Isoxazoline derivative as well as preparation method and application thereof

Abstract

The invention relates to an isoxazoline derivative as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. Specifically, the invention discloses an isoxazoline derivative as shown in a general formula (I), a pharmaceutical composition containing the derivative and application of the isoxazoline derivative and the pharmaceutical composition in preparation of anti-parasitic drugs. The structural general formula (I) of the isoxazoline derivative is # imgabs0. The isoxazoline derivative disclosed by the invention has a remarkable effect in the aspects of resisting parasites, vector insects, agricultural and forestry pests and the like, and has a wide application prospect.

Description

Technical Field

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

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

[0003] There are four isoxazoline insecticides on the market: Fluralaner, Sarolaner, Afoxolaner and Lotilaner, all of which contain the classic isoxazole ring in their structures and are mainly used for external insecticides in animals such as cats and dogs. Other isoxazoline drugs are only used in the agricultural field, such as Fluxametamide and Isocycloseram as broad-spectrum insecticides and miticides, used for fruit trees and vegetables, grains, rice, corn, soybeans, sugar beets, cotton and other crops.

[0004] The compounds involved in the present invention are studied in the aspects of veterinary parasiticides and pesticides to obtain compounds with good activity, which 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 a preparation method and application thereof. 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 as 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 the second aspect of the present invention, enantiomers, diastereomers, racemates and salts of the isoxazoline derivatives are provided, which are converted into compounds of the general formula (I) in vivo.

[0016] Preferably, the salt of the isoxazoline derivative is a salt formed by an 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.

[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 the general 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 are reacted in a certain dosage 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 through 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 react in a certain amount ratio to obtain intermediate 3 through condensation reaction, and the pure intermediate 3 is obtained through column chromatography or recrystallization.

[0033] Step 2: Deacetylating the protecting group with concentrated hydrochloric acid to obtain intermediate 4, and then column chromatography or recrystallization to obtain the 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 should realize that the above schemes are helpful for understanding the present invention, but are not limited to the present invention. Unless otherwise specified, the variables are defined as mentioned in the general formula (I).

[0036] The fourth aspect of the present invention provides a pharmaceutical composition, which comprises an isoxazoline derivative represented by general formula (I) or its 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, binders, 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 the general formula (I) or its enantiomer, diastereomer, racemate or salt or its pharmaceutical composition in the preparation of a drug for treating parasites, vector insects, agricultural pest infestations or for deworming the living environment.

