An isoxazoline derivative and its preparation method and application

Abstract

The present invention relates to an isoxazoline derivative, its preparation method, and its application, belonging to the technical field of pharmaceutical synthesis. Specifically, the present invention discloses an isoxazoline derivative represented by general formula (I), a pharmaceutical composition containing the derivative, and its application in the preparation of an antiparasitic drug. The structural formula (I) of the isoxazoline derivative is: The isoxazoline derivative of the present invention is significantly effective in combating parasites, insect vectors, agricultural and forestry pests, and has broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to an isoxazoline derivative and a preparation method and application thereof. Background Art

[0002] γ-Aminobutyric acid (GABA), an important functional non-protein amino acid, is a crucial inhibitory neurotransmitter in the mammalian central nervous system. GABA receptors are important targets for pharmaceuticals, veterinary drugs, and pesticides. Research targeting the γ-Aminobutyric acid-gated chloride (GABA-Cl) channel has led to the development of several marketed drugs, including dieldrin and endosulfan, which were introduced in the mid-to-late 20th century, and isoxazoline and isophthalamide insecticides, which have been released in recent years. With the successful development of new compounds with novel chemical structures and unique modes of action, GABA-Cl insecticides have once again become a hot topic in research and development. Isoxazoline insecticides demonstrate high mammalian safety and insecticidal activity, injecting new vitality into the development of GABA-Cl insecticides.

[0003] Currently, there are four isoxazoline insecticides on the market: Fluralaner, Sarolaner, Afoxolaner, and Lotilaner. All contain the classic isoxazole ring in their structures and are primarily used for external insecticides against cats, dogs, and other animals. Other isoxazoline drugs, such as Fluxametamide and Isocycloseram, are used exclusively in agriculture as broad-spectrum insecticides and acaricides for crops such as fruit trees and vegetables, grains, rice, corn, soybeans, sugar beets, and cotton.

[0004] The compounds involved in the present invention have been studied in the fields of veterinary parasiticides and pesticides to obtain compounds with good activity. They have the potential to develop new pesticides and are expected to achieve huge economic benefits in the treatment of parasites. Summary of the Invention

[0005] The present invention aims to solve the technical problems in the prior art and provide an isoxazoline derivative and its preparation method and application. The technical solution of the present invention is as follows:

[0006] In a first aspect, the present invention provides an isoxazoline derivative, wherein the general structural formula of the isoxazoline derivative is shown in formula (I):

[0007]

[0008] wherein R1 is selected from methyl, methoxy, fluorine, chlorine, and bromine;

[0009] X1 and X2 are each independently selected from carbon and nitrogen;

[0010] R2 is selected from

[0011] Preferably, the isoxazoline derivatives include but are not limited to the following compound structures (1-27):

[0012]

[0013]

[0014]

[0015] In a second aspect, the present invention provides enantiomers, diastereomers, racemates and salts of the isoxazoline derivatives, which are converted into compounds of formula (I) in vivo.

[0016] Preferably, the salt of the isoxazoline derivative is a salt formed by an isoxazoline derivative with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, salicylic acid or phenylacetic acid.

[0017] The third aspect of the present invention also provides a synthetic route for compounds of general formula (I):

[0018] General synthetic route 1:

[0019]

[0020] General synthetic route 2:

[0021]

[0022] General synthetic route 3:

[0023]

[0024] The compound of formula I of the present invention can be obtained by the above or similar preparation methods, and the corresponding starting materials can be selected according to the different substituents and the different positions of the substituents.

[0025] The synthesis steps of the synthetic route 1 include:

[0026] Step 1: The starting materials react in a certain amount ratio to obtain intermediate 1 through condensation reaction.

[0027] Step 2: Intermediate 1 is subjected to condensation reaction to obtain the target compound (isoxazoline derivative), which is then purified by column chromatography to obtain a pure target compound.

[0028] The synthesis steps of the synthetic route 2 include:

[0029] Step 1: The starting materials react in a certain amount ratio to obtain intermediate 2 through condensation reaction, and the pure product of intermediate 2 is obtained by column chromatography.

[0030] Step 2: The target compound (isoxazoline derivative) is obtained by condensation reaction, and purified by column chromatography to obtain a pure target compound.

[0031] The synthesis steps of the synthetic route 3 include:

[0032] Step 1: The starting materials are reacted in a certain amount ratio to obtain intermediate 3 through condensation reaction, and the pure intermediate 3 is obtained by column chromatography or recrystallization.

[0033] Step 2: Deacetyl protecting group is removed by concentrated hydrochloric acid to obtain intermediate 4, which is then purified by column chromatography or recrystallization to obtain pure intermediate 4.

[0034] Step 3: Intermediate 4 is subjected to condensation reaction to obtain the target compound (isoxazoline derivative), which is then purified by column chromatography to obtain a pure target compound.

[0035] Those skilled in the art will appreciate that the above schemes are helpful for understanding the present invention, but are not intended to limit the present invention. Unless otherwise specified, the variables are defined as mentioned in the general formula (I).

[0036] In a fourth aspect, the present invention provides a pharmaceutical composition comprising an isoxazoline derivative represented by general formula (I) or an enantiomer, diastereomer or salt thereof and a pharmaceutically acceptable carrier and / or excipient.

[0037] The pharmaceutical composition of the present invention can be used to prepare various pharmaceutical preparations, such as oral preparations, injections, and external preparations. The pharmaceutical composition of the present invention can be administered alone or in combination with other active pharmaceutical ingredients.

