A kind of heteroaryl ethyl carboxamide compound and its preparation method and application

Abstract

The present invention provides heteroarylethylcarboxamide compounds, their preparation methods, and uses, belonging to the field of pesticides. The novel heteroarylethylcarboxamide compounds provided herein have the structure represented by Formula I and exhibit excellent inhibitory activity against agricultural pathogens. Some compounds exhibited inhibitory activity against Sclerotinia sclerotiorum at a median concentration of less than 1 μM, demonstrating a 5- to 10-fold increase in antibacterial activity compared to the positive control, fluopyram. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and in particular to a heteroaryl ethyl carboxamide compound, a preparation method and an application thereof. Background Art

[0002] Fluopyram, chemically known as N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-trifluoromethylbenzamide, is a new benzamide fungicide developed by Bayer CropScience. Fluopyram belongs to the succinate dehydrogenase inhibitor class of fungicides. It inhibits mitochondrial respiration by blocking electron transfer in the pathogen's respiratory chain, preventing energy production and growth, ultimately leading to its death. Within plants, fluopyram can be transported and transferred within the xylem, inhibiting spore germination, germ tube growth, mycelial growth, and spore formation.

[0003] Literature reports show that some pathogens have different degrees of resistance risks to fluopyram, and its inhibitory effect on plant fungal diseases is not significant: for example, cucumber target spot disease strains in different regions of Shandong Province have developed different degrees of resistance to fluopyram, among which the frequency of S73P point mutation in the SdhC subunit is relatively high, resulting in a decrease in the affinity of the pathogen's succinate dehydrogenase to fluopyram; under the conditions of indoor agent subculture screening, with the increase of agent selection pressure, cucumber powdery mildew fungi can begin to produce drug-resistant mutants at the 9th generation, and the resistance of the mutants can be stably inherited, with no significant difference in pathogenicity and fitness compared with sensitive strains, and their competitiveness is significantly better than that of sensitive strains; 100 sunflower sclerotinia disease strains from areas with severe disease in Inner Mongolia Autonomous Region, Xinjiang Uygur Autonomous Region and Gansu Province were collected, and the EC value of the strain to fluopyram was determined by the mycelial growth rate method. 50 The results showed that 4 resistant strains were detected in Chifeng City, Inner Mongolia Autonomous Region, with a resistance ratio of 8.3%. The EC of the least sensitive strain was 50 The value was 84 times that of the most sensitive strain. Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a heteroarylethylcarboxamide compound and its preparation method and application. The heteroarylethylcarboxamide compound provided by the present invention exhibits excellent inhibitory activity against agricultural harmful pathogens.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a heteroaryl ethyl carboxamide compound having a structure shown in Formula I:

[0007]

[0008] wherein R1 and R2 are independently -H, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylaminocarbonyl or C1-C6 alkyloxysulfonyl;

[0009] or R1+R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0010] is a six-membered non-fused heterocyclic group or a six-membered fused heteroaryl group;

[0011] B is a five-membered non-fused heterocyclic group, a six-membered non-fused heterocyclic group or a substituted phenyl group.

[0012] Preferably, the six-membered non-fused heterocyclic group has a structure shown in Formula A1 or A2:

[0013]

[0014] Wherein, n and m are integers from 1 to 3;

[0015] P and Q are independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a hydrocarbon thio group, a carbamoyl group, a carbamate group, a C1-C6 hydrocarbon group, a C1-C6 halogenated hydrocarbon group, a C1-C6 hydrocarbon carbonyl group, a C1-C6 halogenated hydrocarbon carbonyl group, a C1-C6 hydrocarbon carbonyloxy group, a C1-C6 halogenated hydrocarbon carbonyloxy group, a C1-C6 hydrocarbon carbonylamino group, a C1-C6 halogenated hydrocarbon carbonylamino group, a C1-C6 hydrocarbon oxy group, , C1~C6 halogenated alkyloxy, C1~C6 alkyloxycarbonyl, C1~C6 halogenated alkyloxycarbonyl, C1~C6 alkylaminocarbonyl, C1~C6 halogenated alkylaminocarbonyl, C1~C6 alkylsulfinyl, C1~C6 halogenated alkylsulfinyl, C1~C6 alkylsulfonyl, C1~C6 halogenated alkylsulfonyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, phenoxy or phenylamino.

[0016] Preferably, the six-membered fused heteroaryl group has a structure shown in any one of Formulas A3 to A6:

[0017]

[0018] wherein o and p are independently integers from 1 to 6, and q and r are independently integers from 1 to 4;

[0019] R, S, T and U are independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a hydrocarbon thio group, a carbamoyl group, a carbamate group, a C1-C6 hydrocarbon group, a C1-C6 halogenated hydrocarbon group, a C1-C6 hydrocarbon carbonyl group, a C1-C6 halogenated hydrocarbon carbonyl group, a C1-C6 hydrocarbon carbonyloxy group, a C1-C6 halogenated hydrocarbon carbonyloxy group, a C1-C6 hydrocarbon carbonylamino group, a C1-C6 halogenated hydrocarbon carbonylamino group, a C1-C6 hydrocarbon oxy, C1-C6 halogenated alkyloxy, C1-C6 alkyloxycarbonyl, C1-C6 halogenated alkyloxycarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 halogenated alkylaminocarbonyl, C1-C6 alkylsulfinyl, C1-C6 halogenated alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 halogenated alkylsulfonyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, phenoxy or phenylamino.

[0020] Preferably, the five-membered non-fused heterocyclic group has a structure represented by any one of formulas B1 to B20:

[0021]

[0022] wherein R3-R5 and R7-R8 are independently hydrogen atoms, halogen atoms, nitro groups, C1-C4 hydrocarbon groups or C1-C4 halogenated hydrocarbon groups;

[0023] R6, R 16 、R 42 are independently a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group or a C1-C4 halogenated hydrocarbon group;

[0024] R9, R 26 、R 30 、R 32 、R 43 、R 46 、R 47 、R 48 、R 49 、R 51 are independently a halogen atom, a C1-C4 hydrocarbon group or a C1-C4 halogenated hydrocarbon group;

[0025] R 10 is a hydrogen atom, a C1-C4 hydrocarbon group, or a C1-C4 halogenated hydrocarbon group;

[0026] R 11 and R 12 are independently a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbon thio group, a C1-C4 hydrocarbon sulfonyl group, a substituted phenyl group or a substituted pyridyl group;

[0027] R 13is a halogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, or a C1-C4 halogenated hydrocarbonoxy group;

[0028] R 14 and R 15 are independently a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group, a C1-C4 hydrocarbonoxy group or a C1-C4 halogenated hydrocarbon group;

[0029] R 17 、R 23 are independently a hydrogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group, a hydroxy-C1-C4-hydrocarbon group, a C1-C4 hydrocarbon sulfonyl group, a C1-C6 hydrocarbon carbonyl group, a phenylsulfonyl group, or a benzoyl group;

[0030] R 18 ~R 20 are independently a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, or a C1-C4 hydrocarbon carbonyl group;

[0031] R 21 、R 22 and R 24 are independently a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbon group, or a C1-C4 halogenated hydrocarbon group;

[0032] R 25 、R 27 is a hydrogen atom or a C1-C4 hydrocarbon group;

[0033] R 28 is a halogen atom, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group or a substituted phenyl group;

[0034] R 29 is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbylamino group, a C1-C4 hydrocarbyl group, a C1-C4 halogenated hydrocarbyl group, or a substituted phenyl group;

[0035] R 31 is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbylamino group, a C1-C4 hydrocarbyl group, or a C1-C4 halogenated hydrocarbyl group;

[0036] R 33 、R 39 are independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C3-C6 cycloalkyl group, a C1-C4 hydrocarbonoxy group, a C1-C4 halogenated hydrocarbonoxy group, a C1-C4 hydrocarbonthio group, a halogenated hydrocarbonthio group, or an aminocarbonyl group;

[0037] R 34 、R40 are independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 hydrocarbon group, a C1-C4 hydrocarbon group or a C1-C4 hydrocarbonthio group;

[0038] R 35 、R 38 、R 41 are independently a hydrogen atom, a substituted phenyl group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a hydroxy-C1-C4-hydrocarbon group, a C3-C6 cycloalkyl group, a C1-C4 hydrocarbonthio-C1-C4-hydrocarbon group, a C1-C4 halogenated hydrocarbonthio-C1-C4-hydrocarbon group, a C1-C4 hydrocarbonoxy-C1-C4-hydrocarbon group, or a C1-C4 halogenated hydrocarbonoxy-C1-C4-hydrocarbon group;

[0039] R 36 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C3-C6 cycloalkyl group, a C1-C4 hydrocarbonoxy group, a C1-C4 halogenated hydrocarbonoxy group, a C1-C4 hydrocarbonthio group, a C1-C4 halogenated hydrocarbonthio group, or an aminocarbonyl group;

[0040] R 37 is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group, or a C1-C4 halogenated hydrocarbonoxy group;

[0041] R 44 、R 45 are independently a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group or a substituted phenyl group;

[0042] R 50 It is a hydrogen atom, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group or a substituted phenyl group.

[0043] Preferably, the six-membered non-fused heterocyclic group has a structure shown in any one of formulas B21 to B24:

[0044]

[0045] where R 52 is a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group, or a C1-C4 halogenated hydrocarbon group;

[0046] W, X and Y are independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group, a C1-C4 hydrocarbonthio group or a C1-C4 hydrocarbonsulfonyl group;

[0047] t, u and v are independently 1, 2, 3 or 4.

