Triazine derivative, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a triazine derivative, a preparation method therefor and the use thereof, belonging to the technical field of drug synthesis. Specifically, disclosed in the present invention are a triazine derivative represented by general formula (I), a pharmaceutical composition containing the triazine derivative, and the use thereof in the preparation of an anthelmintic drug for humans or animals. The general structural formula (I) of the triazine derivative is shown as follows. The triazine derivative of the present invention has a significant effect in resisting zoonotic helminths such as nematodes and heartworms, and has a broad application prospect.

Description

Triazine derivative and preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical compounds, and particularly relates to a triazine derivative and a preparation method and application thereof. BACKGROUND

[0002] The most common intestinal parasitic worms in the world include intestinal nematodes, roundworms, filarial worms, and blood flukes. Filarial disease is a parasitic disease caused by thread-like filarial nematodes, and is also a vector-borne disease transmitted through insect bites. The main causes of human filarial disease are filarial nematodes, Brugia malayi, Brugia timori, Wuchereria bancrofti, Mansonella, and the like. At present, nematode infection is still the root cause of high morbidity and increased mortality in some parts of the world.

[0003] Currently, praziquantel, ivermectin, and albendazole and the like used in clinical practice can kill the larvae of parasitic nematodes, but these drugs have poor efficacy on adult worms. For parasitic worms, only waiting for their natural death, and persisting in long-term medication to kill the larvae, on the one hand, leads to drug resistance of the parasites, and on the other hand, brings great pain to the infected persons. Especially, filarial worms can parasitize in the human and animal bodies, and may cause serious and life-threatening diseases to humans.

[0004] The present application relates to the study of the compounds in killing parasitic worms, and good active compounds are obtained, which have the potential to become new insecticides, and are expected to achieve great economic benefits in parasitic worm treatment. SUMMARY

[0005] The present application aims to solve the technical problems in the prior art, and provides a triazine derivative and a preparation method and application thereof.

[0006] To achieve the above-mentioned purposes, the specific technical solutions of the present application are as follows:

[0007] The present application provides a triazine derivative as shown in general formula (I):

[0008] wherein R1 and R2 are each independently selected from the group consisting of 2-pyridyl, 3-pyridyl, pyrazinyl, phenyl, 2-4,5,6,7-tetrahydrothiazolo[5,4-B]pyridyl, pyrimidinyl, benzotriazolyl, and the above-mentioned groups are unsubstituted or substituted with one or more substituents; the substituents are independently selected from halogen, -CN, -CH3, -OCH3, -CF3, -OCH(CH3)2, -OCH2CH3, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 3-6-membered heterocyclyl, -NH2, -NSO2CH3, -NSO2(CH2)1-3 CH3, -COOCH3, -COOCH2CH3, -SO2CH3, -SO2CH(CH3)2, -N(CH3)2, -CONH2, -N(CH2CH3)2, -CONHCH3, -CON(CH3)2, and substituted or unsubstituted aryl; R3 is selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy.

[0009] Preferably, the derivative is one of structures 1-42 in Table 1:

[0010] Table 1 Triazine derivatives 1-42

[0011] In a second aspect of the present application, enantiomers, diastereomers, racemates of the triazine derivatives, and salts of the triazine derivatives are provided, which are converted into the compound of general formula (I) in vivo.

[0012] The salt of the triazine derivative is a salt of the triazine derivative of formula (I) with 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; and also salts of the compound of general formula (I) with inorganic bases or organic salts formed from basic amines.

[0013] In a third aspect of the present application, a synthesis route of the triazine derivative is also provided.

[0014] The compound of general formula (I) can be obtained by the above or similar preparation method, and the corresponding starting material is selected according to the difference of the substituent group and the difference of the substituent group position.

[0015] When the triazine ring R2 and R1 are the same substituent group, the target compound can be synthesized in one step according to step 1, and the starting material is reacted in a molar ratio of 1:2. When the triazine ring R2 and R1 are different substituent groups, step 1 of the synthesis route is reacted in a molar ratio of 1:1 according to the starting material, and the intermediate product is obtained by substitution reaction, and the pure product is obtained by column chromatography; step 2 is also obtained by substitution reaction to obtain the target compound, and the pure product is obtained by column chromatography purification.

[0016] In a fourth aspect of the present application, a pharmaceutical composition is provided, which comprises the triazine derivative or the salt or the enantiomers, diastereomers, racemates and one or more than one pharmaceutical carrier and / or excipient.

[0017] The pharmaceutical composition further comprises one or more than one antiparasitic active ingredient.

[0018] The antiparasitic active ingredient is selected from one or more than one of flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, cambendazole, ivermectin, abamectin, diethylcarbamazine, suramin, tribendimidine, pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, morantel, oxyclozanide, oxfendazole, pomegranate alkaloid sulfate, and moxidectin.

[0019] In a fifth aspect, the present application provides the use of the triazine derivative of the general formula (I) or the salt or the enantiomer, diastereomer, racemate or the pharmaceutical composition thereof in the preparation of a medicament for the prevention and treatment of parasitic infection in humans or animals.

[0020] Preferably, the parasite is a helminth.

[0021] More preferably, the parasite is a nematode. Advantages:

[0022] 1. The triazinyl derivative provided by the present application exhibits strong insecticidal activity against animal parasites, particularly helminths, especially nematodes, thereby laying a solid foundation for the development of new drugs.

[0023] 2. The preparation process of the present application is simple, energy-saving and environmentally friendly, and is easy to industrialize. DETAILED DESCRIPTION

[0024] The above will be further described in detail through the specific embodiments in the form of examples. However, this should not be understood as limiting the scope of the above subject matter to the following examples. Any technology realized based on the content of the present application is within the scope.

[0025] The starting materials and reaction reagents used in the specific embodiments of the present application are commercially available. The present application can be prepared into a salt form by using the salt formation method commonly used in the art.

[0026] The experimental methods not specified in the embodiments of the present application are usually carried out according to the conventional conditions, or according to the conditions suggested by the manufacturers of raw materials or commodities.

[0027] The structures of all compounds in the examples are characterized by waters QDa mass spectrometry and nuclear magnetic resonance hydrogen spectrum (H-NMR). 1 H-NMR).

