Benzoxazole derivative containing dithioacetal unit as well as preparation method and application of benzoxazole derivative

Abstract

The invention relates to a benzoxazole derivative containing a dithioacetal unit as well as a preparation method and application of the benzoxazole derivative. The compound disclosed by the invention has excellent antiviral activity on cucumber green mottle mosaic virus and the like, and can be used for medicines or medicaments for preventing and treating plant virus diseases such as cucumber green mottle mosaic disease and the like. The structure and the preparation process are simple, and the production cost is low; the benzoxazole derivative containing the dithioacetal unit comprises a benzoxazole compound with the dithioacetal unit, or a stereoisomer of the benzoxazole compound, or a salt of the benzoxazole compound or a solvate of the benzoxazole compound. Structural formula of benzoxazole compound with dithioacetal unit is as follows: # imgabs0 #

Description

Technical Field

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

[0002] Cucumber green mottle mosaic virus (CGMMV) is a member of the genus Tobamovirus. It was first reported by Ainsworth in 1935. It mainly infects Cucurbitaceae plants such as cucumber, melon, gourd, and watermelon, and is one of the most important diseases of Cucurbitaceae crops. CGMMV was first prevalent in England. It slowly spread to other countries and regions between 1935 and 1985. Its spread accelerated between 1986 and 2006. However, in the past 10 years (2007-2016), it has spread rapidly around the world and has become one of the main diseases of Cucurbitaceae crops such as cucumber. Many countries and regions have listed it as an important quarantine object. In 2006, CGMMV was identified as a national agricultural plant quarantine pest by the Ministry of Agriculture and Rural Affairs of my country, and is a national Class III quarantine disease. CGMMV is a single-stranded positive-sense RNA virus. Its genome is about 6400bp long, with a non-coding region at each end and four open reading frames (ORF) in the middle. The four open reading frames encode 17.3kDa coat protein (CP), 29kDa movement protein (MP), 129kDa and 186kDa replication proteins (RNA-dependent RNA Polymerase, RdRp). In the structure of the CGMMV genome, there is a 14-nucleotide overlap between RdRp and MP, and 26 nucleotides overlap between MP and CP. RdRp-RNA encodes replication protein RdRp (129kDa and 186kDa), which is closely related to viral replication and transcription. CP-RNA encodes coat protein CP (17.3kDa), which is an important structural subunit of the virus and has the function of preventing the destruction of viral nucleic acid. It can also participate in the long-distance transport of the virus. 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 dithioacetals using vanillin as raw material. The results of biological activity assays showed that compound 6f exhibited the best therapeutic and protective activity against PVY and CMV, and its effective concentration EC 50 They were 217.6 mg / L, 205.7 mg / L and 206.3 mg / L, 186.2 mg / L respectively, which were better than ribavirin (848.0 mg / L, 808.1 mg / L and 858.2 mg / L, 766.5 mg / L respectively), 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 strobilurin moiety. J. Agric. Food Chem. 2018, 66, 5335–5345.) from the applicant's team reported that the dithioacetal compound C14 containing methoxyacrylate had a good inhibitory effect on PVY, CMV and TMV. The protective activity was 148.4, 113.2 and 214.6 mg / L, respectively, and the therapeutic activity EC 50The concentrations of ribavirin and viravir were 125.3, 108.9 and 181.7 mg / L, respectively, which were significantly higher than those of acyclovir (652.7, 665.4, 653.4 mg / L and 677.4, 690.3, 686.5 mg / L, respectively), chitosan oligosaccharide (547.3, 570.6, 507.9 mg / L and 553.4, 582.8, 513.8 mg / L, respectively), ningnanmycin (425.3, 513.3, 242.7 mg / L and 440.5, 549.1, 373.8 mg / L, respectively) and compound 6f (281.5, 244.3, 546.3 mg / L and 297.6, 259.6, 582.4 mg / L, respectively).

