A benzoxazole derivative containing a dithioacetal unit and its preparation method and use

Abstract

The present invention relates to a benzoxazole derivative containing a dithioacetal unit, its preparation method, and use. The compound of the present invention exhibits excellent antiviral activity against cucumber green mottle mosaic virus and other viruses, and can be used as a pharmaceutical or medicament for preventing and treating plant viral diseases such as cucumber green mottle mosaic. Its structure and preparation process are simple, and its production cost is low. The benzoxazole derivative containing a dithioacetal unit includes a benzoxazole compound containing a dithioacetal unit, or a stereoisomer thereof, or a salt or solvate thereof. The structural formula of the benzoxazole compound containing a dithioacetal unit is as follows: #imgabs0#

Description

Technical Field

[0001] The present invention relates to the fields of chemical industry and pesticides, and in particular to benzoxazole derivatives of dithioacetal units, and preparation methods and uses thereof. Background Art

[0002] Cucumber green mottle mosaic virus (CGMMV), a member of the genus Tobamovirus, was first reported by Ainsworth in 1935. It primarily infects cucurbits, including cucumber, melon, gourd, and watermelon, and is a major disease of these crops. Initially endemic in England, CGMMV slowly spread to other countries and regions between 1935 and 1985. Its spread accelerated between 1986 and 2006, but over the past decade (2007-2016), it has rapidly spread globally, becoming a major disease of cucumber and other cucurbit crops, garnering numerous quarantine regulations. In 2006, CGMMV was designated a national agricultural plant quarantine pest by my country's Ministry of Agriculture and Rural Affairs, a Category III national quarantine disease. CGMMV is a single-stranded, positive-sense RNA virus with a genome of approximately 6400 bp, flanked by a noncoding region at each end and four open reading frames (ORFs) in between. These four ORFs encode a 17.3 kDa coat protein (CP), a 29 kDa movement protein (MP), and 129 kDa and 186 kDa replication proteins (RNA-dependent RNA polymerase, RdRp). Within the CGMMV genome, the RdRp and MP overlap by 14 nucleotides, while the MP and CP overlap by 26 nucleotides. The RdRp-RNA encoding the replication proteins RdRp (129 kDa and 186 kDa) is closely involved in viral replication and transcription. The CP-RNA encoding the coat protein CP (17.3 kDa) is a critical structural subunit of the virus, protecting the viral nucleic acid from destruction and participating in long-distance transport. MP-RNA encodes the coat protein MP (29 kDa), which is essential for the intercellular movement of CGMMV.

[0003] In 2017, Zhang Jian et al. (Zhang, J.; Zhao, L.; Zhu, C.; Wu, ZX; Zhan G.P.; Gan, XH; Liu, DY; Pan, JK; Hu, DY; Song, B.A.) from the applicant's team reported a series of vanillin derivatives containing dithioacetal 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 The concentrations of ribavirin and cypermethrin in the blood were 217.6 mg / L, 205.7 mg / L and 206.3 mg / L, 186.2 mg / L, respectively, which were better than those in ribavirin (848.0 mg / L, 808.1 mg / L and 858.2 mg / L, 766.5 mg / L, respectively), chlorpyrifos (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 strobilurinmoiety. 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 the two compounds were 125.3, 108.9 and 181.7 mg / L, respectively, which were significantly higher than those of ribavirin (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; Zhang, J.; Yang, HY; Liu, YW; Hu, DY; Song, BA) from the applicant's team introduced the active structural unit dithioacetal into the glycoside skeleton through click chemistry to design and synthesize a series of novel glycoside derivatives containing dithioacetal structures. The study targeted ToCV-CP and determined the binding constants of the compounds to ToCV-CP by MST. The MST results showed that the binding constants of compounds 6b and 8a to ToCV-CP were 0.12 and 0.21 μM, respectively, which were better than ningnanmycin (0.26 μM) and ribavirin (37.26 μM). In addition, at a concentration of 50 μg / mL, the expression of the ToCV-CP gene in tomato plants infected with ToCV was significantly inhibited after treatment with compounds 6b and 8a, with the reduction values being 92% and 82%, respectively, which were better than the Ningnanmycin treatment group (56%).

[0006] In 2021, Zan Ningning et al. (Zan, NN; Xie, DD; Li, M.; Jiang, DH; Song, BA) from the applicant's team designed and synthesized a series of novel pyrimidine derivatives bearing a dithioacetal moiety that targets ToCV coat protein. J. Agric. Food Chem. 2020, 68, 6280–6285.) using vanillin thioacetal as the lead compound, introduced the active unit dithioacetal at the 2-position of methoxyacrylate, and replaced the benzene ring of vanillin with a pyrimidine ring. The team designed and synthesized a series of novel pyrimidine derivatives containing dithioacetal and methoxyacrylate structures. This study targeted ToCV CP and tested the binding constant of the compound to ToCV CP by MST. The results showed that the binding constants of compounds B13 and B23 with ToCV CP were 0.09μM and 0.06μM, respectively, which were superior to those of ningnanmycin (0.19μM) and ribavirin (6.54μM). In addition, in vivo pot experiments showed that compounds B13 and B23 could significantly reduce the expression of the ToCV CP gene, outperforming the control agents ningnanmycin and ribavirin. 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 a4(3H)-quinazolinone pyrimidinering. J.Agric.Food Chem.2021, 69, 14459-14466.) replaced the methoxyacrylate structure with the active unit quinazoline on this basis, and designed and synthesized a series of novel dithioacetal derivatives containing 4(3H)-quinazolinone pyrimidine ring. The study took TSWV CP as the research object, and tested the binding constant of the target compound with TSWV CP by MST. The test results showed that the binding constant of compound D32 with TSWV CP was 4.4μM, which was better than the control agent Ningnanmycin (6.2μM) and the lead compound vanillylthioacetal (59.1μM). In addition, the half-leaf spot assay revealed that compound D32 exhibited excellent inactivation activity against TSWV, with an EC 50The value was 144 μg / mL, which was better than the control agent Ningnanmycin (149 μg / mL) and the lead compound Vanillylthiocarbamate (525 μg / mL).

