Coumarin derivative containing dithioacetal unit as well as preparation method and application of coumarin derivative

Abstract

The invention relates to a coumarin derivative containing a dithioacetal unit as well as a preparation method and application of the coumarin derivative. The compound disclosed by the invention has excellent antiviral activity on cucumber mosaic virus and the like, can be used for preparing medicines or medicaments for preventing and treating plant virus diseases such as cucumber mosaic virus and the like, and is simple in structure and preparation process. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of chemical industry and pesticides, and in particular to a coumarin derivative containing a dithioacetal unit, a preparation method of the coumarin derivative containing a dithioacetal unit, and use of the coumarin derivative in preparing a drug for preventing and treating plant viral diseases. Background Art

[0002] Plant virus diseases are a major disease in agricultural production and are known as "plant cancer". The most common plant virus diseases include cucumber mosaic virus (CMV), tobacco mosaic virus (TMV), potato virus X (PVX), tomato yellow leaf curl virus (TYLCV), rice stripe virus (RSV), southern rice black-streaked dwarf virus (SRBSDV), rice black-streaked dwarf disease (RBSDV), rice ragged dwarf virus (RRSV) and maize rough dwarf virus (MRDV). Among them, cucumber mosaic virus (CMV) belongs to the genus Cucumovirus of the family Bromoviridae. It has a wide host range and can infect more than 1,200 plant species, including important economic crops such as cucumber, watermelon, tomato, pepper, etc. The disease caused by this virus can cause symptoms such as leaf yellowing, wrinkling, mosaic, and plant dwarfing, which seriously affect the yield and quality of crops. Because viruses are absolutely parasitic in plants and lack a complete immune metabolic system, coupled with the lack of highly effective anti-plant virus agents, the prevention and control of plant viral diseases is relatively difficult, causing huge economic losses to agricultural production. In addition, considering problems such as environmental pollution and pesticide residues, there is an urgent need to develop an effective and green prevention and control drug.

[0003] Coumarin is widely distributed in nature and belongs to the benzopyrone class. It consists of a benzene ring connected to a pyrone core. It has a small molecular weight and is relatively simple to synthesize. It also has a wide range of pharmacological characteristics. It is considered to be a promising class of biologically active heterocyclic compounds with antibacterial, insecticidal and antiviral activities.

[0004] In 2017, Hu Qiufen et al. (Hu, QF; Xing, HH; Wang, YD; Yu, ZH; Yan, KL; Zhou, K.; Dong, W.; Zhou, M.; Yang, HY; Zhu, DL; Du, G. Prenylated isocoumarins from the fermentation products of the endophytic fungus aspergillus versicolor and their anti-tobacco mosaic virus activities [J]. Chem. Nat. Compd. 2017, 53, 436-439.) isolated two new prenylated isocoumarins from the fermentation products of the endophytic fungus Aspergillus versicololor, and their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Their anti-tobacco mosaic virus activity was evaluated. The results showed that the compound had moderate anti-TMV activity.

[0005] In 2020, Chen Yahan et al. (Chen, Y.; Guo, D.; Lu, M.; Yue, J.; Liu, Y.; Shang, C.; An, D.; Zhao, M. Inhibitory effect of osthole from cnidium monnieri on tobacco mosaic virus (TMV) infection in nicotiana glutinosa [J]. Molecules 2020, 25, 65.) extracted the coumarin compound osthole from Cnidium monnieri. The antiviral activity of osthole against tobacco mosaic virus (TMV) was determined by the half-leaf spot method. The results showed that the antiviral activity of osthole against TMV infection was stronger than that of eugenol and ningnanmycin, with passivation, protection and therapeutic effects of 72.57%, 70.26% and 61.97%, respectively. Through the observation of TMV particles, we found that osthole can directly affect viral particles. Correspondingly, when the concentration of osthole in the test plants increased, the coat protein level detected by Western blot was significantly reduced compared with the control. These results indicate that osthole has anti-TMV activity and can be used as a biological agent for controlling plant viruses by the semi-leaf method.

[0006] In 2021, Wang Qingmin et al. (Wang Qingmin, Song Hongjian, Guo Zhonglin, Liu Yuxiu, Zhang Jingjing, Li Yongqiang. Application of coumarin derivatives in preventing and controlling plant viruses, sterilization and insecticide [P]. CN113016806A.2021.) published a patent for coumarin derivatives. Most coumarin compounds have inhibitory effects on tobacco mosaic virus. Among them, the compounds showed excellent anti-TMV activity in three models of in vivo passivation, treatment and protection, which was comparable to the effect of the commercial drug ribavirin.

