Cycloalkyl-substituted triazolopyridine amide compounds, methods of making and using the same

Abstract

The application provides a cycloalkyl-substituted triazolopyridine amide compound and a preparation method and application thereof, and belongs to the technical field of pesticides. The cycloalkyl-substituted triazolopyridine amide compound provided by the application introduces an unsubstituted or substituted cyclohexyl group or an unsubstituted or substituted cyclopentyl group on a triazole ring, has excellent inhibitory effect on pepper Phytophthora capsici Leonian, and has an EC 50 as low as 0.3 micromole / L; and the cycloalkyl-substituted triazolopyridine amide compound and derivatives thereof also have broad-spectrum inhibitory activity on rice Helminthosporium leaf spot fungus, wheat Helminthosporium leaf spot fungus, brassica sclerotinia, wheat Gibberella zeae, wheat take-all fungus, tomato botrytis cinerea, potato late blight fungus, pepper Phytophthora capsici Leonian, tomato early blight fungus, rice bacterial wilt fungus, potato dry rot fungus, cucumber anthracnose fungus and rice rice blast fungus, and have a good application prospect in the preparation of anti-plant pathogenic fungus drugs.

Description

Technical Field

[0001] This invention relates to the field of pesticide technology, specifically to a cycloalkyl-substituted triazolidine pyridine amide compound, its preparation method and application, and derivatives of the cycloalkyl-substituted triazolidine pyridine amide compound and their applications. Background Technology

[0002] Methoxyacrylate fungicides have methoxyacrylate (ester / amide) as their active group. They primarily act on the cytochrome bCl complex in the mitochondrial respiratory chain of fungi, inhibiting electron transfer and thus suppressing fungal growth. They possess protective, curative, eradicative, and penetrating effects, and are non-carcinogenic and non-mutagenic. They are effective against diseases caused by fungi such as Ascomycetes, Basidiomycetes, Deuteromycetes, and Oomycetes, and have high environmental safety, making them the most widely used fungicides for plant diseases. However, resistance to methoxyacrylate fungicides has begun to constrain their development. Amide fungicides can effectively overcome the resistance problem of methoxyacrylate fungicides and are among the most actively researched fungicide varieties in recent years. The main representative of amide fungicides is the succinate dehydrogenase inhibitor SDHIs. With the widespread use of SDHIs, many pathogens in the field have developed resistance to these fungicides. Therefore, developing small-molecule chemical pesticides with novel structures provides a new approach to solving this problem.

[0003] A triazolopyridine amide compound (structural formula shown below) has been disclosed in related technologies, exhibiting broad-spectrum and good antifungal effects against plant pathogenic fungi. However, the aforementioned triazolopyridine amide compound shows poor antifungal effects against Phytophthora capsici, an important oomycete disease.

[0004] Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a cycloalkyl-substituted triazolidine pyridine amide compound and its preparation method and application, as well as derivatives of the cycloalkyl-substituted triazolidine pyridine amide compound and their applications. The cycloalkyl-substituted triazolidine pyridine amide compound provided by the present invention has excellent inhibitory effect on Phytophthora capsici.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a cycloalkyl-substituted triazolidine pyridine amide compound having the structure shown in Formula I:

[0008]

[0009] Wherein, X includes oxygen or sulfur;

[0010] R1 and R2 independently include hydrogen, C1-C6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group; when neither R1 nor R2 is hydrogen, * indicates a chiral center; the stereoconfiguration of the carbon chiral center of R1 and R2 is independently R-type or S-type.

[0011] R3 includes hydrogen, C1-C6 alkyl, halogen, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamine or C1-C6 haloalkyl; the number of R3 is 1 to 3;

[0012] R4 includes hydrogen, halogen, C1-C6 alkyl, cyclohexyl, unsubstituted or substituted aryl, phenoxy, C1-C6 haloalkyl, alkylcarbonyl or C1-C6 alkoxy;

[0013] R5 includes unsubstituted or substituted cyclohexyl groups and unsubstituted or substituted cyclopentyl groups.

[0014] Preferably, among R1 and R2,

[0015] The substituents in the substituted phenyl group include phenyl, halogen, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamine or C1-C6 haloalkyl.

[0016] The substituents in the substituted heterocyclic group include heterocyclic groups, halogens, hydroxyl groups, amino groups, C1-C6 alkoxy groups, or C1-C6 alkylamine groups.

[0017] The heterocyclic group in the unsubstituted or substituted heterocyclic group includes pyridinyl, thiophenyl, or furanyl;

[0018] In R4, the substituents in the substituted aryl group include halogen, trifluoromethyl, C1-C6 alkyloxy, C1-C6 alkyl group or C1-C6 alkylamino group;

[0019] In R5, the substituents in the substituted cyclohexyl group and the substituents in the substituted cyclopentyl group independently include C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamine, C1-C3 haloalkyl or halogen.

[0020] Preferably, the C1-C6 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0021] The C1 to C6 alkoxy groups include -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -O(CH2)3CH3, -OCH2CH(CH3)2, -OCHCH3CH2CH3, -O(CH3)3 , -O(CH2)4CH3, -OCH(CH3)CH2CH2CH3, -OCH2CH(CH3)CH2CH3, -OCH2CH2CH(CH3)2, -OCH(CH3)2CH2CH3 or -OCH2C(CH3)3;

[0022] The C1-C6 alkylamine groups include -NHCH3, -NHCH2CH3, -NH(CH2)2CH3, -NHCH(CH3)2, -NH(CH2)3CH3, -NHCH2CH(CH3)2, -NHCH(CH3)CH2CH3, -NH(CH3)3, -NH(CH2)4CH3, -NHCH(CH3)CH2CH2CH3, -NHCH2CH(CH3)CH2CH3, -NHCH2CH2CH(CH3)2, -NHC(CH3)2CH2CH3 or -NHCH2C(CH3)3;

[0023] The C1-C6 haloalkyl groups include -CF2H or -CF3.

[0024] Preferably, the cycloalkyl-substituted triazolidine pyridine amide compound has the structure shown in Formula I-1 or Formula I-2:

[0025]

[0026] This invention provides a method for preparing the cycloalkyl-substituted triazolidine pyridine amide compounds described above, comprising the following steps:

[0027] Compound II, Compound III, condensing agent, triethylamine and organic solvent are mixed and subjected to condensation reaction to obtain the cycloalkyl-substituted triazolidine pyridine amide compound;

[0028]

[0029] Where R1 to R5 are the same as in Formula I.

[0030] Preferably, the condensation reaction is carried out at a temperature of 0–40°C for a time of 12–96 h.

