Pyridine fused ring compound containing sulfur substituent, preparation method therefor, and insecticide composition and use thereof

Abstract

The present invention relates to the field of insecticides, and specifically relates to a pyridine fused ring compound containing a sulfur substituent as shown in formula (I), a stereoisomer thereof, an agriculturally acceptable salt thereof, a preparation method therefor, and an insecticide composition and a use thereof in the field of pest control. R1, R2, R3, R4, R5, R6, X, Y, Z, and Q are as defined herein.

Description

Pyridine fused ring compounds containing sulfur substituents, methods of preparation, insecticide compositions and uses TECHNICAL FIELD

[0001] The present application relates to the field of insecticides, in particular to a pyridine fused ring compound containing sulfur substituents as shown in formula (I), stereoisomers thereof, agriculturally acceptable salts thereof, methods of preparation thereof, insecticide compositions and uses thereof in the field of controlling harmful organisms. BACKGROUND

[0002] Fused bicyclic heterocyclic derivatives having insecticidal properties have been described in the following documents: for example WO 2019 / 219689 A1, EP 3305786 A2, WO 2016 / 091731 A1, WO 2017 / 026384 A1, WO 2018 / 015289 A1, WO 2019 / 008072, WO 2022 / 013417 A1, WO 2022 / 049141, WO 2022 / 049144, WO 2022 / 157334, WO 2023 / 072945 A1, WO 2023 / 148368 A1, WO 2023 / 148369 A1, WO 2024 / 022362 A1.

[0003] However, the development of novel insecticides and acaricides still faces challenges, for example requirements related to their insecticidal or acaricidal activity, duration of action, spectrum of action and potential uses, toxicity, protection of non-target organisms and pollinators, environmental properties, application rates, problems of compatibility with other active compounds or formulation auxiliaries, and chemical complexity issues involved in the synthesis of the active ingredients. In addition, resistance can also occur. In view of this, there is a need to continuously develop new compounds with more optimal properties compared to known compounds.

[0004] It has now surprisingly been found that certain novel pyridine fused ring compounds containing sulfur substituents have better biological or environmental properties, a wider range of application methods, better insecticidal or acaricidal effects, and good compatibility with crop plants as insecticides or acaricides. The pyridine fused ring compounds containing sulfur substituents can be used in combination with other agents to improve efficacy, especially against difficult-to-control insects. SUMMARY

[0005] The present application therefore provides a pyridine fused ring compound containing sulfur substituents as shown in general formula (I), stereoisomers thereof, and agriculturally acceptable salts thereof:

[0006] wherein X, Y are selected from N, N-R7 or S;

[0007] when X is selected from N, Y is selected from N-R7 or S;

[0008] when Y is selected from N, X is selected from N-R7or S;

[0009] wherein Z is selected from CH2, NH or N-R8;

[0010] wherein R1to R5are each independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl or cyano;

[0011] wherein R6, R7and R8are each independently selected from C1-C6alkyl, C3-C6cycloalkyl;

[0012] wherein Q represents a group of the formula Q2-Q8or 32 as depicted below:

[0013] wherein R9is selected from C1-C4haloalkyl, -SC1-C4haloalkyl, C1-C4haloalkylsulfinyl, C1-C4haloalkylsulfonyl, -OC1-C4haloalkyl.

[0014] More preferably,

[0015] wherein X, Y are selected from N, N-CH3or S;

[0016] when X is selected from N, Y is selected from N-CH3or S;

[0017] when Y is selected from N, X is selected from N-CH3or S;

[0018] wherein R6is methyl;

[0019] wherein Z is selected from CH2, NH or N-CH3;

[0020] wherein R1to R5are each independently selected from hydrogen, fluorine, methyl, trifluoromethyl or cyano;

[0021] wherein Q represents a group of the formula Q2-Q8or 10- Q 13 as depicted below:

[0022] wherein R9is selected from trifluoromethyl, pentafluoroethyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl or trifluoromethylsulfonyl.

[0023] Preferably, the compounds of the formula (I), the stereoisomers thereof and the agriculturally acceptable salts thereof, wherein R1to R5are simultaneously hydrogen or at least one of R1to R5is substituted by fluorine, chlorine, bromine, trifluoromethyl or cyano.

[0024] Preferably, the compounds of the formula (I), the stereoisomers thereof and the agriculturally acceptable salts thereof, wherein R1to R5are simultaneously hydrogen or at least one of R1to R5is substituted by fluorine, chlorine or cyano.

[0025] Preferred are compounds of formula (I), stereoisomers and agriculturally acceptable salts thereof, wherein any 1, 2 or 3 of R1-R5 are fluoro, chloro or cyano substituted, and the remainder are hydrogen.

[0026] Preferred are compounds of formula (I), stereoisomers and agriculturally acceptable salts thereof, wherein any 1 or 2 of R1-R5 are fluoro or chloro substituted, and the remainder are hydrogen.

[0027] Preferred are compounds of formula (I), stereoisomers and agriculturally acceptable salts thereof, wherein X and Y are selected from N, N-R7 or S;

[0028] wherein X and Y are selected from N, N-R7 or S;

[0029] wherein X is selected from N, Y is selected from N-R7 or S;

[0030] wherein Y is selected from N, X is selected from N-R7 or S;

[0031] wherein Z is selected from CH2, NH or N-R8; wherein Z is selected from NH or N-R8;

[0032] wherein R1-R5 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or cyano;

[0033] wherein Z is selected from CH2, R1-R5 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, and at least one of R1-R5 is fluoro, chloro, bromo, trifluoromethyl or cyano substituted;

[0034] wherein R6, R7 and R8 are each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0035] wherein Q represents a group of formula Q1:

[0036] R9 is selected from C1-C4 haloalkyl, -SC1-C4 haloalkyl, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl.

[0037] Preferred are compounds of formula (I), stereoisomers and agriculturally acceptable salts thereof, wherein X and Y are selected from N, N-CH3 or S;

[0038] wherein X is selected from N, Y is selected from N-CH3 or S;

[0039] wherein Y is selected from N, X is selected from N-CH3 or S;

[0040] wherein R6 is methyl;

[0041] wherein Z is selected from CH2, NH or N-CH3;

[0042] when Z is selected from NH or N-CH3, R1-R5 are each independently selected from hydrogen, fluorine, methyl, trifluoromethyl or cyano;

[0043] when Z is selected from CH2, R1-R5 are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or cyano, and at least one of R1-R5 is substituted with fluorine, chlorine, bromine, trifluoromethyl or cyano.

[0044] Preferably, a composition comprising at least one of the compounds of formula (I), stereoisomers thereof or salts thereof, wherein the compound of formula (I) is used as an active ingredient, and the weight percentage of the active ingredient in the composition is 0.1-99.9%.

[0045] Preferably, a method for controlling pests, wherein the compound of formula (I), stereoisomers thereof and agriculturally acceptable salts thereof or the composition are applied to the pests or their growth environment.

[0046] Preferably, the use of the compound of formula (I), stereoisomers thereof and agriculturally acceptable salts thereof or the composition in controlling pests.

[0047] Part of the compounds of formula (I) of the present application can be illustrated by the specific compounds listed in Table 1, but the present application is not limited to these compounds.

[0048] Table 1

[0049] The present invention also provides a method for preparing the compound of formula (I) described above, its stereoisomers, and agriculturally acceptable salts thereof, comprising the following schemes:

[0050] Scheme 1: In general formula (I), Z is selected from CH2; X and Y are selected from N, N-CH3, or S; when X is selected from N, Y is selected from N-CH3 or S; when Y is selected from N, X is selected from N-CH3 or S; R6 is selected from methyl; R1-R5 are independently selected from hydrogen, fluorine, methyl, trifluoromethyl, or cyano; and Q is selected from Q1-Q 16 The preparation method includes the following steps:

[0051] (1) The compound of general formula (II-i) undergoes an oxidation reaction to produce the compound of general formula (I);

[0052] (2) The compound of general formula (II-i) undergoes an oxidation reaction to produce the compound of general formula (II-j);

[0053] (3) The compound shown in general formula (II-j) undergoes an oxidation reaction to produce the compound shown in general formula (I);

[0054] Scheme 2: In general formula (I), Q is selected from Q1-Q5; Z is selected from CH2; X and Y are selected from N, N-CH3, or S; when X is selected from N, Y is selected from N-CH3 or S; when Y is selected from N, X is selected from N-CH3 or S; R1-R5 are independently selected from hydrogen, fluorine, methyl, trifluoromethyl, or cyano, R6 is selected from methyl, and n is selected from 0, 1, and 2; the preparation method includes the following steps:

[0055] (1) The compound shown in general formula (II-f) undergoes a condensation reaction with aromatic amines of different substitutions to generate the compound shown in general formula (Vd);

[0056] (2) The compound represented by general formula (Vd) undergoes a cyclization reaction to generate the compound represented by general formula (Ia);

[0057] Scheme 3: The compound shown in Scheme 2 with general formula (II-f), where X is selected from N-CH3 or S and Y is selected from N, can be defined as general formula (II-a) and (II-b); when X is selected from N and Y is selected from N-CH3, the compound can be defined as general formula (II-c). Its preparation method includes the following steps:

[0058] (1) The compound represented by general formula (Va) undergoes a coupling reaction with ammonia water or ammonia gas to generate the compound represented by general formula (VI-a);

[0059] (2) The compound of general formula (VI-a) undergoes a substitution reaction with a brominating or chlorinating reagent to produce the compound of general formula (VII-a);

[0060] (3) The compound shown in general formula (VII-a) undergoes a condensation reaction with cyclopropylformic acid with different substitutions to generate the compound shown in general formula (VIII-a);

[0061] (4) The compound shown in general formula (VIII-a) undergoes substitution and cyclization reactions with methylammonium water to generate tert-butyl ester compounds, which are then hydrolyzed to generate the compound shown in general formula (II-a).

[0062] (5) The compound shown in general formula (VIII-a) undergoes substitution and cyclization reactions with a thioreagent to generate tert-butyl ester compounds, which are then hydrolyzed to generate the compound shown in general formula (II-b).

[0063] (6) The compound of general formula (VIII-a) undergoes a substitution reaction with a methylating agent to generate the compound of general formula (IX-a);

[0064] (7) The compound shown in general formula (IX-a) undergoes substitution and cyclization reactions with ammonia water to generate tert-butyl ester compounds, which are then hydrolyzed to generate the compound shown in general formula (II-c).

[0065] Scheme 4: When the compound shown in Scheme 2 with general formula (II-f), where X is selected from N and Y is selected from S, the compound can be defined as general formula (II-d), and its preparation method includes the following steps:

[0066] (1) The compound of general formula (Vb) undergoes a substitution reaction with a brominated or chlorinated reagent to produce the compound of general formula (VI-b);

[0067] (2) The compound shown in general formula (VI-b) undergoes a condensation reaction with cyclopropylformic acid with different substitutions to generate the compound shown in general formula (VII-b);

[0068] (3) The compound of general formula (VII-b) undergoes a substitution reaction with a thioreagent to produce the compound of general formula (VIII-b);

[0069] (4) The compound of general formula (VIII-b) undergoes a condensation reaction under alkaline conditions to produce the compound of general formula (IX-b);

[0070] (5) The compound of general formula (IX-b) undergoes a hydrolysis reaction to produce the compound of general formula (II-d).

[0071] In the formula R 11 Selected from C1-C4 alkyl groups, X1 is selected from chlorine or bromine.

[0072] Scheme 5: In general formula (I), Q is selected from Q6 or Q7; Z is selected from CH2; X and Y are selected from N, N-CH3, or S; when X is selected from N, Y is selected from N-CH3 or S; when Y is selected from N, X is selected from N-CH3 or S; R1-R5 are independently selected from hydrogen, fluorine, methyl, trifluoromethyl, or cyano; R6 is selected from methyl; the compound can be defined as general formula (Ib); its preparation method includes the following steps:

[0073] (1) The compound represented by general formula (Vc) undergoes a substitution reaction with benzyl bromide with different substitutions to generate the compound represented by general formula (Ve);

[0074] (2) The compound represented by general formula (Ve) loses its Boc protecting group under acidic conditions to generate the compound represented by general formula (VI-e);

[0075] (3) The compound shown in general formula (VI-e) undergoes a hydrolysis reaction to produce the compound shown in general formula (II-h);

[0076] (4) The compound of general formula (II-h) undergoes a condensation reaction to produce the compound of general formula (Ib);

[0077] In the formula R 13 Selected from C1-C4 alkyl groups.

[0078] Scheme 6: In general formula (I), Q is selected from Q8, Z is selected from CH2; X and Y are selected from N, N-CH3, or S; when X is selected from N, Y is selected from N-CH3 or S; when Y is selected from N, X is selected from N-CH3 or S; R1-R5 are independently selected from hydrogen, fluorine, methyl, trifluoromethyl, or cyano; R6 is selected from methyl. The compound can be defined as general formula (Ic), and its preparation method includes the following steps:

[0079] (1) The compound shown in general formula (II-g) undergoes a substitution reaction to produce the compound shown in general formula (Ic);

[0080] Scheme 7: The compounds represented by general formulas (Vc) and (II-g) in Schemes 5 and 6 are prepared by the following steps:

[0081] (1) The compound represented by general formula (II-f) undergoes the Curtius rearrangement reaction to generate the compound represented by general formula (Vc);

[0082] (2) The compound represented by general formula (Vc) loses its Boc protecting group under acidic conditions to generate the compound represented by general formula (VI-c);

[0083] (3) The compound of general formula (VI-c) undergoes a diazotization reaction to produce the compound of general formula (II-g);

[0084] Scheme 8: In general formula (I), Q is taken from Q1-Q5; Z is selected from CH2; R1-R5 are independently selected from hydrogen, fluorine, methyl, trifluoromethyl or cyano, R6 is selected from methyl; and n is selected from 0, 1 and 2. When X is selected from N-CH3 or S and Y is selected from N, the compound can be defined as general formula (Ia-1) and (Ia-2). When X is selected from N and Y is selected from N-CH3, the compound can be defined as general formula (Ia-3). The preparation method includes the following steps:

[0085] (1) The compound represented by general formula (Vf) undergoes a condensation reaction with different substituted aromatic amines to generate the compound represented by general formula (VI-f).

[0086] (2) The compound represented by general formula (VI-f) undergoes a cyclization reaction to generate the compound represented by general formula (VII-f);

[0087] (3) The compound shown in general formula (VII-f) undergoes a condensation reaction with different substituted cyclopropylformic acids to generate the compound shown in general formula (III-a1);

[0088] (4) The compound of general formula (III-a1) undergoes a substitution reaction with a methylating agent to produce the compound of general formula (III-a2).

[0089] (5) The compound of general formula (III-a1) undergoes substitution and cyclization reactions with methylammonium water to generate the compound of general formula (Ia-1);

[0090] (6) The compound of general formula (III-a1) undergoes substitution and cyclization reactions with a thioreagent to generate the compound of general formula (Ia-2);

[0091] (7) The compound of general formula (III-a2) undergoes substitution and cyclization reactions with ammonia to generate the compound of general formula (Ia-3);

[0092] Scheme 9: When Q in general formula (I) is taken from Q1-Q5; Z is selected from CH2; R1-R5 are independently selected from hydrogen, fluorine, methyl, trifluoromethyl or cyano, R6 is selected from methyl; n is selected from 0, 1 and 2; and X is selected from N and Y is selected from S, the compound can be defined as general formula (Ia-4), and its preparation method includes the following steps:

[0093] (1) The compound represented by general formula (Vg) undergoes a condensation reaction with aromatic amines of different substitutions to generate the compound represented by general formula (VI-g);

[0094] (2) The compound of general formula (VI-g) undergoes a cyclization reaction to generate the compound of general formula (VII-g);

[0095] (3) The compound shown in general formula (VII-g) undergoes a condensation reaction with cyclopropylformic acid with different substitutions to generate the compound shown in general formula (III-b1);

[0096] (4) The compound of general formula (III-b1) undergoes a substitution reaction with a thioreagent to produce the compound of general formula (III-b2);

[0097] (5) The compound of general formula (III-b2) undergoes a cyclization reaction to generate the compound of general formula (Ia-4).

[0098] Scheme 10: In general formula (I), Z is selected from N or N-CH3, and X and Y are selected from N, N-CH3, or S; when X is selected from N, Y is selected from N-CH3 or S; when Y is selected from N, X is selected from N-CH3 or S; R6 is selected from methyl; R1-R5 are independently selected from hydrogen, fluorine, methyl, trifluoromethyl, or cyano; the compound can be defined as general formula (Id) and general formula (Ie), and its preparation method includes the following steps:

[0099] (1) The compound of general formula (Ia) undergoes a substitution reaction with benzyl mercaptan to produce the compound of general formula (Vj);

[0100] (2) The compound represented by general formula (Vj) undergoes an oxidation reaction to produce the compound of general formula (VI-j);

[0101] (3) The compound of general formula (VI-j) undergoes a substitution reaction with methylamine to produce the compound of general formula (Id);

[0102] (4) The compound of general formula (VI-j) undergoes a substitution reaction with dimethylamine to produce the compound of general formula (Ie);

[0103] (5) The compound of general formula (Id) undergoes a substitution reaction with a methylating agent to generate the compound of general formula (Ie);

[0104] In the definitions of compounds of formula (I) given above, the terms used in the compilation are generally defined as follows:

[0105] Alkyl groups refer to saturated straight-chain or branched hydrocarbon groups having a specified number of carbon atoms in each case, such as C1-C6-alkyl groups, including methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, etc. 1-Methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl.