[0007] In 2021, Fan Zhijin et al. (Fan Zhijin, Lv You, Wang Lifan, Li Kun, Hao Zesheng, Zhang Nailou, Wang Weibo, Liu Xiaoyu, Shang Wei, Tang Liangfu. A class of coumarin derivatives containing 3,4-dichloroisothiazole and their preparation methods and uses [P]. CN112480103 A.2021.) introduced 3,4-dichloroisothiazole heterocycle into the lead structure of coumarin, designed and synthesized a class of 4-position 3,4-dichloroisothiazole heterocycle 7- or 5-hydroxy coumarin derivatives, and carried out systematic screening and evaluation of biological activity. The coumarin derivatives containing 3,4-dichloroisothiazole are combined with any one or two of the antiviral agents to form an antiviral composition for preventing and controlling viral diseases of agricultural, forestry and horticultural plants; rice dwarf disease, stripe leaf blight, yellow dwarf disease, pepper mosaic virus disease, tomato fern leaf virus disease, corn dwarf mosaic disease, tobacco vein necrosis virus disease, Jianlan orchid leaf virus, cauliflower mosaic virus, Jianlan ringspot virus, citrus virus disease and other viruses.

[0008] In 2021, Wang Qingmin et al. (Guo, ZL; Zhou, P.; Song, HJ; Liu, Y.; Zhang, JJ; Li, YQ; Wang, QM Design, synthesis, and bioactivities of phthalide and coumarinderivatives based on the biosynthesis and structure simplification of gossypol [J]. J. Agric. Food Chem. 2021, 69, 15123-15135.) designed and synthesized a series of phthalide and coumarin derivatives with simpler structures. The results of biological activity bioassays showed that the target compounds of these two series had good activity against tobacco mosaic virus, which was better than the commercial antiviral agent ningnanmycin at the same dose. Therefore, this compound is a promising candidate for the development of new antiviral agents for plants.

[0009] In summary, coumarin compounds are widely present in many plants in nature and have a broad spectrum of biological activities. In pesticide chemistry research, coumarin structures are often used as carriers of various pharmacophores, but at present, coumarin compounds are rarely used in anti-plant viruses, and their application and research in anti-cucumber mosaic virus are even less. Therefore, it is of great significance to fill the gap in the application of coumarin compounds in anti-cucumber mosaic virus.

[0010] The dithioacetal active unit usually has strong biological activity, can effectively inhibit the replication and spread of plant viruses, and also has inhibitory effects on a variety of plant viruses. It can provide a wide range of protective effects and is suitable for a variety of crops and virus types. In addition, dithioacetal compounds can reduce the risk of viruses developing drug resistance and have low toxicity to non-target organisms (such as beneficial insects, animals and humans), which is in line with the development trend of green pesticides.

[0011] In 2017, Zhang Jian et al. (Zhang, J.; Zhao, L.; Zhu, C.; Wu, ZX; Zhang, GP; Gan, XH; Liu, DY; Pan, JK; Hu, DY; Song, B.A.) from our team reported a series of vanillin derivatives containing dithioacetals using vanillin as raw material. The results of biological activity assays showed that most compounds showed the best therapeutic and protective activities against PVY and CMV, exceeding those of the control drugs. Among them, the optimal compound showed the best therapeutic and protective activities 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, all better than ningnanmycin (440.5 mg / L, 425.3 mg / L and 426.1 mg / L, 405.3 mg / L respectively) and ribavirin (848.0 mg / L, 808.1 mg / L and 858.2 mg / L, 766.5 mg / L respectively).

[0012] In 2018, Chen Jin et al. (Chen, J.; Shi, J.; Yu, L.; Liu, DY; Gan, XH; Song, BA; Hu, DY Design, synthesis, antiviral bioactivity, and defense mechanisms of novel dithioacetal derivatives bearing a strobilurin moiety [J]. J. Agric. Food Chem. 2018, 66, 5335–5345.) from our team reported dithioacetal compounds containing methoxyacrylates, most of which showed good activity against PVY, CMV and TMV, all exceeding the control drug. The optimal compound has a good inhibitory effect on PVY, CMV and TMV. The protective activities were 148.4, 113.2 and 214.6 mg / L, respectively, and the therapeutic activity EC 50 They were 125.3, 108.9 and 181.7 mg / L respectively, which were significantly higher than ningnanmycin (425.3, 513.3, 242.7 mg / L and 440.5, 549.1, 373.8 mg / L respectively), ribavirin (652.7, 665.4, 653.4 mg / L and 677.4, 690.3, 686.5 mg / L respectively) and chitosan oligosaccharide (547.3, 570.6, 507.9 mg / L and 553.4, 582.8, 513.8 mg / L respectively).