[0031] The compound II includes compound II-1 or compound II-2;

[0032]

[0033] The preparation method of compound II-1 includes the following steps:

[0034] Compound 1, compound 2, catalyst and benzene solvent were mixed and subjected to Witte seeliger cyclization reaction to give compound II-1;

[0035] The preparation method of compound II-2 includes method one or method two, wherein:

[0036] Method 1: Mix the compound II-1, phosphorus pentasulfide, and a benzene solvent to carry out a displacement reaction to obtain compound II-2;

[0037] Method 2: Compound 7, Compound 2 and a cyclic solvent were mixed and subjected to a decarboxylation and amidation reaction to obtain Compound 8;

[0038] Compound 8, phosphorus pentasulfide, and a heterocyclic solvent were mixed and subjected to a cyclization reaction to obtain compound II-2.

[0039]

[0040] Where R1 to R3 are the same as in Equation I.

[0041] Preferably, the preparation method of compound III includes the following steps:

[0042] Compound 3, hydrazine hydrate, and a heterocyclic solvent were mixed to carry out a substitution reaction, yielding compound 4;

[0043]

[0044] Compound 4, compound 5, oxidant and organic solvent were mixed and subjected to a condensation oxidation reaction to obtain compound 6;

[0045]

[0046] Compound 6, lithium hydroxide, and an organic solvent were mixed and subjected to a hydrolysis reaction to obtain compound III;

[0047] R4 and R5 are the same as in Equation I.

[0048] The present invention provides derivatives of the cycloalkyl-substituted triazolidine pyridine amide compounds described in the above technical solution, wherein the derivatives include pesticide-chemically acceptable salts.

[0049] This invention provides the application of the cycloalkyl-substituted triazolidine pyridine amide compounds or derivatives thereof described in the above-mentioned technical solutions in the preparation of drugs against plant pathogenic fungi.

[0050] Preferably, the plant pathogenic fungi include one or more of the following: rice sheath blight fungus, wheat sheath blight fungus, rapeseed sclerotinia sclerotiorum fungus, wheat scab fungus, wheat take-all fungus, tomato gray mold fungus, potato late blight fungus, pepper phytophthora, tomato early blight fungus, rice bakanae disease fungus, potato dry rot fungus, cucumber anthracnose fungus, and rice blast fungus.

[0051] This invention provides a cycloalkyl-substituted triazolidine pyridine amide compound having the structure shown in Formula I; wherein, X comprises oxygen or sulfur; R1 and R2 independently comprise hydrogen, C1-C6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group; the stereoconfiguration of the carbon chiral center of R1 and R2 is independently R-type or S-type; when neither R1 nor R2 is hydrogen, * indicates a chiral center; R3 comprises hydrogen, C1-C6 alkyl, halogen, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamine or C1-C6 haloalkyl; the number of R3 is 1 to 3; R4 comprises hydrogen, halogen, C1-C6 alkyl, cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted heterocyclic group, C1-C6 haloalkyl, alkylcarbonyl or C1-C6 alkoxy; R5 comprises unsubstituted or substituted cyclohexyl or unsubstituted or substituted cyclopentyl. This invention provides cycloalkyl-substituted triazolidine pyridine amides with unsubstituted or substituted cyclohexyl groups and unsubstituted or substituted cyclopentyl groups introduced onto the triazole ring. These compounds exhibit excellent inhibitory activity against *Phytophthora capsici*, a major oomycete disease, with an EC50 (intermediate inhibitory concentration) as low as 0.3 μmol / L. Furthermore, the cycloalkyl-substituted triazolidine pyridine amides and their derivatives provided by this invention possess broad-spectrum antifungal activity against *Rhizoctonia solani*, *Rhizoctonia solani*, *Sclerotinia sclerotiorum*, *Fusarium graminearum*, *Tricholoma materia rubra*, *Botrytis cinerea*, *Phytophthora capsici*, *Phytophthora capsici*, *Phytophthora blight*, *Phytophthora jasminoides ...

[0052] This invention provides a method for preparing the cycloalkyl-substituted triazolidine pyridine amide compounds described above. The preparation method provided by this invention is simple to operate, uses low-cost raw materials, is environmentally friendly, and is suitable for industrial production. Detailed Implementation

[0053] This invention provides a cycloalkyl-substituted triazolidine pyridine amide compound having the structure shown in Formula I:

[0054]

[0055] In this invention, X in Formula I includes oxygen or sulfur.

[0056] In this invention, in Formula I, R1 includes hydrogen, C1-C6 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heterocyclic group; when R1 is not hydrogen, * indicates a chiral center; the stereoconfiguration of the carbon chiral center of R1 is R-type or S-type. In this invention, the C1-C6 alkyl preferably includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0057] In this invention, the substituents in the substituted phenyl group preferably include phenyl, halogen, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamine, or C1-C6 haloalkyl. In this invention, the C1-C6 alkoxy group preferably includes -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -O(CH2)3CH3, -OCH2CH(CH3)2, -OCHCH3CH2CH3, -O(CH3)3, -O(CH2)4CH3, -OCH(CH3)CH2CH2CH3, -OCH2CH(CH3)CH2CH3, -OCH2CH2CH(CH3)2, -OCH(CH3)2CH2CH3, or -OCH2C(CH3)3; the C1-C6 alkylamine group preferably includes -NHCH3, -NHC H2CH3, -NH(CH2)2CH3, -NHCH(CH3)2, -NH(CH2)3CH3, -NHCH2CH(CH3)2, -NHCH(CH3)CH2CH3, -NH(CH3)3, -NH(CH2)4CH3, -NHCH(CH3)CH2CH2CH3, -NHCH2CH(CH3)CH2CH3, -NHCH2CH2CH(CH3)2, -NHC(CH3)2CH2CH3 or -NHCH2C(CH3)3; the C1 to C6 haloalkyl group preferably includes -CF2H or -CF3; the halogen preferably includes fluorine, chlorine, bromine or iodine.

[0058] In this invention, the substituents in the substituted heterocyclic group preferably include heterocyclic substituents, halogens, hydroxyl groups, amino groups, C1-C6 alkoxy groups, or C1-C6 alkylamine groups. In this invention, the heterocyclic substituents preferably include pyridinyl, thiophene, or furanyl groups; the heterocyclic groups in the unsubstituted or substituted heterocyclic groups preferably include pyridinyl, thiophene, or furanyl groups. In this invention, the optional substituent types for the halogen, C1-C6 alkoxy, and C1-C6 alkylamine groups are preferably the same as those for the aforementioned optional substituent types for the halogen, C1-C6 alkoxy, and C1-C6 alkylamine groups, and will not be described in detail here.

[0059] In this invention, in Formula I, R2 includes hydrogen, C1-C6 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heterocyclic group; when R2 is not hydrogen, * indicates a chiral center; the stereoconfiguration of the carbon chiral center of R2 is R-type or S-type.

[0060] In this invention, the optional substituents of the C1-C6 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heterocyclic groups are preferably the same as those of the aforementioned C1-C6 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted heterocyclic groups, and will not be described in detail here.

