A 5-aryl-cyclopentenopyridine compound, a preparation method and application thereof, and a plant protection agent

Abstract

The application provides a 5-aryl-cyclopentenopyridine compound and a preparation method and application thereof and a plant protection agent, and relates to the technical field of plant protection. The 5-aryl-cyclopentenopyridine compound provided by the application introduces an aromatic group Ar, which can not only increase the stability of the compound molecule, but also interact with amino acids in a receptor protein, thereby improving the biological activity of the compound. The 5-aryl-cyclopentenopyridine compound provided by the application has good antiviral, antibacterial and insecticidal effects, and has a good application prospect in plant protection.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of plant protection agents, and particularly relates to a 5-aryl-cyclopentenopyridine compound, a preparation method and application thereof, and a plant protection agent. BACKGROUND

[0002] Because the traditional pesticides are widely used, potential threats are caused to the ecological system and human health, and ecological problems such as drug resistance, residue and toxicity are caused in the process of preventing and treating pests. Therefore, the efficient, safe and environmentally friendly pesticides are paid more and more attention by people.

[0003]

[0004] Natural products and their derivatives are an important source of drugs, and play an important role in the development of pesticides. For example, Cerbinal (1) is first isolated from the bark of sea buckthorn, and then isolated from gardenia, and has anti-tobacco mosaic virus (TMV) activity, insecticidal activity and fungicidal activity. However, the above-mentioned compound has poor structural stability, and has low biological activity when used as a pesticide. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a 5-aryl-cyclopentenopyridine compound, a preparation method and application thereof, and a plant protection agent. The 5-aryl-cyclopentenopyridine compound provided by the present application has high structural stability and high biological activity.

[0006] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions.

[0007] The present application provides a 5-aryl-cyclopentenopyridine compound, which has the structure shown in formula I:

[0008]

[0009] Preferably, the Ar includes any one of the following structures:

[0010]

[0011] The R1 includes C1-C6 alkoxy;

[0012] The R2-R6 independently includes hydrogen, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, nitro, aldehyde, hydroxyl, C1-C6 haloalkoxy and one or more of the following structures:

[0013]

[0014] The R7-R 12Independently includes C1 to C6 alkyl.

[0015] Preferably, the C1-C6 alkoxy group is methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy;

[0016] The C1-C6 alkyl group is methyl, ethyl, propyl, butyl, pentyl or hexyl;

[0017] The C1-C6 haloalkyl group is a halomethyl group, a haloethyl group, a halopropyl group, a halobutyl group, a halopentyl group or a halohexyl group;

[0018] The C1-C6 haloalkoxy group is a halomethoxy group, a haloethoxy group, a halopropoxy group, a halobutoxy group, a halopentyloxy group or a halohexyloxy group.

[0019] Preferably, Ar has any one of the following structures:

[0020]

[0021] The present invention also provides a method for preparing the 5-aryl-cyclopenta-pyridine compound described in the above technical solution, comprising the following steps: subjecting compound 3 to a Suzuki coupling reaction with ArB(OH)2 to obtain the 5-aryl-cyclopenta-pyridine compound;

[0022]

[0023] Preferably, the molar ratio of compound 3 to ArB(OH)2 is 1:1-2;

[0024] The Suzuki coupling reaction is carried out under the conditions of a mixed solvent, a catalyst and an inorganic salt;

[0025] The mixed solvent includes an organic solvent and water, and the organic solvent includes one or more of 1,4-dioxane, tetrahydrofuran, acetonitrile, ethanol and methanol;

[0026] The catalyst includes a palladium-containing catalyst;

[0027] The inorganic salt includes one or more of alkali metal phosphates, alkali metal carbonates and alkali metal halides;

[0028] The temperature of the Suzuki coupling reaction is 60-120° C., and the time is 5-24 hours.

[0029] Preferably, the preparation method of compound 3 comprises the following steps: mixing compound 2 and a bromination reagent, performing a bromination reaction, and obtaining compound 3;

[0030]

[0031] The present invention also provides the use of the 5-aryl-cyclopentapyridine compounds described in the above technical solution in plant protection agents.

[0032] Preferably, the plant protection agent comprises one or more of an anti-plant virus agent, an agricultural insecticide and an agricultural fungicide.

[0033] The present invention also provides a plant protection agent, characterized in that it comprises an active component and an auxiliary material; the active component comprises the 5-aryl-cyclopentapyridine compound described in the above technical solution.

[0034] The 5-aryl-cyclopenta-pyridine compounds provided by the present invention incorporate an aromatic group, Ar, which not only increases the stability of the compound molecule, but also allows the conjugated π electrons of the aromatic ring and different substituents to interact with amino acids in receptor proteins, enhancing the compound's interaction with the target and thereby increasing the compound's biological activity. The 5-aryl-cyclopenta-pyridine compounds provided by the present invention have excellent antiviral, antibacterial, and insecticidal effects and have promising application prospects in plant protection.

[0035] As shown in the test results of the examples, compounds 4d, 4e, 4f, 4g, and 4k from the 5-aryl-cyclopentapyridine compounds provided by the present invention exhibit higher levels of anti-TMV activity than commercial ribavirin. In particular, the most active compound 4k exhibits low or even mild toxicity to zebrafish. The 5-aryl-cyclopentapyridine compounds provided by the present invention are active against aphids and diamondback moth larvae. In particular, compounds 4d, 4e, 4h, and 4o exhibit 100% insecticidal activity against diamondback moth larvae at a concentration of 600 μg / mL. These compounds also exhibit significant insecticidal activity at lower concentrations of 200 μg / mL and 100 μg / mL. The 5-aryl-cyclopentapyridine compounds provided by the present invention exhibit fungicidal activity against nine pathogens, including rapeseed sclerotia, apple ring spot, wheat sheath blight, rice blast, cucumber gray mold, peanut brown spot, tomato early blight, wheat gibberellum, and rice sheath blight. In particular, compound 4i has a fungicidal activity of 91.9% against rapeseed sclerotia at a concentration of 50 μg / mL.

[0036] The preparation method of the 5-aryl-cyclopentapyridine compound provided by the present invention has simple and efficient process, low production cost, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The figure shows the survival rate of zebrafish exposed to compound 4k. DETAILED DESCRIPTION

[0038] The present invention provides a 5-aryl-cyclopentapyridine compound having a structure shown in Formula I:

[0039]

[0040] In the present invention, Ar in Formula I preferably includes any one of the following structures:

[0041]

[0042] The R1 preferably includes a C1-C6 alkoxy group; the R2-R6 independently preferably include hydrogen, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, nitro, aldehyde, hydroxyl, C1-C6 haloalkoxy and one or more of the following structures:

[0043]

[0044] The R7~R 12 Independently preferably includes C1 to C6 alkyl.

[0045] In the present invention, the halogen preferably includes fluorine, chlorine, bromine or iodine.

[0046] In the present invention, the C1-C6 alkoxy group is preferably a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group or a hexyloxy group.

[0047] In the present invention, the C1-C6 alkyl group is preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group or a hexyl group.