[0013] In summary, dithioacetals have been widely used by our team in the creation of agricultural antiviral agents in recent years, and all have excellent biological activity. At the same time, a large number of derivatives have been carried out, but their application in the coumarin structure has not been seen. Therefore, it is meaningful to introduce the dithioacetal active unit into the coumarin structure, design and synthesize coumarin derivatives containing dithioacetals, and study their antiviral activity. Summary of the invention

[0014] One of the purposes of the present invention is to provide the coumarin derivative containing dithioacetal unit and a preparation method thereof.

[0015] A second object of the present invention is to provide a composition of the above-mentioned coumarin derivatives containing dithioacetal units.

[0016] Another object of the present invention is to provide the above-mentioned coumarin derivative containing dithioacetal unit, or the use of the composition.

[0017] Another object of the present invention is to provide a method for preventing and controlling agricultural viral diseases using the above-mentioned coumarin derivatives containing dithioacetal units, or the composition, specifically allowing the coumarin derivatives containing dithioacetal units, or the composition to act on harmful substances or their living environment. More specifically, the method steps of contacting the pests with the coumarin derivatives containing dithioacetal units or the composition.

[0018] Another object of the present invention is to provide a mechanism of action for preventing and treating viral diseases using the above-mentioned compound or its stereoisomer, or its salt or solvate, or the composition.

[0019] The purpose of the present invention and the solution of its main technical problems are achieved by adopting the following technical solutions:

[0020] The coumarin derivative containing a dithioacetal unit of the present invention is a compound having a structure as shown in formula (I) or a stereoisomer thereof, or a salt thereof or a solvate thereof:

[0021]

[0022] Where:

[0023] R 1 and R 2 Each is independently selected from one or more of hydrogen, deuterium, halogen, nitro, hydroxyl, amino, thiol, phenyl, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl;

[0024] R 3 is independently selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;

[0025] R 4 Independently selected from one or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.

[0026] Preferably, R 4 Independently selected from methyl, ethyl, n-propyl, sec-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2OH, -CH2CH2CH2OH, phenyl, benzyl.

[0027] Preferred specific compounds are as follows:

[0028] Compound D1: (E)-methyl 2-(2-(((8-(bis(ethylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate;

[0029] Compound D2: (E)-methyl 2-(2-(((8-(bis(propylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0030] Compound D3: (E)-methyl 2-(2-(((8-(bis(butylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate;

[0031] Compound D4: (E)-methyl 2-(2-(((8-(bis(cyclohexylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0032] Compound D5: methyl (E)-2-(2-(((8-(1,3-disulfan-2-yl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0033] Compound D6: (E)-methyl 2-(2-(((8-(bis(isopropylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0034] Compound D7: methyl (E)-2-(2-(((8-(bis(tert-butylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0035] Compound D8: (E)-methyl 2-(2-(((8-(bis(ethylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate;

[0036] Compound D9: (E)-methyl 2-(2-(((8-(bis(propylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0037] Compound D10: (E)-methyl 2-(2-(((8-(bis(butylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate;

[0038] Compound D11: (E)-methyl 2-(2-(((8-(bis(cyclohexylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0039] Compound D12: methyl (E)-2-(2-(((8-(1,3-disulfan-2-yl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0040] Compound D13: methyl (E)-2-(2-(((8-(bis(isopropylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0041] Compound D14: methyl (E)-2-(2-(((8-(bis(tert-butylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0042] Compound D15: (E)-2-(2-(((8-(bis(ethylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate;

[0043] Compound D16: (E)-methyl 2-(2-(((8-(bis(propylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0044] Compound D17: (E)-2-(2-(((8-(bis(butylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate;

[0045] Compound D18: (E)-methyl 2-(2-(((8-(bis(cyclohexylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0046] Compound D19: methyl (E)-2-(2-(((8-(1,3-disulfan-2-yl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0047] Compound D20: (E)-methyl 2-(2-(((8-(bis(isopropylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0048] Compound D21: (E)-methyl 2-(2-(((8-(bis(tert-butylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0049] Compound D22: (E)-2-(2-(((8-(bis(ethylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate;

[0050] Compound D23: (E)-methyl 2-(2-(((8-(bis(propylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0051] Compound D24: (E)-2-(2-(((8-(bis(butylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate;

[0052] Compound D25: (E)-methyl 2-(2-(((8-(bis(cyclohexylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0053] Compound D26: methyl (E)-2-(2-(((8-(1,3-disulfan-2-yl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0054] Compound D27: (E)-methyl 2-(2-(((8-(bis(isopropylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0055] Compound D28: (E)-methyl 2-(2-(((8-(bis(tert-butylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate;

[0056] Compound D29: methyl (E)-2-(2-(((8-(bis((4-chlorophenyl)thio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0057] Compound D30: (E)-methyl 2-(2-(((8-(bis((2,4-dichlorophenyl)thio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0058] Compound D31: (E)-methyl 2-(2-(((8-(bis((4-fluorophenyl)thio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate;

[0059] Compound D32: (E)-methyl 2-(2-(((8-(bis(p-tolyl)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate;

[0060] Compound D33: (E)-methyl 2-(2-(((8-(bis(benzylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate;

[0061] Compound D34: methyl (E)-2-(2-(((8-(bis((4-methoxyphenyl)thio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate.