[0007] In 2021, Zan Ningning et al. (Zan, NN; Li, J.; He, HF; Hu, DY; Song, BA Discovery of novel chromone derivatives as potential anti-TSWVagents. J. Agric. Food Chem. 2021, 69, 10819-10829.) from the applicant's team used natural product chromone as the lead compound, introduced a dithioacetal structure at the 3-position of chromone, and designed and synthesized a series of novel chromone derivatives containing dithioacetal structures. The study took TSWVN protein as the research object, and tested the binding constants of some compounds with TSWVN by MST. The MST experiment showed that compound A33 exhibited excellent binding to TSWVN, and its K d The value was 10.22 μM, which was better than the control agents Ningnanmycin (16.55 μM) and Ribavirin (126.56 μM). In addition, molecular docking experiments showed that the carbonyl and ether bonds of compound A33 could be It forms two conventional hydrogen bonds with amino acid AR G60 at a distance of .

[0008] In 2021, Zhao Lei et al. (Zhao, L.; Zhang, J.; Liu, T.; Mou, HL; Wei, CL; Hu, DY; Song, BA Design, Synthesis, and Antiviral Activities of Coumarin Derivatives Containing Dithioacetal Structures. J. Agric. Food Chem. 2020, 68, 975-981.) from the applicant's team used vanillyl thioacetal and coumarin as lead compounds. Based on the principle of skeleton transition, they introduced the active unit dithioacetal at the 4-position of coumarin to design and synthesize a series of novel coumarin derivatives containing dithioacetal structures. Using TMV-CP as the target, the binding constant of the compound to TMV-CP was determined by MST. The MST structure shows that the binding constant of compound B21 to TMV-CP is 2.9 μM. In addition, the biological activity of the compound against TMV was tested by the half-leaf spot method. The activity results showed that compound B21 exhibited excellent deactivation activity against TMV, and its EC 50The value was 54.2 mg / L, which was better than the control drug ribavirin (134.2 mg / L). In addition, the results of molecular docking showed that compound B21 and amino acid residue GLN257 of TMV-CP ASN73 TYR139 LYS268 and AR G134 Through hydrogen bonding.

[0009] In 2021, Liu Yuewen et al. (Liu, YW; Chen, JX; Xie, DD; Song, BA; Hu, DY) from the applicant's team reported on anti-TSWV activities of quinazolinone derivatives containing a dithioacetal moiety. J. Agric. Food Chem. 2021, 69, 12135–12142.) reported on the design and synthesis of a series of novel quinazolinone derivatives containing a dithioacetal structure by structural derivatization at the 3-position of quinazolinone. Taking TSWV coat protein as the target, the binding ability of the target compound to TSWV coat protein was tested by MST. Among them, compound 6n has the strongest binding ability to TSWV coat protein, and its Kd value is 9.4μM, which is better than the control agent Ningnanmycin (24.3μM). In addition, the passivation activity of the compound against TSWV was tested by the half-leaf spot method. The activity results showed that compound 6n has good passivation activity against TSWV, and its EC 50 The value was 188 μg / mL, which was better than the control agent Ningnanmycin (257 μg / mL). The binding mode of compound 6n with TSWV CP was studied by molecular docking technology. The results of molecular docking showed that compound 6n interacted with amino acid residues ARG94 and ARG95 of TSWV coat protein through four π-alkyl bonds.

[0010] In 2021, Zu Guangcheng et al. (Zu, GC; Gan, XH; Xie, DD; Yang, HY; Zhang, AW; Li, SY; Hu, DY; Song, BA Design, synthesis, and anti-ToCV activity of novel 4(3H)-quinazolinone derivatives bearing dithioacetalmoiety. J. Agric. Food Chem. 2020, 68, 5539-5544.) from the applicant's team used vanillyl thioacetal as the lead compound, introduced a dithioacetal structure at the 2-position of the quinazolinone ring, and designed and synthesized a series of novel quinazolinone derivatives containing dithioacetal structures. The study took ToCV-CP as the research object, and tested the binding constants of the target compounds with ToCV-CP by MST. The MST results showed that the binding constants of compounds C5 and C22 with ToCV-CP were 0.24 and 0.25 μM, respectively. In addition, the bioactivity of compounds C5 and C22 against ToCV was tested in pot experiments. qPCR experiments showed that compounds C5 and C22 could significantly inhibit the expression of the ToCV-CP gene, with inhibitory effects of 81.05 and 87.59%, respectively, which were superior to the control agent ningnanmycin (43.88%) and the lead compound vanillylthiocarbamate (63.56%).

[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 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 its therapeutic, protective and passivation activities being 63.0, 56.6 and 74.1%, respectively. Its protective activity and passivation EC values were 0.04, 0.13 and 0.06, respectively. 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 vanillylthiocarbamate (624.9 and 300.0 μg / mL).

[0012] In 2024, Zhou Yuanxiang et al. (Zhou, YX; Sun, ZL; Zhou, Q.; Zeng, W.; Zhang, MH; Feng, S.; Xue, W. Novel flavonol derivatives containing benzoxazole as potential antiviral agents: design, synthesis, and biological evaluation. MolDivers. 2024) from Xue Wei's team designed and synthesized a series of novel flavonol derivatives containing benzoxazole structures using natural product flavonols as lead compounds, and tested the target compounds' anti-TMV biological activity. The activity results showed that compound X17 exhibited excellent therapeutic and protective activity against TMV, and its EC 50 The values were 127.6 μg / mL and 101.2 μg / mL, respectively, which were better than the control agent Ningnanmycin (320.0 μg / mL and 234.6 μg / mL).

[0013] In 2024, Zhang Han et al. (Zhang, N.; Zeng, W.; Zhou, Q.; Sun, ZL; Meng, KN; Qing, YS; Hu, YZ; Xue, W. Design, synthesis, antibacterial and antiviral evaluation of chalcone derivatives containing benzoxazole. Arabian Journal of Chemistry. 2024, 17: 105368) from Xue Wei's team designed and synthesized a series of novel benzoxazole-containing chalcone derivatives using natural product chalcone as the lead compound, and tested the target compound's anti-TMV biological activity. The activity results showed that compound Z15 exhibited excellent therapeutic activity against TMV, and its EC 50 The value was 101.97 μg / mL, which was better than the control drug Ningnanmycin (294.27 μg / mL). Compound Z16 showed excellent protective activity against TMV, and its EC 50 The binding affinity of compounds Z15 and Z16 to TMV-CP was 104.05 μg / mL, which was superior to that of the control agent Ningnanmycin (185.73 μg / mL). Furthermore, the binding affinity of compounds Z15 and Z16 to TMV-CP was determined by MST. MST results showed that the binding affinity of Z15 and Z16 to TMV-CP was significantly higher than that of NNM.