[0048] In the present invention, the C1-C6 haloalkyl group is preferably a halomethyl group, a haloethyl group, a halopropyl group, a halobutyl group, a halopentyl group or a halohexyl group; and the halogen in the C1-C6 haloalkyl group preferably includes fluorine, chlorine, bromine or iodine.

[0049] In the present invention, the C1-C6 haloalkoxy group is preferably a halomethoxy group, a haloethoxy group, a halopropoxy group, a halobutoxy group, a halopentoxy group or a halohexyloxy group; and the halogen in the C1-C6 haloalkoxy group preferably includes fluorine, chlorine, bromine or iodine.

[0050] In the present invention, Ar preferably has any one of the structures:

[0051]

[0052] The 5-aryl-cyclopenta-pyridine compounds provided by the present invention introduce an aromatic group (Ar) into the structural modification of the natural product pesticide molecule Cerbinal (1), which not only increases the stability of the compound molecule but also enhances the biological activity of the compound by interacting with amino acids in receptor proteins. The 5-aryl-cyclopenta-pyridine compounds provided by the present invention have excellent antiviral, antibacterial and insecticidal effects and have good application prospects in plant protection.

[0053] The present invention also provides a method for preparing the 5-aryl-cyclopenta-pyridine compound described in the above technical solution, comprising the following steps: subjecting compound 3 to a Suzuki coupling reaction with ArB(OH)2 to obtain the 5-aryl-cyclopenta-pyridine compound;

[0054]

[0055] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0056] In the present invention, the Suzuki coupling reaction is preferably carried out in the presence of a mixed solvent, a catalyst and an inorganic salt. Specifically, compound 3, ArB(OH)2, an inorganic salt, a catalyst and a mixed solvent are mixed to carry out the Suzuki coupling reaction.

[0057] In the present invention, the molar ratio of compound 3 to ArB(OH)2 is preferably 1:1-2, and in specific embodiments can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0058] In the present invention, the inorganic salt preferably includes one or more of alkali metal phosphates, alkali metal carbonates and alkali metal halides; the alkali metal phosphate preferably includes one or more of potassium phosphate, sodium phosphate and cesium phosphate; the alkali metal carbonate preferably includes one or more of potassium carbonate, sodium carbonate and cesium carbonate; the alkali metal halide preferably includes one or more of alkali metal fluoride, alkali metal chloride and alkali metal bromide; the alkali metal fluoride preferably includes one or more of sodium fluoride, potassium fluoride and cesium fluoride; the alkali metal chloride preferably includes one or more of sodium chloride, potassium chloride and cesium chloride; the alkali metal bromide preferably includes one or more of sodium bromide, potassium bromide and cesium bromide. In the present invention, the molar ratio of compound 3 to the inorganic salt is preferably 1:1 to 4, and in specific embodiments it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0059] In the present invention, the catalyst preferably includes a palladium-containing catalyst, and the palladium-containing catalyst preferably includes one or more of Pd(PPh3)4, PdCl2, PdCl2(dppf), Pd(OAc)2 and Pd(PPh3)2Cl2. In the present invention, the molar ratio of the compound 3 to the catalyst is preferably 1:0.0005 to 0.05, and in specific embodiments can be 1:0.0005, 1:0.001, 1:0.002, 1:0.005, 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.035, 1:0.04, 1:0.045 or 1:0.05.

[0060] In the present invention, the mixed solvent preferably includes an organic solvent and water, and the organic solvent preferably includes one or more of 1,4-dioxane, tetrahydrofuran, acetonitrile, ethanol and methanol; the volume ratio of water to organic solvent in the mixed solvent is preferably 1:2 to 8, and in specific embodiments, it can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8. In the present invention, the ratio of the amount of compound 3 to the volume of the mixed solvent is preferably 1 mol:8 to 100 L, and in specific embodiments, it can be 1 mol:8 L, 1 mol:10 L, 1 mol:15 L, 1 mol:20 L, 1 mol:30 L, 1 mol:40 L, 1 mol:50 L, 1 mol:60 L, 1 mol:70 L, 1 mol:80 L, 1 mol:90 L or 1 mol:100 L.

[0061] In the present invention, the mixing preferably includes: dissolving compound 3, ArB(OH)2 and an inorganic salt in a mixed solvent, and then adding a catalyst and mixing.

[0062] In the present invention, the temperature of the Suzuki coupling reaction is preferably 60-120°C, and in specific embodiments, it can be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C or 120°C; the time of the Suzuki coupling reaction is preferably 5-24h, and in specific embodiments, it can be 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h or 24h; the Suzuki coupling reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, argon or helium.

[0063] After completing the Suzuki coupling reaction, the present invention preferably further comprises: filtering the reaction solution obtained from the Suzuki coupling reaction through diatomaceous earth, the filtrate is spin-dried and then washed with water, and then extracted with dichloromethane. The resulting organic phase is dried over anhydrous magnesium sulfate and then purified on a silica gel column to obtain the 5-aryl-cyclopentapyridine compound. In the present invention, the purpose of the diatomaceous earth filtration is to remove insoluble impurities. In the present invention, the number of dichloromethane extractions is preferably 2 to 5, more preferably 3 to 4. In the present invention, the eluent used for the silica gel column purification preferably includes a petroleum ether-ethyl acetate mixed solvent or a dichloromethane-methanol mixed solvent; the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solvent is preferably 1:1 to 5; the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is preferably 20:1 to 10.

[0064] In the present invention, the preparation method of compound 3 preferably comprises the following steps: mixing compound 2 and a bromination reagent, and performing a bromination reaction to obtain compound 3;

[0065]

[0066] In the present invention, the bromination reagent preferably includes one or more of N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, and pyridinium bromide (PyHBr3). In the present invention, the molar ratio of compound 2 to the bromination reagent is preferably 1:1 to 1.5, and in specific embodiments, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0067] In the present invention, the organic solvent used in the bromination reaction preferably includes one or more of toluene, dimethylformamide, chloroform, acetonitrile and dichloromethane, more preferably an acetonitrile-dichloromethane mixed solvent, and the volume ratio of acetonitrile to dichloromethane in the acetonitrile-dichloromethane mixed solvent is preferably 1:0.2-4, and in specific embodiments can be 1:0.2, 1:0.5, 1:1, 1:2, 1:3 or 1:4; the organic solvent is preferably an anhydrous organic solvent.

[0068] In the present invention, the ratio of the amount of compound 2 to the volume of the organic solvent is preferably 1 mol: 5 to 50 L. In specific embodiments, it can be 1 mol: 5 L, 1 mol: 10 L, 1 mol: 15 L, 1 mol: 20 L, 1 mol: 25 L, 1 mol: 30 L, 1 mol: 35 L, 1 mol: 40 L, 1 mol: 45 L or 1 mol: 50 L.

[0069] The present invention preferably dissolves compound 2 in an organic solvent, adds a bromination reagent at a bromination reaction temperature, and performs a bromination reaction. In the present invention, the temperature of the bromination reaction is preferably 0 to 50°C, and in specific embodiments, it can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 50°C, more preferably carried out under ice-water bath conditions; the time of the bromination reaction is preferably 2 to 3 hours, and in specific embodiments, it can be 2 hours, 2.5 hours or 3 hours.