[0062] The present invention provides a method for preparing a coumarin derivative containing a dithioacetal unit, and the synthesis route is as follows:

[0063]

[0064] Further as follows:

[0065]

[0066] The preferred synthetic route is as follows:

[0067]

[0068] The present invention also provides a composition, which contains the coumarin derivative containing a dithioacetal unit, and an adjuvant or fungicide, antiviral agent or herbicide available in agriculture; 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).

[0069] The invention provides a coumarin derivative containing a dithioacetal unit, or use of a composition thereof in preparing a drug for preventing and treating agricultural viral diseases.

[0070] Preferably, the agricultural viral disease is cucumber mosaic virus disease.

[0071] 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.

[0072] 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.

[0073] "Alkenyl" is a hydrocarbon group that includes both straight and branched structures and has one or more carbon-carbon double bonds occurring at any stable point in the chain. For example, "C 2-6 "Alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.

[0074] 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.

[0075] The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine and iodine.

[0076] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11 to 14-membered tricyclic groups, having at least one heteroatom (O, S or N) in at least one ring, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms and / or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the nitrogen and other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom in any ring. If the other ring is a cycloalkyl or heterocycle, it is additionally optionally substituted with =0 (oxygen) when valence permits.

[0077] Compared with the prior art, the present invention has the following significant beneficial effects: the present invention uses the natural product coumarin as a leading raw material to synthesize a series of compounds that retain coumarin and contain a dithioacetal structure. The synthetic route of the present invention can obtain a higher reaction yield, and the derivatives of the present invention have good therapeutic, protective and passivating effects on CMV, and the structure and preparation process are simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 The results of the anti-CMV therapeutic activity of compound D3 and Ningnanmycin at a concentration of 500 μg / mL, wherein the left figure is the D3 treatment group and the right figure is the Ningnanmycin treatment group;

[0079] Figure 2 The results of the anti-CMV protective activity of compound D3 and Ningnanmycin at a concentration of 500 μg / mL, wherein the left figure is the D3 protection group and the right figure is the Ningnanmycin protection group;

[0080] Figure 3 The results of the anti-CMV passivation activity of compound D3 and Ningnanmycin at a concentration of 500 μg / mL, where the left figure is the D3 passivation group and the right figure is the Ningnanmycin passivation group. Specific embodiments

[0081] 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.

[0082] Example 1: Synthesis of methyl (E)-2-(2-(((8-(bis(ethylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate (compound number D1), the synthesis method is as follows:

[0083] (1) Synthesis of 7-hydroxy-2-oxo-2H-benzopyran-8-carboxaldehyde:

[0084] The raw materials 7-hydroxy-2H-benzopyran-2-one (12 mmol) and urotropine (50 mmol) were added to acetic acid (30 mL), heated to 75° C., refluxed for 6 h, and then 20% hydrochloric acid (30 mL) was added. The temperature was maintained at 75° C. and the reaction was continued for 1 h. The reaction was stopped and cooled to room temperature, poured into crushed ice, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 7-hydroxy-2-oxo-2H-benzopyran-8-carboxaldehyde as a yellow solid (1.60 g). The yield was 72%.

[0085] (2) Synthesis of methyl (E)-2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate:

[0086] Methoxyacrylate (24.13mmol, 5g), N-bromosuccinimide (26.54mmol, 4.72g) and azobisisobutyronitrile (2.41mmol, 396mg) were placed in a 100mL three-necked flask, 50mL of carbon tetrachloride was added as solvent, and the mixture was stirred and heated under reflux. TLC was used to track the reaction. After the raw material disappeared, the reaction was stopped, the mixture was cooled to room temperature, the insoluble solid was removed by filtration, the filtrate was collected, the solvent was removed, and 5.92g of light yellow liquid (E)-2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetic acid methyl ester was purified by column chromatography, and the yield was 86%.

