CN116535357A - Arylamino benzamide derivative containing substituted pyrazole structure, preparation method and application - Google Patents

Abstract

The invention discloses an arylaminobenzamide derivative containing a substituted pyrazole structure, a preparation method and an application thereof, wherein the structural formula of the arylaminobenzamide derivative containing a substituted pyrazole structure is as follows: I), Wherein, R ₁ is trifluoromethyl or difluoromethyl; R ₂ is hydrogen, fluorine or chlorine; R ₃ is hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluorine, Chlorine or its multiple substitution combinations. The present invention organically combines a diarylamine structure with a substituted pyrazole fragment through an amide bond, and synthesizes a new class of arylaminobenzamide derivatives containing a substituted pyrazole structure. This type of compound has excellent antifungal activity. In particular, it showed excellent antibacterial activity against apple rot pathogen and Sclerotinia sclerotiorum. The invention provides a basis for developing a novel fungicide with arylaminobenzamide derivatives containing substituted pyrazole structures as active ingredients.

Description

Aromatic aminobenzamide derivatives containing substituted pyrazole structure, preparation method and application

Technical Field

The present invention relates to the fields of chemical technology and pharmaceutical chemistry technology, in particular to an aromatic aminobenzamide derivative containing a substituted pyrazole structure capable of inhibiting fungal activity, a preparation method and application thereof.

Background Art

Pesticides are important means of production in the grain production process and play a vital role in ensuring high and stable yields of agricultural crops. According to statistics, plant pathogen infection causes a 20% reduction in global crop yields each year, and another 10% reduction after harvest, which not only brings huge economic losses to farmers, but also seriously threatens global food production security. The application of fungicides is currently the most effective measure to prevent and control plant pathogens, which can save a lot of losses every year. Among the many fungicides, SDHI fungicides are widely used because of their high efficiency and broad-spectrum antibacterial activity. Its mechanism of action is: by acting on protein complex II to affect the respiratory chain electron transfer system of pathogens, hindering energy metabolism, inhibiting the growth of pathogens, and causing their death, thereby achieving the purpose of preventing diseases.

The most notable feature of SDHI fungicides in terms of chemical structure is that they contain amide groups. The newly developed fungicides of this type are derived from known structures by replacing groups. From 1996 to 2022, 24 SDHIs fungicides have been launched on the market, of which 54.17% (13/24) contain pyrazole rings. This type of fungicide is widely used to treat fungal diseases on a variety of crops due to its broad-spectrum and high-efficiency antifungal activity, and has become an important fungicide variety in production. However, due to its abuse and irrational use, the resistance of pathogens to this type of fungicide has become increasingly severe. In 2009, the International Fungicide Resistance Committee (FRAC) classified SDHIs fungicides as medium to high resistance risk fungicides. Therefore, the development of new fungicides and the solution to the problem of fungal resistance play a very important role in the sustainable development of agriculture.

Summary of the invention

The technical problem to be solved by the present invention is: to overcome the deficiencies in the prior art and provide an aromatic aminobenzamide derivative containing a substituted pyrazole structure, a preparation method and an application thereof. The diarylamine structure is the advantageous structure of the present invention. The present invention organically combines it with the substituted pyrazole through an amide bond to synthesize a novel aromatic aminobenzamide derivative containing a substituted pyrazole structure, which becomes a compound with high efficiency and broad-spectrum inhibitory activity against plant pathogens.

The technical solution adopted by the present invention to solve the technical problem is: an aromatic aminobenzamide derivative containing a substituted pyrazole structure, and its general structural formula (I) is as follows:

Wherein, _R1 is trifluoromethyl or difluoromethyl; _R2 is hydrogen, fluorine or chlorine; _R3 is hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluorine, chlorine or a multiple substitution combination thereof substituted at different positions.

Furthermore, the aromatic aminobenzamide derivatives containing a substituted pyrazole structure are preferably the following compounds:

A method for preparing the above-mentioned aromatic aminobenzamide derivatives containing a substituted pyrazole structure comprises the following synthetic route:

Furthermore, the synthetic route specifically comprises the following steps:

Step S1, using o-iodobenzoyl chloride (II) and substituted pyrazole amine (III) as raw materials, and using an acid-binding agent (such as triethylamine) to undergo a condensation reaction in a first solvent to generate an o-iodobenzamide compound containing a substituted pyrazole structure corresponding to the general formula (IV), and the obtained product is purified by column chromatography to obtain a pure product;

Step S2, using an o-iodobenzamide compound (IV) containing a substituted pyrazole structure and a substituted aniline (V) as raw materials, and using a copper catalyst to carry out an Ullmann coupling reaction in a second solvent and alkaline conditions to generate an aromatic aminobenzamide derivative containing a substituted pyrazole structure, namely, general formula (I), and the obtained product is purified by column chromatography to obtain a pure product.

An application of the above-mentioned aromatic aminobenzamide derivatives containing a substituted pyrazole structure in preventing and controlling plant pathogens such as rapeseed sclerotinia, apple rot, rice sheath blight, grape gray mold, and pepper phytophthora.

In addition, the aromatic aminobenzamide derivatives containing substituted pyrazole structures can be used to prepare various pesticide preparations to prevent and control plant diseases caused by plant pathogens.

The beneficial effects of the present invention are as follows: the present invention organically combines a diarylamine structure with a substituted pyrazole fragment through an amide bond, synthesizes a novel aromatic aminobenzamide derivative containing a substituted pyrazole structure, and selects common plant fungi and oomycetes, such as rapeseed sclerotinia pathogen, apple rot pathogen, rice sheath blight pathogen, grape gray mold pathogen, and pepper phytophthora pathogen as control targets for antibacterial activity determination. The results show that the compounds exhibit broad-spectrum antibacterial activity against plant pathogenic fungi, especially against apple rot pathogen and rapeseed sclerotinia pathogen. Structure-activity relationship analysis shows that halogen (F, Cl) substitution on the trifluoromethylpyrazole ring of the molecular skeleton plays a vital role in maintaining the high-efficiency and broad-spectrum antibacterial activity of the compounds. The compounds have original novelty in structure, simple synthesis, and are completely different from the existing commercial fungicide structure, and are expected to be developed into a novel green fungicide that is efficient, safe, economical and environmentally friendly.