[0070] After the bromination reaction is completed, the present invention preferably further comprises: adding water to the reaction solution obtained from the bromination reaction, extracting with dichloromethane, washing the resulting organic phase with an aqueous sodium bicarbonate solution, washing with saturated brine, drying with anhydrous sodium sulfate, and purifying with flash silica gel column chromatography to obtain compound 3. In the present invention, the number of dichloromethane extractions is preferably 3 to 5 times, more preferably 4 times. In the present invention, the eluent used for the silica gel column purification preferably includes a petroleum ether-dichloromethane mixed solvent or a petroleum ether-ethyl acetate mixed solvent; the volume ratio of petroleum ether to dichloromethane in the petroleum ether-dichloromethane mixed solvent is preferably 10:0.1-10; the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solvent is preferably 10:0.1-10.

[0071] The preparation method of the 5-aryl-cyclopentapyridine compound provided by the present invention has simple and efficient process, low production cost, and is suitable for industrial production.

[0072] The present invention also provides the use of the 5-aryl-cyclopentapyridine compounds described in the above technical solution in pesticides.

[0073] In the present invention, the pesticide preferably includes one or more of an anti-plant virus agent, an agricultural insecticide and an agricultural fungicide. In the present invention, the anti-plant virus agent preferably includes an anti-tobacco mosaic virus agent. In the present invention, the agricultural insecticide preferably includes an insecticide for aphids and / or diamondback moth larvae. In the present invention, the agricultural fungicide preferably includes a fungicide for any one or more of rapeseed sclerotia (Ss), apple ring spot (Pp), wheat sheath blight (Rc), potato late blight (Pi), cucumber gray mold (Bc), peanut brown spot (Ch), tomato early blight (As), wheat fusarium (Fg) and rice sheath blight (Rs).

[0074] The 5-aryl-cyclopenta-pyridine compounds provided by the present invention are active against tobacco mosaic virus, and the activity of many compounds is higher than that of ribavirin; they are low-toxic or even slightly toxic to adult zebrafish; they show good activity against the larvae of the diamondback moth, and they are active against nine plant pathogens, including rapeseed sclerotia, apple ring spot, wheat sheath blight, rice blast, cucumber gray mold, peanut brown spot, tomato early blight, wheat gibberellum, and rice sheath blight. The 5-aryl-cyclopenta-pyridine compounds provided by the present invention have good antiviral, antibacterial and insecticidal effects, and have good application prospects in plant protection.

[0075] The present invention also provides a plant protection agent comprising an active ingredient and an excipient; the active ingredient comprises the 5-aryl-cyclopentapyridine compound described in the above technical solution. The present invention does not particularly limit the excipient, and any excipient familiar to those skilled in the art can be used.

[0076] To further illustrate the present invention, the 5-aryl-cyclopentapyridine compounds, their preparation methods and applications, and plant protection agents provided by the present invention are described in detail below with reference to the following examples. However, these examples should not be construed as limiting the scope of protection of the present invention.

[0077] The ArB(OH)2 used in compounds 4a-4cc prepared in Examples 1-29 and the Ar in the products are as follows:

[0078]

[0079] Example 1

[0080] Compound 2 (5.82 mmol) was dissolved in anhydrous acetonitrile (165 mL) and dichloromethane (55 mL). N-bromosuccinimide (NBS, 9.52 mmol) was added under an ice-water bath and stirred for 2 to 3 hours until the reaction was complete. Water was added and the mixture was extracted four times with dichloromethane. The organic phases were combined, washed with sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and purified by flash silica gel column chromatography (petroleum ether / dichloromethane volume ratio of 5:1 to 1:1) to obtain compound 3 with a yield of 81% and a melting point of 135 to 136°C. 1 H NMR (400MHz, CDCl3) δ9.83 (s, 1H), 9.10 (s, 1H), 7.80-7.75 (m, 2H), 4.31 (q, J = 7.3Hz, 2H), 4.03 (s, 3H), 1.63 (t, J = 7.3Hz, 3H); 13C NMR (100MHz, CDCl3) δ184.17,165.93,144.65,133.76,128.84,128.26,126.01,120.06,119.23,93.08,54.38,52.56,16.87; HRMS(APCI) calculated for C 13 H 14 BrNO3[M+H] + 310.0073,found 310.0070.

[0081] Compound 3 (1.61 mmol), ArB(OH)2 (2.415 mmol), K3PO4 (3.22 mmol), 1,4-dioxane (16 mL) and H2O (3.8 mL) were added, dissolved, and then Pd(PPh3)4 (0.322 mmol) was added. The mixture was reacted at 95°C for 8 h under argon protection. Insoluble impurities were removed by filtration through diatomaceous earth. The filtrate was spin-dried and washed with water. The mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous magnesium sulfate, and purified on a silica gel column (petroleum ether-ethyl acetate mixed solvent or dichloromethane-methanol mixed solvent, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solvent was 1:1-5, and the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent was 20:1-10) to obtain compound 4a with a yield of 64% and a melting point of 181-183°C. 1 H NMR (400MHz, CDCl3) δ9.94(s,1H),9.17(d,J=1.1Hz,1H),7.89(s,1H),7.83(d,J=1.5Hz,1H),7.41-7.36 (m,2H),7.34-7.31(m,2H),7.29-7.24(m,1H),4.34(q,J=7.3Hz,2H),3.23(s,3H),1.65(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.83,167.03,144.07,138.98,133.96,128.70,128.65,128.17,128 .04,127.40,125.81,123.47,120.11,119.40,54.24,51.83,16.95; HRMS(APCI)calculated for C 19 H 18 NO3[M+H] + 308.1281, found 308.1270.

[0082] Example 2

[0083] Compound 4b was prepared according to the method of Example 1 with a yield of 72% and a melting point of 191.5-193°C; 1 HNMR (400MHz, CDCl3) δ9.97 (s, 1H), 9.25 (d, J = 1.3Hz, 1H), 7.96 (s, 1H), 7.91-7.87 (m, 2H), 7.82 (d, J = 8.2Hz, 1H), 7.66 (d, J = 8 .4Hz,1H),7.55-7.50(m,1H),7.48-7.41(m,2H),7.37-7.32(m,1H),4.36(q,J=7.3Hz,2H),2.58(s,3H),1.67(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.82,166.71,145.78,137.50,133.97,133.52,132.96,130.33,129.14,128.10,127.52,126 .48,126.43,126.01,125.88,125.59,125.41,121.03,120.06,119.22,54.26,51.24,16.95; HRMS(APCI)calculated for C 22 H 20 NO3[M+H] + 358.1438, found 358.1424.

[0084] Example 3

[0085] Compound 4c was prepared according to the method of Example 1 with a yield of 61% and a melting point of 168.8-171°C; 1 HNMR (400MHz, CDCl3) δ9.96 (s, 1H), 9.23 (d, J = 1.4Hz, 1H), 8.45 (s, 2H), 8.02 (d, J = 1.5Hz, 1H),7.83(s,1H),4.37(q,J=7.3Hz,2H),4.07(s,3H),3.57(s,3H),1.67(t,J=7.3Hz,3H); 13 CNMR(100MHz,CDCl3)δ184.99,165.94,164.09,158.17,144.33,134.42,130.14,129.17,1 27.87,126.88,20.69,118.35,115.34,54.99,54.54,52.53,17.03; HRMS(APCI)calculated for C18 H 18 N3O4[M+H] + 340.1292, found 340.1284.