[0048] Preferably, the substituted phenyl group has a structure shown in Formula B25:

[0049]

[0050] Where w is 1, 2, 3 or 4;

[0051] Z is independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a hydrocarbon thio group, a carbamoyl group, a carbamate group, a C1-C6 hydrocarbon group, a C1-C6 halogenated hydrocarbon group, a C1-C6 hydrocarbon carbonyl group, a C1-C6 halogenated hydrocarbon carbonyl group, a C1-C6 hydrocarbon carbonyloxy group, a C1-C6 halogenated hydrocarbon carbonyloxy group, a C1-C6 hydrocarbon carbonylamino group, a C1-C6 halogenated hydrocarbon carbonylamino group, a C1-C6 hydrocarbon oxy group, C1-C6 halogenated alkyloxy, C1-C6 alkyloxycarbonyl, C1-C6 halogenated alkyloxycarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 halogenated alkylaminocarbonyl, C1-C6 alkylsulfinyl, C1-C6 halogenated alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 halogenated alkylsulfonyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, phenoxy or phenylamino.

[0052] The present invention also provides a method for preparing the heteroarylethylcarboxamide compound described in the above technical solution, comprising the following steps:

[0053] Mixing a heteroaryl halide, a cyano compound, a catalyst, and an organic solvent to perform CC coupling to obtain a series of heteroaryl acetonitrile intermediates, wherein the heteroaryl halide has a structure shown in Formula 1, and the cyano compound has a structure shown in Formula 2;

[0054]

[0055] The heteroaryl acetonitrile series intermediate, borane tetrahydrofuran complex and organic solvent are mixed to carry out cyano reductive amination reaction to obtain heteroaryl ethylamine series intermediate;

[0056] The heteroarylethylamine series intermediate, carboxylic acid, 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic solvent are mixed to carry out a condensation reaction to obtain the heteroarylethylcarboxamide compound.

[0057] Preferably, the catalyst comprises sodium hexamethyldisilazide or potassium hexamethyldisilazide.

[0058] The present invention also provides the use of the heteroarylethylcarboxamide compounds described in the above technical solution or the heteroaryl and carboxamide compounds prepared by the preparation method described in the above technical solution in preventing and controlling plant fungal diseases.

[0059] Preferably, the plant fungal diseases are caused by plant pathogenic fungi, including rice sheath blight, wheat sheath blight, rapeseed sclerotinia, wheat head blight, wheat take-all, tomato gray mold, potato late blight, pepper phytophthora, tomato early blight, rice seedling bakanae, potato dry rot, cucumber anthracnose and rice blast.

[0060] The present invention provides a heteroaryl ethyl carboxamide compound having a structure shown in Formula I:

[0061]

[0062] wherein R1 and R2 are independently -H, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylaminocarbonyl or C1-C6 alkyloxysulfonyl;

[0063] or R1+R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0064] is a six-membered non-fused heterocyclic group or a six-membered fused heteroaryl group;

[0065] B is a five-membered non-fused heterocyclic group, a six-membered non-fused heterocyclic group or a substituted phenyl group.

[0066] Compared with the prior art, the present invention has the following beneficial effects:

[0067] The novel heteroarylethylcarboxamide compounds provided by the present invention exhibit excellent inhibitory activity against agricultural harmful pathogens. The inhibitory concentration of some compounds against Sclerotinia sclerotiorum is less than 1 μM, and the antibacterial activity of the positive control fluopyram against Sclerotinia sclerotiorum is increased by 5 to 10 times.

[0068] The present invention also provides a method for preparing the heteroarylethylcarboxamide compounds described in the above technical solution. The preparation method provided by the present invention has readily available raw materials and simple and practical synthesis steps, which has positive significance for the creation of new pesticides. DETAILED DESCRIPTION

[0069] The present invention provides a heteroaryl ethyl carboxamide compound having a structure shown in Formula I:

[0070]

[0071] wherein R1 and R2 are independently -H, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylaminocarbonyl or C1-C6 alkyloxysulfonyl;

[0072] or R1+R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0073] is a six-membered non-fused heterocyclic group or a six-membered fused heteroaryl group;

[0074] B is a five-membered non-fused heterocyclic group, a six-membered non-fused heterocyclic group or a substituted phenyl group.

[0075] In the present invention, the C1-C6 hydrocarbon carbonyl group preferably has a structure shown in Formula II:

[0076]

[0077] The C1-C6 alkoxycarbonyl group preferably has a structure shown in Formula III:

[0078]

[0079] The C1-C6 hydrocarbylaminocarbonyl group preferably has a structure shown in Formula IV:

[0080]

[0081] The C1-C6 alkoxysulfonyl group preferably has a structure shown in Formula V:

[0082]

[0083] In the present invention, the six-membered non-fused heterocyclic group preferably has a structure shown in Formula A1 or A2:

[0084]

[0085] Wherein, n and m are independently preferably integers of 1 to 3;

[0086] P and Q are preferably independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a hydrocarbon thio group, a carbamoyl group, a carbamate group, a C1-C6 hydrocarbon group, a C1-C6 halogenated hydrocarbon group, a C1-C6 hydrocarbon carbonyl group, a C1-C6 halogenated hydrocarbon carbonyl group, a C1-C6 hydrocarbon carbonyloxy group, a C1-C6 halogenated hydrocarbon carbonyloxy group, a C1-C6 hydrocarbon carbonylamino group, a C1-C6 halogenated hydrocarbon carbonylamino group, a C1-C6 hydrocarbon oxy group, a C1-C6 halogenated hydrocarbon oxy group, a C1-C6 hydrocarbon oxycarbonyl group, a C1-C6 halogenated hydrocarbon Hydrocarbyloxycarbonyl, C1-C6 hydrocarbylaminocarbonyl, C1-C6 halogenated hydrocarbylaminocarbonyl, C1-C6 hydrocarbylsulfinyl, C1-C6 halogenated hydrocarbylsulfinyl, C1-C6 hydrocarbylsulfonyl, C1-C6 halogenated hydrocarbylsulfonyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, phenoxy or phenylamino, wherein the number of halogen atoms in the C1-C6 halogenated hydrocarbyl is preferably 1-5, the number of halogen atoms in the C1-C6 halogenated hydrocarbylcarbonyl is preferably 1-5, and the number of halogen atoms in the C1-C6 halogenated hydrocarbylcarbonyloxy is preferably 1-5. The number of halogen atoms is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated hydrocarbon carbonyl amino group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated hydrocarbon oxy group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated hydrocarbon oxycarbonyl group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated hydrocarbon aminocarbonyl group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated hydrocarbon sulfinyl group is preferably 1 to 5, and the number of halogen atoms in the C1-C6 halogenated hydrocarbon sulfonyl group is preferably 1 to 5. The substituents on the phenyl group of the substituted benzyl group are preferably C1-C6 hydrocarbon groups, hydrocarbonoxy groups or halogenated hydrocarbon groups, and the number of substituents is preferably 1-5. The substituents on the phenyl group of the substituted benzyloxy group are preferably C1-C6 hydrocarbon groups, hydrocarbonoxy groups or halogenated hydrocarbon groups, and the number of substituents is preferably 1-5. The substituents on the phenyl group of the phenylamino group are preferably C1-C6 hydrocarbon groups, hydrocarbonoxy groups or halogenated hydrocarbon groups, and the number of substituents is preferably 1-5.

[0087] In the present invention, the six-membered fused heteroaryl group preferably has a structure represented by any one of Formulas A3 to A6:

[0088]

[0089] wherein o and p are independently preferably integers of 1 to 6, and q and r are independently preferably integers of 1 to 4;

[0090] R, S, T and U are preferably independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a hydrocarbon thio group, a carbamoyl group, a carbamate group, a C1-C6 hydrocarbon group, a C1-C6 halogenated hydrocarbon group, a C1-C6 hydrocarbon carbonyl group, a C1-C6 halogenated hydrocarbon carbonyl group, a C1-C6 hydrocarbon carbonyloxy group, a C1-C6 halogenated hydrocarbon carbonyloxy group, a C1-C6 hydrocarbon carbonylamino group, a C1-C6 halogenated hydrocarbon carbonylamino group, a C1-C6 hydrocarbon oxy group, a C1-C6 halogenated hydrocarbon oxy group, a C1-C6 hydrocarbon oxycarbonyl ... C6 halogenated alkyloxycarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 halogenated alkylaminocarbonyl, C1-C6 alkylsulfinyl, C1-C6 halogenated alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 halogenated alkylsulfonyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, phenoxy or phenylamino, the number of halogen atoms in the C1-C6 halogenated alkyl is preferably 1-5, the number of halogen atoms in the C1-C6 halogenated alkylcarbonyl is preferably 1-5), C1-C6 halogenated The number of halogen atoms in the C1-C6 halogenated alkylcarbonyloxy group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated alkylcarbonylamino group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated alkyloxy group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated alkyloxycarbonyl group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated alkylaminocarbonyl group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated alkylsulfinyl group is preferably 1 to 5, the number of halogen atoms in the C1-C6 halogenated alkylsulfonyl group is preferably 1 to 5. The substituents of the substituted benzyl group are preferably C1-C6 hydrocarbon groups, hydrocarbonoxy groups or halogenated hydrocarbon groups, and the number of substituents is preferably 1-5. The substituents of the substituted benzyloxy group are preferably C1-C6 hydrocarbon groups, hydrocarbonoxy groups or halogenated hydrocarbon groups, and the number of substituents is preferably 1-5. The substituents on the phenyl group of the phenoxy group are preferably C1-C6 hydrocarbon groups, hydrocarbonoxy groups or halogenated hydrocarbon groups, and the number of substituents is preferably 1-5. The substituents on the phenyl group of the phenylamino group are preferably C1-C6 hydrocarbon groups, hydrocarbonoxy groups or halogenated hydrocarbon groups, and the number of substituents is preferably 1-5.