[0042] Preferably, the parasite is a zoonosis 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 which 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 cryptosporidium, which is a zoonosis, 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 preparation methods of the compounds of the general formula (I) of the present invention are described below in conjunction with specific examples, but these specific methods do not constitute any limitation to the present invention. 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, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0052] The starting materials, reaction reagents, etc. used in the specific examples of the present invention are all commercially available. The experimental methods in the examples of the present invention without specifying specific conditions are usually carried out 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] 0.42g of the starting material 1 was dissolved in 10mL of dichloromethane, 0.14g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath, the temperature was raised and refluxed for reaction for 30 minutes, the solvent was removed by vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.08g of glycine 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 organic phases were combined and washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product, and 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] 0.24g of intermediate 2 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 vacuum rotary evaporation, 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and 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, i.e., 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] 0.24g 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 vacuum rotary evaporation, 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and the organic phase was dried under vacuum to obtain a crude product, and the pure product was obtained by column chromatography, 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] 0.84g of the starting material 1 was dissolved in 15mL of dichloromethane, 0.25g 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.5g of triethylamine and 0.29g of the starting material 2 were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction bottle, the pH was adjusted to 1, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined and washed once with saturated brine, and the organic phases were 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] + :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, and 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, and the pure product was obtained 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 vacuum rotary evaporation, 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and the organic phase was dried under vacuum to obtain a crude product, and the pure product was obtained by column chromatography, 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] 0.41g of the starting material 1 was dissolved in 10mL of dichloromethane, and 0.43g of thionyl chloride and 1 drop of N,N-dimethylformamide were added under ice bath. After the addition, the temperature was raised to reflux for reaction for 30 minutes, and vacuum dried under reduced pressure. The residue was dissolved in 15mL of dichloromethane, and 0.3g of triethylamine and 0.38g of the starting material 2 were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction bottle for extraction, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed once with saturated brine, and vacuum dried under reduced pressure to obtain a crude product. The pure product was obtained by column chromatography, namely 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 to extract 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, i.e., 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 vacuum rotary evaporation, 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and the organic phase was dried under vacuum to obtain a 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] 0.42g of the starting material 1 was dissolved in 10mL of dichloromethane, 0.14g 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.12g of the 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined and washed once with saturated brine, and the organic phases were 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] + :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 reaction for 30 minutes, the solvent was removed by vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.05g of 2,2,2-trifluoroethylamine 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and 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, i.e., 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] 0.44g of the starting material 1 was dissolved in 10mL of dichloromethane, 0.14g 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.08g of glycine (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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and 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] Dissolve 0.25g of intermediate 3 in 10mL of dichloromethane, add 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide in an ice bath, heat and reflux for 30 minutes, remove the solvent by vacuum evaporation, and dissolve the residue in 10mL of dichloromethane, add 0.04g of hydroxylamine hydrochloride and 0.2g of triethylamine, and react at room temperature for 1 hour. Add 30mL of water to the reaction bottle, separate and extract, extract the aqueous phase twice with dichloromethane, combine the organic phases and wash once with saturated brine, dry the organic phase under vacuum to obtain a crude product, and obtain a pure product by column chromatography, an off-white solid, i.e., 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 vacuum rotary evaporation, 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and 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, 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] 0.44g of the starting material 1 was dissolved in 10mL of dichloromethane, 0.14g 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.08g of glycine (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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and 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] Dissolve 0.25g of intermediate 3 in 10mL of dichloromethane, add 0.08g of thionyl chloride and 1 drop of N,N-dimethylformamide under ice bath, heat and reflux for 30 minutes, remove the solvent by vacuum rotary evaporation, dissolve the residue in 10mL of dichloromethane, add 0.06g of methylsulfonylmethylamine and 0.2g of triethylamine, and react at room temperature for 1 hour. Add 30mL of water to the reaction bottle, separate and extract, extract the aqueous phase twice with dichloromethane, combine the organic phases and wash once with saturated brine, dry the organic phase under vacuum to obtain a crude product, and obtain a pure product by column chromatography, 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] 0.44g of the starting material 1 was dissolved in 10mL of dichloromethane, 0.14g 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.08g of glycine (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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and 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 vacuum rotary evaporation, 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined and washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product, and the pure product was obtained by column chromatography as an off-white solid, i.e., 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] Embodiment 11

[0118] Preparation of compound 11:

[0119]

[0120] Step 1:

[0121] 0.86g of the starting material 1 was dissolved in 15mL of dichloromethane, 0.25g 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.5g of triethylamine and 0.29g of the starting material 2 were added, and the reaction was carried out at room temperature for 1 hour. 30mL of water was added to the reaction bottle, the pH was adjusted to 1, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined and washed once with saturated brine, and the organic phases were 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] + :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] 0.46g of intermediate 3 was dissolved in 10mL of N,N-dimethylformamide, and 0.13g of 2-chloro-1,1,1-fluoroethane and 0.8g of cesium carbonate were added, and the mixture was reacted at room temperature for 2 hours. 40mL of water and 20mL 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, and the pure product was obtained 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 vacuum rotary evaporation, 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and the organic phase was dried under vacuum to obtain a crude product, and 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] Embodiment 13

[0129] Preparation of compound 13:

[0130]

[0131] 0.5 g of the 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 and refluxed for reaction 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 the 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, the organic phases were combined and washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product, and 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] Embodiment 14

[0133] Preparation of compound 14:

[0134]

[0135] Step 1:

[0136] 0.48g of the starting material 1 was dissolved in 10mL of dichloromethane, 0.14g 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.12g of the 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, the organic phase was combined and washed once with saturated brine, and 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] + :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 reaction for 30 minutes, the solvent was removed by vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.05g of 2,2,2-trifluoroethylamine 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and 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, i.e., 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] Embodiment 15