[0028] Preparation of compound 1 in example 1

[0029] Step 1: Dissolve cyanuric chloride 1.8 g in acetone 20 mL, add 2-amino-5- methylpyridine 1.1 g, heat to reflux for 3 h, after reaction, remove solvent by vacuum evaporation, dissolve the residue in dichloromethane 20 mL, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] + : 256.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.90 (d, 1H), 7.31 (t, 1H), 6.54 (t, 1H), 2.16 (s, 3H).

[0030] Step 2: Dissolve 2.5 g compound 3 in isopropanol 20 mL, add 1.3 g m- methoxyaniline, heat to reflux for 2 h, after reaction, remove solvent by vacuum evaporation, dissolve the residue in dichloromethane 20 mL, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] + : 343.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 7.90 (d, 1H), 7.31 (t, 1H), 7.29 (d, 1H), 7.21 (t, 1H), 6.82 (s, 1H), 6.54 (t, 1H), 6.49 (d, 1H), 3.74 (s, 3H), 2.16 (s, 3H).

[0031] Preparation of compound 2 of Example 2

[0032] Step 1: Dissolve cyanuric chloride 1.8 g in acetone 20 mL, add 2-amino-5- methylpyridine 2.2 g, heat to reflux for 3 h, after reaction, remove solvent by vacuum evaporation, dissolve the residue in dichloromethane 20 mL, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] + : 328.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 7.90 (d, 2H), 7.31 (m, 2H), 6.54 (m, 2H), 2.16 (s, 6H).

[0033] Preparation of compound 3 of Example 3

[0034] Step 1: Dissolve cyanuric chloride 1.8 g in acetone 20 mL, add 5-(1-piperidinyl)-2- aminopyridine 1.8 g, heat to reflux for 3 h, reaction complete, remove solvent by vacuum rotary evaporation under reduced pressure, dissolve residue in 20 mL dichloromethane, add water to separate, extract with dichloromethane three times, combine organic phase, wash with saturated brine once, remove solvent to get crude product, column chromatography to get pure product. Off-white solid. [M+H] + : 325.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.90 (d, 1H), 7.31 (t, 1H), 6.54 (t, 1H), 3.06 (m, 4H), 1.66-1.60 (m, 6H).

[0035] Step 2: Dissolve 3.2 g compound 3 in isopropanol 20 mL, add 1.3 g 2-amino-5- chloropyridine, heat to reflux for 2 h, reaction complete, remove solvent by vacuum rotary evaporation under reduced pressure, dissolve residue in 20 mL dichloromethane, add water to separate, extract with dichloromethane three times, combine organic phase, wash with saturated brine once, remove solvent to get crude product, column chromatography to get pure product. Off-white solid. [M+H] + : 417.2, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 7.98 (s, 1H), 7.42 (d, 1H), 7.17 (s, 1H), 6.79 (d, 1H), 6.65 (t, 2H), 3.06 (m, 4H), 1.66 (m, 4H), 1.60 (m, 2H).

[0036] Preparation of compound 4 of Example 4

[0037] Step 1: Dissolve cyanuric chloride 1.8 g in acetone 20 mL, add 5-(1-piperidinyl)-2- aminopyridine 1.8 g, heat to reflux for 3 h, reaction complete, remove solvent by vacuum rotary evaporation under reduced pressure, dissolve residue in 20 mL dichloromethane, add water to separate, extract with dichloromethane three times, combine organic phase, wash with saturated brine once, remove solvent to get crude product, column chromatography to get pure product. Off-white solid. [M+H] + : 242.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.18 (s, 1H), 8.04 (s, 1H), 7.92 (d, 1H), 7.36 (t, 1H), 7.15 (d, 1H).

[0038] Step 2: 2.4 g of compound 3 was dissolved in isopropanol 20 mL, 1.3 g of 3- methoxyaniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The combined organic phase was washed once with saturated brine and then desolventized to obtain a crude product, which was column chromatographed to obtain a pure product. White solid. [M+H] + :328.7, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.92 (d, 1H), 7.36 (m, 2H), 7.21 (m, 2H), 6.82 (s, 1H), 6.49 (d, 1H), 3.74 (s, 3H).

[0039] Preparation of compound 5 in Example 5

[0040] Step 1: 1.8 g of cyanuric chloride was dissolved in acetone 20 mL, 1.4 g of 2- amino-3-isopropoxy pyridine was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The combined organic phase was washed once with saturated brine and then desolventized to obtain a crude product, which was column chromatographed to obtain a pure product. White solid. [M+H] + :301.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.14 (s, 1H), 7.92 (m, 2H), 4.69 (t, 1H), 1.31 (s, 6H).

[0041] Step 2: 3.0 g of compound 3 was dissolved in isopropanol 20 mL, 1.0 g of 6- methyl-2 amino pyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The combined organic phase was washed once with saturated brine and then desolventized to obtain a crude product, which was column chromatographed to obtain a pure product. White solid. [M+H] + :372.8, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 7.71 (s, 1H), 7.42 (m, 1H), 6.98 (d, 1H), 6.79 (m, 2H), 6.30 (d, 1H), 4.69 (m, 1H), 1.31 (s, 6H).

[0042] Preparation of compound 6 in Example 6

[0043] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 7-amino-4,5,6,7- tetrahydrothiazolo[5,4-B]pyridine 1.6 g was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane. Water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Saturated brine was washed once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :304.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.25 (s, 1H), 6.79 (s, 1H), 6.74 (t, 1H), 3.81 (t, 1H), 3.09 (m, 2H), 1.92 (m, 2H).

[0044] Step 2: 3.0 g of compound 3 was dissolved in isopropanol 20 mL, 1.0 g of 6-methyl-2- aminopyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane. Water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Saturated brine was washed once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :372.8, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 8.25 (s, 1H), 7.42 (m, 1H), 6.74 (t, 1H), 6.67 (m, 2H), 6.30 (d, 1H), 3.92 (s, 3H), 3.81 (t, 1H), 3.09 (m, 2H), 2.46 (s, 3H), 1.92 (m, 2H).

[0045] Preparation of compound 7 of Example 7

[0046] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 7-amino-4,5,6,7- tetrahydrothiazolo[5,4-B]pyridine 1.6 g was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane. Water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Saturated brine was washed once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :233.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.06 (s, 1H), 8.38 (d, 1H), 7.32 (s, 1H), 6.82 (d, 1H).