[0087] (3) Synthesis of methyl ((E)-2-(2-((((8-formyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate:

[0088] Potassium carbonate (10 mmol) was added to a solution of 7-hydroxy-2-oxo-2H-benzopyran-8-carbaldehyde (5 mmol) in N,N-dimethylformamide (30 mL), and the mixture was heated at 80°C for 1 h. The mixture was cooled to room temperature, and then the intermediate (E)-2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetic acid methyl ester (Example 1(2)) (5 ​​mmol) and potassium iodide (5 mmol) were added. The mixture was heated to 80°C and the reaction was monitored by TLC. The reaction was stopped when the starting material completely disappeared. The mixture was cooled to room temperature and poured into ice water. The pH was adjusted to acidic with dilute hydrochloric acid. The filter cake was collected by filtration and purified by column chromatography to obtain the intermediate (E)-2-(2-((((8-formyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetic acid methyl ester as a yellow solid (1.23 g). The yield was 62%.

[0089] (4) Synthesis of methyl (E)-2-(2-(((8-(bis(ethylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate:

[0090] (E)-2-(2-((((8-formyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetic acid methyl ester (Example 1(3)) (1 mmol) and thiol (2.2 mmol) were dissolved in dichloromethane (15 mL) at room temperature, and then catalyst NaHSO4·SiO2 (5 mmol) was added. The reaction was monitored by TLC. After the raw material was completely converted, the solid silica was removed by filtration, and the filtrate was concentrated in vacuo to give a crude product, which was purified by column chromatography to give a white solid (E)-2-(2-(((8-(bis(ethylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetic acid methyl ester, 417 mg, yield: 83%.

[0091] Example 2: (E)-methyl 2-(2-(((8-(bis(propylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D2), the synthesis method is as follows:

[0092] The method and conditions of Example 1(4) were used for synthesis, except that propylthiol was used as the starting material.

[0093] Example 3: (E)-2-(2-(((8-(bis(butylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate (Compound No. D3), the synthesis method is as follows:

[0094] The method and conditions of Example 1(4) are used for synthesis, except that butanethiol is used as the raw material.

[0095] Example 4: Methyl ((E)-2-(2-(((8-(bis(cyclohexylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D4), the synthesis method is as follows:

[0096] The method and conditions of Example 1(4) are used for synthesis, except that cyclohexanethiol is used as the raw material.

[0097] Example 5: Methyl (E)-2-(2-(((8-(1,3-disulfan-2-yl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D5), the synthesis method is as follows:

[0098] The method and conditions of Example 1(4) are used for synthesis, except that ethanedithiol is used as the raw material.

[0099] Example 6: (E)-methyl 2-(2-(((8-(bis(isopropylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D6), the synthesis method is as follows:

[0100] The method and conditions of Example 1(4) are used for synthesis, except that isopropyl mercaptan is used as the raw material.

[0101] Example 7: Methyl (E)-2-(2-(((8-(bis(tert-butylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D7), the synthesis method is as follows:

[0102] The method and conditions of Example 1(4) were used for synthesis, except that tert-butyl mercaptan was used as the starting material.

[0103] Example 8: (E)-methyl 2-(2-(((8-(bis(ethylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate (Compound No. D8), the synthesis method is as follows:

[0104] (1) Synthesis of 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde

[0105] The method and conditions of Example 1(1) were used for synthesis, except that 7-hydroxy-4-methyl-2H-chromone-2-one was used as the starting material.

[0106] (2) Synthesis of methyl (E)-2-(2-((((8-formyl-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate

[0107] The product was synthesized using the same method and conditions as in Example 1(3), except that 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (Example 8(1)) was used as the starting material.

[0108] (3) Synthesis of methyl (E)-2-(2-(((8-(bis(ethylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate (Compound No. D8)

[0109] The synthesis was carried out according to the method and conditions of Example 1(4), except that (E)-methyl 2-(2-((((8-formyl-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate was used as the starting material.

[0110] Example 9: (E)-methyl 2-(2-(((8-(bis(propylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D9), the synthesis method is as follows:

[0111] The method and conditions of Example 8(3) were used for synthesis, except that propylthiol was used as the starting material.

[0112] Example 10: (E)-methyl 2-(2-(((8-(bis(butylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate (Compound No. D10), the synthesis method is as follows:

[0113] The method and conditions of Example 8(3) were used for synthesis, except that butanethiol was used as the starting material.

[0114] Example 11: ((E)-2-(2-(((8-(bis(cyclohexylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetic acid methyl ester (Compound No. D11), the synthesis method is as follows:

[0115] The method and conditions of Example 8(3) were used for synthesis, except that cyclohexanethiol was used as the starting material.

[0116] Example 12: Methyl (E)-2-(2-(((8-(1,3-disulfan-2-yl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D12), the synthesis method is as follows:

[0117] The method and conditions of Example 8(3) were used for synthesis, except that ethanedithiol was used as the starting material.

