Triazine derivatives, processes for their preparation and use

Abstract

The application discloses a triazine derivative, a preparation method and application thereof, and belongs to the technical field of drug synthesis. Specifically, the application discloses a triazine derivative shown in general formula (I) and a pharmaceutical composition containing the triazine derivative, and application of the triazine derivative in preparation of human or animal anti-helminth drugs. The structural general formula (I) of the triazine derivative is shown in the following formula: The triazine derivative has remarkable effects on anti-helminth of human and animal shared nematodes and heartworms, and has wide application prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compound technology, specifically relating to a triazine derivative, its preparation method, and its application. Background Technology

[0002] The most common intestinal parasitic worms worldwide include intestinal nematodes, roundworms, filarial worms, and schistosomes. Filariasis is a parasitic disease caused by thread-like filarial worms, and it is also a vector-borne disease transmitted through insect bites. The main causes of human filariasis are filarial worms, such as *Brucella malayi*, *Brucella imperialis*, *Discocercaria spiralis*, and *Nematodeus mansoni*, which are present in human hosts. Currently, nematode infection remains a major cause of high morbidity and increased mortality in some parts of the world.

[0003] Currently, drugs such as diethylcarbazine, ivermectin, and albendazole are used clinically to kill the larvae of parasitic nematodes, but these drugs are not very effective against adult worms. For adult parasites, the only option is to wait for them to die naturally. Long-term medication to kill the larvae leads to drug resistance in the parasites and causes great suffering to the infected person. In particular, filarial worms can parasitize both humans and animals, potentially causing serious and life-threatening diseases in humans.

[0004] The compounds involved in this invention have been studied for their effectiveness in killing parasitic worms, resulting in compounds with good activity that have the potential to become novel insecticides and are expected to bring significant 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 a triazine derivative, its preparation method and application.

[0006] To achieve the above objectives, the specific technical solution of the present invention is as follows:

[0007] This invention provides a triazine derivative as shown in general formula (I):

[0008]

[0009] R1 and R2 are each selected from the groups 2-pyridyl, 3-pyridyl, pyrazinyl, phenyl, 2-4,5,6,7-tetrahydrothiazolyl[5,4-B]pyridyl, pyrimidinyl, and benzotriazolyl, respectively, and the above groups are unsubstituted or substituted by one or more substituents; the substituents are independently selected from halogens, -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 heterocyclic groups, -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 groups; R3 is selected from fluorine, chlorine, bromine, methyl, and methoxy.

[0010] Preferably, the derivative is one of structures 1-42 in Table 1:

[0011] Table 1 Triazine Derivatives 1-42

[0012]

[0013]

[0014]

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

[0016] The salts of the triazine derivatives are salts formed by the triazine derivatives 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 also include salts formed by compounds of general formula (I) with inorganic bases or organic salts formed by basic amines.

[0017] In a third aspect, the present invention also provides a synthetic route for the triazine derivatives:

[0018]

[0019] The compound of general formula (I) of the present invention can be obtained by the preparation method described above or similar to the above method, and the corresponding starting material can be selected according to the different substituents and the different positions of the substituents.

[0020] When the triazine rings R2 and R1 have the same substituent, the target compound can be synthesized in one step according to step 1, with the starting materials reacting in a molar ratio of 1:2. When the triazine rings R2 and R1 have different substituents, step 1 of the synthetic route reacts with the starting materials reacting in a molar ratio of 1:1, yielding an intermediate product through substitution reaction, which is then purified by column chromatography to obtain a pure product; step 2 also yields the target compound through substitution reaction, which is then purified by column chromatography to obtain a pure product.

[0021] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the aforementioned triazine derivative or the aforementioned salt or the aforementioned enantiomer, diastereomer, racemate, and one or more pharmaceutical carriers and / or excipients.

[0022] The pharmaceutical composition also includes one or more antiparasitic active ingredients.

