Disulphide acetal derivatives containing a sulfonyl piperazine unit, processes for their preparation and uses thereof

Abstract

The present application relates to a kind of sulfonamides containing unit of sulfonyl piperazine disulfide acetal derivative and its preparation method and use.The present application compound has excellent antiviral activity to tomato spotted wilt virus and the like, which can be used for preventing and treating tomato spotted wilt virus and the like plant viral disease drug or medicament. Its structure and preparation process are simple, and production cost is low.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical industry and pesticides, 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 a medicine for preventing and treating tomato spotted wilt virus and the like plant viruses. BACKGROUND

[0002] Tomato spotted wilt virus (TSWV) is a representative species of Orthotospovirus in the family Tospoviridae of the order Bunyavirales, and is one of the top ten viruses that cause serious harm to agricultural production. It can infect more than 80 families and more than 1000 species of plants such as impatiens, lettuce, potato, chrysanthemum, celery, tobacco, soybean, pepper and tomato, and is a virus that seriously damages the yield and quality of economic crops such as tomatoes. It is mainly transmitted by western flower thrips as a transmission medium, and is transmitted in a cyclic multiplication mode. Thrips can multiply and replicate in the body in a cyclic multiplication mode after being infected in the larval stage, and carry the virus for life. It was first discovered in Australia in 1915. It occurs in various parts of the world, and the virus disease caused by TSWV causes losses of more than 1 billion US dollars per year. TSWV is a trisomic single-stranded RNA (ssRNA) virus. The genome contains three RNAs, namely small (S), medium (M) and large (L). The non-structural protein NSs (52.4KDa) encoded by S-RNA is related to gene silencing, and the nucleocapsid protein (N) (28.8KDa) encoded by its complementary strand is a major structural protein that can assemble and transform genomic RNA into ribonucleoprotein complex (RNP), which is very important for TSWV infection and is closely related to virus movement. M-RNA encodes non-structural protein NSm (33.6KDa) and glycoprotein Gn-Gc (127.4KDa), and NSm has a significant impact on the intercellular movement of TSWV. The RNA-dependent RNA polymerase (RdRp) (331.5KDa) encoded by L-RNA is closely related to the replication and transcription of the virus.

[0003] In 2017, Zhang et al. (Zhang, J.; Zhao, L.; Zhu, C.; Wu, Z. X.; Zhang, G. P.; Gan, X. H.; Liu, D. Y.; Pan, J. K.; Hu, D. Y.; Song, B. A. Facile Synthesis of novel vanillin derivatives incorporating a bis(2-hydroxyethyl)dithioacetal moiety as antiviral agents [J]. J. Agric. Food Chem. 2017, 65, 4582-4588.) of the present applicant's team reported a series of vanillin derivatives containing dithioacetal, the biological activity determination results showed that compound 6f showed the best treatment and protection activity against PVY and CMV, the effective concentration EC 50 were 217.6 mg / L, 205.7 mg / L and 206.3 mg / L, 186.2 mg / L, respectively, which were all better than anilin (848.0 mg / L, 808.1 mg / L and 858.2 mg / L, 766.5 mg / L, respectively), difenzoquat, 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 et al. (Chen, J.; Shi, J.; Yu, L.; Liu, D. Y.; Gan, X. H.; Song, B. A.; Hu, D. Y. Design, synthesis, antiviral bioactivity, and defense mechanisms of novel dithioacetal derivatives bearing a strobilurin moiety [J]. J. Agric. Food Chem. 2018, 66, 5335-5345.) of the present applicant's team reported that the dithioacetal compound C14 containing methoxy acrylate had good inhibition effect on PVY, CMV and TMV. The protection activity was 148.4, 113.2 and 214.6 mg / L, respectively, and the treatment activity EC 50125.3, 108.9 and 181.7 mg / L, significantly higher than anisomycin (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, D.D. et al. (Xie, D.D.; Shi, J.; Zhang, A.W.; Lei, Z.W.; Zu, G.C.; Fu, Y.; Gan, X.H.; Yin, L.M.; Song, B.A.; Hu, D.Y. Syntheses, antiviral

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

[0007] In 2019, Zhang, G.P. et al. (Zhang, G.P., Wang, H., Shi, W.M., Tian, D.Y., Miao, T.F., Wei, Z.Z. A naphthalene derivative containing dithioacetal and its preparation method, drug and application. 2019, CN 109651216 A) reported that a naphthalene derivative containing dithioacetal had good activity against cucumber mosaic virus disease and tobacco mosaic virus disease, especially against cucumber mosaic virus disease. At the same time, this kind of compound also had good activity against rice bacterial leaf blight.