[0091] In the present invention, the five-membered non-fused heterocyclic group preferably has a structure shown in any one of formulas B1 to B20:

[0092]

[0093] Wherein, R3 to R5 and R7 to R8 are preferably independently a hydrogen atom, a halogen atom, a nitro group, a C1 to C4 hydrocarbon group or a C1 to C4 halogenated hydrocarbon group, and the number of halogen atoms in the C1 to C4 halogenated hydrocarbon group is preferably 1 to 5;

[0094] R6, R 16 、R 42They are independently preferably hydrogen atoms, halogen atoms, C1-C4 hydrocarbon groups or C1-C4 halogenated hydrocarbon groups, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon groups is preferably 1-5;

[0095] R9, R 26 、R 30 、R 32 、R 43 、R 46 、R 47 、R 48 、R 49 、R 51 They are independently preferably halogen atoms, C1-C4 hydrocarbon groups or C1-C4 halogenated hydrocarbon groups, wherein the number of halogen atoms in the C1-C4 halogenated hydrocarbon groups is preferably 1 to 5;

[0096] R 10 It is preferably a hydrogen atom, a C1-C4 hydrocarbon group or a C1-C4 halogenated hydrocarbon group, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon group is preferably 1-5;

[0097] R 11 and R 12 The substituents of the substituted phenyl group are preferably halogen atoms, C1-C4 hydrocarbon groups, C1-C4 halogenated hydrocarbon groups, C1-C4 hydrocarbon thio groups, C1-C4 hydrocarbon sulfonyl groups, substituted phenyl groups or substituted pyridyl groups. The number of halogen atoms in the C1-C4 halogenated hydrocarbon groups is preferably 1-5. The substituents of the substituted phenyl group are preferably halogen atoms or C1-C6 hydrocarbon groups, and the number of substituents is preferably 1-5. The substituents of the substituted pyridyl group are preferably halogen atoms or C1-C6 hydrocarbon groups, and the number of substituents is preferably 1-5.

[0098] R 13 Preferably, it is a halogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group or a C1-C4 halogenated hydrocarbonoxy group, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon group and the C1-C4 halogenated hydrocarbonoxy group is independently preferably 1 to 5;

[0099] R 14 and R 15 Preferably, they are independently a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group, a C1-C4 hydrocarbonoxy group or a C1-C4 halogenated hydrocarbon group, and the number of halogen atoms in the C1-C4 hydrocarbonoxy group and the C1-C4 halogenated hydrocarbon group is independently preferably 1 to 5;

[0100] R 17 、R 23They are independently preferably a hydrogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group, a hydroxy-C1-C4-hydrocarbon group, a C1-C4 hydrocarbon sulfonyl group, a C1-C6 hydrocarbon carbonyl group, a phenylsulfonyl group or a benzoyl group, the substituent on the phenyl group of the phenylsulfonyl group is preferably a halogen atom or a C1-C6 hydrocarbon group, and the number of the substituents is preferably 1-5, the substituent on the phenyl group of the benzoyl group is preferably a halogen atom or a C1-C6 hydrocarbon group, and the number of the substituents is preferably 1-5;

[0101] R 18 ~R 20 They are independently preferably hydrogen atoms, halogen atoms, cyano groups, C1-C4 hydrocarbon groups, C1-C4 halogenated hydrocarbon groups or C1-C4 hydrocarbon carbonyl groups, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon groups is preferably 1-5;

[0102] R 21 、R 22 and R 24 They are independently preferably hydrogen atoms, halogen atoms, cyano groups, C1-C4 hydrocarbon groups or C1-C4 halogenated hydrocarbon groups, wherein the number of halogen atoms in the C1-C4 halogenated hydrocarbon groups is preferably 1-5;

[0103] R 25 、R 27 Preferably, it is a hydrogen atom or a C1 to C4 hydrocarbon group;

[0104] R 28 Preferably, it is a halogen atom, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group or a substituted phenyl group, wherein the number of halogen atoms in the C1-C4 halogenated hydrocarbon group is preferably 1-5, and the substituent on the phenyl group of the substituted phenyl group is preferably a halogen atom or a C1-C6 hydrocarbon group, and the number of substituents is preferably 1-5;

[0105] R 29 Preferably, it is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbylamino group, a C1-C4 hydrocarbyl group, a C1-C4 halogenated hydrocarbyl group or a substituted phenyl group, wherein the number of halogen atoms in the C1-C4 halogenated hydrocarbyl group is preferably 1-5, and the substituent on the phenyl group of the substituted phenyl group is preferably a halogen atom or a C1-C6 hydrocarbyl group, and the number of substituents is preferably 1-5;

[0106] R 31 Preferably, it is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbylamino group, a C1-C4 hydrocarbyl group or a C1-C4 halogenated hydrocarbyl group, wherein the number of halogen atoms in the C1-C4 halogenated hydrocarbyl group is preferably 1 to 5;

[0107] R 33 、R 39The alkyl radicals are independently preferably hydrogen, halogen, cyano, nitro, C1-C4 hydrocarbon, C1-C4 halogenated hydrocarbon, C3-C6 cycloalkyl, C1-C4 hydrocarbonoxy, C1-C4 halogenated hydrocarbonoxy, C1-C4 hydrocarbonthio, halogenated hydrocarbonthio or aminocarbonyl, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon, C1-C4 halogenated hydrocarbonoxy and halogenated hydrocarbonthio is independently preferably 1-5;

[0108] R 34 、R 40 are independently preferably a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 hydrocarbon group, a C1-C4 hydrocarbon group or a C1-C4 hydrocarbonthio group;

[0109] R 35 、R 38 、R 41 The substituted phenyl groups are independently preferably hydrogen atoms, substituted phenyl groups, C1-C4 hydrocarbon groups, C1-C4 halogenated hydrocarbon groups, hydroxyl-C1-C4-hydrocarbon groups, C3-C6 cycloalkyl groups, C1-C4 hydrocarbonthio-C1-C4-hydrocarbon groups, C1-C4 halogenated hydrocarbonthio-C1-C4-hydrocarbon groups, C1-C4 hydrocarbonoxy-C1-C4-hydrocarbon groups or C1-C4 halogenated hydrocarbonoxy-C1-C4-hydrocarbon groups, wherein the substituents on the phenyl groups are preferably halogen atoms or C1-C6 hydrocarbon groups, and the number of substituents is preferably 1-5, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon groups, the C1-C4 halogenated hydrocarbonthio-C1-C4-hydrocarbon groups and the C1-C4 halogenated hydrocarbonoxy-C1-C4-hydrocarbon groups is independently preferably 1-5;

[0110] R 36 Preferably, it is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C3-C6 cycloalkyl group, a C1-C4 hydrocarbonoxy group, a C1-C4 halogenated hydrocarbonoxy group, a C1-C4 hydrocarbonthio group, a C1-C4 halogenated hydrocarbonthio group or an aminocarbonyl group, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon group, the C1-C4 halogenated hydrocarbonoxy group and the C1-C4 halogenated hydrocarbonthio group is independently preferably 1 to 5;

[0111] R 37 Preferably, it is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group or a C1-C4 halogenated hydrocarbonoxy group, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon group and the C1-C4 halogenated hydrocarbonoxy group is independently preferably 1 to 5;

[0112] R 44 、R 45The substituents on the phenyl group of the substituted phenyl group are preferably halogen atoms, C1-C4 hydrocarbon groups, C1-C4 halogenated hydrocarbon groups or substituted phenyl groups, the number of halogen atoms in the C1-C4 halogenated hydrocarbon groups is preferably 1-5, and the substituents on the phenyl group of the substituted phenyl group are preferably halogen atoms or C1-C6 hydrocarbon groups, and the number of substituents is preferably 1-5;

[0113] R 50 It is preferably a hydrogen atom, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group or a substituted phenyl group, the number of halogen atoms in the C1-C4 halogenated hydrocarbon group is preferably 1-5, and the substituent on the phenyl group of the substituted phenyl group is preferably a halogen atom or a C1-C6 hydrocarbon group, and the number of substituents is preferably 1-5.

[0114] In the present invention, the six-membered non-fused heterocyclic group preferably has a structure shown in any one of formulas B21 to B24:

[0115]

[0116] where R 52 Preferably, it is a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group or a C1-C4 halogenated hydrocarbon group, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon group is preferably 1-5;

[0117] W, X and Y are preferably independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group, a C1-C4 hydrocarbonthio group or a C1-C4 hydrocarbonsulfonyl group, and the number of halogen atoms in the C1-C4 halogenated hydrocarbon group is preferably 1 to 5;

[0118] t, u and v are preferably independently 1, 2, 3 or 4.