[0023] The active ingredient of the antiparasitic drug is selected from one or more of the following: flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, trichlorobenzazole, ivermectin, avermectin, diethylcarbazine, suramin, tribenzamidin, dihydroxynaphthyl acid, levamisole, niclosamide, nizoxinide, hydroxychlorosalisamide, praziquantel, emoticonide, mononitrate, detrifendazole, ocfendaazole, punicine sulfate, and moxifloxacin.

[0024] In a fifth aspect, the invention provides the use of a triazine derivative of general formula (I) of the invention, or the salt thereof, or the enantiomer, diastereomer, racemate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention and treatment of parasitic infections in humans or animals.

[0025] Preferably, the parasite is a worm.

[0026] More preferably, the parasite is a nematode.

[0027] Beneficial effects:

[0028] 1. The triazine-line derivatives provided by this invention exhibit strong insecticidal activity against animal parasites, especially worms, particularly nematodes, laying a solid foundation for the development of new drugs.

[0029] 2. The preparation process of this invention is simple, energy-saving and environmentally friendly, and easy to industrialize. Detailed Implementation

[0030] The above content will be further described in detail below through specific embodiments. However, this should not be construed as limiting the scope of the above subject matter to the following embodiments. All technologies implemented based on the content of this invention fall within the scope.

[0031] The starting materials and reaction reagents used in the specific embodiments of this invention are all commercially available. This invention can prepare salts using methods commonly used in the art.

[0032] Experimental methods not specified in the embodiments of the present invention are generally performed under conventional conditions or under conditions recommended by the raw material or product manufacturer.

[0033] The structures of all compounds in the examples were obtained by Waters QDa mass spectrometry and proton nuclear magnetic resonance spectroscopy (1H NMR).1 Characterization by H-NMR.

[0034] Example 1

[0035] Preparation of Compound 1

[0036]

[0037] Step 1: Dissolve 1.8 g of cyanuric chloride in 20 mL of acetone, add 1.1 g of 2-amino-5-methylpyridine, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 256.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 7.90 (d, 1H), 7.31 (t, 1H), 6.54 (t, 1H), 2.16 (s, 3H).

[0038] Step 2: Dissolve 2.5 g of compound 3 in 20 mL of isopropanol, add 1.3 g of m-methoxyaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 343.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0039] Example 2

[0040] Preparation of compound 2

[0041]

[0042] Step 1: Dissolve 1.8 g of cyanuric chloride in 20 mL of acetone, add 2.2 g of 2-amino-5-methylpyridine, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] +328.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 2H), 7.90 (d, 2H), 7.31 (m, 2H), 6.54 (m, 2H), 2.16 (s, 6H).

[0043] Example 3

[0044] Preparation of compound 3

[0045]

[0046] Step 1: Dissolve 1.8 g of cyanuric chloride in 20 mL of acetone, add 1.8 g of 5-(1-piperidinyl)-2-aminopyridine, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 325.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0047] Step 2: Dissolve 3.2 g of compound 3 in 20 mL of isopropanol, add 1.3 g of 2-amino-5-chloropyridine, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 417.2, 1 H-NMR(DMSO-d6,300MHz)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).

[0048] Example 4

[0049] Preparation of compound 4

[0050]

[0051] Step 1: Dissolve 1.8 g of cyanuric chloride in 20 mL of acetone, add 0.9 g of 3-aminopyridine, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + :242.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.18 (s, 1H), 8.04 (s, 1H), 7.92 (d, 1H), 7.36 (t, 1H), 7.15 (d, 1H).

[0052] Step 2: Dissolve 2.4 g of compound 3 in 20 mL of isopropanol, add 1.3 g of 3-methoxyaniline, 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] + 328.7 1 H-NMR(DMSO-d6,300MHz)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).

[0053] Example 5

[0054] Preparation of compound 5

[0055]

[0056] Step 1: Dissolve 1.8 g of cyanuric chloride in 20 mL of acetone, add 1.4 g of 2-amino-3-isopropoxypyridine, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 301.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 7.14 (s, 1H), 7.92 (m, 2H), 4.69 (t, 1H), 1.31 (s, 6H).