[0014] In 2014, Li Yunming et al. (Li Yunming, Shi Haiping, Gu Yunqin, Li Chengqiao, Cai Meiyan. Effectiveness of morphoguanidine-copper acetate in controlling cucumber green mottle mosaic virus. Zhejiang Agricultural Sciences, 2014, 12:1860-1861.) tested the effectiveness of a 500-fold dilution of 20% morphoguanidine-copper acetate wettable powder against cucumber green mottle mosaic virus using the watermelon variety Zaojia 84-24. The results showed that three consecutive sprays, one every seven days, achieved an 83.4% control efficacy seven days after the third spray.

[0015] In 2015, Li Junxiang et al. (Li Junxiang, Gu Qinsheng. Preliminary report on the use of four chemical elicitors for the control of cucumber green mottle mosaic virus. Chinese Vegetables, 2015, 7:40-44) aimed to screen for agents that could induce resistance to cucumber green mottle mosaic virus in gourds. They sprayed gourd seedlings with different concentrations of 2,1,3-benzothiadiazole, brassinolide, chitosan, and salicylic acid, then inoculated them with CGMMV by friction. The results showed that 2,1,3-benzothiadiazole, brassinolide, chitosan, and salicylic acid all induced resistance to CGMMV in gourds.

[0016] In summary, the dithioacetal structure is a novel skeleton structure with anti-plant virus activity discovered by our research group in the early stage. Benzoxazole compounds are an important class of heterocyclic compounds with excellent biological activity against plant viruses, but there are few studies on the prevention and control of CGMMV using compounds containing dithioacetal structures or benzoxazoles. In addition, CGMMV is hidden and persistent in propagation materials such as seeds, and its transmission pathways are diverse. At the same time, there is a lack of effective anti-CGMMV agents. Therefore, the introduction of a dithioacetal unit into the benzoxazole parent structure has significance and value for furthering pesticide research and development. Summary of the Invention

[0017] One of the objectives of the present invention is to provide a benzoxazole derivative containing a dithioacetal unit, a preparation method and use thereof.

[0018] Another object of the present invention is to provide a composition containing the above derivatives.

[0019] Another object of the present invention is to provide uses of the above derivatives or compositions.

[0020] Another object of the present invention is to provide the use of the above-mentioned derivatives or compositions in preventing and treating agricultural viral diseases.

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

[0022] The benzoxazole derivatives containing dithioacetal units of the present invention include benzoxazole compounds having dithioacetal units, or stereoisomers thereof, or salts thereof, or solvates thereof; the structural formula of the benzoxazole compound having dithioacetal units is as follows:

[0023]

[0024] wherein R1 and R2 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, thiol, phenyl, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, or optionally substituted or unsubstituted alkenyl;

[0025] 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.

[0026] Further preferably, R1 and R2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, and propyl;

[0027] 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.

[0028] More preferably, the benzoxazole derivative containing a dithioacetal unit is: compound C1-C36.

[0029] Compound C1: 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole

[0030] Compound C2: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-methylbenzo[d]oxazole

[0031] Compound C3: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-6-methylbenzo[d]oxazole

[0032] Compound C4: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-6-chlorobenzo[d]oxazole

[0033] Compound C5: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole

[0034] Compound C6: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole

[0035] Compound C7: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-chlorobenzo[d]oxazole

[0036] Compound C8: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole

[0037] Compound C9: 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)benzo[d]oxazole

[0038] Compound C10: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole

[0039] Compound C11: 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole

[0040] Compound C12: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole

[0041] Compound C13: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole

[0042] Compound C14: 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole

[0043] Compound C15: 12-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole

[0044] Compound C16: 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole

[0045] Compound C17: 2-(4-(isopropylthiomethyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole

[0046] Compound C18: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole

[0047] Compound C19: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole

[0048] Compound C20: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-fluorobenzo[d]oxazole

[0049] Compound C21: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methylbenzo[d]oxazole

[0050] Compound C22: 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-6-chlorobenzo[d]oxazole

[0051] Compound C23: 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole

[0052] Compound C24: 2-((4-(bis((4-fluorobenzyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole

[0053] Compound C25: 2-((4-(bis((4-fluorobenzyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole

[0054] Compound C26: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole

[0055] Compound C27: 2-((4-(bis(propylthio)methyl)-2-methoxyphenoxy)methyl ester)-6-fluorobenzo[d]oxazole

[0056] Compound C28: 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)methyl]-6-chlorobenzo[d]oxazole

[0057] Compound C29: 2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole

[0058] Compound C30: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole

[0059] Compound C31: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole

[0060] Compound C32: 2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole

[0061] Compound C33: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl-4-methylbenzo[d]oxazole

[0062] Compound C34: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole

[0063] Compound C35: 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole

[0064] Compound C36: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole

[0065] The preparation method of the benzoxazole compound having a dithioacetal unit comprises:

[0066]

[0067] Preferably, it further comprises:

[0068]

[0069] Most preferably, it includes:

[0070]

[0071] The present invention also provides a composition comprising the benzoxazole derivative containing a dithioacetal unit and an agriculturally applicable adjuvant or fungicide, antiviral agent or herbicide.

[0072] Preferably, the dosage form of the composition is selected from 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).

[0073] Application of the benzoxazole derivative containing dithioacetal units or the composition in preventing and controlling agricultural pests and diseases.

[0074] Preferably, the benzoxazole derivatives or compositions containing dithioacetal units are used in the preparation of drugs for preventing and controlling agricultural pests and diseases.

[0075] Further preferably, the benzoxazole derivative containing a dithioacetal unit, or the composition is used in preventing and treating agricultural viral diseases.

[0076] The agricultural viral disease is a plant positive-strand RNA virus; preferably, the agricultural viral disease is cucumber green mottle mosaic virus disease, cucumber mosaic virus disease, or potato virus Y disease.