[0119] In the present invention, the substituted phenyl group preferably has a structure shown in Formula B25:

[0120]

[0121] wherein w is preferably 1, 2, 3 or 4;

[0122] Z is preferably independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a hydrocarbon thio group, a carbamoyl group, a carbamate group, a C1-C6 hydrocarbon group, a C1-C6 halogenated hydrocarbon group, a C1-C6 hydrocarbon carbonyl group, a C1-C6 halogenated hydrocarbon carbonyl group, a C1-C6 hydrocarbon carbonyloxy group, a C1-C6 halogenated hydrocarbon carbonyloxy group, a C1-C6 hydrocarbon carbonylamino group, a C1-C6 halogenated hydrocarbon carbonylamino group, a C1-C6 hydrocarbonoxy group, a C1-C6 halogenated hydrocarbonoxy group, a C1-C6 hydrocarbonoxycarbonyl group, a C1-C6 halogenated hydrocarbonoxycarbonyl group, a C1-C6 hydrocarbon aminocarbonyl group, a C1-C6 halogenated hydrocarbon aminocarbonyl group, a C1-C6 hydrocarbon sulfinyl group, a C1-C6 halogenated hydrocarbon sulfinyl group, a C1-C6 hydrocarbon sulfonyl group, Acyl, C1-C6 halogenated alkylsulfonyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, phenoxy or phenylamino, the number of halogen atoms in the C1-C6 halogenated alkyl, C1-C6 halogenated alkylcarbonyl, C1-C6 halogenated alkylcarbonyloxy, C1-C6 halogenated alkylcarbonylamino, C1-C6 halogenated alkyloxy, C1-C6 halogenated alkyloxycarbonyl, C1-C6 halogenated alkylaminocarbonyl, C1-C6 halogenated alkylsulfinyl and C1-C6 halogenated alkylsulfonyl groups is independently preferably 1-5, and the substituents on the phenyl group of the substituted benzyl, phenoxy, phenylamino and substituted benzyloxy groups are independently preferably C1-C6 alkyl, alkyloxy or halogenated alkyl groups, and the number of substituents is independently preferably 1-5.

[0123] In the present invention, the heteroarylethylcarboxamide compound preferably has a structure represented by any one of formulas C0 to C15:

[0124]

[0125] The present invention also provides a method for preparing the heteroarylethylcarboxamide compound described in the above technical solution, comprising the following steps:

[0126] Mixing a heteroaryl halide, a cyano compound, a catalyst, and an organic solvent to perform CC coupling to obtain a series of heteroaryl acetonitrile intermediates, wherein the heteroaryl halide has a structure shown in Formula 1, and the cyano compound has a structure shown in Formula 2;

[0127]

[0128] The heteroaryl acetonitrile series intermediate, borane tetrahydrofuran complex and organic solvent are mixed to carry out cyano reductive amination reaction to obtain heteroaryl ethylamine series intermediate;

[0129] The heteroarylethylamine series intermediate, carboxylic acid, 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic solvent are mixed to carry out a condensation reaction to obtain the heteroarylethylcarboxamide compound.

[0130] In the present invention, unless otherwise specified, the raw materials used are commercially available products in the art.

[0131] The present invention mixes a heteroaryl halide, a cyano compound, a catalyst and an organic solvent to perform CC coupling to obtain a series of heteroaryl acetonitrile intermediates, wherein the heteroaryl halide has a structure shown in Formula 1, and the cyano compound has a structure shown in Formula 2.

[0132] In the present invention, the catalyst preferably includes sodium hexamethyldisilazide (NaHMDS) or potassium hexamethyldisilazide (KHMDS).

[0133] In the present invention, the catalyst is preferably added in the form of a catalyst solution, the solvent of the catalyst solution is preferably tetrahydrofuran, and the concentration of the catalyst solution is preferably 1 to 2 mol / L.

[0134] In the present invention, the molar ratio of the heteroaryl halide to the cyano compound is preferably 1:1.

[0135] In the present invention, the organic solvent is preferably toluene, methoxycyclopentane or tetrahydrofuran.

[0136] In the present invention, the usage ratio of the heteroaryl halide and the organic solvent is preferably 1 mol: 2-5 mL.

[0137] In a specific embodiment of the present invention, the heteroaryl halide (1 times the amount) and the cyano compound (the molar amount is preferably 1 times the amount) are preferably added to a Shrek tube, N2 is replaced 3 times, and then toluene is added to dissolve and transferred to 0 ° C., and a tetrahydrofuran solution of sodium hexamethyldisilazide (NaHMDS) or potassium hexamethyldisilazide (KHMDS) is slowly added dropwise (when the heteroaryl halide is a heteroaryl chloride / bromide, a 2 mol / L tetrahydrofuran solution of sodium hexamethyldisilazide (NaHMDS); when the heteroaryl halide is a heteroaryl fluoride, a 1 mol / L tetrahydrofuran solution of hexamethyldisilazide is preferably added dropwise). A tetrahydrofuran solution of potassium silane diazonium (KHMDS); when the cyano compound is a tertiary nitrile, preferably 1 to 1.5 times the amount of base; when the cyano compound is a primary nitrile or a secondary nitrile, preferably 2 to 4 times the amount of base), after the dropwise addition is completed, the mixture is stirred at 0°C for 1 hour, then transferred to room temperature and monitored by TLC. After 8 to 12 hours, the reaction is complete, and a saturated ammonium chloride solution is used to quench the reaction. Dichloromethane is added for extraction, and the mixture is washed with a saturated ammonium chloride solution. The organic phase is dried over anhydrous sodium sulfate, and the mixture is concentrated and purified by silica gel (200 to 300 mesh) column chromatography to obtain the heteroaryl acetonitrile series intermediates.

[0138] After obtaining the heteroaryl acetonitrile series intermediate, the present invention mixes the heteroaryl acetonitrile series intermediate, a borane tetrahydrofuran complex and an organic solvent to carry out a cyano reductive amination reaction to obtain the heteroaryl ethylamine series intermediate.

[0139] In the present invention, the borane tetrahydrofuran complex is preferably used in the form of a borane tetrahydrofuran complex solution, and the concentration of the borane tetrahydrofuran complex solution is preferably 1 mol / L.

[0140] In the present invention, the molar ratio of the heteroaryl acetonitrile series intermediates to the borane tetrahydrofuran complex is preferably 1:3-5.

[0141] In the present invention, the organic solvent is preferably tetrahydrofuran.

[0142] In the present invention, the usage ratio of the heteroaryl acetonitrile series intermediates and the organic solvent is preferably 1 mol: 2-5 mL.

[0143] In a specific embodiment of the present invention, the heteroaryl acetonitrile series intermediate is preferably added to a Shrek tube, N2 is replaced three times, and then tetrahydrofuran is added to dissolve and transferred to 0°C. A 1 mol / L borane tetrahydrofuran complex solution (BH3·THF) is slowly added dropwise. After the addition is complete, the reaction is heated under reflux and stirred, and TLC tracking is monitored. After 3 to 5 hours, the substrate conversion is complete, and a 6 mol / L aqueous solution of hydrogen chloride is added dropwise to quench the reaction. The reaction is refluxed for another 2 hours, cooled, and the pH of the reaction system is adjusted to 9 with a 6 mol / L aqueous solution of sodium hydroxide. The reaction solution is filtered, the filtrate is washed with a saturated sodium carbonate solution, extracted with dichloromethane, the organic phase is dried over anhydrous sodium sulfate, and the organic phase is concentrated to obtain the heteroaryl ethylamine series intermediate. The heteroaryl ethylamine series intermediate is a crude product and is directly used in the next reaction without further purification.

[0144] After obtaining the heteroaryl acetonitrile series intermediate, the present invention mixes the heteroaryl ethylamine series intermediate, carboxylic acid, 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and an organic solvent to carry out a condensation reaction to obtain the heteroaryl ethyl carboxamide compound.

[0145] In the present invention, the carboxylic acid is preferably an aryl carboxylic acid, a C1-C6 substituted aryl carboxylic acid, a halogen substituted aryl carboxylic acid, a trifluoromethyl substituted aryl carboxylic acid, a difluoromethyl substituted aryl carboxylic acid, a 5- to 6-membered heterocyclic carboxylic acid, a C1-C6 substituted 5- to 6-membered heterocyclic carboxylic acid, a halogen substituted 5- to 6-membered heterocyclic carboxylic acid, a trifluoromethyl substituted 5- to 6-membered heterocyclic carboxylic acid or a difluoromethyl substituted 5- to 6-membered heterocyclic carboxylic acid.

[0146] In the present invention, the molar ratio of the heteroarylethylamine series intermediate to the carboxylic acid is preferably 1:1 to 1.5.

[0147] In the present invention, the molar ratio of the heteroarylethylamine series intermediates to 4-dimethylaminopyridine is preferably 1:0.2.

[0148] In the present invention, the molar ratio of the heteroarylethylamine series intermediate to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is preferably 1:1.3.

[0149] In the present invention, the organic solvent is preferably dichloromethane.

[0150] In the present invention, the usage ratio of the heteroarylethylamine series intermediates and the organic solvent is preferably 1 mol: 3-5 mL.

[0151] In a specific embodiment of the present invention, the heteroarylethylamine intermediate and the carboxylic acid are preferably placed in a dry pear-shaped flask, dichloromethane is added thereto to dissolve, and then 4-dimethylaminopyridine is added, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added under ice bath conditions at 5°C, and stirred overnight at room temperature. The reaction system is washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and purified by silica gel (200-300 mesh) column chromatography to obtain the heteroarylethylcarboxamide compound.