[0047] Step 2: 2.3 g of compound 3 was dissolved in isopropanol 20 mL, 1.2 g of 3- ethylaniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :318.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.38 (d, 1H), 7.53 (m, 2H), 7.29 (m, 3H), 6.82 (m, 2H), 2.72 (m, 2H), 1.18 (t, 3H).

[0048] Preparation of compound 8 of Example 8

[0049] Step 1: 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.1 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :236.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.85 (d, 1H), 6.52 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H).

[0050] Step 2: 2.4 g of compound 3 was dissolved in isopropanol 20 mL, 1.1 g of 6-methyl-2- aminopyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :318.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.38 (d, 1H), 7.53 (m, 2H), 7.29 (m, 3H), 6.82 (m, 2H), 2.72 (m, 2H), 1.18 (t, 3H).

[0051] Preparation of compound 9 of Example 9

[0052] Step 1 : 1.5 g of compound 1 was dissolved in acetone 20 mL, 1.9 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Once washed with saturated brine, the crude product was obtained by desolventization, and the pure product was obtained by column chromatography. White solid. [M+H] + :305.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.06 (s, 1H), 7.85 (d, 1H), 6.52 (m, 2H), 2.68 (m, 1H), 2.51 (m, 2H), 2.39 (m, 2H), 2.18 (s, 3H), 1.75 (m, 2H), 1.50 (m, 2H).

[0053] Step 2: 3.1 g of compound 3 was dissolved in isopropanol 20 mL, 1.1 g of 6-methyl-2- aminopyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Once washed with saturated brine, the crude product was obtained by desolventization, and the pure product was obtained by column chromatography. White solid. [M+H] + :377.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 7.85 (d, 1H), 7.42 (m, 2H), 6.67 (m, 2H), 6.52 (s, 1H), 6.30 (d, 1H), 2.68 (m, 1H), 2.51 (m, 2H), 2.45 (s, 3H), 2.39 (m, 2H), 2.18 (s, 3H), 1.75 (m, 2H), 1.50 (m, 2H).

[0054] Preparation of compound 10 of Example 10

[0055] Step 1 : 1.5 g of compound 1 was dissolved in acetone 20 mL, 1.9 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Once washed with saturated brine, the crude product was obtained by desolventization, and the pure product was obtained by column chromatography. White solid. [M+H] + :286.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.18 (s, 1H), 7.68 (d, 2H), 6.77 (s, 1H), 2.92 (s, 6H).

[0056] Step 2: 2.9 g of compound 3 was dissolved in isopropanol 20 mL, 1.6 g of 3- trifluoromethylaniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + :410.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 8.18 (s, 1H), 7.68 (m, 2H), 7.56 (m, 2H), 7.23 (m, 2H), 6.77 (s, 1H), 2.92 (s, 6H).

[0057] Preparation of compound 11 of Example 11

[0058] Step 1: 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.4 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + :286.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.68 (d, 2H), 5.89 (m, 2H), 3.03 (s, 6H).

[0059] Step 2: 2.9 g of compound 3 was dissolved in isopropanol 20 mL, 1.6 g of 3- trifluoromethylaniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + :377.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 7.68 (d, 1H), 7.51 (m, 1H), 7.40 (s, 1H), 7.20 (m, 2H), 5.89 (m, 2H), 3.03 (s, 6H).

[0060] Preparation of compound 12 of Example 12

[0061] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.5 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 300.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 8.34 (s, 1H), 7.90 (d, 1H), 6.86 (d, 1H), 3.90 (s, 3H).

[0062] Step 2: 3.0 g of compound 3 was dissolved in isopropanol 20 mL, 1.3 g of 3-methoxyaniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 387.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.34 (s, 1H), 7.90 (d, 1H), 7.31 (m, 2H), 6.82 (m, 2H), 6.49 (d, 1H), 3.90 (s, 3H), 3.74 (s, 3H).

[0063] Preparation of compound 13 of Example 13

[0064] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.5 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 359.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 8.34 (s, 1H), 7.90 (d, 1H), 6.86 (d, 1H), 3.90 (s, 3H).

[0065] Step 2: 3.6 g of compound 3 was dissolved in isopropanol 20 mL, 1.6 g of 3- trifluoromethylaniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The combined organic phase was washed once with saturated brine and desolventized to obtain a crude product, which was column chromatographed to obtain a pure product. White solid. [M+H] + : 484.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 7.73 (s, 1H), 7.63 (d, 1H), 7.17 (m, 3H), 6.65 (m, 2H), 3.76 (m, 4H), 3.64 (m, 4H).

[0066] Preparation of compound 14 of Example 14

[0067] Step 1: 1.5 g of compound 1 was dissolved in acetone 20 mL, 1.1 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The combined organic phase was washed once with saturated brine and desolventized to obtain a crude product, which was column chromatographed to obtain a pure product. White solid. [M+H] + : 222.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.06 (s, 1H), 7.90 (s, 1H), 7.31 (d, 1H), 6.54 (d, 1H), 2.16 (s, 3H).

[0068] Step 2: 2.2 g of compound 3 was dissolved in isopropanol 20 mL, 1.4 g of 2-amino-6- ethoxy pyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The combined organic phase was washed once with saturated brine and desolventized to obtain a crude product, which was column chromatographed to obtain a pure product. White solid. [M+H] + : 324.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 7.90 (s, 1H), 7.44 (s, 1H), 7.35 (m, 2H), 6.54 (d, 1H), 5.76 (m, 2H), 4.41 (m, 2H), 2.16 (s, 3H), 1.36 (t, 3H).

[0069] Preparation of compound 15 of Example 15

[0070] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.5 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 300.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 8.30 (s, 1H), 8.18 (t, 1H), 7.87 (d, 1H), 6.88 (d, 1H), 2.81 (s, 3H).

[0071] Step 2: 3.1 g of compound 3 was dissolved in isopropanol 20 mL, 1.1 g of 3-methylaniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 370.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.87 (d, 1H), 7.47 (m, 2H), 7.24 (t, 1H), 6.82 (m, 2H), 2.81 (s, 3H), 2.33 (s, 3H).

[0072] Preparation of compound 16 of Example 16

[0073] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.5 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 286.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.65 (d, 1H), 5.91 (t, 2H), 3.03 (s, 3H).