[0077] Further preferably, the application method is: allowing the benzoxazole derivative containing a dithioacetal unit, or the composition to act on harmful substances or their living environment.

[0078] More preferably, the application method comprises contacting the benzoxazole derivative containing a dithioacetal unit or the composition with pests.

[0079] The term "alkyl" as used herein includes both branched and straight chain saturated hydrocarbon groups having the specified number of carbon atoms. For example, "C 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 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. The alkyl group may 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 (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl), and the like.

[0080] The term "cycloalkyl" refers to cyclic alkyl groups, including mono-, bi- or polycyclic ring systems. 3-7Cycloalkyl 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 ring 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 carbocycle (e.g., [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 monocycle into a bicycle. When a ring is bridged, the substituents of the ring are also present on the bridge.

[0081] 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.

[0082] The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine and iodine.

[0083] Beneficial effects:

[0084] The derivatives of the present invention have the characteristics of novel structure, simple preparation process, low production cost, high yield and good antiviral activity, especially having excellent antiviral activity against cucumber green mottle mosaic virus, cucumber mosaic virus and potato virus Y. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Figure 1 This is a diagram showing the protective activity of compounds C26, C27, C28, C29 and C36 and Ningnanmycin against cucumber green mottle mosaic virus at a drug concentration of 500 μg / mL.

[0086] Figure 2 This is a graph showing the therapeutic activity of compounds C2, C10, C20, C26 and C28 and Ningnanmycin against cucumber green mottle mosaic virus at a drug concentration of 500 μg / mL.

[0087] Figure 3This is a diagram showing the inactivation activity of compounds C1, C6, C17, C21 and C23 and Ningnanmycin against cucumber green mottle mosaic virus at a concentration of 500 μg / mL. Specific embodiments

[0088] The present invention is further illustrated by the following examples. It should be understood that the methods described in the examples are merely illustrative of the present invention and are not intended to limit the present invention. Simple modifications to the preparation methods of the present invention within the scope of the present invention fall within the scope of the present invention. All raw materials and solvents used in the examples are commercially available reagents of corresponding purity.

[0089] Example 1: 2-(4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole (C1):

[0090] (1) Preparation of 2-(chloromethyl)-6-methylbenzo[d]oxazole:

[0091] 2-Amino-5-methylphenol (40.60 mmol) and 2-chloro-1,1,1-trimethoxyethane (81.20 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 67.81%.

[0092] (2) Preparation of 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde:

[0093] To a three-necked flask, add 2-(chloromethyl)-6-methylbenzo[d]oxazole (8.26 mmol), 20 mL of DMF, KCO (20.65 mmol), and vanillin (9.91 mmol). The reaction system was heated to 40°C and stirred for 12 hours. TLC monitoring revealed that after complete reaction, the system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 81.45%.

[0094] (3) Preparation of 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole:

[0095] To a single-necked flask were added the intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.7 mmol), and 20 mL of dichloromethane. Ethanethiol (3.36 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.31 g of a white solid with a melting point of 50.2-51.4°C and a yield of 79.20%.

[0096] Example 2: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-methylbenzo[d]oxazole (C2):

[0097] (1) Preparation of 2-(chloromethyl)-5-methylbenzo[d]oxazole:

[0098] 2-Amino-4-methylphenol (44.66 mmol) and 2-chloro-1,1,1-trimethoxyethane (89.32 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 73.97%.

[0099] (2) Preparation of 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde:

[0100] To a three-necked flask, add 2-(chloromethyl)-5-methylbenzo[d]oxazole (11.01 mmol), 20 mL of DMF, KCO (27.53 mmol), and vanillin (13.21 mmol). The reaction system was heated to 40°C and stirred for 12 hours. TLC monitored the reaction. After the starting materials reacted completely, the system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 61.09%.

[0101] (3) Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-methylbenzo[d]oxazole:

[0102] To a single-necked flask were added the intermediate 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.51 mmol), ZrCl4 (0.75 mmol), and 20 mL of dichloromethane. Isopropyl mercaptan (3.78 mmol) was then added to the reaction system with stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.46 g of a white solid with a melting point of 40.3-41.2°C and a yield of 79.22%.

[0103] Example 3: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-6-methylbenzo[d]oxazole (C3):

[0104] Steps (1) to (2) are the same as steps (1) to (2) in Example 1.

[0105] (3) Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-6-methylbenzo[d]oxazole:

[0106] To a single-necked flask were added the intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.18 mmol), ZrCl4 (0.58 mmol), and 20 mL of dichloromethane. Isopropyl mercaptan (2.94 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.41 g of a white solid with a melting point of 53.2-54.3°C and a yield of 80.69%.

[0107] Example 4: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-6-chlorobenzo[d]oxazole (C4):

[0108] (1) Preparation of 6-chloro-2-(chloromethyl)benzo[d]oxazole:

[0109] 2-Amino-5-chlorophenol (34.83 mmol) and 2-chloro-1,1,1-trimethoxyethane (69.65 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 85.27%.

[0110] (2) Preparation of 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde:

[0111] To a three-necked flask, add 6-chloro-2-(chloromethyl)benzo[d]oxazole (9.90 mmol), 20 mL of DMF, KCO (24.75 mmol), and vanillin (11.88 mmol). The reaction system was heated to 40°C and stirred for 12 hours. TLC monitoring revealed that after complete reaction, the system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 63.59%.

[0112] (3) Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-6-chlorobenzo[d]oxazole:

[0113] To a single-necked flask were added the intermediate 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.10 mmol), ZrCl4 (0.55 mmol), and 20 mL of dichloromethane. Isopropyl mercaptan (2.75 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.36 g of a white solid with a melting point of 53.2-54.3°C and a yield of 72.30%.

[0114] Example 5: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole (C5):

[0115] Steps (1) to (2) are the same as steps (1) to (2) in Example 1.

[0116] (3) Preparation of 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole:

[0117] To a single-necked flask were added the intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane. Then, with stirring, 4-fluorothiophenol (3.36 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.67 g of a white solid with a melting point of 51.0-52.0°C and a yield of 92.97%.

[0118] Example 6: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole (C6):

[0119] Steps (1) to (2) are the same as steps (1) to (2) in Example 1.