[0106] Halogen-substituted alkyl groups (halogenated alkyl groups) refer to the following straight-chain or branched alkyl groups in which some or all of the hydrogen atoms can be replaced by halogen atoms, such as C1-C2 haloalkyl groups, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and 1,1,1-trifluoropropyl-2-yl.

[0107] Alkoxy refers to a saturated straight-chain or branched alkoxy group having a specified number of carbon atoms in each case, such as C1-C6-alkoxy groups, including methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1,1-dimethylpropoxy, and 1,2-dimethylpropoxy. The compounds are: 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, and 1-ethyl-2-methylpropoxy. Halogen-substituted alkoxy groups refer to the following straight-chain or branched alkoxy groups having a specified number of carbon atoms in each case: wherein in these groups, some or all of the hydrogen atoms may be replaced by halogen atoms as described above, such as C1-C2 haloalkoxy groups, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and 1,1,1-trifluoroprop-2-oxy.

[0108] The term "halogen" refers to fluorine, chlorine, bromine, or iodine. If the term is used with a group, then "halogen" or "halogen atom" refers to a fluorine, chlorine, bromine, or iodine atom.

[0109] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0110] The present invention also provides a composition, characterized in that it comprises at least one of the compound of formula (I) described above, its stereoisomer or salt thereof, wherein the compound of formula (I) is used as the active component, and the weight percentage of the active component in the composition is 0.1-99.9%.

[0111] Compositional forms include, for example, liquid irrigation, drip irrigation, and spraying. Optionally, the application form contains other pesticides and / or adjuvants that enhance action, such as penetrants, like vegetable oils (e.g., rapeseed oil, sunflower oil), mineral oils (e.g., paraffin oil), alkyl esters of vegetable fatty acids (e.g., rapeseed oil methyl ester or soybean oil methyl ester), or alkanol alkoxylates; and / or spreaders, such as alkylsiloxanes and / or salts (e.g., organic or inorganic ammonium salts or phosphonium salts, such as ammonium sulfate or diammonium hydrogen phosphate); and / or retention promoters, such as dioctyl sulfosuccinate or hydroxypropyl guar gum polymers; and / or wetting agents, such as glycerin; and / or fertilizers, such as ammonium-, potassium-, or phosphorus-containing fertilizers.

[0112] Conventional formulations include: water-soluble liquid formulations (SL), emulsion concentrates (EC), emulsions (EW), suspension concentrates (SC, SE, FS, OD), water-dispersible granules (WG), granules (GR), and capsule concentrates (CS); these formulations and other possible formulation types are documented by Crop Life International and described in the following documents: Pesticide Standards, FAO / WHO Manual on the Development and Use of Pesticide Standards, and FAO Document on Plant Production and Protection-173 (prepared by the FAO / WHO Joint Conference on Pesticide Standards, 2004, ISBN: 9251048576). In addition to one or more compounds of formula (I), the formulations may optionally contain other agrochemically active compounds.

[0113] Preferred formulations or application forms include at least one adjuvant, such as a extender, solvent, spontaneous growth promoter, carrier, emulsifier, dispersant, antifreeze, biocide, thickener; and / or other adjuvants, such as adjuvants. In the context of this invention, an adjuvant is a component that enhances the biological efficacy of the formulation, while the component itself does not possess any biological efficacy. Examples of adjuvants are agents that promote retention, spreading, adhesion to leaf surfaces, or penetration.

[0114] These formulations are prepared in a known manner, for example by mixing a compound of formula (I) with an adjuvant such as a extender, a solvent, and / or a solid carrier and / or other adjuvants such as a surfactant. The formulation is prepared in a suitable facility or before or during application.

[0115] The adjuvants used may be substances suitable for imparting specific properties (e.g., certain physical, technical, and / or biological properties) to formulations of compounds of formula (I) or application forms prepared from such formulations (e.g., ready-to-use pesticides, such as spray liquids or seed dressing products). Furthermore, compounds of formula (I) may be mixed with other active compounds or chemical pheromones such as attractants and / or bird repellents and / or plant activators and / or growth regulators and / or fertilizers. Similarly, compounds of formula (I) can be used to improve plant performance, such as the growth, yield, and quality of harvested crops.

[0116] The present invention also provides a method for controlling pests, characterized in that the compound of formula (I) described above, its stereoisomers and agriculturally acceptable salts thereof, or the composition described above are applied to the pest or its growth environment.

[0117] Harmful organisms include agricultural or non-agricultural invertebrate pests, such as:

[0118] Eggs, larvae, and adults of lepidopteran pests, such as armyworms, caterpillars, inchworms, and bollworms (e.g., corn borer (Sesamia inferens Walker), corn borer (Sesamia nonagrioides Lefebvre), southern gray-winged armyworm (Spodoptera eridania Cramer), fall armyworm (Spodoptera frugiperda JESmith), beet armyworm (Spodoptera exigua Hübner), cotton leafworm (Spodoptera littoralis Boisduval), yellow-banded armyworm (Spodoptera ornithogalli Guenée), cutworm (Agrotis ipsilon Hufnagel), velvet bean hairy caterpillar (Anticarsia gemmatalis Hübner), green-fruit winter armyworm (Lithophane antennata Walker), cabbage armyworm (Barathra brassicae Linnaeus), soybean armyworm (Pseudoplusia includens)). Walker), cabbage silver-striped noctuid moth (Trichoplusiani Hübner), tobacco aphid (Heliothis virescens Fabricius);Pyralidae (Moth Borers) include borers, sheath moths, web-forming caterpillars, pine cone shoot borers, cabbage caterpillars, and leaf-carving insects (such as the European corn borer (Ostrinia nubilalis Hübner), the navel orange borer (Amyelois transitella Walker), the corn root web-forming caterpillar (Crambus caliginosellus Clemens), and meadow moths (Pyralidae: Pyralinae subfamily) such as the rice leaf cutter borer (Herpetogramma licarsisalis Walker), the sugarcane two-spotted borer (Chilo infuscatellus Snellen), the tomato borer (Neoleucinodes elegantalis Guenée), the rice leaf roller (Cnaphalocrocis medinalis), the grape leaf roller (Desmiafuneralis Hübner), the melon borer (Diaphania nitidalis Stoll), and the cabbage core grub (Hellualahydralis). Guenée, Scirpophaga incertulas Walker, Scirpophaga infuscatellus Snellen, Scirpophaga innotata Walker, Scirpophaga nivella Fabricius, Chilo polychrysus Meyrick, Chilo suppressalis Walker, Crocidolomia binotalis English;Leafrollers, bud borers, seed borers, and fruit borers (e.g., apple leafroller (Cydia pomonella Linnaeus), grape berry moth (Endopiza viteana Clemens), pear fruit moth (Grapholita molesta Busck), apple heterocarpa (Cryptophlebia leucotreta Meyrick), citrus longhorn beetle (Ecdytolopha aurantiana Lima), red-banded leafroller (Argyrotaenia velutinana Walker), rose-banded leafroller (Choristoneura rosaceana Harris), apple light brown leafroller (Epiphyas postvittana Walker), privet leafroller (Eupoecilia ambiguella Hübner), apple terminal bud leafroller (Pandemis pyrusana Kearfott), omnivorous leafroller (Platynota stultana Walsingham), grape brown leafroller (Pandemis cerasana)) Hübner, apple leafroller (Pandemis heparana Denis & Schiffermüller); and many other economically important lepidopteran insects (such as diamondback moth (Plutella xylostella Linnaeus), bollworm (Pectinophora gossypiella Saunders), gypsy moth (Lymantria dispar Linnaeus), peach fruit moth (Carposina niponensis Walsingham), peach striped wheat moth (Anarsia lineatella Zeller), potato tuber moth (Phthorimaea operculella Zeller), striped leaf miner (Lithocolletis blancardella Fabricius), apple golden leafminer (Lithocolletis ringoniella Matsumura), rice leaf roller (Lerodea eufala Edwards), and spiral leafminer (Leucoptera scitella Zeller)).The eggs, pupae, and adults of cockroaches, including cockroaches of the families Blattodea and Blattidae (such as the Oriental cockroach (Blatta orientalis Linnaeus), the Asian cockroach (Blatella asahinai Mizukubo), the German cockroach (Blattella germanica Linnaeus), the brown-banded cockroach (Supella longipalpa Fabricius), the American cockroach (Periplaneta americana Linnaeus), the brown cockroach (Periplaneta brunnea Burmeister), the Madeira cockroach (Leucophaea maderae Fabricius), the black-breasted cockroach (Periplaneta fuliginosa Service), the Australian cockroach (Periplaneta australasiae Fabr.), the lobster cockroach (Nauphoeta cinerea Olivier), and the pale-tailed cockroach (Symploce pallens). Stephens); Coleoptera pests, including their eggs, larvae, and adults that feed on leaves, fruits, roots, seeds, and vesicle tissue, such as weevils of the families Anthonomus, Fabaceae, and Cestidae (e.g., cottonseed weevil (Anthonomus grandis Boheman), rice water weevil (Lissorhoptrus oryzophilus Kuschel), grain weevil (Sitophilus granarius Linnaeus), rice weevil (Sitophilus oryzae Linnaeus)), Kentucky bluegrass weevil (Listronotus maculicollis Dietz), forage weevil (Sphenophorus parvulus Gyllenhal), hunter weevil (Sphenophorus venatus vestitus), and Denver weevil (Sphenophorus cicatristriatus). Fahraeus; Leaf beetles, including flea beetles, melon beetles, root worms, leaf beetles, potato beetles, and leaf miners (e.g., Colorado potato beetle (Leptinotarsa ​​decemlineata Say) and western corn root worm (Diabrotica virgifera LeConte));Scarab beetles and other beetles (e.g., Japanese scarab beetle (Popillia japonica Newman), Oriental scarab beetle (Anomala orientalis waterhouse, Exomala orientalis (waterhouse) Baraud), Northern round-headed rhinoceros beetle (Cyclocephala borealis Arrow), Southern round-headed rhinoceros beetle (Cyclocephala immaculata Olivier or C. lurida Bland), dung beetles and grubs (genus *Cyclocephala*), black turf beetle (Ataenius spretulus Haldeman), green scarab beetle (Cotinis nitida Linnaeus), chestnut velvet scarab beetle (Maladera castanea Arrow), June-gill scarab (genus *Phyllophaga*), and European scarab beetle (Rhizotrogus majalis Razoumowsky)); dermatophytes (family Dermestidae); nematodes (family Click beetles); bark beetles (family Bark beetles); and face weevils (family Tenebrionidae).

[0119] In addition, agricultural and non-agricultural pests include: eggs, adults, and larvae of Dermaptera pests, including earwigs (e.g., the European ball earwig (Forficula auricularia Linnaeus) and the black earwig (Chelisoches morioFabricius)); eggs, larvae, adults, and pupae of Hemiptera and Homoptera pests, such as mirid bugs (Miridae), cicadas (Cicadae), leafhoppers (e.g., Empoasca), and bedbugs (e.g., Cimex lectularius). Linnaeus, planthoppers of the families Cicadaidae and Cnidiidae, treehoppers of the family Cicadaidae, psyllids of the family Psyllididae, whiteflies of the family Aphididae, aphids of the family Aphididae, root aphids of the family Aphididae, mealybugs of the family Mealybugidae, scale insects of the families Scale Insecta, scale insects of the families Scale Insecta and Scale Insecta, lace bugs of the family Lacebugidae, stink bugs of the family Stink Bugidae, long bugs of the family Long bugidae (e.g., hairy long bug (Blissus leucopterus hirtus Montandon) and southern wheat bug (Blissus insularis Barber)) and other long bugs of the family Long bugidae, grasshoppers of the family Flea-like bugs, cucurbit grasshoppers of the family Marginaceae, and red bugs and cotton bollworms of the family Red bugidae.

[0120] Agricultural and non-agricultural pests also include the eggs, larvae, pupae, and adults of mites, such as spider mites and red spider mites (e.g., apple red spider mite (Panonychus ulmi Koch), two-spotted spider mite (Tetranychus urticae Koch), and McDaniel spider mite (Tetranychus mcdanieli McGregor)); grape mites (e.g., citrus red spider mite (Brevipalpus lewisi McGregor)); rust ticks and bud ticks (Gallidae) and other leaf-feeding mites, dust mites (Gallidae), demodicid mites (Demodex mites), and grain mites (Gallidae); and hard ticks (Ixodes scapularis Say, Ixodes holocyclus Neumann, Dermacentor variabilis Say, and Amblyomma americanum). Linnaeus and ticks commonly known as soft ticks (e.g., relapsing thermos tick (Ornithodoros turicata), common chicken tick (Argasradiatus)); itch mites and scabies mites of the families Ophiopogonidae, Pyratidae, and Sarcoptera; eggs, adults, and larvae of orthoptera pests, including grasshoppers, locusts, and crickets (e.g., migratory grasshoppers (e.g. Melanoplus sanguinipes Fabricius, M. differentialis Thomas)), American grasshoppers (e.g., Schistocerca americana Drury), desert locusts (Schistocerca gregaria Forskal), migratory locusts (Locusta migratoria Linnaeus), shrub locusts (Zonocerus), house crickets (Acheta domesticus Linnaeus), mole crickets (e.g., yellowish mole cricket (Scapteriscus vicinus Scudder) and southern mole crickets (Scapteriscus borellii)). Giglio-Tos));Eggs, adults, and larvae of Diptera pests include leaf miners (e.g., *Liriomyza*, such as the vegetable leafminer *Liriomyzasativae* Blanchard), midges, fruit flies (*Tephritidae*), eye flies (e.g., *Oscinella frit* Linnaeus), maggots, houseflies (e.g., *Musca domestica* Linnaeus), summer toilet flies (e.g., *Fannia canicularis* Linnaeus, *F. femoralis* Stein), stable flies (e.g., *Stomoxys calcitrans* Linnaeus), autumn houseflies, hornflies, blowflies (e.g., *Chrysomya*, *Phormia*) and other housefly pests, horseflies (e.g., *Tabanus*), skin flies (e.g., *Gastrophilus*, *Oestrus*), cow flies (e.g., *Hypoderma*), deer flies (e.g., *Chrysops*), and sheep ticks (e.g., *Melophagus ovinus*). Linnaeus and other short-horned insects, mosquitoes (e.g., Aedes, Anopheles, Culex), black flies (e.g., Prosimulium, Simulium), midges, sandflies, fungus gnats, and other long-horned insects; eggs, adults, and larvae of Thysanura pests, including onion thrips (Thrips tabaci Lindeman), flower thrips (Frankliniella), and other leaf-feeding thrips; Hymenoptera insect pests, including formic ants, including Florida carpenter ants (Camponotus floridanus Buckley), red carpenter ants (Camponotus ferrugineus Fabricius), black carpenter ants (Camponotus pennsylvanicus De Geer), white-legged ants (Technomyrmex albipes fr. Smith), big-headed ants (Pheidole), and black-headed sour ants (Tapinoma melanocephalum Fabricius);Pharaoh ants (Monomorium pharaonis Linnaeus), small fire ants (Wasmannia auropunctata Roger), fire ants (Solenopsis geminata Fabricius), invasive red fire ants (Solenopsis invicta Buren), Argentine ants (Iridomyrmex humilis Mayr), crazy ants (Paratrechina longicornis Latreille), pavement ants (Tetramorium caespitum Linnaeus), corn hairy ants (Lasius alienus Forster), and stink ants (Tapinoma sessile Say). Other hymenopteran pests include bees (including carpenter bees), giant hornets, wasps, and sawflies (genus *Neodiprion*; *Cephus*); isoptera insect pests include termites of the families Macrotermes (e.g., *Macrotermes*, *Odontotermes obesus* Rambur), wood termites (e.g., *Cryptotermes*), and rhinoceros termites (e.g., *Reticulitermes*, *Coptotermes*, *Heterotermes tenuis* Hagen), North American subterranean termites (*Reticulitermes flavipes* Kollar), western subterranean termites (*Reticulitermes hesperus* Banks), yellow subterranean termites (*Coptotermes formosanus* Shiraki), western Indian drywood termites (*Incisitermes immigrans* Snyder), sand termites (*Cryptotermes brevis* Walker), drywood termites (*Incisitermes snyderi* Light), and southern subterranean termites (*Reticulitermes virginicus*). Banks, western drywood termites (Incisitermes minor Hagen), tree termites such as the Elephant genus, and other economically important termites;Thysanura insect pests, such as silver beetles (Lepisma saccharina Linnaeus) and domestic silverfish (Thermobia domestica Packard). Other arthropod pests involved include: spiders such as the brown recluse spider (Loxosceles reclusa Gertsch & Mulaik) and the black widow spider (Latrodectus mactans Fabricius), and centipedes such as the house centipede (Scutigera coleoptrata Linnaeus).

[0121] Examples of invertebrate pests that infest stored grains include the large grain beetle (Prostephanus truncatus), the grain beetle (Rhyzopertha dominica), the rice weevil (Stiophilus oryzae), the maize weevil (Stiophilus zeamais), the four-striped bean weevil (Callosobruchus maculatus), the red flour beetle (Tribolium castaneum), the grain weevil (Stiophilus granarius), the Indian flour borer (Plodia interpunctella), the Mediterranean flour borer (Ephestia kuhniella), and the rusty red flat flour beetle (Cryptolestis ferrugineus).

