has good activity against cucumber mosaic virus disease and tobacco mosaic virus disease, especially cucumber mosaic virus disease. At the same time, this type of compound also has good activity against rice bacterial blight.

[0008] In 2021, Zan Ningning et al. (Zan, NN; Li, J.; He, HF; Hu, DY; Song, BA Discovery of novel chromone derivatives as potential anti-TSWV agents [J]. J. Agric. Food Chem. 2021, 69, 10819-10829.) from the applicant's team used chromone as the backbone unit and reported the anti-TSWV activity of chromone derivatives containing dithioacetal structure, and analyzed the compound structure and its anti-TSWV passivation activity EC by 3D-QSAR. 50 The compound A33 optimized according to the model has better anti-TSWV activity, and its passivation, protection and therapeutic activities are 78.9%, 64.5% and 55.0%, respectively, which are better than Ningnanmycin (76.4%, 70.6% and 54.5%, respectively). Molecular docking shows that the compound can form two conventional hydrogen bonds with the amino acid residue ARG60 of TSWV N protein, and can form hydrophobic interactions with amino acid residues PHE93, ILE179, TYR184 and LYS183, and its binding energy is -6.2 kcal / mol.

[0009] In 2021, Liu Yuewen et al. (Liu, YW; Chen, JX; Xie, DD; Song, BA; Hu, DY) from the applicant's team reported the anti-TSWV activities of novel quinazolinone derivatives containing a dithioacetal moiety [J]. J. Agric. Food Chem. 2021, 69, 12135-12142.) reported the anti-TSWV activities of compound 6n. 50 The value was 188 mg / L, which was higher than that of acyclovir (642 mg / L), thiothiophene (420 mg / L) and ningnanmycin (257 mg / L). Molecular docking showed that compound 6n formed four π-alkyl interactions with ARG94 and ARG95, and its binding force with TSWV N protein was 9.4 μM, which was better than that of ningnanmycin (24.3 μM), thiothiophene (33.8 μM) and acyclovir (67.8 μM).

[0010] In 2021, Zu Guangcheng et al. (Zu, GC; Chen, JX; Song, BA; Hu, DYSynthesis, anti-tomato spotted wilt virus activities, and interaction mechanisms of novel dithioacetal derivatives containing a 4(3H)-quinazolinonepyrimidine ring[J]. J.Agric.Food Chem.2021, 69, 14459-14466.) from the applicant's team reported that novel dithioacetal derivatives containing a 4(3H)-quinazolinonepyrimidine ring have anti-TSWV activity, and established a 3D-QSAR model to analyze the compound structure and its anti-TSWV passivation activity EC 50 Compound D32 was synthesized based on the model design. Compound D32 has better anti-TSWV passivation activity, EC 50 The value was 144 mg / L, which was better than Ningnanmycin (149 mg / L) and the lead compound vanillylthiocarbazine (525 mg / L). MST was further used to test the binding ability of compound D32 to TSWV N protein, and its binding constant value was 4.4 μM, which was better than Ningnanmycin (6.2 μM) and vanillylthiocarbazine (59.1 μM).

[0011] In 2022, Wang Yanju et al. (Wang, YJ; Luo, YQ; Hu, DY; Song, BA Design, synthesis, anti-tomato spotted wilt virus activity, and mechanism of action of thienopyrimidine-containing dithioacetal derivatives [J]. J Agri Food Chem. 2022, 70 (20): 6015-6025.) from the applicant's team prepared a series of dithioacetal-substituted derivatives using thienopyrimidine as the parent and tested their anti-tomato spotted wilt virus activity. The results of the biological activity test showed that compound D35 had good anti-tomato spotted wilt virus activity, with therapeutic, protective and passivation activities of 63.0, 56.6 and 74.1%, respectively. Its protective activity and passivation EC 50 The values ​​were 252.8 and 113.5 μg / mL, respectively, which were comparable to those of ningnanmycin (284.8 and 144.7 μg / mL) and vanillylthiocarbamide (624.9 and 300.0 μg / mL).

[0012] In 2020, Wang Qingmin et al. (Wang Qingmin, Song Hongjian, Li Lili, Liu Yuxiu, Wang Ziwen, Li Yongqiang. Piperazinedione acylhydrazone derivatives and their preparation methods and applications in controlling plant viruses, sterilization and insecticides. 2020, CN 110759896A) reported that piperazinedione derivatives have the ability to control tobacco mosaic virus, insecticide and fungicide.

[0013] In summary, piperazine is an important nitrogen-containing heterocyclic organic compound with a wide range of biological activities. Studies have been reported on its anti-plant virus activity, but its antiviral activity is general. Sulfonamide compounds also have good anti-plant virus activity. In addition, the dithioacetal structure is a new antiviral active skeleton discovered by the research team in the early stage. For this reason, the introduction of the sulfonylpiperazine unit into the dithioacetal parent structure has the significance and value of further drug research and development. Summary of the invention

[0014] One of the purposes of the present invention is to provide a type of dithioacetal derivatives containing sulfonylpiperazine units and a preparation method thereof.

[0015] Another object of the present invention is to provide a composition containing the above compound or its stereoisomer, or its salt or solvate.

[0016] Another object of the present invention is to provide the use of the above compound or its stereoisomer, or its salt or solvate, or the composition.

[0017] Another object of the present invention is to provide a method for preventing and controlling agricultural viral diseases using the above-mentioned compound or its stereoisomer, or its salt or solvate, or the composition.

[0018] Another object of the present invention is to provide a mechanism of action for controlling tomato spotted wilt virus disease by using the above compound or its stereoisomer, or its salt or solvate, or the composition.

[0019] The dithioacetal derivatives containing sulfonylpiperazine units of the present invention have the following general structural formula:

[0020]

[0021] To achieve the above object, the present invention adopts the following preferred technical solutions:

[0022]

[0023] in

[0024] X is selected from

[0025] n is independently selected from 1, 2, or any Arabic numeral;

[0026] R1 and R2 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, phenyl, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl;

[0027] R3 is independently selected from optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted hydroxyalkyl, and optionally substituted or unsubstituted aryl.