[0005] In 2018, Xie Dandan et al. (Xie, DD; 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, and designed and synthesized a series of novel glycoside derivatives containing dithioacetal structures. The study targeted ToCV-CP and determined the binding constants of the compounds with ToCV-CP by MST. The MST results showed that the binding constants of compounds 6b and 8a with ToCV-CP were 0.12 and 0.21 μM, respectively, which were better than Ningnanmycin (0.26 μM) and Viravirin (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 Design, synthesis, and anti-ToCV activity of novel pyrimidine derivatives bearing a dithioacetal moiety that targets ToCV coat protein. J. Agric. Food Chem. 2020, 68, 6280–6285.) from the applicant's team used 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, and 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 with ToCVCP 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 better than Ningnanmycin (0.19μM) and Ribavirin (6.54μM). In addition, the in vivo pot experiment showed that compounds B13 and B23 could significantly reduce the expression of ToCV CP gene, which was better than 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, and designed and synthesized a series of novel dithioacetal derivatives containing 4(3H)-quinazolinone pyrimidine ring. This 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 vanillyl thioacetal (59.1μM). In addition, the half-leaf dead spot assay revealed that compound D32 exhibited excellent passivation 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 vanillylthiocarbazone (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-TSWV agents. 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. This study took TSWVN protein as the research object, and tested the binding constants of some compounds with TSWVN by MST. MST experiments showed that compound A33 exhibited excellent binding affinity with TSWVN, and its K d The value was 10.22 μM, which was better than the control drugs 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, and based on the principle of skeleton transition, introduced the active unit dithioacetal at the 4-position of coumarin to design and synthesize a series of novel coumarin derivatives containing dithioacetal structures. Taking 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 passivation 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), and 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 the 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 dithioacetal moiety. 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. This 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 by pot experiments. qPCR experiments showed that compounds C5 and C22 could significantly inhibit the expression of ToCV-CP gene, with the inhibition effects of 81.05 and 87.59%, respectively, which were better than the control agent Ningnanmycin (43.88%) and the lead compound vanillylthiocarbazone (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 therapeutic, protective and passivation activities of 63.0, 56.6 and 74.1%, respectively. Its protective activity and passivation EC 50 The values ​​were 252.8 and 113.5 μg / mL, respectively, which were comparable to those of ningnanmycin (284.8 and 144.7 μg / mL) and vanillylthiocarbamide (624.9 and 300.0 μg / mL).

[0012] In 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 used natural product flavonols as lead compounds to design and synthesize a series of novel flavonol derivatives containing benzoxazole structures, and tested the biological activity of the target compounds against TMV. 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 used natural product chalcone as the lead compound to design and synthesize a series of novel benzoxazole-containing chalcone derivatives, and tested the biological activity of the target compounds against TMV. 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 value was 104.05 μg / mL, which was better than the control drug Ningnanmycin (185.73 μg / mL). In addition, the binding ability of compounds Z15 and Z16 to TMV-CP was determined by MST. The MST results showed that the affinity of Z15 and Z16 to tobacco 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. Effect of morphoguanidine·copper acetate on cucumber green mottle mosaic virus disease. Zhejiang Agricultural Sciences, 2014, 12: 1860-1861.) used watermelon variety Zaojia 84-24 as test material to test the effect of 20% morphoguanidine·copper acetate wettable powder 500 times diluted on cucumber green mottle mosaic virus disease. The experimental results showed that if the spraying was continued for 3 times every 7 days, the control effect reached 83.4% 7 days after the third spraying.

[0015] In 2015, Li Junxiang et al. (Li Junxiang, Gu Qinsheng. Preliminary report on the experiment of four chemical inducers to control cucumber green mottle mosaic virus disease. Chinese Vegetables, 2015, 7: 40-44) in order to screen out the agents that can induce gourd to produce cucumber green mottle mosaic virus resistance, sprayed different concentrations of 2,1,3-benzothiadiazole, brassinolide, chitosan and salicylic acid on gourd seedlings, and then inoculated CGMMV by friction. The results showed that 2,1,3-benzothiadiazole, brassinolide, chitosan and salicylic acid can induce gourd to produce resistance to CGMMV.