[0008] In 2021, Zan, N. N.; Li, J.; He, H. F.; Hu, D. Y.; Song, B. A. Discovery of novel chromone derivatives as potential anti-TSWV agents [J]. J. Agric. Food Chem. 2021, 69, 10819-10829. reported the anti-TSWV activity of chromone derivatives containing a dithioacetal moiety, and analyzed the relationship between the structure of the compounds and their anti-TSWV inactivation activity EC 50 According to the model, the compound A33 optimized has better anti-TSWV activity, and its inactivation, protection and treatment 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 amino acid residues 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, Y. W.; Chen, J. X.; Xie, D. D.; Song, B. A.; Hu, D. Y. First report on anti-TSWV activities of quinazolinone derivatives containing a dithioacetal moiety [J]. J. Agric. Food Chem. 2021, 69, 12135-12142. reported the anti-TSWV activity of novel quinazolinone derivatives containing a dithioacetal moiety, and the EC 50 value of compound 6n is 188 mg / L, which is higher than that of anilofos (642 mg / L), thiophanate-methyl (420 mg / L) and ningnanmycin (257 mg / L). Molecular docking shows that compound 6n forms four π-alkyl interactions with ARG94 and ARG95, and its binding force with TSWV N protein is 9.4 μM, which is better than ningnanmycin (24.3 μM), thiophanate-methyl (33.8 μM) and anilofos (67.8 μM).

[0010] In 2021, Zu, G. C.; Chen, J. X.; Song, B. A.; Hu, D. Y. Synthesis, anti-tomato spotted wilt virus activities, and interaction mechanisms of novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring [J]. J. Agric. Food Chem. 2021, 69, 14459-14466. reported that novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring had anti-TSWV activity, and a 3D-QSAR model was established to analyze the relationship between the structure of the compound and its anti-TSWV inactivation activity EC 50 , and compound D32 was synthesized according to the model, which had more excellent anti-TSWV inactivation activity, with an EC 50 value of 144 mg / L, better than ningnanmycin (149 mg / L) and the lead compound vanillyl thioacetal disease ether (525 mg / L). Further MST was used to test the binding ability of compound D32 and TSWV N protein, and the binding constant value was 4.4 μM, better than ningnanmycin (6.2 μM) and vanillyl thioacetal disease ether (59.1 μM).

[0011] In 2022, Wang, Y. J.; Luo, Y. Q.; Hu, D. Y.; Song, B. A. 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. prepared a series of dithioacetal substituted derivatives with thienopyrimidine as the parent, and tested their anti-tomato spotted wilt virus activity. The results of biological activity test showed that compound D35 had good anti-tomato spotted wilt virus activity, with treatment, protection and inactivation activities of 63.0, 56.6 and 74.1%, respectively, and the EC 50 values of its protection activity and inactivation were 252.8 and 113.5 μg / mL, respectively, which were comparable to ningnanmycin (284.8 and 144.7 μg / mL) and vanillyl thioacetal disease ether (624.9 and 300.0 μg / mL).

[0012] In 2020, Wang Qingmin et al. (Wang Qingmin, Song Hongjian, Li Lili, Liu Yuxiu, Wang Zisheng, Li Yongqiang. Piperazine diketone acylhydrazone derivatives, their preparation method and application in preventing and treating plant viruses, fungicidal and insecticidal. 2020, CN 110759896A) reported that piperazine diketone derivatives have the activities of preventing and treating tobacco mosaic virus, insecticidal and fungicidal.

[0013] In summary, piperazine is an important nitrogen-containing heterocyclic organic compound with a wide range of biological activities. There have been research reports on its anti-plant virus activity, but its anti-viral activity is generally low. Sulfonamide compounds also have good anti-plant virus activity. In addition, the dithioacetal structure is a new anti-viral active skeleton found by the research group in the early stage. Therefore, the introduction of the sulfonylpiperazine unit into the dithioacetal parent structure has significance and value for further drug research and development. SUMMARY

[0014] One of the purposes of the present application is to provide a kind of dithioacetal derivative containing sulfonylpiperazine unit and its preparation method.

[0015] Another purpose of the present application is to provide a composition containing the above-mentioned compound or its stereoisomer, or its salt or its solvate.

[0016] Another purpose of the present application is to provide the use of the above-mentioned compound or its stereoisomer, or its salt or its solvate, or the composition.

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

[0018] Another purpose of the present application is to provide the mechanism of action of using the above-mentioned compound or its stereoisomer, or its salt or its solvate, or the composition for preventing and treating tomato spotted wilt virus disease.