[0061] In this invention, in Formula I, R3 includes hydrogen, C1-C6 alkyl, halogen, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamine, or C1-C6 haloalkyl; the number of R3 is 1 to 3, specifically 1, 2, or 3. In this invention, the optional substituents of the C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkylamine, and C1-C6 haloalkyl are preferably the same as those of the aforementioned optional substituents of the C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkylamine, and C1-C6 haloalkyl, and will not be described in detail here.

[0062] In this invention, in Formula I, R4 includes hydrogen, halogen, C1-C6 alkyl, cyclohexyl, unsubstituted or substituted aryl, phenoxy, C1-C6 haloalkyl, alkylcarbonyl, or C1-C6 alkoxy. In this invention, the alkyl carbonyl preferably includes methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl, n-butyl carbonyl, sec-butyl carbonyl, tert-butyl carbonyl, or benzyl carbonyl; the substituents in the substituted aryl preferably include halogen, trifluoromethyl, C1-C6 alkyloxy, C1-C6 alkyl, or C1-C6 alkylamino, more preferably halogen, trifluoromethyl, methyl, methoxy, ethoxy, methylamino, or ethylamino; the C1-C6 alkoxy preferably includes methoxy, ethoxy, isopropoxy, or cyclopropyloxy; the aryl in the unsubstituted or substituted aryl preferably includes phenyl. In this invention, the optional substituent types of the halogen, C1-C6 alkyl and C1-C6 haloalkyl are preferably the same as the optional substituent types of the aforementioned halogen, C1-C6 alkyl and C1-C6 haloalkyl, and will not be described in detail here.

[0063] In this invention, in Formula I, R5 comprises unsubstituted or substituted cyclohexyl, unsubstituted or substituted cyclopentyl. In this invention, the substituents in the substituted cyclohexyl and the substituted cyclopentyl preferably independently comprise C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamine, C1-C3 haloalkyl, or halogen. In this invention, the C1-C3 alkyl preferably comprises methyl or ethyl; the C1-C3 alkoxy preferably comprises methoxy, ethoxy, isopropoxy, or cyclopropoxy; the C1-C3 alkylamine preferably comprises methylamino, ethylamino, isopropylamino, or cyclopropylamino; the C1-C3 haloalkyl preferably comprises chloromethyl, dichloromethyl, difluoromethyl, or trifluoromethyl; and the halogen preferably comprises fluorine, chlorine, bromine, or iodine.

[0064] In this invention, the cycloalkyl-substituted triazolidine pyridine amide compounds preferably have the structure shown in Formula I-1 or Formula I-2:

[0065]

[0066] This invention provides a method for preparing the cycloalkyl-substituted triazolidine pyridine amide compounds described above, comprising the following steps:

[0067] Compound II, Compound III, condensing agent, triethylamine and organic solvent are mixed and subjected to condensation reaction to obtain the cycloalkyl-substituted triazolidine pyridine amide compound;

[0068]

[0069] Where R1 to R5 are the same as in Formula I.

[0070] Unless otherwise specified, all raw materials used in this invention are commercially available products well known to those skilled in the art.

[0071] In this invention, compound II preferably includes compound II-1 or compound II-2;

[0072]

[0073] In this invention, the preparation route of compound II is shown in route 1:

[0074]

[0075] Where R1 to R3 are the same as in Equation I.

[0076] In this invention, the preparation method of compound II-1 preferably includes the following steps: mixing compound 1, compound 2, catalyst and benzene solvent, and carrying out Witte seeliger cyclization reaction to obtain compound II-1;

[0077]

[0078] Where R1 to R3 are the same as in Equation I.

[0079] In this invention, the molar ratio of compound 1 (o-aminobenzonitrile) to compound 2 (chiral amino alcohol) is preferably 1:1 to 1.5, more preferably 1:1.1 to 1.4, and most preferably 1:1.2 to 1.3. In this invention, the catalyst preferably comprises a zinc salt, which preferably comprises one or more of zinc chloride, zinc fluoride, zinc bromide, and zinc acetate; more preferably anhydrous zinc chloride. In this invention, the molar ratio of compound 1 to the catalyst is preferably 1:0.5 to 3, more preferably 1:1 to 2.5, and most preferably 1:1.5 to 2. In this invention, the benzene solvent preferably comprises one or more of chlorobenzene, toluene, xylene, fluorobenzene, and bromobenzene; the benzene solvent is preferably anhydrous benzene solvent. This invention does not have a special limitation on the amount of benzene solvent used, as long as it allows the Witte seeliger cyclization reaction to proceed smoothly. This invention does not have a special limitation on the mixing method, as long as the raw materials are mixed evenly, specifically, stirring. In this invention, the temperature of the Witteseeliger cyclization reaction is preferably 100-150°C, more preferably 110-140°C, and most preferably 120-130°C; the time of the Witteseeliger cyclization reaction is preferably 12-96 h, more preferably 20-80 h, and most preferably 30-50 h.

[0080] After completing the Witte seeliger cyclization reaction, the present invention preferably further includes concentrating the cyclized feed solution obtained from the Witte seeliger cyclization reaction, adding a quencher to quench the reaction, extracting with an extractant, drying and purifying the extracted organic phase to obtain compound II-1. The present invention does not have a specific limitation on the concentration method; any concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention does not have a specific limitation on the vacuum distillation method, as long as the solvent can be removed. In the present invention, the quencher preferably comprises an aqueous hydroxide solution; the hydroxide in the aqueous hydroxide solution preferably comprises sodium hydroxide and / or ammonium hydroxide; the mass concentration of the hydroxide in the aqueous hydroxide solution is preferably 0-35%, more preferably 10-20%, and most preferably 15-18%; the molar ratio of compound II-1 to the volume of the quencher is preferably 1 mmol: 0.2-1 mL, more preferably 1 mmol: 0.5-0.8 mL, and most preferably 1 mmol: 0.6-0.7 mL. In this invention, the extractant preferably includes ethyl acetate or dichloromethane; the ratio of the amount of compound 1 to the volume of the extractant is preferably 1 mmol: 5-15 mL, more preferably 1 mmol: 8-12 mL, and most preferably 1 mmol: 9-10 mL.

[0081] In this invention, the drying agent preferably includes anhydrous sodium sulfate. The amount of the drying agent is not particularly limited, as long as it is sufficient to completely dry the water in the organic phase. In this invention, the purification preferably includes column chromatography; the column packing material used for the column chromatography preferably includes silica gel (i.e., silica packing); the eluent used for the column chromatography preferably includes an ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; during the gradient elution process, the volume ratio of petroleum ether to ethyl acetate in the ethyl acetate-petroleum ether mixed solvent is preferably 1:1 to 1.5, more preferably 1:1.1 to 1.4, and even more preferably 1:1.2 to 1.3. In specific embodiments of this invention, the volume ratios of petroleum ether to ethyl acetate in the ethyl acetate-petroleum ether mixed solvent are successively 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, and 1:1.5.