[0086] Example 4

[0087] Compound 4d was prepared according to the method of Example 1 with a yield of 57% and a melting point of 222-223.6°C; 1 HNMR (400MHz, CDCl3) δ9.92(s,1H),9.17(s,1H),7.85(d,J=1.4Hz,1H),7.84(s,1H),7.27(dd,J= 7.2,4.4Hz,2H),7.08(t,J=8.6Hz,2H),4.34(q,J=7.3Hz,2H),3.32(s,3H),1.65(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.90,166.97,162.71,160.28,144.13,135.24(d,J c-f =7.7Hz),134.15,129.76(d,J c-f =7.7Hz),128.83(d,J c-f =18.3Hz),127.46,122.41,120.22,119.31,114.89(d,J=21.2Hz),77.48,77.36,77.16,76.84,54.39,52.05,17.05; 19 FNMR(376MHz, CDCl3)δ-117.08; HRMS(APCI) calculated for C 19 H 17 FNO3[M+H] + 326.1187,found326.1174.

[0088] Example 5

[0089] Compound 4e was prepared according to the method of Example 1 with a yield of 83% and a melting point of 167.5-168.7; 1HNMR (400MHz, CDCl3) δ9.93(s,1H),9.18(s,1H),7.87(s,2H),7.33(dd,J=14.1,7.8Hz,1H),7.06(dd,J=12.3,9.2 Hz,2H),6.96(td,J=8.5,2.3Hz,1H),4.35(q,J=7.3Hz,2H),4.02(s,1H),3.34(s,3H),1.65(dd,J=9.4,5.2Hz,4H); 13 C NMR (100MHz, CDCl3) δ185.01,166.89,164.07,161.63,143.99,141.47(d,J c-f =8.3Hz),134.25,129.38(d,J c-f =8.7Hz),129.04,128.71,127.57,124.15(d,J c-f =2.7Hz),122.19,119.85(d,J c-f =98.2Hz),115.15(d,J c-f =21.1Hz),112.62(d,J c-f =21.1Hz),54.44,52.02,17.05. 19 F NMR(376MHz, CDCl3)δ-114.22; HRMS(APCI)calculated for C 19 H 17 FNO3[M+H] + 326.1187, found 326.1175.

[0090] Example 6

[0091] Compound 4f was prepared according to the method of Example 1 with a yield of 69% and a melting point of 163.5-164.8; 1 HNMR (400MHz, CDCl3) δ9.95 (s, 1H), 9.20 (s, 1H), 8.00 (d, J = 1.1Hz, 1H), 7.91 (s, 1H), 7.47 (t, J = 7.6Hz, 1H), 7. 26(m,1H),7.20(t,J=7.4Hz,1H),7.12-7.04(m,1H),4.35(q,J=7.3Hz,2H),3.41(s,3H),1.66(t,J=7.3Hz,3H); 13C NMR (100MHz, CDCl3) δ184.95,166.62,159.02,145.25,134.06,130.42(d,J c-f =4.1Hz),129.70,129.64,128.00,127.53(d,J c-f =8.1Hz),123.89(d,J c-f =3.2Hz),120.49,119.50,116.45,114.98,114.76,54.42,51.98,17.06. 19 FNMR(376MHz, CDCl3)δ-113.54; HRMS(APCI) calculated for C 19 H 17 FNO3[M+H] + 326.1187, found 326.1180.

[0092] Example 7

[0093] 4 g of compound was prepared according to the method of Example 1 with a yield of 73% and a melting point of 189-190.8°C; 1 HNMR(400MHz, CDCl3) δ9.93(s,1H),9.20(d,J=1.5Hz,1H),8.01(d,J=1.6Hz,1H),7.85(s,1H),7.41(td,J=8.5,6.6Hz,1H),6. 95(ddd,J=8.2,2.6,1.3Hz,1H),6.85(ddd,J=10.3,9.0,2.6Hz,1H),4.35(q,J=7.3Hz,2H),3.50(s,3H),1.66(t,J=7.4Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.84,166.36,162.75(d,J c-f =11.9Hz),160.79(dd,J c-f =99.2,11.9Hz),158.83(d,J c-f =11.8Hz),145.06,134.13,130.86(dd,J c-f =9.1,5.7Hz),129.67(d,J c-f =19.0Hz),127.92,123.39(dd,J c-f =16.4,3.7Hz),120.46,119.22,115.43,110.81(dd,J c-f=20.8,3.5Hz),104.08-102.26(m),54.43,52.10,17.02. 19 F NMR(376MHz,CDCl3)δ-109.39(d,J f-f =6.8Hz),-113.40(d,J f-f =6.7Hz); HRMS(APCI)calculated for C 19 H 16 F2NO3[M+H] + 344.1093, found 344.1083.

[0094] Example 8

[0095] Compound 4h was prepared according to the method of Example 1 with a yield of 70% and a melting point of 195.2-196.5; 1 HNMR (400MHz, CDCl3) δ9.95 (s, 1H), 9.22 (d, J = 1.3Hz, 1H), 8.04 (d, J = 1.4Hz, 1H), 7.89 (s, 1H), 7.22 ( dd,J=7.9,5.6Hz,1H),7.14-7.07(m,2H),4.36(q,J=7.3Hz,2H),3.53(s,3H),1.66(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ185.02,166.26,145.07,134.21,129.89,129.69,128.05,125.15 ,123.51,120.61,119.34,115.18,114.67,114.50,58.61,54.51,52.11,18.59,17.06.; 19 F NMR(376MHz,CDCl3)δ-138.97(d,J f-f =21.3Hz),-140.13(d,J f-f =21.5Hz); HRMS(APCI)calculated for C 19 H 17 F2NO3[M+H] + 344.1093, found 344.1081.

[0096] Example 9

[0097] Compound 4i was prepared according to the method of Example 1 with a yield of 64% and a melting point of 224.3-225.8; 1HNMR (400MHz, CDCl3) δ9.94 (s, 1H), 9.21 (s, 1H), 7.92 (d, J = 1.3Hz, 1H), 7.81 (s, 1H), 6 .91(dd,J=8.5,6.7Hz,2H),4.36(q,J=7.3Hz,2H),3.55(s,3H),1.66(t,J=7.3Hz,3H); 13 C NMR(100MHz,CDCl3)δ185.05,166.32,152.10(d,J c-f =4.4Hz),149.63(d,J c-f =4.4Hz),143.78,139.34(d,J c-f =15.4Hz),136.93,135.44(d,J c-f =4.7Hz),134.47,129.46,128.41,127.54,120.41,120.23,118.87,112.32(dd,J=15.3,5.5Hz),54.56,52.31,17.06; HRMS(APCI)calculated for C 19 H 17 F3NO3[M+H] + 362.0999,found 362.0984.