[0057] Step 2: Dissolve 3.0 g of compound 3 in 20 mL of isopropanol, add 1.0 g of 6-methyl-2-aminopyridine, 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] + 372.8, 1 H-NMR(DMSO-d6,300MHz)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).

[0058] Example 6

[0059] Preparation of compound 6

[0060]

[0061] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.6 g of 7-amino-4,5,6,7-tetrahydrothiazolium[5,4-B]pyridine, 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 the pure product by column chromatography. Off-white solid. [M+H] + 304.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0062] Step 2: Dissolve 3.0 g of compound 3 in 20 mL of isopropanol, add 1.0 g of 6-methyl-2-aminopyridine, 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] + 372.8, 1H-NMR(DMSO-d6,300MHz)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).

[0063] Example 7

[0064] Preparation of compound 7

[0065]

[0066] Step 1: Dissolve 1.5g of compound 1 in 20mL of acetone, add 1.2g of compound 2, and reflux for 3 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + :233.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 9.06 (s, 1H), 8.38 (d, 1H), 7.32 (s, 1H), 6.82 (d, 1H).

[0067] Step 2: Dissolve 2.3g of compound 3 in 20mL of isopropanol, add 1.2g of 3-ethylaniline, reflux for 2h. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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] + 318.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0068] Example 8

[0069] Preparation of compound 8

[0070]

[0071] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.1 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 236.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 7.85 (d, 1H), 6.52 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H).

[0072] Step 2: Dissolve 2.4 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 6-methyl-2-aminopyridine, 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] + 318.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0073] Example 9

[0074] Preparation of compound 9

[0075]

[0076] Step 1: Dissolve 1.5g of compound 1 in 20mL of acetone, add 1.9g of compound 2, and reflux for 3 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 305.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0077] Step 2: Dissolve 3.1 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 6-methyl-2-aminopyridine, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 377.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0078] Example 10

[0079] Preparation of compound 10

[0080]

[0081] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.4 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 286.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.18 (s, 1H), 7.68 (d, 2H), 6.77 (s, 1H), 2.92 (s, 6H).

[0082] Step 2: Dissolve 2.9 g of compound 3 in 20 mL of isopropanol, add 1.6 g of 3-trifluoromethylaniline, 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] + 410.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0083] Example 11

[0084] Preparation of compound 11

[0085]

[0086] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.4 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 286.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 7.68 (d, 2H), 5.89 (m, 2H), 3.03 (s, 6H).

[0087] Step 2: Dissolve 2.9 g of compound 3 in 20 mL of isopropanol, add 1.3 g of 3-chloroaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 377.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0088] Example 12

[0089] Preparation of compound 12

[0090]

[0091] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.5 g of compound 2, 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] + 300.1, 1H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 8.34 (s, 1H), 7.90 (d, 1H), 6.86 (d, 1H), 3.90 (s, 3H).

[0092] Step 2: Dissolve 3.0 g of compound 3 in 20 mL of isopropanol, add 1.3 g of 3-methoxyaniline, 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] + 387.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0093] Example 13

[0094] Preparation of compound 13

[0095]

[0096] Step 1: Dissolve 1.7g of compound 1 in 20mL of acetone, add 2.3g of compound 2, and reflux for 3 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 359.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 8.34 (s, 1H), 7.90 (d, 1H), 6.86 (d, 1H), 3.90 (s, 3H).

[0097] Step 2: Dissolve 3.6 g of compound 3 in 20 mL of isopropanol, add 1.6 g of 3-trifluoromethylaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 484.1, 1H-NMR(DMSO-d6,300MHz)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).