[0082] In this invention, the preparation method of compound II-2 preferably includes method one or method two, wherein:

[0083] Method 1: Mix the compound II-1, phosphorus pentasulfide, and a benzene solvent to carry out a displacement reaction to obtain compound II-2;

[0084] Method 2: Compound 7, Compound 2 and a cyclic solvent were mixed and subjected to a decarboxylation and amidation reaction to obtain Compound 8;

[0085] Compound 8, phosphorus pentasulfide, and a heterocyclic solvent were mixed and subjected to a cyclization reaction to obtain compound II-2.

[0086]

[0087] Method 1: In this invention, compound II-1, phosphorus pentasulfide, and a benzene solvent are mixed and subjected to a displacement reaction to obtain compound II-2.

[0088] In this invention, the molar ratio of compound II-1 to phosphorus pentasulfide is preferably 1:1.5-3, more preferably 1:2-2.5, and most preferably 1:2.2-2.4. In this invention, the benzene solvent preferably includes one or more of toluene and xylene; the benzene solvent is preferably anhydrous benzene solvent; the amount of benzene solvent used is not particularly limited, as long as it allows the displacement reaction to proceed smoothly. The mixing process is not particularly limited, as long as the raw materials are mixed evenly, such as by stirring. In this invention, the temperature of the displacement reaction is preferably 90-110℃, more preferably 95-105℃, and most preferably 100℃; the time of the displacement reaction is preferably 6-72 h, more preferably 20-60 h, and most preferably 30-50 h.

[0089] After the displacement reaction is completed, the present invention preferably further includes cooling the displacement reaction solution obtained from the displacement reaction to room temperature, adding a quencher to quench the reaction, performing solid-liquid separation, separating the resulting liquid components into phases, drying the resulting organic phase with a desiccant, concentrating and purifying it to obtain compound II-2. The present invention does not have a specific limitation on the cooling process; any cooling method well known to those skilled in the art can be used, such as natural cooling. In the present invention, the quencher preferably includes an alkaline aqueous solution, more preferably one or more of NaOH aqueous solution, NaHCO3 aqueous solution, and Na2CO3 aqueous solution. The mass concentration of the alkaline aqueous solution is preferably 10-50%, more preferably 15-40%, and most preferably 20-30%. The molar ratio of compound II-1 to the volume of the quencher is preferably 1 mmol: 0.4-1 mL, more preferably 1 mmol: 0.5-0.8 mL, and most preferably 1 mmol: 0.6-0.7 mL. The present invention does not have a specific limitation on the solid-liquid separation process; any solid-liquid separation method well known to those skilled in the art can be used, such as centrifugation, filtration, or vacuum filtration. In this invention, the phase separation preferably includes phase separation using a separatory funnel. In this invention, the desiccant preferably includes anhydrous sodium sulfate. This invention does not have a particular limitation on the amount of the desiccant used, as long as it is sufficient to completely dry the water in the organic phase. This invention does not have a particular limitation on the concentration; a concentration method well known to those skilled in the art can be used, such as vacuum distillation. This invention does not have a particular limitation on the conditions of the vacuum distillation, as long as the solvent is removed. In this invention, the purification preferably includes column chromatography; the column packing material used for the column chromatography preferably includes silica gel; the eluent used for the column chromatography preferably includes an ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; during the gradient elution process, the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:1 to 15, more preferably 1:5 to 12, and most preferably 1:8 to 10.

[0090] Method 2: In this invention, compound 7 (indorubicin anhydride), compound 2 and a cyclic solvent are mixed and subjected to a decarboxylation and amidation reaction to obtain compound 8.

[0091] In this invention, the molar ratio of compound 7 to compound 2 is preferably 1:1 to 1.5, more preferably 1:1.1 to 1.4, and most preferably 1:1.2 to 1.3. In this invention, the cyclic solvent preferably includes 1,4-dioxane; the amount of the cyclic solvent is not particularly limited, as long as it allows the decarboxylation amidation reaction to proceed smoothly. The mixing process is not particularly limited, as long as the raw materials are mixed evenly, specifically by stirring. In this invention, the temperature of the decarboxylation amidation reaction is preferably 40 to 150°C, more preferably 50 to 100°C, and most preferably 60 to 80°C; the time of the decarboxylation amidation reaction is preferably 12 to 18 hours, more preferably 14 to 17 hours, and most preferably 15 to 16 hours; the decarboxylation amidation reaction is preferably carried out under reflux conditions.

[0092] After completing the decarboxylation and amidation reaction, the present invention preferably further includes concentrating the amidation reaction solution obtained from the decarboxylation and amidation reaction, adding a quencher to quench the reaction, extracting with an extractant, drying and purifying the extracted organic phase to obtain compound 8. The present invention does not have a specific limitation on the concentration; any concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention does not have a specific limitation on the vacuum distillation, as long as the solvent can be removed. In the present invention, the quencher preferably includes an aqueous solution of hydroxide; the hydroxide in the aqueous solution preferably includes sodium hydroxide and / or ammonium hydroxide; the mass concentration of hydroxide in the aqueous solution is preferably 0-35%, more preferably 10-20%, and most preferably 15-18%; the molar ratio of compound 7 to the volume of the quencher is preferably 1 mmol: 5-10 mL, more preferably 1 mmol: 6-9 mL, and most preferably 1 mmol: 7-8 mL. In the present invention, the extractant preferably includes ethyl acetate or dichloromethane. In the present invention, the drying agent preferably includes anhydrous sodium sulfate. The present invention does not have a particular limitation on the amount of the desiccant used, as long as it is sufficient to completely dry the water in the organic phase. In the present invention, the purification preferably includes column chromatography; the column packing material used for the column chromatography is preferably silica gel; the eluent used for the column chromatography is preferably a dichloromethane-methanol mixed solvent; the elution method is preferably gradient elution; during the gradient elution process, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is preferably 20:0.5-5, more preferably 20:0.8-3, and most preferably 20:1-2.

[0093] After obtaining compound 8, the present invention mixes compound 8, phosphorus pentasulfide and a heterocyclic solvent to carry out a cyclization reaction to obtain compound II-2.

[0094] In this invention, the molar ratio of compound 8 to phosphorus pentasulfide is preferably 1:1.5-3, more preferably 1:2-2.5, and most preferably 1:2.2-2.4. In this invention, the heterocyclic solvent preferably includes pyridine; the heterocyclic solvent is preferably anhydrous heterocyclic solvent; the amount of the heterocyclic solvent used is not particularly limited, as long as it allows the cyclization reaction to proceed smoothly. The mixing process is not particularly limited, as long as the raw materials are mixed evenly, such as by stirring. In this invention, the temperature of the cyclization reaction is preferably 90-110°C, more preferably 95-105°C, and most preferably 100°C; the time of the cyclization reaction is preferably 4-24 h, more preferably 8-20 h, and most preferably 12-16 h.