[0016] In summary, the dithioacetal structure is a new type of 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 with dithioacetal structures or benzoxazole compounds. In addition, CGMMV is hidden and persistent in seeds and other propagation materials, and its transmission routes are diverse, and there is a lack of effective anti-CGMMV agents. For this reason, the introduction of dithioacetal units into the benzoxazole parent structure has the significance and value of further carrying out pesticide research and development. Summary of the invention

[0017] One of the purposes of the present invention is to provide a benzoxazole derivative containing a dithioacetal unit and 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 derivatives or the composition in preventing and controlling agricultural viral diseases.

[0021] To achieve the above object, 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 compounds having dithioacetal units is as follows:

[0023]

[0024] Among them, R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, phenyl, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl;

[0025] R 3 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, R 1 and R 2 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, propyl;

[0027] R 3 independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, sec-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 CH 2 OH, -CH 2 OH, -CH 2 CH 2 CH 2 OH, 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, which contains the benzoxazole derivative containing dithioacetal unit and an adjuvant or fungicide, antiviral agent or herbicide applicable to agriculture.

[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 concentrate (FU), emulsion in water (EW), water dispersible granule (WG).

[0073] The application of the benzoxazole derivative containing dithioacetal unit 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 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 Y virus disease.

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

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

[0079] The term "alkyl" as used herein includes both branched and straight chain saturated hydrocarbon groups having a specified number of carbon atoms. 1-10 "alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, for example, "C 1-6 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (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 or 7, 8, 9, 10, 11, 12 or 13-membered bi- or tricyclic ring, which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of these carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As described above, bridged rings are also included in the definition of carbocycles (such as [2.2.2]bicyclooctane). If not otherwise specified, preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, substituents on the ring may also be present on the bridge.

[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 invention have the characteristics of novel structure, simple preparation process, low production cost, high yield and good antiviral activity, and especially have 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 graph showing the protective activity of compounds C26, C27, C28, C29 and C36 and Ningnanmycin against cucumber green mottle mosaic virus at a 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 graph 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 described below by way of examples. It should be understood that the methods described in the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, and simple improvements to the preparation methods of the present invention under the premise of the concept of the present invention belong to the scope of protection claimed in the present invention. All raw materials and solvents used in the examples are commercially available reagents of corresponding purity.

[0089] Example 1: 2-(4-(bis(ethylthio)methyl)-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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 67.81%.

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

[0093] 2-(Chloromethyl)-6-methylbenzo[d]oxazole (8.26 mmol), 20 mL of DMF, and K 2 CO 3 (20.65mmol) and vanillin (9.91mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 81.45%.

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

[0095] The intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4(0.7mmol) and 20mL dichloromethane, then add ethanethiol (3.36mmol) to the reaction system under stirring. The reaction is carried out at room temperature and monitored by TLC until the reaction is completed. Extract with dichloromethane, separate and purify the crude product by column chromatography to obtain 0.31g of white solid, melting point 50.2-51.4℃, yield 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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 73.97%.

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

[0100] 2-(Chloromethyl)-5-methylbenzo[d]oxazole (11.01 mmol), 20 mL of DMF, and K 2 CO 3 (27.53mmol) and vanillin (13.21mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 61.09%.

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

[0102] The intermediate 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.51 mmol), ZrCl 4 (0.75mmol) and 20mL of dichloromethane, then under stirring, isopropyl mercaptan (3.78mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.46g 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] The intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.18 mmol), ZrCl 4 (0.58mmol) and 20mL of dichloromethane, then under stirring, isopropyl mercaptan (2.94mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.41g 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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 85.27%.

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

[0111] 6-Chloro-2-(chloromethyl)benzo[d]oxazole (9.90 mmol), 20 mL of DMF, and K 2 CO 3 (24.75mmol) and vanillin (11.88mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 63.59%.

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

[0113] The intermediate 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.10 mmol), ZrCl 4 (0.55mmol) and 20mL of dichloromethane, then under stirring, isopropyl mercaptan (2.75mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.36g 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] The intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4 (0.67mmol) and 20mL of dichloromethane, then 4-fluorothiophenol (3.36mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.67g 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] The intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.51 mmol), ZrCl4 (0.75mmol) and 20mL of dichloromethane, then 4-chlorothiophenol (3.78mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.46g 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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 78.96%.