[0038] The oral preparations include, but are not limited to, tablets, granules, capsules, emulsions, suspensions, and oral solutions.

[0039] The pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, adhesives, colorants, fillers, emulsifiers, flavoring agents, and the like.

[0040] Injections can be prepared according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents.

[0041] The fifth aspect of the present invention provides the use of an isoxazoline derivative represented by general formula (I) or its enantiomers, diastereomers, racemates or salts or pharmaceutical compositions thereof in the preparation of drugs for treating parasites, vector insects, agricultural pest infestations or for deworming living environments.

[0042] Preferably, the parasite is a zoonotic parasite or a parasite to which non-human mammals are susceptible.

[0043] More preferably, the parasite is one or more of Cryptosporidium, nematodes, fleas, ticks, Demodex, scabies, ear mites, and lice.

[0044] Preferably, the vector insects are selected from mosquitoes and flies.

[0045] Preferably, the agricultural pests are one or more of the diamondback moth, armyworm, fall armyworm, cotton bollworm, corn borer, mosquito larvae, aphids, spider mites, whiteflies, psyllids, leafhoppers, scale insects, and beetles.

[0046] Preferably, the living environment includes but is not limited to furniture, cars, fabrics, carpets, glass, etc.

[0047] Beneficial effects:

[0048] 1. The present invention provides a novel isoxazoline derivative that exhibits strong insecticidal activity against animal parasites, insects, agricultural pests, etc.

[0049] 2. The isoxazoline derivatives of the present invention have a strong killing effect on animal parasites such as ticks and nematodes, agricultural pests such as diamondback moths and scale insects, and the zoonotic Cryptosporidium, and the overall efficacy is stronger than that of flurella.

[0050] 3. The preparation process of the present invention is simple, energy-saving and environmentally friendly, and easy to industrialize. DETAILED DESCRIPTION

[0051] The following describes the preparation methods of the compounds of general formula (I) of the present invention in conjunction with specific examples, but these specific methods do not limit the present invention in any way. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0052] The starting materials and reaction reagents used in the specific examples of the present invention are all commercially available. Experimental methods in the examples of the present invention where specific conditions are not specified are generally performed under conventional conditions or under conditions recommended by the raw material or product manufacturers.

[0053] The structures of all compounds in the examples were determined by Waters QDa mass spectrometry and H NMR spectra ( 1H-NMR) characterization.

[0054] Example 1

[0055] Preparation of compound 1:

[0056]

[0057] Step 1:

[0058] 0.42 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.14 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.08 g of glycine and 0.2 g of triethylamine were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product. The pure product was obtained by column chromatography as an off-white solid, namely intermediate 2, [M+H] + :477.1, 1 H-NMR(DMSO-d6,300MHz)δ:12.95(s,1H),8.14(s,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d, 1H),7.58(s,1H),7.30-7.41(m,2H),3.84(s,2H),3.18-3.27(t,1H),3.12(d,2H),2.38(s,3H).

[0059] Step 2:

[0060] 0.24 g of intermediate 2 was dissolved in 10 mL of dichloromethane, 0.08 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10 mL of dichloromethane, 0.04 g of hydroxylamine hydrochloride and 0.2 g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30 mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain a crude product, which was purified by column chromatography as an off-white solid, namely compound 1, [M+H] + :491.1, 1H-NMR(DMSO-d6,300MHz)δ:10.05(s,1H),8.14(s,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d,1H),7 .58(s,1H),7.30-7.41(m,2H),7.01(d,1H),4.08(d,2H),3.24(s,2H),3.18-3.27(t,1H),2.38(s,3H).

[0061] Example 2

[0062] Preparation of compound 2:

[0063]

[0064] 0.24 g of intermediate 2 (prepared in Example 1) was dissolved in 10 mL of dichloromethane, 0.08 g of thionyl chloride and 1 drop of N, N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10 mL of dichloromethane, 0.05 g of methoxyamine and 0.2 g of triethylamine were added, and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product. The pure product was obtained by column chromatography as an off-white solid, i.e., compound 2, [M+H] + :505.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.14(s,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d,1H),7.58(s,1H),7. 30-7.41(m,2H),7.01(d,1H),4.08(d,2H),3.89(s,3H),3.24(s,2H),3.18-3.27(t,1H),2.38(s,3H).

[0065] Example 3

[0066] Preparation of compound 3:

[0067]

[0068] Step 1:

[0069] 0.84 g of starting material 1 was dissolved in 15 mL of dichloromethane. 0.25 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice-cooling. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.5 g of triethylamine and 0.29 g of starting material 2 were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask, and the pH was adjusted to 1. The separation was carried out. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product. The pure product was obtained by column chromatography as an off-white solid, namely intermediate 3, [M+H] + :447.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.84(t,1H),8.45(t,2H),8.14(d,1H),8.08(d,1H),7.94(s,1H),7.78-7. 86(d,1H),7.58(s,1H),7.30-7.41(m,1H),4.56(s,2H),3.18-3.27(t,1H),3.12(d,2H),2.38(s,3H).