[0098] Example 14

[0099] Preparation of compound 14

[0100]

[0101] Step 1: Dissolve 1.5g of compound 1 in 20mL of acetone, add 1.1g of compound 2, and reflux for 3 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + :222.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0102] Step 2: Dissolve 2.2 g of compound 3 in 20 mL of isopropanol, add 1.4 g of 2-amino-6-ethoxypyridine, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 324.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0103] Example 15

[0104] Preparation of compound 15

[0105]

[0106] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.5 g of compound 2, 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] + 300.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0107] Step 2: Dissolve 3.1 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 3-methylaniline, 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] + 370.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0108] Example 16

[0109] Preparation of compound 16

[0110]

[0111] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.4 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 286.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 7.65 (d, 1H), 5.91 (t, 2H), 3.03 (s, 3H).

[0112] Step 2: Dissolve 2.9 g of compound 3 in 20 mL of isopropanol, add 1.2 g of 3-aminobenzonitrile, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 367.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0113] Example 17

[0114] Preparation of compound 17

[0115]

[0116] Step 1: Dissolve 1.5g of compound 1 in 20mL of acetone, add 1.8g of compound 2, and reflux for 3 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 293.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0117] Step 2: Dissolve 2.9 g of compound 3 in 20 mL of isopropanol, add 1.2 g of 3-trifluoromethylaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 418.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0118] Example 18

[0119] Preparation of compound 18

[0120]

[0121] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.7 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 313.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 8.30 (s, 1H), 7.87 (d, 1H), 6.88 (d, 1H), 2.93 (s, 6H).

[0122] Step 2: Dissolve 3.1 g of compound 3 in 20 mL of isopropanol, add 1.0 g of 3-methylaniline, 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] + 384.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0123] Example 19

[0124] Preparation of compound 19

[0125]

[0126] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.9 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 341.1, 1H-NMR (DMSO-d6, 300MHz) 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).

[0127] Step 2: Dissolve 3.4 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 2-amine-3-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] + 413.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0128] Example 20

[0129] Preparation of compound 20

[0130]

[0131] Step 1: Dissolve 2.5g 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] + :216.1.

[0132] Step 2: Dissolve 2.2g of compound 2 in 20mL of acetone, add 1.8g of cyanuric chloride, and reflux for 3 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 363.2, 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),3.10(t,2H),1.69(m,2H),0.97(t,3H).

[0133] Step 3: Dissolve 3.6 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] + 435.1, 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),3.10(t,2H),2.22(s,3H),1.69(m,2H),0.97(t,3H).

[0134] Example 21

[0135] Preparation of compound 21

[0136]

[0137] Step 1: Dissolve 2.2g 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] + :188.2.

[0138] Step 2: Dissolve 1.9 g of compound 2 in 20 mL of acetone, add 1.8 g of cyanuric chloride, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 336.2, 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), 3.95 (s, 3H).

[0139] 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] + 407.1, 1H-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),3.95(s,3H),2.22(s,3H).

[0140] Example 22

[0141] Preparation of compound 22

[0142]

[0143] 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.

[0144] 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).

[0145] 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).

[0146] Example 23

[0147] Preparation of compound 23

[0148]

[0149] 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.

[0150] Step 2: Dissolve 2.3g of compound 2 in 20mL of acetone, add 2.3g of 2-bromo-4,6-dichlorotriazine, and reflux for 3 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 then perform column chromatography to obtain the pure product. Pale yellow solid. [M+H] + 421.6, 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),3.10(t,2H),1.61(m,2H),1.30(m,2H),0.89(t,3H).

[0151] Step 3: Dissolve 4.2 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. Pale yellow solid. [M+H] + 492.1, 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),3.10(m,2H),2.22(s,3H),1.61(m,2H),1.30(m,2H),0.89(t,3H).

[0152] Example 24

[0153] Preparation of compound 24

[0154]

[0155] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.4 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 285.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 8.30 (s, 1H), 7.87 (d, 1H), 7.70 (s, 2H), 6.88 (d, 1H).

[0156] Step 2: Dissolve 2.9 g of compound 3 in 20 mL of isopropanol, add 1.6 g of 3-(1-pyrrolidinyl)aniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 411.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0157] Example 25

[0158] Preparation of compound 25

[0159]

[0160] Step 1: Dissolve 2.3g of compound 1 in 20mL of acetone, add 1.1g of compound 2, and reflux for 3 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 301.9, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.47 (s, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 2.42 (s, 3H).