[0074] Step 2: 2.9 g of compound 3 was dissolved in isopropanol 20 mL, 1.2 g of 3- aminobenzonitrile was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Once washed with saturated brine, the crude product was obtained by desolventization, and the pure product was obtained by column chromatography. White solid. [M+H] + : 367.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 8.18 (s, 1H), 7.91 (d, 1H), 7.68 (d, 2H), 7.47 (m, 2H), 7.36 (t, 1H), 2.92 (s, 6H).

[0075] Preparation of compound 17 of Example 17

[0076] Step 1: 1.5 g of compound 1 was dissolved in acetone 20 mL, 1.8 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Once washed with saturated brine, the crude product was obtained by desolventization, and the pure product was obtained by column chromatography. White solid. [M+H] + : 293.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.06 (s, 1H), 7.17 (s, 1H), 6.65 (m, 2H), 3.72 (m, 4H), 3.18 (m, 4H).

[0077] Step 2: 2.9 g of compound 3 was dissolved in isopropanol 20 mL, 1.2 g of 3- aminobenzonitrile was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. Once washed with saturated brine, the crude product was obtained by desolventization, and the pure product was obtained by column chromatography. White solid. [M+H] + : 418.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.44 (s, 1H), 7.17 (m, 3H), 6.65 (m, 2H), 3.72 (m, 4H), 3.18 (m, 4H).

[0078] Preparation of compound 18 of Example 18

[0079] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.7 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 313.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 8.30 (s, 1H), 7.87 (d, 1H), 6.88 (d, 1H), 2.93 (s, 6H).

[0080] Step 2: 3.1 g of compound 3 was dissolved in isopropanol 20 mL, 1.0 g of 3-methylaniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 384.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.30 (s, 1H), 7.87 (d, 1H), 7.47 (m, 2H), 7.24 (t, 1H), 6.88 (m, 2H), 2.93 (s, 6H), 2.33 (s, 3H).

[0081] Preparation of compound 19 of Example 19

[0082] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.9 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 341.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.17 (s, 1H), 6.65 (m, 2H), 3.15 (m, 4H), 2.35 (m, 4H), 2.21 (s, 3H).

[0083] Step 2: 3.4 g of compound 3 was dissolved in isopropanol 20 mL, 1.1 g of 2-amine-3 methylpyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :413.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 7.85 (d, 1H), 7.17 (s, 1H), 6.79 (d, 1H), 6.65 (m, 3H), 3.15 (m, 4H), 2.35 (m, 4H), 2.26 (s, 3H), 2.21 (s, 3H).

[0084] Preparation of compound 20 of example 20

[0085] Step 1: 2.5 g of compound 1 was dissolved in methanol, 0.2 g of palladium-carbon was added, and the reaction was carried out by hydrogenation at 30°C for 4 h. After filtration, the solvent was removed by vacuum rotary evaporation under reduced pressure to obtain the product, which was a light yellow solid. [M+H] + :216.1.

[0086] Step 2: 2.2 g of compound 2 was dissolved in acetone 20 mL, 1.8 g of cyanuric chloride was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :363.2, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.58 (s, 1H), 10.18 (s, 1H), 7.17 (s, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 3.10 (t, 2H), 1.69 (m, 2H), 0.97 (t, 3H).

[0087] Step 3: 3.6 g of compound 3 was dissolved in isopropanol 20 mL, 1.1 g of 2-amine-4 methylpyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :435.1, 1H-NMR (DMSO-d6, 300 MHz) δ: 10.58 (s, 1H), 10.18 (s, 2H), 7.85 (d, 1H), 7.17 (s, 1H), 6.79 (d, 1H), 6.65 (m, 3H), 3.10 (t, 2H), 2.22 (s, 3H), 1.69 (m, 2H), 0.97 (t, 3H).

[0088] Preparation of compound 21 of example 21

[0089] Step 1: 2.2 g of compound 1 was dissolved in methanol, 0.2 g of palladium carbon was added, hydrogen was replaced at 30 °C for 4 h, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the product as a light yellow solid. + : 188.2.

[0090] Step 2: 1.9 g of compound 2 was dissolved in acetone 20 mL, 1.8 g of cyanuric chloride was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, dichloromethane was extracted three times, and the organic phase was combined. Saturated brine was washed once, and the crude product was obtained by desolventizing. The pure product was obtained by column chromatography. White solid. [M+H] + : 336.2, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.58 (s, 1H), 10.18 (s, 1H), 7.17 (s, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 3.95 (s, 3H).

[0091] Step 3: 3.4 g of compound 3 was dissolved in isopropyl alcohol 20 mL, 1.1 g of 2-amine-4-methylpyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, dichloromethane was extracted three times, and the organic phase was combined. Saturated brine was washed once, and the crude product was obtained by desolventizing. The pure product was obtained by column chromatography. White solid. [M+H] + : 407.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.58 (s, 1H), 10.18 (s, 2H), 7.85 (d, 1H), 7.17 (s, 1H), 6.79 (d, 1H), 6.65 (m, 3H), 3.95 (s, 3H), 2.22 (s, 3H).

[0092] Preparation of compound 22 of example 22

[0093] Step 1: Dissolve 2.3g of compound 1 in methanol, add 0.2g of palladium on carbon, displace hydrogen gas, and react at 30°C for 4 hours. Filter, remove the solvent by vacuum rotary evaporation under reduced pressure to obtain the product, a pale yellow solid. [M+H] + :202.2.

[0094] Step 2: Dissolve 2.2 g of compound 2 in 20 mL of acetone, add 2.3 g of 2-bromo-4,6-dichlorotriazine, and reflux for 3 h. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20 mL of dichloromethane, add water, extract three times with dichloromethane, combine the organic phases, wash once with saturated brine, remove the solvent to obtain the crude product, and precipitate by column chromatography to obtain the pure product. Off-white solid. [M+H] + 393.6, 1 H-NMR(DMSO-d6,300MHz)δ:10.58(s,1H),10.18(s,1H),7.17(s,1H),6.79(d,1H),6.65(d,1H),3.45(m,2H),1.22(t,3H).