DETAILED DESCRIPTION

The present invention will now be described in further detail with reference to preferred embodiments.

Example 1 Compound IV-1

N-(1,4-dimethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-iodobenzamide

The specific preparation method of compound IV-1 in this embodiment is as follows: in a dry round-bottom flask, weigh the raw material trifluoromethylpyrazolamine (1.00 g, 6.06 mmol) and dissolve it in 30 mL (5 mL/mmol) of 1,2-dichloroethane, then add triethylamine (0.64 g, 6.36 mmol), and then add o-iodobenzoyl chloride (3.17 g, 8.04 mmol) at 0°C, react at 40°C for 4 hours, and track the reaction until the raw material point disappears or there is no change on TLC (petroleum ether/ethyl acetate = 2:1). After the reaction is completed, the mixture is distilled under reduced pressure to obtain a mixture, water (20 mL) is added to the mixture to dilute it, and it is extracted with ethyl acetate (15×3 mL), the organic phases are combined, and the organic phases are washed and separated with water (10×3 mL) and saturated brine (10×3 mL) in turn. Anhydrous magnesium sulfate was added for drying, suction filtration, and distillation under reduced pressure to obtain a yellow solid, which was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 5:1) to obtain a light yellow solid, compound IV-1 (1.77 g, yield 74%), mp = 159.5-161.0 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.61-7.50 (m, 2H), 7.28 (t, J = 7.5 Hz, 1H), 6.77 (s, 1H), 3.88 (s, 3H); ¹³ C NMR (101 MHz, DMSO-d ₆ )δ166.9,140.9,138.6,138.1,137.1,131.0,127.9,127.5,122.0,96.9,92.9,36.3.

Example 2 Compound I-1

N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-(phenylamino)benzamide

The specific preparation method of compound I-1 in this embodiment is as follows: Compound IV-1 (0.59 g, 1.50 mmol), aniline (0.15 g, 1.65 mmol), anhydrous potassium carbonate (0.41 g, 3 mmol), cuprous iodide (0.28 g, 1.5 mmol) were added in sequence into a 10 mL dry pressure tube, 1,4-dioxane (3 mL) was added, the oil bath was heated to 100 ° C, and refluxed overnight. TLC (petroleum ether/ethyl acetate = 2:1) was used to track the reaction until the raw material point disappeared or there was no change. After the reaction was completed, the mixture was filtered through diatomaceous earth, water (10 mL) was added to the mixture to dilute it, and it was extracted with ethyl acetate (10×3 mL). The organic phases were combined, and the organic phases were washed with water (10×3 mL) and saturated brine (10×3 mL) in sequence to separate the organic phases. Anhydrous magnesium sulfate was added to dry it, and it was filtered and distilled under reduced pressure to obtain a crude product. The compound I-1 was purified by column chromatography as a white solid (0.36 g, yield 67%), mp = 127.5–128.7°C; ¹ H NMR(400MHz,Chloroform-d)δ8.33(s,1H),7.70–7.66(m,1H),7.42–7.35(m,2H),7.34–7.30(m,2H),7.17–7.12(m,2H),7.07(t,J＝7.4Hz,1H),6.92–6.87(m,1H) ),6.54(s,1H),3.77(s,3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.5,146.3,141.2(q,J＝38.5Hz),141.3,136.5,134.1,129.6(2C),128.4,123.5,121.1(q,J＝268.6Hz),121.2(2C),119.3,117 .4,116.7,99.3,36.4; ESI-MS calculated for C ₁₈ H ₁₅ F ₃ N ₄ NaO ⁺ [M+Na] ⁺ ,383.1090; found, 383.1099.

Example 3 Compound I-2

N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-(o-toluidine)benzamide

The preparation method of compound I-2 in this example is as follows: the method described in Example 2 is adopted, 2-methylaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-2 is a brown solid (0.38 g, yield 67%), mp = 103.3-104.8 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 7.89 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.25 (s, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 8.6 Hz, 2H), 6.82 (t, J = 7.5 Hz, 1H), 6.57 (s, 1H), 3.84 (s, 3H), 2.28 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.9,147.7,141.2(q,J＝38.6Hz),139.2,136.5,134.2,131.9,131.3,128.1,126.9,121.1(q,J＝268.6Hz),124.5,122.7,117.8 ,116.2,114.8,99.6,36.5,18.1.

Example 4 Compound I-3

N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-(m-toluamino)benzamide

The preparation method of compound I-3 in this example is as follows: the method described in Example 2 is used, 3-methylaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-3 is a yellow solid (0.28 g, yield 50%), mp = 125.1-126.8 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.23 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.43-7.32 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 6.99-6.86 (m, 4H), 6.56 (s, 1H), 3.80 (s, 3H), 2.32 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.4,146.3,141.2(q,J＝38.4Hz),141.3,139.6,136.6,134.1,129.4,128.5,121.1(q,J＝268.5Hz),124.3,121.9,119.2,118.1 ,117.6,116.8,99.3,36.4,21.5.

Example 5 Compound I-4

N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-(p-tolylamino)benzamide

The preparation method of compound I-4 in this example is as follows: the method described in Example 2 is used, 4-methylaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-4 is a yellow solid (0.35 g, yield 63%), mp = 81.3-82.4 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.82 (s, 1H), 8.27 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.84 (t, J = 7.5 Hz, 1H), 6.54 (s, 1H), 3.79 (s, 3H), 2.33 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.9,147.5,141.5(q,J＝38.5Hz),138.8,136.9,134.4,133.8,130.5(2C),128.6,121.4(q,J＝268.6Hz),122.3(2C),118.9,117 .2,116.1,99.6,36.8,21.3.