[0140] Preparation of compound 15:

[0141]

[0142] 0.44g of the 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.21g of the 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined and washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product, which was recrystallized to obtain a pure product, 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] 0.44g of the 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.11g of the 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined and washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product, which was recrystallized to obtain a pure product, 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] Embodiment 17

[0148] Preparation of compound 17:

[0149]

[0150] The operation was the same as in Example 4 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] Embodiment 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, namely 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] Embodiment 19

[0156] Preparation of compound 19:

[0157]

[0158] 0.41g of the 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.21g of the 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined and washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product, which was recrystallized to obtain a pure product, 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] Embodiment 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, namely 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] Embodiment 21

[0164] Preparation of compound 21:

[0165]

[0166] 0.41g of the 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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.11g of the 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, the organic phases were combined and washed once with saturated brine, and the organic phases were dried under vacuum to obtain a crude product, and the pure product was obtained by column chromatography as a light 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] Embodiment 22

[0168] Preparation of compound 22:

[0169]

[0170] 0.21g of the 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 reaction for 30 minutes, the solvent was removed by vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.05g of 2,2,2-trifluoroethylamine hydrochloride hydroxylamine (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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and 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, 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] Embodiment 23

[0172] Preparation of compound 23:

[0173]

[0174] 0.26g of intermediate 3 (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 vacuum rotary evaporation, the residue was dissolved in 10mL of dichloromethane, 0.05g 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 bottle, and the liquid was separated and extracted. The aqueous phase was extracted twice with dichloromethane, the organic phase was combined and washed once with saturated brine, and the organic phase was dried under vacuum to obtain a crude product, and 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] Embodiment 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, namely 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] Embodiment 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, namely 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] Embodiment 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, namely 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] Embodiment 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, namely 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 drugs of the compounds of Examples 1-27 were weighed, dissolved and diluted to 6 different gradient concentrations (50 μg / mL, 12.5 μg / mL, 3.1 μg / mL, 0.78 μg / mL, 0.2 μg / mL, 0.05 μg / mL), and flurellana was used as a positive control group. A blank control group was set up at the same time to conduct an in vitro tick larvae drug activity test. 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 4th instar larvae before the experiment.

[0196] Toxicity test: Weigh the drugs of the compounds of Examples 1-27, dissolve and dilute to 6 different gradient concentrations (1000 μg / mL, 100 μg / mL, 1 μg / mL, 0.1 μg / mL, 0.01 μg / mL), and prepare 20 mL of each solution for standby use. Fluorella was used as the positive control group, and a blank control group was set up to test the drug activity of mosquito larvae in vitro. 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 drugs of the compounds of Examples 1-27 were weighed, dissolved and diluted to 6 different gradient concentrations (1000 μg / mL, 100 μg / mL, 10 μg / mL, 1 μg / mL, 0.1 μg / mL, 0.01 μg / mL), and flurellana was used as a positive control group. A blank control group was set up at the same time to conduct an in vitro drug activity test on the toothed esophagostomum nematode. The in vitro toxicity results of compounds 1-27 on the toothed esophagostomum nematode 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 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] Beagles were divided into a blank control group, a flurellana positive group, and an experimental group (compounds of the present invention) with half male and half female dogs. The flurellana dosage 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 dosage of 40 mg / kg. The experimental dogs were attacked by 50 unfed adult ticks (Rhipicephalus sanguinosa). The dogs were treated on day 0, and the average detection rate of ticks in the external body of the dogs was calculated on days 0, 5, 10, 20, and 30 after administration. After the treatment, the dogs were observed for any immediate reaction to the treatment, and the adverse reactions, skin irritation, and other phenomena after the treatment were observed. The detection rate of ticks in the body of the compounds is shown in Table 2.

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

[0206] sample Day 0 5 days 10 days 20 days 30 days Blank Group 100％ 100％ 100％ 100％ 100％ Flurellana 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 examples of the present invention have tick repellent activity in vivo, and the drug activity is significantly better than that of the marketed drug flurellana after 20 days of medication, and the effect is more prominent after 30 days.