[0122] Examples of Lepidoptera pests include *Alabama argillacea* Hübner (clothes moth), *Archips argyrospila* Walker (fruit tree leafroller), *A. rosana* Linnaeus (European leafroller), and other species of the genus *Chilo suppressalis* Walker (rice stem borer), *Cnaphalocrosis medinalis* Guenée (rice leafroller), *Crambus caliginosellus* Clemens (corn root webbing caterpillar), *Crambus teterrellus* Zincken (bluegrass leaf borer), *Cydia pomonella* Linnaeus (apple leafroller), *Earias insulana* Boisduval (diamond borer), *Earias vittella* Fabricius (green bollworm), *Helicoverpa armigera* Hübner (American bollworm), *Helicoverpa zea* Boddie (cotton bollworm), *Heliothis virescens* Fabricius (tobacco aphid), and *Herpetogramma licarsisalis*. Walker (grass moth), Lobesia botrana Denis & Schiffermüller (grape berry moth), Pectinophora gossypiella Saunders (cotton bollworm), Phyllocnistis citrella Stainton (citrus leafminer), Pieris brassicae Linnaeus (cabbage white butterfly), Pieris rapae Linnaeus (cabbage white moth), Plutellaxylostella Linnaeus (diamond moth), Spodoptera exigua Hübner (beet armyworm), Spodoptera litura Fabricius (beet armyworm, tea silkworm), Spodoptera frugiperda JESmith (fall armyworm), Trichoplusia ni Hübner (cabbage silver-striped armyworm), and Tuta absoluta Meyrick (tomato leafminer).

[0123] Examples of Hemiptera pests include: *Acyrthosiphon pisum Harris* (bean aphid), *Aphis craccivora Koch* (black bean aphid), *Aphis fabae Scopoli* (broad bean aphid), *Aphis gossypii Glover* (cotton aphid, melon aphid), *Aphis pomi De Geer* (apple aphid), *Aphis spiraecola Patch* (leaf-rolling aphid), *Aulacorthum solani Kaltenbach* (eggplant aphid), *Chaetosiphon fragaefolii Cockerell* (strawberry aphid), *Diuraphis noxia Kurdjumov / Mordvilko* (Russian wheat aphid), *Dysaphis plantaginea Paaserini* (rose aphid), *Eriosoma lanigerum Hausmann* (apple aphid), *Hyalopterus pruni Geoffroy* (peach aphid), *Lipaphis erysimi Kaltenbach* (radish aphid), *Metopolophium dirrhodum Walker* (wheat aphid), and *Macrosiphum*. *Euphorbiae Thomas* (potato aphid), *Myzus persicae Sulzer* (peach aphid), *Nasonovia ribisnigri* Mosley (lettuce aphid), *Pemphigus* (root aphid and gall aphid), *Rhopalosiphum maidis Fitch* (corn leaf aphid), *Rhopalosiphumpadi Linnaeus* (grain tube aphid), *Schizaphis graminum Rondani* (wheat two-forked aphid), *Sitobionavenae Fabricius* (wheat long-tube aphid), *Therioaphis maculata Buckton* (alfalfa spotted aphid), *Toxoptera aurantii Boyer de Fonscolombe* (orange two-forked aphid), and *Toxoptera citricida Kirkaldy* (brown orange aphid); *Adelges* (ball aphid); *Phylloxera devastatrix Pergande* (American pecan root phylloxera);Bemisiatabaci Gennadius (sweet potato whitefly), Bemisia argentifolii Bellows & Perring (silver leaf whitefly), Dialeurodes citri Ashmead (citrus whitefly), and Trialeurodes vaporariorum Westwood (greenhouse whitefly); Empoasca fabae Harris (potato leafhopper), Laodelphax striatellus Fallen (gray leafhopper), Macroleses quadrilineatus Forbes (two-spotted leafhopper), Nephotettix cinticeps Uhler (green leafhopper), Nephotettix nigropictus Stal (black-tailed leafhopper), Nilaparvatalugens Stal (brown leafhopper), Peregrinus maidis Ashmead (corn planthopper), Sogatella furcifera Horvath (white-backed leafhopper), Sogatodes orizicola Muir (rice planthopper), Typhlocyba pomaria McAtee (apple leafhopper), *Erythroneoura* (grape leafhopper); *Magicidada septendecim* Linnaeus (periodic leafhopper); *Icerya purchasi* Maskell (cotyledonous scale insect), *Quadraspidiotus perniciosus* Comstock (Saint Joseph's leafhopper); *Planococcus citri Risso* (citrus mealybug); *Pseudococcus* (other mealybug complex); *Cacopsylla pyricola* Foerster (pear psyllid), *Trioza diospyri* Ashmead (persimmon psyllid).

[0124] Members of the order Hemiptera are active and include: *Acrosternum hilare* Say (rice green bug), *Anasa tristis* De Geer (pumpkin bug), *Blissus leucopterus* Say (sorghum long bug), *Cimex lectularius* Linnaeus (bed bug), *Corythuca gossypii* Fabricius (cotton web bug), *Cyrtopeltis modesta* Distant (tomato bug), *Dysdercus suturellus* Herrich-Schaffer (cotton weevil), *Euchistus servus* Say (tea-winged bug), *Euchistus variolarius* Palisot de Beauvois (single-spotted bug), *Graptosthetus* (long bug complex), *Halymorpha halys* Stal (tea-winged bug), *Leptoglossus corculus* Say (pine nut bug of the family Lygus lineolaris), and *Lygus lineolaris* Palisot de Beauvois (pasture mirid bug), Nezara viridula Linnaeus (southern rice green bug), Oebalus pugnax Fabricius (rice brown bug), Oncopeltus fasciatus Dallas (large milkweed bug), Pseudatomoscelis seriatus Reuter (cotton mirid bug). Other insect orders that can be controlled by the compounds of this invention include Thysanura (e.g., Frankliniella occidentalis Pergande (western flower thrips), Scirthothrips citri Moulton (citrus thrips), Sericothrips variabilis Beach (soybean thrips), and Thrips tabaci Lindeman (onion thrips); and Coleoptera (e.g., Leptinotarsa ​​decemlineata Say (Colorado potato beetle), Epilacachna varivestis Mulsant (Mexican bean ladybug), and nematodes of the genera *Clickworm*, *Clickworm*, or *Clickworm*).

[0125] In some classification systems, Hemiptera is classified as a suborder within Hemiptera.

[0126] The growth environment of pests includes plants and plant parts, all of which can be treated according to the methods provided in this invention. In this document, "plant" should be understood to mean all plants and plant populations, such as desired and undesired wild plants or crop plants (including naturally occurring crop plants), such as cereals (wheat, rice, rye, barley, rye, oats), corn, soybeans, potatoes, sugar beets, sugarcane, tomatoes, bell peppers, cucumbers, melons, carrots, watermelons, onions, lettuce, spinach, leeks, legumes, cabbage (such as head cabbage) and other vegetable varieties, cotton, tobacco, rapeseed, and fruit plants (fruits include apples, pears, citrus fruits, and grapes). Crop plants can be plants that can be obtained through conventional breeding and optimization methods or through biotechnological methods and genetic engineering methods or a combination of these methods, including transgenic plants and plant cultivars that may or may not be protected by plant breeders' rights. "Plant" should be understood to mean all developmental stages, such as seeds, seedlings, and early (immature) plants up to and including mature plants. Plant parts should be understood to refer to all above-ground and underground parts and organs of a plant, such as buds, leaves, flowers, and roots. Examples given include leaves, needles, stems, branches, flowers, fruiting bodies, fruits, and seeds, as well as roots, tubers, and rhizomes. Plant parts also include harvested plants or harvested plant parts, as well as materials for asexual and sexual reproduction, such as cuttings, tubers, rhizomes, slips, and seeds.

[0127] The present invention also provides the use of a compound of formula (I) as described above, its stereoisomers, and agriculturally acceptable salts thereof, or the composition described above, in the control of pests.

[0128] Conventional treatment methods utilize the compound of formula (I) to directly treat plants and plant parts, or to treat them by acting on their environment, habitat, or storage space. These conventional treatment methods include, for example, soaking, spraying, atomizing, irrigating, evaporating, dusting, misting, sowing, foaming, smearing, spreading, injection, watering (soaking), drip irrigation, and, in the case of propagation material, especially seeds, dry seed treatment as powder, wet seed treatment as solution, slurry treatment as water-soluble powder, treatment by crusting, or coating with one or more layers. The compound of formula (I) can also be applied using ultra-low volume methods or injected into the soil in its application form or the compound of formula (I) itself.

[0129] The present invention also relates to the use of the compound of formula (I) for treating seeds to protect the seeds and the resulting plants from animal pests.

[0130] Furthermore, the use of the compound of formula (I) to treat seeds can promote the germination and emergence of the treated seeds.

[0131] Furthermore, compounds of formula (I) can also be used specifically for transgenic seeds.

[0132] Furthermore, the compound of formula (I) can be used in combination with signal technology compositions or compounds to enable better colonization and / or optimization of nitrogen fixation through symbionts (e.g., rhizobia, mycorrhizae, and / or endophytic bacteria or fungi).

[0133] Compound (I) is suitable for protecting the seeds of any plant variety used in agriculture, greenhouses, forestry, or horticulture. Specifically, it is suitable for the protection of the seeds of the following plants: cereals (e.g., wheat, barley, rye, millet, and oats), corn, cotton, soybeans, rice, potatoes, sunflowers, coffee, tobacco, canola, rapeseed, sugar beets (e.g., sugar beets and forage beets), peanuts, vegetables (e.g., tomatoes, cucumbers, beans, cruciferous vegetables, onions, and lettuce), fruiting plants, turfgrass, and ornamental plants. Of particular importance are the treatment of the seeds of cereals (wheat, barley, rye, oats), corn, soybeans, cotton, canola, rapeseed, vegetables, and rice.

[0134] The compound of formula (I) provided by this invention can also be applied to the field of animal health.

[0135] In the field of animal health, specifically veterinary medicine, compounds of formula (I) are active against animal parasites, particularly ectoparasites or endoparasites. The term "endoparasites" specifically includes worms and protozoa, such as coccidia. Ectoparasites are generally and preferably arthropods, especially insects or mites.

[0136] In the field of veterinary medicine, compounds of formula (I) with favorable warm-blooded animal toxicity are suitable for the prevention and control of parasites in animal breeding and reproduction of livestock, breeding animals, zoo animals, laboratory animals, experimental animals, and domestic animals. They are active against all or specific developmental stages of parasites.

[0137] Agricultural livestock include, for example, mammals such as sheep, goats, horses, donkeys, camels, buffalo, rabbits, reindeer, deer, and especially cattle and pigs; or poultry such as turkeys, ducks, geese, and especially chickens; or fish or crustaceans in aquaculture; or, depending on the circumstances, insects such as bees.

[0138] Domestic animals include mammals such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, especially dogs, cats, caged birds; reptiles, amphibians, or ornamental fish.

[0139] According to one specific embodiment, the compound of formula (I) is applied to a mammal.

[0140] According to another specific embodiment, the compound of formula (I) is applied to poultry, i.e., caged birds or, in particular, domestic poultry.

[0141] By using compounds of formula (I) to control animal parasites, the aim is to reduce or prevent disease, mortality, and performance decline (in the case of meat, milk, wool, hides, eggs, honey, etc.), thereby making animal husbandry more economical and simpler, and achieving better animal health.

[0142] In the field of animal health, the term "control" or "controlling" as used herein refers to compound (I) effectively reducing the incidence of various parasites in animals infected with parasites to a harmless level. More specifically, "control" as used herein refers to compound (I) effectively killing various parasites, inhibiting their growth, or suppressing their proliferation.

[0143] Therefore, one embodiment of the present invention relates to a compound of formula (I) used as a medicament.

[0144] Another aspect involves compounds of formula (I) used as endoparasitic agents for antibodies.

[0145] Another specific aspect involves compounds of formula (I) used as an anti-worm agent, and more particularly as a nematicide, flatworm agent, acanthocephalan agent or lingulate agent.

[0146] Another specific aspect involves compounds of formula (I) used as antigenic agents for animals.

[0147] On the other hand, it relates to compounds of formula (I) used as antiparasitic agents, especially arthropod scavengers, and even more particularly insecticides or acaricides.

[0148] Other aspects of the invention are veterinary formulations comprising an effective amount of at least one compound of formula (I) and at least one of the following substances: pharmaceutically acceptable excipients (e.g., solid or liquid diluents), pharmaceutically acceptable adjuvants (e.g., surfactants), particularly pharmaceutically acceptable excipients and / or pharmaceutically acceptable adjuvants commonly used in veterinary formulations.

[0149] A related aspect of the present invention is a method for preparing a veterinary formulation as described herein, comprising the steps of: mixing at least one compound of formula (I) with a pharmaceutically acceptable excipient and / or adjuvant, particularly with a pharmaceutically acceptable excipient and / or adjuvant commonly used in veterinary formulations.

[0150] Another specific aspect of the present invention is a veterinary preparation and its preparation method, wherein the veterinary preparation is selected from preparations that kill ectoparasites and preparations that kill endoparasites, and more particularly from the above-mentioned anthelmintic, antiprotozoan, and arthropod preparations, and even more particularly from preparations that kill nematodes, flatworms, acanthocephalans, lingula, insects, and mites.

[0151] On the other hand, it relates to a method for treating parasitic infections, particularly those caused by parasites selected from the ectoparasites and endoparasites mentioned herein, by administering an effective amount of a compound of formula (I) to animals requiring treatment, especially non-human animals.

[0152] On the other hand, it relates to a method of treating parasitic infections, particularly those caused by parasites selected from ectoparasites and endoparasites mentioned herein, by administering veterinary preparations as defined herein to animals in need of treatment, especially non-human animals.

[0153] On the other hand, the use of compounds of formula (I) in the treatment of parasitic infections in animals, especially non-human animals, particularly infections caused by parasites selected from the ectoparasites and endoparasites mentioned herein.

[0154] In the context of the animal health or veterinary field of this invention, the term "treatment" includes preventative, remedial, or therapeutic treatment.

[0155] In one specific embodiment, at least one compound of formula (I) for use in the veterinary field is provided in combination with other active ingredients, particularly with mixtures of endoparasite-killing agents and ectoparasite-killing agents.

[0156] In the field of animal health, a "mixture" refers not only to a product containing two (or more) different active ingredients formulated as a combined preparation and administered together, but also to a product containing individual formulations of each active compound. Therefore, when administering two or more active compounds, all active compounds may be formulated as a combined preparation or as individual formulations; alternatively, they may be in a mixture form, where some active compounds are formulated together and others are formulated individually. Individual formulations may be administered individually or sequentially with respect to the active compounds.

[0157] The compound of formula (I) provided by this invention can also be applied to the field of vector control.

[0158] The vectors are arthropods, especially insects or arachnids, which can transmit pathogens such as viruses, worms, single-celled organisms, and bacteria from a host (plant, animal, human, etc.) to a host. Pathogens can be transmitted to the host mechanically (e.g., trachoma transmitted by non-stinging flies) or by injection (e.g., malaria parasites transmitted by mosquitoes).

[0159] The compound of formula (I) provided by this invention can also be used in the field of hygiene for the prevention and control of animal pests.

[0160] Compounds of Formula (I) are suitable for controlling animal pests in the sanitation field. In particular, the present invention can be used for the protection of indoor, sanitation, and stored products, especially for controlling insects, arachnids, ticks, and mites encountered in enclosed spaces such as dwellings, factory lobbies, offices, vehicle cabins, and livestock farms. For controlling animal pests, compounds of Formula (I) can be used alone or in combination with other active compounds and / or adjuvants. They are preferably used in indoor insecticide products. Compounds of Formula (I) are effective against susceptible and resistant species, as well as their entire developmental stages.

[0161] These pests include, for example, the following: Arachnida, Scorpiones, Araneae, and Opiliones; Chilopoda and Diplopoda; Insecta, Blattodea, Coleoptera, Dermaptera, Diptera, Heteroptera, Hymenoptera, Isoptera, Lepidoptera, Psittacoidea, Saltatoria, Orthoptera, Siphonaptera, and Silverfish; Malacostraca, Isopoda.

[0162] They are used in, for example, aerosols, unpressurized spray products such as pump-operated sprays and atomized sprays, automatic atomization systems, sprays, foams, gels, evaporation products with evaporating tablets made of cellulose or plastic, liquid evaporators, gel and film evaporators, propeller-driven evaporators, energy-free or passive evaporation systems, moth traps, moth traps and moth traps, as granules or powders, for use in spread baits or bait stations.

[0163] Based on the properties of the substituents defined above, compounds of formula (I) are acidic and can form salts, and, if suitable, can form internal salts, or form adducts with inorganic or organic bases or with metal ions. If compounds of formula (I) contain a hydroxyl group, a carboxyl group, or other groups that cause acidity, these compounds can react with bases to form salts. Suitable bases are, for example, hydroxides, carbonates, and bicarbonates of alkali metals and alkaline earth metals, particularly sodium, potassium, magnesium, and calcium; and ammonia; primary, secondary, and tertiary amines having C1-C4-alkyl groups; monoalkylolamines, dialkylolamines, and trialkylolamines of C1-C4-alkanols; choline and choline chloride; and organic amines such as trialkylamines, morpholine, piperidine, or pyridine. These salts are compounds in which the acidic hydrogen is replaced by an agriculturally suitable cation, for example, metal salts, especially alkali metal salts or alkaline earth metal salts, particularly sodium and potassium salts; or ammonium salts, organic amine salts, or quaternary ammonium salts, such as salts of cations having the formula [NRR′R″R″′]+ (where R to R″′ each independently represents an organic group, particularly alkyl, aryl, aralkyl, or alkylaryl). Also suitable are alkyl sulfonium salts and alkyl oxide sulfonium salts, such as C1-C4-trialkyl sulfonium salts and C1-C4-trialkyl oxide sulfonium salts.