[0019] The dithioacetal derivative containing sulfonylpiperazine unit of the present application has the following general structure:

[0020]

[0021] To achieve the above-mentioned purposes, the following preferred technical solutions are adopted in the present application:

[0022]

[0023] wherein

[0024] X is selected from

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

[0026] R1and R2are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxyl, amino, thiol, phenyl, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl;

[0027] R3is independently selected from the group consisting of 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, optionally substituted or unsubstituted aryl.

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

[0029] R1and R2are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, propyl;

[0030] R3is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, s-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2OH, -CH2CH2CH2OH, phenyl, benzyl.

[0031] Preferred compounds are the following compounds C1-C33.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0046] Compound C15: l-(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-l-yl)ethoxy)- 3-methoxyphenyl)methylene)bis(sulfanediyl))bis(ethane-l-one)

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

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

[0050] Compound C19: 2-(4-(bis(ethylthio)methyl)-2-methoxyphenoxy)-l-(4- toluenesulfonylpiperazin-l-yl)ethan-l-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-p-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-(di(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 C31: 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-p- toluenesulfonylpiperazin-1-yl)ethan-1-one

[0065] The preparation method of the compound comprises:

[0066]

[0067] Preferably, further comprising:

[0068]

[0069] Most preferably, comprising:

[0070]

[0071] The present application also provides a composition containing the compound or its stereoisomer, or its salt or its solvate, and an agriculturally acceptable adjuvant or a fungicide, an antiviral agent or a herbicide; preferably, the dosage form of the composition is selected from the group consisting of emulsifiable concentrate (EC), dustable powder (DP), wettable powder (WP), granule (GR), aqueous suspension (AS), suspension concentrate (SC), ultra-low volume spray (ULV), soluble powder (SP), microcapsule (MC), fumigant (FU), emulsion in water (EW), water dispersible granule (WG).

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

[0073] The present application provides a method for preventing and treating agricultural viral diseases, and the compound or its stereoisomer, or its salt or its solvate, or the composition is applied to the harmful object or its 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" used herein includes branched and straight chain saturated hydrocarbon groups having a specified number of carbon atoms. For example, "C 1-10"Alkyl" (or alkylene) groups are intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10alkyl groups. Additionally, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. The alkyl group can be unsubstituted or substituted such 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 (e.g., n-propyl and i-propyl), butyl (n-butyl, i-butyl, t-butyl), pentyl (e.g., n-pentyl, i-pentyl, neopentyl), and the like.

[0075] The term "cycloalkyl" refers to cycloalkyl groups, including mono-, bi- or polycyclic ring systems. C 3-7 Cycloalkyl groups are intended to include C3, C4, C5, C6, and C7cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocyclic" or "carbocyclic ring" means any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring which can be saturated, partially unsaturated, unsaturated, or aromatic. Examples of such carbocyclic rings 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, anthryl, and tetrahydronaphthyl (tetrahydronaphthalene). As noted above, bridged rings are also included within the definition of carbocyclic rings (e.g., [2.2.2]bicyclooctane). If not otherwise specified, the preferred carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocyclic" is used, it is intended to include "aryl". A bridge is a one or two carbon atom linkage between non-adjacent carbon atoms. Preferably, the bridge is one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When the ring is bridged, substituents on the ring are also present on the bridge.

[0076] The term "aryl" means 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 can be substituted.

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

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

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

[0080] The application will be further described in the following examples. It should be understood that the described methods of the examples are only used to illustrate the application, but not limit the application, and simple improvements of the preparation methods of the application under the concept of the application are within the scope of the application. 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] Into a three-necked flask was added 3-methoxy-4-hydroxybenzaldehyde (41.0 mmol), 40 mL of acetonitrile, K2CO3 (82.0 mmol), and the reaction was stirred for 10 minutes. Then 1,2-dibromoethane (69.6 mmol) was added and the reaction was heated to 65 °C. TLC monitoring was performed until the reaction was completed. The crude product was extracted with ethyl acetate and washed with saturated brine, and then 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 4-toluenesulfonylpiperazine-1-carboxylic acid tert-butyl ester:

[0085] Into a three-necked flask was added N-Boc-piperazine (16.0 mmol), 20 mL of dichloromethane, and triethylamine (20.9 mmol) and the reaction was stirred. After 10 minutes, 4-methylbenzenesulfonyl chloride (17.7 mmol) was added to the system. TLC monitoring was performed until the reaction was completed. The crude product was extracted with dichloromethane and washed with dilute HBr until the pH was 2-3. Then the crude product was recrystallized with 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-toluenesulfonylpiperazine:

[0087] 4-toluenesulfonylpiperazine-1-carboxylic acid tert-butyl ester was deprotected by removing Boc at room temperature in the presence of trifluoroacetic acid to obtain 4-toluenesulfonylpiperazine.