[0120] (3) Preparation of 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole:

[0121] To a single-necked flask were added the intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.51 mmol), ZrCl4 (0.75 mmol), and 20 mL of dichloromethane. Then, with stirring, 4-chlorothiophenol (3.78 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.46 g of a white solid with a melting point of 4.3-85.4°C and a yield of 80.91%.

[0122] Example 7: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-chlorobenzo[d]oxazole (C7):

[0123] (1) Preparation of 5-chloro-2-(chloromethyl)benzo[d]oxazole:

[0124] 2-Amino-4-chlorophenol (31.34 mmol) and 2-chloro-1,1,1-trimethoxyethane (62.69 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 78.96%.

[0125] (2) Preparation of 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde:

[0126] To a three-necked flask, add 5-chloro-2-(chloromethyl)benzo[d]oxazole (10.89 mmol), 20 mL of DMF, KCO (27.22 mmol), and vanillin (13.07 mmol). The reaction system was heated to 40°C and stirred for 12 hours. TLC monitoring revealed that the reaction was complete. The system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 60.70%.

[0127] (3) Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-chlorobenzo[d]oxazole:

[0128] To a single-necked flask were added the intermediate 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.42 mmol), ZrCl4 (0.70 mmol), and 20 mL of dichloromethane. Isopropyl mercaptan (3.54 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.53 g of a white solid with a melting point of 78.4-79.1°C and a yield of 82.79%.

[0129] Example 8: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole (C8):

[0130] Steps (1) to (2) are the same as steps (1) to (2) in Example 7.

[0131] (3) Preparation of 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole:

[0132] To a single-necked flask, the intermediate 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl4 (0.63 mmol), and 20 mL of dichloromethane were added. Then, under stirring, 4-chlorobenzenethiol (3.15 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.56 g of a white solid with a melting point of 115.1-116.4°C and a yield of 75.53%.

[0133] Example 9: 2-(4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)benzo[d]oxazole (C9):

[0134] (1) Preparation of 2-(chloromethyl)benzo[d]oxazole:

[0135] 2-Aminophenol (36.65 mmol) and 2-chloro-1,1,1-trimethoxyethane (73.31 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 81.39%.

[0136] (2) Preparation of 4-(benzo[d]oxazol-2-ylmethoxy)-3-methoxybenzaldehyde:

[0137] To a three-necked flask, add 2-(chloromethyl)benzo[d]oxazole (13.13 mmol), 20 mL of DMF, KCO (32.82 mmol), and vanillin (15.75 mmol). The reaction system was heated to 40°C and stirred for 12 hours. TLC monitoring revealed that after complete reaction, the system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 56.47%.

[0138] (3) Preparation of 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)benzo[d]oxazole:

[0139] To a single-necked flask were added the intermediate 4-(benzo[d]oxazol-2-ylmethoxy)-3-methoxybenzaldehyde (1.59 mmol), ZrCl4 (0.80 mmol), and 20 mL of dichloromethane. Ethanethiol (3.97 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.51 g of a white solid with a melting point of 44.2-45.0°C and a yield of 82.42%.

[0140] Example 10: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole (C10):

[0141] Steps (1) to (2) are the same as steps (1) to (2) in Example 2.

[0142] (3) Preparation of 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole:

[0143] To a single-necked flask were added the intermediate 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane. Then, under stirring, 4-chlorobenzenethiol (3.36 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.60 g of a white solid with a melting point of 101.0-102.1°C and a yield of 78.44%.

[0144] Example 11: 2-(4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole (C11):

[0145] Steps (1) to (2) are the same as steps (1) to (2) in Example 2.

[0146] (3) Preparation of 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole:

[0147] To a single-necked flask were added the intermediate 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane. Ethanethiol (3.36 mmol) was then added to the reaction system with stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.35 g of a white solid with a melting point of 48.5-49.4°C and a yield of 64.46%.

[0148] Example 12: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole (C12):

[0149] Steps (1) to (2) are the same as steps (1) to (2) in Example 2.

[0150] (3) Preparation of 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-methylbenzo[d]oxazole:

[0151] To a single-necked flask, the intermediate 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane were added. Then, with stirring, 4-fluorothiophenol (3.36 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.63 g of a white solid with a melting point of 102.1-103.8°C and a yield of 87.42%.

[0152] Example 13: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole (C13):

[0153] (1) Preparation of 2-(chloromethyl)-5-fluorobenzo[d]oxazole:

[0154] 2-Amino-4-fluorophenol (31.47 mmol) and 2-chloro-1,1,1-trimethoxyethane (62.93 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 85.62%.

[0155] (2) Preparation of 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde:

[0156] To a three-necked flask, 2-(chloromethyl)-5-fluorobenzo[d]oxazole (11.85 mmol), 20 mL of DMF, KCO (29.64 mmol), and vanillin (14.23 mmol) were added. The reaction system was heated to 40°C and stirred for 12 hours. TLC monitoring revealed that the reaction was complete. The system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 58.80%.

[0157] (3) Preparation of 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole:

[0158] To a single-necked flask were added the intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl4 (0.66 mmol), and 20 mL of dichloromethane. Then, with stirring, 4-chlorothiophenol (3.32 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.55 g of a white solid with a melting point of 94.5-95.7°C and a yield of 72.36%.

[0159] Example 14: 2-(4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole (C14):

[0160] Steps (1) to (2) are the same as steps (1) to (2) in Example 13.

[0161] (3) Preparation of 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole:

[0162] To a single-necked flask were added the intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl4 (0.63 mmol), and 20 mL of dichloromethane. Ethanethiol (3.15 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.41 g of a white solid with a melting point of 39.4-40.0°C and a yield of 75.78%.

[0163] Example 15: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole (C15):

[0164] Steps (1) to (2) are the same as steps (1) to (2) in Example 13.

[0165] (3) Preparation of 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole:

[0166] To a single-necked flask, the intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.49 mmol), ZrCl4 (0.75 mmol), and 20 mL of dichloromethane were added. Then, with stirring, 4-fluorothiophenol (3.73 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.52 g of a white solid with a melting point of 85.1-86.4°C and a yield of 72.58%.

[0167] Example 16: 2-(4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole (C16):

[0168] (1) Preparation of 2-(chloromethyl)-6-fluorobenzo[d]oxazole:

[0169] 2-Amino-5-fluorophenol (29.89 mmol) and 2-chloro-1,1,1-trimethoxyethane (59.79 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 90.13%.