[0118] Example 13: Methyl (E)-2-(2-(((8-(bis(isopropylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D13), the synthesis method is as follows:

[0119] The method and conditions of Example 8(3) were used for synthesis, except that isopropyl mercaptan was used as the starting material.

[0120] Example 14: Methyl (E)-2-(2-(((8-(bis(tert-butylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D14), the synthesis method is as follows:

[0121] The method and conditions of Example 8(3) were used for synthesis, except that tert-butyl mercaptan was used as the starting material.

[0122] Example 15: (E)-2-(2-(((8-(bis(ethylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate (Compound No. D15), the synthesis method is as follows:

[0123] (1) Synthesis of methyl (E)-2-(2-(chloromethyl)phenyl)-3-methoxyacrylate:

[0124] 3-Isochromone (5.0 g) and trimethyl orthoformate (35.8 g) were mixed and heated to 50°C, and then boron trifluoride etherate (5 mL) was added. After continuing the reaction for 1 h, the mixture was cooled to room temperature, and the filtrate was collected by filtration. After desolventization, a brown solid was obtained. Then, thionyl chloride (33 g) was slowly added dropwise under an ice bath. After the addition was completed, the system was heated to reflux. After 8 h, the reaction was stopped, and the mixture was cooled to room temperature. Then, methanol (10 mL) was added dropwise under an ice bath. After the addition was completed, the reaction was continued for 1 h, and then the reaction was stopped. After desolventization, 6.3 g of yellow solid (E)-2-(2-(chloromethyl)phenyl)-3-methoxyacrylate was purified by column chromatography, and the yield was 65%.

[0125] (2) Synthesis of methyl (E)-2-(2-((((8-formyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate

[0126] The method and conditions of Example 1(3) were used for synthesis, except that (E)-methyl 2-(2-(chloromethyl)phenyl)-3-methoxyacrylate was used as the starting material.

[0127] Synthesis of (E)-2-(2-(((8-(bis(ethylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate

[0128] The product was synthesized using the same method and conditions as in Example 1(4), except that (E)-methyl 2-(2-((((8-formyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate was used as the starting material.

[0129] Example 16: (E)-2-(2-(((8-(bis(propylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D16), the synthesis method is as follows:

[0130] The method and conditions of Example 15(3) were used for synthesis, except that propylthiol was used as the starting material.

[0131] Example 17: (E)-2-(2-(((8-(bis(butylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate (Compound No. D17), the synthesis method is as follows:

[0132] The method and conditions of Example 15(3) were used for synthesis, except that butanethiol was used as the starting material.

[0133] Example 18: (E)-2-(2-(((8-(bis(cyclohexylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D18), the synthesis method is as follows:

[0134] The method and conditions of Example 15(3) were used for synthesis, except that cyclohexanethiol was used as the raw material.

[0135] Example 19: Methyl (E)-2-(2-(((8-(1,3-disulfan-2-yl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D19), the synthesis method is as follows:

[0136] The method and conditions of Example 15(3) are used for synthesis, except that ethanedithiol is used as the raw material.

[0137] Example 20: (E)-methyl 2-(2-(((8-(bis(isopropylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D20), the synthesis method is as follows:

[0138] The method and conditions of Example 15(3) were used for synthesis, except that isopropyl mercaptan was used as the starting material.

[0139] Example 21: (E)-methyl 2-(2-(((8-(bis(tert-butylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D21), the synthesis method is as follows:

[0140] The method and conditions of Example 15(3) were used for synthesis, except that tert-butyl mercaptan was used as the starting material.

[0141] Example 22: (E)-2-(2-(((8-(bis(ethylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate (Compound No. D22), the synthesis method is as follows:

[0142] (1) Synthesis of methyl (E)-2-(2-((((8-formyl-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate

[0143] The product was synthesized using the same method and conditions as in Example 15(2), except that 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde was used as the starting material.

[0144] (2) Synthesis of (E)-2-(2-(((8-(bis(ethylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate

[0145] The synthesis was carried out according to the method and conditions of Example 15(3), except that (E)-methyl 2-(2-((((8-formyl-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Example 22(1)) was used as the starting material.

[0146] Example 23: (E)-2-(2-(((8-(bis(propylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D23), the synthesis method is as follows:

[0147] The method and conditions of Example 22(1) were used for synthesis, except that propylthiol was used as the starting material.

[0148] Example 24: (E)-2-(2-(((8-(bis(butylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-3-methoxyacrylate (Compound No. D24), the synthesis method is as follows:

[0149] The method and conditions of Example 22(1) are used for synthesis, except that butanethiol is used as the starting material.