[0161] Step 2: Dissolve 3.0 g of compound 3 in 20 mL of isopropanol, add 1.4 g of 2-amino-5-nitropyridine, 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] + 404.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0162] Step 3: Dissolve 3.0 g of compound 4 in methanol, add 0.3 g of palladium on carbon, displace hydrogen gas, react at 30 °C for 4 h, filter, and remove the solvent by vacuum rotary evaporation under reduced pressure to obtain the product, which is an off-white solid. [M+H]+: 374.2 1 H-NMR(DMSO-d6,300MHz)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).

[0163] Example 26

[0164] Preparation of compound 26

[0165]

[0166] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.1 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 256.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 7.90 (s, 1H), 7.31 (d, 1H), 6.54 (d, 1H), 2.16 (s, 3H).

[0167] Step 2: Dissolve 2.6 g of compound 3 in 20 mL of isopropanol, add 1.4 g of 2-amino-5-methylpiperazine, 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] + 328.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0168] Example 27

[0169] Preparation of compound 27

[0170]

[0171] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.1 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 256.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 9.43 (s, 1H), 7.53 (d, 1H), 7.47 (s, 1H), 6.89 (m, 2H), 2.33 (s, 3H).

[0172] Step 2: Dissolve 2.6 g of compound 3 in 20 mL of isopropanol, add 1.4 g of 5-aminobenzotriazole, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 353.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0173] Example 28

[0174] Preparation of compound 28

[0175]

[0176] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.0 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 243.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.47 (s, 1H), 8.23 ​​(d, 2H), 6.89 (t, 1H).

[0177] Step 2: Dissolve 2.4 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 3-methylaniline, 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] + 353.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0178] Example 29

[0179] Preparation of compound 29

[0180]

[0181] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.3 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 273.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.47 (s, 1H), 7.54 (s, 2H), 3.83 (s, 3H).

[0182] Step 2: Dissolve 2.7 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 3-methylaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 344.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0183] Example 30

[0184] Preparation of compound 30

[0185]

[0186] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.6 g of compound 2, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 311.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.41 (t, 4H), 2.04 (t, 4H).

[0187] Step 2: Dissolve 3.1 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 3-methylaniline, 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] + 381.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0188] Example 31

[0189] Preparation of compound 31

[0190]

[0191] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.8 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 324.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0192] Step 2: Dissolve 3.2 g of compound 3 in 20 mL of isopropanol, add 1.1 g of 3-methylaniline, 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] + 397.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0193] Example 32

[0194] Preparation of compound 32

[0195]

[0196] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.4 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 284.1, 1H-NMR (DMSO-d6, 300MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.06 (s, 6H).

[0197] Step 2: Dissolve 2.8 g of compound 3 in 20 mL of isopropanol, add 1.6 g of 3-cyclopentylaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 410.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0198] Example 33

[0199] Preparation of compound 33

[0200]

[0201] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.4 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 284.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.06 (s, 6H).

[0202] Step 2: Dissolve 2.8 g of compound 3 in 20 mL of isopropanol, add 1.9 g of 3-cycloheptylaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 410.1, 1H-NMR(DMSO-d6,300MHz)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).

[0203] Example 34

[0204] Preparation of compound 34

[0205]

[0206] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.6 g of compound 2, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 313.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.86 (s, 1H), 7.02 (d, 2H), 6.76 (d, 2H), 3.36 (m, 4H), 1.15 (t, 6H).

[0207] Step 2: Dissolve 2.8 g of compound 3 in 20 mL of isopropanol, add 1.8 g of 3-cyclohexylaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + :452.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0208] Example 35

[0209] Preparation of compound 35

[0210]

[0211] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.1 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 256.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 10.18 (s, 1H), 7.90 (d, 1H), 7.31 (t, 1H), 6.54 (t, 1H), 2.16 (s, 3H).