[0070] Step 2:

[0071] 0.45 g of intermediate 3 was dissolved in 10 mL of N,N-dimethylformamide, and 0.13 g of 2-chloro-1,1,1-fluoroethane and 0.8 g of cesium carbonate were added. The mixture was reacted at room temperature for 2 hours. 40 mL of water and 20 mL of dichloromethane were added to the reaction flask, and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed four times with saturated brine. The organic phase was dried under vacuum to obtain a crude product, which was then purified by column chromatography as an off-white solid, namely compound 3, [M+H] + :491.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.87(t,1H),8.14(d,1H),8.08(d,1H),7.94(s,1H),7.58(s,1H),7.30-7. 41(m,2H),4.38(d,2H),3.32(t,1H),3.24(t,1H),3.18-3.27(d,2H),3.02-3.13(s,2H),2.38(s,3H).

[0072] Example 4

[0073] Preparation of compound 4:

[0074]

[0075] 0.24g of intermediate 2 (prepared in Example 1) was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.06g of methylsulfonylmethylamine and 0.2g of triethylamine were added, and the reaction was continued at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product. The pure product was obtained by column chromatography as a light yellow solid, i.e., compound 4, [M+H] + :567.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.20(t,1H),8.14(s,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d,2H),7.58(s, 1H),7.30-7.41(m,2H),5.35(d,2H),4.08(d,2H),3.24(s,2H),3.18-3.27(t,1H),2.30(s,3H),2.38(s,3H).

[0076] Example 5

[0077] Preparation of compound 5:

[0078]

[0079] Step 1:

[0080] 0.41 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.43 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. After addition, the mixture was heated to reflux for 30 minutes and dried under reduced pressure. The residue was dissolved in 15 mL of dichloromethane and 0.3 g of triethylamine and 0.38 g of starting material 2 were added. The mixture was reacted at room temperature for 1 hour. 30 mL of water was added to the reaction flask for extraction. The mixture was extracted twice with dichloromethane. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain a crude product. The pure product, i.e., intermediate 3, [M+H] + :249.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.10(s,1H),4.21(s,2H),3.92-4.03(m,1H),3.62 -3.78(m,2H),3.32-3.46(m,2H),2.88(s,3H),2.21-2.36(m,2H),1.97(s,3H).

[0081] Step 2:

[0082] 0.5 g of intermediate 3 was dissolved in 15 mL of methanol, 0.45 g of concentrated hydrochloric acid was added, the temperature was raised to react for 2 hours, and the residue was dried under reduced pressure. The residue was dissolved in water, the pH was adjusted to 10, and dichloromethane was added for extraction three times. The organic phases were combined, washed once with saturated brine, and dried under reduced pressure to obtain a crude product. The pure product was recrystallized from ethyl acetate, namely intermediate 4, [M+H] + :207.1, 1 H-NMR(DMSO-d6,300MHz)δ:4.28(s,2H),3.92-4.03(m,1H),3.62-3.78(m,2H),3.32-3.46(m,2H),2.88(s,3H),2.21-2.36(m,2H),1.5(d,2H).

[0083] Step 3:

[0084] 0.21g of intermediate 5 was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.2g of intermediate 4 and 0.2g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain the crude product, and the pure product was obtained by column chromatography as a light yellow solid, i.e., compound 5, [M+H] + :607.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.20(t,1H),8.09(s,1H),7.94(s,1H),7.78-7.86(d,2H),7.58(s,1H),7.30-7.41(m,2H),5.35(d,2H),4 .31(s,2H),3.58-3.72(m,2H),3.26-3.41(m,2H),3.12-3.25(t,1H),2.98-3.09(d,2H),2.91(s,3H),2.48(s,3H),2.13-2.30(m,2H).

[0085] Example 6

[0086] Preparation of compound 6:

[0087]

[0088] Step 1:

[0089] 0.42 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.14 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice-cooling. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.12 g of starting material 2 and 0.2 g of triethylamine were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product. The pure product was obtained by column chromatography as an off-white solid, namely intermediate 3, [M+H] + :516.1, 1 H-NMR(DMSO-d6,300MHz)δ:10.84(s,1H),7.94(s,1H),7.78-7.86(d,2H),7.58(s,1H),7.30-7.41(m,2H),3.74-3.86 (m,2H),3.42-3.57(m,2H),3.12-3.23(t,1H),2.98-3.07(m,2H),2.56-2.62(m,1H),3.12(s,3H),1.90-2.08(m,2H).

[0090] Step 2:

[0091] 0.26g of intermediate 3 was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.05g of 2,2,2-trifluoroethylamine hydroxylamine hydrochloride and 0.2g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain the crude product, and the pure product was obtained by column chromatography as an off-white solid, namely compound 6, [M+H] + :597.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.14(d,1H),8.08(t,1H),7.94(s,1H),7.78-7.86(d,1H),7.58(s,1H),7.30-7.41(m,2H),3.67-3.81(m,2H) ,3.61(d,2H),3.42-3.56(m,2H),2.73(m,1H),3.34-3.45(t,1H),3.18-3.27(t,1H),3.01-3.13(d,2H),1.92-2.15(m,2H),2.38(s,3H).

[0092] Example 7

[0093] Preparation of compound 7:

[0094]

[0095] Step 1:

[0096] 0.44 g of starting material 1 was dissolved in 10 mL of dichloromethane, 0.14 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised to reflux and the reaction was carried out for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10 mL of dichloromethane, 0.08 g of glycine (starting material 2) and 0.2 g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30 mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain a crude product, and the pure product was obtained by column chromatography as an off-white solid, namely intermediate 3, [M+H] + :477.1, 1 H-NMR(DMSO-d6,300MHz)δ:12.95(s,1H),8.14(s,1H),8.08(d,1H),7.78-7.86(d,2H),7 .58(s,1H),7.30-7.41(m,2H),3.84(s,2H),3.18-3.27(t,1H),3.12(d,2H),2.38(s,3H).