[0164] Compounds of formula (I) can form salts by adding a suitable inorganic or organic acid to a basic group; the inorganic acid being, for example, HCl, HBr, H₂SO₄, H₃PO₄, or HNO₃, the organic acid being, for example, a carboxylic acid (e.g., formic acid, acetic acid, propionic acid, oxalic acid, lactic acid, or salicylic acid) or a sulfonic acid (e.g., p-toluenesulfonic acid), and the basic group being, for example, an amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, or pyridinyl group. In this case, the salts contain the conjugate base of the acid as an anion.

[0165] Suitable substituents (e.g., sulfonic acids or carboxylic acids) in deprotonated form can form internal salts with groups that are themselves protonable (e.g., amino groups).

[0166] In this invention, if there is a conflict between the naming of compounds and their structural formulas, the structural formula shall prevail, unless the structural formula is obviously incorrect. Detailed Implementation

[0167] The following embodiments are for illustrative purposes only and should not be construed as limiting the invention in any way. The scope of protection of this invention is defined by the claims. Simple substitutions or modifications made to this invention by those skilled in the art are all within the scope of the technical solutions protected by this invention.

[0168] Several methods for preparing the compounds of the present invention are described in detail in the following schemes and examples. The raw materials can be commercially available or prepared by methods known in the literature or as detailed in the description. Those skilled in the art will understand that other synthetic routes can also be used to synthesize the compounds of the present invention. Although specific raw materials and conditions in the synthetic routes have been described below, they can be easily replaced with other similar raw materials and conditions. Such variations or modifications to the preparation methods of the present invention, such as various isomers of the compounds, are all included within the scope of the present invention. Furthermore, the preparation methods described below can be further modified according to the disclosure of the present invention using conventional chemical methods well known to those skilled in the art. For example, protecting appropriate groups during the reaction process, etc.

[0169] The following method examples are provided to further illustrate the preparation methods of the present invention. The specific substances, types, and conditions used are intended to further explain the invention and are not intended to limit its reasonable scope. The reagents used in the synthetic compounds described below are either commercially available or can be easily prepared by those skilled in the art.

[0170] The analytical instruments described in the examples are as follows:

[0171] I. High Performance Liquid Chromatography (hereinafter referred to as HPLC): Using an Agilent Technologies 1260 Infinity II instrument.

[0172] Column: Agilent Eclipse Plus C 18 3.5μm, 4.6*100mm

[0173] Mobile phase: A: water + 0.1% phosphoric acid; B: acetonitrile; Temperature: 30℃

[0174] Gradient: 10%B to 95%B over 15 minutes; 95%B over 3 minutes

[0175] Flow rate: 1 mL / min

[0176] II. Ultra-high performance liquid chromatography-tandem mass spectrometry (hereinafter referred to as LC-MS): Using a Waters, ACQUITY H-Class UPLC-SQ Detector 2 instrument.

[0177] Column: ACQUITY BEH C 18 1.7μm, 2.1*50 mm Column

[0178] Mobile phase: A: Water + 0.2% formic acid; B: Acetonitrile; Temperature: 30℃

[0179] Gradient: 10%B to 95%B over 5 min; 95%B over 1 min

[0180] Flow rate: 0.5 mL / min

[0181] MS method: ESI positive, negative, quality range (m / z): 100-800

[0182] III. Gas Chromatography-Tandem Mass Spectrometry (hereinafter referred to as GC-MS): Agilent Technologies, 7890B GC System-5977AMSD equipment was used.

[0183] Column: Agilent Technologies, HP-5MS UI 0.25μm, 30 m*0.250 mm

[0184] Injector temperature: 250℃

[0185] Column flow rate: Helium 1 mL / min

[0186] Method: Hold at 40℃ for 2 min, increase temperature to 280℃ at 20℃ / min, hold at 280℃ for 5 min, total time 19 min.

[0187] MSD transmission line temperature: 280℃

[0188] EI ion source temperature: 230℃, MS quadrupole temperature: 150℃, scan range: 30.00-400.00

[0189] In addition, the proton nuclear magnetic resonance spectra described below (hereinafter referred to as...) 1 The chemical shift values ​​of H-NMR were measured at 400 MHz (Bruker, AVANCE III HD 400M) in deuterated chloroform (CDCl3) using Me4Si (tetramethylsilane) as the reference material. When measured in deuterated dimethyl sulfoxide, the chemical shift values ​​are shown as "(DMSO-d6)" in the data. It should be noted that... 1 The symbols in the chemical shift values ​​of H-NMR have the following meanings:

[0190] s: singlet, d: doublet, dd: doublett, dt: doublettuplet, td: triplettuplet, ddd: doublettuplet, t: triplet, q: quartet, sep: septet, m: multiplet, brs: broad singlet. Furthermore, in cases where two or more stereoisomers are present, the chemical shift values ​​for the resolvable signal are marked with "and".

[0191] Examples of representative compounds are given below. The synthesis methods of other compounds are similar and will not be described in detail here.

[0192] Example 1-1: Preparation of 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridine (compound 1-1)

[0193] Step 1: Preparation of tert-butyl 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 1-1-a)

[0194] At room temperature, 12.7 g (0.036 mol) of 5-bromo-3-(ethylsulfonyl)pyridinecarboxylate tert-butyl ester, 1.03 g (7.2 mmol) of cuprous oxide, and 40 mL of dimethyl sulfoxide were added to a 350 mL pressure-resistant flask. The flask was purged with nitrogen for 10 min, and 100 mL (0.72 mol) of 7M ammonia-methanol solution was added. The flask was then sealed and the mixture was heated to 80 °C for 20 h. After the reaction was complete, the methanol was removed by rotary evaporation, and 200 mL of water was added to the system. The mixture was extracted three times with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 5-amino-3-(ethylsulfonyl)pyridinecarboxylate tert-butyl ester. The crude product was used as is in the next step.

[0195] At room temperature, 10.4 g (0.036 mol) of tert-butyl 5-amino-3-(ethylsulfonyl)pyridinecarboxylate, 2.98 g (0.036 mol) of sodium acetate, and 50 mL of acetic acid were added to a 250 mL single-necked flask. A solution of bromine (6.97 g, 0.043 mol) in 10 mL of acetic acid was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with sodium sulfite solution, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated organic phase was purified by silica gel column chromatography to obtain tert-butyl 5-amino-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 1-1-a).

[0196] 1 H NMR (400 MHz, CDCl3-d) δ7.54 (s, 1H), 4.72 (s, 2H), 3.54 (q, J = 7.4 Hz, 2H), 1.62 (s, 9H), 1.33 (t, J = 7.4 Hz, 3H).

[0197] Step 2: Preparation of tert-butyl 6-bromo-3-(ethylsulfonyl)-5-(1-fluorocyclopropane-1-carbamate)pyridinecarboxylate (intermediate 1-1-b)

[0198] At room temperature, 1-fluorocyclopropanecarboxylic acid (516 mg, 4.96 mmol) and N,N-dimethylformamide (8 mL) were added to a 100 mL single-necked flask, followed by N,N'-carbonyldiimidazole (806 mg, 4.96 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After 2 hours, 1,8-diazacyclo[5,4,0]undecene-7 (1133 mg, 7.44 mmol) and tert-butyl 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylate (as intermediate 1-1-a prepared above) (903 mg, 2.48 mmol) were added at room temperature and reacted for 30 minutes. After the reaction was completed, 40 mL of water and 40 mL of ethyl acetate were added for extraction and separation twice. After separation, the organic phase was washed twice with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain tert-butyl 6-bromo-3-(ethylsulfonyl)-5-(1-fluorocyclopropane-1-carbamate)pyridinecarboxylate (intermediate 1-1-b) (950 mg).

[0199] Step 3: Preparation of 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)thiazo[5,4-b]pyridine-5-carboxylic acid tert-butyl ester (intermediate 1-1-c)

[0200] At room temperature, tert-butyl 6-bromo-3-(ethylsulfonyl)-5-(1-fluorocyclopropane-1-carboxamido)pyridinecarboxylate (intermediate 1-1-b prepared above) (950 mg, 2.11 mmol), Lawson's reagent (2.56 g, 6.33 mmol), and dioxane (10 mL) were added to a 100 mL single-necked flask, and the mixture was heated to reflux for 8 h. After the reaction was completed, the reaction solution was directly evaporated to dryness, and silica gel column chromatography was performed to obtain tert-butyl 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)thiazo[5,4-b]pyridine-5-carboxylic acid (intermediate 1-1-c) (652 mg).

[0201] Step 4: Preparation of 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)thiazo[5,4-b]pyridine-5-carboxylic acid (intermediate 1-1-d)

[0202] 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)thiazo[5,4-b]pyridine-5-carboxylic acid tert-butyl ester (as intermediate 1-1-c prepared above) (652 mg, 1.69 mmol) and dichloromethane (5 ml) were added to a 50 mL single-necked flask. Then, trifluoroacetic acid (2 ml) was slowly added dropwise to the reaction flask. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed by vacuum distillation to obtain 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)thiazo[5,4-b]pyridine-5-carboxylic acid (intermediate 1-1-d) (502 mg). The crude product was used as is in the next step.

[0203] Step 5: Preparation of 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-N-(2-(methylamino)-5-(trifluoromethyl)pyridin-3-yl)thiazo[5,4-b]pyridine-5-carboxamide (intermediate 1-1-e)

[0204] At room temperature, 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)thiazo[5,4-b]pyridine-5-carboxylic acid (intermediate 1-1-d prepared above) (502 mg, 1.52 mmol), tetrahydrofuran (5 mL), and N... 2 2,3-Diamine (290 mg, 1.29 mmol) and triethylamine (130 mg, 1.29 mmol) were added to a 25 mL single-necked flask, followed by the addition of 2-chloro-1-methylpyridine iodide (461 mg, 1.81 mmol) in portions. The mixture was stirred at room temperature for 0.5 h, then heated to 50 °C for 2 h. After the reaction was complete, the mixture was extracted three times with 20 mL of water and 20 mL of ethyl acetate. The organic phase was washed twice with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-N-(2-(methylamino)-5-(trifluoromethyl)pyridin-3-yl)thiazo[5,4-b]pyridine-5-carboxamide (intermediate 1-1-e) (1.2 g). The crude product was used as is in the next step.

[0205] Step 6: Preparation of 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridine (compound 1-1)

[0206] At room temperature, 1.2 g of 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-N-(2-(methylamino)-5-(trifluoromethyl)pyridin-3-yl)thiazo[5,4-b]pyridine-5-carboxamide (intermediate 1-1-e) and 10 mL of acetic acid were added to a 50 mL single-necked flask. The mixture was heated to 110 °C and stirred for 8 h. After the reaction was completed, the reaction solution was poured into water (50 mL) and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed twice with saturated sodium chloride solution. The mixture was dried with anhydrous sodium sulfate and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridine (compound 1-1) (369 mg).

[0207] 1 H NMR (400MHz, CDCl3-d) δ8.93(s,1H),8.78(d,J=1.3Hz,1H),8.33(d,J=1.4Hz,1H ),3.90(s,3H),3.85(q,J=7.4Hz,2H),1.92–1.77(m,4H),1.38(t,J=7.4Hz,3H).

[0208] Examples 1-49: Preparation of 2-cyclopropyl-N-methyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridin-6-sulfonamide (compound 1-49)

[0209] Step 1: Preparation of 6-(benzylthio)-2-cyclopropyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridine (compound 1-49-a)

[0210] Under a nitrogen atmosphere, 1.0 g (2.14 mmol) of 2-cyclopropyl-6-(ethylsulfonyl)-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridine (synthesized according to the method described in patent CN 115181116 A, Synthesis of Compound I-73) and 10 mL of N,N-dimethylformamide were added to a 100 mL single-necked flask. Benzyl mercaptan (452 ​​mg, 3.64 mmol) and 60% sodium hydride (214 mg, 5.35 mmol) were added sequentially, and the mixture was reacted at 100 °C. After 10 minutes, the mixture was extracted three times with water (50 mL) and ethyl acetate (50 mL). The organic phase was concentrated under reduced pressure and then subjected to silica gel column chromatography to give 6-(benzylthio)-2-cyclopropyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridine (intermediate 1-49-a).

[0211] Step 2: Preparation of 2-cyclopropyl-N-methyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridin-6-sulfonamide (compounds 1-49)

[0212] Under ice bath conditions, 6-(benzylthio)-2-cyclopropyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridine (intermediate 1-49-a) (150 mg, 0.30 mmol), acetonitrile (2 mL), and acetic acid (0.2 mL) were added to a 25 mL single-necked flask. 1,3-dichloro-5,5-dimethylhydantoin (147.7 mg, 0.75 mmol) was added, and the mixture was reacted for 10 minutes to obtain sulfonyl chloride. Maintaining an ice bath, the reaction mixture was added dropwise to a 40% aqueous methylamine solution (4 mL), and the reaction was allowed to proceed for 10 minutes. After the reaction was complete, a saturated sodium thiosulfate aqueous solution (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture for extraction and separation twice. The organic phase was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain 2-cyclopropyl-N-methyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridin-6-sulfonamide (compound 1-49).

[0213] 1 H NMR(400MHz, CDCl3-d)δ8.86(s,1H),8.78(s,1H),8.34(s,1H),7.53(d,J=5.1Hz ,1H),4.05(s,3H),2.83(d,J=5.2Hz,3H),2.58–2.46(m,1H),1.48–1.38(m,4H).

[0214] Example 1-101: Preparation of 2-cyclopropyl-N,N-dimethyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridin-6-sulfonamide (compound 1-101)

[0215] Under ice bath conditions, 6-(benzylthio)-2-cyclopropyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridine (intermediate 1-49-a) (150 mg, 0.30 mmol), acetonitrile (2 mL), and acetic acid (0.2 mL) were added to a 25 mL single-necked flask. 1,3-dichloro-5,5-dimethylhydantoin (147.7 mg, 0.75 mmol) was added, and the mixture was reacted for 10 minutes to obtain sulfonyl chloride. Maintaining an ice bath, the reaction mixture was added dropwise to a 40% dimethylamine tetrahydrofuran solution (4 mL), and the reaction was allowed to proceed for 10 minutes. After the reaction was complete, saturated sodium thiosulfate aqueous solution (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture for extraction and separation twice. The organic phase was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain 2-cyclopropyl-N,N-dimethyl-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)thiazo[5,4-b]pyridin-6-sulfonamide (compound 1-101).

[0216] 1 H NMR (400MHz, CDCl3-d) δ8.76(s,1H),8.73(s,1H),8.30(d,J=2.0Hz,1H),3.76(s,3H),2.79(s,6H),2.55–2.44(m,1H),1.46–1.39(m,4H).

[0217] Examples 2-6: Preparation of 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)thiazo[4,5-b]pyridine (compounds 2-6)

[0218] Step 1: Preparation of methyl 6-amino-5-bromo-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 2-6-a)

[0219] At room temperature, methyl 3,6-bis(ethylsulfonyl)pyridinecarboxylate (93 g, 0.29 mmol), ammonia (68.9 g, 1.01 mmol), and acetonitrile (450 mL) were added to a pressure-resistant flask, and the mixture was heated to 80 °C and stirred for 5 h. After the reaction was complete, the solvent was removed by vacuum distillation to obtain methyl 6-amino-3-(ethylsulfonyl)pyridinecarboxylate (yellow solid, 74 g), which was used as is in the next step.

[0220] At room temperature, methyl 6-amino-3-(ethylsulfonyl)pyridinecarboxylate (74 g, 0.30 mol), sodium acetate (19.85 g, 0.33 mol), ferric chloride (4.91 g, 0.03 mol), and acetic acid (1.25 L) were added to a 2 L four-necked flask. A solution of bromine (58.09 g, 0.36 mol) in acetic acid (500 mL) was added dropwise, and the mixture was stirred at room temperature for 3 h. After the reaction was complete, a saturated solution of sodium thiosulfate was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and silica gel column chromatography was used to obtain methyl 6-amino-5-bromo-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 2-6-a) (white solid, 69.24 g).

[0221] 1 H NMR (400MHz, CDCl3-d) δ8.22(s,1H),5.66(s,2H),3.99(s,3H),3.43(q,J=7.4Hz,2H),1.34(t,J=7.4Hz,3H).

[0222] Step 2: Preparation of 6-amino-5-bromo-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 2-6-b)

[0223] At room temperature, methyl 6-amino-5-bromo-3-(ethylsulfonyl)pyridinecarboxylate (as prepared above as intermediate 2-6-a) (1.0 g, 3.09 mmol), water (8 mL), and tetrahydrofuran (12 mL) were added to a 100 mL single-necked flask, along with anhydrous lithium hydroxide (148 mg, 6.18 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the tetrahydrofuran was evaporated under reduced pressure. 20 mL of water was added to the resulting mixture, and the pH was adjusted to 1 with 36% hydrochloric acid. The mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then purified by reverse-phase rapid column chromatography to obtain 6-amino-5-bromo-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 2-6-b) (800 mg).