[0095] After the cyclization reaction is completed, the present invention preferably further includes cooling the cyclization reaction solution obtained from the cyclization reaction to room temperature, adding a quencher to quench the reaction, performing solid-liquid separation, separating the resulting liquid components into phases, drying the resulting organic phase with a desiccant, concentrating and purifying it to obtain compound II-2. The present invention does not have a specific limitation on the cooling process; any cooling method well known to those skilled in the art can be used, such as natural cooling. In the present invention, the quencher preferably includes an acidic aqueous solution, more preferably one or more of hydrochloric acid aqueous solutions, and the mass concentration of the acidic aqueous solution is preferably 5-25%, more preferably 10-22%, and most preferably 15-20%; the ratio of the amount of compound 8 to the volume of the quencher is preferably 1 mmol: 5-10 mL, more preferably 1 mmol: 6-9 mL, and most preferably 1 mmol: 7-8 mL. The present invention does not have a specific limitation on the solid-liquid separation process; any solid-liquid separation method well known to those skilled in the art can be used, such as centrifugation, filtration, or vacuum filtration. In the present invention, the phase separation preferably includes phase separation using a separatory funnel. In the present invention, the desiccant preferably includes anhydrous sodium sulfate. This invention does not impose a specific limit on the amount of the desiccant used, as long as it is sufficient to completely dry the water in the organic phase. This invention also does not impose a specific limit on the concentration method; any concentration method well-known to those skilled in the art can be used, such as vacuum distillation. Furthermore, this invention does not impose a specific limit on the conditions of the vacuum distillation, as long as the solvent is removed. In this invention, the purification preferably includes column chromatography; the column packing material used for the column chromatography is preferably silica gel; the eluent used for the column chromatography is preferably an ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; during the gradient elution process, the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:1 to 15, more preferably 1:5 to 12, and most preferably 1:8 to 10.

[0096] In this invention, the preparation method of compound III preferably includes the following steps: mixing compound 3, hydrazine hydrate and a heterocyclic solvent to carry out a substitution reaction to obtain compound 4;

[0097]

[0098] Compound 4, compound 5, oxidant and organic solvent were mixed and subjected to a condensation oxidation reaction to obtain compound 6;

[0099]

[0100] Compound 6, lithium hydroxide, and an organic solvent are mixed and hydrolyzed to obtain compound III; wherein R4 and R5 are the same as those in formula I.

[0101] In this invention, the preparation route of compound III is shown in route 2.

[0102]

[0103] Route 2

[0104] In this invention, compound 3 (ethyl nicotinate), hydrazine hydrate, and a heterocyclic solvent are mixed to carry out a substitution reaction to obtain compound 4.

[0105] In this invention, the mass concentration of the hydrazine hydrate is preferably 40-81%, more preferably 50-81%, and most preferably 70-81%; the molar ratio of compound 3 to hydrazine hydrate is preferably 1:1-5, more preferably 1:2-4, and most preferably 1:3-4. In this invention, the heterocyclic solvent preferably includes dioxane and / or tetrahydrofuran; the amount of the heterocyclic solvent is not particularly limited, as long as it allows the substitution reaction to proceed smoothly. The mixing is not particularly limited, as long as the raw materials are mixed evenly, such as by stirring. In this invention, the temperature of the substitution reaction is preferably 20-100℃, more preferably 30-80℃, and most preferably 50-60℃; the time of the substitution reaction is preferably 2-40 h, more preferably 5-30 h, and most preferably 10-20 h.

[0106] After the substitution reaction is completed, the present invention preferably further cools the substitution reaction solution obtained from the substitution reaction to room temperature, concentrates and purifies it to obtain compound 4. The present invention does not have a specific limitation on the cooling process; any cooling method well known to those skilled in the art can be used, such as natural cooling. The present invention also does not have a specific limitation on the concentration process; any concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention does not have a specific limitation on the vacuum distillation process, as long as the solvent can be removed. In the present invention, the purification preferably includes column chromatography; the column packing material used for the column chromatography preferably includes silica gel for column chromatography; the eluent used for the column chromatography preferably includes an ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; during the gradient elution process, the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:0.5–5, more preferably 1:1.5–4, and most preferably 1:2.5–3.

[0107] After obtaining compound 4, the present invention mixes compound 4, compound 5, oxidant and organic solvent, and carries out a condensation oxidation reaction to obtain compound 6.

[0108] In this invention, the molar ratio of compound 4 to compound 5 is preferably 1:1 to 1.2, more preferably 1:1.05 to 1.15, and most preferably 1:1.1 to 1.12. In this invention, the oxidant preferably includes iodophenyl diacetic acid (PIDA), iodophenyl ditrifluoroacetic acid, manganese dioxide, or potassium permanganate; the organic solvent preferably includes one or more of alcohol solvents, heterocyclic solvents, and benzene solvents, more preferably one or more of ethanol, methanol, tetrahydrofuran, and dioxane; the organic solvent is preferably an anhydrous organic solvent; this invention does not have a special limitation on the amount of the organic solvent used, as long as it allows the condensation oxidation reaction to proceed smoothly.

[0109] In this invention, the preferred method of mixing compound 4, compound 5, oxidant, and organic solvent to carry out a condensation oxidation reaction includes: mixing compound 4, compound 5, and organic solvent to carry out a condensation reaction to obtain a condensation product; and mixing the condensation product, a dichloroalkane solvent, and an oxidant to carry out an oxidation reaction to obtain compound 6.

[0110] In this invention, the dichloroalkane solvent preferably includes dichloromethane and / or dichloroethane; the temperature of the condensation reaction is preferably 60-70°C, more preferably 62-68°C, and most preferably 64-65°C; the time of the condensation reaction is preferably 1-6 hours, more preferably 2-5 hours, and most preferably 3-4 hours.

[0111] After the condensation reaction is completed, the present invention preferably further includes concentrating the condensation reaction solution obtained from the condensation reaction to obtain the condensation product. The present invention does not have any particular limitation on the concentration method; any concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention does not have any particular limitation on the vacuum distillation method, as long as it can remove the solvent.

[0112] After obtaining the condensation product, the present invention mixes the condensation product, dichloromethane and iodophenyl diacetic acid oxidant, and carries out an oxidation reaction to obtain compound 6.

[0113] In the oxidation reaction process, the present invention preferably further includes thin-layer chromatography (TLC) detection until the condensation product reacts completely. In the present invention, the eluent used for the TLC detection preferably includes an ethyl acetate-petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent during elution is preferably 1:0.1–10, more preferably 1:1–8, and most preferably 1:2–5. In the present invention, the temperature of the oxidation reaction is preferably room temperature, more preferably 15–40°C, and most preferably 25–30°C. The present invention does not have a particular limitation on the time of the oxidation reaction, as long as the condensation product reacts completely. In the present invention, compounds 4 and 5 are first mixed with an organic solvent for dehydration condensation cyclization, and then mixed with an oxidant for dehydrogenation oxidation to obtain compound 6.