[0097] Step 2:

[0098] 0.25g of intermediate 3 was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.04g of hydroxylamine hydrochloride and 0.2g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain the crude product, and the pure product was obtained by column chromatography as an off-white solid, namely compound 7, [M+H] + :511.1, 1 H-NMR(DMSO-d6,300MHz)δ:10.05(s,1H),8.14(s,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d, 1H),7.58(s,1H),7.30-7.41(m,2H),7.01(d,1H),4.08(d,2H),3.24(s,2H),3.18-3.27(t,1H).

[0099] Example 8

[0100] Preparation of compound 8:

[0101]

[0102] 0.25g of intermediate 3 (prepared in Example 7) was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.05g of methoxyamine and 0.2g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product. The pure product was obtained by column chromatography as an off-white solid, i.e., compound 8, [M+H] + :525.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.14(s,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d,1H),7.58(s, 1H),7.30-7.41(m,2H),7.01(d,1H),4.08(d,2H),3.89(s,3H),3.24(d,2H),3.13-3.21(t,1H).

[0103] Example 9

[0104] Preparation of compound 9:

[0105]

[0106] Step 1:

[0107] 0.44 g of starting material 1 was dissolved in 10 mL of dichloromethane, 0.14 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised to reflux and the reaction was carried out for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10 mL of dichloromethane, 0.08 g of glycine (starting material 2) and 0.2 g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30 mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain a crude product, and the pure product was obtained by column chromatography as an off-white solid, namely intermediate 3, [M+H] + :477.1, 1H-NMR(DMSO-d6,300MHz)δ:12.95(s,1H),8.14(s,1H),8.08(d,1H),7.78-7.86(d,1H),7.58(s, 1H),7.30-7.41(m,2H),3.84(s,2H),3.77(s,3H),3.18-3.27(t,1H),3.12(d,2H),2.38(s,3H).

[0108] Step 2:

[0109] 0.25g of intermediate 3 was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.06g of methylsulfonylmethylamine and 0.2g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain the crude product, and the pure product was obtained by column chromatography as a light yellow solid, i.e., compound 9, [M+H] + :583.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.20(t,1H),8.14(s,1H),8.08(s,1H),7.94(s,1H),7.78-7.86(d,2H),7.58(s,1H),7. 30-7.41(m,2H),5.35(d,2H),4.08(d,2H),3.76(s,3H),3.24(s,2H),3.18-3.27(t,1H),2.30(s,3H),2.38(s,3H).

[0110] Example 10

[0111] Preparation of compound 10:

[0112]

[0113] Step 1:

[0114] 0.44 g of starting material 1 was dissolved in 10 mL of dichloromethane, 0.14 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised to reflux and the reaction was carried out for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10 mL of dichloromethane, 0.08 g of glycine (starting material 2) and 0.2 g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30 mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain a crude product, and the pure product was obtained by column chromatography as an off-white solid, namely intermediate 3, [M+H] + :477.1, 1 H-NMR(DMSO-d6,300MHz)δ:12.95(s,1H),8.14(s,1H),8.08(d,1H),7.78-7.86(d,2H),7 .58(s,1H),7.30-7.41(m,2H),3.84(s,2H),3.18-3.27(t,1H),3.12(d,2H),2.38(s,3H).

[0115] Step 2:

[0116] 0.25g of intermediate 3 was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.05g of methoxyamine and 0.2g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain the crude product, and the pure product was obtained by column chromatography as an off-white solid, namely compound 10, [M+H] + :509.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.15(s,1H),8.08(d,1H),7.98(s,1H),7.78-7.86(d,1H),7.58(s, 1H),7.30-7.41(m,2H),7.01(d,1H),4.08(d,2H),3.89(s,3H),3.24(d,2H),3.13-3.21(t,1H).

[0117] Example 11

[0118] Preparation of compound 11:

[0119]

[0120] Step 1:

[0121] 0.86 g of starting material 1 was dissolved in 15 mL of dichloromethane. 0.25 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice-cooling. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.5 g of triethylamine and 0.29 g of starting material 2 were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask, and the pH was adjusted to 1. The separation was carried out. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product. The pure product was obtained by column chromatography as an off-white solid, namely intermediate 3, [M+H] + :467.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.84(t,1H),8.45(t,2H),8.08(d,1H),7.94(s,1H),7.78-7.86(d, 1H),7.58(s,1H),7.30-7.41(m,1H),4.56(s,2H),3.18-3.27(t,1H),3.12(d,2H),2.38(s,3H).

[0122] Step 2:

[0123] Dissolve 0.46 g of intermediate 3 in 10 mL of N,N-dimethylformamide, add 0.13 g of 2-chloro-1,1,1-fluoroethane and 0.8 g of cesium carbonate, and react at room temperature for 2 hours. Add 40 mL of water and 20 mL of dichloromethane to the reaction flask, separate the liquids, extract the aqueous phase twice with dichloromethane, and wash the combined organic phases four times with saturated brine. Dry the organic phase under vacuum to obtain the crude product, which is then purified by column chromatography as an off-white solid, namely, compound 11. [M+H] + :549.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.87(t,1H),8.14(d,1H),8.08(s,1H),7.94(s,1H),7.58(s,1H),7 .30-7.41(m,2H),4.38(d,2H),3.32(t,1H),3.24(t,1H),2.98-3.12(d,2H),3.02-3.13(s,2H).