[0224] Step 3: Preparation of 6-amino-5-bromo-3-(ethylsulfonyl)-N-(5-(methylamino)-2-(trifluoromethyl)pyridin-4-yl)pyridine amide (intermediate 2-6-c)

[0225] At room temperature, 6-amino-5-bromo-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 2-6-b prepared above) (400 mg, 1.29 mmol), tetrahydrofuran (10 mL), and N... 32-Methyl-6-(trifluoromethyl)pyridin-3,4-diamine (246 mg, 1.29 mmol) and triethylamine (130 mg, 1.29 mmol) were added to a 50 mL single-necked flask, followed by the addition of 2-chloro-1-methylpyridine iodide (330 mg, 1.29 mmol) in portions. The mixture was stirred at room temperature for 0.5 h, then heated to 50 °C for 2 h. After the reaction was complete, 40 mL of water and 40 mL of ethyl acetate were added for extraction and separation three times. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 6-amino-5-bromo-3-(ethylsulfonyl)-N-(5-(methylamino)-2-(trifluoromethyl)pyridin-4-yl)pyridineamide (intermediate 2-6-c). The crude product was used as is in the next step.

[0226] Step 4: Preparation of 3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (intermediate 2-6-d)

[0227] At room temperature, 450 mg of 6-amino-5-bromo-3-(ethylsulfonyl)-N-(5-(methylamino)-2-(trifluoromethyl)pyridin-4-yl)pyridine amide (as intermediate 2-6-c prepared above) and 10 mL of acetic acid were added to a 50 mL single-necked flask. The mixture was heated to 110 °C and stirred for 8 h. After the reaction was completed, the reaction solution was poured into water (50 mL), and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain 3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridine-2-amine (intermediate 2-6-d) (280 mg).

[0228] Step 5: Preparation of N-(3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (intermediate 2-6-e)

[0229] At room temperature, 1-fluorocyclopropanecarboxylic acid (125 mg, 1.20 mmol) and N,N-dimethylformamide (5 mL) were added to a 25 mL single-necked flask, followed by N,N'-carbonyldiimidazole (195 mg, 1.20 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After 2 hours, 1,8-diazacyclo[5,4,0]undecene-7 (274 mg, 1.80 mmol) and 3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (as intermediate 2-6-d prepared above) (278 mg, 0.60 mmol) were added and reacted for 30 minutes. After the reaction was completed, 30 mL of water and 40 mL of ethyl acetate were added for extraction and separation three times. After separation, the organic phase was washed twice with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain N-(3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (intermediate 2-6-e) (420 mg). The crude product was used in the next step.

[0230] Step 6: Preparation of N-(3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-yl)-1-fluorocyclopropane-1-methylthioamide (intermediate 2-6-f)

[0231] At room temperature, N-(3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (as intermediate 2-6-e prepared above) (420 mg, 0.76 mmol) and 1,4-dioxane (4 mL) were added to a 25 mL single-necked flask, Lawson's reagent (619 mg, 1.53 mmol) was added, and the mixture was heated to reflux for 2 hours. After the reaction was completed, the insoluble matter was filtered off, and the solvent was removed by vacuum distillation to obtain N-(3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-yl)-1-fluorocyclopropane-1-methylthioamide (intermediate 2-6-f) (380 mg). The crude product was used as is in the next step.

[0232] Step 7: Preparation of 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)thiazo[4,5-b]pyridine (compounds 2-6)

[0233] At room temperature, N-(3-bromo-5-(ethylsulfonyl)-6-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-yl)-1-fluorocyclopropane-1-methylthioamide (as intermediate 2-6-f prepared above) (380 mg, 0.67 mmol), cesium carbonate (436 mg, 1.34 mmol), and tetrahydrofuran (10 mL) were added to a 50 mL single-necked flask, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was completed, the insoluble matter was filtered off, and the concentrated organic phase was purified by silica gel column chromatography to obtain 6-(ethylsulfonyl)-2-(1-fluorocyclopropyl)-5-(3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)thiazo[4,5-b]pyridine (compound 2-6).

[0234] 1 H NMR (400MHz, CDCl3-d) δ9.12 (s, 1H), 9.00 (s, 1H), 8.12 (d, J = 1.1Hz, 1H), 3.95 (s, 3 H),3.91–3.83(m,2H),1.95–1.91(m,1H),1.92–1.86(m,3H),1.40(t,J=7.4Hz,3H).

[0235] Examples 3-9: Preparation of 6-(ethanesulfonyl)-2-((1S,2R)-2-fluorocyclopropyl)-5-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)thiazo[5,4-b]pyridine (compounds 3-9)

[0236] Step 1: Preparation of 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 3-9-a)

[0237] At room temperature, tert-butyl 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylate (as prepared above, intermediate 1-1-a) (1.0 g, 2.74 mmol) and dichloromethane (10 mL) were added to a 50 mL single-necked flask, followed by the addition of trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solvent was removed by vacuum distillation, and the mixture was purified by reverse-phase rapid column chromatography to obtain 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 3-9-a) (850 mg).

[0238] Step 2: Preparation of 5-amino-6-bromo-3-(ethylsulfonyl)-N-(3-(methylamino)-6-(trifluoromethyl)pyridazin-4-yl)pyridine amide (intermediate 3-9-b)

[0239] At room temperature, 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylic acid (as intermediate 3-9-a prepared above) (400 mg, 1.29 mmol), N 3 248 mg (1.29 mmol) of methyl-6-(trifluoromethyl)pyridazine-3,4-diamine and 10 mL of tetrahydrofuran were added to a 50 mL single-necked flask. Triethylamine (260 mL, 2.58 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (247 mg, 1.29 mmol) were then added, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, 50 mL of water and 50 mL of ethyl acetate were added for extraction and separation three times. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 5-amino-6-bromo-3-(ethylsulfonyl)-N-(3-(methylamino)-6-(trifluoromethyl)pyridazine-4-yl)pyridineamide (intermediate 3-9-b). The crude product was used as is in the next step.

[0240] Step 3: Preparation of 2-bromo-5-(ethylsulfonyl)-6-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)pyridine-3-amine (intermediate 3-9-c)

[0241] At room temperature, 450 mg of 5-amino-6-bromo-3-(ethylsulfonyl)-N-(3-(methylamino)-6-(trifluoromethyl)pyridazin-4-yl)pyridine amide (as intermediate 3-9-b prepared above) and 10 mL of acetic acid were added to a 50 mL single-necked flask. The mixture was heated to 110 °C and stirred for 8 h. After the reaction was completed, the reaction solution was poured into water (50 mL), and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain 2-bromo-5-(ethylsulfonyl)-6-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)pyridine-3-amine (intermediate 3-9-c) (280 mg).

[0242] Step 4: Preparation of (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)pyridin-3-yl)-2-fluorocyclopropane-1-carboxamide (intermediate 3-9-d)

[0243] At room temperature, (1R,2R)-2-fluorocyclopropanecarboxylic acid (125 mg, 1.20 mmol) and N,N-dimethylformamide (5 mL) were added to a 25 mL single-necked flask, followed by N,N'-carbonyldiimidazole (195 mg, 1.20 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. Then, 1,8-diazacyclo[5,4,0]undecene-7 (274 mg, 1.80 mmol) and 2-bromo-5-(ethylsulfonyl)-6-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)pyridine-3-amine (as intermediate 3-9-c prepared above) (280 mg, 0.60 mmol) were added and reacted for 30 minutes. After the reaction was completed, 30 mL of water and 40 mL of ethyl acetate were added for extraction and separation three times. After separation, the organic phase was washed twice with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)pyridin-3-yl)-2-fluorocyclopropane-1-carboxamide (intermediate 3-9-d) (300 mg). The crude product was used in the next step.

[0244] Step 5: Preparation of 6-(ethanesulfonyl)-2-((1S,2R)-2-fluorocyclopropyl)-5-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)thiazo[5,4-b]pyridine (compounds 3-9)

[0245] At room temperature, (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)pyridin-3-yl)-2-fluorocyclopropane-1-carboxamide (as intermediate 3-9-d prepared above) (300 mg, 0.54 mmol), dioxane (5 mL), and Lawson's reagent (440 mg, 1.09 mL) were added. mol) was added to a 48 mL pressure-resistant bottle and heated to 100 °C for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation, and the crude compound was purified by reverse-phase column chromatography to obtain a white solid 6-(ethanesulfonyl)-2-((1S,2R)-2-fluorocyclopropyl)-5-(7-methyl-3-(trifluoromethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)thiazo[5,4-b]pyridine (compounds 3-9).

[0246] 1H NMR(400MHz, CDCl3-d)δ8.88(s,1H),8.19(s,1H),5.27–5.20(m,0.5H),5.11–5.04(m,0.5H),4 .07(s,3H),3.77(q,J=7.4Hz,2H),2.99–2.86(m,1H),2.06–1.83(m,2H),1.39(t,J=7.4Hz,3H).

[0247] Example 4-132: Preparation of 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl))-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)sulfinyl)benzo[d]oxazole (compound 4-132)

[0248] Step 1: Preparation of tert-butyl 6-bromo-3-(ethylsulfonyl)-5-(1R,2R)-2-fluorocyclopropane-1-carbamate)pyridinecarboxylate (intermediate 4-132-a)

[0249] At room temperature, (1R,2R)-2-fluoro-cyclopropionic acid (387 mg, 3.73 mmol) and N,N-dimethylformamide (8 mL) were added to a 50 mL single-necked flask, followed by N,N'-carbonyldiimidazole (806 mg, 4.97 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After 2 hours, 1,8-diazacyclo[5,4,0]undecene-7 (1130 mg, 7.45 mmol) and tert-butyl 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylate (as described above for preparing intermediate 1-1-a) (800 mg, 2.48 mmol) were added at room temperature and reacted for 30 minutes. After the reaction was completed, 40 mL of water and 40 mL of ethyl acetate were added for extraction and separation twice. After separation, the organic phase was washed twice with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain tert-butyl 6-bromo-3-(ethylsulfonyl)-5-((1R,2R)-2-fluorocyclopropane-1-carbamate)pyridinecarboxylate (intermediate 4-132-a) (880 mg).

[0250] Step 2: Preparation of 6-bromo-3-(ethylsulfonyl)-5-((1R,2R)-2-fluorocyclopropane-1-carboxamido)pyridinecarboxylic acid (intermediate 4-132-b)

[0251] At room temperature, 8 mL of trifluoroacetic acid was added to a 100 mL single-necked flask, and the temperature was lowered to 5-10 °C. Tert-butyl 6-bromo-3-(ethylsulfonyl)-5-((1R,2R)-2-fluorocyclopropane-1-carboxamido)pyridinecarboxylic acid (intermediate 4-132-a as described above) (880 mg, 1.95 mmol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction was stopped, and the solvent was removed under reduced pressure to obtain 6-bromo-3-(ethylsulfonyl)-5-((1R,2R)-2-fluorocyclopropane-1-carboxamido)pyridinecarboxylic acid (intermediate 4-132-b) (600 mg). The crude product was used as is in the next step.

[0252] Step 3: Preparation of 6-bromo-3-(ethylsulfonyl)-5-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(2-hydroxy-5-((trifluoromethyl)thio)phenyl)pyridinecarboxamide (intermediate 4-132-c)

[0253] At room temperature, 6-bromo-3-(ethylsulfonyl)-5-((1R,2R)-2-fluorocyclopropane-1-carbamoyl)pyridinecarboxylic acid (as prepared as intermediate 4-132-b above) (600 mg, 1.52 mmol), 2-amino-4-((trifluoromethyl)thio)phenol (377 mg, 1.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (350 mg, 1.83 mmol) and pyridine (6 mL) were added to a 100 mL single-necked flask and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by vacuum distillation, and the compound 6-bromo-3-(ethylsulfonyl)-5-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(2-hydroxy-5-((trifluoromethyl)thio)phenyl)pyridinecarboxamide (intermediate 4-132-c) (418 mg) was obtained by column chromatography.

[0254] Step 4: Preparation of (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(5-((trifluoromethyl)thio)benzo[d]oxazol-2-yl)pyridin-3-yl)-2-fluorocyclopropane-1-carboxamide (intermediate 4-132-d)

[0255] At room temperature, 6-bromo-3-(ethylsulfonyl)-5-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(2-hydroxy-5-((trifluoromethyl)thio)phenyl)pyridinecarboxamide (as prepared as intermediate 4-132-c above) (418 mg, 0.70 mmol), triphenylphosphine (365 mg, 1.39 mmol) and 1,4-dioxane (8 mL) were added to a 100 mL single-necked flask. A solution of bis-2-methoxyethylazodicarboxylic acid ester (326 mg, 1.39 mmol) and toluene (2 mL) was added dropwise. After the addition was complete, the temperature was raised to 100 °C and the reaction was carried out for 30 minutes. After the reaction was completed, 20 mL of water and 20 mL of ethyl acetate were added for extraction and separation twice. After separation, the organic phase was washed twice with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The compound (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(5-((trifluoromethyl)thio)benzo[d]oxazol-2-yl)pyridin-3-yl)-2-fluorocyclopropane-1-carboxamide (intermediate 4-132-d) (300 mg) was obtained by column chromatography.

[0256] Step 5: Preparation of (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(5-(trifluoromethyl)thio)benzo[d]oxazol-2-yl)pyridin-3-yl)-2-fluoro-N-methylcyclopropane-1-carboxamide (compound 4-132-e)

[0257] At room temperature, compound (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(5-((trifluoromethyl)thio)benzo[d]oxazol-2-yl)pyridin-3-yl)-2-fluorocyclopropane-1-carboxamide (as intermediate 4-132-d above) (300 mg, 0.51 mmol), potassium carbonate (105.5 mg, 0.76 mmol), and N,N-dimethylformamide (5 mL) were added to a 50 mL single-necked flask, followed by iodomethane (108 mg, 0.76 mmol), and the reaction was allowed to proceed for 2 hours. After the reaction was completed, the reaction solution was filtered and purified by reverse phase to obtain compound (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(5-(trifluoromethyl)thio)benzo[d]oxazol-2-yl)pyridin-3-yl)-2-fluoro-N-methylcyclopropane-1-carboxamide (compound 4-132-e) (265 mg).

[0258] Step 6: Preparation of 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl)-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-((trifluoromethyl)thio)benzo[d]oxazole (compound 4-132-f)

[0259] At room temperature, compound (1R,2R)-N-(2-bromo-5-(ethylsulfonyl)-6-(5-(trifluoromethyl)thio)benzo[d]oxazol-2-yl)pyridin-3-yl)-2-fluoro-N-methylcyclopropane-1-carboxamide (as intermediate 4-132-e prepared above) (265 mg, 0.45 mmol), 28% ammonia (1 mL), and acetonitrile (4 mL) were added to a 48 mL pressure-resistant flask, and the mixture was heated to 80 °C and reacted overnight. After the reaction was completed, the reaction solution was purified by reverse-phase column chromatography to obtain compound 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl)-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-((trifluoromethyl)thio)benzo[d]oxazol (compound 4-132-f) (200 mg).

[0260] Step 7: Preparation of 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl))-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)sulfinyl)benzo[d]oxazole (compound 4-132)

[0261] At room temperature, compound 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl)-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-((trifluoromethyl)thio)benzo[d]oxazole (compound 4-132-f) (100 mg, 0.20 mmol) and dichloromethane (2 mL) were added to a 25 mL single-necked flask, followed by the addition of 85% m-chloroperoxybenzoic acid (44.67 mg, 0.22 mmol). After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated sodium thiosulfate solution was added to quench the phases, and the phases were separated. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. After reverse phase purification, compound 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl))-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)sulfinyl)benzo[d]oxazole (compound 4-132) (82 mg) was obtained.

[0262] 1 H NMR (400MHz, CDCl3-d) δ8.52(s,1H),8.32(s,1H),7.88(d,J=8.5Hz,1H),7.84(d,1H),5.26–5.06(m, 1H), 4.09 (q, J = 7.4Hz, 2H), 4.07 (s, 3H), 2.64–2.54 (m, 1H), 1.96–1.85 (m, 2H), 1.44 (t, J = 7.4Hz, 3H).

[0263] Example 4-492: Preparation of 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl))-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)sulfonyl)benzo[d]oxazole (compound 4-492)

[0264] At room temperature, compound 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl)-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-((trifluoromethyl)thio)benzo[d]oxazole (compound 4-132-f) (100 mg, 0.20 mmol) and dichloromethane (2 mL) were added to a 25 mL single-necked flask. The temperature was raised to 70 °C, and 85% m-chloroperoxybenzoic acid (101.51 mg, 0.50 mmol) was added. After the addition was complete, the mixture was kept warm and stirred for 1 hour. After the reaction was completed, saturated sodium thiosulfate solution was added to quench the phases, and the phases were separated. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. After reverse-phase purification, compound 2-(6-(ethylsulfonyl)-2-((1R,2R)-2-fluorocyclopropyl))-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)sulfonyl)benzo[d]oxazole (compound 4-492) (56 mg) was obtained.

[0265] 1 H NMR (400MHz, CDCl3-d) δ8.55(s,1H),8.52(s,1H),8.14(d,J=8.6,1.8Hz,1H),7.92(d,J=8.6Hz,1H),5.26–5 .06(m,1H),4.07(s,3H),4.05(q,J=7.4Hz,2H),2.66–2.54(m,1H),1.98–1.84(m,2H),1.44(t,J=7.4Hz,3H).