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

[0126] 5-Chloro-2-(chloromethyl)benzo[d]oxazole (10.89 mmol), 20 mL DMF, and K 2 CO 3 (27.22mmol) and vanillin (13.07mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 60.70%.

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

[0128] The intermediate 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.42 mmol), ZrCl 4 (0.70mmol) and 20mL of dichloromethane, then under stirring, isopropyl mercaptan (3.54mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.53g 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] The intermediate 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl 4 (0.63mmol) and 20mL of dichloromethane, then, under stirring, 4-chlorobenzenethiol (3.15mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.56g 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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 81.39%.

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

[0137] 2-(Chloromethyl)benzo[d]oxazole (13.13 mmol), 20 mL DMF, and K 2 CO 3 (32.82mmol) and vanillin (15.75mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 56.47%.

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

[0139] The intermediate 4-(benzo[d]oxazol-2-ylmethoxy)-3-methoxybenzaldehyde (1.59 mmol), ZrCl 4 (0.80mmol) and 20mL of dichloromethane, then ethanethiol (3.97mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.51g 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] The intermediate 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4 (0.67mmol) and 20mL of dichloromethane, then, under stirring, 4-chlorobenzenethiol (3.36mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.60g 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] The intermediate 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4(0.67mmol) and 20mL of dichloromethane, then ethanethiol (3.36mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and purified by column chromatography to obtain 0.35g 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] The intermediate 3-methoxy-4-((5-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4 (0.67mmol) and 20mL of dichloromethane, then 4-fluorothiophenol (3.36mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.63g 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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 85.62%.

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

[0156] 2-(Chloromethyl)-5-fluorobenzo[d]oxazole (11.85 mmol), 20 mL DMF, K 2 CO3 (29.64mmol) and vanillin (14.23mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 58.80%.

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

[0158] The intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl 4 (0.66mmol) and 20mL of dichloromethane, then 4-chlorothiophenol (3.32mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.55g 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] The intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl 4 (0.63mmol) and 20mL of dichloromethane, then ethanethiol (3.15mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.41g 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] The intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.49 mmol), ZrCl 4 (0.75mmol) and 20mL of dichloromethane, then 4-fluorothiophenol (3.73mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.52g 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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 90.13%.

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

[0171] 2-(Chloromethyl)-6-fluorobenzo[d]oxazole (10.78 mmol), 20 mL of DMF, and K 2 CO 3 (26.94mmol) and vanillin (12.93mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 61.60%.

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

[0173] The intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl 4(0.63mmol) and 20mL of dichloromethane, then ethanethiol (3.32mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.50g 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] The intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl 4 (0.66mmol) and 20mL of dichloromethane, then under stirring, isopropyl mercaptan (3.32mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.46g 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] The intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl 4 (0.66mmol) and 20mL of dichloromethane, then 4-chlorothiophenol (3.32mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.57g 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] The intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.49 mmol), ZrCl 4 (0.75mmol) and 20mL of dichloromethane, then 4-fluorobenzenethiol (3.73mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.60g 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] The intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl 4 (0.66mmol) and 20mL of dichloromethane, then under stirring, isopropyl mercaptan (3.32mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.43g 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] The intermediate 4-(benzo[d]oxazol-2-ylmethoxy)-3-methoxybenzaldehyde (1.41 mmol), ZrCl 4 (0.71mmol) and 20mL dichloromethane, then under stirring, isopropyl mercaptan (3.53mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.38g 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] The intermediate 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl 4 (0.62mmol) and 20mL dichloromethane, then add ethanethiol (3.15mmol) to the reaction system under stirring. The reaction is carried out at room temperature and monitored by TLC until the reaction is completed. Extract with dichloromethane, separate and purify the crude product by column chromatography to obtain 0.44g of white solid, melting point 56.3-57.8℃, yield 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] The intermediate 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl 4(0.63mmol) and 20mL dichloromethane, then add ethanethiol (3.15mmol) to the reaction system under stirring. The reaction is carried out at room temperature and monitored by TLC until the reaction is completed. Extract with dichloromethane, separate and purify the crude product by column chromatography to obtain 0.41g of white solid, melting point 52.6-53.8℃, yield 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] The intermediate 4-((5-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl 4 (0.63mmol) and 20mL of dichloromethane, then 4-fluorothiophenol (3.15mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.58g 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] The intermediate 4-((5-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl 4 (0.66mmol) and 20mL of dichloromethane, then 4-fluorothiophenol (3.32mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.44g 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] The intermediate 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl 4 (0.63mmol) and 20mL of dichloromethane, then 4-chlorothiophenol (3.15mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.60g 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] The intermediate 4-((6-fluorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.33 mmol), ZrCl 4 (0.66mmol) and 20mL of dichloromethane, then, under stirring, propylthiol (3.32mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.41g 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] The intermediate 4-((6-chlorobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.26 mmol), ZrCl 4 (0.63mmol) and 20mL of dichloromethane, then, under stirring, propylthiol (3.15mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.48g 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] The intermediate 3-methoxy-4-((6-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4 (0.67mmol) and 20mL of dichloromethane, then tert-butyl mercaptan (3.36mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.37g 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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 84.76%.