[0028] Preferably, n is independently selected from 1, 2, 3, 4;

[0029] R1 and R2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, propyl;

[0030] R3 is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, sec-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2OH, -CH2CH2CH2OH, phenyl, benzyl.

[0031] Preferred compounds are compounds C1 to C33 described below.

[0032] Compound C1: 1-(2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine

[0033] Compound C2: 1-(2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine

[0034] Compound C3: 1-(2-(4-(bis(butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine

[0035] Compound C4: 1-(2-(4-(bis(propylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine

[0036] Compound C5: 1-(2-(4-(bis(isopropylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine

[0037] Compound C6: 1-(2-(4-(bis(butylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine

[0038] Compound C7: 1-(2-(4-(bis(ethylthio)methyl)phenoxy)ethyl)-4-toluenesulfonylpiperazine

[0039] Compound C8: 1-(2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine

[0040] Compound C9: 1-(3-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)propyl)-4-((2-chlorophenyl)sulfonyl)piperazine

[0041] Compound C10: 1-(2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine

[0042] Compound C11: 1-(2-(4-(bis(ethylthio)methyl)phenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine

[0043] Compound C12: 1-(2-(4-(bis(propylthio)methyl)phenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine

[0044] Compound C13: 1-(3-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)propyl)-4-((4-bromophenyl)sulfonyl)piperazine

[0045] Compound C14: 1-(3-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)propyl)-4-((4-bromophenyl)sulfonyl)piperazine

[0046] Compound C15: 1-(2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine

[0047] Compound C16: 2,2'-(((4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethoxy)-3-methoxyphenyl)methylene)bis(sulfanediyl))bis(ethane-1-one)

[0048] Compound C17: 1-(2-(4-(bis(sec-butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine

[0049] Compound C18: 2-(4-(bis(butylthio)methyl)-2-methoxyphenoxy)-1-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0050] Compound C19: 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-toluenesulfonylpiperazin-1-yl)ethan-1-one

[0051] Compound C20: 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)-1-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0052] Compound C21: 2-(4-(bis(butyl)methyl)-2-methoxyphenoxy)-1-(4-p-toluenesulfonylpiperazin-1-yl)ethan-1-one

[0053] Compound C22: 2-(4-(sec-butyl)methyl)-2-methoxyphenoxy)-1-(4-toluenesulfonylpiperazin-1-yl)ethan-1-one

[0054] Compound C23: 2-(4-(di(propylthio)methyl)-2-methoxyphenoxy)-1-(4-p-toluenesulfonylpiperazin-1-yl)ethan-1-one

[0055] Compound C24: 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0056] Compound C25: 2-(4-(sec-butyl)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0057] Compound C26: 2-(4-(bis(butyl)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0058] Compound C27: 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0059] Compound C28: 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0060] Compound C29: 2-(4-(bis(tert-butyl)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0061] Compound C30: 2-(4-(bis((2-hydroxyethyl)thio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0062] Compound C3 1: 2-(4-(bis(cyclohexylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0063] Compound C32: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one

[0064] Compound C33: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)-1-(4-toluenesulfonylpiperazin-1-yl)ethan-1-one

[0065] The preparation method of the compound comprises:

[0066]

[0067] Preferably, it further comprises:

[0068]

[0069] Most preferably, it includes:

[0070]

[0071] The present invention also provides a composition, which contains the compound or its stereoisomer, or its salt or solvate, and an agriculturally usable adjuvant or fungicide, antiviral agent or herbicide; preferably, the composition is in the form of emulsifiable concentrate (EC), dust (DP), wettable powder (WP), granule (GR), aqueous solution (AS), suspension (SC), ultra low volume spray (ULV), soluble powder (SP), microcapsule (MC), smoke agent (FU), emulsion in water (EW), water dispersible granule (WG).

[0072] The compound or its stereoisomer, or its salt or solvate, or the composition can be used to prevent and control agricultural pests and diseases, and the agricultural viral disease is a plant virus; preferably, the agricultural viral disease is tomato spotted wilt virus disease.

[0073] The present invention provides a method for preventing and controlling agricultural viral diseases, wherein the compound or its stereoisomer, or its salt or solvate, or the composition acts on harmful substances or their living environment; preferably, the agricultural viral disease is a plant viral disease; more preferably, the agricultural viral disease is tomato spotted wilt virus disease.

[0074] The term "alkyl" as used herein includes both branched and straight chain saturated hydrocarbon groups having a specified number of carbon atoms. 1-10"alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, for example, "C 1-6 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl) and the like.

[0075] The term "cycloalkyl" refers to cyclic alkyl groups, including mono-, bi- or polycyclic ring systems. 3-7 Cycloalkyl is intended to include C3, C4, C5, C6 and C7 cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, butyl, cyclopentyl, cyclohexyl, norbornyl and the like. As used herein, "carbocycle" or "carbocycle residue" refers to any stable 3, 4, 5, 6 or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bi- or tricyclic ring, which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of these carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As described above, bridged rings are also included in the definition of carbocycles (such as [2.2.2]bicyclooctane). If not otherwise specified, preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, substituents on the ring may also be present on the bridge.

[0076] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.

[0077] The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine and iodine. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 It is a graph showing the therapeutic activity of compounds C1, C4, C5, C8, C10, C13, C15, C20, C22, C24, C26 and C29 and ribivirin against tomato spotted wilt virus at a concentration of 500 μg / mL;

[0079] Figure 2 The inactivation activity of active compounds C13, C20, C29 and ribivirin against tomato spotted wilt virus at different concentrations. Example

[0080] The present invention is further described below by way of examples. It should be understood that the methods described in the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, and simple improvements to the preparation methods of the present invention under the premise of the concept of the present invention belong to the scope of protection claimed in the present invention. All raw materials and solvents used in the examples are commercially available reagents of corresponding purity.