[0266] Example 4-617: Preparation of 2-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)-5-(trifluoromethyl)benzo[d]oxazole (compound 4-617)

[0267] Step 1: Preparation of tert-butyl 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)pyridinecarboxylate (4-617-a)

[0268] At room temperature, cyclopropionic acid (321 mg, 3.73 mmol) and N,N-dimethylformamide (8 mL) were added to a 100 mL single-necked flask, followed by N,N'-carbonyldiimidazole (806 mg, 4.97 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After 2 hours, 1,8-diazacyclo[5,4,0]undecene-7 (1130 mg, 7.45 mmol) and tert-butyl 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylate (as intermediate 1-1-a prepared above) (800 mg, 2.48 mmol) were added at room temperature and reacted for 30 minutes. After the reaction was completed, 40 mL of water and 40 mL of ethyl acetate were added for extraction and separation twice. After separation, the organic phase was washed twice with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain tert-butyl 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 4-617-a) (764 mg).

[0269] Step 2: Preparation of 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 4-617-b)

[0270] At room temperature, 8 mL of trifluoroacetic acid was added to a 100 mL single-necked flask, and the temperature was lowered to 5-10 °C. Tert-butyl 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 4-617-a prepared above) (764 mg, 1.77 mmol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 4-617-b) (610 mg).

[0271] Step 3: Preparation of 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)-N-(2-hydroxy-5-(trifluoromethyl)phenyl)pyridinecarboxamide (intermediate 4-617-c)

[0272] At room temperature, 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 4-617-b prepared above) (610 mg, 1.62 mmol), 2-amino-4-trifluoromethylphenol (296 mg, 1.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (350 mg, 1.83 mmol), and pyridine (6 mL) were added to a 100 mL single-necked flask and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was purified by silica gel column chromatography to obtain 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)-N-(2-hydroxy-5-(trifluoromethyl)phenyl)pyridinecarboxamide (intermediate 4-617-c) (580 mg).

[0273] Step 4: Preparation of N-(2-bromo-5-(ethylsulfonyl)-6-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)pyridin-3-yl)cyclopropaneformamide (intermediate 4-617-d)

[0274] At room temperature, 6-bromo-5-(cyclopropanecarbamate)-3-(ethylsulfonyl)-N-(2-hydroxy-5-(trifluoromethyl)phenyl)pyridinecarboxamide (as intermediate 4-617-c prepared above) (580 mg, 1.12 mmol), triphenylphosphine (551 mg, 2.10 mmol), and 1,4-dioxane (10 mL) were added to a 100 mL single-necked flask. A solution of bis-2-methoxyethylazodicarboxylic acid ester (492 mg, 2.10 mmol) and toluene (5 mL) was added dropwise. After the addition was complete, the temperature was raised to 100 °C and the reaction was carried out for 0.5 hours. After the reaction was completed, 20 mL of water and 20 mL of ethyl acetate were added for extraction and separation twice. After separation, the organic phase was washed twice with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The compound N-(2-bromo-5-(ethylsulfonyl)-6-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)pyridin-3-yl)cyclopropanecarboxamide (intermediate 4-617-d) (650 mg) was obtained by column chromatography.

[0275] Step 5: Preparation of 2-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)-5-(trifluoromethyl)benzo[d]oxazole (compound 4-617)

[0276] At room temperature, N-(2-bromo-5-(ethylsulfonyl)-6-(5-(trifluoromethyl)benzo[d]oxazol-2-yl)pyridin-3-yl)cyclopropanecarboxamide (as intermediate 4-617-d prepared above) (650 mg, 1.25 mmol) and 1,4-dioxane (6 mL) were added to a 100 mL single-necked flask, Lawson's reagent (1.51 g, 3.75 mmol) was added, and the mixture was heated to reflux for 2 hours. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was purified by reverse phase to obtain compound 2-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)-5-(trifluoromethyl)benzo[d]oxazole (compound 4-617) (300 mg).

[0277] 1 H NMR(400MHz, CDCl3-d)δ8.83(s,1H),8.07(s,1H),7.78–7.64(m,2H),4.03– 3.89(m,2H),2.49–2.38(m,1H),1.42–1.37(m,4H),1.20(t,J=12.2Hz,3H).

[0278] Example 5-3: Preparation of 6-(2-cyclopropyl-6-(ethylsulfonyl)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazolium (compound 5-3)

[0279] Step 1: Preparation of 5-amino-6-bromo-N-(2,2-difluoro-6-(methylamino)benzo[d][1,3]dihydroxy-5-yl)-3-(ethylsulfonyl)pyridine amide (intermediate 5-3-a)

[0280] At room temperature, 5-amino-6-bromo-3-(ethylsulfonyl)pyridinecarboxylic acid (intermediate 3-9-a prepared above) (400 mg, 1.29 mmol), tetrahydrofuran (10 mL), and 2,2-difluoro-N... 55-Methylbenzo[d][1,3]dioxane-5,6-diamine (261 mg, 1.29 mmol) and triethylamine (130 mg, 1.29 mmol) were added to a 50 mL single-necked flask. 2-Chloro-1-methylpyridine iodide (330 mg, 1.29 mmol) was added in portions, and the mixture was stirred at room temperature for 0.5 h, followed by heating to 50 °C for 2 h. After the reaction was complete, 40 mL of water and 40 mL of ethyl acetate were added for extraction and separation three times. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 5-amino-6-bromo-N-(2,2-difluoro-6-(methylamino)benzo[d][1,3]dihydroxy-5-yl)-3-(ethylsulfonyl)pyridine amide (intermediate 5-3-a). The crude product was used as is in the next step.

[0281] Step 2: Preparation of 2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridine-3-amine (intermediate 5-3-b)

[0282] At room temperature, 600 mg of 5-amino-6-bromo-N-(2,2-difluoro-6-(methylamino)benzo[d][1,3]dihydroxy-5-yl)-3-(ethylsulfonyl)pyridine amide (as intermediate 5-3-a prepared above) and 10 mL of acetic acid were added to a 50 mL single-necked flask, heated to 110 °C and stirred for 8 h. After the reaction was completed, the reaction solution was poured into water (50 mL) and extracted three times with ethyl acetate. 20 mL × 3), combine the organic phases, wash the organic phases twice with saturated sodium chloride solution, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify the crude product by silica gel column chromatography to obtain 2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridine-3-amine (intermediate 5-3-b) (480 mg).

[0283] Step 3: Preparation of N-(2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridin-3-yl)cyclopropaneformamide (intermediate 5-3-c)

[0284] At room temperature, cyclopropylformic acid (174 mg, 2.02 mmol) and N,N-dimethylformamide (5 mL) were added to a 25 mL single-necked flask, followed by N,N'-carbonyldiimidazole (327 mg, 2.02 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After 2 hours, 1,8-diazacyclo[5,4,0]undecene-7 (460 mg, 3.03 mmol) and 2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridine-3-amine (as intermediate 5-3-b prepared above) (480 mg, 1.01 mmol) were added and reacted for 30 minutes. After the reaction was completed, 40 mL of water and 40 mL of ethyl acetate were added for extraction and separation three times. After separation, the organic phase was washed twice with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain N-(2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridin-3-yl)cyclopropanecarboxamide (intermediate 5-3-c) (500 mg). The crude product was used in the next step.

[0285] Step 4: Preparation of 6-(2-cyclopropyl-6-(ethylsulfonyl)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazolium (compound 5-3)

[0286] At room temperature, N-(2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridin-3-yl)cyclopropaneformamide (as intermediate 5-3-c prepared above) (500 mg, 0.92 mmol), acetonitrile (5 mL), and an aqueous solution of methylamine (1.42 mL, 18.4 mmol) were added... The mixture was placed in a 48 mL pressure-resistant bottle and heated to 80 °C for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation. The crude compound was purified by reversed-phase column chromatography to obtain a white solid 6-(2-cyclopropyl-6-(ethylsulfonyl)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazolium (compound 5-3).

[0287] 1H NMR(400MHz, CDCl3-d)δ8.63(s,1H),7.43(s,1H),7.12(s,1H),3.98(s,3H), 3.68–3.58(m,5H),2.17–2.07(m,1H),1.45–1.39(m,2H),1.34–1.20(m,5H).

[0288] Example 5-25: Preparation of 6-(2-(2,2-difluorocyclopropyl)-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)-2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazolium (compound 5-25)

[0289] Step 1: Preparation of N-(2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (5-25-a)

[0290] Using 2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridin-3-amine (intermediate 5-3-b) as the starting material, N-(2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (intermediate 5-25-a) was prepared similarly to intermediate 5-3-c above.

[0291] Step 2: Preparation of 6-(2-(2,2-difluorocyclopropyl)-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)-2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazolium (compound 5-25)

[0292] Using N-(2-bromo-6-(2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-5-(ethylsulfonyl)pyridin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (intermediate 5-25-a) as the starting material, 6-(2-(2,2-difluorocyclopropyl)-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)-2,2-difluoro-5-methyl-5H-[1,3]dioxane[4',5':4,5]benzo[1,2-d]imidazolium (compound 5-25) was prepared similarly to compound 4-617 above.

[0293] 1 H NMR (400MHz, CDCl3-d) δ8.99(s,1H),7.43(s,1H),7.14(s,1H),3.82(q,J=7.4Hz,2H),3.7 4(s,3H),3.37–3.24(m,1H),2.60–2.47(m,1H),2.27–2.16(m,1H),1.36(t,J=7.4Hz,3H).

[0294] Example 6-1: Preparation of 6-(2-cyclopropyl-6-(ethylsulfonyl)thiazolyl[5,4-b]pyridin-5-yl)-3-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridyl-5-one (compound 6-1)

[0295] Step 1: Preparation of 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-carboxylic acid tert-butyl ester (intermediate 6-1-a)

[0296] At room temperature, 2.75 g (6.34 mmol) of 6-bromo-5-(cyclopropanecarboxamide)-3-(ethylsulfonyl)pyridinecarboxylic acid tert-butyl ester (as prepared above, intermediate 4-617-a), Lawson's reagent (7.68 g, 19.02 mmol), and dioxane (50 mL) were added to a 250 mL single-necked flask and the mixture was heated to reflux for 8 h. After the reaction was completed, the reaction solution was evaporated to dryness and subjected to silica gel column chromatography to obtain 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-carboxylic acid tert-butyl ester (intermediate 6-1-a) (1.8 g).

[0297] Step 2: Preparation of 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-carboxylic acid (intermediate 6-1-b)

[0298] 1.8 g (4.89 mmol) of tert-butyl 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-carboxylic acid (as intermediate 6-1-a prepared above) and 5 ml of dichloromethane were added to a 50 mL single-necked flask. Then, 5 ml of trifluoroacetic acid was slowly added dropwise to the reaction flask. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed by vacuum distillation to obtain 1.48 g of 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-carboxylic acid (intermediate 6-1-b). The crude product was used in the next step as is.

[0299] Step 3: Preparation of (2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)carbamate tert-butyl ester (intermediate 6-1-c)

[0300] At room temperature, 1.0 g (3.2 mmol) of 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-carboxylic acid (intermediate 6-1-b prepared above), 971 mg (9.6 mmol) of triethylamine, and 10 mL of tert-butanol were added to a 50 mL single-necked flask. The temperature was raised to 80 °C, and then diphenyl azidophosphate (1.05 g, 3.84 mmol) was added dropwise. The reaction was carried out at this temperature for 3 h. After the reaction was completed, the reaction was quenched with ice water, the aqueous phase was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography to obtain tert-butyl 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-yl)carbamate (intermediate 6-1-c) (297 mg).

[0301] Step 4: Preparation of ethyl 2-((tert-butoxycarbonyl)(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid (intermediate 6-1-d)

[0302] At room temperature, tert-butyl (2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)carbamate (as prepared above as intermediate 6-1-c) (200 mg, 0.446 mmol), cesium carbonate (254.46 mg, 0.781 mmol), and acetonitrile (12 mL) were added to a 50 mL single-necked flask, followed by ethyl 2-(bromomethyl)-5-(trifluoromethyl)nicotinate (209.1 mg, ...). 0.67 mmol), heated to 50 °C, reacted at this temperature for 2 h, quenched with ice water after the reaction was completed, the aqueous phase was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography to obtain ethyl 2-((tert-butoxycarbonyl)(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid (intermediate 6-1-d) (380 mg).

[0303] Step 5: Preparation of ethyl 2-((2-cyclopropyl-6-(ethylsulfonyl)thiazolyl[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid (intermediate 6-1-e)

[0304] At room temperature, ethyl 2-((tert-butoxycarbonyl)(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid (intermediate 6-1-d prepared above) (380 mg, 0.618 mmol) and trifluorotoluene (6 mL) were added to a 50 mL single-necked flask, followed by the addition of trifluoroacetic acid (1 mL). The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction was quenched with ice water, and the reaction system was neutralized with saturated sodium bicarbonate aqueous solution. The aqueous phase was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain ethyl 2-((2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid (intermediate 6-1-e) (288 mg). The crude product was used in the next step as is.

[0305] Step 6: Preparation of 2-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid (intermediate 6-1-f)

[0306] At room temperature, 2-((2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid ethyl ester (as intermediate 6-1-e prepared above) (288 mg, 0.56 mmol), tetrahydrofuran (12 mL), and water (4 mL) were added to a 50 mL single-necked flask and cooled to 0 °C in an ice bath. Then, lithium hydroxide (28 mg, 1.17 mmol) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was poured into water, the pH was adjusted to 3, and the aqueous phase was extracted three times with ethyl acetate. The solution was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid (intermediate 6-1-f) (250 mg). The crude product was used as is in the next step.

[0307] Step 7: Preparation of 6-(2-cyclopropyl-6-(ethylsulfonyl)thiazolyl[5,4-b]pyridin-5-yl)-3-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridyl-5-one (compound 6-1)

[0308] At room temperature, 2-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)amino)methyl)-5-(trifluoromethyl)nicotinic acid (as intermediate 6-1-f prepared above) (250 mg, 0.515 mmol) and pyridine (5 mL) were added to a 50 mL single-necked flask, cooled to 0 °C, and phosphorus oxychloride (157.75 mg, 1.03 mmol) was added dropwise, followed by heating. The reaction was carried out at 10°C for 20 min. After the reaction was completed, the reaction was quenched with ice water. The aqueous phase was then extracted three times with ethyl acetate. The solvent was removed under reduced pressure and purified by silica gel column chromatography to obtain 6-(2-cyclopropyl-6-(ethylsulfonyl)thiazolyl[5,4-b]pyridin-5-yl)-3-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridyl-5-one (compound 6-1) (white solid, 141 mg).

[0309] 1 H NMR (400MHz, CDCl3-d) δ9.12(s,1H),8.78(s,1H),8.45(s,1H),5.17(s,2H),3.66–3.33(m,2H),2.54–2.38(m,1H),1.48–1.34(m,7H).

[0310] Example 7-2: Preparation of 6-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)-2,2-difluoro-6,7-dihydro-5H-[1,3]dioxo[4,5-f]isoindol-5-one (compound 7-2)

[0311] Step 1: Preparation of methyl 5-bromo-6-(cyclopropanecarboxamide)-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 7-2-a)

[0312] At room temperature, cyclopropyl carboxylic acid (3.2 g, 0.037 mol), N,N'-carbonyldiimidazole (6.64 g, 0.041 mol), and N,N-dimethylformamide (30 mL) were added to a 100 mL single-necked flask and stirred at room temperature for 2 h. Then, 1,8-diazacyclo[5,4,0]undecene-7 (8.52 g, 0.056 mmol) and methyl 6-amino-5-bromo-3-(ethylsulfonyl)pyridinecarboxylate (as intermediate 2-6-a prepared above) (6 g, 0.019 mol) were added to the reaction system and stirred for 30 min. After the reaction was completed, water was added to the reaction system, followed by extraction twice with dichloromethane. The organic phase was concentrated under reduced pressure and obtained by silica gel column chromatography to obtain methyl 5-bromo-6-(cyclopropanecarboxamide)-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 7-2-a) (7.3 g).

[0313] Step 2: Preparation of methyl 5-bromo-6-(cyclopropanethioamino)-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 7-2-b)

[0314] At room temperature, methyl 5-bromo-6-(cyclopropanecarboxamide)-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 7-2-a prepared above) (1.7 g, 4.34 mmol) and 1,4-dioxane (50 mL) were added to a 250 mL single-necked flask, Lawson's reagent (3.5 g, 8.67 mmol) was added, and the mixture was heated to reflux for 8 hours. After the reaction was completed, the insoluble matter was filtered off by cooling, and the solvent was removed by evaporation under reduced pressure to obtain methyl 5-bromo-6-(cyclopropanethioamino)-3-(ethylsulfonyl)pyridinecarboxylate (intermediate 7-2-b) (1.8 g). The crude product was used as is in the next step.

[0315] Step 3: Preparation of methyl 2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridine-5-carboxylic acid (intermediate 7-2-c)

[0316] At room temperature, methyl 5-bromo-6-(cyclopropanethioamino)-3-(ethylsulfonyl)pyridinecarboxylate (as prepared above, intermediate 7-2-b) (1.8 g, 4.41 mmol), cesium carbonate (2.1 g, 6.62 mmol), and tetrahydrofuran (20 mL) were added to a 100 mL single-necked flask, and the mixture was heated to reflux for 2 h. After the reaction was completed, the reaction solution was diluted with water, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solution was purified by silica gel column chromatography to obtain methyl 2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridine-5-carboxylic acid (intermediate 7-2-c) (white solid, 1.5 g).

