CN114751889A - A class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamides and their applications - Google Patents

Abstract

The invention discloses an N-heterocycle-1, 5-disubstituted-4-pyrazole formamide compound, which is characterized in that: the structural formula is as follows:

wherein R is₁Is methyl, chloromethyl, difluoromethyl, trifluoromethyl or trichloromethyl; r₂Is isopropyl, tert-butyl, cyclohexyl, phenyl or ortho-substituted phenyl; r₃Is 4-pyridyl, 2-substituted-4-pyridyl, 3-thienyl or 2-substituted-3-thienyl. The compound has the effect on fusarium graminearum and black spore mold causing fungal diseases of riceHas excellent activity, and simultaneously, part of the compounds show good bacteriostatic activity to various plant pathogenic bacteria and show obvious broad-spectrum activity. In addition, part of the compounds show excellent protection and treatment activity on corn plants infected by fusarium graminearum pathogens and rice plants infected by fusarium oryza virgatum pathogens.

Description

A class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamides and their applications

technical field

The invention relates to the field of medicinal chemistry, in particular to a class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compounds and their application in anti-phytopathogenic fungi.

Background technique

Plant fungal diseases reduce the production of major food and cash crops worldwide by up to 20% annually; in addition, some fungi can also produce mycotoxins, posing a major threat to human health. However, chemical means is still the main method to prevent and control fungal diseases. Among them, fungicides play an important role in protecting agricultural production and promoting stable grain income. In recent years, major pesticide companies have made rapid progress in the research and development of fungicides with new structures, and obtained a variety of fungicides with new mechanisms of action, such as fungicides that interfere with the synthesis of metabolites, affect cell structure, and hinder respiration, etc. . However, succinate dehydrogenase inhibitors stand out in recent years because they can hinder the respiratory metabolism of fungi and show high-efficiency and broad-spectrum bactericidal activity, and become one of the hot spots in new pesticide research. Analysis of commercial succinate dehydrogenase inhibitors and their derivative structures found that most of them contained a five-membered heterocyclic "pyrazole" and a classical functional group "amide"; further analysis of the substituent positions on the pyrazole ring found that most of them were "1,3-disubstituted" and "1,3,5-trisubstituted", rarely "1,5-disubstituted".

In the previous work of our group, we discovered a unique active skeleton of "1-phenyl-5-trifluoromethyl-4-pyrazolecarboxamide", and its derivatives serve as potential succinate dehydrogenase inhibitors The agent showed good inhibitory activity against Fusarium graminearum. On the basis of the previous work, a series of new 1,5-disubstituted-4-pyrazole methyls were designed by expanding the "1-position" and "5-position" substituents of pyrazole and the "amine" part of the amide. Amide derivatives, it is expected that a class of N-heterocyclic-1,5-disubstituted-4-pyrazolecarboxamide compounds with high anti-phytopathogenic fungi activity can be found, and can be used in the control of plant fungal diseases.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is: to provide an N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compound with anti-phytopathogenic fungi activity, which is used to control plants caused by phytopathogenic fungi fungal diseases.

其中R₁为甲基、一氯甲基、二氟甲基、三氟甲基或三氯甲基；R₂为异丙基、叔丁基、环己基、苯基或邻取代苯基，其中取代基为甲基、三氟甲基、乙基或卤素；R₃为4-吡啶基、2-取代-4-吡啶基、3-噻吩基或2-取代-3-噻吩基，其中所述的2-取代-4-吡啶基中的取代基为甲基或卤素；其中所述的2-取代-3-噻吩基中的取代基为支链烷烃。Technical scheme of the present invention: a class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compounds, the structural formula of which is as follows:

wherein R ₁ is methyl, monochloromethyl, difluoromethyl, trifluoromethyl or trichloromethyl; R ₂ is isopropyl, tert-butyl, cyclohexyl, phenyl or o-substituted phenyl, wherein The substituent is methyl, trifluoromethyl, ethyl or halogen; R ₃ is 4-pyridyl, 2-substituted-4-pyridyl, 3-thienyl or 2-substituted-3-thienyl, wherein the The substituent in the 2-substituted-4-pyridyl group is methyl or halogen; the substituent in the 2-substituted-3-thienyl group is a branched alkane.