[0170] (2) Preparation of 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde:

[0171] To a three-necked flask, add 2-(chloromethyl)-6-fluorobenzo[d]oxazole (10.78 mmol), 20 mL of DMF, KCO (26.94 mmol), and vanillin (12.93 mmol). The reaction system was heated to 40°C and stirred for 12 hours. TLC monitoring revealed that the reaction was complete. The system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 61.60%.

[0172] (3) Preparation of 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole:

[0173] To a single-necked flask were added the intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl4 (0.63 mmol), and 20 mL of dichloromethane. Ethanethiol (3.32 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.50 g of a white solid with a melting point of 57.1-58.3°C and a yield of 92.41%.

[0174] Example 17: 2-(4-(isopropylthiomethyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole (C17):

[0175] Steps (1) to (2) are the same as steps (1) to (2) in Example 16.

[0176] (3) Preparation of 2-(4-(isopropylthiomethyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole:

[0177] To a single-necked flask were added the intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl4 (0.66 mmol), and 20 mL of dichloromethane. Isopropyl mercaptan (3.32 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.46 g of a white solid with a melting point of 48.2-50.0°C and a yield of 79.54%.

[0178] Example 18: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole (C18):

[0179] Steps (1) to (2) are the same as steps (1) to (2) in Example 16.

[0180] (3) Preparation of 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole:

[0181] To a single-necked flask, the intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl4 (0.66 mmol), and 20 mL of dichloromethane were added. Then, with stirring, 4-chlorothiophenol (3.32 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.57 g of a white solid with a melting point of 93.6-94.8°C and a yield of 74.99%.

[0182] Example 19: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole (C19):

[0183] Steps (1) to (2) are the same as steps (1) to (2) in Example 16.

[0184] (3) Preparation of 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-fluorobenzo[d]oxazole:

[0185] To a single-necked flask were added the intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.49 mmol), ZrCl4 (0.75 mmol), and 20 mL of dichloromethane. Then, with stirring, 4-fluorothiophenol (3.73 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.60 g of a white solid with a melting point of 87.8-89.1°C and a yield of 83.75%.

[0186] Example 20: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-fluorobenzo[d]oxazole (C20):

[0187] Steps (1) to (2) are the same as steps (1) to (2) in Example 13.

[0188] (3) Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl]-5-fluorobenzo[d]oxazole:

[0189] To a single-necked flask were added the intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl4 (0.66 mmol), and 20 mL of dichloromethane. Isopropyl mercaptan (3.32 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.43 g of a white solid with a melting point of 47.3-48.9°C and a yield of 74.35%.

[0190] Example 21: 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methylbenzo[d]oxazole (C21):

[0191] Steps (1) to (2) are the same as steps (1) to (2) in Example 9.

[0192] (3) Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methylbenzo[d]oxazole:

[0193] To a single-necked flask, the intermediate 4-(benzo[d]oxazol-2-ylmethoxy)-3-methoxybenzaldehyde (1.41 mmol), ZrCl4 (0.71 mmol), and 20 mL of dichloromethane were added. Isopropyl mercaptan (3.53 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.38 g of a white solid with a melting point of 43.5-44.1°C and a yield of 64.45%.

[0194] Example 22: 2-(4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)-6-chlorobenzo[d]oxazole (C22):

[0195] Steps (1) to (2) are the same as steps (1) to (2) in Example 4.

[0196] (3) Preparation of 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-6-chlorobenzo[d]oxazole:

[0197] To a single-necked flask were added the intermediate 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl4 (0.62 mmol), and 20 mL of dichloromethane. Ethanethiol (3.15 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.44 g of a white solid with a melting point of 56.3-57.8°C and a yield of 82.43%.

[0198] Example 23: 2-(4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole (C23):

[0199] Steps (1) to (2) are the same as steps (1) to (2) in Example 7.

[0200] (3) Preparation of 2-(4-(bis(ethylthiomethyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole:

[0201] To a single-necked flask were added the intermediate 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl4 (0.63 mmol), and 20 mL of dichloromethane. Ethanethiol (3.15 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.41 g of a white solid with a melting point of 52.6-53.8°C and a yield of 74.94%.

[0202] Example 24: 2-((4-(bis((4-fluorobenzyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole (C24):

[0203] Steps (1) to (2) are the same as steps (1) to (2) in Example 7.

[0204] (3) Preparation of 2-((4-(bis((4-fluorobenzyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-chlorobenzo[d]oxazole:

[0205] To a single-necked flask, the intermediate 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl4 (0.63 mmol), and 20 mL of dichloromethane were added. Then, with stirring, 4-fluorothiophenol (3.15 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.58 g of a white solid with a melting point of 107.2-108.6°C and a yield of 82.85%.

[0206] Example 25: 2-((4-(bis((4-fluorobenzyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole (C25):

[0207] Steps (1) to (2) are the same as steps (1) to (2) in Example 13.

[0208] (3) Preparation of 2-((4-(bis((4-fluorobenzyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-fluorobenzo[d]oxazole f:

[0209] To a single-necked flask, the intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl4 (0.66 mmol), and 20 mL of dichloromethane were added. Then, under stirring, 4-fluorothiophenol (3.32 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.44 g of a white solid with a melting point of 115.4-116.3°C and a yield of 61.42%.

[0210] Example 26: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-chlorobenzo[d]oxazole (C26):

[0211] Steps (1) to (2) are the same as steps (1) to (2) in Example 4.

[0212] (3) Preparation of 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-6-chlorobenzo[d]oxazole:

[0213] To a single-necked flask were added the intermediate 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl4 (0.63 mmol), and 20 mL of dichloromethane. Then, with stirring, 4-chlorothiophenol (3.15 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.60 g of a white solid with a melting point of 116.5-117.4°C and a yield of 80.92%.

[0214] Example 27: 2-((4-(bis(propylthio)methyl)-2-methoxyphenoxy)methyl ester)-6-fluorobenzo[d]oxazole (C27):

[0215] Steps (1) to (2) are the same as steps (1) to (2) in Example 16.