[0152] In the present invention, the preparation principle of the heteroarylethylcarboxamide compound is shown in the following formula:

[0153]

[0154] The present invention also provides the use of the heteroarylethylcarboxamide compounds described in the above technical solution in preventing and treating plant fungal diseases.

[0155] In the present invention, the plant fungal diseases are preferably caused by plant pathogenic fungi, and the plant pathogenic fungi preferably include Rhizoctonia solani, Rhizoctonia cerealis, Sclerotinia scleotiorum, Fusarium graminearum, Gaeumanomyce graminis, Botrytis cinerea, Phytophthora infestans, Phytophthora capsici, Alternaria solani, Fusarium fujikuroi, Fusarium sulphureum, Colletotrichum lagenarium and Pyricularia oryzae.

[0156] To further illustrate the present invention, the heteroarylethylcarboxamide compounds provided by the present invention, their preparation methods and applications are described in detail below with reference to examples, but they should not be construed as limiting the scope of protection of the present invention.

[0157] Example 1

[0158]

[0159] 2-Chloropyrazine (1.3 g, 10 mmol) and isobutyronitrile (690 mg, 10 mmol) were added to a Shrek tube. The mixture was replaced with nitrogen three times, and then toluene (20 mL) was added to dissolve the mixture. The mixture was then transferred to 0°C. A 2 mol / L sodium hexamethyldisilazide (NaHMDS) solution in tetrahydrofuran (5 mL, 10 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0°C for 1 hour and then transferred to room temperature. TLC monitoring indicated that the reaction was complete after 8 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL), extracted with dichloromethane (20 mL × 2), and washed with saturated ammonium chloride solution (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to 0.07 MPa. The mixture was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to obtain 1.12 g of light yellow solid A1 in a yield of 76%.

[0160] 1 H NMR (400MHz, CDCl3) δ: 8.91 (d, J = 1.45Hz, 1H, aromaticHinpyrazine ring), 8.55-8.60 (m, 2H, aromaticHinpyrazine ring), 1.80 (s, 6H, 2×CH3).

[0161] 13 C NMR (126MHz, CDCl3) δ: 155.15, 144.16, 144.01, 141.69, 123.0, 37.71, 27.59 (2C).

[0162] Example 2

[0163]

[0164] 2-Chlorobenzothiazole (1.69 g, 10 mmol) and isobutyronitrile (690 mg, 10 mmol) were added to a Shrek tube. The mixture was purged with nitrogen three times, and then toluene (20 mL) was added to dissolve the mixture. The mixture was then transferred to 0°C. A 2 mol / L sodium hexamethyldisilazide (NaHMDS) solution in tetrahydrofuran (5 mL, 10 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0°C for 1 hour and then transferred to room temperature. TLC monitoring indicated that the reaction was complete after 8 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL), extracted with dichloromethane (20 mL × 2), and washed with saturated ammonium chloride solution (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to 0.07 MPa. The mixture was purified by column chromatography on silica gel (200-300 mesh) (eluent: petroleum ether / ethyl acetate = 6:1) to obtain 1.45 g of light yellow solid A2 in a yield of 72%.

[0165] 1 H NMR (400MHz, CDCl3) δ: 8.07-8.04 (d, J=8.5Hz, 1H, aromatic H inphenylring), 7.88-7.91 (m, 1H, aromatic H inphenyl ring), 7.54-7.50 (m, 1H, aromatic Hinphenyl ring),7.42-7.45(m,1H,aromaticHinphenyl ring),1.95(s,6H,2×CH3).

[0166] 13 C NMR (126MHz, CDCl3) δ: 170.11, 152.82, 134.96, 126.62, 125.82, 123.53, 122.29, 121.77, 37.96, 28.24 (2C).

[0167] Example 3

[0168]

[0169] (1) 2-Chloroquinoline (1.79 g, 10 mmol) and cyclohexylcarbonitrile (1.09 g, 10 mmol) were added to a Shrek tube. The mixture was replaced with nitrogen three times. Toluene (30 mL) was then added to dissolve the mixture and the mixture was transferred to 0°C. A 2 mol / L sodium hexamethyldisilazide (NaHMDS) solution in tetrahydrofuran (5 mL, 10 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0°C for 1 hour and then transferred to room temperature. TLC was used for monitoring. After 8 hours, the reaction was complete. The mixture was quenched with saturated ammonium chloride solution (5 mL). Dichloromethane (30 mL × 2) was added for extraction and the mixture was washed with saturated ammonium chloride solution (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to 0.07 MPa. The mixture was purified by silica gel (200-300 mesh) column chromatography (eluent: V petroleum ether / V ethyl acetate = 15:1) to obtain 1.48 g of light yellow oil A3 with a yield of 63%.

[0170] 1H NMR (400MHz, CDCl3) δ: 8.18 (d, J=8.4Hz, 1H, aromatic H inpyridine ring), 8.04 (d, J=8.8Hz, 1H, aromatic H in phenyl ring), 7.81 (d, J=8.5Hz, 1H, aromatic Hin phenyl ring), 7.74-7.69 (m, 1H, aromatic Hinphenyl ring),7.71-7.68(d,J=8.8Hz,1H,aromaticH inpyridine ring),7.56-7.52(m,1H,aromatic Hinphenyl ring),2.46-2.42(m,4H),2.09-1.94(m,4H),1.72-1.62(m,2H).

[0171] 13 C NMR (126MHz, CDCl3) δ: 158.23, 147.59, 137.36, 129.98, 129.54, 127.59, 127.28, 126.88, 124.59, 119.12, 50.42, 39.81 (2C), 29.80, 25.03 (2C).

[0172] (2) Intermediate A3 (472 mg, 2 mmol) was added to a Shrek tube and replaced with N2 three times. Then, tetrahydrofuran (6 mL) was added to dissolve the mixture and the mixture was transferred to 0°C. 1 mol / L borane tetrahydrofuran complex solution (BH3·THF, 6 mL, 6 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated under reflux and stirred for reaction. TLC was used for monitoring. After 3 hours, the substrate conversion was complete. 6 mol / L aqueous hydrogen chloride solution (1 mL) was added dropwise to quench the reaction. The mixture was refluxed for another 2 hours. After cooling, the pH of the reaction system was adjusted to 9 with 6 mol / L aqueous sodium hydroxide solution. The reaction solution was filtered, and the filtrate was washed with saturated sodium carbonate solution (5 mL×2). The mixture was extracted with dichloromethane (6 mL×2). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to 0.07 MPa. The organic phase was concentrated to obtain 249 mg of crude product B3 as a yellow-brown oil, which was used directly in the next step without further purification.

[0173] (3) Intermediate B3 (240 mg, 1.0 mmol) and 3,4,5-trifluorobenzoic acid (211 mg, 1.2 mmol) from the previous step were dissolved in dichloromethane (5 mL), followed by the addition of 4-dimethylaminopyridine (DMAP, 25 mg, 0.2 mmol). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice-bath conditions at 5°C. The mixture was stirred overnight at room temperature. The reaction system was washed with water (5 mL × 2), saturated sodium bicarbonate solution (5 mL × 2), and saturated sodium chloride solution (5 mL × 2), respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and purified by silica gel (200-300 mesh) column chromatography (eluent: V petroleum ether / V ethyl acetate = 4:1) to obtain 258 mg of white solid C3 in a yield of 65%.

[0174] 1 H NMR(400MHz, CDCl3)δ:8.21(d,J=8.8Hz,1H,aromatic H inpyridine ring),8.20(m,1H,NH),8.09-8.06(d,J=8.6Hz,1H,aromatic H inphenyl ring),7.86-7.82(d,J=9.2Hz,1H,aromatic H inphenyl ring),7.80-7.75(m,1H,aromatic H inphenylring),7.60-7.58(d,J=8.5Hz,1H,aromaticHinpyridine ring),7.57-7.54(m,1H,aromaticHinphenyl ring),7.42-7.48(m,2H,aromatic H in phenyl ring),3.75(d,J=5.7Hz,2H,CH2),2.32-2.26(m,2H),1.88-1.42(m,8H).

[0175] 13 C NMR(126MHz, CDCl3)δ:166.24,163.89,152.18,150.15,147.18,142.82(m),140.18(m),137.39,131.09,130.11,1 28.74,127.72,126.76,126.64,124.30(m),119.09,111.68,111.55,47.38,44.48,34.00(2C),26.15,22.23(2C).

[0176] Example 4

[0177]

[0178] (1) Intermediate A3 (472 mg, 2 mmol) was added to a Shrek tube and replaced with N2 three times. Then, tetrahydrofuran (6 mL) was added to dissolve the mixture and the mixture was transferred to 0°C. 1 mol / L borane tetrahydrofuran complex solution (BH3·THF, 6 mL, 6 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated under reflux and stirred for reaction. TLC was used for monitoring. After 3 hours, the substrate conversion was complete. 6 mol / L aqueous hydrogen chloride solution (1 mL) was added dropwise to quench the reaction. The mixture was refluxed for another 2 hours. After cooling, the pH of the reaction system was adjusted to 9 with 6 mol / L aqueous sodium hydroxide solution. The reaction solution was filtered, and the filtrate was washed with saturated sodium carbonate solution (5 mL×2). The mixture was extracted with dichloromethane (6 mL×2). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to 0.07 MPa. The organic phase was concentrated to obtain 249 mg of crude product B3 as a yellow-brown oil, which was used directly in the next step without further purification.