[0095] Step 3: Dissolve 3.4 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 2-amine-4-methylpyridine, and reflux for 2 h. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20 mL of dichloromethane, add water, extract three times with dichloromethane, combine the organic phases, wash once with saturated brine, remove the solvent to obtain the crude product, and precipitate by column chromatography to obtain the pure product. Off-white solid. [M+H] + 466.1, 1 H-NMR(DMSO-d6,300MHz)δ:10.58(s,1H),10.18(s,2H),7.85(d,1H),7.17 (s,1H),6.79(d,1H),6.65(m,3H),3.45(m,2H),2.22(s,3H),1.22(t,3H).

[0096] Example 23 Preparation of Compound 23

[0097] Step 1: Dissolve 2.6 g of compound 1 in methanol, add 0.2 g of palladium on carbon, displace hydrogen gas, and react at 30 °C for 4 h. Filter, remove the solvent by rotary evaporation under reduced pressure to obtain the product, a pale yellow solid. [M+H] + :230.2.

[0098] Step 2: Dissolve 2.3 g of compound 2 in acetone 20 mL, add 2.3 g of 2-bromo-4,6-dichlorotriazine, heat to reflux for 3 h, after the reaction is completed, remove the solvent by vacuum rotary evaporation under reduced pressure, dissolve the residue in 20 mL of dichloromethane, add water to separate, extract with dichloromethane three times, combine the organic phase, wash with saturated brine once, and desolventize to obtain the crude product, and column chromatography to obtain the pure product. Light yellow solid. [M+H] + :421.6, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.58 (s, 1H), 10.18 (s, 1H), 7.17 (s, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 3.10 (t, 2H), 1.61 (m, 2H), 1.30 (m, 2H), 0.89 (t, 3H).

[0099] Step 3: Dissolve 4.2 g of compound 3 in isopropyl alcohol 20 mL, add 1.1 g of 2-amine-4-methylpyridine, heat to reflux for 2 h, after the reaction is completed, remove the solvent by vacuum rotary evaporation under reduced pressure, dissolve the residue in 20 mL of dichloromethane, add water to separate, extract with dichloromethane three times, combine the organic phase, wash with saturated brine once, and desolventize to obtain the crude product, and column chromatography to obtain the pure product. Light yellow solid. [M+H] + :492.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.58 (s, 1H), 10.18 (s, 1H), 7.17 (s, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 3.10 (t, 2H), 1.61 (m, 2H), 1.30 (m, 2H), 0.89 (t, 3H).

[0100] Preparation of compound 24 of example 24

[0101] Step 1: Dissolve 1.8 g of compound 1 in acetone 20 mL, add 1.4 g of compound 2, heat to reflux for 3 h, after the reaction is completed, remove the solvent by vacuum rotary evaporation under reduced pressure, dissolve the residue in 20 mL of dichloromethane, add water to separate, extract with dichloromethane three times, combine the organic phase, wash with saturated brine once, and desolventize to obtain the crude product, and column chromatography to obtain the pure product. Light yellow solid. [M+H] + :285.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 8.30 (s, 1H), 7.87 (d, 1H), 7.70 (s, 2H), 6.88 (d, 1H).

[0102] Step 2: 2.9 g of compound 3 was dissolved in isopropanol 20 mL, 1.6 g of 3-(1- pyrrolidinyl) aniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :411.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 9.43 (s, 1H), 8.30 (s, 1H), 7.85 (d, 1H), 7.70 (s, 2H), 7.13 (t, 1H), 6.80 (m, 2H), 6.35 (s, 1H), 3.41 (m, 4H), 2.04 (m, 4H).

[0103] Preparation of compound 25 of Example 25

[0104] Step 1: 2.3 g of compound 1 was dissolved in acetone 20 mL, 1.1 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :301.9, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.47 (s, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 2.42 (s, 3H).

[0105] Step 2: 3.0 g of compound 3 was dissolved in isopropanol 20 mL, 1.4 g of 2-amino-5- nitropyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times. The combined organic phase was washed with saturated brine once, and the crude product was obtained by desolventization. The pure product was obtained by column chromatography. White solid. [M+H] + :404.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 8.89 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 6.89 (s, 1H), 2.42 (s, 3H).

[0106] Step 3: 3.0 g of compound 4 was dissolved in methanol, 0.3 g of palladium on carbon was added, hydrogen was replaced at 30 °C for 4 h, filtered, and the solvent was removed by vacuum rotary evaporation under reduced pressure to obtain the product as a white solid. [M+H]+: 374.2, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 8.47 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.17 (s, 1H), 6.79 (m, 2H), 6.62 (s, 2H), 2.42 (s, 3H).

[0107] Preparation of compound 26 of Example 26

[0108] Step 1: 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.1 g of compound 2 was added, and the reaction was carried out at reflux for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times and combined. The organic phase was washed with saturated brine once and desolventized to obtain the crude product, which was column chromatographed to obtain the pure product as a white solid. [M+H]+: 256.1. + 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.90 (s, 1H), 7.31 (d, 1H), 6.54 (d, 1H), 2.16 (s, 3H).

[0109] Step 2: 2.6 g of compound 3 was dissolved in isopropyl alcohol 20 mL, 1.4 g of 2-amino-5-methylpiperazine was added, and the reaction was carried out at reflux for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was extracted with dichloromethane three times and combined. The organic phase was washed with saturated brine once and desolventized to obtain the crude product, which was column chromatographed to obtain the pure product as a white solid. [M+H]+: 328.1. + 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 2H), 8.47 (s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.31 (d, 1H), 6.54 (d, 1H), 2.42 (s, 3H), 2.16 (s, 3H).

[0110] Preparation of compound 27 of Example 27

[0111] ​​Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.1 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane. Water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. It was washed once with saturated brine and desolventized to obtain a crude product, and the pure product was obtained by column chromatography. White solid. [M+H] + : 256.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 7.53 (d, 1H), 7.47 (s, 1H), 6.89 (m, 2H), 2.33 (s, 3H).

[0112] Step 2: 2.6 g of compound 3 was dissolved in isopropanol 20 mL, 1.4 g of 5- aminobenzotriazole was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane. Water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. It was washed once with saturated brine and desolventized to obtain a crude product, and the pure product was obtained by column chromatography. White solid. [M+H] + : 353.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 12.95 (s, 1H), 9.43 (s, 2H), 7.92 (d, 1H), 7.76 (s, 1H), 7.53 (d, 2H), 7.23 (m, 2H), 6.82 (d, 1H), 2.33 (s, 3H).