[0216] (3) Preparation of 2-((4-(bis(propylthio)methyl)-2-methoxyphenoxy)methyl ester)-6-fluorobenzo[d]oxazole:

[0217] To a single-necked flask were added the intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl4 (0.66 mmol), and 20 mL of dichloromethane. Propanethiol (3.32 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.41 g of a white solid with a melting point of 48.4-49.9°C and a yield of 70.91%.

[0218] Example 28: 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)methyl]-6-chlorobenzo[d]oxazole (C28):

[0219] Steps (1) to (2) are the same as steps (1) to (2) in Example 4.

[0220] (3) Preparation of 2-(4-(bis(propylthio)methyl)-2-methoxyphenoxy)methyl]-6-chlorobenzo[d]oxazole:

[0221] To a single-necked flask, the intermediate 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl4 (0.63 mmol), and 20 mL of dichloromethane were added. Propanethiol (3.15 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.48 g of a white solid with a melting point of 45.6-46.9°C and a yield of 84.35%.

[0222] Example 29: 2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole (C29):

[0223] Steps (1) to (2) are the same as steps (1) to (2) in Example 1.

[0224] (3) Preparation of 2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)methyl)-6-methylbenzo[d]oxazole:

[0225] To a single-necked flask were added the intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane. Tert-butyl mercaptan (3.36 mmol) was then added to the reaction system with stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.37 g of a white solid with a melting point of 64.2-65.1°C and a yield of 59.83%.

[0226] Example 30: 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole (C30):

[0227] (1) Preparation of 2-(chloromethyl)-4-methylbenzo[d]oxazole:

[0228] 2-Amino-3-methylphenol (32.48 mmol) and 2-chloro-1,1,1-trimethoxyethane (64.96 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 84.76%.

[0229] (2) Preparation of 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde:

[0230] To a three-necked flask, add 2-(chloromethyl)-4-methylbenzo[d]oxazole (11.01 mmol), 20 mL of DMF, KCO (27.53 mmol), and vanillin (13.21 mmol). The reaction system was heated to 40°C and stirred for 12 hours. TLC monitored the reaction. After the starting materials reacted completely, the system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 61.09%.

[0231] (3) Preparation of 2-((4-(bis(4-chlorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole:

[0232] To a single-necked flask, the intermediate 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane were added. Then, with stirring, 4-chlorothiophenol (3.36 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.49 g of a white solid with a melting point of 69.7-71.9°C and a yield of 64.60%.

[0233] Example 31: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole (C31):

[0234] Steps (1) to (2) are the same as steps (1) to (2) in Example 30.

[0235] (3): Preparation of 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole:

[0236] To a single-necked flask, the intermediate 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane were added. Then, with stirring, 4-fluorothiophenol (3.36 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.41 g of a white solid with a melting point of 79.1-80.4°C and a yield of 56.89%.

[0237] Example 32: 2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole (C32):

[0238] Steps (1) to (2) are the same as steps (1) to (2) in Example 30.

[0239] (3): Preparation of 2-(4-(bis(tert-butylthio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole:

[0240] To a single-necked flask were added the intermediate 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane. Tert-butyl mercaptan (3.36 mmol) was then added to the reaction system with stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.38 g of a white solid with a melting point of 59.2-61.4°C and a yield of 61.45%.

[0241] Example 33: 2-((4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl)-4-methylbenzo[d]oxazole (C33):

[0242] Steps (1) to (2) are the same as steps (1) to (2) in Example 30.

[0243] (3): Preparation of 2-(4-(bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl-4-methylbenzo[d]oxazole:

[0244] To a single-necked flask were added the intermediate 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl4 (0.67 mmol), and 20 mL of dichloromethane. Isopropyl mercaptan (3.36 mmol) was then added to the reaction system with stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to yield 0.43 g of a white solid with a melting point of 55.4-55.6°C and a yield of 74.05%.

[0245] Example 34: 2-((4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole (C34):

[0246] (1) Preparation of 5-bromo-2-(chloromethyl)benzo[d]oxazole:

[0247] 2-Amino-4-bromophenol (21.27 mmol) and 2-chloro-1,1,1-trimethoxyethane (42.55 mmol) were added to a three-necked flask and heated to 120°C for reaction. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by column chromatography to obtain a colorless oil in a yield of 95.35%.

[0248] (2) Preparation of 4-((5-bromobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde:

[0249] To a three-necked flask, add 5-bromo-2-(chloromethyl)benzo[d]oxazole (8.11 mmol), 20 mL of DMF, KCO (20.28 mmol), and vanillin (9.74 mmol). The reaction system was heated to 40°C and stirred for 12 hours. TLC monitoring revealed that after complete reaction, the system was poured into 100 mL of water, whereupon a large amount of gray solid precipitated. This was filtered and dried to obtain a gray solid in a yield of 68.06%.

[0250] (3) Preparation of 2-((4-(bisethylthiomethyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole:

[0251] To a single-necked flask, the intermediate 4-((5-bromobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.10 mmol), ZrCl4 (0.55 mmol), and 20 mL of dichloromethane were added. Ethanethiol (2.76 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.40 g of a white solid with a melting point of 59.7-61.1°C and a yield of 77.32%.

[0252] Example 35: 2-(4-bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole (C35):

[0253] Steps (1) to (2) are the same as steps (1) to (2) in Example 34.

[0254] (3) Preparation of 2-(4-bis(isopropylthio)methyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole:

[0255] To a single-necked flask, the intermediate 4-((5-bromobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.10 mmol), ZrCl4 (0.55 mmol), and 20 mL of dichloromethane were added. Isopropyl mercaptan (2.76 mmol) was then added to the reaction system under stirring. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to afford 0.43 g of a white solid in a yield of 78.42%.

[0256] Example 36: 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole (C36):

[0257] Steps (1) to (2) are the same as steps (1) to (2) in Example 34.

[0258] (3) Preparation of 2-((4-(bis(4-fluorophenyl)thio)methyl)-2-methoxyphenoxy)methyl)-5-bromobenzo[d]oxazole:

[0259] To a single-necked flask, the intermediate 4-((5-bromobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.10 mmol), ZrCl4 (0.55 mmol), and 20 mL of dichloromethane were added. Then, under stirring, 4-fluorothiophenol (2.76 mmol) was added to the reaction system. The reaction proceeded at room temperature and was monitored by TLC until completion. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.56 g of a white solid with a melting point of 112.5-113.8°C and a yield of 84.44%.