[0081] Example 1: 1-(2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine (C1):

[0082] (1) Preparation of 4-(2-bromoethoxy)-3-methoxybenzaldehyde:

[0083] 3-Methoxy-4-hydroxybenzaldehyde (41.0 mmol), 40 mL acetonitrile, and K2CO3 (82.0 mmol) were added to a three-necked flask, and 1,2-dibromoethane (69.6 mmol) was added after reacting for 10 minutes, and the mixture was heated to 65°C for reaction. TLC monitoring was performed until the reaction was completed, and the mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was separated and purified by column chromatography to obtain a white solid with a melting point of 64.7-66.1°C and a yield of 65.9%.

[0084] (2) Preparation of tert-butyl 4-toluenesulfonylpiperazine-1-carboxylate:

[0085] N-Boc-piperazine (16.0 mmol), 20 mL of dichloromethane and triethylamine (20.9 mmol) were added to a three-necked flask and stirred. After 10 minutes, 4-methylbenzenesulfonyl chloride (17.7 mmol) was added to the system. TLC was monitored until the reaction was complete, extracted with dichloromethane and washed with dilute HBr until pH = 2-3. The crude product was then recrystallized from anhydrous ethanol to obtain a white solid with a melting point of 96.0-98.0°C and a yield of 95.2%.

[0086] (3) Preparation of 4-tosylpiperazine:

[0087] In the presence of an appropriate amount of trifluoroacetic acid, tert-butyl 4-toluenesulfonylpiperazine-1-carboxylate is de-Bocated at room temperature to give 4-toluenesulfonylpiperazine.

[0088] (4) Preparation of 3-methoxy-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde:

[0089] To a three-necked flask, add the intermediate 4-toluenesulfonylpiperazine (4.6 mmol) and 20 mL of acetonitrile, adjust to alkalinity with an appropriate amount of triethylamine, stir at room temperature for 2 h, add K2CO3 (9.2 mmol), KI (0.05 mmol) and the intermediate 4-(2-bromoethoxy)-3-methoxybenzaldehyde (4.6 mmol) to the system, heat to reflux, monitor by TLC until the reaction is completed, extract with ethyl acetate, wash with saturated brine, separate and purify by column chromatography to obtain a yellow solid with a melting point of 122.5-124.5°C and a yield of 78.3%.

[0090] (5) Preparation of 1-(2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine:

[0091] The intermediate 3-methoxy-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and isopropyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 38.5%.

[0092] Example 2: 1-(2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine (C2):

[0093] Steps (1) to (4) are the same as steps (1) to (4) in Example 1.

[0094] (5) Preparation of 1-(2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine:

[0095] The intermediate 3-methoxy-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and propanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography. White solid, melting point 53.0-55.0℃, yield 56.4%.

[0096] Example 3: 1-(2-(4-(bis(butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine (C3):

[0097] Steps (1) to (4) are the same as steps (1) to (4) in Example 1.

[0098] (5) Preparation of 1-(2-(4-(bis(butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine:

[0099] The intermediate 3-methoxy-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and butanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography. White solid, melting point 69.0-71.0℃, yield 47.1%.

[0100] Example 4: 1-(2-(4-(bis(propylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine (C4):

[0101] (1) Preparation of 4-(2-bromoethoxy)-3-chlorobenzaldehyde:

[0102] 3-Chloro-4-hydroxybenzaldehyde (41.0 mmol), 40 mL acetonitrile, and K2CO3 (82.0 mmol) were added to a three-necked flask, and 1,2-dibromoethane (69.6 mmol) was added after reacting for 10 minutes, and the mixture was heated to 65° C. for reaction. TLC was monitored until the reaction was completed, and the mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was separated and purified by column chromatography to obtain a white solid with a melting point of 59.4-60.7° C. and a yield of 47.5%.

[0103] Steps (2) to (3) are the same as steps (2) to (3) in Example 1.

[0104] (4) Preparation of 3-chloro-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde:

[0105] To a three-necked flask, add the intermediate 4-toluenesulfonylpiperazine (4.6 mmol) and 20 mL of acetonitrile, adjust to alkalinity with an appropriate amount of triethylamine, stir at room temperature for 2 h, add K2CO3 (9.2 mmol), KI (0.05 mmol) and the intermediate 4-(2-bromoethoxy)-3-chlorobenzaldehyde (4.6 mmol) to the system, heat to reflux, monitor by TLC until the reaction is completed, extract with ethyl acetate, wash with saturated brine, separate and purify by column chromatography to obtain a white solid with a melting point of 91.0-93.0°C and a yield of 54.5%.

[0106] (5) Preparation of 1-(2-(4-(bis(propylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine:

[0107] The intermediate 3-chloro-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and propanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 64.1%.

[0108] Example 5: 1-(2-(4-(bis(isopropylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine (C5):

[0109] Steps (1) to (4) are the same as steps (1) to (4) of Example 4.

[0110] (5) Preparation of 1-(2-(4-(bis(isopropylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine:

[0111] The intermediate 3-chloro-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and isopropyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 71.8%.

[0112] Example 6: 1-(2-(4-(bis(butylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine (C6):

[0113] Steps (1) to (4) are the same as steps (1) to (4) of Example 4.

[0114] (5) Preparation of 1-(2-(4-(bis(butylthio)methyl)-2-chlorophenoxy)ethyl)-4-toluenesulfonylpiperazine:

[0115] The intermediate 3-chloro-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and butanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a white solid with a melting point of 61.0-63.0°C and a yield of 78.0%.

[0116] Example 7: 1-(2-(4-(bis(ethylthio)methyl)phenoxy)ethyl)-4-toluenesulfonylpiperazine (C7):

[0117] Steps (1) to (4) are the same as steps (1) to (4) of Example 4.