Preferably, R ₁ is monochloromethyl, difluoromethyl or trifluoromethyl; R ₂ is phenyl or o-substituted phenyl, wherein the substituent is methyl, trifluoromethyl, ethyl or halogen; R ₃ is 4-pyridyl, 2-substituted-4-pyridyl or 3-thienyl, wherein the substituent is methyl or halogen.

The preparation method of a class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compounds, the reaction formula is as follows:

The application of a class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compounds in plant fungal diseases caused by phytopathogenic fungi.

The application of a class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compounds in the preparation of anti-phytopathogenic bacteria living medicines. Preferably, the R ₁ is monochloromethyl, difluoromethyl or trifluoromethyl; R ₂ is phenyl or o-substituted phenyl, wherein the substituent is ethyl or halogen; R ₃ is 4-pyridine base, 2-substituted-4-pyridyl or 3-thienyl, wherein the substituent in the 2-substituted-4-pyridyl is methyl or halogen.

Beneficial effects of the present invention: On the basis of the active skeleton of "1-phenyl-5-trifluoromethyl-4-pyrazolecarboxamide" found in the previous work of the research group, the present invention is , the "5-position" substituent and the "amine" part of the amide were expanded, and a series of new 1,5-disubstituted-4-pyrazolecarboxamide derivatives were synthesized. , these compounds not only show excellent antibacterial activity against Fusarium graminearum and C. oryzae that cause fungal diseases of rice; at the same time, some compounds show good antibacterial activity against a variety of plant pathogens, showing obvious broad-spectrum antibacterial activity. In addition, some compounds showed excellent protective and therapeutic activities on corn plants infected by Fusarium graminearum and rice plants infected by S. and creation provide an important scientific basis, and has the prospect of industrialization.

Description of drawings

Fig. 1 shows the protective activity of the compound against Fusarium graminearum-infected corn plants at a concentration of 100 mg/L. A: blank; B: cyanobactin; C: compound E63; therapeutic activity D: blank; E: cyanogen Methoxystrobin; F: Compound E63;

Figure 2 shows the in vivo activity of the compound on rice plants infected with S. oryzae pathogen at a concentration of 40 mg/L; protective activity A: blank; B: compound E77; therapeutic activity C: blank; D: compound E77.

Detailed ways

Synthesis of a class of N-heterocycle-1,5-disubstituted-4-pyrazole carboxamides:

Using substituted ethyl acetoacetate (A) as the starting material, the target compound E was synthesized through ring closure, hydrolysis, acyl chloride and substitution reaction.

Preparation of Intermediate B: Taking 1-(2-Fluoro-phenyl)-5-monochloromethyl-1H-4-pyrazolecarboxylic acid ethyl ester as an example

In a round bottom flask, ethyl monochloroacetoacetate (0.1 mol), triethyl orthoformate (0.2 mol) and acetic anhydride (0.3 mol) were mixed, stirred at 130°C for 4 hours, and then distilled under reduced pressure to obtain an intermediate body. o-Fluorophenylhydrazine (7.9 g, 49.5 mmol) was dissolved in ethanol (100 mL), the intermediate was added, and the reaction was carried out at 100° C. for 2 hours. The solvent was removed by distillation under reduced pressure, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography (PE/EA=50/1). Brown oily liquid, yield 86%. ¹ H NMR (500MHz, DMSO-d ₆ )δ8.17(s,1H,pyrazole H),7.71-7.65(m,2H,phenyl H),7.57-7.53(m, 1H, phenyl H), 7.46-7.43 (m, 1H, phenyl H), 4.87 (s, 2H, CH ₂ Cl), 4.31 (q, J=7.0 Hz, 2H, O CH ₂ CH ₃ ), 1.32 (t , J=7.1Hz, 3H, OCH ₂ CH ₃ ); ¹³ C NMR (126MHz, DMSO-d ₆ ) δ 161.88, 157.76, 155.76, 143.08, 141.84, 132.60 (d, J=7.9Hz), 129.24, 125.32 (d , J=3.4Hz), 117.02 (d, J=19.2Hz), 112.87, 60.31, 32.87, 14.13; ¹⁹ F NMR (471MHz, DMSO-d ₆ )δ-122.00.