[0098] Example 10

[0099] Compound 4j was prepared according to the method of Example 1 with a yield of 69% and a melting point of 181.5-183.3°C. 1 HNMR (400MHz, CDCl3) δ9.91 (s, 1H), 9.15 (s, 1H), 7.82 (d, J = 17.0Hz, 2H), 7.28-7.22 (m, 2H), 6 .94(d,J=8.5Hz,2H),4.32(q,J=7.3Hz,2H),3.85(s,3H),3.31(s,3H),1.64(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.79,167.18,158.09,144.18,133.93,131.65,129.27,128.74,128.58 ,127.41,123.27,120.12,119.52,113.61,55.50,54.27,52.14,17.02; HRMS(APCI)calculated for C 20 H 20NO4[M+H] + 338.1387, found 338.1380.

[0100] Example 11

[0101] Compound 4k was prepared according to the method of Example 1 with a yield of 85% and a melting point of 196.5-197.8; 1 HNMR (400MHz, CDCl3) δ9.93(s,1H),9.16(s,1H),7.89(s,1H),7.81(s,1H),7.28(dd,J=13.5,5.4Hz,1H),6.91(d,J=7 .5Hz,1H),6.88(s,1H),6.82(d,J=8.2Hz,1H),4.32(q,J=7.2Hz,2H),3.82(s,3H),3.29(s,3H),1.64(t,J=7.2Hz,3H); 13 CNMR (100MHz, CDCl3) δ184.84,167.15,159.49,143.82,140.25,134.00,129.02,128.72,128.48,127.3 3,123.24,120.71,120.08,119.57,113.10,111.94,55.21,54.26,51.91,16.96; HRMS(APCI)calculated forC 20 H 20 NO4[M+H] + 338.1387,found338.1378.

[0102] Example 12

[0103] Compound 41 was prepared according to the method of Example 1 with a yield of 85% and a melting point of 174.6-175.8; 1 HNMR (400MHz, CDCl3) δ9.93 (s, 1H), 9.18 (s, 1H), 7.91 (d, J = 1.4Hz, 1H), 7.89 (s, 1H), 7.47 (dd, J = 7.4, 1.4Hz, 1H), 7.29 (d, J = 7. 8Hz,1H),7.05(t,J=7.4Hz,1H),6.89(d,J=8.2Hz,1H),4.34(q,J=7.3Hz,2H),3.65(s,3H),3.30(s,3H),1.65(t,J=7.3Hz,3H); 13C NMR (100MHz, CDCl3) δ184.70,166.93,156.53,145.35,133.87,129.77,128.55,128.30,127.93,12 7.25,120.72,120.54,120.23,119.30,109.58,55.03,54.26,51.55,17.03; HRMS(APCI)calculated for C 20 H 20 NO4[M+H] + 338.1387, found 338.1374.

[0104] Example 13

[0105] Compound 4m was prepared according to the method of Example 1 with a yield of 68% and a melting point of 186.3-188.5°C; 1 HNMR (400MHz, CDCl3) δ9.92 (s, 1H), 9.16 (s, 1H), 7.87 (s, 1H), 7.78 (d, J = 1.5Hz, 1H), 6.94-6.8 5(m,3H),4.33(q,J=7.3Hz,2H),3.93(s,3H),3.89(s,3H),3.32(s,3H),1.65(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.88,167.44,148.78,147.51,143.90,134.04,131.98,128.70,128.35,127.35,12 3.29,120.27,120.20,119.78,111.68,111.31,56.22,55.91,54.34,52.19,17.05; HRMS(APCI)calculated for C 21 H 21 NO5[M+H] + 368.1493,found368.1480.

[0106] Example 14

[0107] Compound 4n was prepared according to the method of Example 1 with a yield of 69% and a melting point of 214.8-216.5°C; 1HNMR (400MHz, CDCl3) δ9.91 (s, 1H), 9.15 (d, J = 1.1Hz, 1H), 7.83 (s, 1H), 7.81 (d, J = 1.4Hz, 1H), 6.84 (dd, J = 4.7, 3.0Hz,2H),6.76(dd,J=8.0,1.5Hz,1H),5.98(s,2H),4.33(q,J=7.3Hz,2H),3.42(s,3H),1.64(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.85,167.05,147.48,145.86,144.09,134.01,133.18,128.69,128.64,127.35 ,123.20,121.50,120.10,119.47,109.06,108.08,101.01,54.32,52.20,17.03; HRMS(APCI)calculated for C 20 H 18 NO5[M+H] + 352.1180, found 352.1171.

[0108] Example 15

[0109] Compound 4o was prepared according to the method of Example 1 with a yield of 66% and a melting point of 202.7-205.6°C; 1 HNMR(400MHz, CDCl3)δ9.93(s,1H),9.16(d,J=1.2Hz,1H),7.90(s,1H),7.78(d,J=1.5Hz,1H),6 .57(s,2H),4.34(q,J=7.3Hz,2H),3.89(s,3H),3.88(s,6H),3.34(s,3H),1.65(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.93,167.60,153.20,143.41,136.41,134.72,134.20,128.78,128.27,12 7.30,123.31,120.24,119.99,105.19,61.11,56.18,54.42,52.16,17.07; HRMS(APCI)calculated for C 22 H 24 NO6[M+H] + 98.1598,found 3398.1584.

[0110] Example 16

[0111] Compound 4p was prepared according to the method of Example 1 with a yield of 51% and a melting point of 223.5-225°C; 1 HNMR(400MHz, CDCl3)δ9.93(s,1H),9.18(s,1H),7.86(d,J=7.3Hz,2H),7.36(d,J=8.3H z,2H),7.26(t,J=5.7Hz,2H),4.35(q,J=7.3Hz,2H),3.34(s,3H),1.65(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.91,166.86,143.99,137.69,134.21,131.63,129.57,129.04,128 .71,128.15,127.56,122.13,120.33,119.28,54.41,52.01,17.04; HRMS(APCI)calculated for C 19 H 17 ClNO3[M+H] + 342.0892,found 342.0882.

[0112] Example 17

[0113] Compound 4q was prepared according to the method of Example 1 with a yield of 85% and a melting point of 170-172°C; 1 HNMR (400MHz, CDCl3) δ9.93 (s, 1H), 9.18 (s, 1H), 7.88 (d, J = 0.9Hz, 1H), 7.87 (s, 1H), 7.33-7.28 (m, 2H), 7.24(d,J=8.1Hz,1H),7.20(d,J=7.5Hz,1H),4.35(q,J=7.3Hz,2H),3.37(s,3H),1.65(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.88,166.70,143.86,140.86,134.11,133.74,129.12,128.98,128.56,128 .33,127.47,126.39,125.72,121.78,120.26,119.17,54.32,51.99,16.92; HRMS(APCI)calculated for C 19 H 17 ClNO3[M+H]+ 342.0892,found342.0883.