[0124] Example 12

[0125] Preparation of compound 12:

[0126]

[0127] 0.25g of intermediate 3 (intermediate 3 prepared in Example 7) was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.06g of methylsulfonylmethylamine and 0.2g of triethylamine were added, and the reaction was continued at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product. The pure product was obtained by column chromatography as a light yellow solid, i.e., compound 12, [M+H] + :586.99, 1 H-NMR(DMSO-d6,300MHz)δ:8.20(t,1H),8.14(s,1H),8.09(s,1H),7.94(s,1H),7.78-7.86(d,2H),7.58(s, 1H),7.30-7.41(m,2H),5.35(d,2H),4.08(d,2H),3.76(s,3H),3.24(d,2H),3.18-3.27(t,1H),2.30(s,3H).

[0128] Example 13

[0129] Preparation of compound 13:

[0130]

[0131] 0.5 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.08 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.21 g of starting material 2 and 0.2 g of triethylamine were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product. The pure product was obtained by column chromatography as a light yellow solid, i.e., compound 13, [M+H] + :627.1, 1H-NMR(DMSO-d6,300MHz)δ:8.20(t,1H),8.09(s,1H),7.94(s,1H),7.78-7.86(d,1H),7.58(s,1H),7.30-7.41(m,2H),5.35(d,2H),4 .31(s,2H),4.07(m,1H),3.58-3.72(m,2H),3.26-3.41(m,2H),3.12-3.25(t,1H),2.98-3.09(d,2H),2.91(s,3H),2.13-2.30(m,2H).

[0132] Example 14

[0133] Preparation of compound 14:

[0134]

[0135] Step 1:

[0136] 0.48 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.14 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.12 g of starting material 2 and 0.2 g of triethylamine were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product. The pure product was obtained by column chromatography as an off-white solid, namely intermediate 3, [M+H] + :579.9, 1 H-NMR(DMSO-d6,300MHz)δ:10.84(s,1H),8.09(s,1H),7.78-7.86(d,2H),7.58(s,1H),7.30-7.41(m,2H),3.74-3.86 (m,2H),3.42-3.57(m,2H),3.12-3.23(t,1H),2.98-3.07(m,2H),2.56-2.62(m,1H),3.12(s,3H),1.90-2.08(m,2H).

[0137] Step 2:

[0138] 0.29g of intermediate 3 was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.05g of 2,2,2-trifluoroethylamine hydroxylamine hydrochloride and 0.2g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain the crude product, which was purified by column chromatography as an off-white solid, namely compound 14, [M+H] + :661.2, 1 H-NMR(DMSO-d6,300MHz)δ:8.14(d,1H),8.08(t,1H),7.94(s,1H),7.81-7.92(d,1H),7.58(s,1H),7.30-7.41(m,2H),3.67 -3.81(m,2H),3.61(d,2H),3.42-3.56(m,2H),3.34-3.45(t,1H),3.18-3.27(t,1H),3.01-3.13(d,2H),1.92-2.15(m,2H).

[0139] Example 15

[0140] Preparation of compound 15:

[0141]

[0142] 0.44 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.08 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.21 g of starting material 2 and 0.2 g of triethylamine were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product, which was recrystallized to obtain the pure product as a light yellow solid, i.e., compound 15, [M+H] + :628.1, 1H-NMR(DMSO-d6,300MHz)δ:8.92(s,1H),8.67(s,1H),8.32(s,1H),7.58(s,1H),7.30-7.41(m,2H),4.31(s,2H),4.07 (m,1H),3.58-3.72(m,2H),3.26-3.41(m,2H),3.12-3.25(t,1H),2.98-3.09(d,2H),2.91(s,3H),2.13-2.30(m,2H).

[0143] Example 16

[0144] Preparation of compound 16:

[0145]

[0146] 0.44 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.08 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.11 g of starting material 2 and 0.2 g of triethylamine were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product, which was recrystallized to obtain the pure product as a light yellow solid, i.e., compound 16, [M+H] + :530.9, 1 H-NMR(DMSO-d6,300MHz)δ:8.92(s,1H),8.67(s,1H),8.32(s,1H),7.58(s,1H),7 .30-7.41(m,2H),5.08(s,2H),3.12-3.25(t,1H),2.98-3.09(d,2H),2.91(s,3H).

[0147] Example 17

[0148] Preparation of compound 17:

[0149]

[0150] The operation was the same as in Example 4 above to obtain a light yellow solid, namely compound 17, [M+H] + :581.1, 1H-NMR(DMSO-d6,300MHz)δ:8.20(t,1H),8.14(t,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d,1H),7.58(s,1H),7.30 -7.41(m,2H),5.35(d,2H),4.09(s,2H),3.30(s,2H),3.18-3.27(t,1H),2.85-2.92(m,2H),2.48(s,3H),1.22(t,3H).