Preparation of Intermediate C: 1-(2-Fluoro-phenyl)-5-monochloromethyl-1H-4-pyrazolecarboxylic acid as an example

In a round bottom flask, Intermediate B (28.5 mmol), THF (30 mL) and water (30 mL) were added. After the solution was uniformly stirred, lithium hydroxide (114.2 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h. After distillation under reduced pressure, the pH was adjusted to about 4 using hydrochloric acid (2M), filtered and dried to give C.

Preparation of Intermediate D: 1-(2-Fluoro-phenyl)-5-monochloromethyl-1H-4-pyrazolecarbonyl chloride as an example

According to the method reported in the literature, using SOCl ₂ as solvent, the acylating reagent D was synthesized. After the reaction was completed, the solvent was removed in vacuo, and the crude product was directly used in the next reaction.

Synthesis of target compounds E1-E96

In a 100 mL round bottom flask, substituted amine (3.2 mmol), intermediate D (3.5 mmol) and NaH (6.4 mmol) were stirred in dry THF (5 mL) overnight at room temperature. The mixture was distilled under reduced pressure to remove the solvent, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the target compound Compound E.

Structural and physicochemical data of target compounds:

Test method for biological activity of target compounds against phytopathogenic fungi

Preparation of test materials and media

Plant fungi: Sclerotinia sclerotiorum, Fusarium graminearum, Verticillium wilt of eggplant, Rhizoctonia solani, Sclerotinia solani, Tomato early blight, Soybean stalk canker, Rice ear rot, Capsicum wilt, Long stalk Alternaria, blueberry root rot, cucumber Fusarium wilt, tomato botrytis cinerea and rice niger.

Control agents: penthiopyrad (98% original drug, Hanxiang Biotechnology Co., Ltd.), boscalid (98% original drug, Shanghai Adamas Reagent Co., Ltd.), cyanodoxystrobin (98% original drug, Dr.Ehrenstorfer GmbH, Germany).

Preparation of PDA medium: Weigh 800 grams of peeled potatoes, boil the juice and filter, add 80 g of agar and 80 g of glucose, mix and dissolve, transfer 90 mL of each bottle to a 200-mL conical flask, seal and sterilize under high pressure at 120°C 30 minutes, set aside to cool.

Preparation of liquid: Weigh 10 mg of the compound to be tested and dissolve it into 1.0 mL of DMSO, transfer it to a 15 mL centrifuge tube containing 9.0 mL of sterile Tween water in a sterile ultra-clean bench, and add it to 90 mL of sterilized PDA medium to mix. Evenly, the final concentration of the medicinal liquid was 100 μg/mL, and the culture medium was poured into 9 petri dishes on average for cooling for later use, and an equal amount of DMSO Tween water was used as a blank control. Cyanostrobin was used as a control drug.

Activity testing of compounds against phytopathogens

The inhibitory activities of the target compounds against fourteen phytopathogenic fungi were determined by the mycelial growth rate method. Take the edge of the pre-activated fungus and make a hole to make a fungus cake with a diameter of 4.0mm, transfer it to the center of the drug-containing medium with a sterile inoculation needle, and place it in a constant temperature incubator at 28°C for 2-6 days.

When the colonies of the blank control group grew to about 6.0 cm, the diameter of the hyphae was measured by the cross method with a ruler. The inhibition rate is calculated according to the following formula, and the calculation formula is as follows, wherein I is the inhibition rate, C is the measured diameter of the blank control hyphae, and T is the measured diameter of the drug treatment group.

I(%)=[(C-T)/(C-0.4)]×100

Regression equation and EC ₅₀ value determination of compounds against phytopathogenic fungi

According to the preliminary screening data of activity, the virulence regression equation and EC ₅₀ value were determined for the highly active compound and the control drug. The medicinal solution to be tested was configured into 5 gradient concentrations respectively, and an equal amount of DMSO Tween water was used as a blank control. The calculation method of the inhibition rate is the same as above, and the logarithm of the concentration and the inhibition rate are used to do a linear regression equation to obtain the EC ₅₀ value.

Data analysis of in vitro activity of target compounds against phytopathogens

The inhibitory activity of the target compounds against fourteen phytopathogenic fungi and oomycetes at a concentration of 100 μg/mL was determined by the mycelial growth rate method, and the results are shown in Tables 1-4.