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

[0230] 2-(Chloromethyl)-4-methylbenzo[d]oxazole (11.01 mmol), 20 mL of DMF, and K 2 CO 3 (27.53mmol) and vanillin (13.21mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 61.09%.

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

[0232] The intermediate 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4 (0.67mmol) and 20mL of dichloromethane, then 4-chlorothiophenol (3.36mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.49g 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] The intermediate 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4(0.67mmol) and 20mL of dichloromethane, then 4-fluorobenzenethiol (3.36mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.41g 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] The intermediate 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4 (0.67mmol) and 20mL of dichloromethane, then, under stirring, tert-butyl mercaptan (3.36mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.38g 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] The intermediate 3-methoxy-4-((4-methylbenzo[d]oxazol-2-yl)methoxy)benzaldehyde (1.35 mmol), ZrCl 4 (0.67mmol) and 20mL of dichloromethane, then under stirring, isopropyl mercaptan (3.36mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.43g 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. The reaction was monitored by TLC until completion, extracted with ethyl acetate and washed with saturated brine, and the crude product was separated and purified by column chromatography to obtain a colorless oil with a yield of 95.35%.

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

[0249] 5-Bromo-2-(chloromethyl)benzo[d]oxazole (8.11 mmol), 20 mL of DMF, and K 2 CO 3 (20.28mmol) and vanillin (9.74mmol), the reaction system was heated to 40°C and stirred for 12h. The reaction system was monitored by TLC. After the reaction of the raw materials was complete, the system was poured into 100mL of water, and a large amount of gray solid was precipitated. It was filtered and dried to obtain a gray solid with a yield of 68.06%.

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

[0251] The intermediate 4-((5-bromobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.10 mmol), ZrCl 4 (0.55mmol) and 20mL of dichloromethane, then ethanethiol (2.76mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.40g 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] The intermediate 4-((5-bromobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.10 mmol), ZrCl 4 (0.55mmol) and 20mL of dichloromethane, then under stirring, isopropyl mercaptan (2.76mmol) was added to the reaction system. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.43g of a white solid with 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] The intermediate 4-((5-bromobenzo[d]oxazol-2-yl)methoxy)-3-methoxybenzaldehyde (1.10 mmol), ZrCl 4 (0.55mmol) and 20mL of dichloromethane, then 4-fluorothiophenol (2.76mmol) was added to the reaction system under stirring. The reaction was carried out at room temperature and monitored by TLC until the reaction was completed. The crude product was extracted with dichloromethane and separated and purified by column chromatography to obtain 0.56g 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 diluted, the solution of the test compound was obtained at a concentration of 500, 250, 125, 62.5 and 31.25 mg / L.