[0113] Preparation of compound 28 of Example 28

[0114] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.0 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane. Water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. It was washed once with saturated brine and desolventized to obtain a crude product, and the pure product was obtained by column chromatography. White solid. [M+H] + : 243.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.47 (s, 1H), 8.23 (d, 2H), 6.89 (t, 1H).

[0115] Step 2: 2.4 g of compound 3 was dissolved in isopropanol 20 mL, 1.1 g of 3- methyl aniline was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane. Water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. It was washed once with saturated brine and desolventized to obtain a crude product, and the pure product was obtained by column chromatography. White solid. [M+H]+ :353.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 8.47 (s, 1H), 8.27 (d, 2H), 7.73 (d, 1H), 7.53 (s, 1H), 7.23 (t, 1H), 6.82 (m, 2H), 2.33 (s, 3H).

[0116] Preparation of compound 29 of example 29

[0117] Step 1: dissolve 1.8 g compound 1 in acetone 20 mL, add 1.3 g compound 2, heat to reflux for 3 h, after reaction, remove solvent by vacuum rotary evaporation, dissolve the residue in 20 mL dichloromethane, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] + :273.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.47 (s, 1H), 7.54 (s, 2H), 3.83 (s, 3H).

[0118] Step 2: dissolve 2.7 g compound 3 in isopropanol 20 mL, add 1.1 g 3-methylaniline, heat to reflux for 2 h, after reaction, remove solvent by vacuum rotary evaporation, dissolve the residue in 20 mL dichloromethane, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] + :344.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 8.47 (s, 1H), 7.54 (d, 2H), 7.33 (d, 2H), 7.15 (t, 1H), 6.82 (d, 1H), 3.83 (s, 3H), 2.33 (s, 3H).

[0119] Preparation of compound 30 of example 30

[0120] Step 1: dissolve 1.8 g compound 1 in acetone 20 mL, add 1.6 g compound 2, heat to reflux for 3 h, after reaction, remove solvent by vacuum rotary evaporation, dissolve the residue in 20 mL dichloromethane, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] + :311.1, 1H-NMR (DMSO-d6, 300 MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.41 (t, 4H), 2.04 (t, 4H).

[0121] Step 2: 3.2 g of compound 3 was dissolved in isopropanol 20 mL, added 1.1 g of 3-methylaniline, heated to reflux for 2 h, the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added to liquid, dichloromethane was extracted three times, the organic phase was combined, washed with saturated brine once, and the crude product was obtained by desolventizing. Column chromatography to obtain pure product. White solid. [M+H] + : 381.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 8.86 (s, 1H), 7.54 (d, 2H), 7.23 (t, 1H), 7.02 (d, 2H), 6.95 (d, 1H), 6.73 (d, 2H), 3.43 (t, 4H), 2.33 (s, 3H), 2.04 (t, 4H).

[0122] Preparation of compound 31 of example 31

[0123] Step 1: 1.8 g of compound 1 was dissolved in acetone 20 mL, added 1.8 g of compound 2, heated to reflux for 3 h, the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added to liquid, dichloromethane was extracted three times, the organic phase was combined, washed with saturated brine once, and the crude product was obtained by desolventizing. Column chromatography to obtain pure product. White solid. [M+H] + : 324.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.46 (t, 4H), 1.62 (m, 4H), 1.52 (m, 2H).

[0124] Step 2: 3.2 g of compound 3 was dissolved in isopropanol 20 mL, added 1.1 g of 3-methylaniline, heated to reflux for 2 h, the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added to liquid, dichloromethane was extracted three times, the organic phase was combined, washed with saturated brine once, and the crude product was obtained by desolventizing. Column chromatography to obtain pure product. White solid. [M+H] + : 397.1, 1H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (d, 2H), 7.85 (s, 1H), 7.17 (s, 1H), 6.65 (m, 2H), 6.45 (m, 2H), 3.06 (t, 4H), 2.22 (s, 3H), 1.66 (m, 4H), 1.52 (m, 2H).

[0125] Preparation of compound 32 of example 32

[0126] Step 1: dissolve 1.8 g of compound 1 in acetone 20 mL, add 1.4 g of compound 2, heat to reflux for 3 h, after reaction, remove solvent by vacuum rotary evaporation, dissolve the residue in 20 mL of dichloromethane, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] + : 284.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.06 (s, 6H).

[0127] Step 2: dissolve 2.8 g of compound 3 in isopropanol 20 mL, add 1.6 g of 3- cyclopentyl aniline, heat to reflux for 2 h, after reaction, remove solvent by vacuum rotary evaporation, dissolve the residue in 20 mL of dichloromethane, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] + : 410.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 7.53 (m, 2H), 7.17 (m, 2H), 6.94 (d, 1H), 6.70 (m, 2H), 2.92 (s, 6H), 2.79 (m, 1H), 1.93 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H), 1.52 (m, 2H).

[0128] Preparation of compound 33 of example 33

[0129] Step 1: dissolve 1.8 g of compound 1 in acetone 20 mL, add 1.4 g of compound 2, heat to reflux for 3 h, after reaction, remove solvent by vacuum rotary evaporation, dissolve the residue in 20 mL of dichloromethane, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove the solvent to get the crude product, purify by column chromatography to get the pure product. White solid. [M+H] +:284.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.06 (s, 6H).

[0130] Step 2: 2.8 g of compound 3 was dissolved in isopropanol 20 mL, added 1.9 g 3- cycloheptane aniline, warmed to reflux for 2 h, the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL dichloromethane, added water to liquid, dichloromethane was extracted three times, the organic phase was combined, washed with saturated brine once, desolventized to get the crude product, column chromatography to get the pure product. White solid. [M+H] + :410.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 7.53 (m, 2H), 7.17 (m, 2H), 6.94 (d, 1H), 6.70 (m, 2H), 2.92 (s, 6H), 2.62 (m, 1H), 1.75 (m, 2H), 1.56 (m, 4H), 1.42 (m, 2H), 1.32 (m, 4H).