[0114] Example 18

[0115] Compound 4r was prepared according to the method of Example 1 with a yield of 51% and a melting point of 187.5-189.5°C; 1 HNMR (400MHz, CDCl3) δ9.94 (s, 1H), 9.20 (s, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.43 (dd, J = 12. 0,4.9Hz,2H),7.18-7.13(m,1H),4.36(q,J=7.3Hz,2H),3.46(s,3H),1.66(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ185.03,166.58,143.90,139.27,134.36,131.87,130.17,129.80,129.56,129 .34,128.59,127.72,127.64,120.73,120.48,119.11,54.51,52.23,17.05; HRMS(APCI)calculated for C 19 H 17 Cl2NO3[M+H] + 376.0502,found376.0492.

[0116] Example 19

[0117] Compound 4s was prepared according to the method of Example 1 with a yield of 41% and a melting point of 223-225°C; 1 HNMR(400MHz, CDCl3)δ9.95(s,1H),9.21(s,1H),7.90(d,J=1.3Hz,1H),7.89(s,1H),7.64(d,J =7.9Hz,2H),7.42(d,J=8.1Hz,2H),4.36(q,J=7.3Hz,2H),3.27(s,3H),1.66(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ185.04,166.77,143.91,143.02,134.40,129.32,128.84,128 .51,128.03,127.71,125.97,124.96,121.84,120.54,119.26,54.52,51.86,17.06; 19FNMR(376MHz, CDCl3)δ-62.16; HRMS(APCI)calculated for C 20 H 17 F3NO3[M+H] + 376.1155,found376.1142.

[0118] Example 20

[0119] Compound 4t was prepared according to the method of Example 1 with a yield of 80% and a melting point of 202.4-203.8°C. 1 HNMR (400MHz, CDCl3) δ9.94(s,1H),9.21(s,1H),7.94(d,J=1.1Hz,1H),7.87(s,1H),7.65(d,J =8.2Hz,2H),7.40(d,J=8.2Hz,2H),4.37(q,J=7.3Hz,2H),3.36(s,3H),1.66(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ185.06,166.47,144.18,143.83,134.53,131.76,129.62,128.82,128.71 ,127.89,121.29,120.79,119.45,119.10,108.95,54.58,52.02,17.03; HRMS(APCI)calculated for C 20 H 17 N2O3[M+H] + 333.1234, found 333.1225.

[0120] Example 21

[0121] Compound 4u was prepared according to the method of Example 1 with a yield of 76% and a melting point of 183.8-186°C; 1 HNMR (400MHz, CDCl3) δ9.97 (s, 1H), 9.24 (s, 1H), 8.25 (d, J = 8.6Hz, 2H), 7.97 (s, 1H), 7.92 (s,1H),7.45(d,J=8.6Hz,2H),4.39(q,J=7.3Hz,2H),3.41(s,3H),1.68(t,J=7.3Hz,3H); 13CNMR(100MHz,CDCl3)δ185.07,166.25,146.15,145.52,143.85,134.51,129.72,128.78,12 8.50,127.93,123.26,120.83,120.76,119.01,54.55,52.03,16.96; HRMS(APCI)calculated for C 19 H 17 N2O5[M+H] + 353.1166, found 353.1120.

[0122] Example 22

[0123] Compound 4v was prepared according to the method of Example 1 with a yield of 68% and a melting point of 193-195°C; 1 HNMR(400MHz, CDCl3)δ9.96(s,1H),9.23(s,1H),7.97-7.93(m,3H),7.90(s,1H),7.50( d,J=8.3Hz,2H),4.38(q,J=7.3Hz,2H),3.33(s,3H),3.10(s,3H),1.67(t,J=7.3Hz,3H); 13 CNMR (100MHz, CDCl3) δ184.99,166.37,145.06,143.79,137.27,134.46,129.57,128.80,128.7 6,127.76,126.99,120.98,120.64,119.03,54.51,51.90,44.68,16.97; HRMS(APCI)calculated for C 20 H 20 NO5S[M+H] + 386.1057, found 386.104.

[0124] Example 23

[0125] Compound 4w was prepared according to the method of Example 1 with a yield of 71% and a melting point of 215-216.2°C; 1HNMR (400MHz, CDCl3) δ10.03 (s, 1H), 9.95 (s, 1H), 9.21 (d, J = 1.1Hz, 1H), 7.92 (s, 2H), 7.89 (d, J=8.2Hz,2H),7.47(d,J=8.1Hz,2H),4.37(q,J=7.3Hz,2H),3.31(s,3H),1.66(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ191.94,185.10,166.65,145.80,144.03,134.46,134.01,129.64,129.49 ,128.92,128.69,127.97,121.97,120.81,119.38,54.58,52.01,17.05; HRMS(APCI)calculated for C 20 H 18 NO4[M+H] + 336.1230, found 336.1220.

[0126] Example 24

[0127] Compound 4x was prepared according to the method of Example 1 with a yield of 77% and a melting point of 253-255°C; 1 H NMR (400MHz, DMSO) δ9.84(s,1H),9.28(s,1H),9.21(d,J=1.1Hz,1H),8.19(d,J=1.4Hz,1H),7.76(s, 1H),7.05-7.02(m,2H),6.78-6.75(m,2H),4.49(d,J=7.2Hz,2H),3.30(s,3H),1.49(t,J=7.2Hz,3H); 13 C NMR (100MHz, DMSO) δ182.73,166.39,155.40,134.21,129.15,128.91,128.62,127 .57,122.00,119.07,118.93,114.75,53.15,51.69,16.80; HRMS(APCI)calculated for C 19 H 18 NO4[M+H] + 324.1230, found 324.1222.

[0128] Example 25

[0129] Compound 4y was prepared according to the method of Example 1 with a yield of 89% and a melting point of 163.6-165.2°C; 1 HNMR(400MHz, CDCl3)δ9.94(s,1H),9.19(d,J=1.4Hz,1H),7.87(d,J=1.4Hz,1H),7.86(s,1H),7 .36-7.31(m,2H),7.27-7.23(m,2H),4.35(q,J=7.4Hz,2H),3.27(s,3H),1.66(t,J=7.4Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.86,166.85,147.32,143.79,138.12,134.16,129.41, 129.01,128.70,127.39,121.77,120.69,120.18,119.13,54.33,51.73,16.94; 19 FNMR(376MHz, CDCl3)δ-57.89; HRMS(APCI)calculated for C 20 H 17 F3NO4[M+H] + 392.1104, found 392.1091.

[0130] Example 26

[0131] Compound 4z was prepared according to the method of Example 1 with a yield of 66% and a melting point of 209-212°C; 1 HNMR (400MHz, CDCl3) δ9.94(s,1H),9.19(d,J=1.2Hz,1H),7.88(s,1H),7.87(d,J=1.5Hz,1H),7.46(d,J=8.2H z,2H),7.35(d,J=8.2Hz,2H),4.35(q,J=7.3Hz,2H),3.30(s,3H),3.10(d,J=8.2Hz,6H),1.65(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ184.97,171.77,166.99,144.06,140.68,134.24,133.66,129.09,128.78 ,128.04,127.68,127.20,122.58,120.43,119.45,54.44,51.99,17.05; HRMS(APCI)calculated for C 22 H 23N2O4[M+H] + 379.1652, found 379.1642.