Example 6 Compound I-5

2-((2-methoxyphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-5 in this example is as follows: using the method described in Example 2, replacing aniline with 2-methoxyaniline, and the other steps are the same as in Example 2. The obtained compound I-5 was a yellow solid (0.38 g, yield 65%), mp = 112.3-114.6 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.01 (dd, J = 12.2, 7.8 Hz, 2H), 6.94 (d, J = 7.7 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.61 (s, 1H), 3.90 (s, 3H), 3.69 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ165.9,150.1,144.1,141.2(q,J＝38.4Hz),136.9,133.9,131.9,129.6,121.2(q,J＝268.5Hz),123.0,121.7,121.3,121.0,120.8 ,118.1,111.0,98.5,55.8,36.1.

Example 7 Compound I-6

2-((3-methoxyphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-6 in this example is as follows: using the method described in Example 2, replacing aniline with 3-methoxyaniline, and the other steps are the same as in Example 2. The obtained compound I-6 was a yellow solid (0.39 g, yield 66%), mp = 155.1-156.1 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 8.34 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 3.7 Hz, 2H), 7.22 (dd, J = 16.7, 8.6 Hz, 1H), 6.93-6.88 (m, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.55 (s, 1H), 3.77 (s, 6H); ¹³ C NMR(101MHz,Chloroform-d)δ167.4,160.8,145.9,142.7,141.2(q,J＝38.6Hz),136.5,134.1,130.4,128.5,121.1(q,J＝269.7Hz),119.5,117.9,117.1,113.2 ,108.7,106.7,99.3,55.4,36.5.

Example 8 Compound I-7

2-((4-methoxyphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-7 in this example is as follows: the method described in Example 2 is used, 4-methoxyaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-7 is a yellow solid (0.32 g, yield 55%), mp = 167.5-168.9 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 8.36 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 3H), 6.88 (d, J = 8.8 Hz, 2H), 6.75 (t, J = 7.5 Hz, 1H), 6.51 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.3,156.9,148.7,141.3(q,J＝38.5Hz),137.0,134.5,134.0,128.5,121.3(q,J＝268.5Hz),125.1(2C),117.9,116.0,115.2(2 C),114.7,99.7,55.9,36.7.

Example 9 Compound I-8

2-((2-Fluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-8 in this example is as follows: the method described in Example 2 is used, 2-fluoroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-8 is a gray solid (0.25 g, yield 44%), mp = 108.4-109.6 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.29 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.28-7.23 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.17-7.01 (m, 3H), 6.93 (t, J = 7.5 Hz, 1H), 6.56 (s, 1H), 3.79 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.3,155.32(d,J＝245.3Hz),145.5,141.17(q,J＝38.5Hz),136.4,134.1,129.3(d,J＝11.5Hz),128.4,124.65(d,J＝3.7Hz),124.3 2(d,J=7.4Hz),122.3,119.8,117.4,117.3,116.4,116.2,99.3,36.4.

Example 10 Compound I-9

2-((3-Fluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-9 in this example is as follows: the method described in Example 2 is used, 3-fluoroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-9 is a white solid (0.24 g, yield 43%), mp = 138.9-140.4 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.52 (dd, J = 7.6, 1.2 Hz, 1H), 7.31-7.24 (m, 2H), 7.17-7.06 (m, 1H), 6.83-6.67 (m, 3H), 6.62-6.51 (m, 1H), 6.39 (s, 1H), 3.63 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.5,163.6(d,J＝245.5Hz),145.4,142.9(d,J＝10.1Hz),141.1(q,J＝38.6Hz),136.3,134.2,130.7(d,J＝9.7Hz),128.3,125.9(q, J＝268.5Hz),119.8,117.5,117.0,116.2(d,J＝2.8Hz),109.8(d,J＝21.3Hz),107.3(d,J＝24.2Hz),99.5,36.6; ESI-MS calculated for C ₁₈ H ₁₅ F ₄ N ₄ O ⁺ [M+H] ⁺ ,379.1177;found,379.1185.

Example 11 Compound I-10

2-((4-Fluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-10 in this example is as follows: the method described in Example 2 is used, 4-fluoroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-10 is a white solid (0.33 g, yield 59%), mp = 133.2-134.4 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.62 (dd, J = 8.0, 1.5 Hz, 1H), 7.40-7.34 (m, 1H), 7.20-7.12 (m, 3H), 7.04 (t, J = 8.6 Hz, 2H), 6.84 (t, J = 7.5 Hz, 1H), 6.56 (s, 1H), 3.84 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,159.5(d,J＝243.2Hz),147.7,141.2(q,J＝38.6Hz),136.8(d,J＝2.8Hz),136.4,134.3,128.0,124.5,124.4,121.1(q,J＝268 .6Hz),118.2,116.5,116.3,115.8,114.8,99.5,36.6; ESI-MScalculated for C ₁₈ H ₁₅ F ₄ N ₄ O ⁺ [M+H] ⁺ ,379.1177; found, 379.1188.

Example 12 Compound I-11

2-((2-chlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-11 in this example is as follows: the method described in Example 2 is used, 2-chloroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-11 is a red solid (0.31 g, yield 53%), mp = 133.4-135.0 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.43-7.33 (m, 2H), 7.22 (d, J = 18.6 Hz, 1H), 7.18-7.07 (m, 2H), 7.03-6.83 (m, 2H), 6.50 (s, 1H), 3.68 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ166.6,144.0,141.1(q,J＝38.6Hz),138.9,136.5,134.0,130.3,129.0,127.7,125.3,123.6,122.4,121.2,119.7,119.6,119.2 ,99.1,36.4.