[0212] Step 2: Dissolve 2.6 g of compound 3 in 20 mL of isopropanol, add 1.8 g of 3-cyclohexylaniline, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 395.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0213] Example 36

[0214] Preparation of compound 36

[0215]

[0216] Step 1: Dissolve 1.7 g of compound 1 in 20 mL of isopropanol, add 2.6 g of compound 2, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 390.1, 1H-NMR(DMSO-d6,300MHz)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).

[0217] Example 37

[0218] Preparation of compound 37

[0219]

[0220] Step 1: Dissolve 1.7 g of compound 1 in 20 mL of isopropanol, add 2.6 g of compound 2, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 391.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0221] Example 38

[0222] Preparation of compound 38

[0223]

[0224] Step 1: Dissolve 2.0 g of compound 1 in 20 mL of isopropanol, add 2.6 g of compound 2, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 419.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0225] Example 39

[0226] Preparation of compound 39

[0227]

[0228] Step 1: Dissolve 1.6 g of compound 1 in 20 mL of isopropanol, add 2.6 g of compound 2, 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] + 379.1, 1 H-NMR(DMSO-d6,300MHz)δ:10.18(s,1H),9.43(s,1H),7.90(d,2H),7.63(t,2H),7.61(d,1H),7.33(m,3H),6.56(m,2H),2.16(s,3H).

[0229] Example 40

[0230] Preparation of compound 40

[0231]

[0232] Step 1: Dissolve 1.5g of compound 1 in 20mL of isopropanol, add 2.6g of compound 2, reflux for 2 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve the residue in 20mL 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 374.1, 1 H-NMR(DMSO-d6,300MHz)δ:9.43(s,1H),8.25(s,1H),7.53(t,2H),7.21(t,1H),6.92( d,1H),6.79(s,1H),6.56(s,1H),3.81(t,1H),3.09(t,2H),2.33(s,3H),1.92(t,2H).

[0233] Example 41

[0234] Preparation of compound 41

[0235]

[0236] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.6 g of compound 2, 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 obtain the pure product by column chromatography. Off-white solid. [M+H] + 310.1, 1 H-NMR (DMSO-d6, 300MHz) 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).

[0237] Step 2: Dissolve 3.1 g of compound 3 in 20 mL of isopropanol, add 1.6 g of 7-aminotetrahydrothiazole [5,4-B]pyridine, 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] + 429.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0238] Example 42

[0239] Preparation of compound 42

[0240]

[0241] Step 1: Dissolve 1.8 g of compound 1 in 20 mL of acetone, add 1.1 g of compound 2, 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 then perform column chromatography to obtain the pure product. Off-white solid. [M+H] + 257.1, 1 H-NMR (DMSO-d6, 300MHz) δ: 8.47 (s, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 2.42 (s, 3H).

[0242] Step 2: Dissolve 2.6 g of compound 3 in 20 mL of isopropanol, add 1.6 g of 7-aminotetrahydrothiazolium [5,4-B]pyridine, 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 the pure product by column chromatography. Off-white solid. [M+H] + 429.1, 1 H-NMR(DMSO-d6,300MHz)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).

[0243] Example 43

[0244] 1. In vitro activity test of the compound against Haemonchus twistus.

[0245] Compound solutions in descending concentrations in DMSO were prepared, diluted with nutrient medium, and dispensed into 96-well microtiter plates. Sheathed L3 Haemaphysema contortus larvae were incubated in a 37°C water bath for 20 min, separated by centrifugation, and added to wells at 200 larvae / well. Motility was assessed using an automated microscope after 7 days of incubation. Avermectin was used as a positive control, and DMSO as a negative control. Expiratory Response (ED) was calculated. 50 The value represents the concentration of the compound that reduces motility by 50% in an individual compared to the positive control. Specific experimental data are shown in Table 2 below.

[0246] 2. In vitro agonistic activity of the compound against Caenorhabditis elegans SLO-1

[0247] A stable CHO K1 cell line transfected with *C. elegans* SLO-1 was established. Cells were seeded at a concentration of 10,000 cells / well in microtiter plates and cultured in 25 μL of medium 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 μL of LMP dye Blue-Tyrode was added to each well and incubated at room temperature for 30 min.