[0131] Preparation of compound 34 of example 34

[0132] Step 1: 1.8 g of compound 1 was dissolved in acetone 20 mL, added 1.6 g of compound 2, warmed to reflux for 3 h, the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL dichloromethane, added water to liquid, dichloromethane was extracted three times, the organic phase was combined, washed with saturated brine once, desolventized to get the crude product, column chromatography to get the pure product. White solid. [M+H] + :313.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.36 (m, 4H), 1.15 (t, 6H).

[0133] Step 2: 2.8 g of compound 3 was dissolved in isopropanol 20 mL, added 1.8 g 3- cyclohexane aniline, warmed to reflux for 2 h, the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL dichloromethane, added water to liquid, dichloromethane was extracted three times, the organic phase was combined, washed with saturated brine once, desolventized to get the crude product, column chromatography to get the pure product. White solid. [M+H] + :452.1, 1H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 7.53 (m, 2H), 7.17 (m, 2H), 6.94 (d, 1H), 6.70 (m, 2H), 3.11 (m, 4H), 2.62 (m, 1H), 1.86 (m, 2H), 1.61 (m, 2H), 1.42 (m, 4H), 1.32 (m, 2H), 1.15 (t, 6H).

[0134] Preparation of compound 35 of example 35

[0135] Step 1: dissolve 1.8 g compound 1 in acetone 20 mL, add 1.1 g compound 2, heat to reflux for 3 h, after reaction, remove solvent by vacuum rotary evaporation, dissolve the residue in 20 mL dichloromethane, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove solvent to get the crude product, column chromatography to get the pure product. White solid. [M+H] + : 256.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 7.90 (d, 1H), 7.31 (t, 1H), 6.54 (t, 1H), 2.16 (s, 3H).

[0136] Step 2: dissolve 2.6 g compound 3 in isopropanol 20 mL, add 1.8 g 3-cyclohexyl aniline, heat to reflux for 2 h, after reaction, remove solvent by vacuum rotary evaporation, dissolve the residue in 20 mL dichloromethane, add water to separate, extract with dichloromethane for three times, combine the organic phase, wash with saturated brine once, remove solvent to get the crude product, column chromatography to get the pure product. White solid. [M+H] + : 395.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 7.90 (s, 1H), 7.53 (m, 2H), 7.31 (d, 1H), 7.21 (t, 1H), 6.94 (d, 1H), 6.55 (d, 1H), 2.72 (m, 1H), 2.16 (s, 3H), 1.86 (m, 2H), 1.61 (m, 2H), 1.42 (m, 4H), 1.32 (m, 2H).

[0137] Preparation of compound 36 of example 36

[0138] Step 1 : 1.7 g of compound 1 was dissolved in isopropanol 20 mL, 2.6 g of compound 2 was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 390.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 9.24 (s, 1H), 8.70 (d, 1H), 8.42 (d, 1H), 7.90 (s, 1H), 7.73 (d, 1H), 7.55 (t, 2H), 7.21 (t, 2H), 7.15 (d, 1H), 6.64 (d, 1H), 2.16 (s, 3H).

[0139] Preparation of compound 37 of example 37

[0140] Step 1 : 1.7 g of compound 1 was dissolved in isopropanol 20 mL, 2.6 g of compound 2 was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 391.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.72 (t, 1H), 7.56 (t, 2H), 6.62 (d, 2H), 3.32 (s, 3H), 2.22 (s, 3H).

[0141] Preparation of compound 38 of example 38

[0142] Step 1 : 1.7 g of compound 1 was dissolved in isopropanol 20 mL, 2.6 g of compound 2 was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after being extracted three times with dichloromethane. The crude product was obtained after washing with saturated brine once and desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 419.1, 1H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.60 (t, 2H), 7.56 (d, 1H), 6.62 (d, 2H), 3.32 (m, 1H), 2.22 (s, 3H), 1.33 (d, 6H).

[0143] Preparation of compound 39 of example 39

[0144] Step 1: 1.6 g of compound 1 was dissolved in isopropanol 20 mL, 2.6 g of compound 2 was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, the organic phase was combined after dichloromethane extraction three times, and saturated brine was washed once. The crude product was obtained by desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 379.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.60 (t, 2H), 7.56 (d, 1H), 6.62 (d, 2H), 3.32 (m, 1H), 2.22 (s, 3H), 1.33 (d, 6H).

[0145] Preparation of compound 40 of example 40

[0146] Step 1: 1.6 g of compound 1 was dissolved in isopropanol 20 mL, 2.6 g of compound 2 was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, the organic phase was combined after dichloromethane extraction three times, and saturated brine was washed once. The crude product was obtained by desolventizing, and the pure product was obtained by column chromatography. White solid. [M+H] + : 374.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.18 (s, 1H), 9.43 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.60 (t, 2H), 7.56 (d, 1H), 6.62 (d, 2H), 3.32 (m, 1H), 2.22 (s, 3H), 1.33 (d, 6H).

[0147] Preparation of compound 41 of example 41

[0148] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.6 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. It was washed once with saturated brine and desolventized to obtain a crude product, and the pure product was obtained by column chromatography. White solid. [M+H] + :310.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 7.13 (d, 1H), 6.97 (d, 1H), 6.60 (d, 1H), 6.38 (s, 1H), 3.41 (t, 4H), 2.04 (m, 4H).

[0149] Step 2: 3.1 g of compound 3 was dissolved in isopropanol 20 mL, 1.6 g of 7- aminotetrahydrothiazole [5, 4-B] pyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. It was washed once with saturated brine and desolventized to obtain a crude product, and the pure product was obtained by column chromatography. White solid. [M+H] + :429.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 9.43 (s, 1H), 8.25 (s, 1H), 6.97 (m, 2H), 6.80 (s, 1H), 6.60 (t, 2H), 6.38 (s, 1H), 3.81 (t, 1H), 3.41 (t, 4H), 2.99 (t, 2H), 2.04 (m, 4H), 1.92 (t, 2H).

[0150] Preparation of compound 42 of example 42

[0151] Step 1 : 1.8 g of compound 1 was dissolved in acetone 20 mL, 1.6 g of compound 2 was added, and the reaction was refluxed for 3 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, the residue was dissolved in 20 mL of dichloromethane, water was added for liquid separation, and the organic phase was combined after dichloromethane extraction three times. It was washed once with saturated brine and desolventized to obtain a crude product, and the pure product was obtained by column chromatography. White solid. [M+H] + :257.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.47 (s, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 2.42 (s, 3H).