Example 13 Compound I-12

2-((3-chlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-12 in this example is as follows: using the method described in Example 2, 3-chloroaniline replaces aniline, and the other steps are the same as in Example 2. The obtained compound I-12 is a yellow solid (0.21 g, yield 35%), mp = 133.8-135.0 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.01 (s, 1H), 7.68-7.60 (m, 1H), 7.47-7.35 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 2.0 Hz, 1H), 7.04-7.00 (m, 2H), 6.97-6.88 (m, 1H), 6.56 (s, 1H), 3.82 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.5,145.7,142.6,141.3(d,J＝38.6Hz),136.3,135.2,134.2,130.6,128.2,121.1(q,J＝268.4Hz),123.2,120.6,119.6,119.0 ,117.2,116.7,99.5,36.6; ESI-MS calculated for C ₁₈ H ₁₄ ClF ₃ N ₄ NaO ⁺ [M+Na] ⁺ ,417.0700; found, 417.0701.

Example 14 Compound I-13

2-((4-chlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-13 in the embodiment is as follows: the method described in Example 2 is adopted, 4-chloroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-13 is a white solid (0.33 g, yield 55%), mp = 147.9-149.1 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 7.99 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.33-7.25 (m, 3H), 7.10 (d, J = 8.7 Hz, 2H), 6.89 (t, J = 7.5 Hz, 1H), 6.56 (s, 1H), 3.82 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.5,146.3,141.4(q,J＝38.8Hz),139.5,136.2,134.1,129.5(2C),128.3,128.0,121.0(q,J＝268.5Hz),122.6(2C),118.9,116 .4,115.8,99.4,36.4; ESI-MS calculated forC ₁₈ H ₁₅ ClF ₃ N ₄ O ⁺ [M+H] ⁺ ,395.0881; found, 395.0886.

Example 15 Compound I-14

2-((2-Trifluoromethylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-14 in the embodiment is as follows: the method described in Example 2 is adopted, aniline is replaced by 2-trifluoromethylaniline, and the other steps are the same as in Example 2. The obtained compound I-14 is a yellow solid (0.22 g, yield 35%), mp = 130.6-132.4 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.13 (s, 1H), 7.68 (dd, J = 14.4, 7.9 Hz, 2H), 7.50-7.38 (m, 3H), 7.28-7.21 (m, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.51 (s, 1H), 3.77 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.2,145.5,141.1(q,J＝38.5Hz),139.9,136.3,134.1,132.9,128.5,123.3,122.8,127.3(q,J＝5.2Hz),124.20(q,J＝272.9Hz), 122.5(q,J＝29.7Hz),121.1(q,J＝268.5Hz),120.2,118.0,117.8,99.6,36.5.

Example 16 Compound I-15

2-((3-Trifluoromethylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-15 in the embodiment is as follows: the method described in Example 2 is adopted, aniline is replaced by 3-trifluoromethylaniline, and the other steps are the same as in Example 2. The obtained compound I-15 is a yellow solid (0.23 g, yield 36%), mp = 129.9-131.7 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.27 (s, 1H), 7.90 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.49-7.37 (m, 4H), 7.31 (dd, J = 15.5, 7.9 Hz, 2H), 6.95 (t, J = 7.4 Hz, 1H), 6.56 (s, 1H), 3.84 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.7,145.7,141.7,141.3(q,J＝38.8Hz),136.2,134.3,132.0(q,J＝32.4Hz),130.2,128.2,124.0(q,J＝272.5Hz),123.9,123.7( q,J＝269.7Hz),119.7(d,J＝3.9Hz),119.6,116.7,117.2(q,J＝3.9Hz),116.5,99.6,36.6; ESI-MS calculated for C ₁₉ H ₁₅ F ₆ N ₄ O ⁺ [M+H] ⁺ ,429.1145; found, 429.1152.

Example 17 Compound I-16

2-((4-trifluoromethylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-16 in the embodiment is as follows: the method described in Example 2 is adopted, 4-trifluoromethylaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-16 is a gray solid (0.23 g, yield 36%), mp = 127.5-129.8 ° C; ¹ H NMR (400MHz, Chloroform-d) δ9.23 (s, 1H), 7.98 (s, 1H), 7.68 (d, J = 7.9Hz, 1H), 7.54 (d, J = 8.4Hz, 2H), 7.47 (q, J = 8.5Hz, 2H), 7.22 (d, J = 8.4Hz, 2H), 6.99 (t, J = 7.1Hz, 1H), 6.56 (s, 1H), 3.82 (s, 3H); ¹³ CNMR(101MHz,Chloroform-d)δ167.6,144.8,144.5,141.2(q,J＝38.8Hz),136.1,134.2,128.3,126.8(q,J＝3.7Hz)(2C),124.3(q,J＝271.3Hz),124.2(q,J＝32.8 Hz), 120.9 (q, J=268.5Hz), 120.3, 119.3 (2C), 117.6, 117.5, 99.6, 36.6; ESI-MS calculated for C ₁₉ H ₁₅ F ₆ N ₄ O ⁺ [M+H] ⁺ , 429.1145; found, 429.1146.

Example 18 Compound I-17

N-3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-(phenylamino)benzamide

The preparation method of compound I-17 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, IV-2 and aniline as raw materials, the other steps are the same as in Example 2. The obtained compound I-17 was a yellow solid (0.22 g, yield 43%), mp = 98.5-100.8 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 7.67 (dd, J = 7.9, 1.4 Hz, 1H), 7.41-7.29 (m, 4H), 7.16-7.13 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.90-6.85 (m, 1H), 6.60 (t, J = 55.2 Hz, 1H), 6.46 (s, 1H), 3.73 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.7,146.3,145.4(t,J＝29.3Hz),141.3,136.5,133.9,129.6(2C),128.4,123.4,121.2(2C),119.0,117.1,116.7,111.3(t,J =234.2Hz),98.5,36.2.