[0179] (2) Intermediate B3 (240 mg, 1.0 mmol) and 2-iodobenzoic acid (296 mg, 1.2 mmol) from the previous step were dissolved in dichloromethane (5 mL), followed by the addition of 4-dimethylaminopyridine (DMAP, 25 mg, 0.2 mmol). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice-bath conditions at 5°C. The mixture was stirred overnight at room temperature. The reaction system was washed with water (5 mL × 2), saturated sodium bicarbonate solution (5 mL × 2), and saturated sodium chloride solution (5 mL × 2), respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and purified by silica gel (200-300 mesh) column chromatography (eluent: V petroleum ether / V ethyl acetate = 5:1) to obtain 291 mg of white solid C4 in a yield of 62%.

[0180] 11H NMR (500 MHz, CDCl3) δ: 8.14 - 8.11 (d, J = 8.7 Hz, 1H, aromatic H in pyridine ring), 7.96 - 7.94 (d, J = 8.4 Hz, 1H, aromatic H in phenyl ring), 7.81 - 7.79 (d, J = 6.5 Hz, 1H, aromatic H in phenyl ring), 7.78 - 7.75 (d, J = 7.3 Hz, 1H, aromatic H in phenyl ring), 7.66 - 7.62 (m, 1H, aromatic H in phenyl ring), 7.58 - 7.54 (d, J = 8.3 Hz, 1H, aromatic H in pyridine ring), 7.49 - 7.44 (m, 1H, aromatic H in phenyl ring), 7.32 - 7.30 (d, J = 8.8 Hz, 1H, aromatic H in phenyl ring), 7.29 - 7.26 (m, 1H, aromatic H in phenyl ring), 7.22 - 7.18 (s, 1H, NH), 7.02 - 6.98 (m, 1H, aromatic H in phenyl ring), 3.92 (d, J = 5.5 Hz, 2H, CH2), 2.21 - 2.17 (m, 2H), 1.95 - 1.44 (m, 8H).

[0181] 13 13C NMR (126 MHz, CDCl3) δ: 169.21, 166.36, 147.25, 142.67, 140.11, 136.90, 130.96, 129.52, 129.28, 128.26, 128.12, 127.50, 126.67, 126.33, 123.12 (m), 119.14, 46.32, 45.21, 34.01 (2C), 26.15, 22.26 (2C).

[0182] Example 5

[0183]

[0184] (1) Intermediate A3 (472 mg, 2 mmol) was added to a Shrek tube and replaced with N2 three times. Then, tetrahydrofuran (6 mL) was added to dissolve the mixture and the mixture was transferred to 0°C. 1 mol / L borane tetrahydrofuran complex solution (BH3·THF, 6 mL, 6 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated under reflux and stirred for reaction. TLC was used for monitoring. After 3 hours, the substrate conversion was complete. 6 mol / L aqueous hydrogen chloride solution (1 mL) was added dropwise to quench the reaction. The mixture was refluxed for another 2 hours. After cooling, the pH of the reaction system was adjusted to 9 with 6 mol / L aqueous sodium hydroxide solution. The reaction solution was filtered, and the filtrate was washed with saturated sodium carbonate solution (5 mL×2). The mixture was extracted with dichloromethane (6 mL×2). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to 0.07 MPa. The organic phase was concentrated to obtain 249 mg of crude product B3 as a yellow-brown oil, which was used directly in the next step without further purification.

[0185] (2) Intermediate B3 (240 mg, 1.0 mmol) and 3,5-dichlorobenzoic acid (226 mg, 1.2 mmol) from the previous step were dissolved in dichloromethane (5 mL), followed by the addition of 4-dimethylaminopyridine (DMAP, 25 mg, 0.2 mmol). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice-bath conditions at 5°C. The mixture was stirred overnight at room temperature. The reaction system was washed with water (5 mL × 2), saturated sodium bicarbonate solution (5 mL × 2), and saturated sodium chloride solution (5 mL × 2), respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and purified by silica gel (200-300 mesh) column chromatography (eluent: V petroleum ether / V ethyl acetate = 4:1) to obtain 296 mg of white solid C5 with a yield of 72%.

[0186] 11H NMR (500 MHz, CDCl3) δ: 8.32 - 8.28 (s, 1H, NH), 8.20 - 8.18 (d, J = 8.4 Hz, 1H, aromatic H in pyridine ring), 8.14 - 8.12 (d, J = 8.5 Hz, 1H, aromatic H in phenyl ring), 7.83 - 7.80 (d, J = 9.3 Hz, 1H, aromatic H in phenyl ring), 7.76 - 7.72 (m, 1H, aromatic H in phenyl ring), 7.70 - 7.68 (d, J = 5.2 Hz, 2H, aromatic H in phenyl ring), 7.59 - 7.54 (d, J = 10.3 Hz, 1H, aromatic H in pyridine ring), 7.55 - 7.51 (m, 1H, aromatic H in phenyl ring), 7.44 - 7.41 (t, J = 1.82 Hz, 1H, aromatic H in phenyl ring), 3.71 (d, J = 4.6 Hz, 2H, CH2), 2.32 - 2.21 (m, 2H), 1.85 - 1.40 (m, 8H).

[0187] 13 13C NMR (126 MHz, CDCl3) δ: 166.08, 164.38, 147.22, 137.95, 137.37, 135.42, 131.05, 13 = 0.05, 129.04, 127.65, 127.3 = 5, 126.75 (m), 126.62, 125.71, 120.00 (m), 119.03, 47.70, 44.31, 34.01 (2C), 26.19, 22.27 (2C).

[0188] Example 6

[0189]

[0190] (1) Intermediate A3 (472 mg, 2 mmol) was added to a Shrek tube and replaced with N2 three times. Then, tetrahydrofuran (6 mL) was added to dissolve the mixture and the mixture was transferred to 0°C. 1 mol / L borane tetrahydrofuran complex solution (BH3·THF, 6 mL, 6 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated under reflux and stirred for reaction. TLC was used for monitoring. After 3 hours, the substrate conversion was complete. 6 mol / L aqueous hydrogen chloride solution (1 mL) was added dropwise to quench the reaction. The mixture was refluxed for another 2 hours. After cooling, the pH of the reaction system was adjusted to 9 with 6 mol / L aqueous sodium hydroxide solution. The reaction solution was filtered, and the filtrate was washed with saturated sodium carbonate solution (5 mL×2). The mixture was extracted with dichloromethane (6 mL×2). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to 0.07 MPa. The organic phase was concentrated to obtain 249 mg of crude product B3 as a yellow-brown oil, which was used directly in the next step without further purification.

[0191] (2) Intermediate B3 (240 mg, 1.0 mmol) and 3-methyl-2-thiophenecarboxylic acid (170 mg, 1.2 mmol) from the previous step were dissolved in dichloromethane (3 mL), followed by the addition of 4-dimethylaminopyridine (DMAP, 25 mg, 0.2 mmol). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice-bath conditions at 5°C. The mixture was stirred overnight at room temperature. The reaction system was washed with water (5 mL × 2), saturated sodium bicarbonate solution (5 mL × 2), and saturated sodium chloride solution (5 mL × 2), respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and purified by silica gel (200-300 mesh) column chromatography (eluent: V petroleum ether / V ethyl acetate = 4:1) to obtain 273 mg of white solid C6 with a yield of 75%.

[0192] 11H NMR (500 MHz, CDCl3) δ: 8.16 - 8.14 (d, J = 8.3 Hz, 1H, aromatic H in pyridine ring), 8.09 - 8.07 (d, J = 8.6 Hz, 1H, aromatic H in phenyl ring), 7.80 - 7.76 (d, J = 9.1 Hz, 1H, aromatic H in phenyl ring), 7.71 - 7.68 (m, 1H, aromatic H in phenyl ring), 7.58 - 7.54 (d, J = 7.5 Hz, 1H, aromatic H in pyridine ring), 7.52 - 7.50 (m, 1H, aromatic H in phenyl ring), 7.21 - 7.17 (d, J = 8.2 Hz, 1H, aromatic H in thiophene ring), 6.82 - 6.80 (d, J = 8.8 Hz, 1H, aromatic H in thiophene ring), 3.84 (d, J = 5.7 Hz, 2H, CH2), 2.43 (s, 3H, CH3), 2.22 - 2.11 (m, 2H), 1.89 - 1.40 (m, 8H).

[0193] 13 13C NMR (126 MHz, CDCl3) δ: 166.60, 163.00, 147.26, 140.02, 136.96, 132.47, 132.00, 129.60, 129.21, 127.56, 126.67, 126.50, 126.33, 119.08, 46.41, 44.99, 33.97 (2C), 26.20, 22.25 (2C), 15.88.

[0194] Example 7

[0195]

[0196] (1) Intermediate A3 (472 mg, 2 mmol) was added to a Shrek tube and replaced with N2 three times. Then, tetrahydrofuran (6 mL) was added to dissolve the mixture and the mixture was transferred to 0°C. 1 mol / L borane tetrahydrofuran complex solution (BH3·THF, 6 mL, 6 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated under reflux and stirred for reaction. TLC was used for monitoring. After 3 hours, the substrate conversion was complete. 6 mol / L aqueous hydrogen chloride solution (1 mL) was added dropwise to quench the reaction. The mixture was refluxed for another 2 hours. After cooling, the pH of the reaction system was adjusted to 9 with 6 mol / L aqueous sodium hydroxide solution. The reaction solution was filtered, and the filtrate was washed with saturated sodium carbonate solution (5 mL×2). The mixture was extracted with dichloromethane (6 mL×2). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to 0.07 MPa. The organic phase was concentrated to obtain 249 mg of crude product B3 as a yellow-brown oil, which was used directly in the next step without further purification.