[0114] After the oxidation reaction is completed, the present invention preferably further includes adding a saturated sodium bicarbonate solution to the oxidation reaction solution obtained from the oxidation reaction to quench the reaction, performing organic solvent extraction and phase separation, drying the obtained organic phase with a desiccant, concentrating and purifying it to obtain compound 6. In the present invention, the organic solvent used for extraction preferably includes dichloromethane. In the present invention, the phase separation preferably includes phase separation using a separatory funnel. In the present invention, the desiccant preferably includes anhydrous sodium sulfate. In the present invention, the column chromatography separation preferably uses a silica column for gradient elution; the eluent used for the column chromatography separation preferably includes an ethyl acetate-petroleum ether mixed solvent, wherein the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:1 to 2, more preferably 1:1.2 to 1.8, and most preferably 1:1.4 to 1.6.

[0115] After obtaining compound 6, the present invention mixes compound 6, lithium hydroxide and organic solvent, and performs a hydrolysis reaction to obtain compound III.

[0116] In this invention, the molar ratio of compound 6 to lithium hydroxide is preferably 1:1 to 10, more preferably 1:2 to 8, and most preferably 1:3 to 5. In this invention, the organic solvent is preferably methanol and / or tetrahydrofuran; the amount of organic solvent used is not particularly limited, as long as it allows the hydrolysis reaction to proceed smoothly. The mixing process is not particularly limited, as long as the raw materials are mixed evenly, such as by stirring. In this invention, the temperature of the hydrolysis reaction is preferably 0 to 80°C, more preferably 10 to 60°C, and most preferably 20 to 40°C; the time of the hydrolysis reaction is preferably 6 to 72 hours, more preferably 10 to 60 hours, and most preferably 30 to 50 hours.

[0117] After the hydrolysis reaction is completed, the present invention preferably further includes concentrating the hydrolysis reaction solution obtained after the hydrolysis reaction, adding water, adjusting the pH value to 5-8, and performing solid-liquid separation to obtain compound III. The present invention does not have a specific limitation on the concentration method; any concentration method well known to those skilled in the art can be used, such as vacuum distillation. The present invention does not have a specific limitation on the vacuum distillation method; any method capable of removing the solvent is acceptable. In the present invention, the pH adjusting agent preferably includes sulfuric acid, hydrochloric acid, acetic acid, or malic acid. The present invention does not have a specific limitation on the solid-liquid separation method; any solid-liquid separation method well known to those skilled in the art can be used, such as centrifugation, filtration, or vacuum filtration.

[0118] After obtaining compounds II and III, the present invention mixes compounds II and III, neutralizing reagent, condensing agent and organic solvent, and carries out condensation reaction to obtain the cycloalkyl-substituted triazolidine pyridine amide compounds.

[0119] In this invention, the condensing agent preferably comprises one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), and O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU). In this invention, the molar ratio of compound III to compound II is preferably 1:0.8–2, more preferably 1:0.8–1.2, and most preferably 1:0.9–1. In this invention, the molar ratio of compound III to the condensing agent is preferably 1:1.1–3, more preferably 1:1.5–2.5, and most preferably 1:1.8–2.

[0120] In this invention, the neutralizing agent preferably includes triethylamine; the molar ratio of compound III to the neutralizing agent is preferably 1:1.3-2, more preferably 1:1.4-1.8, and most preferably 1:1.5-1.6. In this invention, the organic solvent preferably includes heterocyclic solvents and / or substituted benzene solvents, more preferably one or more of dichloromethane, tetrahydrofuran, dioxane, toluene, and chlorobenzene; the organic solvent is preferably an anhydrous solvent; this invention does not have a particular limitation on the amount of the organic solvent used, as long as it allows the condensation reaction to proceed smoothly. In a specific embodiment of this invention, the mixing is preferably performed by dissolving compound III in an organic solvent, adding the condensing agent under ice bath (0°C) conditions, mixing for 12-96 hours (more preferably 20-80 hours, and most preferably 30-60 hours), and then adding the neutralizing agent and compound II and mixing. In this invention, the temperature of the condensation reaction is preferably 0-40°C, more preferably 10-30°C, and even more preferably 20-25°C; the time of the condensation reaction is preferably 12-96h, more preferably 20-80h, and most preferably 30-60h.

[0121] After the condensation reaction is completed, the present invention preferably further includes adding a quencher to the condensation reaction solution obtained from the condensation reaction to quench the reaction, washing with water, concentrating and purifying to obtain the cycloalkyl-substituted triazolidine pyridine amide compound. In the present invention, the quencher preferably includes an alkaline aqueous solution, more preferably one or more of NH4Cl aqueous solution, NaHCO3 aqueous solution and Na2CO3 aqueous solution, the mass concentration of the alkaline aqueous solution is preferably 10-50%, more preferably 20-40%; the molar ratio of compound III to the volume of the quencher is preferably 1 mmol: 2-10 mL, more preferably 1 mmol: 5-8 mL. The present invention does not have a special limitation on the water washing, washing until neutral is sufficient. The present invention does not have a special limitation on the concentration, concentration methods well known to those skilled in the art can be used, such as vacuum distillation; the present invention does not have a special limitation on the vacuum distillation, as long as the solvent can be removed. In this invention, the purification preferably includes column chromatography; the column packing material used in the column chromatography is preferably silica gel; the eluent used in the column chromatography is preferably an ethyl acetate-petroleum ether mixed solvent; the elution method is preferably gradient elution; during the gradient elution process, the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:1 to 15, more preferably 1:5 to 12, and most preferably 1:8 to 10.

[0122] This invention provides derivatives of the cycloalkyl-substituted triazolidine pyridine amide compounds described above, wherein the derivatives include pesticide-chemically acceptable salts. In this invention, the pesticide-chemically acceptable salts preferably include one or more of sodium salts, potassium salts, phosphates, hydrochlorides, sulfates, oxalates, citrates, succinates, malates, maleates, salicylates, and sulfonates.

[0123] This invention provides the application of the cycloalkyl-substituted triazolidine pyridine amide compounds or derivatives thereof described in the above-mentioned technical solutions in the preparation of drugs against plant pathogenic fungi. In this invention, the plant pathogenic fungi preferably include one or more of the following: *Rhizoctonia solani* (rice sheath blight), *Rhizoctonia cerealis* (wheat sheath blight), *Sclerotinias cleotiorum* (rapeseed sclerotium rot), *Fusarium graminearum* (wheat scab), *Gaeumanomycegraminis* (wheat take-all rot), *Botrytis cinerea* (tomato gray mold), *Phytophthora infestans* (potato late blight), *Phytophthora capsici* (pepper phytosis), *Alternaria solani* (tomato early blight), *Fusarium fujikuroi* (rice bakanae disease), *Fusarium sulphureum* (potato dry rot), *Colletotrichum lagenarium* (cucumber anthracnose), and *Pyricularia oryzac* (rice blast). This invention provides cycloalkyl-substituted triazolidine pyridine amides with unsubstituted or substituted cyclohexyl groups and unsubstituted or substituted cyclopentyl groups introduced onto the triazole ring. These compounds exhibit excellent inhibitory activity against *Phytophthora capsici*, a major oomycete disease, with an EC50 (intermediate inhibitory concentration) as low as 0.3 μmol / L. Furthermore, the cycloalkyl-substituted triazolidine pyridine amides and their derivatives provided by this invention possess broad-spectrum antifungal activity against *Rhizoctonia solani*, *Rhizoctonia solani*, *Sclerotinia sclerotiorum*, *Fusarium graminearum*, *Tricholoma materia rubra*, *Botrytis cinerea*, *Phytophthora capsici*, *Phytophthora capsici*, *Phytophthora blight*, *Phytophthora jasminoides ...