[0152] Step 2: 2.6 g of compound 3 was dissolved in isopropanol 20 mL, 1.6 g of 7- aminotetrahydrothiazole [5,4-B] pyridine was added, and the reaction was refluxed for 2 h. After the reaction was completed, the solvent was removed by vacuum rotary evaporation under reduced pressure, and the residue was dissolved in 20 mL of dichloromethane. Water was added for liquid-liquid separation, and the organic phase was extracted three times with dichloromethane. The combined organic phase was washed once with saturated brine and desolventized to obtain a crude product. The pure product was obtained by column chromatography. White solid. [M+H] 429.1. + :429.1, 1 H-NMR (DMSO-d6, 300 MHz) δ: 8.47 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 6.80 (s, 1H), 6.74 (s, 1H), 3.81 (t, 1H), 3.09 (t, 2H), 2.42 (s, 3H), 2.04 (t, 2H).

[0153] Example 43

[0154] 1. In vitro activity test of compounds against Haemonchus contortus

[0155] A compound solution with a concentration gradient in DMSO was prepared, diluted with a nutrient medium, and distributed into a 96-well microtiter plate. Sheathed L3 Haemonchus contortus larvae were incubated in a water bath at 37°C for 20 min, separated by centrifugation, and added to the wells at 200 larvae / well. After 7 days of incubation, motility was evaluated by an automated microscope. Abamectin was used as a positive control, and DMSO was used as a negative control. The ED50 value, representing the concentration of the individual compound that reduces motility by 50% relative to the positive control, was calculated. The specific experimental data are shown in Table 2 below. 50

[0156] 2. In vitro agonistic activity of compounds against Caenorhabditis elegans SLO-1

[0157] A CHO K1 cell line stably transfected with Caenorhabditis elegans SLO-1 was established. The cells were seeded in a microtiter plate at a concentration of 10,000 cells / well in 25 uL of medium and incubated at 37°C and 5% CO2 for 20-24 hours. The cell culture medium was removed, and the cells were washed with Tyrode solution. 25 uL of FMP dye Blue-Tyrode was added to each well and incubated at room temperature for 30 min.

[0158] ​For membrane potential measurements, prepared cell plates and substance plates were placed in a FLIPR Tetra (Molecular Devices). A baseline measurement of fluorescence was taken for 20 seconds (Exc. 510-545 nm, Emm. 565-625 nm). Cells were depolarized by the addition of 25 uL of diluted test compound (final assay concentration of KCl-Tyrode: 70 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 0.8 mM NaH2PO4, 5 mM glucose, 28 mM Hepes, pH 7.4, including voltage-sensitive dye). The complete measurement took 150 s. Abamectin was used as a positive control and DMSO as a negative control, and the ED 50 values were calculated.

[0159] 3. In vitro activity of compounds against D. immitis

[0160] Compound solutions were prepared in DMSO at decreasing concentrations, diluted with nutrient medium and distributed into 96-well microtiter plates. Dog heartworm larvae were incubated for 20 min in a water bath at 37 °C, separated by centrifugation and added to the wells at 100 larvae per well. After 3 days of incubation, motility was assessed by automated microscopy. Abamectin was used as a positive control and DMSO as a negative control, and the ED 50 values were calculated, which represent the individual compound concentration that reduces motility by 50% relative to the positive control. The specific experimental data are shown in Table 2 below.

[0161] The ED 50 values were determined in triplicates using a dilution series of the compounds. The data were determined in at least two independent tests. By processing the data using the ActivityBase XE Runner software (IDBS), curve fitting and calculation of the half maximal effective concentration were performed. The specific experimental data are shown in Table 2 below.

[0162] Table 2. Anti-worm activity of compounds 1-42

Claims

1. A triazine derivative as shown in general formula (Ⅰ):

2. A triazine derivative as shown in general formula (I) according to claim 1, characterized in that, R1and R2are each independently selected from the group consisting of 2-pyridyl, 3-pyridyl, pyrazinyl, phenyl, 2-4,5,6,7-tetrahydrothiazolo[5,4-B]pyridinyl, pyrimidinyl, benzotriazolyl, said groups being unsubstituted or substituted with one or more substituents; said substituents being independently selected from the group consisting of halogen, -CN, -CH3, -OCH3, -CF3, -OCH(CH3)2, -OCH2CH3, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, -NH2, -NSO2CH3, -NSO2(CH2) 1-3 CH3, -COOCH3, -COOCH2CH3, -SO2CH3, -SO2CH(CH3)2, -N(CH3)2, -CONH2, -N(CH2CH3)2, -CONHCH3, -CON(CH3)2, and substituted or unsubstituted aryl; R3is selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy.

3. The triazine derivative according to claim 2, characterized in that, The derivative is one of structures 1-42:

4. A salt of a triazine derivative according to any one of claims 1 to 3, characterized in that, The salt of the triazine derivative includes the salt of the triazine derivative of formula (I) 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; and the salt of the compound of general formula (I) with inorganic bases or organic salts formed by basic amines.

5. An enantiomer, diastereomer, racemate of the triazine derivative according to any one of claims 1-3.

6. A pharmaceutical composition, characterized by, The pharmaceutical composition includes the triazine derivative according to any one of claims 1-3 or the salt according to claim 4 or the enantiomer, diastereomer, racemate according to claim 5 and one or more than one pharmaceutical carrier and / or excipient.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition further includes one or more than one antiparasitic active ingredient; the antiparasitic active ingredient is selected from one or more than one of flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, cambendazole, ivermectin, abamectin, diethylcarbamazine, suramin, tribendimidine, dihydroxyphenylpropylamine, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, morantel, dichlophen, oxfendazole, pomegranate alkaloid sulfate, moxidectin.

8. Use of a triazine derivative according to any one of claims 1-3 or a salt according to claim 4 or an enantiomer, diastereomer, racemate according to claim 5 or a pharmaceutical composition according to claim 6 for the preparation of a medicament for the prevention or treatment of parasitic infections in humans or animals.

9. Use according to claim 8, characterized in that, The parasite is a helminth.

10. Use according to claim 9, characterized in that, The helminth is a nematode.

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