Table 1 Activity test results of target compounds E1-E96 against six phytopathogens at a concentration of 100 μg/mL ^a

^a Each group of experiments was repeated three times, "--" means not tested.

Table 2 Part of the test results of the activity of the target compounds against three phytopathogens at a concentration of 100 μg/mL ^a

^a Each group of experiments was repeated three times, "--" means not tested.

Table 3 Part of the test results for the activity of target compounds against four phytopathogens at a concentration of 100 μg/mL ^a

^a Each group of experiments was repeated three times, "--" means not tested.

Table 4 Part of the target compounds at 100 μg/mL concentration of oryzae fungus activity test results ^a

Numbering Oryza sativa Numbering Oryza sativa Numbering Oryza sativa E17 88.8±2.1 E41 25.5±1.1 E68 92.3±1.2 E18 55.9±1.1 E42 15.9±0.0 E69 90.7±2.5 E19 62.9±1.4 E43 6.5±0.0 E76 100 E20 89.7±2.3 E44 53.0±15.7 E77 100 E21 96.2±3.3 E45 33.0±1.1 E78 55.7±7.1 E22 91.7±2.0 E46 0 E79 100 E23 26.0±1.1 E47 63.6±1.9 E80 100 E24 88.6±2.5 E48 25.5±1.1 E81 100 E25 50.5±1.9 E49 64.4±0.5 E82 100 E26 100 E50 22.2±2.9 E83 29.7±0.6 E27 71.4±1.4 E51 67.9±1.1 E84 72.3±3.8 E28 89.4±4.6 E52 81.9±5.7 E85 92.7±1.5 E29 94.9±1.5 E53 52.7±0.5 E86 54.0±4.6 E30 21.0±1.9 E54 49.5±1.0 E87 49.3±0.6 E31 92.4±1.0 E55 91.7±0.5 E88 79.7±0.6 E32 24.1±1.1 E56 90.5±2.5 E90 29.3±0.6 E33 35.5±1.9 E57 43.2±1.5 E91 86.0±1.0 E34 15.9±0.0 E58 15.9±1.5 E92 67.7±3.1 E35 15.6±0.5 E59 93.7±5.8 E93 67.7±5.5 E36 50.5±1.9 E60 0 E94 78.3±3.1 E37 71.0±1.9 E61 69.8±0.5 E95 100 E38 0 E62 96.2±3.3 E96 100 E39 0 E63 91.7±2.0 boscalid 76.7±3.2 E40 68.2±0.9 E64 88.6±2.5

^a Each group of experiments was repeated three times, "--" means not tested.

According to the preliminary fungal activity screening results in Tables 1-4, it was found that the target compound at a concentration of 100 μg/mL was effective against Sclerotinia sclerotiorum, Fusarium graminearum, Verticillium wilt of eggplant, Rhizoctonia oryzae, Pseudomonas spp. Tomato early blight, soybean stem canker, rice ear rot, pepper fusarium wilt, Alternaria longum, blueberry root rot, cucumber fusarium wilt, tomato botrytis cinerea and rice niger showed significant isolation. body inhibitory activity. Among them, most of the compounds showed good antibacterial activity against Fusarium graminearum, Verticillium wilt of eggplant and Nigella oryzae. Some compounds showed good broad-spectrum antibacterial activities such as E9, E13, E59, E63 and E64.

From the results in Tables 5-7, it was found that the EC ₅₀ values of compound E9 against Fusarium graminearum, Pseudomonas spp., P. oryzae and Fusarium wilt of pepper were 13.1, 14.4, 13.3 and 18.2 μg/mL, respectively; The EC ₅₀ values of Fusarium and Vitis vinifera were 16.8 and 13.9 μg/mL, respectively; the EC ₅₀ values of E59 were 6.6 and 10.6 μg/mL for Rhizoctonia solani and Verticillium dahliae, respectively; E63 was against Rhizoctonia solani The EC ₅₀ values of the fungus, Fusarium graminearum and Verticillium aubergine were 12.8, 5.5 and 17.6 μg/mL, respectively.

The _EC50 values of compounds E63, E76, E77 and E81 against S. oryzae were 9.8, 5.8, 3.7 and 5.5 μg/mL, respectively. The _EC50 values of compounds E63 and E64 against F. graminearum were 5.5 and 6.5 μg/mL, respectively.