Example 19 Compound I-18

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-(o-tolylamino)benzamide

The preparation method of compound I-18 in the example is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1, to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, replacing aniline with 2-methylaniline, and the other steps are the same as in Example 2. The obtained compound I-18 was a white solid (0.21 g, yield 40%), mp = 125.7-127.0 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.02 (s, 1H), 7.93 (s, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.29-7.24 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.1 Hz, 2H), 6.81 (t, J = 7.5 Hz, 1H), 6.62 (t, J = 55.2 Hz, 1H), 6.48 (s, 1H), 3.79 (s, 3H), 2.28 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.0,147.7,145.4(t,J＝29.2Hz),139.2,136.4,134.0,132.0,131.3,128.0,126.8,124.4,122.7,117.7,116.0,114.9,111.3 (t,J＝234.2Hz),98.8,36.3,18.1.

Example 20 Compound I-19

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-(m-tolylamino)benzamide

The preparation method of compound I-19 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, and replacing aniline with 3-methylaniline, the other steps are the same as in Example 2. The obtained compound I-19 was a yellow solid (0.32 g, yield 60%), mp = 115.5-118.5 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.26 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.41-7.32 (m, 2H), 7.20 (t, J = 8.1 Hz, 1H), 6.96 (d, J = 5.8 Hz, 2H), 6.87 (t, J = 7.2 Hz, 2H), 6.60 (t, J = 55.2 Hz, 1H), 6.46 (s, 1H), 3.74 (s, 3H), 2.32 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.6,146.4,145.4(t,J＝29.3Hz),141.3,139.6,136.5,133.9,129.4,128.4,124.3,121.9,119.0,118.2,117.3,116.7,111.3 (t,J＝234.2Hz),98.5,36.2,21.5.

Example 21 Compound I-20

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-(p-tolylamino)benzamide

The preparation method of compound I-20 in the example is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1, to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, and replacing aniline with 4-methylaniline, the other steps are the same as in Example 2. The obtained compound I-20 was a green solid (0.35 g, yield 66%), mp = 88.1-90.1 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 9.7 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.37-7.31 (m, 1H), 7.28-7.23 (m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 6.82 (t, J = 7.3 Hz, 1H), 6.60 (t, J = 55.2 Hz, 1H), 6.46 (s, 1H), 3.74 (s, 3H), 2.33 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,147.2,145.4(t,J＝29.4Hz),138.4,136.5,134.0,133.4,130.1(2C),128.3,122.0(2C),118.4,116.6,115.8,111.3(t,J =234.2Hz),98.5,36.2,20.9.

Example 22 Compound I-21

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((2-methoxyphenyl)amino)benzamide

The preparation method of compound I-21 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, replacing aniline with 2-methoxyaniline, and the other steps are the same as in Example 2. The obtained compound I-21 was a brown solid (0.31 g, yield 55%), mp = 134.5-137.0 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 7.84 (dd, J = 7.9, 1.6 Hz, 1H), 7.44-7.39 (m, 1H), 7.33 (dd, J = 8.4, 1.2 Hz, 1H), 7.08 (dd, J = 7.8, 1.3 Hz, 1H), 7.03-6.97 (m, 2H), 6.94-6.85 (m, 2H), 6.58 (t, J = 55.2 Hz, 1H), 6.50 (s, 1H), 3.88 (s, 3H), 3.66 (s, 3H); ¹³ CNMR(101MHz,Chloroform-d)δ166.3,150.3,145.3(t,J＝29.2Hz),144.4,136.8,133.7,131.7,129.4,122.9,121.2,120.9,120.8,120.1,118.3,111.3(t,J＝ 234.1Hz),111.0,97.8,55.8,35.9.

Example 23 Compound I-22

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((3-methoxyphenyl)amino)benzamide

The preparation method of compound I-22 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, and replacing aniline with 3-methoxyaniline, the other steps are the same as in Example 2. The obtained compound I-22 was a white solid (0.27 g, yield 48%), mp = 113.4-116.7 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.41-7.36 (m, 2H), 7.22 (t, J = 8.1 Hz, 1H), 6.92-6.87 (m, 1H), 6.77-6.73 (m, 1H), 6.69 (s, 1H), 6.63-6.59 (m, 1H), 6.61 (t, J = 57.2 Hz, 1H), 6.48 (s, 1H), 3.77 (d, J = 8.2 Hz, 6H); ¹³ C NMR (101MHz, Chloroform-d) δ167.6,160.8,146.0,145.4(t,J＝29.5Hz),142.7,136.4,133.9,130.3,128.4,119.3,117.6,117.0,113.4,111.3(t,J＝234.2Hz) ,108.7,106.8,98.5,55.4,36.2.

Example 24 Compound I-23

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((4-methoxyphenyl)amino)benzamide

The preparation method of compound I-23 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, and replacing aniline with 4-methoxyaniline, the other steps are the same as in Example 2. The obtained compound I-23 was a brown solid (0.45 g, yield 80%), mp = 113.5-151.0°C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.14-7.07 (m, 3H), 6.89 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.61 (t, J = 57.2 Hz, 1H), 6.46 (s, 1H), 3.79 (d, J = 11.4 Hz, 6H); ¹³ C NMR(101MHz,Chloroform-d)δ168.0,156.7,148.5,145.4(t,J＝29.3Hz),136.5,134.1,133.7,128.0,125.0(2C),117.4,115.5,114.9(2C),114.3,111.3(t,J ＝234.1Hz),98.6,55.6,36.3.

Example 25 Compound I-24

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((2-fluorophenyl)amino)benzamide

The preparation method of compound I-24 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, replacing aniline with 2-fluoroaniline, and the other steps are the same as in Example 2. The obtained compound I-24 was a green solid (0.25 g, yield 46%), mp = 115.0-116.0 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.25 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.40 (t, 1H), 7.30-7.25 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.16-7.00 (m, 3H), 6.91 (t, J = 7.5 Hz, 1H), 6.59 (t, J = 55.2 Hz, 1H), 6.47 (s, 1H), 3.75 (s, 3H); ¹³ C NMR (101MHz, Chloroform-d) δ 167.5, 155.3 (d, J = 245.4Hz), 145.5, 145.3 (t, J = 29.2Hz), 136.3, 133.9, 129.2 (d, J = 11.5Hz), 128.3, 124.5 (d, J = 3.7Hz), 124.1 (d, J＝7.5Hz),122.3,119.4,117.1,117.0,116.2(d,J＝19.5Hz),111.2(t,J＝234.2Hz),98.4,36.1.