[0150] Example 25: (E)-2-(2-(((8-(bis(cyclohexylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D25), the synthesis method is as follows:

[0151] The method and conditions of Example 22(1) were used for synthesis, except that cyclohexanethiol was used as the raw material.

[0152] Example 26: Methyl (E)-2-(2-(((8-(1,3-disulfan-2-yl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D26), the synthesis method is as follows:

[0153] The method and conditions of Example 22(1) are used for synthesis, except that ethanedithiol is used as the raw material.

[0154] Example 27: (E)-2-(2-(((8-(bis(isopropylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D27), the synthesis method is as follows:

[0155] The method and conditions of Example 22(1) were used for synthesis, except that isopropyl mercaptan was used as the starting material.

[0156] Example 28: (E)-methyl 2-(2-(((8-(bis(tert-butylthio)methyl)-4-methyl-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-3-methoxyacrylate (Compound No. D28), the synthesis method is as follows:

[0157] The method and conditions of Example 22(1) were used for synthesis, except that tert-butyl mercaptan was used as the starting material.

[0158] Example 29: Methyl (E)-2-(2-(((8-(bis((4-chlorophenyl)thio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D29), the synthesis method is as follows:

[0159] The method and conditions of Example 1(1) were used for synthesis, except that 4-chlorobenzenethiol was used as the starting material.

[0160] Example 30: (E)-methyl 2-(2-(((8-(bis((2,4-dichlorophenyl)thio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D30), the synthesis method is as follows:

[0161] The method and conditions of Example 1(1) were used for synthesis, except that 2,4-dichlorobenzenethiol was used as the starting material.

[0162] Example 31: Methyl ((E)-2-(2-(((8-(bis((4-fluorophenyl)thio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D31), synthesized as follows:

[0163] The method and conditions of Example 1(1) were used for synthesis, except that 4-fluorobenzenethiol was used as the starting material.

[0164] Example 32: (E)-2-(2-(((8-(bis(p-tolyl)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate (Compound No. D32), the synthesis method is as follows:

[0165] The method and conditions of Example 1(1) were used for synthesis, except that 4-methylthiophenol was used as the starting material.

[0166] Example 33: (E)-methyl 2-(2-(((8-(bis(benzylthio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methylmethyl)phenyl)-2-(methoxyimino)acetate (Compound No. D33), the synthesis method is as follows:

[0167] The method and conditions of Example 1(1) are used for synthesis, except that benzyl mercaptan is used as the starting material.

[0168] Example 34: Methyl (E)-2-(2-(((8-(bis((4-methoxyphenyl)thio)methyl)-2-oxo-2H-benzopyran-7-yl)oxy)methyl)phenyl)-2-(methoxyimino)acetate (Compound No. D34), the synthesis method is as follows:

[0169] The method and conditions of Example 1(1) were used for synthesis, except that 4-methoxythiol was used as the starting material.

[0170] Table 1 Physicochemical properties of target compounds in the examples

[0171]

[0172]

[0173] The compound has a hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) and carbon spectroscopy ( 13 C NMR) data are shown in Table 2.

[0174] Table 2 Spectral data of Examples 1-34 (Compounds D1-D34)

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183] Bioassay Example 1: Therapeutic, protective activity and passivation test of the target compound of the example against cucumber mosaic virus.

[0184] (1) Extraction method

[0185] a. Virus purification:

[0186] The method reported by Zhou Xueping et al. (Zhou Xueping, Xu Zhixin, Xu Jing, Li Debao. Study on Cucumber Mosaic Virus Infecting Sponge Gourd [J]. Journal of South China Agricultural University 1995, 16 (2), 74-79.) was used to select the upper leaves of the host common tobacco K326 plant that had been inoculated for more than 3 weeks and infected by CMV system. The leaves were homogenized in phosphate buffer, filtered through double gauze, centrifuged at 8000g, treated with polyethylene glycol twice, and centrifuged again. The precipitate was suspended in phosphate buffer to obtain CMV extract. The entire experiment was carried out at 4°C. The absorbance value at a wavelength of 260nm was measured using an ultraviolet spectrophotometer, and the virus concentration was calculated according to the formula.

[0187] Virus concentration (mg / mL) = (A 260 × dilution factor) / E.

[0188] Where E represents the extinction coefficient, which is the light absorption value of a suspension with a concentration of 0.1% (1 mg / mL) at a wavelength of 260 nm and a light path of 1 cm. The extinction coefficient of CMV is 5.0.