[0197] (2) Intermediate B3 (240 mg, 1.0 mmol) and 2-methyl-3-furoic acid (151 mg, 1.2 mmol) from the previous step were dissolved in dichloromethane (3 mL), followed by the addition of 4-dimethylaminopyridine (DMAP, 25 mg, 0.2 mmol). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice-bath conditions at 5°C. The mixture was stirred overnight at room temperature. The reaction system was washed with water (5 mL × 2), saturated sodium bicarbonate solution (5 mL × 2), and saturated sodium chloride solution (5 mL × 2), respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and purified by silica gel (200-300 mesh) column chromatography (eluent: V petroleum ether / V ethyl acetate = 4:1) to obtain 146 mg of white solid C7 in a yield of 42%.

[0198] 11H NMR (500 MHz, CDCl3) δ: 8.16 - 8.14 (d, J = 8.2 Hz, 1H, aromatic H in pyridine ring), 8.04 - 8.02 (d, J = 8.4 Hz, 1H, aromatic H in phenyl ring), 7.80 - 7.76 (d, J = 8.5 Hz, 1H, aromatic H in phenyl ring), 7.71 - 7.68 (m, 1H, aromatic H in phenyl ring), 7.56 - 7.54 (d, J = 8.3 Hz, 1H, aromatic H in pyridine ring), 7.52 - 7.50 (m, 1H, aromatic H in phenyl ring), 7.31 - 7.25 (s, 1H, NH), 7.19 - 7.17 (d, J = 6.1 Hz, 1H, aromatic H in furan ring), 6.38–6.35 (d, J = 3.2 Hz, 1H, aromatic H in furan ring), 3.74 (d, J = 5.5 Hz, 2H, CH2), 2.52 (s, 3H, CH3), 2.24 - 2.10 (m, 2H), 1.86 - 1.40 (m, 8H).

[0199] 13 13C NMR (126 MHz, CDCl3) δ: 166.55, 163.80, 156.12, 147.29, 140.21, 136.98, 132.00, 129.69, 129.00, 127.63, 126.67, 126.37, 119.16, 116.21, 46.24, 44.85, 33.92 (2C), 26.21, 22.27 (2C), 13.56.

[0200] Example 8

[0201]

[0202] (1) Intermediate A4 (444 mg, 2 mmol) was added to a Shrek tube and replaced with N2 three times. Then, tetrahydrofuran (6 mL) was added to dissolve the mixture and the mixture was transferred to 0°C. 1 mol / L borane tetrahydrofuran complex solution (BH3·THF, 6 mL, 6 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated under reflux and stirred for reaction. TLC was used for monitoring. After 3 hours, the substrate conversion was complete. 6 mol / L aqueous hydrogen chloride solution (1 mL) was added dropwise to quench the reaction. The mixture was refluxed for another 2 hours. After cooling, the pH of the reaction system was adjusted to 9 with 6 mol / L aqueous sodium hydroxide solution. The reaction solution was filtered, the filtrate was washed with saturated sodium carbonate solution (5 mL×2), extracted with dichloromethane (6 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and the organic phase was concentrated to obtain 289 mg of crude yellow oil B4, which was used directly in the next step without further purification.

[0203] (2) Intermediate B4 (226 mg, 1.0 mmol) and 2-trifluoromethylbenzoic acid (228 mg, 1.2 mmol) from the previous step were dissolved in dichloromethane (5 mL), followed by the addition of 4-dimethylaminopyridine (DMAP, 25 mg, 0.2 mmol). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice-bath conditions at 5°C. The mixture was stirred overnight at room temperature. The reaction system was washed with water (5 mL × 2), saturated sodium bicarbonate solution (5 mL × 2), and saturated sodium chloride solution (5 mL × 2), respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and purified by silica gel (200-300 mesh) column chromatography (eluent: V petroleum ether / V ethyl acetate = 4:1) to obtain 322 mg of white solid C8 with a yield of 80%.

[0204] 1 H NMR (400MHz, CDCl3) δ: 8.33 (d, J=6.1Hz, 1H, aromatic H inpyridine ring), 8.30 (d, J=8.6Hz, 1H, aromatic H in phenyl ring), 7.80 (d, J=8.8Hz, 1H, aromatic Hin phenyl ring), 7.63-7.58 (m, 2H, aromatic H),7.57-7.52(m,1H,aromatic H inphenyl ring),7.51-7.37(m,4H,aromaticH),7.04-6.97(m,1H,NH),3.98(d,J=6.2Hz,2H,CH2),2.55-2.45(m,2H),2.20-1.97(m,6H).

[0205] 13 C NMR(126MHz, CDCl3)δ:168.11,165.50,140.23,137.64,136.54,131.98,129.62,129.50,128.71,128.49, 127.37(m),126.46,126.35(m),126.21,126.02,122.55(m),120.30,55.88,48.00,37.34(2C),26.19(2C).

[0206] Example 9

[0207]

[0208] (1) Intermediate A5 (484 mg, 2 mmol) was added to a Shrek tube and replaced with N2 three times. Then, tetrahydrofuran (8 mL) was added to dissolve the mixture and the mixture was transferred to 0°C. 1 mol / L borane tetrahydrofuran complex solution (BH3·THF, 7 mL, 7 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated under reflux and stirred for reaction. TLC was used for monitoring. After 3 hours, the substrate conversion was complete. 6 mol / L aqueous hydrogen chloride solution (1.5 mL) was added dropwise to quench the reaction. The mixture was refluxed for another 2 hours. After cooling, the pH of the reaction system was adjusted to 9 with 6 mol / L aqueous sodium hydroxide solution. The reaction solution was filtered, the filtrate was washed with saturated sodium carbonate solution (5 mL×2), extracted with dichloromethane (6 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and the organic phase was concentrated to obtain 321 mg of crude product B5 as a pale yellow solid, which was used directly in the next step without further purification.

[0209] (2) Intermediate B5 (246 mg, 1.0 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (211 mg, 1.2 mmol) from the previous step were dissolved in dichloromethane (5 mL), followed by the addition of 4-dimethylaminopyridine (DMAP, 25 mg, 0.2 mmol). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice-bath conditions at 5°C. The mixture was stirred overnight at room temperature. The reaction system was washed with water (5 mL × 2), saturated sodium bicarbonate solution (5 mL × 2), and saturated sodium chloride solution (5 mL × 2), respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to 0.07 MPa and purified by silica gel (200-300 mesh) column chromatography (eluent: V petroleum ether / V ethyl acetate = 2:1) to obtain 214 mg of white solid C9 with a yield of 53%.

[0210] 1H NMR(400MHz, CDCl3)δ:7.99-7.96(d,J=8.5Hz,1H,aromatic H inphenylring),7.87-7.85(d,J=8.1Hz,1H,aromatic H in phenyl ring),7.81-7.77(s,1H,aromatic H in pyrazole ring),7.46-7.42(m,1H,aromaticHinphenyl ring),7.36-7.31(m,1H,aromaticHinphenyl ring),7.30-7.26(m,1H,NH),7.02-6.65(m,1H,CHF2),3.88(s,3H,CH3),3.86-3.83(d,J=5.3Hz,2H,CH2),2.22-2.10(m,2H),1.73-1.32(m,8H).

[0211] 13 C NMR (126 MHz, CDCl3) δ: 173.24, 158.42, 154.33, 142.32 (m), 138.46, 133.55, 132.66, 122.32, 120.43, 118.31, 113.21, 111.63 (m), 45.88, 45.34, 39.40, 33.70 (2C), 25.95, 22.18 (2C). Example 10: Compound C10 was prepared in the same manner as in Example 8, except that the Replace with Example 11: Preparation of compound C11 was the same as in Example 8, except that Replace with Example 12: Preparation of compound C12 was the same as in Example 8, except that Replace with Example 13: Preparation of compound C13 was the same as in Example 8, except that Replace with Example 14: Compound C14 was prepared in the same manner as in Example 8, except that Replace with Example 15: Preparation of compound C15 was the same as in Example 8, except that Replace with Application Examples

[0212] Determination of Antibacterial Activity of Heteroarylethylcarboxamides

[0213] The in vitro antibacterial activity was evaluated by the mycelial growth rate inhibition method. The test strains, including rice sheath blight pathogen (Rhizoctonia solani), wheat sheath blight pathogen (Rhizoctonia cerealis), rapeseed sclerotinia (sclerotinia scleotiorum), wheat fusarium (Fusarium graminearum), wheat take-all pathogen (Gaeumanomyce graminis), tomato gray mold (Botrytis cinerea), potato late blight pathogen (Phytophthora infestans), pepper phytophthora (Phytophthora capsici), tomato early blight pathogen (Alternaria solani), rice seedling rust pathogen (Fusarium fujikuroi), potato dry rot pathogen (Fusarium sulphureum), cucumber anthracnose pathogen (Colletotrichum lagenarium), and rice blast pathogen (Pyricularia oryzae), were selected for activation on PDA plates. The compound was prepared into a series of gradient concentrations of PDA drug-containing plates. The test strain was made into a 5 mm diameter bacterial cake and placed in the center of the drug-containing culture dish. The test strain in the blank control dish was cultured at 25°C until it grew close to the edge of the culture dish. The colony diameter of each drug-containing plate was measured using the cross method. The inhibition rate of the compound on mycelial growth was calculated. The inhibition rate on the disease was calculated according to the following formula:

[0214]

[0215] The statistical software SPSS 26.0 was used to calculate the concentration of the compound at which the inhibition rate was 50%, i.e., EC 50 The results were repeated 3 times and the average value was taken. Fluopyram was used as the positive control in the experiment. The results are shown in Table 1.