[0118] (5) Preparation of 1-(2-(4-(bis(ethylthio)methyl)phenoxy)ethyl)-4-toluenesulfonylpiperazine:

[0119] The intermediate 3-chloro-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and ethanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 53.6%.

[0120] Example 8: 1-(2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine (C8):

[0121] Steps (1) to (4) are the same as steps (1) to (4) in Example 1.

[0122] (5) Preparation of 1-(2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)ethyl)-4-toluenesulfonylpiperazine:

[0123] The intermediate 3-chloro-4-(2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and ethanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 70.4%.

[0124] Example 9: 1-(3-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)propyl)-4-((2-chlorophenyl)sulfonyl)piperazine (C9):

[0125] (1) Preparation of 4-(3-bromopropoxy)-3-methoxybenzaldehyde:

[0126] Substituted hydroxybenzaldehyde (41.0 mmol), 40 mL acetonitrile, K2CO3 (82.0 mmol) were added to a three-necked flask, and 1,3-dibromopropane (69.6 mmol) was added after reacting for 10 minutes, and the mixture was heated to 65° C. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a white solid with a melting point of 70.5-71.3° C. and a yield of 73.3%.

[0127] (2) Preparation of tert-butyl 4-((2-chlorophenyl)sulfonyl)piperazine-1-carboxylate:

[0128] N-Boc-piperazine (16.0 mmol), 20 mL of dichloromethane and triethylamine (20.9 mmol) were added to a three-necked flask and stirred. After 10 minutes, 2-chlorobenzenesulfonyl chloride (17.7 mmol) was added to the system. TLC was monitored until the reaction was complete, extracted with dichloromethane and washed with dilute HBr until pH = 2-3. The crude product was then recrystallized from anhydrous ethanol to obtain a white solid with a melting point of 90.0-92.0 ° C and a yield of 56.2%.

[0129] (3) Preparation of 4-((2-chlorophenyl)sulfonyl)piperazine:

[0130] In the presence of an appropriate amount of trifluoroacetic acid, tert-butyl 4-((2-chlorophenyl)sulfonyl)piperazine-1-carboxylate is subjected to the removal of Boc at room temperature to give 4-((2-chlorophenyl)sulfonyl)piperazine.

[0131] (4) Preparation of 4-(3-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)propoxy)-3-methoxybenzaldehyde:

[0132] To a three-necked flask, add the intermediate 4-((2-chlorophenyl)sulfonyl)piperazine (4.6 mmol) and 20 mL of acetonitrile, adjust to alkalinity with an appropriate amount of triethylamine, stir at room temperature for 2 h, add K2CO3 (9.2 mmol), KI (0.05 mmol) and the intermediate 4-(3-bromopropoxy)-3-methoxybenzaldehyde (4.6 mmol) to the system, heat to reflux, monitor by TLC until the reaction is completed, extract with ethyl acetate, wash with saturated brine, separate and purify by column chromatography to obtain a yellow solid with a melting point of 77.5-79.5°C and a yield of 76.8%.

[0133] (5) Preparation of 1-(3-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)propyl)-4-((2-chlorophenyl)sulfonyl)piperazine:

[0134] The intermediate 4-(3-(4-(2-chlorophenyl)sulfonyl)piperazine-1-yl)propoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and propanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 77.1%.

[0135] Example 10: 1-(2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine (C10):

[0136] Step (1) is the same as step (1) of Example 1, and steps (2) to (3) are the same as steps (2) to (3) of Example 9.

[0137] (4) Preparation of 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethoxy)-3-methoxybenzaldehyde:

[0138] To a three-necked flask, add the intermediate 4-((2-chlorophenyl)sulfonyl)piperazine (4.6 mmol) and 20 mL of acetonitrile, adjust to alkalinity with an appropriate amount of triethylamine, stir at room temperature for 2 h, add K2CO3 (9.2 mmol), KI (0.05 mmol) and the intermediate 4-(2-bromoethoxy)-3-methoxybenzaldehyde (4.6 mmol) to the system, heat to reflux, monitor by TLC until the reaction is completed, extract with ethyl acetate, wash with saturated brine, separate and purify by column chromatography to obtain a yellow solid with a melting point of 107.0-109.0°C and a yield of 72.6%.

[0139] (5) Preparation of 1-(2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine:

[0140] The intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazine-1-yl)ethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and tert-butyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 79.3%.

[0141] Example 11: 1-(2-(4-(bis(ethylthio)methyl)phenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine (C11):

[0142] (1) Preparation of 4-(2-bromoethoxy)benzaldehyde:

[0143] Add p-hydroxybenzaldehyde (41.0 mmol), 40 mL acetonitrile, and K2CO3 (82.0 mmol) to a three-necked flask, and add 1,2-dibromoethane (69.6 mmol) after reacting for 10 minutes, and heat to 65° C. to react. Monitor by TLC until the reaction is complete, extract with ethyl acetate and wash with saturated brine, separate and purify the crude product by column chromatography to obtain a white solid with a melting point of 74.0-76.0° C. and a yield of 58.9%.

[0144] Steps (2) to (3) are the same as steps (2) to (3) of Example 9.

[0145] (4) Preparation of 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethoxy)benzaldehyde:

[0146] To a three-necked flask, add the intermediate 4-((2-chlorophenyl)sulfonyl)piperazine (4.6 mmol) and 20 mL of acetonitrile, adjust to alkalinity with an appropriate amount of triethylamine, stir at room temperature for 2 h, add K2CO3 (9.2 mmol), KI (0.05 mmol) and the intermediate 4-(3-bromoethoxy)benzaldehyde (4.6 mmol) to the system, heat to reflux, monitor by TLC until the reaction is completed, extract with ethyl acetate, wash with saturated brine, separate and purify by column chromatography to obtain a yellow oil in a yield of 70.9%.