Example 26 Compound I-25

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((3-fluorophenyl)amino)benzamide

The preparation method of compound I-25 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, replacing aniline with 3-fluoroaniline, and the other steps are the same as in Example 2. The obtained compound I-25 was a yellow solid (0.23 g, yield 42%), mp = 123.2-125.4 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 8.16 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 3.9 Hz, 2H), 7.28-7.21 (m, 1H), 6.95-6.86 (m, 3H), 6.73 (d, J = 4.7 Hz, 1H), 6.60 (t, J = 42.4 Hz, 1H), 6.46 (s, 1H), 3.75 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.7,163.6(d,J＝245.3Hz),145.3,145.3(t,J＝29.3Hz),143.0(d,J＝10.2Hz),136.2,133.9,130.7(d,J＝9.7Hz),128.3,119.5,11 7.2, 117.0, 116.1, 111.1 (t, J = 234.2Hz), 109.6 (d, J = 21.3Hz), 107.2 (d, J = 24.2Hz), 98.6, 36.1.

Example 27 Compound I-26

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((4-fluorophenyl)amino)benzamide

The preparation method of compound I-26 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, replacing aniline with 4-fluoroaniline, and the other steps are the same as in Example 2. The obtained compound I-26 was a white solid (0.28 g, yield 52%), mp = 131.0-133.5 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 8.09 (s, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.35 (t, 1H), 7.19-7.10 (m, 3H), 7.02 (t, J = 8.6 Hz, 2H), 6.82 (t, J = 7.5 Hz, 1H), 6.60 (t, J = 55.2 Hz, 1H), 6.45 (s, 1H), 3.76 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.0,159.4(d,J＝242.9Hz),147.5,145.4(t,J＝29.3Hz),136.8,136.4,134.1,128.1,124.3,124.2,118.2,116.4,116.2,115.7 ,115.0,111.2(t,J=234.2Hz),98.7,36.2.

Example 28 Compound I-27

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((2-chlorophenyl)amino)benzamide

The preparation method of compound I-27 in the example is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, replacing aniline with 2-chloroaniline, and the other steps are the same as in Example 2. The obtained compound I-27 was a white solid (0.25 g, yield 45%), mp = 128.2-130.0°C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.43 (s, 1H), 7.79-7.76 (m, 1H), 7.46-7.40 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 (dd, J = 8.1, 1.4 Hz, 1H), 7.21-7.16 (m, 1H), 7.04-6.94 (m, 2H), 6.59 (t, J = 55.2 Hz, 1H), 6.49 (s, 1H), 3.73 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ166.8,145.4(t,J＝29.2Hz),144.2,138.9,136.4,133.9,130.3,128.9,127.6,125.4,123.5,120.9,119.9,119.5,118.9,111.3 (t,J＝234.2Hz),98.4,36.2.

Example 29 Compound I-28

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((3-chlorophenyl)amino)benzamide

The preparation method of compound I-28 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, replacing aniline with 3-chloroaniline, and the other steps are the same as in Example 2. The obtained compound I-28 was a brown solid (0.23 g, yield 41%), mp = 104.2-106.9 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.11 (s, 1H), 7.65 (dd, J = 8.0, 1.5 Hz, 1H), 7.44-7.35 (m, 2H), 7.22 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 2.0 Hz, 1H), 7.02-6.99 (m, 2H), 6.94-6.89 (m, 1H), 6.59 (t, J = 55.2 Hz, 1H), 6.45 (s, 1H), 3.74 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,145.5,145.4(t,J＝29.3Hz),142.6,136.2,135.1,134.0,130.6,128.3,123.1,120.5,119.6,118.9,117.1,116.9,111.2 (t,J＝234.3Hz),98.7,36.2.

Example 30 Compound I-29

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((4-chlorophenyl)amino)benzamide

The preparation method of compound I-29 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, replacing aniline with 4-chloroaniline, and the other steps are the same as in Example 2. The obtained compound I-29 was a gray solid (0.22 g, yield 40%), mp = 164.5-166.7 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 7.94 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.32-7.24 (m, 3H), 7.10 (d, J = 8.7 Hz, 2H), 6.91-6.85 (m, 1H), 6.61 (t, J = 54.8 Hz, 1H), 6.48 (s, 1H), 3.78 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,146.5,145.5(t,J＝29.1Hz),139.7,136.3,134.1,129.6(2C),128.4,128.2,122.7(2C),118.9,116.4,116.0,111.3(t,J =234.1Hz),98.7,36.3.

Example 31 Compound I-30

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((2-(trifluoromethyl)phenyl)amino)benzamide

The preparation method of compound I-30 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, and replacing aniline with 2-trifluoromethylaniline, the other steps are the same as in Example 2. The obtained compound I-30 was a white solid (0.18 g, yield 30%), mp = 130.5-133.5 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.11 (s, 1H), 7.71-7.64 (m, 2H), 7.50-7.36 (m, 3H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.97-6.92 (m, 1H), 6.58 (t, J = 55.2 Hz, 1H), 6.43 (s, 1H), 3.73 (s, 3H); ¹³ C NMR (101MHz, Chloroform-d) δ 167.4, 145.6, 145.3 (t, J = 29.3Hz), 140.0, 136.2, 133.9, 132.8, 128.5, 127.3 (q, J = 5.3Hz), 125.6, 123.2, 122.8, 122.5 (q, J = 29. 6Hz), 120.0, 117.8, 117.8, 111.3 (t, J = 234.2Hz), 98.8, 36.2.