Table 5 EC ₅₀ values of some target compounds against three phytopathogenic bacteria ^a

^a Each group of experiments was repeated three times, "--" means not tested.

Table 6 EC ₅₀ values of some target compounds against three phytopathogenic bacteria ^a

^a Each group of experiments was repeated three times, "--" means not tested.

Table 7 EC ₅₀ values of some target compounds against S. oryzae ^a

Numbering EC₅₀(μg/mL) Numbering EC₅₀(μg/mL) E26 41.2±2.1 E78 20.0±1.3 E28 12.1±1.2 E79 16.1±0.6 E59 41.0±1.5 E80 17.0±0.5 E63 9.8±0.8 E81 5.5±1.3 E64 10.5±0.4 E82 16.8±0.4 E68 32.2±1.0 E83 37.8±9.2 E69 17.3±0.4 E84 22.5±8.1 E75 11.4±0.3 E85 26.3±2.9 E76 5.8±0.6 E95 37.1±0.6 E77 3.7±0.1 E96 13.8±4.7

^a Values are the mean ± SD of three replicates.

Test method for in vivo activity of compounds against phytopathogenic fungi

(1) Compounds E9 and E63 with better in vitro activity against Rhizoctonia solani were selected, and maize plants were used as hosts to conduct in vivo treatment and protection activity tests; sterile water containing the same amount of DMSO was used as blank control.

Therapeutic activity experiment: The corn seeds (Zhengdan 958) were planted in moist soil and cultivated in a constant temperature incubator at 25°C until germination. Seedlings with the same growth and health were transferred to pots and incubated for 6 days. The corn leaves were polished with sandpaper, then the mycelium was placed on the damaged part, moistened with a damp cotton cloth, and after standing for 24 hours, the solution containing the active compound E9 (100 μg/mL) was sprayed on the leaves, and the leaves were sprayed with DMSO (1% ) aqueous solution was used as blank control, and the lesion length was measured after 5 days. The protective effect is calculated as follows: protective effect (%)=(A ₀ -A ₁ )/A ₀ ×100%, where A ₀ represents the lesion length of the blank control group, and A ₁ represents the lesion length of compound treatment.

Protective activity experiment: The corn seeds (Zhengdan 958) were planted in moist soil and cultivated in a constant temperature incubator at 25°C until germination. Seedlings with the same growth and health were transferred into pots and incubated for 4 days. A solution of compound E9 (100 μg/mL) was sprayed on the leaves. Aqueous DMSO (1%) was used as blank control. After two days in the incubator, the corn leaves were sanded clean, and the hyphae were placed on the wound, moistened with a damp cotton cloth. Sick shift length was measured after 10 days. The protection effect was calculated as follows: protection effect (%)=(A ₀ -A ₁ )/A ₀ ×100%, wherein A ₀ represents the lesion length of the blank control group, and A ₁ represents the lesion length protected by the compound. (2) Select the compound E77 with better in vitro activity against C. oryzae, and use rice plants as the host to conduct in vivo treatment and protection activity tests; sterile water containing the same amount of DMSO is used as a blank control.

Therapeutic activity experiment: rice seeds (Xiang Liangyou) were planted in moist soil, and transplanted when most of the rice seeds germinated and the tooth tips grew to about 0.5-1 cm in a constant temperature incubator at 25°C. When the rice seedlings grow to about 40cm, and each rice plant has 3 leaves that can be inoculated, the inoculation is carried out. The rice seedlings were polished with sandpaper, then the hyphae were placed on the damaged area, moistened with a damp cotton cloth, and after standing for 24 h, the solution containing compound E77 (40 μg/mL) was sprayed on the leaves, and the leaves were sprayed with DMSO (1%). The aqueous solution was used as blank control, and the lesion length was measured after 5 days. The protective effect is calculated as follows: protective effect (%)=(A ₀ -A ₁ )/A ₀ ×100%, where A ₀ represents the lesion length of the blank control group, and A ₁ represents the lesion length of compound treatment.