[0147] (5) Preparation of 1-(2-(4-(bis(ethylthio)methyl)phenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine:

[0148] The intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and ethanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 48.8%.

[0149] Example 12: 1-(2-(4-(bis(propylthio)methyl)phenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine (C12):

[0150] Step (1) is the same as step (1) of Example 11, steps (2) to (3) are the same as steps (2) to (3) of Example 9, and step (4) is the same as step (4) of Example 11.

[0151] (5) Preparation of 1-(2-(4-(bis(propylthio)methyl)phenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine:

[0152] The intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and propanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 65.2%.

[0153] Example 13: 1-(3-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)propyl)-4-((4-bromophenyl)sulfonyl)piperazine (C13):

[0154] Step (1) is the same as step (1) of Example 9.

[0155] (2) Preparation of tert-butyl 4-(4-bromophenyl)sulfonyl)piperazine-1-carboxylate:

[0156] N-Boc-piperazine (16.0 mmol), 20 mL of dichloromethane and triethylamine (20.9 mmol) were added to a three-necked flask and stirred. After 10 minutes, 4-bromobenzenesulfonyl chloride (17.7 mmol) was added to the system. TLC was monitored until the reaction was complete, extracted with dichloromethane and washed with dilute HBr until pH = 2-3. The crude product was then recrystallized from anhydrous ethanol to obtain a white solid with a melting point of 146.5-148.5°C and a yield of 41.1%.

[0157] (3) Preparation of 4-((4-bromophenyl)sulfonyl)piperazine:

[0158] In the presence of an appropriate amount of trifluoroacetic acid, tert-butyl 4-((4-bromophenyl)sulfonyl)piperazine-1-carboxylate is subjected to the removal of Boc at room temperature to give 4-((4-bromophenyl)sulfonyl)piperazine.

[0159] (4) Preparation of 4-(3-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)propoxy)-3-methoxybenzaldehyde:

[0160] To a three-necked flask, add the intermediate 4-((4-bromophenyl)sulfonyl)piperazine (4.6 mmol) and 20 mL of acetonitrile, adjust to alkalinity with an appropriate amount of triethylamine, stir at room temperature for 2 h, add K2CO3 (9.2 mmol), KI (0.05 mmol) and the intermediate 4-(3-bromopropoxy)-3-methoxybenzaldehyde (4.6 mmol) to the system, heat to reflux, monitor by TLC until the reaction is completed, extract with ethyl acetate, wash with saturated brine, separate and purify by column chromatography to obtain a white solid with a melting point of 114.0-116.0°C and a yield of 50.0%.

[0161] (5) Preparation of 1-(3-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)propyl)-4-((4-bromophenyl)sulfonyl)piperazine:

[0162] The intermediate 4-(3-(4-(4-bromophenyl)sulfonyl)piperazine-1-yl)propoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and ethanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a white oil with a yield of 90.5%.

[0163] Example 14: 1-(3-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)propyl)-4-((4-bromophenyl)sulfonyl)piperazine (C14):

[0164] Step (1) is the same as step (1) of Example 9, and steps (2) to (4) are the same as steps (2) to (4) of Example 13.

[0165] (5) Preparation of 1-(3-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)propyl)-4-((4-bromophenyl)sulfonyl)piperazine:

[0166] The intermediate 4-(3-(4-(4-bromophenyl)sulfonyl)piperazine-1-yl)propoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and propanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 56.8%.

[0167] Example 15: 1-(2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine (C15):

[0168] Step (1) is the same as step (1) of Example 1, steps (2) to (3) are the same as steps (2) to (3) of Example 9, and step (4) is the same as step (4) of Example 10.

[0169] (5) Preparation of 1-(2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine:

[0170] The intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazine-1-yl)ethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and isopropyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 74.4%.

[0171] Example 16: 2,2'-(((4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethoxy)-3-methoxyphenyl)methylene)bis(sulfanediyl))bis(ethane-1-one) (C16):

[0172] Step (1) is the same as step (1) of Example 1, steps (2) to (3) are the same as steps (2) to (3) of Example 9, and step (4) is the same as step (4) of Example 10.

[0173] (5) Preparation of 2,2′-(((4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethoxy)-3-methoxyphenyl)methylene)bis(sulfanediyl))bis(ethane-1-one) (C16):

[0174] The intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazine-1-yl)ethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and mercaptoethanol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 64.1%.

[0175] Example 17: 1-(2-(4-(bis(sec-butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine (C17):

[0176] Step (1) is the same as step (1) of Example 1, steps (2) to (3) are the same as steps (2) to (3) of Example 9, and step (4) is the same as step (4) of Example 10.

[0177] (5) Preparation of 1-(2-(4-(bis(sec-butylthio)methyl)-2-methoxyphenoxy)ethyl)-4-((2-chlorophenyl)sulfonyl)piperazine:

[0178] The intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazine-1-yl)ethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and mercaptoethanol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow oil with a yield of 73.2%.

[0179] Example 18: 2-(4-(bis(butylthio)methyl)-2-methoxyphenoxy)-1-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C18):

[0180] Steps (1) to (2) are the same as steps (2) to (3) of Example 9.

[0181] (3) Preparation of 2-chloro-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethane-1-one:

[0182] The intermediate 4-((2-chlorophenyl)sulfonyl)piperazine (11.5 mmol), 40 mL of dichloromethane and triethylamine (34.4 mmol) were added and stirred. After stirring at room temperature for 1 h, chloroacetyl chloride (12.6 mmol) was dissolved in dichloromethane and added to the system. TLC was monitored until the reaction no longer changed. A white solid was obtained by column chromatography separation and purification, with a melting point of 102.5-104.5° C. and a yield of 46.5%.