Example 32 Compound I-31

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide

The preparation method of compound I-31 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, and replacing aniline with 3-trifluoromethylaniline, the other steps are the same as in Example 2. The obtained compound I-31 was a white solid (0.20 g, yield 33%), mp = 119.7-121.9 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.27 (s, 1H), 8.03 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.46-7.36 (m, 4H), 7.33-7.26 (m, 2H), 6.93 (t, J = 7.3 Hz, 1H), 6.60 (t, J = 55.2 Hz, 1H), 6.46 (s, 1H), 3.77 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.9,145.6,145.4(t,J＝29.3Hz),141.9,136.2,134.1,132.0(q,J＝32.3Hz),130.2,128.3,124.0(q,J＝272.4Hz),123.8,119.6, 119.5(q,J＝3.8Hz),117.1(q,J＝3.8Hz),116.8,116.6,111.2(t,J＝234.3Hz),98.8,36.2.

Example 33 Compound I-32

N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide

The preparation method of compound I-32 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with difluoromethylpyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-2. Then, using the method described in Example 2, replacing IV-1 with IV-2, and replacing aniline with 4-trifluoromethylaniline, the other steps are the same as in Example 2. The obtained compound I-32 was a yellow solid (0.18 g, yield 30%), mp = 133.1-135.8 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.24 (s, 1H), 8.06 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.49-7.41 (m, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.01-6.95 (m, 1H), 6.60 (t, J = 55.2 Hz, 1H), 6.46 (s, 1H), 3.76 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,145.5(t,J＝29.4Hz),144.7,144.6,136.1,134.0,128.3,126.8(q,J＝3.7Hz)(2C),124.4(q,J＝271.2Hz),124.2(q,J＝32.8Hz) ,120.2,119.2(2C),117.8,117.6,111.2(t,J=234.3Hz),98.7,36.2.

Example 34 Compound I-33

2-((2,6-Dimethylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-33 in the embodiment is as follows: the method described in Example 2 is adopted, 2,6-dimethylaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-33 is a gray solid (0.39 g, yield 67%), mp = 174.2-176.8 ° C; ¹ H NMR (400MHz, Chloroform-d) δ9.02 (s, 1H), 7.88 (s, 1H), 7.58 (d, J = 7.0Hz, 1H), 7.28-7.22 (m, 1H), 7.14 (s, 3H), 6.70 (t, J = 7.5Hz, 1H), 6.60 (s, 1H), 6.31 (d, J = 8.5Hz, 1H), 3.87 (s, 3H), 2.21 (s, 6H); ¹³ CNMR(101MHz,Chloroform-d)δ168.2,149.6,141.2(q,J＝38.6Hz),137.0,136.7,136.5(2C),134.5,128.7(2C),127.7,126.7,121.1(q,J＝268.6Hz),116.1,11 4.0,112.0,99.6,36.5,18.4(2C).

Example 35 Compound I-34

2-((2,6-difluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-34 in the embodiment is as follows: adopt the method described in Example 2, replace aniline with 2,6-difluoroaniline, and the other steps are the same as in Example 2. The obtained compound I-34 is a red solid (0.33g, yield 56%), mp = 118.4-120.3℃; ^1H NMR (400MHz, Chloroform-d) δ8.95 (s, 1H), 7.96 (s, 1H), 7.59 (d, J = 7.8Hz, 1H), 7.37 (t, J = 7.8Hz, 1H), 7.18-7.09 (m, 1H), 6.98 (t, J = 8.1Hz, 2H), 6.85 (t, J = 7.5Hz, 1H), 6.71 (d, J = 8.4Hz, 1H), 6.57 (s, 1H), 3.83 (s, 3H); ^13C NMR (101MHz, Chloroform-d) δ 168.0, 157.92 (d, J = 249.1Hz), 157.87 (d, J = 249.1Hz) 146.7, 141.2 (q, J = 38.3Hz), 136.4, 134.1, 127.6, 125.5 (t, J = 9.7Hz), 121.1 ( q, J＝268.7Hz), 118.6, 117.5 (t, J＝15.6Hz), 115.5, 115.1, 112.20 (d, J＝18.0Hz), 112.15 (d, J＝18.0Hz), 99.6, 36.5.

Example 36 Compound I-35

2-((2,6-diethylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-35 in the embodiment is as follows: the method described in Example 2 is adopted, 2,6-diethylaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-35 is a white solid (0.40 g, yield 65%), mp = 142.6-145.0 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1H), 7.82 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.26-7.16 (m, 4H), 6.67 (t, J = 7.5 Hz, 1H), 6.60 (s, 1H), 6.30 (d, J = 8.5 Hz, 1H), 3.86 (s, 3H), 2.66-2.45 (m, 4H), 1.13 (t, J = 7.5 Hz, 6H); ¹³ C NMR(101MHz,Chloroform-d)δ168.2,150.5,142.7,141.2(q,J＝38.5Hz),136.7,135.7,134.4(2C),127.6,127.4,127.0(2C),121.1(q,J＝268.5Hz),115.9,114 .1,111.5,99.6,36.6,24.9(2C),14.9(2C).

Example 37 Compound I-36

2-((2,6-Dichlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-36 in the embodiment is as follows: the method described in Example 2 is adopted, 2,6-dichloroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-36 is a white solid (0.22 g, yield 35%), mp = 169.3-172.1 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 8.22 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.62 (s, 1H), 6.48 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.6,146.1,141.2(q,J＝38.5Hz),136.5,135.5,133.8,133.1(2C),129.0(2C),128.0,127.0,121.1(q,J＝268.6Hz),119.1,116 .1,115.7,99.4,36.5.