Protective activity experiment: The rice seeds (Xiang Liangyou) were planted in moist soil, and transplanted when most of the rice seeds germinated and the tooth tips grew to about 0.5-1 cm in a constant temperature incubator at 25°C. When the rice seedlings grew to about 40 cm, the solution of compound E77 (40 μg/mL) was sprayed on the leaves. Aqueous DMSO (1%) was used as blank control. After two days in the incubator, the corn leaves were sanded clean, and the hyphae were placed on the wound, moistened with a damp cotton cloth. The length of the sick shift was measured after 5 days. The protection effect was calculated as follows: protection effect (%)=(A ₀ -A ₁ )/A ₀ ×100%, wherein A ₀ represents the lesion length of the blank control group, and A ₁ represents the lesion length protected by the compound.

Data analysis of in vivo activity of target compounds against phytopathogenic bacteria

Table 8 Protective activity of compound E9 against Fusarium graminearum-infected in vivo maize (100 μg/mL)

Note: The significant difference analysis adopts Duncan's test method, and the data processing software is IBM SPSS Statistics20. Marks with different letters in the same column in the table indicate significant differences, p<0.05.

Table 9 Protective and therapeutic activity of compound E63 against Fusarium graminearum-infected living maize (100 μg/mL)

Note: The significant difference analysis adopts Duncan's test method, and the data processing software is IBM SPSS Statistics20. Marks with different letters in the same column in the table indicate significant differences, p<0.05.

As shown in Tables 8 and 9, at a concentration of 100 μg/mL, Compound E9 exhibited significant protective activity (50.7%) against maize plants infected by F. graminearum; while Compound E63 exhibited significant protective activity ( 57.2%) and therapeutic activity (44.2%) (Figure 1). Compared with the protective activity of compound E9 under the same conditions, it can be seen that the protective effect of compound E63 on maize plants has been significantly improved.

Table 10 In vivo protection and therapeutic activity of compound E77 on rice infected by S. oryzae pathogen (40 μg/mL)

Note: The significant difference analysis adopts Duncan's test method, and the data processing software is IBM SPSS Statistics20. Marks with different letters in the same column in the table indicate significant differences, p<0.05.

As shown in Table 10, at the concentration of 40 μg/mL, compound E77 exhibited excellent protective activity (92.6%) and obvious therapeutic activity (53.0%) against rice plants infected with S. oryzae pathogen (Fig. 2). ).

Claims (6)

1. a class of N-heterocycle-1,5-disubstituted-4-pyrazole carboxamide compounds, is characterized in that: its structural formula is as follows:

wherein R ₁ is methyl, monochloromethyl, difluoromethyl, trifluoromethyl or trichloromethyl; R ₂ is isopropyl, tert-butyl, cyclohexyl, phenyl or o-substituted phenyl, wherein The substituent is methyl, trifluoromethyl, ethyl or halogen; R ₃ is 4-pyridyl, 2-substituted-4-pyridyl, 3-thienyl or 2-substituted-3-thienyl, wherein the The substituent in the 2-substituted-4-pyridyl group is methyl or halogen; the substituent in the 2-substituted-3-thienyl group is a branched alkane. 2. a class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compounds according to claim 1, is characterized in that: preferably, R ₁ is a chloromethyl group, a difluoromethyl group base or trifluoromethyl; R ₂ is phenyl or o-substituted phenyl, wherein the substituent is methyl, trifluoromethyl, ethyl or halogen; R ₃ is 4-pyridyl, 2-substituted-4-pyridine or 3-thienyl, wherein the substituent is methyl or halogen. 3. the preparation method of a class of N-heterocycle-1,5-disubstituted-4-pyrazole carboxamide compounds as claimed in claim 1 or 2, is characterized in that: reaction formula is as follows:

4. The application of a class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compounds according to claim 1 or 2 in the preparation of medicines for preventing and controlling plant fungal diseases caused by plant pathogens. 5 . The application of a class of N-heterocycle-1,5-disubstituted-4-pyrazolecarboxamide compounds according to claim 1 or 2 in the preparation of anti-phytopathogenic bacteria living medicines. 6 . 6. application according to claim 5 is characterized in that: described R ₁ is monochloromethyl, difluoromethyl or trifluoromethyl; R ₂ is phenyl or o-substituted phenyl, wherein substituent is ethyl or halogen; R ₃ is 4-pyridyl, 2-substituted-4-pyridyl or 3-thienyl, wherein the substituent in the 2-substituted-4-pyridyl is methyl or halogen.

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