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

[0089] To a three necked flask was added intermediate 4-toluenesulfonylpiperazine (4.6 mmol) and 20 mL of acetonitrile, made basic with an appropriate amount of triethylamine, stirred at room temperature for 2 h, to the system was added K2CO3 (9.2 mmol), KI (0.05 mmol) and intermediate 4-(2-bromoethoxy)-3-methoxybenzaldehyde (4.6 mmol), heated to reflux, monitored by TLC until completion of the reaction, extracted with ethyl acetate, washed with saturated brine, column chromatography to isolate and purify 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] To a single necked flask was added intermediate 3-methoxy-4-(2-(4- toluenesulfonylpiperazin-1-yl)ethoxy)benzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and isopropyl mercaptan (1.4 mmol) were added to the system with stirring. The reaction was carried out at room temperature, monitored by TLC until completion of the reaction. The crude product was isolated and purified by column chromatography to obtain a yellow oil with a yield of 38.5%.

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

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

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

[0095] To a single necked flask was added intermediate 3-methoxy-4-(2-(4- toluenesulfonylpiperazin-1-yl)ethoxy)benzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and isopropyl mercaptan (1.4 mmol) were added to the system with stirring. The reaction was carried out at room temperature, monitored by TLC until completion of the reaction. The crude product was isolated and purified by column chromatography to obtain a yellow oil with a yield of 38.5%.

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

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

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

[0099] Into a single necked flask was added intermediate 3-methoxy-4-(2-(4- toluenesulfonylpiperazin-1-yl)ethoxy)benzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and butanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product was obtained. White solid, melting point 69.0-71.0 °C, 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] Into a three necked flask was added 3-chloro-4-hydroxybenzaldehyde (41.0 mmol), 40 mL of acetonitrile, K2CO3 (82.0 mmol), after 10 minutes of reaction 1,2-dibromoethane (69.6 mmol) was added, heating to 65 °C. TLC monitoring until completion of the reaction, extraction with ethyl acetate and washing with saturated brine, column chromatography separation and purification of the crude product was obtained as a white solid, melting point 59.4-60.7 °C, yield 47.5 %.

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

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

[0105] Into a three necked flask was added intermediate 4-toluenesulfonylpiperazine (4.6 mmol) and 20 mL of acetonitrile, adjusting to basic with an appropriate amount of triethylamine, stirring at room temperature for 2 h, to the system was added K2CO3 (9.2 mmol), KI (0.05 mmol) and intermediate 4-(2-bromoethoxy)-3-chlorobenzaldehyde (4.6 mmol), heating to reflux, TLC monitoring until completion of the reaction, extraction with ethyl acetate, washing with saturated brine, column chromatography separation and purification was obtained as a white solid, melting point 91.0-93.0 °C, yield 54.5 %.

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

[0107] To a single necked flask was added intermediate 3-chloro-4-(2-(4- methylbenzenesulfonylpiperazin-l-yl)ethoxy)benzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and propanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC was used to monitor the reaction until completion. The crude product was isolated and purified by column chromatography to give a yellow oil in 64.1% yield.

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

[0109] Steps (1) to (4) were same as steps (1) to (4) of example 4.

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

[0111] To a single necked flask was added intermediate 3-chloro-4-(2-(4- methylbenzenesulfonylpiperazin-l-yl)ethoxy)benzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and propanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC was used to monitor the reaction until completion. The crude product was isolated and purified by column chromatography to give a yellow oil in 64.1% yield.

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

[0113] Steps (1) to (4) were same as steps (1) to (4) of example 4.

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

[0115] To a single necked flask was added intermediate 3-chloro-4-(2-(4- methylbenzenesulfonylpiperazin-l-yl)ethoxy)benzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and propanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC was used to monitor the reaction until completion. The crude product was isolated and purified by column chromatography to give a yellow oil in 64.1% yield.

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

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

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

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

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

[0121] Steps (1) to (4) are same as steps (1) to (4) of example 1.