[0260] The physicochemical data of the compound are shown in Table 1.

[0261] Table 1. Physicochemical data of compounds of Examples C1-C36

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275] Bioassay Example 1: Determination of the biological activity of the target compound against cucumber green mottle mosaic virus (C GMMV).

[0276] The test compound was dissolved in DMSO and then diluted with 1% Tween 80 to obtain a 500 mg / L test compound solution. 50 When the concentration was 500, 250, 125, 62.5 and 31.25 mg / L, the solution of the compound to be tested was diluted.

[0277] (1) Testing of anti-CGMMV therapeutic activity

[0278] Select 5-6-leaf Amaranthaceae plants of similar growth. Remove the top and bottom leaves. Sprinkle diamond grit evenly over the entire plant. Apply the CGMMV virus solution with a brush. After 50 minutes, rinse the diamond grit with water. After drying, apply the target compound solution with a brush to the right side of the leaves. The plants are then incubated in an artificial climate chamber at 27°C and 65% humidity for 12 hours during the day and 25°C and 60% humidity for 12 hours at night. Each treatment is replicated three times. After 7 days, the number of necrotic spots is recorded, and the inhibition rate is calculated.

[0279] Inhibition rate (%) = [(number of blemishes in blank control - number of blemishes in drug treatment) / number of blemishes in blank control] × 100%

[0280] (2) Test of anti-CGMMV protective activity

[0281] Amaranthaceae plants at the 5-6 leaf stage, with similar growth, were selected. The top and bottom leaves were removed and the target compound solution was applied to the right side of all leaves using a brush. After 24 hours, diamond granules were evenly sprinkled over the leaves, and the CGMMV virus solution was applied to the entire plant using a brush. After 50 minutes, the diamond granules were rinsed with water. The plants were then incubated in an artificial climate chamber under conditions of 27°C and 65% humidity for 12 hours during the day and 25°C and 60% humidity for 12 hours at night. Each treatment was replicated three times. After 7 days, the number of necrotic spots was recorded, and the inhibition rate was calculated.

[0282] Inhibition rate (%) = [(number of blemishes in blank control - number of blemishes in drug treatment) / number of blemishes in blank control] × 100%

[0283] (3) Test of anti-CGMMV passivation activity

[0284] Select 5-6 leaf-stage Amaranthaceae plants with basically the same growth, remove the top and bottom leaves, sprinkle diamond sand evenly on the leaves of the whole plant, use a brush to dip CGMMV virus solution and compound solution in equal volumes and mix them for 30 minutes, then apply the mixture on the right side of the leaves of the whole plant, and use a brush to dip CGMMV virus solution diluted 2 times and apply it on the left side of the leaves of the whole plant. Rinse the silicon carbide with clean water after 50 minutes. Then place the plants in an artificial climate chamber for cultivation. The cultivation conditions are 27℃ and 65% humidity for 12 hours during the day and 25℃ and 60% humidity for 12 hours at night. Each treatment is repeated three times. After 7 days, the number of necrotic spots is recorded and the inhibition rate is calculated.

[0285] Table 1 Anti-CGMMV activity of target compounds C1-C36 at 500 μg / mL

[0286]

[0287]

[0288] a Average of three replicates. b Ningnanmycin was used as control agents.

[0289] The anti-CGMMV bioactivity of benzoxazole derivatives containing a dithioacetal structure was tested using the half-leaf spot assay with Chenopodium album as the necrotic host. Table 1 shows that the target compounds exhibited moderate bioactivity against CGMMV at a concentration of 500 μg / mL. Among them, the protective therapy, therapeutic activity and passivation activity of compounds C1, C8, C9, C23, C26, C29, C31, C33 and C35 against CGMMV were 56.9%, 58.9%, 61.6%, 53.0%, 51.2%, 58.4%, 53.6%, 56.7%, 67.9%, 49.9%, 51.1%, 59.2%, 62.3%, 54.5%, 59.4%, 62.9%, 56.1%, 56.6%, 62.9%, 48.0%, 53.8%, 49.0%, 51.4%, 55.6% and 56.1%, 62.5%, 59.3%, respectively, which were better than the control agent Ningnanmycin (39.2%, 23.4% and 44.5%).

[0290] Table 2 Anti-CGMMV bioactivity EC of target compounds C1-C36 50

[0291]

[0292] As shown in Table 2, the EC values of compounds C1 and C26 for protection, therapeutic activity and passivation activity against CGMMV 50 The values were: 326.21μg / mL, 284.94μg / mL, 222.63μg / mL and 156.19μg / mL, 271.09μg / mL, 183.35μg / mL, respectively, which were better than the control agent Ningnanmycin (872.44μg / mL, 1474.79μg / mL and 690.92μg / mL).

[0293] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Any simple modification, equivalent change and modification made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention shall still fall within the scope of the technical solution of the present invention.

Claims

1. A benzoxazole derivative containing a dithioacetal unit, characterized in that: The structural formula of the benzoxazole compound having a dithioacetal unit is as follows: wherein R1 and R2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, and 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.

2. A benzoxazole derivative containing a dithioacetal unit, characterized in that: Selected from the following compounds:

3. The method for preparing a benzoxazole derivative containing a dithioacetal unit according to claim 1 or 2, characterized in that: The process route of the preparation method includes:

4. The method for preparing a benzoxazole derivative containing a dithioacetal unit according to claim 1 or 2, characterized in that: The process route of the preparation method is:

5. A composition, characterized in that A benzoxazole derivative containing a dithioacetal unit according to claim 1 or 2, and an agriculturally useful adjuvant, fungicide, antiviral agent or herbicide.

6. A composition according to claim 5, characterized in that The dosage form of the composition is selected from emulsifiable concentrate, dust, wettable powder, granule, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion, and water-dispersible granule.

7. The benzoxazole derivative containing a dithioacetal unit according to claim 1 or 2, or the benzoxazole derivative containing a dithioacetal unit according to claim 3 or 4 Use of the derivatives prepared by the preparation method of oxazole derivatives or the composition according to claim 5 in preventing and controlling cucumber green mottle mosaic virus disease.

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