[0151] Example 18

[0152] Preparation of compound 18:

[0153]

[0154] The preparation steps were the same as those in Example 4 above to obtain a pale yellow solid, compound 18, [M+H] + :595.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.20(t,1H),8.14(t,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d,1H),7.58(s,1H),7.30-7.41(m, 2H),5.35(d,2H),4.09(s,2H),3.30(s,2H),3.18-3.27(t,1H),2.85-2.92(m,2H),2.48(s,3H),1.62-1.71(m,2H),1.02(t,3H).

[0155] Example 19

[0156] Preparation of compound 19:

[0157]

[0158] 0.41 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.08 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.21 g of starting material 2 and 0.2 g of triethylamine were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product, which was recrystallized to obtain the pure product as a light yellow solid, i.e., compound 13, [M+H] + :595.1, 1H-NMR(DMSO-d6,300MHz)δ:9.22(d,2H),8.29(s,1H),7.58(s,1H),7.30-7.41(m,2H),4.31(s,2H),4.07(m,1H ),3.58-3.72(m,2H),3.26-3.41(m,2H),3.12-3.25(t,2H),2.98-3.09(d,2H),2.32-2.43(d,2H),2.91(s,3H).

[0159] Example 20

[0160] Preparation of compound 20:

[0161]

[0162] The preparation steps were the same as those in Example 2 above to obtain an off-white solid, compound 20, [M+H] + :521.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.16(d,1H),8.14(s,1H),7.60-7.73(d,1H),7.58(s,1H),7.45-7.53(s,1H),7 .30-7.41(m,2H),7.0(s,1H),4.08(d,2H),3.89(s,3H),3.76(s,3H),3.18-3.27(t,1H),3.02-3.13(d,2H).

[0163] Example 21

[0164] Preparation of compound 21:

[0165]

[0166] 0.41 g of starting material 1 was dissolved in 10 mL of dichloromethane. 0.08 g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. The temperature was raised to reflux for 30 minutes. The solvent was removed by rotary evaporation under vacuum. The residue was dissolved in 10 mL of dichloromethane. 0.11 g of starting material 2 and 0.2 g of triethylamine were added and the reaction was continued at room temperature for 1 hour. 30 mL of water was added to the reaction flask and the mixture was separated and extracted. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine. The organic phases were dried under vacuum to obtain the crude product. The pure product was obtained by column chromatography as a pale yellow solid, i.e., compound 21, [M+H] + :531.9, 1H-NMR(DMSO-d6,300MHz)δ:9.62(s,1H),9.38(s,1H),7.58(s,1H),7.30-7. 41(m,2H),5.08(s,2H),3.12-3.25(t,1H),2.98-3.09(d,2H),2.91(s,3H).

[0167] Example 22

[0168] Preparation of compound 22:

[0169]

[0170] 0.21g of starting material 1 was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.05g of 2,2,2-trifluoroethylamine hydrochloride (starting material 2) and 0.2g of triethylamine were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The organic phase was dried under vacuum to obtain a crude product, which was purified by column chromatography as an off-white solid, i.e., compound 22, [M+H] + :521.9, 1 H-NMR(DMSO-d6,300MHz)δ:9.62(s,1H),8.97(s,1H),7.58(s,1H),7.30-7.41(m,2H),3.48(s,2H),3.12-3.25(t,1H),2.98-3.09(d,2H).

[0171] Example 23

[0172] Preparation of compound 23:

[0173]

[0174] 0.26g of intermediate 3 (prepared in Example 6) was dissolved in 10mL of dichloromethane, 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for 30 minutes, the solvent was removed by rotary evaporation under vacuum, the residue was dissolved in 10mL of dichloromethane, 0.05g of methylsulfonylmethylamine and 0.2g of triethylamine were added, and the reaction was continued at room temperature for 1 hour. 30mL of water was added to the reaction flask, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product. The pure product was obtained by column chromatography as a light yellow solid, i.e., compound 23, [M+H] + :607.1,1 H-NMR(DMSO-d6,300MHz)δ:8.21-8.27(t,1H),8.03-8.07(d,1H),7.92(s,1H),7.76-7.82(d,1H),7.58(s,1H),7.30-7.41(m,2H),5.32(s,2H) ,3.58-3.72(m,2H),3.26-3.41(m,2H),3.12-3.25(t,2H),2.98-3.09( d,2H),2.91(s,3H),2.63-2.75(m,1H),2.32-2.43(d,2H),2.48(d,3H).

[0175] Example 24

[0176] Preparation of compound 24:

[0177]

[0178] The preparation steps were the same as those in Example 5 above to obtain a pale yellow solid, compound 24, [M+H] + :621.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.18(d,1H),7.94(s,1H),7.78-7.86(d,1H),7.72-7.80(d,1H),7.58(s,1H),7.30-7.41(m,2H),5.35(d,2H),4.31 (s,2H),4.07(m,1H),3.58-3.72(m,2H),3.26-3.41(m,2H),3.12-3.24( t,1H),2.98-3.09(d,2H),2.91(s,3H),2.13-2.30(m,2H),1.12(t,3H).

[0179] Example 25

[0180] Preparation of compound 25:

[0181]

[0182] The preparation steps were the same as those in Example 23 above to obtain a pale yellow solid, compound 25, [M+H] + :632.1, 1H-NMR(DMSO-d6,300MHz)δ:8.21-8.27(t,1H),8.03-8.07(d,1H),7.92(s,1H) ,7.76-7.82(d,1H),7.58(s,1H),7.30-7.41(m,2H),5.32(s,2H),3.58-3.72( m,2H),3.26-3.41(m,2H),3.12-3.25(t,2H),2.98-3.09(d,2H),2.63-2.75(m ,1H),2.48(d,3H),1.62-1.72(m,1H),1.12-1.20(m,2H),1.22-.1.32(m,2H).