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

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

[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] To a three-necked flask was added substituted hydroxybenzaldehyde (41.0 mmol), 40 mL of acetonitrile, K2CO3(82.0 mmol) and the reaction was stirred for 10 minutes before 1,3-dibromopropane (69.6 mmol) was added and heated to 65 °C. TLC monitoring was performed until the reaction was complete, extracted with ethyl acetate and washed with saturated brine, and the crude product was isolated and purified by column chromatography to yield 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] To a three-necked flask was added N-Boc-piperazine (16.0 mmol), 20 mL of dichloromethane and triethylamine (20.9 mmol) and stirred. After 10 minutes, 2-chlorobenzenesulfonyl chloride (17.7 mmol) was added to the system. TLC monitoring was performed until the reaction was complete, extracted with dichloromethane and washed with dilute HBr until pH = 2-3. The crude product was then recrystallized with absolute ethanol to yield 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] Removal of the Boc group from tert-butyl 4-((2-chlorophenyl)sulfonyl)piperazine-1-carboxylate in the presence of trifluoroacetic acid at room temperature resulted in 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 was added intermediate 4-((2-chlorophenyl)sulfonyl)piperazine (4.6 mmol) and 20 mL of acetonitrile, which was made alkaline with an appropriate amount of triethylamine, and stirred at room temperature for 2 h. K2CO3(9.2 mmol), KI (0.05 mmol) and intermediate 4-(3-bromopropoxy)-3-methoxybenzaldehyde (4.6 mmol) were added to the system, which was heated to reflux. TLC monitoring was performed until the reaction was complete, extracted with ethyl acetate and washed with saturated brine, and column chromatography was used to isolate and purify the product to yield 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] To a single necked flask was added intermediate 4-(3-(4-(2-chlorophenyl)sulfonyl)piperazin-l-yl)propoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and propanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product to obtain a yellow oil, yield 77.1%.

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

[0136] Step (1) same as example 1 step (1), steps (2)-(3) same as example 9 steps (2)-(3).

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

[0138] To a three necked flask was added intermediate 4-((2-chlorophenyl)sulfonyl)piperazine (4.6 mmol) and 20 mL of acetonitrile, made basic with appropriate amount of triethylamine, stirred at room temperature for 2 h, to the system was added K2CO3 (9.2 mmol), KI (0.05 mmol) and intermediate 4-(2-bromoethoxy)-3-methoxybenzaldehyde (4.6 mmol), heated to reflux, TLC monitoring until completion of the reaction, extraction with ethyl acetate, washed with saturated brine, column chromatography separation and purification to obtain a yellow solid, melting point 107.0-109.0 °C, yield 72.6%.

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

[0140] To a single necked flask was added intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazin-l-yl)ethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and propanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product to obtain a yellow oil, yield 77.1%.

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

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

[0143] To a three-necked flask was added p-hydroxybenzaldehyde (41.0 mmol), 40 mL of acetonitrile, K2CO3(82.0 mmol), and the reaction was stirred for 10 minutes before the addition of 1,2-dibromoethane (69.6 mmol) and heating 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 isolated and purified by column chromatography to give a white solid with a melting point of 74.0-76.0 °C and a yield of 58.9%.

[0144] Steps (2)-(3) were the same as in Example 9, steps (2)-(3).

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

[0146] To a three-necked flask was added intermediate 4-((2-chlorophenyl)sulfonyl)piperazine (4.6 mmol) and 20 mL of acetonitrile, and the reaction was stirred for 2 h at room temperature before the addition of K2CO3(9.2 mmol), KI (0.05 mmol), and intermediate 4-(3-bromoethoxy)benzaldehyde (4.6 mmol) and heating to reflux. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was isolated and purified by column chromatography to give a yellow oil with a yield of 70.9%.

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

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

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

[0150] Step (1) was the same as in Example 11, steps (2)-(3) were the same as in Example 9, and step (4) was the same as in Example 11.

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

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

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

[0154] Step (1) Same as step (1) of example 9.

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

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

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

[0158] 4-((4-bromophenyl)sulfonyl)piperazine-1-carboxylic acid tert-butyl ester was deprotected from Boc in the presence of trifluoroacetic acid at room temperature to obtain 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 was added intermediate 4-((4-bromophenyl)sulfonyl)piperazine (4.6 mmol) and 20 mL of acetonitrile, made basic with appropriate amount of triethylamine, stirred at room temperature for 2 h, to the system was added K2CO3 (9.2 mmol), KI (0.05 mmol) and intermediate 4-(3-bromopropoxy)-3-methoxybenzaldehyde (4.6 mmol), heated to reflux, monitored by TLC until completion of the reaction, extracted with ethyl acetate, washed with saturated brine, column chromatography gave the product as a white solid with a melting point of 114.0-116.0 °C in 50.0% yield.

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

[0162] To a single necked flask was added intermediate 4-(3-(4-(4-bromophenyl)sulfonyl)piperazin-1- yl)propoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and ethanethiol (1.4 mmol) were added to the system with stirring. The reaction was carried out at room temperature, monitored by TLC until completion of the reaction. The crude product was purified by column chromatography to give a yellow oil in 56.8% yield.

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

[0164] Step (1) was the same as step (1) of Example 9, and steps (2)-(4) were the same as steps (2)-(4) of Example 13.

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

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

[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 in example 1 step (1), steps (2)-(3) are the same as in example 9 steps (2)-(3), step (4) is the same as in example 10 step (4).