[0208] Example 30 In vitro toxicity test on Plutella xylostella

[0209] The diamondback moth larvae were randomly divided into groups, and blank control, flurellana control drug group, and experimental group (compounds of Examples 2, 4, 5, 6, 9, 10, 13, 17, 20, 23, 24, and 27) were set. The concentration of the drug to be tested was 100 ug / mL. Thirty diamondback moth larvae were placed on 12-day-old radish plants in each experimental group, and each group of radish plants was medicated by spraying. After 48 hours, the plant feeding damage was assessed based on the leaves ingested and the mortality of diamondback moth was counted. The diamondback moth toxicity results are shown in Table 3.

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

[0211] sample Day 0 2 days Blank Group 100％ 100％ Flurellana 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] The scale insects were randomly divided into groups, and blank control, flurellana control drug group, and experimental group (compounds of Examples 2, 4, 5, 6, 9, 10, 13, 17, 20, 23, 24, and 27) were set. The concentration of the drug to be tested was set to 100 ug / mL. 30 diamondback moth larvae were placed on 12-day-old radish plants in each experimental group, and each group of radish plants was medicated by spraying. After 48 hours, the plant feeding damage was assessed based on the leaves ingested and the 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 flurellana.

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

[0220] Nitazoxanide was used as a control drug, and a positive control group, a blank control group, and an experimental group (compounds of Examples 1-10, 12, 13, 17, 20, 23, 24, and 27) were set up. The compounds to be tested were administered according to 6 concentration gradients (200 μg / mL, 40 μg / mL, 8 μg / mL, 1.6 μg / mL, 0.32 μg / mL, and 0.064 μg / mL) and added to infected HCT-8 cells, incubated for 48 hours, and the drug activity was evaluated by staining. The results of the in vitro activity test of HTC-8 cells against Cryptosporidium 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 activity of some of the compounds in the examples is significantly better than that of nitazoxanide.

[0224] Through the above experiments, it is verified that the isoxazoline derivatives represented by the general formula (I) of the present invention have strong antiparasitic, insect vector and agricultural and forestry pest killing activities and living environment anthelmintic activity, and have better effects than existing compounds and have great application prospects.

Claims

1. An isoxazoline derivative, the structure of which is shown in the general formula (I): Wherein R1 is selected from methyl, methoxy, fluorine, chlorine, and bromine; X1 and X2 are each independently selected from carbon and nitrogen; R2 is selected from 2. The isoxazoline derivative according to claim 1, characterized in that The isoxazoline derivative is one of structures 1-27:

3. An enantiomer, diastereomer or racemate of the isoxazoline derivative as claimed in claim 1 or 2.

4. A salt of an isoxazoline derivative as claimed in claim 1 or 2, 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.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the isoxazoline derivative according to claim 1 or 2, or the enantiomer, diastereomer, racemate according to claim 3, or the salt according to claim 4, and one or more pharmaceutically acceptable carriers and / or excipients.

6. Use of an isoxazoline derivative as claimed in claim 1 or 2, or an enantiomer, diastereomer, racemate as claimed in claim 3, or a salt as claimed in claim 4, or a pharmaceutical composition as claimed in claim 5 in the preparation of a medicament for controlling parasites, vector insects, agricultural pests or for anthelmintics in living environments.

7. The use according to claim 6, characterized in that: The parasite is a zoonosis parasite or a parasite that non-human mammals are susceptible to.

8. The use according to claim 7, characterized in that: The parasites are one or more of Cryptosporidium, nematodes, fleas, ticks, Demodex, scabies, ear mites, and lice.

9. The use according to claim 6, characterized in that: The vector insects are selected from mosquitoes and flies.

10. The use according to claim 6, characterized in that: The agricultural pests are one or more of diamondback moth, armyworm, fall armyworm, cotton bollworm, corn borer, mosquito larvae, aphids, spider mites, whiteflies, psyllids, leafhoppers, scale insects and beetles.

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