[0124] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0125] Example 1

[0126] Synthesis of Z46, a cycloalkyl-substituted triazolidinepyridine amide compound

[0127]

[0128] (R)-2-amino-1-butanol (10 mmol) was added to a stirred solution of indomethacin (10 mmol) and 1,4-dioxane, and the mixture was refluxed for 16 h until the starting material was completely consumed by TLC. The mixture was cooled to room temperature, diluted with 30 mL of ice water, and extracted three times with ethyl acetate (each extraction volume was 15 mL, recorded as 15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (200–300 mesh, petroleum ether:ethyl acetate volume ratio = 20:1) to give intermediate B1, a white solid, 1265 mg, with a yield of 61%.

[0129]

[0130] In a stirred solution of ethyl 2-chloronicotinate (50 mmol) and 1,4-dioxane, hydrazine hydrate (60 mmol) was added. The mixture was refluxed for 18 h until the starting material was completely consumed as monitored by TLC. The mixture was then cooled to room temperature, concentrated under vacuum, and separated by silica gel column chromatography (200–300 mesh, petroleum ether:ethyl acetate volume ratio = 1:2) to give ethyl 2-hydrazinotinate 4-A, a yellow filamentous solid, 7241 mg, in a yield of 41%.

[0131] To a clean, dry round-bottom flask, 10 mmol of 2-hydrazinoic acid ethyl ester 4-A and 11 mmol of cyclohexylformaldehyde were added sequentially, followed by dissolution in 50 mL of methanol. The mixture was stirred at 65 °C for 2 hours until the starting material was completely consumed, as monitored by TLC. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in 20 mL of anhydrous dichloromethane, and 13 mmol of iodophenyldiacetic acid (PIDA) was slowly added. The reaction was stirred at room temperature until the starting material was completely reacted, as monitored by TLC. The mixture was quenched with 20 mL of saturated sodium bicarbonate solution, and the aqueous phase was extracted three times with anhydrous dichloromethane (each extraction using 10 mL, recorded as 10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (200–300 mesh, petroleum ether:ethyl acetate volume ratio = 1:1) to give the intermediate triazolidine pyridine carboxylate 6-A, a yellow solid, 1146 mg, in a yield of 42%.

[0132] Lithium hydroxide (2.0 mmol) was added to a tetrahydrofuran solution of triazolidine pyridine carboxylate 6-A (1.0 mmol). The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and dissolved in water. The mixture was adjusted to pH 2 with hydrochloric acid to give intermediate pZ46, a yellow solid, 214 mg, in 87% yield.

[0133] Add triazolidinepyridinecarboxylic acid pZ46 (0.5 mmol) and intermediate B1 (0.5 mmol) sequentially to a clean, dry round-bottom flask, and dissolve in 10.0 mL of anhydrous dichloromethane. Add HATU (1.3 mmol) and triethylamine (0.8 mmol) under ice bath conditions, allow the system to return to room temperature, and stir at room temperature until the reactants are completely consumed as monitored by TLC. Wash the mixture twice with sodium bicarbonate solution (each wash using 10 mL, recorded as 10.0 mL × 2), dry to anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Separation was performed by silica gel column chromatography (200-300 mesh, petroleum ether:ethyl acetate volume ratio = 2:1) to obtain the target compound 3-cyclohexyl-N-(2-(4-ethyl-4,5-dihydrothiazol-2-yl))phenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Z46), a white solid in 55% yield.

[0134] The proton and carbon spectra of the cycloalkyl-substituted triazolidinepyridine amide compound Z46 are as follows:

[0135] 1H NMR(400MHz,Chloroform-d)δ13.04(s,1H),8.76-8.68(m,1H),8.09(dd,J=15.1,6.8Hz,2H), 7.65(dd,J=7.8,1.5Hz,1H),7.47(dd,J=8.6,7.4,1.6Hz,1H),7.20-7.12(m,1H),6.97(t,J=6 .9Hz,1H),4.75(m,J=8.5,6.7Hz,1H),3.47(dd,J=10.7,8.4Hz,1H),3.13-2.96(m,2H),2.15- 1.78(m,8H),1.77-1.67(m,1H),1.63-1.55(m,1H),1.53-1.39(m,3H),0.71(t,J=7.4Hz,3H);

[0136] 13 C NMR(101MHz,Chloroform-d)δ166.1,161.4,150.9,147.1,137.4,131.2,131.0,129.9,124 .5,123.8,123.3,122.3,113.2,79.8,37.1,34.7,30.6,30.5,28.0,25.9,25.8,24.9,10.7.

[0137] Example 2

[0138] Synthesis of Z47, a cycloalkyl-substituted triazolidinepyridine amide compound

[0139]

[0140] In a stirred solution of ethyl 2-chloronicotinate (50 mmol) and 1,4-dioxane, hydrazine hydrate (60 mmol) was added. The mixture was refluxed for 18 h until the starting material was completely consumed as monitored by TLC. The mixture was then cooled to room temperature, concentrated under vacuum, and separated by silica gel column chromatography (200–300 mesh, petroleum ether:ethyl acetate volume ratio = 1:2) to give ethyl 2-hydrazinotinate 4-A, a yellow filamentous solid, 7241 mg, in a yield of 41%.

[0141] To a clean, dry round-bottom flask, ethyl 2-hydrazinoic acid ester 4-A (10 mmol) and cyclopentylformaldehyde (11 mmol) were added sequentially, followed by dissolution in 50 mL of methanol. The mixture was stirred at 65 °C for 2 hours until the starting material was completely consumed as monitored by TLC. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in 20 mL of anhydrous dichloromethane, followed by slow addition of iodophenyl diacetic acid (PIDA, 13 mmol). The reaction was stirred at room temperature until the starting material was completely reacted as monitored by TLC. The mixture was quenched with 20 mL of saturated sodium bicarbonate solution, and the aqueous phase was extracted three times with anhydrous dichloromethane (each extraction using 10 mL, recorded as 10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (200–300 mesh, petroleum ether:ethyl acetate volume ratio = 1:1) to give the intermediate triazolidine pyridine carboxylate 6-B, a yellow solid, 1632 mg, in a yield of 63%.