[0169] (5) Preparation of 2,2'-(((4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-l- yl)ethoxy)-3-methoxyphenyl)methylene)bis(sulfanediyl))bis(ethane-l- one) (C16):

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

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

[0172] Step (1) is the same as in example 1 step (1), steps (2)-(3) are the same as in example 9 steps (2)-(3), step (4) is the same as in example 10 step (4).

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

[0174] To a single necked flask was added intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazin-l-yl)ethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and isopropyl mercaptan (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC was monitored until completion of the reaction. The crude product was isolated and purified by column chromatography to get a yellow oil with 74.4% yield.

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

[0176] Step (1) is the same as in example 1 step (1), steps (2)-(3) are the same as in example 9 steps (2)-(3), step (4) is the same as in example 10 step (4).

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

[0178] To a single necked flask was added intermediate 4-(2-(4-(2-chlorophenyl)sulfonyl)piperazin- 1 -yl)ethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL tetrahydrofuran, then ZrCl4 (0.07 mmol) and mercaptoethanol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until the reaction was complete. Extraction with ethyl acetate, column chromatography separation and purification of the crude product to obtain a yellow oil, yield 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)-(2) are the same as in example 9 steps (2)-(3).

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

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

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

[0184] To a three necked flask was added 3-methoxy-4-hydroxybenzaldehyde (5.2 mmol), 40 mL of acetonitrile, K2CO3(9.4 mmol) and KI (0.5 mmol), stirred at room temperature for 30 minutes, then added intermediate 2-chloro-l-(4-(2-chlorophenyl)sulfonyl)piperazin-l-yl)ethan-l-one (4.7 mmol), heated to reflux, monitored by TLC until the reaction was complete, extracted with ethyl acetate, washed with saturated brine, column chromatography to isolate and purify the product 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)-l-(4-((2- chlorophenyl)sulfonyl)piperazin-l-yl)ethan-l-one:

[0186] To a single necked flask was added intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-l-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and butyl mercaptan (1.4 mmol) were added to the system while stirring. The reaction was carried out at room temperature, monitored by TLC until the reaction was complete. 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)-l-(4-p-toluenesulfonylpiperazin-l-yl)ethan-l-one (C19):

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

[0189] (3) Preparation of 2-chloro-l-(4-toluenesulfonylpiperazin-l-yl)ethan-l-one:

[0190] Intermediate 4-toluenesulfonylpiperazine (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, which was monitored by TLC until the reaction no longer changed. The product was isolated and purified by column chromatography to obtain a white solid 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-toluenesulfonylpiperazin-l-yl)ethoxy)benzaldehyde:

[0192] To a three necked flask was added 3-methoxy-4-hydroxybenzaldehyde (5.2 mmol), 40 mL of acetonitrile, K2CO3(9.4 mmol) and KI (0.5 mmol), stirred at room temperature for 30 minutes, then added intermediate 2-chloro-l-(4-toluenesulfonylpiperazin-l-yl)ethan-l-one (4.7 mmol), heated to reflux, monitored by TLC until the reaction was complete, extracted with ethyl acetate, washed with saturated brine, column chromatography to isolate and purify the product to get white solid, melting point 158.5-160.1 °C, yield 45.3%.

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

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

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

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

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

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

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

[0200] Steps (1) to (2) are same as steps (2) to (3) of example 1 and steps (3) to (4) are same as steps (3) to (4) of example 19.

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

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

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

[0204] Steps (1) to (2) are same as steps (2) to (3) of example 1 and steps (3) to (4) are same as steps (3) to (4) of example 19.

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

[0206] To a single necked flask was added intermediate 3-methoxy-4-(2-oxo-2-(4- toluenesulfonylpiperazin-1-yl)ethoxy)benzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4 (0.07 mmol) and propanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC was monitored until completion of the reaction. The crude product was isolated and purified by column chromatography to get a white solid with melting point 122.0-124.0 °C and yield 64.1 %.

[0207] Example 23: 2-(4-(bis(butyl)methyl)-2-methoxyphenoxy)-1 -(4-p-tolylsulfonylpiperazin- 1 -yl)ethan-1 -one (C23):

[0208] Steps (1) to (2) are the same as steps (2) to (3) of example 1, steps (3) to (4) are the same as steps (3) to (4) of example 19.

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

[0210] To a single necked flask was added intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and isobutyl mercaptan (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC was used to monitor the reaction until completion. The crude product was isolated and purified by column chromatography to give a white solid with a melting point of 111.0-113.0 °C and a yield of 91.2 %.

[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, 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] To a single necked flask was added intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and isobutyl mercaptan (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC was used to monitor the reaction until completion. The crude product was isolated and purified by column chromatography to give 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, 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] To a single necked flask was added intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and isobutyl mercaptan (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until the reaction was complete. Extraction with ethyl acetate, column chromatography separation and purification of the crude product 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) of Example 13.