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

[0278] Select 5-6 leaf-stage Amaranthaceae 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 brush it on the leaves of the whole plant, rinse the diamond sand with clean water after 50 minutes, dry it and use a brush to dip the target compound solution and brush it on the right side of the leaves of the whole plant. Then place the plants in an artificial climate chamber for cultivation, the cultivation conditions are 27℃, 65% humidity for 12 hours during the day and 25℃, 60% humidity for 12 hours at night, each treatment is repeated three times, the number of dead spots is recorded after 7 days, and the inhibition rate is calculated.

[0279] Inhibition rate (%) = [(number of necrotic spots in blank control - number of necrotic spots treated with drug) / number of necrotic spots in blank control] × 100%

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

[0281] Select 5-6 leaf amaranths with basically the same growth, remove the top and bottom leaves, and apply the target compound solution to the right side of the leaves of the whole plant with a brush. After 24 hours, sprinkle diamond sand evenly on the leaves of the whole plant, and use a brush to apply CGMMV virus solution to the leaves of the whole plant. After 50 minutes, rinse the diamond sand with clean water, and then place the plants in an artificial climate chamber for cultivation. The cultivation conditions are 27℃, 65% humidity for 12 hours during the day and 25℃, 60% humidity for 12 hours at night. Each treatment is repeated three times. After 7 days, the number of dead spots is recorded and the inhibition rate is calculated.

[0282] Inhibition rate (%) = [(number of necrotic spots in blank control - number of necrotic spots treated with drug) / number of necrotic spots 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 CGMMV virus solution diluted 2 times to apply it on the left side of the leaves of the whole plant. After 50 minutes, rinse the silicon carbide with clean water. Then place the plants in an artificial climate chamber for culture. The culture conditions are 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 repeated three times. After 7 days, the number of dead 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] Chenopodium album was used as the necrosis host, and the half-leaf necrosis method was used to test the anti-CGMMV biological activity of benzoxazole derivatives containing dithioacetal structure. As shown in Table 1, when the target compound was at a concentration of 500 μg / mL, the target compound had a certain biological activity against CGMMV. Among them, the protective treatment, 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%, 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 only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still falls within the scope of the technical solution of the present invention.

Claims

1. A benzoxazole derivative containing a dithioacetal unit, characterized in that: The invention comprises a benzoxazole compound having a dithioacetal unit, or a stereoisomer thereof, or a salt thereof, or a solvate thereof; 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, halogen, nitro, hydroxyl, amino, thiol, phenyl, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl; R3 is independently selected from optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted hydroxyalkyl, and optionally substituted or unsubstituted aryl.

2. A benzoxazole derivative containing a dithioacetal unit according to claim 1, 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.

3. A benzoxazole derivative containing a dithioacetal unit according to claim 1, characterized in that: Selected from the following compounds:

4. The method for preparing a benzoxazole derivative containing a dithioacetal unit according to any one of claims 1 to 3, characterized in that: The process route of the preparation method comprises:

5. The method for preparing a benzoxazole derivative containing a dithioacetal unit according to any one of claims 1 to 3, characterized in that: The process route of the preparation method is: 。 6. A composition, characterized in that A benzoxazole derivative containing a dithioacetal unit according to any one of claims 1 to 3, and an agriculturally usable adjuvant or fungicide, antiviral agent or herbicide.

7. A composition according to claim 6, 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.

8. Use of the benzoxazole derivative containing a dithioacetal unit according to any one of claims 1 to 3, or the derivative prepared by the method for preparing a benzoxazole derivative containing a dithioacetal unit according to claim 4, or the composition according to claim 6 in preventing and controlling agricultural pests and diseases.

9. Use of the benzoxazole derivative containing a dithioacetal unit according to any one of claims 1 to 3, or the derivative prepared by the preparation method of the benzoxazole derivative containing a dithioacetal unit according to claim 4, or the composition according to claim 6 in preventing and controlling agricultural viral diseases.

10. The use according to claim 9, characterized in that The agricultural virus diseases are cucumber green mottle mosaic virus disease, cucumber mosaic virus disease and potato Y virus disease.

Images