[0183] Example 26

[0184] Preparation of compound 26:

[0185]

[0186] The preparation steps were the same as those in Example 5 above to obtain a pale yellow solid, compound 26, [M+H] + :633.1, 1 H-NMR(DMSO-d6,300MHz)δ:8.18(d,1H),7.94(s,1H),7.78-7.86(d,1H),7 .72-7.80(d,1H),7.58(s,1H),7.30-7.41(m,2H),5.35(d,2H),4.31(s,2H) ,4.07(m,1H),3.58-3.72(m,2H),3.26-3.41(m,2H),3.12-3.24(t,1H),2. 98-3.09(d,2H),1.62-1.72(m,1H),1.12-1.20(m,2H),1.22-.1.32(m,2H).

[0187] Example 27

[0188] Preparation of compound 27:

[0189]

[0190] The preparation steps were the same as those in Example 4 above to obtain a pale yellow solid, compound 27, [M+H] + :593.1, 1H-NMR(DMSO-d6,300MHz)δ:8.20(t,1H),8.14(s,1H),8.08(d,1H),7.94(s,1H),7.78-7.86(d,2H),7.58(s,1H),7.30-7.41(m,2H) ,5.35(d,2H),4.08(d,2H),3.24(s,2H),3.18-3.27(t,1H),2.30(s,3H),1.62-1.72(m,1H),1.12-1.20(m,2H),1.22-.1.32(m,2H).

[0191] Example 28 In vitro insecticidal activity test

[0192] 1. In vitro tick larvae toxicity test

[0193] The compounds of Examples 1-27 were weighed and dissolved and diluted to six different concentration gradients (50 μg / mL, 12.5 μg / mL, 3.1 μg / mL, 0.78 μg / mL, 0.2 μg / mL, and 0.05 μg / mL). Flurellan was used as a positive control group, and a blank control group was set up. In vitro tick larvae toxicity tests were performed. The in vitro tick larvae toxicity results of Compounds 1-27 are shown in Table 1.

[0194] 2. In vitro mosquito larvae toxicity test

[0195] Rearing of mosquito larvae: temperature 25±2℃, relative humidity 75±5%, natural light, mosquitoes were reared to the fourth instar larvae before the experiment.

[0196] Toxicity testing: The compounds of Examples 1-27 were weighed and dissolved and diluted to six different concentrations (1000 μg / mL, 100 μg / mL, 10 μg / mL, 1 μg / mL, 0.1 μg / mL, and 0.01 μg / mL). 20 mL of each solution was prepared for use. Flurellan was used as a positive control group, and a blank control group was also set up. In vitro mosquito larvae toxicity testing was performed. The in vitro mosquito larvae toxicity results of Compounds 1-27 are shown in Table 1.

[0197] 3. In vitro toxicity test of Oesophagostomum dentata

[0198] The compounds of Examples 1-27 were weighed, dissolved, and diluted to six different concentration gradients (1000 μg / mL, 100 μg / mL, 10 μg / mL, 1 μg / mL, 0.1 μg / mL, and 0.01 μg / mL). Flurellanine was used as a positive control group, and a blank control group was set up. The in vitro toxicity results against Oesophagostomum dentata of Compounds 1-27 are shown in Table 1.

[0199] Table 1 In vitro insecticidal activity test results of compounds 1-27

[0200]

[0201]

[0202] The results show that the in vitro toxicity of some of the compounds of the present invention to tick larvae, mosquito larvae and odontostomum dentata is significantly better than that of the marketed drug flurellana, and has certain development value.

[0203] Example 29 Evaluation of the efficacy of tick repellent in vivo

[0204] Beagle dogs, half male and half female, were assigned a blank control group, a flurella-positive group, and an experimental group (compounds of the present invention). The flurella dose was 40 mg / kg, and the compounds of the present invention (Examples 2, 4, 5, 6, 9, 10, 13, 17, 20, 23, 24, 27) were administered at a dose of 40 mg / kg. The experimental dogs were infested with 50 unfed adult ticks (Rhipicephalus sanguinosa). The dogs were treated on day 0, and the average detection rate of external ticks in each group of drugs was calculated on days 0, 5, 10, 20, and 30 after administration. The dogs were observed for any immediate reaction to the treatment after treatment, and adverse reactions, skin irritation, and other phenomena after treatment were observed. The detection rate of ticks in vivo by the compounds is shown in Table 2.

[0205] Table 2 Detection rate of compounds for repelling ticks in vivo

[0206] sample 0 days 5 days 10 days 20 days 30 days Blank group 100％ 100％ 100％ 100％ 100％ Flurella 100％ 5％ 2％ 4％ 8％ Compound 2 100％ 4％ 3％ 3％ 1％ Compound 4 100％ 5％ 0％ 2％ 1％ Compound 5 100％ 3％ 1％ 2％ 1％ Compound 6 100％ 3％ 0％ 1％ 1％ Compound 9 100％ 4％ 1％ 2％ 2％ Compound 10 100％ 6％ 1％ 3％ 3％ Compound 13 100％ 7％ 2％ 1％ 2％ Compound 17 100％ 3％ 2％ 1％ 2％ Compound 20 100％ 5％ 2％ 3％ 3％ Compound 23 100％ 6％ 4％ 1％ 1％ Compound 24 100％ 5％ 2％ 1％ 2％ Compound 27 100％ 4％ 1％ 1％ 2％

[0207] The results show that the compounds of the present invention have tick repellent activity in vivo, and their drug activity is significantly better than that of the marketed drug flurellan after 20 days of administration, and the effect is even more prominent after 30 days.