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

[0222] To a single necked flask was added intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and isobutyl mercaptan (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until the reaction was complete. Extraction with ethyl acetate, column chromatography separation and purification of the crude product to obtain a white solid with a melting point of 91.0-93.0 °C and a yield of 90.2%.

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

[0224] To a single necked flask was added intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and isobutyl mercaptan (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until the reaction was complete. Extraction with ethyl acetate, column chromatography separation and purification of the crude product to obtain a white solid with a melting point of 91.0-93.0 °C and a yield of 90.2%.

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

[0226] To a single necked flask was added intermediate 4-(2-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and butanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product gave a white solid with a melting point of 126.5-128.5 °C, in 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)-(2) are the same as steps (2)-(3) of Example 13, steps (3)-(4) are the same as steps (3)-(4) of Example 26.

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

[0230] To a single necked flask was added intermediate 4-(2-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and butanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product gave a white solid with a melting point of 126.5-128.5 °C, in a yield of 88.0%.

[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)-(2) are the same as steps (2)-(3) of Example 13, steps (3)-(4) are the same as steps (3)-(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] To a single necked flask was added intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and ethanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product to obtain a white solid, melting point 67.0-69.0 °C, yield 58.9 %.

[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)-(2) are the same as steps (2)-(3) of Example 9, steps (3)-(4) are the same as steps (3)-(4) of Example 18.

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

[0238] To a single necked flask was added intermediate 4-(2-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and ethanethiol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product to obtain a white solid, melting point 67.0-69.0 °C, yield 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)-(2) are the same as steps (2)-(3) of Example 9, steps (3)-(4) are the same as steps (3)-(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] To a single necked flask was added intermediate 4-(2-(4-((2- chlorophenyl)sulfonyl)piperazin-l-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and mercaptoethanol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product gave a white solid with a melting point of 99.0-101.0 °C, in a yield of 77.7%.

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

[0244] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, 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)-l-(4-(2- chlorophenyl)sulfonyl)piperazin-l-yl)ethan-l-one:

[0246] To a single necked flask was added intermediate 4-(2-(4-((2- chlorophenyl)sulfonyl)piperazin-l-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and mercaptoethanol (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product gave a white solid with a melting point of 99.0-101.0 °C, in a yield of 77.7%.

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

[0248] Steps (1) to (2) are the same as steps (2) to (3) of Example 9, 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)-l-(4-(2- chlorophenyl)sulfonyl)piperazin-l-yl)ethan-l-one:

[0250] To a single necked flask was added intermediate 4-(2-(4-((2- chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and isopropyl mercaptan (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product gave a white solid, melting point 92.0-94.0 °C, yield 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) of Example 1, steps (3) to (4) are the same as steps (3) to (4) of Example 19.

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

[0254] To a single necked flask was added intermediate 4-(2-(4-((2- chlorophenyl)sulfonyl)piperazin-1-yl)-2-oxoethoxy)-3-methoxybenzaldehyde (0.7 mmol) and 6 mL of tetrahydrofuran, then ZrCl4(0.07 mmol) and isopropyl mercaptan (1.4 mmol) were added to the system under stirring. The reaction was carried out at room temperature, TLC monitoring until completion of the reaction. Extraction with ethyl acetate, column chromatography separation and purification of the crude product gave a white solid, melting point 92.0-94.0 °C, yield 84.8 %.

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

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

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269] Test Example 1: Determination of the in vivo biological activity of the target compound against TSWV.

[0270] The compound to be tested was dissolved in N,N-dimethylformamide and then diluted with 2% Tween 80 to obtain a 500 mg / L solution of the compound to be tested. At the time of testing, the concentration was diluted to obtain solutions of the compound to be tested at concentrations of 500, 250, 125, 62.5 and 31.25 mg / L. 50

[0271] (1) Test of the therapeutic activity against TSWV

[0272] Plants of Nicotiana glutinosa at the 5-6 leaf stage, which were substantially uniform in growth, were selected, the top and bottom leaves were removed, and silicon carbide was evenly spread over the leaves. The plants were then brushed with TSWV virus solution using a brush, and 50 minutes later, the silicon carbide was washed off with water. After drying, the right side of the plants was brushed with the target compound solution using a brush. The plants were then placed in a growth chamber, and the conditions were controlled to be 25°C and 50% humidity for 14 hours during the day and 23°C and 40% humidity for 10 hours at night. Each treatment was repeated three times, and the number of dead spots was recorded after 2-3 days, and the inhibition rate was calculated.