[0132] Example 27

[0133] Compound 4aa was prepared according to the procedure of Example 1 in a yield of 67% and a melting point of 206-208°C; 1 HNMR (400 MHz, CDC13) δ 9.91 (s, 1H), 9.12 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 7.8 Hz, 2H), 4.31 (q, J = 7.4 Hz, 2H), 3.31 (s, 3H), 2.98 (s, 6H), 1.64 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 184.80, 167.45, 149.24, 144.23, 133.75, 128.87, 128.72, 128.31, 127.57, 127.42, 123.96, 120.12, 119.73, 112.76, 54.21, 52.30, 41.05, 17.05; HRMS (APCI) calculated for C 21 H 23 N2O3[M+H] + 351.1703, found 351.1693.

[0134] Example 28

[0135] Compound 4bb was prepared according to the procedure of Example 1 in a yield of 59% and a melting point of 175-177.6°C; 1 HNMR (400 MHz, CDC13) δ 9.95 (s, 1H), 9.20 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.91 (s, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.39 (d, J = 8.3 Hz, 2H), 4.36 (q, J = 7.3 Hz, 2H), 3.94 (s, 3H), 3.29 (s, 3H), 1.66 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDC13) δ 184.95, 167.19, 166.68, 143.95, 134.22, 129.33, 129.14, 128.72, 127.98, 127.69, 127.22, 122.14, 120.49, 119.28, 54.38, 52.03, 51.87, 16.94; HRMS (APCI) calculated for C 21 H 20 NO5[M+H] + 366.1336, found 366.1329.

[0136] Example 29

[0137] Compound 4cc was prepared according to the procedure of Example 1 in a yield of 50% and a melting point of 183-185°C; 1 HNMR (400 MHz, CDC13) δ 9.93 (s, 1H), 9.16 (d, J = 1.3 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 4.34 (q, J = 7.4 Hz, 2H), 3.73 (t, 4H), 3.55 (s, 2H), 3.25 (s, 3H), 2.49 (s, 4H), 1.66 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 184.92, 167.14, 144.23, 137.97, 135.25, 134.08, 129.03, 128.77, 128.73, 128.11, 127.53, 123.32, 120.24, 119.49, 67.15, 63.37, 54.35, 53.75, 51.86, 17.05; HRM (APCI) calculated for C 24 H 27 N2O4[M+H] + 407.1965, found 407.1949.

[0138] Test Example 1

[0139] Test for Anti-Tobacco Mosaic Virus Activity

[0140] The test compound was dissolved in DMF to make 1 x 10 5The compound stock solution was prepared at a concentration of 500 μg / mL and 100 μg / mL with a 1 wt‰ Tween-80 aqueous solution. The positive control, ribavirin, was diluted with water to a concentration of 500 μg / mL and 100 μg / mL to obtain a ribavirin solution.

[0141] In vivo inactivation: Select uniformly growing Sansi tobacco plants at the 3-5 leaf stage. Mix the agent solution with an equal volume of virus sap and inactivate for 30 minutes. Then, inoculate by friction at a virus concentration of 20 μg / mL. Immediately rinse with running water after inoculation. Repeat three times. Use a 1 wt‰ Tween-80 aqueous solution as a control. Count the number of lesions after three days and calculate the results.

[0142] In vivo therapeutic effect: Select uniformly growing Sanxi tobacco plants at the 3-5 leaf stage. Use a brush to inoculate the entire leaf with the virus at a concentration of 10 μg / mL. Rinse with running water after inoculation. After the leaves have dried, spray the entire plant with the virus. Each treatment is replicated three times, with a 1‰ Tween-80 aqueous solution control. After three days, record the number of lesions and calculate the control efficacy.

[0143] In vivo protection: Select uniformly growing Sanxi tobacco plants at the 3-5 leaf stage and spray the entire plant with the pesticide. Each treatment was repeated three times, with a 1‰ Tween-80 aqueous solution as a control. After 24 hours, sprinkle the leaves with emery (500 mesh). Use a brush dipped in the virus solution and gently rub the entire leaf surface twice along the veins, supporting the underside of the leaf with the palm of your hand. The virus concentration was 10 μg / mL. After inoculation, rinse with running water. Three days later, the number of lesions was recorded and the efficacy was calculated. The results are shown in Table 1.

[0144] Inhibition rate (%) = [(number of control necrosis spots - number of treated necrosis spots) / number of control necrosis spots] × 100%.

[0145] Table 1 Test results of compounds and ribavirin against tobacco mosaic virus

[0146]

[0147]

[0148] In Table 1, “-” means not measured.

[0149] As shown in Table 1, the inhibitory activity of the target compounds against tobacco mosaic virus (TMV) was evaluated using commercial ribavirin as a positive control. At a concentration of 500 μg / mL, compounds 4d, 4h, 4k, 4m, and 4y exhibited higher levels of activity than ribavirin (inactivation efficacy 39.1±2.6%, therapeutic efficacy 38.4±1.5%, and protective efficacy 39.6±3.8%). Notably, even at a low concentration of 100 μg / mL, compounds 4d, 4e, 4f, 4g, and 4k exhibited higher anti-TMV activity than ribavirin. In particular, compound 4k, which contains a m-methoxyphenyl substituent, exhibited the most potent anti-TMV activity (inactivation efficacy 51.1±1.9%, therapeutic efficacy 50.7±3.6%, and protective efficacy 53.8±2.8% at 500 μg / mL).

[0150] Test Example 2

[0151] Toxicity of compound 4k to adult zebrafish

[0152] Before the experiment, adult zebrafish (2.5-3.0 cm) were cultured for 7-14 days, fed twice a day, with 14 hours of light and 10 hours of darkness, and the temperature was 21-25°C. The toxicity of zebrafish was evaluated using a static test method. First, 500 mg of compound 4k was weighed, dissolved in 5 mL of DMSO, and then diluted to 100 mL with deionized water for use as a stock solution. Seven experimental groups were set up: 0 μg / mL, 1 μg / mL, 2 μg / mL, 4 μg / mL, 6 μg / mL, 8 μg / mL, and 10 μg / mL. Three parallel experiments, A, B, and C, were set up for each concentration gradient experimental group, and each parallel group had 8 zebrafish. The DMSO content in the blank control group was consistent with the DMSO content in the highest concentration group.

[0153] Within 6 hours of the start of the experiment, observe and record the poisoning symptoms and mortality of zebrafish at any time, then observe and record every 24 hours, and change the water every 48 hours. During this period, remove dead fish in a timely manner.

[0154] Figure 1 The figure shows the survival rate of zebrafish exposed to compound 4k. The 0μg / mL, 1μg / mL, 2μg / mL, 4μg / mL, and 6μg / mL experimental groups experienced no mortality during the eight-day exposure experiment, with a survival rate of 100%. The 8μg / mL experimental group experienced mortality on the seventh day, but no further mortality occurred over time, resulting in a survival rate of 96% at the end of the experiment. In the highest concentration group (10μg / mL), no mortality occurred until the sixth day (parallel experiments B and C), with the survival rate dropping to 92%. There was no significant increase in mortality on the seventh day, and the survival rate was 88% at the end of the experiment. These results demonstrate that compound 4k has a low toxicity to zebrafish, even a mild toxic effect.