[0142] Lithium hydroxide (2.0 mmol) was added to a tetrahydrofuran solution of triazolidine pyridine carboxylate 6-B (1.0 mmol). The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and dissolved in water. The mixture was adjusted to pH 2 with hydrochloric acid to give intermediate pZ47, a yellow solid, 183 mg, in a yield of 79%.

[0143] Triazolidinediolic acid pZ47 (0.5 mmol) and intermediate B1 (0.5 mmol) were added sequentially to a clean, dry round-bottom flask, followed by dissolution in 10.0 mL of anhydrous dichloromethane. HATU (1.3 mmol) and triethylamine (0.8 mmol) were added under ice-bath conditions, and the system was allowed to return to room temperature. The mixture was stirred at room temperature until TLC monitoring showed complete consumption of the starting materials. The mixture was washed twice with sodium bicarbonate solution (each wash using 10 mL, recorded as 10.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Separation was performed by silica gel column chromatography (200-300 mesh, petroleum ether: ethyl acetate volume ratio = 2:1) to obtain the target compound 3-cyclopentyl-N-(2-(4-ethyl-4,5-dihydrothiazol-2-yl))phenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (Z47), a yellow solid in 42% yield.

[0144] The 1H NMR spectrum of cycloalkyl-substituted triazolidinepyridine amide compound Z47 is as follows:

[0145] 1HNMR(500MHz,Chloroform-d)δ9.86(s,1H),8.56(dd,J=9.3,1.3Hz,1H),8.11(dd,J=8.2,1.3 Hz,1H),7.96(dd,J=8.0,1.4Hz,1H),7.59(dd,J=7.1,1.7Hz,1H),7.55(m,J=7.9,1.7Hz,1H), 7.41(dd,J=9.4,8.3Hz,1H),7.24(m,J=8.2,7.1,1.4Hz,1H),4.26-4.17(m,1H),3.29-3.18(m ,2H),2.87(p,J=4.5Hz,1H),2.07-1.96(m,2H),1.87-1.63(m,6H),1.02(t,J=7.2,1.5Hz,3H).

[0146] Comparative Example 1

[0147] The triazolidine pyridine amide compound, cytosyl amide, has the following structural formula.

[0148]

[0149] Test case

[0150] Antibacterial activity assay of cycloalkyl-substituted triazolidine pyridine amides

[0151] The in vitro antibacterial activity was evaluated using the mycelial growth rate inhibition method. Test strains, including *Rhizoctonia solani* (rice sheath blight), *Sclerotinia sclerotiorum* (rapeseed sclerotiorum), *Botrytis cinerea* (tomato gray mold), and *Phytophthora capsici* (pepper phytodes), were activated on PDA plates. Cycloalkyl-substituted triazolidine pyridine amides were prepared into a series of gradient concentrations (30 μmol / L, 10 μmol / L, 3.3 μmol / L, 1.1 μmol / L, 0.37 μmol / L, 0.12 μmol / L, and 0.04 μmol / L) on PDA plates. Test strains were prepared into 5 mm diameter mycelial discs and placed in the center of the drug-containing plates. The plates were incubated at 25°C until the test strains in the blank control plates reached near the edge of the plates. The colony diameter on each drug-containing plate was measured using the cross-crossing method. The inhibition rate of the compounds on mycelial growth was calculated, and the inhibition rate on diseases was calculated according to Formula I.

[0152] Disease inhibition rate (%) = (colon diameter of control group - colony diameter of drug group) / colony diameter of control group × 100% Formula I.

[0153] The concentration of cycloalkyl-substituted triazolidine pyridine amide compounds, i.e., EC, was calculated using SPSS 20.0 statistical software at an inhibition rate of 50%. 50The values ​​were calculated by repeating the experiment three times and taking the average. Boscalid was used as a positive control in the experiment. The test results are shown in Table 1.

[0154] Table 1 shows the median inhibitory concentrations of the compounds obtained in Examples 1-2 and Comparative Examples 1-4 against four agricultural fungi.

[0155]

[0156] Table 1 shows that cycloalkyl-substituted triazolidine amides have good inhibitory effects on common agricultural fungi, and the substituents on the triazole ring and the amine fragment of the amide have a significant impact on the antibacterial activity. When cyclohexyl or other cycloalkyl groups are introduced into the triazole ring of pyridotriazole compounds, the antibacterial activity is significantly higher than that of the positive control, boscalid, and the antibacterial spectrum is significantly different from that of the original aryl-substituted triazolidine carboxylic acid amides. Cycloalkyl-substituted triazolidine amides can effectively inhibit *Phytophthora capsici*, an important oomycete disease, and show significant EC500 against *Phytophthora capsici*. 50 The concentration is as low as 0.3 μmol / L, while boscalid is essentially ineffective against oomycetes. The cycloalkyl-substituted triazolidine pyridine amide compounds provided by this invention are expected to serve as a new class of fungicide candidates or can be used directly as fungicides, which is of great significance for the creation of new pesticides.

[0157] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A cycloalkyl-substituted triazolidine pyridine amide compound, characterized in that, It has the structure shown in Equation I-1: Formula I-1.

2. The method for preparing the cycloalkyl-substituted triazolidine pyridine amide compound according to claim 1, characterized in that, The steps are as follows: Compound II-2, compound III, condensing agent, triethylamine and organic solvent were mixed and subjected to a condensation reaction to obtain the cycloalkyl-substituted triazolidine pyridine amide compound; Compound II-2 Compound III; The condensation reaction is carried out at a temperature of 0~40℃ for a time of 12~96h. The preparation method of compound II-2 is as follows: Compound 7, compound 2 and a cyclic solvent were mixed and subjected to a decarboxylation and amidation reaction to obtain compound 8; Compound 8, phosphorus pentasulfide, and a heterocyclic solvent were mixed and subjected to a cyclization reaction to obtain compound II-2. Compound 2; Compound 7 Compound 8; The preparation method of compound III is as follows: Compound 3, hydrazine hydrate, and a heterocyclic solvent were mixed to carry out a substitution reaction, yielding compound 4; Compound 3 Compound 4; Compound 4, compound 5, oxidant and organic solvent were mixed and subjected to a condensation-oxidation reaction to obtain compound 6; Compound 5 Compound 6; Compound 6, lithium hydroxide, and an organic solvent were mixed and subjected to a hydrolysis reaction to obtain compound III; In this case, R4 is hydrogen and R5 is cyclohexyl.

3. A derivative of the cycloalkyl-substituted triazolidine pyridine amide compound of claim 1, wherein the derivative is a pesticide-chemically acceptable salt.

4. The use of the cycloalkyl-substituted triazolidine pyridine amide compound of claim 1 or the derivative of the cycloalkyl-substituted triazolidine pyridine amide compound of claim 3 in the preparation of a drug against plant pathogenic fungi, wherein the plant pathogenic fungus is Phytophthora capsici.

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