[0216] Table 1 Inhibition rate of heteroarylethylcarboxamide compounds on five agricultural fungi at a concentration of 100 μmol / L (%)

[0217]

[0218]

[0219]

[0220] Table 2 shows the inhibitory concentration (EC50 μmol / L) of heteroarylethylcarboxamide compounds against Sclerotinia sclerotiorum.

[0221] Table 2 The inhibitory concentration of heteroarylethylcarboxamide compounds on Sclerotinia sclerotiorum

[0222]

[0223]

[0224] As shown in Tables 1 and 2, heteroarylethylcarboxamide compounds exhibited moderate inhibitory activity against a variety of plant pathogens. Within the molecular backbone of these compounds, the type of heteroaryl group, the heterocyclic ring at the acyl terminus, and the type of substituents thereon significantly influenced their antibacterial activity. Quinoline as the heteroaryl group significantly enhanced antibacterial activity, while a halobenzoyl acyl terminus significantly enhanced both antibacterial activity and the spectrum of inhibition.

[0225] After structural optimization, when the heteroaryl group is quinoline and the acyl group is 3,4,5-trifluorobenzoyl, 2-iodobenzoyl or 3,5-dichlorobenzoyl, the EC of the antagonist against Sclerotinia sclerotiorum is 50 The values were 0.49, 0.62, and 1.08 μmol / L, respectively, and were 5-10 times higher than the positive control fluopyram. Therefore, this class of heteroarylethylcarboxamide compounds is expected to be a new fungicide candidate or to be used directly as a fungicide, which will be of great significance for the creation of new pesticides.

[0226] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation thereto. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications shall also be considered within the scope of protection of the present invention.

Claims

1. A heteroarylethylcarboxamide compound, characterized in that, It has the structure shown in formula I: Formula I, Wherein, R1+R2 is cyclohexyl; Has the structure shown in formula A3: A3, wherein o is 1 and R is a hydrogen atom; B is a five-membered non-fused heterocyclic group or a substituted phenyl group; The five-membered non-fused heterocyclic group has a structure shown in any one of formulas B1 to B20: B1、 B2、 B3、 B4、 B5、 B6、 B7、 B8、 B9、 B10、 B11、 B12、 B13、 B14、 B15、 B16、 B17, B18, B19 or B20, wherein R3~R5, R7~R8 are independently hydrogen atoms, halogen atoms, nitro groups, C1~C4 hydrocarbon groups or C1~C4 halogenated hydrocarbon groups; R6, R 16 、R 42 are independently a hydrogen atom, a halogen atom, a C1~C4 hydrocarbon group or a C1~C4 halogenated hydrocarbon group; R9, R 26 、R 30 、R 32 、R 43 、R 46 、R 47 、R 48 、R 49 、R 51 are independently a halogen atom, a C1~C4 hydrocarbon group or a C1~C4 halogenated hydrocarbon group; R 10 is a hydrogen atom, a C1~C4 hydrocarbon group or a C1~C4 halogenated hydrocarbon group; R 11 and R 12 are independently a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbon thio group, or a C1-C4 hydrocarbon sulfonyl group; R 13 is a halogen atom, a cyano group, a C1~C4 hydrocarbon group, a C1~C4 halogenated hydrocarbon group, or a C1~C4 halogenated hydrocarbonoxy group; R 14 and R 15 are independently a hydrogen atom, a halogen atom, a C1-C4 hydrocarbon group, a C1-C4 hydrocarbonoxy group or a C1-C4 halogenated hydrocarbon group; R 17 、R 23 are independently a hydrogen atom, a cyano group, a C1~C4 hydrocarbon group, a C1~C4 halogenated hydrocarbon group, a C1~C4 hydrocarbonoxy group, a hydroxy-C1~C4-hydrocarbon group, a C1~C4 hydrocarbon sulfonyl group, or a C1~C6 hydrocarbon carbonyl group; R 18 ~R 20 are independently a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, or a C1-C4 hydrocarbon carbonyl group; R 21 、R 22 and R 24 are independently a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbon group, or a C1-C4 halogenated hydrocarbon group; R 25 、R 27 A hydrogen atom or a C1~C4 hydrocarbon group; R 28 is a halogen atom, a C1~C4 hydrocarbon group, or a C1~C4 halogenated hydrocarbon group; R 29 is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbylamino group, a C1-C4 hydrocarbyl group, or a C1-C4 halogenated hydrocarbyl group; R 31 is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbylamino group, a C1-C4 hydrocarbyl group, or a C1-C4 halogenated hydrocarbyl group; R 33 、R 39 are independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group, a C1-C4 halogenated hydrocarbonoxy group, a C1-C4 hydrocarbonthio group, or an aminocarbonyl group; R 34 、R 40 are independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 hydrocarbon group, a C1-C4 hydrocarbon group or a C1-C4 hydrocarbon thio group; R 35 、R 38 、R 41 are independently a hydrogen atom, a C1~C4 hydrocarbon group, a C1~C4 halogenated hydrocarbon group, a hydroxyl-C1~C4-hydrocarbon group, a C1~C4 hydrocarbonthio-C1~C4-hydrocarbon group, a C1~C4 halogenated hydrocarbonthio-C1~C4-hydrocarbon group, a C1~C4 hydrocarbonoxy-C1~C4-hydrocarbon group or a C1~C4 halogenated hydrocarbonoxy-C1~C4-hydrocarbon group; R 36 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group, a C1-C4 halogenated hydrocarbonoxy group, a C1-C4 hydrocarbonthio group, a C1-C4 halogenated hydrocarbonthio group, or an aminocarbonyl group; R 37 is a hydrogen atom, a halogen atom, a cyano group, a C1-C4 hydrocarbon group, a C1-C4 halogenated hydrocarbon group, a C1-C4 hydrocarbonoxy group, or a C1-C4 halogenated hydrocarbonoxy group; R 44 、R 45 are independently a hydrogen atom, a halogen atom, a C1~C4 hydrocarbon group, or a C1~C4 halogenated hydrocarbon group; R 50 is a hydrogen atom, a C1~C4 hydrocarbon group, or a C1~C4 halogenated hydrocarbon group; The substituted phenyl group has a structure shown in formula B25: B25， Where w is 1, 2, 3 or 4; Z is independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a carbamoyl group, a carbamate group, a C1-C6 hydrocarbon group, a C1-C6 halogenated hydrocarbon group, a C1-C6 hydrocarbon carbonyl group, a C1-C6 halogenated hydrocarbon carbonyl group, a C1-C6 hydrocarbon carbonyloxy group, a C1-C6 halogenated hydrocarbon carbonyloxy group, a C1-C6 hydrocarbon carbonylamino group, a C1-C6 halogenated hydrocarbon carbonylamino group, C1~C6 alkyl, C1~C6 alkyloxy, C1~C6 halogenated alkyloxy, C1~C6 alkyloxycarbonyl, C1~C6 halogenated alkyloxycarbonyl, C1~C6 alkylaminocarbonyl, C1~C6 halogenated alkylaminocarbonyl, C1~C6 alkylsulfinyl, C1~C6 halogenated alkylsulfinyl, C1~C6 alkylsulfonyl, C1~C6 halogenated alkylsulfonyl.

2. The method for preparing the heteroarylethylcarboxamide compound according to claim 1, wherein The following steps are involved: Mixing a heteroaryl halide, a cyano compound, a catalyst, and an organic solvent to perform CC coupling to obtain a series of heteroaryl acetonitrile intermediates, wherein the heteroaryl halide has a structure shown in Formula 1, and the cyano compound has a structure shown in Formula 2; Formula 1, Formula 2; The heteroaryl acetonitrile series intermediate, borane tetrahydrofuran complex and organic solvent are mixed to carry out cyano reductive amination reaction to obtain heteroaryl ethylamine series intermediate; The heteroarylethylamine series intermediate, carboxylic acid, 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic solvent are mixed to carry out a condensation reaction to obtain the heteroarylethylcarboxamide compound; The structure of the heteroaryl acetonitrile series intermediates is shown below: ； The structure of the heteroarylethylamine series intermediates is shown below: ； The structure of the carboxylic acid is shown below: 。 3. The preparation method according to claim 2, characterized in that The catalyst includes sodium hexamethyldisilazide or potassium hexamethyldisilazide.

4. Use of the heteroarylethylcarboxamide compound according to claim 1 or the heteroaryl and carboxamide compounds prepared by the preparation method according to claim 2 or 3 in preventing and controlling plant fungal diseases.

5. The use according to claim 4, characterized in that The plant fungal diseases are caused by plant pathogenic fungi, including rice sheath blight, wheat sheath blight, rapeseed sclerotinia, wheat head blight, wheat take-all, tomato gray mold, potato late blight, pepper phytophthora, tomato early blight, rice seedling blight, potato dry rot, cucumber anthracnose and rice blast.

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