[0155] Test Example 3

[0156] Insecticidal activity test of compounds 4a to 4cc

[0157] The aphidicide activity assay is performed as follows: The test insects are aphids (Aphis laburni Kaltenbach), a normal population raised on laboratory broad bean leaves. The drug is weighed, dissolved in 1 mL of DMF, and two drops of Tween-20 emulsifier are added. A predetermined amount of distilled water is added and stirred thoroughly to obtain the desired concentration. Broad bean leaves infested with approximately 60 aphids are immersed in the drug for 5 seconds, removed, gently shaken dry, and excess drug absorbed with filter paper. A broad bean branch is then inserted into an absorbent sponge, covered with a glass cover, and sealed with gauze. Results are monitored after 96 hours. Repeat three times for each compound. For a control, only the emulsifier and solvent are added to the distilled water and stirred thoroughly.

[0158] Activity test method for Plutella xylostella larvae: Use the leaf dip method recommended by the International Resistance Action Committee (IRAC). Weigh 2 mg of the agent into a 10 mL beaker on an analytical balance. Dissolve it in 50 μL of dimethylformamide (analytical grade). Add 10 mL of water to make a 200 mg / kg solution. Use straight ophthalmic forceps to immerse the cabbage leaves in the solution for 2-3 seconds, shaking off any excess. Apply one leaf at a time, for a total of three leaves per sample. Place the leaves on the treatment paper in the order in which they were labeled. Once the solution has dried, place it in a labeled 10 cm straight tube, inoculate a second-instar Plutella xylostella larva, and cover the tube with gauze. Place the test treatment in a standard treatment chamber and examine the results after 96 hours. Repeat three times for each compound. For the control, add only the emulsifier and solvent to the distilled water and stir thoroughly.

[0159] The insecticidal activity of the compounds against aphids and diamondback moth larvae was evaluated by leaf dipping method using the botanical insecticide rotenone as a positive control. The results are shown in Table 2. The data in the table are mean ± variance.

[0160] Table 2 Insecticidal effects of compounds and rotenone on aphids and diamondback moth larvae

[0161]

[0162]

[0163] Note: “-” in Table 2 means not tested.

[0164] Table 2 shows that at the initial screening concentration, some compounds showed lethality against aphids, while all compounds exhibited insecticidal activity against Plutella xylostella larvae. Most 5-arylcyclopentapyridines exhibited higher lethality against Plutella xylostella larvae than lead compound 2. Compounds 4d, 4e, 4h, and 4o exhibited 100% insecticidal activity at a concentration of 600 μg / mL, and these compounds also showed significant insecticidal activity at lower concentrations of 200 and 100 μg / mL. Most of these compounds with strong insecticidal activity are fluorine-substituted aryl compounds.

[0165] Test Example 4

[0166] In vitro bactericidal activity test

[0167] In vitro bactericidal test, bacterial growth rate determination method (plate method):

[0168] A certain amount of drug was dissolved in an appropriate amount of acetone and then diluted to the desired concentration with an aqueous solution containing 200 μg / mL emulsifier. 1 mL of the drug solution was then pipetted into each culture dish, and 9 mL of culture medium was added. After shaking, a 50 μg / mL drug-containing plate was prepared. A plate containing 1 mL of sterile water was used as a blank control. A 4 mm diameter punch was used to cut the bacterial disc along the outer edge of the mycelium and transfer it to the drug-containing plate. Each treatment was repeated three times. The culture dish was placed in a constant temperature incubator at 24 ± 1 ° C. After 48 hours, the expanded diameter of the bacterial discs of each treatment was measured, the average value was calculated, and the relative inhibition rate was calculated by comparing with the blank control. The results are shown in Table 3. The data in the table are the mean ± variance.

[0169]

[0170] Table 3 In vitro bactericidal activity test results

[0171]

[0172]

[0173] As shown in Table 3, most compounds exhibited enhanced fungicidal activity after structural modification at the fifth position, with particularly significant activity against rapeseed sclerotia and apple ring spot. Compound 4i achieved 92±3% fungicidal activity against rapeseed sclerotia and exhibited strong inhibitory activity against all seven bacterial species, except peanut brown spot.

[0174] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A 5-aryl-cyclopentapyridine compound having the structure shown in Formula I: The Ar has any one of the following structures:

2. The method for preparing the 5-aryl-cyclopentapyridine compound according to claim 1, comprising the following steps: Compound 3 is subjected to a Suzuki coupling reaction with ArB(OH)2 to obtain the 5-aryl-cyclopenta-pyridine compound; Ar in ArB(OH)2 is defined as in claim 1; 3. The preparation method according to claim 2, characterized in that The molar ratio of the compound 3 to ArB(OH)2 is 1:1-2; The Suzuki coupling reaction is carried out under the conditions of a mixed solvent, a catalyst and an inorganic salt; The mixed solvent comprises an organic solvent and water, wherein the organic solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, acetonitrile, ethanol and methanol; The catalyst is selected from palladium-containing catalysts; The inorganic salt is selected from one or more of alkali metal phosphates, alkali metal carbonates and alkali metal halides; The temperature of the Suzuki coupling reaction is 60-120° C., and the time is 5-24 hours.

4. The preparation method according to claim 2 or 3, characterized in that The preparation method of compound 3 comprises the following steps: Compound 2 and a bromination reagent are mixed to carry out a bromination reaction to obtain compound 3; 5. Use of the 5-aryl-cyclopenta-pyridine compound according to claim 1 in a plant protection agent; the plant protection agent is an anti-plant virus agent, and the anti-plant virus agent is an anti-tobacco mosaic virus agent; the 5-aryl-cyclopenta-pyridine compound is one or more of 4a to 4q, 4s to 4z and 4aa.

6. Use of the 5-aryl-cyclopenta-pyridine compound according to claim 1 in a plant protection agent; the plant protection agent is an agricultural insecticide, and the agricultural insecticide is an insecticide for aphids; the 5-aryl-cyclopenta-pyridine compound is one or more of 4b to 4d, 4i, 4m, 4n, 4p, 4q, 4t, 4w, 4x, 4z and 4bb.

7. Use of the 5-aryl-cyclopenta-pyridine compound according to claim 1 in a plant protection agent; the plant protection agent is an agricultural insecticide, and the agricultural insecticide is an insecticide for the larvae of the diamondback moth; the 5-aryl-cyclopenta-pyridine compound is one or more of 4a to 4z and 4aa to 4cc.

8. Use of the 5-aryl-cyclopenta-pyridine compound according to claim 1 in a plant protection agent; the plant protection agent is an agricultural fungicide, and the agricultural fungicide is one or more fungicides selected from the group consisting of rape sclerotia, apple ring rot, wheat sheath blight, potato late blight, cucumber gray mold, peanut brown spot, tomato early blight, wheat gibberellum, and rice sheath blight; the 5-aryl-cyclopenta-pyridine compound is one or more selected from the group consisting of 4a-4z and 4aa-4cc.

9. A plant protection agent, characterized in that The invention comprises active components and auxiliary materials; the active components include the 5-aryl-cyclopentapyridine compound according to claim 1.

Images