[0189] (2) In vivo testing method for the effect of drugs on CMV infection

[0190] a. The in vivo therapeutic effect of the drug on CMV infection:

[0191] The half-leaf spot method was used with a concentration of 500 mg / L. Amaranthus quinoa with 5-6 leaves that grew evenly was selected for pruning. Diamond sand was evenly sprinkled on the entire leaf. The virus solution (6×10 -3 mg / mL) whole leaf was inoculated with virus, and washed with clean water after the Amaranthus quinoa was naturally dried. After the leaves were dried, the agent was lightly applied to the left half of the leaf with a brush, and the right half of the leaf was coated with a solvent of the corresponding concentration as a control. After 4-5 days, the number of dead spots was recorded, and the inhibition rate was calculated according to the following formula.

[0192] b. The protective effect of the agent on CMV infection in vivo:

[0193] The half-leaf spot method was used, and the concentration of the agent was 500 mg / L. Amaranthus quinoa with 5-6 leaves that grew evenly was selected for pruning. The agent was lightly applied to the left half of the leaf with a brush, and the right half of the leaf was coated with a solvent of the corresponding concentration as a control. After 24 hours, diamond dust was evenly sprinkled on the whole leaf, and the virus solution (6×10 -3 mg / mL) whole leaves were inoculated with the virus and rinsed with clean water. After 4-5 days, the number of dead spots was recorded and the inhibition rate was calculated according to the following formula.

[0194] c. The inactivation effect of the drug on CMV infection:

[0195] The half-leaf spot method was used to prune the Amaranthaceae with 5-6 leaves growing evenly. The concentration of the drug was 500 mg / L. The drug and virus solution (12×10 -3 mg / mL) and mixed evenly. After half an hour, use a brush to pick up the virus solution (6×10 -3 mg / mL) inoculated virus on the left leaf as a control, and used a brush to dip the mixture of drug and virus solution to inoculate virus on the right leaf. After half an hour, rinse with clean water, record the number of dead spots after 4-5 days, and calculate the inhibition rate according to the following formula.

[0196] Inhibition rate (%) = (average number of dead spots on half leaf without pesticide application - average number of dead spots on half leaf with pesticide application) / average number of dead spots on half leaf without pesticide application

[0197] Among them, the average number of necrotic spots on the half leaf without the pesticide and the number of necrotic spots on the half leaf with the pesticide were the average of three repetitions in each group.

[0198] Table 3 Anti-CMV therapeutic, protective and inactivating activities of target compounds at a concentration of 500 μg / mL

[0199]

[0200]

[0201] The anti-CMV activity of the coumarin derivatives containing dithioacetal was tested by the half-leaf spot method at a concentration of 500 mg / L and Ningnanmycin as a control agent. The bioassay results in Table 3 show that in terms of the therapeutic, protective and passivation activities of the coumarin derivatives containing dithioacetal, the therapeutic activity, protective activity and passivation activity of the target compound obtained in Example 3 are 58.7%, 61.4% and 87.3%, respectively, which are better than the control agent Ningnanmycin (49.2%, 50.4% and 84.6%).

[0202] 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 coumarin derivative containing a dithioacetal unit, characterized in that: The coumarin derivative containing a dithioacetal unit is a compound having a structure as shown in formula (I) or a stereoisomer thereof, or a salt thereof or a solvate thereof: in R 1 and R 2 Each is independently selected from one or more of hydrogen, deuterium, halogen, nitro, hydroxyl, amino, thiol, phenyl, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl; R 3 is independently selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl; R 4 Independently selected from one or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.

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

3. A method for preparing a coumarin derivative containing a dithioacetal unit as claimed in any one of claims 1 to 2, characterized in that: The steps include:

4. The method for preparing a coumarin derivative containing a dithioacetal unit according to claim 3, characterized in that: The synthesis path is as follows:

5. The method for preparing a coumarin derivative containing a dithioacetal unit according to claim 3 or 4, characterized in that: The synthesis path is as follows:

6. A composition characterized in that A coumarin derivative containing a dithioacetal unit as described in any one of claims 1 to 2, and an agriculturally usable adjuvant or fungicide, antiviral agent or herbicide; the composition is in the form of 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. Use of the coumarin derivative containing dithioacetal units according to any one of claims 1 to 2, or the composition according to claim 6 in the preparation of drugs for preventing and treating agricultural viral diseases.

8. The use according to claim 7, characterized in that The agricultural viral disease is cucumber mosaic virus.

9. A method for preventing and treating agricultural viral diseases, characterized in that: The coumarin derivative containing dithioacetal unit according to any one of claims 1 to 2 or the composition according to claim 6 is allowed to act on harmful substances or their living environment.

10. A method for protecting plants from agricultural viral diseases, comprising a method step in which pests are contacted with the coumarin derivative containing a dithioacetal unit according to any one of claims 1 to 2, or the composition according to claim 5.

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