[0183] (4) Preparation of 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde:

[0184] 3-Methoxy-4-hydroxybenzaldehyde (5.2 mmol), 40 mL of acetonitrile, K2CO3 (9.4 mmol) and KI (0.5 mmol) were added to a three-necked flask. After stirring at room temperature for 30 minutes, the intermediate 2-chloro-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethane-1-one (4.7 mmol) was added and heated to reflux. The reaction was monitored by TLC until completion. The product was extracted with ethyl acetate, washed with saturated brine, and purified by column chromatography to obtain a white solid with a melting point of 112.0-114.0°C and a yield of 60.5%.

[0185] (5) Preparation of 2-(4-(bis(butylthio)methyl)-2-methoxyphenoxy)-1-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0186] The intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and butanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a white solid with a melting point of 72.0-74.0°C and a yield of 73.6%.

[0187] Example 19: 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-p-toluenesulfonylpiperazin-1-yl)ethan-1-one (C19):

[0188] Steps (1) to (2) are the same as steps (2) to (3) in Example 1.

[0189] (3) Preparation of 2-chloro-1-(4-tosylpiperazine-1-yl)ethane-1-one:

[0190] The intermediate 4-tosylpiperazine (11.5 mmol), 40 mL of dichloromethane and triethylamine (34.4 mmol) were added and stirred. After stirring at room temperature for 1 h, chloroacetyl chloride (12.6 mmol) was dissolved in dichloromethane and added to the system. TLC was monitored until the reaction no longer changed. A white solid was obtained by column chromatography separation and purification, with a melting point of 135.0-137.0°C and a yield of 28.8%.

[0191] (4) Preparation of 3-methoxy-4-(2-oxo-2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde:

[0192] 3-Methoxy-4-hydroxybenzaldehyde (5.2mmol), 40mL acetonitrile, K2CO3 (9.4mmol) and KI (0.5mmol) were added to a three-necked flask. After stirring at room temperature for 30 minutes, the intermediate 2-chloro-1-(4-tosylpiperazine-1-yl)ethane-1-one (4.7mmol) was added and heated to reflux. The reaction was monitored by TLC until completion. The product was extracted with ethyl acetate, washed with saturated brine, and separated and purified by column chromatography to obtain a white solid with a melting point of 158.5-160.1°C and a yield of 45.3%.

[0193] (5) Preparation of 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-p-toluenesulfonylpiperazin-1-yl)ethan-1-one:

[0194] The intermediate 3-methoxy-4-(2-oxo-2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and ethanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a yellow solid with a melting point of 124.5-126.5°C and a yield of 64.3%.

[0195] Example 20: 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)-1-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C20):

[0196] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, and steps (3) to (4) are the same as steps (3) to (4) of Example 18.

[0197] (5) Preparation of 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)-1-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0198] The intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and propanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 81.0-83.0°C and a yield of 67.5%.

[0199] Example 21: 2-(4-(Bis(butyl)methyl)-2-methoxyphenoxy)-1-(4-p-toluenesulfonylpiperazin-1-yl)ethan-1-one (C21):

[0200] Steps (1) to (2) are the same as steps (2) to (3) in Example 1, and steps (3) to (4) are the same as steps (3) to (4) in Example 19.

[0201] (5) Preparation of 2-(4-(bis(butyl)methyl)-2-methoxyphenoxy)-1-(4-p-toluenesulfonylpiperazin-1-yl)ethan-1-one

[0202] The intermediate 3-methoxy-4-(2-oxo-2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and propanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a white solid with a melting point of 122.0-124.0°C and a yield of 64.1%.

[0203] Example 22: 2-(4-(sec-butyl)methyl)-2-methoxyphenoxy)-1-(4-toluenesulfonylpiperazin-1-yl)ethan-1-one (C22):

[0204] Steps (1) to (2) are the same as steps (2) to (3) in Example 1, and steps (3) to (4) are the same as steps (3) to (4) in Example 19.

[0205] (5) Preparation of 2-(4-(sec-butyl)methyl)-2-methoxyphenoxy)-1-(4-toluenesulfonylpiperazin-1-yl)ethan-1-one:

[0206] The intermediate 3-methoxy-4-(2-oxo-2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and isobutyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a white solid with a melting point of 122.5-124.5°C and a yield of 53.6%.

[0207] Example 23: 2-(4-(Di(propylthio)methyl)-2-methoxyphenoxy)-1-(4-p-toluenesulfonylpiperazin-1-yl)ethan-1-one (C23):

[0208] Steps (1) to (2) are the same as steps (2) to (3) in Example 1, and steps (3) to (4) are the same as steps (3) to (4) in Example 19.

[0209] (5) Preparation of 2-(4-(di(propylthio)methyl)-2-methoxyphenoxy)-1-(4-toluenesulfonylpiperazin-1-yl)ethan-1-one:

[0210] The intermediate 3-methoxy-4-(2-oxo-2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and isobutyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a white solid with a melting point of 125.5-127.0°C and a yield of 81.4%.

[0211] Example 24: 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C24):

[0212] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, and steps (3) to (4) are the same as steps (3) to (4) of Example 18.

[0213] (5) Preparation of 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0214] The intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and ethanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 111.0-113.0°C and a yield of 91.2%.

[0215] Example 25: 2-(4-(sec-butyl)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C25):

[0216] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, and steps (3) to (4) are the same as steps (3) to (4) of Example 18.

[0217] (5) Preparation of 2-(4-(sec-butyl)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0218] The intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and isobutyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 91.0-93.0°C and a yield of 90.2%.

[0219] Example 26: 2-(4-(bis(butyl)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C26):

[0220] Steps (1) to (2) are the same as steps (2) to (3) in Example 13.

[0221] (3) Preparation of 1-(4-(4-bromophenyl)sulfonyl)piperazine-1-yl)-2-chloroethane-1-one:

[0222] The intermediate 4-((4-bromophenyl)sulfonyl)piperazine (11.5 mmol), 40 mL of dichloromethane and triethylamine (34.4 mmol) were added and stirred. After stirring at room temperature for 1 h, chloroacetyl chloride (12.6 mmol) was dissolved in dichloromethane and added to the system. TLC was monitored until the reaction no longer changed. A white solid was obtained by column chromatography separation and purification, with a melting point of 137.0-139.0° C. and a yield of 41.1%.