[0317] Step 4: Preparation of 2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridine-5-carboxylic acid (intermediate 7-2-d)

[0318] At room temperature, methyl 2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridine-5-carboxylic acid (as prepared above as intermediate 7-2-c) (1.5 g, 4.60 mmol), tetrahydrofuran (15 mL), and water (3 mL) were added to a 50 mL single-necked flask. The mixture was cooled to 0 °C in an ice bath, and lithium hydroxide monohydrate (347 mg, 8.28 mmol) was added. The mixture was then reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into ice water, and the pH was adjusted to 3 with 36% hydrochloric acid. The aqueous phase was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridine-5-carboxylic acid (intermediate 7-2-d) (1.3 g). The crude product was used as is in the next step.

[0319] Step 5: Preparation of (2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)carbamate tert-butyl ester (intermediate 7-2-e)

[0320] Using 2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridine-5-carboxylic acid (as intermediate 7-2-d prepared above) as the starting material, tert-butyl carbamate (intermediate 7-2-e) was prepared similarly to intermediate 6-1-c above.

[0321] Step 6: Preparation of 6-((tert-Butoxycarbonyl)(2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxanepentane-5-carboxylic acid ethyl ester (intermediate 7-2-f)

[0322] Using (2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)carbamate tert-butyl ester (as intermediate 7-2-e prepared above) and 6-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-carboxylic acid ethyl ester as starting materials, 6-((tert-butoxycarbonyl)(2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-carboxylic acid ethyl ester (intermediate 7-2-f) was prepared similarly to intermediate 6-1-d above.

[0323] Step 7: Preparation of 6-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxanepentane-5-carboxylic acid ethyl ester (intermediate 7-2-g)

[0324] Using 6-((tert-butoxycarbonyl)(2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxacyclopenta-5-carboxylic acid ethyl ester (as intermediate 7-2-f prepared above) as the starting material, 6-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxacyclopenta-5-carboxylic acid ethyl ester (intermediate 7-2-g) was prepared similarly to intermediate 6-1-e above.

[0325] Step 8: Preparation of 6-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxanepentane-5-carboxylic acid (intermediate 7-2-h)

[0326] Using ethyl 6-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-carboxylic acid (as intermediate 7-2-g prepared above) as the starting material, 6-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-carboxylic acid (intermediate 7-2-h) was prepared similarly to intermediate 6-1-f above.

[0327] Step 9: Preparation of 6-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)-2,2-difluoro-6,7-dihydro-5H-[1,3]dioxo[4,5-f]isoindol-5-one (compound 7-2)

[0328] Using 6-(((2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)amino)methyl)-2,2-difluorobenzo[d][1,3]dioxacyclopenta-5-carboxylic acid (as intermediate 7-2-h prepared above) as the starting material, 6-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[4,5-b]pyridin-5-yl)-2,2-difluoro-6,7-dihydro-5H-[1,3]dioxa[4,5-f]isoindole-5-one (compound 7-2) was prepared similarly to compound 6-1 above.

[0329] 1 H NMR(400MHz, CDCl3-d)δ8.88(s,1H),7.56(s,1H),7.22(s,1H),5.14–4.94(m,2H),3.64–3. 46(m,2H),2.53–2.41(m,1H),1.56–1.50(m,2H),1.45–1.40(m,2H),1.37(t,J=7.4Hz,3H).

[0330] Example 8-1: Preparation of 2-(2-cyclopropyl-6-(ethylsulfonyl)thiazolyl[5,4-b]pyridin-5-yl)-1-methyl-5-(trifluoromethyl)-1,2-dihydro-3H-pyrazol[3,4-b]pyridyl-3-one (compound 8-1)

[0331] Step 1: Preparation of 2-cyclopropyl-6-(ethylsulfonyl)thiazole[5,4-b]pyridine-5-amine (intermediate 8-1-a)

[0332] At room temperature, tert-butyl (2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)carbamate (as intermediate 6-1-c prepared above) (400 mg, 1.04 mmol) and trifluorotoluene (7 mL) were added to a 50 mL single-necked flask, followed by the addition of trifluoroacetic acid (1.2 mL). The reaction was carried out at room temperature for 2 h. After the reaction was completed, the solvent was removed by vacuum distillation, and 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-amine (intermediate 8-1-a) (259 mg) was obtained by silica gel column chromatography.

[0333] 1H NMR (400MHz, DMSO-d6) δ8.17(s,1H),6.96(s,2H),3.35(q,J=7.2Hz,2H),2.49–2.40(m,1H),1.27–0.93(m,7H).

[0334] Step 2: Preparation of 5-bromo-2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine (intermediate 8-1-b)

[0335] At room temperature, cuprous bromide (252 mg, 1.76 mmol) and acetonitrile (2 mL) were added to a 50 mL single-necked flask. Tert-butyl nitrite (181.51 mg, 1.17 mmol) was added dropwise at room temperature. After the addition was complete, the temperature was raised to 70 °C and a solution of 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-amine (as prepared above as intermediate 8-1-a) (100 mg, 0.353 mmol) in acetonitrile (3 mL) was added dropwise. After the addition was complete, the reaction was carried out at 70 °C for 1 h. After the reaction was completed, the reaction solution was cooled and the pH was adjusted to 2 with 5% hydrochloric acid. The aqueous phase was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 5-bromo-2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine (intermediate 8-1-b).

[0336] Step 3: Preparation of 2-(2-cyclopropyl-6-(ethylsulfonyl)thiazolyl[5,4-b]pyridin-5-yl)-1-methyl-5-(trifluoromethyl)-1,2-dihydro-3H-pyrazol[3,4-b]pyridyl-3-one (compound 8-1)

[0337] At room temperature, 1-methyl-5-(trifluoromethyl)-1,2-dihydro-3H-pyrazol[3,4-b]pyridin-3-one (114.66 mg, 0.528 mmol), cesium carbonate (282.49 mg, 0.867 mmol), and N,N-dimethylformamide (3 mL) were added to a 50 mL single-necked flask, and the mixture was heated to 60 °C. Subsequently, 5-bromo-2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine (as prepared above) was added. Intermediate 8-1-b (100 mg, 0.289 mmol) was reacted at this temperature for 2 h. After the reaction was completed, the reaction was quenched with ice water. The aqueous phase was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solution was obtained by silica gel column chromatography to yield 2-(2-cyclopropyl-6-(ethylsulfonyl)thiazolyl[5,4-b]pyridin-5-yl)-1-methyl-5-(trifluoromethyl)-1,2-dihydro-3H-pyrazol[3,4-b]pyridyl-3-one (compound 8-1).

[0338] 1 H NMR(400MHz, CDCl3-d)δ8.84–8.77(m,2H),8.19(d,J=2.1Hz,1H),4.18(s,3H),3 .63(q,J=7.5Hz,2H),2.37(p,J=6.6Hz,1H),1.41(t,J=7.4Hz,3H),1.30(m,4H).

[0339] Example 10-1: Preparation of 2-cyclopropyl-6-(ethylsulfonyl)-5-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl)thiazo[5,4-b]pyridine (compound 10-1)

[0340] Step 1: Preparation of 2-cyclopropyl-6-(ethanesulfonyl)-N-methoxy-N-methylthiazo[5,4-b]pyridine-5-carboxamide (intermediate 10-1-a)

[0341] At room temperature, compound 2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-carboxylic acid (as intermediate 6-1-b prepared above) (3.0 g, 9.61 mmol), N,N-dimethylformamide (70.2 mg, 0.96 mmol), and dichloromethane (30 mL) were added to a 250 mL single-necked flask, and oxalyl chloride (2.42 g, 19.2 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was evaporated to dryness to obtain the corresponding acyl chloride, and the crude product was used as is in the next step.

[0342] At room temperature, dimethylhydroxylamine hydrochloride (1.87 g, 19.2 mmol), dichloromethane (50 mL), triethylamine (3.87 g, 38.4 mmol), and 4-dimethylaminopyridine (0.94 g, 7.68 mmol) were added to a 250 mL single-necked flask, followed by the addition of a 10 mL solution of the crude acyl chloride. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with dichloromethane, the solvent was removed under reduced pressure, and the solution was purified by silica gel column chromatography to obtain 2-cyclopropyl-6-(ethanesulfonyl)-N-methoxy-N-methylthiazo[5,4-b]pyridine-5-carboxamide.

[0343] Step 2: Preparation of 1-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)ethyl-1-one (intermediate 1-10-b)

[0344] At room temperature, 2-cyclopropyl-6-(ethanesulfonyl)-N-methoxy-N-methylthiazo[5,4-b]pyridine-5-carboxamide (as intermediate 10-1-a prepared above) (2.0 g, 5.63 mmol) and tetrahydrofuran (20 mL) were added to a 250 mL single-necked flask, followed by the dropwise addition of methyl magnesium bromide (1 M) (16.88 mL, 16.88 mmol), and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the reaction solution was slowly poured into a saturated ammonium chloride solution to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine and dried, the solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound 1-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridine-5-yl)ethyl-1-one (intermediate 1-10-b).

[0345] Step 3: Preparation of 2-cyclopropyl-6-(ethylsulfonyl)-5-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl)thiazo[5,4-b]pyridine (compound 10-1)

[0346] At room temperature, 1-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)ethyl-1-one (as intermediate 1-10-b prepared above) (780 mg, 2.51 mmol), chlorobenzene (15 mL), 2-amino-5-trifluoromethylpyrazine (450 mg, 2.77 mmol), anhydrous copper acetate (91 mg, 0.50 mmol), 1,10-phenanthroline (90 mg, 0.50 mmol) and zinc iodide (160 mg, 0.50 mmol) were added to a 100 mL single-necked flask, and then the mixture was heated to 135 °C and stirred under reflux for 40 h. After the reaction was completed, the reaction solution was evaporated to dryness, diluted with water, extracted with ethyl acetate, the organic phases were combined and the solvent was removed under reduced pressure. The solution was purified by silica gel column chromatography to obtain compound 2-cyclopropyl-6-(ethylsulfonyl)-5-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl)thiazo[5,4-b]pyridine (compound 10-1).

[0347] 1 H NMR (400MHz, CDCl3-d) δ9.11(s,1H),8.83(s,1H),8.53(s,1H),8.31(s,1H),3.85–3.76(m,2H),2.45–2.36(m,1H),1.39–1.26(m,7H).

[0348] Example 12-1: Preparation of 2-cyclopropyl-6-(ethylsulfonyl)-5-(7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-2-yl)thiazo[5,4-b]pyridine (compound 12-1)

[0349] At room temperature, 1-(2-cyclopropyl-6-(ethylsulfonyl)thiazo[5,4-b]pyridin-5-yl)ethyl-1-one (as intermediate 1-10-b prepared above) (750 mg, 2.42 mmol), chlorobenzene (15 mL), 4-amino-6-trifluoromethylpyrimidine (473 mg, 2.90 mmol), anhydrous copper acetate (88 mg, 0.48 mmol), 1,10-phenanthroline (87 mg, 0.48 mmol), and zinc iodide (154 mg, 0.48 mmol) were added to a 100 mL single-necked flask, and then the mixture was heated to 135 °C and stirred under reflux for 40 h. After the reaction was completed, the reaction solution was evaporated to dryness, diluted with water, extracted with ethyl acetate, the organic phases were combined and the solvent was removed under reduced pressure. The solution was purified by silica gel column chromatography to obtain 2-cyclopropyl-6-(ethylsulfonyl)-5-(7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-2-yl)thiazo[5,4-b]pyridine (compound 12-1).

[0350] 1 H NMR (400MHz, CDCl3-d) δ9.10(s,1H),8.83(s,1H),8.28(s,1H),7.90(s,1H),3.83–3.75(m,2H),2.44–2.36(m,1H),1.34–1.30(m,4H),1.27(d,3H).

[0351] Compounds 1-1 to 16-24 were prepared in a manner similar to the preparation examples given above.

[0352] The analytical data for compounds 1-1 to 12-1 in Examples are shown in Table 2 below.

[0353] Table 2 shows the analytical data for compound (I).

[0354] The compound of formula (I) of this invention was tested for its control activity against various agricultural pests, including cotton aphids, peach aphids, diamondback moths, rice stem borers, rice leaf rollers, beet armyworms, fall armyworms, cotton bollworms, whiteflies, thrips, brown planthoppers, gray planthoppers, flea beetles, and root-knot nematodes. The tested compound of formula (I) showed superior control efficacy, achieving unexpected technical results compared to existing technologies. Furthermore, the compound of formula (I) of this invention was tested for toxicity against environmental organisms such as bees, large daphnia, zebrafish, earthworms, and algae. The tested compound of formula (I) showed low toxicity.

[0355] Biological Example 1

[0356] Cotton aphid (Aphis gossypii (Glover))

[0357] The activity of cotton aphids was tested using the immersion method. The test unit consisted of a 9cm plastic petri dish containing cucumber leaves that had grown for one month, and was kept moist with absorbent cotton. Healthy adult aphids were inoculated onto the cucumber leaves, and after 24 hours, the adult aphids were removed, and the total number of nymphs on each plate was recorded.

[0358] Prepare the test compound, add an appropriate amount of organic solvent (solvent content not exceeding 2%), and then dilute it to different concentrations with 0.1% Tween-80 aqueous solution. Soak cucumber leaves with 2-day-old aphid nymphs in the solution for 5 seconds, and allow the residual solution to dry completely. Perform three parallel treatments. Place all test units at 25±1℃ and a photoperiod of 16h:8h (L:D) for rearing and observation. Record the number of dead insects 72 hours after treatment and calculate the mortality rate.

[0359] Compounds of formula (I) of the present invention: 1-1, 1-2, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-24, 1-33, 1-35, 1-37, 1-45, 1-50, 1-51, 1-52, 1-103, 1-153, 1-156, 1-157. 1-160,1-161,2-1,2-2,2-3,2-4,2-5,2-6,2-7,2-8,2-10,2-11,2-12,2-13,2-14,2-15,2-16,2-17,2-18,2-19,2-20,2-21,2-22,2-23,2-24,2-25,2-28,2-39,2-40,2-125,2-128,3-1,3-2,3-3,3-4,3 -5,3-6,3-7,3-9,3-10,3-11,3-12,3-15,3-16,3-19,3-23,3-24,3-125,3-128,4-1,4-3,4-4,4-121,4-122,4-123,4-124,4-127,4-128,4-129,4-131,4-132,4-133,4-135,4-136,4-137,4-140,4-14 At a concentration of 50 ppm, the following pesticides showed a mortality rate ≥90% against cotton aphids 3 days after application: 1, 4-148, 4-483, 4-484, 4-485, 4-488, 4-489, 4-493, 4-495, 4-497, 4-500, 4-501, 4-564, 4-618, 5-1, 5-2, 5-4, 5-21, 6-1, 6-2, 6-3, 6-4, 7-2, 7-4, 7-14, 8-1, 10-1, 12-1, etc.

[0360] Biological Example 2

[0361] Diamondback moth (Plutella xylostella (Linnaeus))

[0362] The activity of diamondback moth was tested by leaf immersion feeding. The test unit consisted of a 9cm plastic petri dish containing three fresh cabbage leaves of equal area.

[0363] Prepare the test compound by adding an appropriate amount of organic solvent (solvent content not exceeding 2%), then dilute it to different concentrations with 0.5% Triton X-100 aqueous solution. Soak fresh cabbage leaves in the solution for 10 seconds, and after the residual solution is fully dried, place them in petri dishes. Then, pick 10 third-instar larvae of diamondback moths into each petri dish, and perform three parallel treatments. Place all test units at 25±1℃ and a photoperiod of 16h:8h (L:D) for rearing and observation. Record the number of dead insects 3–5 days after treatment and calculate the mortality rate.

[0364] Compounds of formula (I) of the present invention: 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-13, 1-14, 1-15, 1-17, 1-18, 1-19, 1-21, 1-23, 1-45, 1-51, 1-52, 1-103, 1-153, 1-154, 1-157, 1-158, 1-159, 1-160, 1-161, 2-1, 2-2, 2-5, 2-6, 2-7, 2-10, 2-13, 2- 14,2-18,2-21,2-22,2-25,2-125,2-126,2-128,3-1,3-2,3-3,3-5,3-6,3-7,3-8,3-9,3-10,3-13,3-125,3-128,4-1,4-2,4-3,4-4,4-122,4-123,4-124,4-125,4-127,4-128,4-129,4-130,4-131,4-132,4-133,4-134,4-135,4-13 6,4-137,4-138,4-139,4-140,4-141,4-142,4-143,4-144,4-145,4-147,4-148,4-161,4-244,4-481,4-483,4-484,4-485,4-486,4-487,4-488,4-489,4-491,4-492,4-493,4-494,4-495,4-496,4-497,4-498,4-499,4-500,4-501 At a concentration of 50 ppm, the mortality rate of diamondback moths was ≥90% 3 days after application.

[0365] Biological Example 3

[0366] Rice stem borer (Chilo suppressalis (Walker))

[0367] The activity test of rice stem borer was conducted by leaf-immersion feeding method. The test unit was a 9cm plastic petri dish containing 15 6cm long 1-month-old rice stems.