[0208] Example 30 In vitro toxicity test on diamondback moth

[0209] Plutella xylostella larvae were randomly divided into groups: a blank control, a flurella control group, and experimental groups (compounds from Examples 2, 4, 5, 6, 9, 10, 13, 17, 20, 23, 24, and 27). Thirty larvae were placed on 12-day-old radish plants in each experimental group, and the drug was sprayed onto each group of radish plants. After 48 hours, plant feeding damage was assessed based on leaf ingestion, and Plutella xylostella mortality was counted. The results of Plutella xylostella toxicity are shown in Table 3.

[0210] Table 3 Detection rate of drug toxicity to diamondback moth (based on survival rate)

[0211] sample 0 days 2 days Blank group 100％ 100％ Flurella 100％ 5％ Compound 2 100％ 4％ Compound 4 100％ 2％ Compound 5 100％ 6％ Compound 6 100％ 2％ Compound 9 100％ 3％ Compound 10 100％ 6％ Compound 13 100％ 2％ Compound 17 100％ 3％ Compound 20 100％ 5％ Compound 23 100％ 6％ Compound 24 100％ 3％ Compound 27 100％ 3％

[0212] The results show that the compounds of the present invention have activity in killing Plutella xylostella, and the activity of some of the compounds in the examples is significantly better than that of flurella.

[0213] Example 31 In vitro scale insect toxicity test

[0214] Scale insects were randomly divided into groups: a blank control, a flurella control group, and experimental groups (compounds from Examples 2, 4, 5, 6, 9, 10, 13, 17, 20, 23, 24, and 27). The test drug concentration was set at 100 μg / mL. Thirty diamondback moth larvae were placed on 12-day-old radish plants in each experimental group, and each group of radish plants was dosed by spray. After 48 hours, plant feeding damage was assessed based on leaf ingestion, and scale insect mortality was counted. The scale insect toxicity results are shown in Table 4.

[0215] Table 4 Detection rate of drug toxicity to scale insects (survival rate)

[0216]

[0217]

[0218] The results show that the compounds of the present invention have activity in killing scale insects, and the activity of some of the compounds in the examples is significantly better than that of flurellan.

[0219] Example 32 Human colon cancer (HCT-8) cells were tested for anti-Cryptosporidium in vitro activity

[0220] Using nitazoxanide as the control drug, a positive control group, a blank control group, and experimental groups (compounds of Examples 1-10, 12, 13, 17, 20, 23, 24, and 27) were set up. The test compounds were administered at six concentration gradients (200 μg / mL, 40 μg / mL, 8 μg / mL, 1.6 μg / mL, 0.32 μg / mL, and 0.064 μg / mL) to infected HCT-8 cells. The cells were incubated for 48 hours, and the pharmacodynamic activity was evaluated by staining. The results of the in vitro anti-Cryptosporidium activity test on HCT-8 cells are shown in Table 5.

[0221] Table 5 Results of in vitro anti-Cryptosporidium activity test of HTC-8 cells

[0222] Serial number <![CDATA[IC 50 (μM)]]> Serial number <![CDATA[IC 50 (μM)]]> Serial number <![CDATA[IC 50 (μM)]]> Nitazoxanide 0.11±0.021 Compound 1 0.15±0.11 Compound 2 0.087±0.024 Compound 3 0.093±0.015 Compound 4 0.13±0.057 Compound 5 0.085±0.015 Compound 6 0.089±0.016 Compound 7 0.22±0.14 Compound 8 0.17±0.033 Compound 9 0.048±0.022 Compound 10 0.064±0.010 Compound 12 0.17±0.019 Compound 13 0.073±0.025 Compound 17 0.083±0.033 Compound 20 0.092±0.034 Compound 23 0.042±0.017 Compound 24 0.047±0.015 Compound 27 0.038±0.012

[0223] The results show that the compounds of the present invention have anti-Cryptosporidium activity, and the activities of some of the compounds in the examples are significantly better than nitazoxanide.

[0224] The above experiments have verified that the isoxazoline derivatives represented by the general formula (I) of the present invention have strong antiparasitic, insect-killing and agricultural and forestry pest-killing activities, as well as insect repellent activities in living environments, and exhibit better effects than existing compounds, and have great application prospects.

Claims

1. An isoxazoline derivative having the following structure: 。 2. A salt of an isoxazoline derivative as claimed in claim 1, characterized in that The salt of the isoxazoline derivative is a salt formed by the isoxazoline derivative and the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, salicylic acid or phenylacetic acid.

3. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the isoxazoline derivative according to claim 1 or the salt according to claim 2 and one or more pharmaceutically acceptable carriers and / or excipients.

4. Use of an isoxazoline derivative according to claim 1, or a salt according to claim 2, or a pharmaceutical composition according to claim 3 in the preparation of a medicament for controlling parasites, characterized in that: The parasites are Cryptosporidium, nematodes and ticks.

Images