[0273] Inhibition rate (%) = [(number of dead spots in the blank control - number of dead spots in the treatment with the agent) / number of dead spots in the blank control] x 100%

[0274] (2) Test of the protective activity against TSWV

[0275] Plants of Nicotiana glutinosa at the 5-6 leaf stage, which were substantially uniform in growth, were selected, the top and bottom leaves were removed, and the right side of the plants was brushed with the target compound solution using a brush. After 24 hours, silicon carbide was evenly spread over the leaves, and the plants were brushed with TSWV virus solution using a brush. After 50 minutes, the silicon carbide was washed off with water, and the plants were then placed in a growth chamber, and the conditions were controlled to be 25°C and 50% humidity for 14 hours during the day and 23°C and 40% humidity for 10 hours at night. Each treatment was repeated three times, and the number of dead spots was recorded after 2-3 days, and the inhibition rate was calculated (calculated in the same way as the therapeutic activity).

[0276] ​(3) Test of resistance to TSWV passivation activity

[0277] Select 5-6 leafy tobacco plants with uniform growth, remove the top and bottom leaves, and evenly sprinkle silicon carbide on all leaves. Using a brush, apply an equal volume mixture of TSWV virus solution and compound solution (mixed and incubated for 30 minutes) to the right side of all leaves, and then apply a 2-fold diluted TSWV virus solution to the left side. Rinse the silicon carbide with water after 50 minutes. Then, place the plants in an artificial climate chamber for cultivation, controlling the conditions as follows: 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. Record the number of necrotic spots after 2-3 days and calculate the inhibition rate (using the same calculation method as for 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 of target compounds C1-C33 (EC) 50

[0283]

[0284] The anti-Tomato Spotted Wilt Virus (TSWV) activity of dithioacetal derivatives containing sulfonylpiperazine units was tested using the half-leaf wilt method at a concentration of 500 μg / mL, with ribavirin as a control. The bioassay results in Tables 1, 2, and 3 show that most target compounds exhibited some anti-TSWV activity, and most showed good therapeutic, protective, and inactivating activities against TSWV. For example, compounds C13, C20, C29, C1, C4, C5, C8, C10, C15, C22, C24, and C26 showed high inactivating activity against TSWV (the therapeutic activity of these compounds is shown in the appendix). Figure 1 ), its EC 50 The effective concentrations 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, significantly superior to ribavirin (701.9 μg / mL). In particular, compounds C13, C20, and C29 exhibited the highest inactivation activity. The inactivation activity of these three compounds against tomato spotted wilt virus compared to the control agent is shown in [the table below]. Figure 2 .

[0285] The above merely describes preferred embodiments of the present application, and is not intended to limit the present application in any form. Any simple modification, equivalent change and modification of the above embodiments, without departing from the technical solution content of the present application, according to the technical essence of the present application, still belongs to the scope of the technical solution of the present application.

Claims

1. A dithioacetal compound containing a sulfonylpiperazine unit or a stereoisomer thereof, or a salt thereof, characterized by The compound is selected from the following formula (I) or (II): wherein n is independently selected from 1, 2, 3, 4; R1and R2are each independently selected from hydrogen, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, propyl; R3is independently selected from hydrogen, methyl, ethyl, n-propyl, sec-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2OH, -CH2CH2CH2OH.

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

3. A method of preparing a dithioacetal compound containing a sulfonylpiperazine unit according to claim 1, or a stereoisomer thereof, or a salt thereof, characterized by including:

4. The production method according to claim 3, further comprising:

5. The production method according to claim 3, further comprising:

6. A composition characterized in that a compound according to claim 1 or 2 or a stereoisomer thereof, or a salt thereof, and an agriculturally acceptable adjuvant or a fungicide, an antiviral agent or a herbicide; the dosage form of the composition is selected from the group consisting of emulsifiable concentrate, powder, granule, aqueous agent, suspension, ultra-low volume spray, microcapsule, smoke agent, emulsion in water.

7. Use of a compound according to claim 1 or 2 or a stereoisomer thereof, or a salt thereof, or a composition according to claim 6 for controlling an agricultural virus, which is a plant negative strand RNA virus.

8. Use according to claim 7, characterized in that: The agricultural virus is tomato spotted wilt virus.

9. A method of controlling viral diseases in agriculture, characterized by: exposing an agricultural virus or its living environment to a compound according to claim 1 or 2 or a stereoisomer thereof, or a salt thereof, or a composition according to claim 6; the harmful object is a plant negative strand RNA virus.

10. The method of claim 9, wherein the method is for controlling a viral disease in an agricultural plant. The agricultural virus is tomato spotted wilt virus.

11. A method for protecting a plant from an agricultural virus disease, comprising a method step wherein an agricultural virus is contacted with a compound according to claim 1 or 2 or a stereoisomer thereof, or a salt thereof, or a composition according to claim 6.

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