[0368] Prepare the test compound by adding an appropriate amount of organic solvent (solvent content not exceeding 2%), and then dilute it to different concentrations with 0.5% Triton X-100 aqueous solution. Cut rice plants that have grown for one month at the root, clean them, and let them dry. Soak them in the drug solution for 10 seconds, and let the residual drug solution dry completely. Place them in a petri dish, and place filter paper in the petri dish to keep them moist. Then pick out 10 late second instar larvae of the rice stem borer into the petri dish, cover them with two layers of black cloth, and then cover the petri dish with the petri dish lid. Place all test units under the conditions of 28±1℃ and a photoperiod of 16h:8h (L:D) for rearing and observation. Record the number of dead insects 5 days after the drug treatment and calculate the mortality rate.

[0369] Compounds of formula (I) of the present invention: 1-1, 1-2, 1-4, 1-5, 1-6, 1-9, 1-10, 1-13, 1-15, 1-17, 1-18, 1-19, 1-21, 1-23, 1-37, 1-41, 1-157, 1-158, 1-160, 1-161, 2-1, 2-6, 3-1, 3-2, 3-3, 3-5, 3-9, 3- At a concentration of 50 ppm, the mortality rate of rice stem borer ≥90% 5 days after application of the pesticide.

[0370] Biological Example 4

[0371] Rice leaf roller (Cnaphalocrocis medinalis Guenee)

[0372] The activity test of rice leaf roller was carried out by the leaf immersion method. The test unit consisted of a 7cm glass petri dish containing 10 wheat leaves about 5cm in length. Qualitative filter paper was placed at the bottom of the glass petri dish and moistened with water.

[0373] Prepare the test compound by adding an appropriate amount of organic solvent (solvent content not exceeding 2%), then dilute it to different concentrations with 0.1% Tween-80 aqueous solution. Cut wheat leaves to a length of about 5 cm and set aside. Immerse the wheat leaves in the prepared solutions of different concentrations for 20 seconds, then remove them and allow them to dry thoroughly on tissue paper. Transfer the wheat leaves to corresponding petri dishes, and inoculate 10 rice leaf roller larvae into each dish. Perform three parallel treatments. Place all test units in an incubator at 28±1℃ with a photoperiod of 16h:8h (L:D) for observation. Record the number of dead insects 48 hours after treatment and calculate the mortality rate.

[0374] The compound of formula (I) of this invention has excellent control efficacy against rice leaf roller.

[0375] In the above experiments, for example, the following compounds from the preparation examples showed superior efficacy compared to the prior art: see Tables 3 and 4 below.

[0376] Table 3

[0377] Table 4

[0378] Grading criteria for prevention and control effectiveness (mortality rate):

[0379] Level 10 indicates a mortality rate of 90% to 100% or higher;

[0380] Level 9 indicates a mortality rate of 80% or higher to less than 90%.

[0381] Level 8 indicates a mortality rate of 70% or higher to less than 80%;

[0382] Level 7 indicates a mortality rate of 60% or higher to less than 70%;

[0383] Level 6 indicates a mortality rate of 50% or higher to less than 60%;

[0384] Level 5 indicates a mortality rate of 40% or higher to less than 50%;

[0385] Level 4 indicates a mortality rate of 30% or higher to less than 40%;

[0386] Level 3 indicates a mortality rate of 20% or higher to less than 30%;

[0387] Level 2 indicates a mortality rate of 10% or higher to less than 20%;

[0388] Level 1 indicates a mortality rate of less than 10%.

[0389] Biological Example 5

[0390] Zebrafish (Barchydanio rerio)

[0391] Use healthy, disease-free zebrafish of uniform size. Before the experiment, they should be pre-reared under the same environmental conditions as the experimental one for 7-14 days. During the pre-rearing period, feed them 1-2 times a day, provide 12-16 hours of light per day, and clean up feces and food scraps promptly. Stop feeding 24 hours before the experiment.

[0392] The test unit was a 3L beaker, and a static test method was used. Test compounds were prepared by using organic solvents (DMSO, DMF, etc.) to create stock solutions, with a solvent content not exceeding 2%. Five to seven concentration gradients were prepared using tap water aerated for at least 24 hours. Five zebrafish were placed in each test unit, with a minimum capacity of 500mL. The poisoning symptoms and mortality rate of the fish were observed and recorded continuously for the first 6 hours of the experiment. Subsequently, the poisoning symptoms and mortality rate were observed and recorded at 24h, 48h, 72h, and 96h. The mortality rate was calculated and determined according to LC-125. 50 To determine toxicity level, the ratio of (96h) / (mg ai / L) is used. The toxicity classification standard is as follows: Extremely toxic: LC 50 ≤0.1; Highly toxic: 0.1 < LC 50 ≤1; Poisoning: 1 < LC 50 ≤10; Low toxicity: LC 50 >10.

[0393] The compound of formula (I) of the present invention exhibits low toxicity to fish.

[0394] Biological Example 6

[0395] Large Daphnia magna

[0396] Non-primate daphnia were cultured for at least three generations under laboratory conditions in a parthenogenetic state. The daphnia used in the experiment were healthy daphnia from the same maternal lineage, i.e., those that did not show any signs of stress (such as high mortality, presence of male daphnia and hibernating eggs, delayed primiparity, abnormal body color, etc.).

[0397] The test unit was a 50mL plastic cup. Test compounds were prepared using organic solvents (DMSO, DMF, etc.) to create a stock solution, with a solvent concentration not exceeding 0.1g / L. Five to seven concentration groups were set up. Ten juvenile Daphnia were placed in each test unit. All test units were cultured under conditions of a water temperature of 18℃~22℃ and a photoperiod of 16h:8h (L:D). The mortality rate of the large Daphnia was observed and statistically analyzed after 48 hours, based on EC... 50 To determine toxicity level, the ratio of (48h) / (mg ai / L) is as follows: Extremely toxic: EC 50 ≤0.1; Highly toxic: 0.1 < EC 50≤1; Poisoning: 1 < EC 50 ≤10; Low toxicity: EC 50 >10.

[0398] The compound of formula (I) of the present invention exhibits low toxicity to daphnia.

[0399] Biological Example 7

[0400] Italian worker bee (Apis mellifera L.)

[0401] Using adult Italian worker bees (Apis mellifera L.), test bees should be collected in the early morning; avoid conducting bee tests in early spring and late autumn; bees should not be used for testing within four weeks of receiving antibiotics or anti-mite drugs. Test bees should be healthy individuals of uniform size. Bees used for acute oral toxicity tests should be starved for 2 hours before the test.

[0402] 1. Acute oral toxicity

[0403] Prepare the test compound by using an organic solvent (acetone, etc.) to create a stock solution. Prepare 5-7 gradient concentrations of 50% sucrose solution, with 10 bees per concentration. Then, add 200 μL of the 50% sucrose solution containing different concentrations of the compound to the feeder. Set up a blank control group and a solvent control group. Measure the consumption of the drug solution. After the drug solution is consumed, feed the bees with the sucrose solution without the compound. Observe and record the poisoning symptoms and the number of deaths after 48 hours, calculate the mortality rate, and determine the 48-hour LD50. 50 Value and 95% confidence limit.

[0404] 2. Acute contact toxicity of honeybees

[0405] Prepare the test compound by using an organic solvent (acetone, etc.) to create a stock solution. Prepare 5-7 concentration gradients using a 50% sucrose solution, with 10 bees per concentration. Include a blank control group and a solvent control group. After anesthetizing the bees, apply 2 μL of the different concentrations of the test compound to the mesothorax of the bees. After the solvent evaporates, transfer the bees to test cages and feed them cotton wool soaked in sucrose water. Observe and record the poisoning symptoms and mortality rate of the bees after 48 hours, calculate the mortality rate, and determine the 48-hour LD50. 50 Value and 95% confidence limit.

[0406] According to LD 50 The toxicity level is determined by (48h) / (μg ai / bee). The toxicity levels are classified as follows: Extremely Toxic: LD 50 ≤0.001; Highly toxic: 0.001 < LD50 50 ≤2; Poisoning: 2 < LD 50 ≤11; Low toxicity: LD 50 >11.

[0407] Biological Example 8

[0408] A child loves earthworms (Eisenia foetida)

[0409] Adult Eisenia foetida earthworms, weighing between 0.3 and 0.6 g, were used in the experiment. The experimental temperature was 20℃ ± 2℃, the relative humidity was 70%–90%, and the light intensity was 400 lx–800 lx.

[0410] Prepare the test compound by using an organic solvent (acetone, etc.) to create a stock solution. Set up 5-7 concentration gradients, with the organic solvent volume generally not exceeding 0.1 mL / L. Include a blank control group and a solvent control group. Weigh 500 g of artificial soil into a specimen bottle and add the different concentrations of the drug solution, mixing thoroughly. Place 10 earthworms in each treatment, seal the bottle opening with gauze, and incubate for two weeks. Observe and record the poisoning symptoms and mortality of the earthworms on days 7 and 14, and calculate the median lethal concentration (LC50) of the drug solution for the earthworms. 50 Value and 95% confidence limit.

[0411] According to LC 50 To determine toxicity level using (14d) / (mg ai / kg dry soil), the toxicity levels are classified as follows: Extremely toxic: LD50 50 ≤0.1; Highly toxic: 0.1 < LC 50 ≤1; Poisoning: 1 < LC 50 ≤10; Low toxicity: LC 50 >10.

[0412] Biological Example 9

[0413] Chlorella vulgaris

[0414] The experiment used common Chlorella vulgaris, which was cultured under sterile conditions to achieve synchronous growth. The experimental environment temperature was 21℃~24℃ (the temperature of a single experiment was controlled within ±2℃); continuous and uniform light was provided, with the light intensity difference maintained within ±15%, and the light intensity was 4440lx~8880lx.

[0415] Prepare the test compound by using an organic solvent (acetone, etc.) to create a stock solution. Set up 5-7 concentration gradients, with the organic solvent volume generally not exceeding 0.1 mL / L. Include a blank control group and a solvent control group. Add different concentrations of the drug solution to the Chlorella solution. The experimental observation period is 72 hours, with samples taken every 24 hours. Measure the absorbance of the algae directly using a spectrophotometer. Calculate the algal growth inhibition rate according to EC. 50To determine toxicity level using (72h) / (mg ai / L), the toxicity levels are classified as follows: Highly toxic: EC 50 ≤0.3; Poisoning: 0.3<EC 50 ≤3; Low toxicity: EC 50 >3.

[0416] Biological Example 10

[0417] North American quail (Colinus virginianus)

[0418] The test species is the North American quail (Colinus virginianus). The test birds should be in good health and without obvious deformities. A mortality rate of less than 5% within the first 7 days after introduction into the laboratory, and growth patterns consistent with the species' growth characteristics, are considered to indicate good health. The test birds should pass animal quarantine to ensure they are free of disease. The test birds should come from the same maternal parent and hatch on the same day.

[0419] 1. Acute oral toxicity

[0420] Prepare the test compound by using an organic solvent (acetone, etc.) to form a stock solution. Set up 5-7 concentration gradients, with 10 birds (half male and half female) at each concentration. Include a blank control group and a solvent control group. Administer different doses of the test compound (I) orally at a single dose of 1 mL / 100g body weight. Observe the poisoning and mortality of the test birds for 7 consecutive days and determine the 7-day LD50. 50 Values ​​and 95% confidence limits. Based on LD... 50 To determine toxicity level using / (mg(ai) / kg body weight), the toxicity levels are classified as follows: Extremely Toxic: LD50 50 ≤10; Highly toxic: 10 < LD50 50 ≤50; Poisoning: 50<LD 50 ≤500; Low toxicity: LD 50 >500.

[0421] 2. Acute feeding toxicity

[0422] Prepare the test compound by using an organic solvent (acetone, etc.) to create a stock solution. Set up 5-7 concentration gradients, with 10 birds per concentration (half male and half female), and include a blank control group and a solvent control group. Use a sprayer to spray the different concentrations of the solution onto the food, stirring constantly until evenly mixed. Feed the test birds with feed containing different concentrations of the test compound (I) for 5 days. Starting from day 6, feed them with feed without the test compound for 3 days. Record the poisoning and mortality of the birds daily, and calculate the LC50 over 8 days. 50 Values ​​and 95% confidence limits. According to LC... 50 To determine toxicity level using / (mg(ai) / kg feed), the toxicity levels are classified as follows: Extremely toxic: LC50 ≤50; Highly toxic: 50 < LC 50 ≤500; Poisoning: 500 < LC 50 ≤1000; Low toxicity: LC 50 >1000.

[0423] As shown in the results above, the compounds of the present invention generally exhibit good insecticidal effects, producing excellent insecticidal efficacy even at low application doses. Furthermore, they demonstrate good safety for environmental organisms.

[0424] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several changes and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A pyridine fused ring compound having a sulfur substituent represented by the general formula (I) : ###00001### (I) stereoisomers thereof, and agriculturally acceptable salts thereof. X, Y are selected from N, N-R7 or S; when X is selected from N, Y is selected from N-R7 or S; when Y is selected from N, X is selected from N-R7 or S; Z is selected from CH2, NH or N-R8; R1-R5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl or cyano; R6, R7 and R8 are independently selected from C1-C6 alkyl or C3-C6 cycloalkyl; wherein Q represents a group of the formula Q2-Q 32 R2represents a group of the formula: R9 is selected from C1-C4 haloalkyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl or C1-C4 haloalkoxy.

2. The compound of formula (I) according to claim 1, its stereoisomers and its agriculturally acceptable salts: ###0002### wherein X, Y are selected from N, N-CH3 or S; when X is selected from N, Y is selected from N-CH3 or S; when Y is selected from N, X is selected from N-CH3 or S; R6 is methyl; Z is selected from CH2, NH or N-CH3; R1-R5 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or cyano; R9 is selected from trifluoromethyl, pentafluoroethyl, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl.

2. The compound of formula (I) according to claim 1, its stereoisomers and its agriculturally acceptable salts: ###0002### wherein X, Y are selected from N, N-CH3 or S; when X is selected from N, Y is selected from N-CH3 or S; when Y is selected from N, X is selected from N-CH3 or S; R6 is methyl; Z is selected from CH2, NH or N-CH3; R1-R5 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or cyano; R9 is selected from trifluoromethyl, pentafluoroethyl, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl.

3. The compound of formula (I) according to claim 2, its stereoisomers and its agriculturally acceptable salts: ###0003### wherein R1-R5 are simultaneously hydrogen, or at least one of R1-R5 is substituted by fluorine, chlorine, bromine, trifluoromethyl or cyano.

4. The compound of formula (I) according to claim 3, its stereoisomers and its agriculturally acceptable salts: ###0004### wherein R1-R5 are simultaneously hydrogen, or at least one of R1-R5 is substituted by fluorine, chlorine or cyano.

5. The compound of formula (I) according to claim 4, its stereoisomers and its agriculturally acceptable salts: ###0005### wherein any 1, 2 or 3 of R1-R5 are substituted by fluorine, chlorine or cyano, and the remaining are hydrogen.

6. The compound of formula (I) according to claim 5, its stereoisomers and its agriculturally acceptable salts: ###0006### wherein any 1 or 2 of R1-R5 are substituted by fluorine or chlorine, and the remaining are hydrogen. X, Y are selected from N, N-R7 or S; wherein Q represents a group of the formula Q2-Q8or Q 10- Q 13 as indicated: when X is selected from N, Y is selected from N-R7 or S; when Y is selected from N, X is selected from N-R7 or S; Z is selected from CH2, NH or N-R8; when Z is selected from NH or N-R8; R1-R5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano; when Z is selected from CH2, R1-R5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, and at least one of R1-R5 is substituted by fluorine, chlorine, bromine, trifluoromethyl or cyano; 7. A pyridine fused ring compound having a sulfur substituent represented by the general formula (I) : ###00004### (I) stereoisomers thereof, and agriculturally acceptable salts thereof. R9 is selected from C1-C4 haloalkyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl or C1-C4 haloalkylsulfonyl.

8. The compound of formula (I) according to claim 7, its stereoisomers and its agriculturally acceptable salts: ###0008### wherein X, Y are selected from N, N-CH3 or S; when X is selected from N, Y is selected from N-CH3 or S; R6 is methyl; Z is selected from CH2, NH or N-CH3; R1-R5 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or cyano; R9 is selected from trifluoromethyl, pentafluoroethyl, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl. ​ ​ ​ ​ wherein R6, R7and R8are each independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl; wherein Q represents a group of the formula Q1: ​ ​ ​ ​ when Y is selected from N, X is selected from N-CH3or S; wherein R6is methyl; wherein Z is selected from CH2, NH or N-CH3; when Z is selected from NH or N-CH3, R1-R5are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or cyano; when Z is selected from CH2, R1-R5are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or cyano, and at least one of R1-R5is substituted with fluorine, chlorine, bromine, trifluoromethyl or cyano. wherein R9is selected from trifluoromethyl, pentafluoroethyl, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl.

9. A composition characterized in that, which comprises at least one of the compounds of formula (I), stereoisomers thereof or salts thereof as claimed in any one of claims 1 to 8, as an active ingredient, the active ingredient being contained in an amount of 0.1 to 99.9% by weight in the composition.

10. A method of controlling pests, characterized by, The compound of formula (I), stereoisomers thereof and agriculturally acceptable salts thereof as claimed in any one of claims 1 to 8 or the composition as claimed in claim 9 is applied to a harmful organism or its growth environment.

11. Use of the compound of formula (I), stereoisomers thereof and agriculturally acceptable salts thereof as claimed in any one of claims 1 to 8 or the composition as claimed in claim 9 for controlling a harmful organism.

11. Use of the compound of formula (I), stereoisomers thereof and agriculturally acceptable salts thereof as claimed in any one of claims 1 to 8 or the composition as claimed in claim 9 for controlling a harmful organism.

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