[0248] For membrane potential measurements, the prepared cell and material plates were placed in a FLIPR Tetra (Molecular Devices). A baseline fluorescence measurement was performed for 20 seconds (Exc. 510–545 nm, Emm. 565–625 nm). Cells were depolarized by adding 25 μL of a diluted test compound (final assay concentrations 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). A complete measurement took 150 seconds. Avermectin was used as a positive control, and DMSO as a negative control. ED was calculated. 50 value.

[0249] 3. In vitro activity test of the compound against canine heartworm

[0250] Compound solutions in descending concentrations in DMSO were prepared, diluted with nutrient medium, and dispensed into 96-well microtiter plates. Heartworm larvae were incubated in a 37°C water bath for 20 min, separated by centrifugation, and added to wells at 100 larvae / well. Motility was assessed using an automated microscope after 3 days of incubation. Avermectin was used as a positive control, and DMSO as a negative control. Expiratory Response (ED) was calculated. 50 The value represents the concentration of the compound that reduces motility by 50% in an individual compared to the positive control. Specific experimental data are shown in Table 2 below.

[0251] ED was determined using a compound dilution series in triplicate. 50 Values. Data were determined in at least two independent tests. Data were processed using ActivityBase XE Runner software (IDBS) for curve fitting and calculation of the half-maximum effective concentration. Specific experimental data are shown in Table 2 below.

[0252] Table 2 Insect-resistant activity of compounds 1-42

[0253]

[0254]

Claims

1. A triazine derivative as shown in general formula (Ⅰ): (I); in, R1 is selected from 2-4,5,6,7-tetrahydrothiazolium[5,4-B]pyridyl or benzotriazolyl; R2 is selected from 2-pyridyl, 3-pyridyl, pyrazinyl, and phenyl, wherein the 2-pyridyl, 3-pyridyl, pyrazinyl, and phenyl are optionally replaced by halogen, -CN, -CH3, -OCH3, -CF3, -OCH(CH3)2, -OCH2CH3, or C. 1-4 Alkyl, C 3-7 Cycloalkyl, 3-6 membered heterocyclic groups, -NH2, -NHSO2 CH3, -NHSO2 (CH2 ) 1-3 CH3, -COOCH3, -COOCH2CH3, -SO2CH3, -SO2 CH(CH3 )2, -N(CH3 )2, -CONH2, -N(CH2 CH3 )2, -CONHCH3, -CON(CH3)2 substitution; R3 is selected from fluorine, chlorine, bromine, methyl, and methoxy.

2. The triazine derivative according to claim 1, characterized in that, The derivative is one of structures 6, 27, and 40-42: 。 3. A triazine derivative, characterized in that, The derivative is one of structures 1-5, 7-26, and 28-39: 。 4. A salt of a triazine derivative as described in any one of claims 1-3, characterized in that, The salts of the triazine derivatives are salts formed by the triazine derivatives 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.

5. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any of the triazine derivatives of claims 1-3 or the salt of claim 4, and one or more pharmaceutical carriers and / or excipients.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition further includes one or more antiparasitic active ingredients; the antiparasitic active ingredients are selected from one or more of the following: flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, trichlorobenzyl, ivermectin, avermectin, diethylcarbazine, suramin, tribenzodiamidine, dihydroxynaphthyl acid, levamisole, niclosamide, nizoxinide, hydroxychlorosalisamide, praziquantel, emodydinoside, mononitrate, detrifendazole, oxifenesole, punicine sulfate, and moxifloxacin.

7. The use of a triazine derivative as described in any one of claims 1-3, or a salt as described in claim 4, or a pharmaceutical composition as described in claim 5, in the preparation of a medicament for the prevention and treatment of nematode infections in humans or animals.

8. The application according to claim 7, characterized in that, The nematodes mentioned are *Haemaphysalis contortus*, *Caenorhabditis elegans*, and *Heartworm*.

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