[0223] (4) Preparation of 4-(2-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde:

[0224] 3-Methoxy-4-hydroxybenzaldehyde (5.2mmol), 40mL acetonitrile, K2CO3 (9.4mmol) and KI (0.5mmol) were added to a three-necked flask. After stirring at room temperature for 30 minutes, the intermediate 1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)-2-chloroethane-1-one (4.7mmol) was added and heated to reflux. The reaction was monitored by TLC until completion. The product was extracted with ethyl acetate, washed with saturated brine, and separated and purified by column chromatography to obtain a yellow solid with a melting point of 156.0-158.0°C and a yield of 55.4%.

[0225] (5) Preparation of 2-(4-(bis(butyl)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0226] The intermediate 4-(2-(4-((4-bromophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and butanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 126.5-128.5°C and a yield of 88.0%.

[0227] Example 27: 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C27):

[0228] Steps (1) to (2) are the same as steps (2) to (3) of Example 13, and steps (3) to (4) are the same as steps (3) to (4) of Example 26.

[0229] (5) Preparation of 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0230] The intermediate 4-(2-(4-((4-bromophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and propylthiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 117.0-119.0°C and a yield of 67.5%.

[0231] Example 28: 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C28):

[0232] Steps (1) to (2) are the same as steps (2) to (3) of Example 13, and steps (3) to (4) are the same as steps (3) to (4) of Example 26.

[0233] (5) Preparation of 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-1-(4-(4-bromophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0234] The intermediate 4-(2-(4-((4-bromophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and ethanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 142.0-144.0°C and a yield of 70.9%.

[0235] Example 29: 2-(4-(bis(tert-butyl)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C29):

[0236] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, and steps (3) to (4) are the same as steps (3) to (4) of Example 18.

[0237] (5) Preparation of 2-(4-(bis(tert-butyl)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0238] The intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and tert-butyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 67.0-69.0°C and a yield of 58.9%.

[0239] Example 30: 2-(4-(bis((2-hydroxyethyl)thio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C30):

[0240] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, and steps (3) to (4) are the same as steps (3) to (4) of Example 18.

[0241] (5) Preparation of 2-(4-(bis((2-hydroxyethyl)thio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0242] The intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and mercaptoethanol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a white oil with a yield of 65.7%.

[0243] Example 31: 2-(4-(bis(cyclohexylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C31):

[0244] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, and steps (3) to (4) are the same as steps (3) to (4) of Example 18.

[0245] (5) Preparation of 2-(4-(bis(cyclohexylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0246] The intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and cyclohexanethiol (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 99.0-101.0°C and a yield of 77.7%.

[0247] Example 32: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one (C32):

[0248] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, and steps (3) to (4) are the same as steps (3) to (4) of Example 18.

[0249] (5) Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethan-1-one:

[0250] The intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazine-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and isopropyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and separated and purified by column chromatography to obtain a white solid with a melting point of 92.0-94.0°C and a yield of 84.8%.

[0251] Example 33: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)-1-(4-p-toluenesulfonylpiperazin-1-yl)ethan-1-one (C33):

[0252] Steps (1) to (2) are the same as steps (2) to (3) in Example 1, and steps (3) to (4) are the same as steps (3) to (4) in Example 19.

[0253] (5) Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)-1-(4-toluenesulfonylpiperazin-1-yl)ethan-1-one:

[0254] The intermediate 3-methoxy-4-(2-oxo-2-(4-tosylpiperazine-1-yl)ethoxy)benzaldehyde (0.7mmol) and 6mL tetrahydrofuran were added to a single-necked flask, and then ZrCl4 (0.07mmol) and isopropyl mercaptan (1.4mmol) were added to the system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with ethyl acetate and purified by column chromatography to obtain a white solid with a melting point of 114.5-116.5°C and a yield of 81.0%.

[0255] The physicochemical data of the compound are shown in Table 1.

[0256] Table 1. Physicochemical data of compounds of Examples C1-C33

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269] Bioassay Example 1: Determination of the in vivo anti-TSWV biological activity of the target compound.

[0270] The test compound was dissolved in N,N-dimethylformamide and then diluted with 2% Tween 80 to obtain a 500 mg / L test compound solution. 50 When the concentration was diluted, the solution of the test compound was obtained at a concentration of 500, 250, 125, 62.5 and 31.25 mg / L.

[0271] (1) Testing of anti-TSWV therapeutic activity

[0272] Select 5-6 leaf heartleaf tobacco with basically the same growth, remove the top and bottom leaves, sprinkle silicon carbide evenly on the leaves of the whole plant, use a brush to dip TSWV virus solution and brush it on the leaves of the whole plant, rinse the silicon carbide with clean water after 50 minutes, dry it and use a brush to dip the target compound solution and brush it on the right side of the leaves of the whole plant. Then place the plants in an artificial climate chamber for cultivation, and the control conditions are 25℃, 50% humidity for 14 hours during the day and 23℃, 40% humidity for 10 hours at night. Each treatment is repeated three times, and the number of dead spots is recorded after 2-3 days, and the inhibition rate is calculated.

[0273] Inhibition rate (%) = [(number of necrotic spots in blank control - number of necrotic spots treated with drug) / number of necrotic spots in blank control] × 100%

[0274] (2) Testing of protective activity against TSWV

[0275] Select 5-6 leaf heartleaf tobacco plants with basically the same growth, remove the top and bottom leaves, and apply the target compound solution to the right side of the leaves of the whole plant with a brush. After 24 hours, sprinkle silicon carbide evenly on the leaves of the whole plant, and apply TSWV virus solution to the leaves of the whole plant with a brush. After 50 minutes, rinse the silicon carbide with clean water, and then place the plants in an artificial climate chamber for cultivation. The control conditions are 25°C, 50% humidity for 14 hours during the day and 23°C, 40% humidity for 10 hours at night. Each treatment is repeated three times. After 2-3 days, the number of dead spots is recorded, and the inhibition rate is calculated (the calculation method is the same as the therapeutic activity).

[0276] (3) Test of anti-TSWV passivation activity

[0277] Select 5-6 leaf heartleaf tobacco with basically the same growth, remove the top and bottom leaves, sprinkle silicon carbide evenly on the leaves of the whole plant, use a brush to dip TSWV virus solution and compound solution in equal volumes and mix them for 30 minutes to apply the mixture on the right side of the leaves of the whole plant, dip the 2-fold diluted TSWV virus solution and apply it on the left side of the leaves of the whole plant, and rinse the silicon carbide with clean water after 50 minutes. Then place the plants in an artificial climate chamber for cultivation, and the control conditions are 25℃, 50% humidity for 14 hours during the day and 23℃, 40% humidity for 10 hours at night. Each treatment is repeated three times, and the number of necrotic spots is recorded after 2-3 days, and the inhibition rate is calculated (the calculation method is the same as the therapeutic activity).

[0278] Table 1 Anti-TSWV activity of target compounds C1-C17 at 500 μg / mL

[0279]

[0280] Table 2 Anti-TSWV activity of target compounds C18-C33 at 500 μg / mL

[0281]

[0282] Table 3 Anti-TSWV passivation activity EC of target compounds C1-C33 50

[0283]

[0284] The half-leaf spot method was used to test the anti-tomato spotted wilt virus activity of dithioacetal derivatives containing sulfonylpiperazine units at a concentration of 500 μg / mL, with ribavirin as the control agent. From the bioassay results in Tables 1, 2 and 3, it can be seen that most of the target compounds showed certain anti-tomato spotted wilt virus activity, and most of the target compounds had good anti-TSWV therapeutic, protective and passivation activities, such as compounds C13, C20, C29, C1, C4, C5, C8, C10, C15, C22, C24 and C26 had high anti-TSWV passivation activities (the anti-TSWV therapeutic activity effects of these compounds are shown in the attached Figure 1 ), its EC 50 The inactivation activities of compounds C13, C20 and C29 were 154.0, 121.6, 154.8, 233.7, 186.9, 240.7, 252.0, 223.9, 275.7, 254.6, 163.9 and 210.9 μg / mL, respectively, which were significantly better than ribavirin (701.9 μg / mL). In particular, compounds C13, C20 and C29 had the highest inactivation activities. The inactivation activities of these three compounds against tomato spotted wilt virus compared with the control agent were shown in Table 1. Figure 2 .

[0285] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still falls within the scope of the technical solution of the present invention.

Claims

1. A dithioacetal compound containing a sulfonylpiperazine unit or a stereoisomer thereof, or a salt thereof or a solvate thereof, characterized in that As shown below: in X is selected from n is independently selected from an integer between 1 and 6, or any integer; R1 and R2 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, phenyl, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl; R3 is independently selected from optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted hydroxyalkyl, and optionally substituted or unsubstituted aryl.

2. A dithioacetal compound containing a sulfonylpiperazine unit according to claim 1, or a stereoisomer thereof, or a salt thereof, or a solvate thereof, characterized in that The compound is selected from the following formula (I) or (II):

3. The dithioacetal compound containing a sulfonylpiperazine unit according to claim 1, or its stereoisomer, or its salt or solvate thereof, characterized in that: n is independently selected from 1, 2, 3, 4; R1 and R2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, propyl; R3 is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, sec-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2OH, -CH2CH2CH2OH, phenyl, benzyl.

4. A dithioacetal compound containing a sulfonylpiperazine unit according to claim 1, or a stereoisomer thereof, or a salt thereof, or a solvate thereof, characterized in that Selected from the following specific compounds:

5. An intermediate compound for preparing a dithioacetal compound containing a sulfonylpiperazine unit or a stereoisomer thereof, or a salt thereof or a solvate thereof as claimed in claim 1, characterized in that As shown below: Wherein R1 and R2 are as shown in any one of claims 1-4.

6. The method for preparing a dithioacetal compound containing a sulfonylpiperazine unit or a stereoisomer thereof, or a salt thereof or a solvate thereof according to claim 1, characterized in that include: Preferably, it further comprises: Most preferably, it includes:

7. A composition characterized in that Contains a compound or a stereoisomer thereof, or a salt or a solvate thereof according to any one of claims 1 to 4, and an agriculturally usable adjuvant or fungicide, antiviral agent or herbicide; preferably, the composition is in the form of an emulsifiable concentrate (EC), a dust (DP), a wettable powder (WP), a granule (GR), an aqueous solution (AS), a suspension (SC), an ultra-low volume spray (ULV), a soluble powder (SP), a microcapsule (MC), a smoke concentrate (FU), an emulsion in water (EW), and a water-dispersible granule (WG).

8. Use of the compound or its stereoisomer, or its salt or solvate according to any one of claims 1 to 4, or the composition according to claim 7 for preventing and treating agricultural viral diseases, preferably, the agricultural viral disease is a plant negative-strand RNA virus; more preferably, the agricultural viral disease is tomato spotted wilt virus disease.

9. A method for preventing and treating agricultural viral diseases, characterized in that: The compound or stereoisomer thereof, or salt or solvate thereof according to any one of claims 1 to 4, or the composition according to claim 7 is allowed to act on a pest or its living environment; preferably, the agricultural viral disease is a plant negative-strand RNA virus; more preferably, the agricultural viral disease is tomato spotted wilt virus disease.

10. A method for protecting plants from agricultural viral diseases, comprising a method step in which pests are contacted with a compound or stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 7.

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