Example 38 Compound I-37

2-((2,4-difluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-37 in the embodiment is as follows: the method described in Example 2 is adopted, 2,4-difluoroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-37 is a gray solid (0.33 g, yield 56%), mp = 148.6-150.2 ° C; ¹ H NMR (400MHz, Chloroform-d) δ 8.93 (s, 1H), 8.12 (s, 1H), 7.63 (d, J = 7.8Hz, 1H), 7.40-7.35 (m, 1H), 7.29-7.22 (m, 1H), 6.99 (d, J = 8.5Hz, 1H), 6.94-6.83 (m, 3H), 6.54 (s, 1H), 3.80 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,159.3(dd,J＝246.2,11.1Hz),156.2(dd,J＝249.4,12.1Hz),146.9,141.2(q,J＝38.6Hz),136.4,134.3,128.1,125.3(dd,J＝9.4 ,2.7Hz),124.9(dd,J＝12.1,3.8Hz),121.1(q,J＝268.6Hz),118.7,115.7,115.4,111.6(dd,J＝22.1,3.8Hz),104.9(dd,J＝26.3,23.7Hz),99.5,36.5.

Example 39 Compound I-38

2-((3,4-dichlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-38 in the embodiment is as follows: the method described in Example 2 is adopted, aniline is replaced by 2,4-dichloroaniline, and the other steps are the same as in Example 2. The obtained compound I-38 is a white solid (0.29 g, yield 45%), mp = 129.9-131.7 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.19 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.44-7.37 (m, 2H), 7.22 (d, J = 7.5 Hz, 2H), 7.17-7.11 (m, 1H), 6.96 (t, J = 7.5 Hz, 1H), 3.76 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.0,144.4,141.2(q,J＝38.4Hz),137.4,134.1,130.1,129.2,128.6,127.7,127.5,126.3,121.1(q,J＝269.7Hz),120.8,120.6 ,118.4,117.9,99.5,36.5.

Example 40 Compound I-39

2-((3,4-difluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-39 in the embodiment is as follows: the method described in Example 2 is adopted, aniline is replaced by 3,4-difluoroaniline, and the other steps are the same as in Example 2. The obtained compound I-39 is a green solid (0.26 g, yield 44%), mp = 124.8-126.3 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 8.04 (s, 1H), 7.63 (dd, J = 8.0, 1.3 Hz, 1H), 7.43-7.37 (m, 1H), 7.27-7.24 (m, 1H), 7.15-7.06 (m, 1H), 7.04-6.97 (m, 1H), 6.91-6.84 (m, 2H), 6.54 (s, 1H), 3.81 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,150.7(dd,J＝248.3,13.5Hz),146.8(dd,J＝244.4,12.8Hz),146.6,141.2(q,J＝38.6Hz),137.6(dd,J＝8.0,3.0Hz),136.4,134.3 ,128.1,121.1(q,J＝268.6Hz),119.0,118.0(d,J＝1.4Hz),117.9,116.1,115.6,111.0(d,J＝19.2Hz),99.6,36.5.

Example 41 Compound I-40

2-((3,4-dichlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-40 in the embodiment is as follows: the method described in Example 2 is adopted, aniline is replaced by 3,4-dichloroaniline, and the other steps are the same as in Example 2. The obtained compound I-40 is a brown solid (0.35 g, yield 55%), mp = 96.3-97.4 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 7.93 (s, 1H), 7.64 (dd, J = 8.0, 1.4 Hz, 1H), 7.46-7.41 (m, 1H), 7.37-7.33 (m, 2H), 7.28 (d, J = 2.6 Hz, 1H), 7.00 (dd, J = 8.7, 2.6 Hz, 1H), 6.96-6.91 (m, 1H), 6.55 (s, 1H), 3.82 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.7,145.6,141.3(q,J＝38.7Hz),140.8,136.2,134.3,133.3,131.1,128.1,126.2,122.3,121.0(q,J＝268.7Hz),120.4,119.6 ,116.7,116.4,99.6,36.6; ESI-MS calculated for C ₁₈ H ₁₄ Cl ₂ F ₃ N ₄ O ⁺ [M+H] ⁺ ,429.0491; found, 429.0492.

Example 42 Compound I-41

N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((3,4,5-trifluorophenyl)amino)benzamide

The preparation method of compound I-41 in the embodiment is as follows: using the method described in Example 2, 3,4,5-trifluoroaniline replaces aniline, and the other steps are the same as in Example 2. The obtained compound I-41 is a gray solid (0.12 g, yield 20%), mp = 168.7-171.2 ° C; ¹ H NMR (400MHz, Chloroform-d) δ9.22 (s, 1H), 7.89 (s, 1H), 7.68-7.61 (m, 1H), 7.49-7.43 (m, 1H), 7.34 (d, J = 8.0Hz, 1H), 6.99-6.93 (m, 1H), 6.79 (dd, J = 9.2, 5.9Hz, 2H), 6.55 (s, 1H), 3.83 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.7,151.9(ddd,J＝248.6,10.4,5.7Hz)(2C),145.5,141.3(q,J＝38.7Hz),137.1(tdd,J＝11.1Hz),136.1,134.4,128.4(d,J＝184.4Hz ),128.1,121.0(q,J＝268.6Hz),119.8,116.7,116.4,105.0(d,J＝23.5Hz),105.0(d,J＝10.2Hz),99.7(d,J＝2.1Hz),36.6; ESI-MScalculated for C ₁₈ H ₁₃ F ₆ N ₄ O ⁺ [M+ H] ⁺ ,415.0988;found,415.0997.

Example 43 Compound I-42

N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((3,4,5-trichlorophenyl)amino)benzamide

The preparation method of compound I-42 in the embodiment is as follows: using the method described in Example 2, 3,4,5-trichloroaniline replaces aniline, and the other steps are the same as in Example 2. The obtained compound I-42 is a white solid (0.35 g, yield 50%), mp = 166.4-168.0 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.28 (s, 1H), 7.84 (s, 1H), 7.64 (dd, J = 8.0, 1.3 Hz, 1H), 7.48 (td, J = 7.9, 7.3, 1.4 Hz, 1H), 7.39 (dd, J = 8.4, 0.9 Hz, 1H), 7.20 (s, 2H), 7.01-6.96 (m, 1H), 6.56 (s, 1H), 3.83 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.6,144.8,141.3(q,J＝38.4Hz),140.7,136.0,134.8(2C),134.4,128.1,124.6,123.7(q,J＝269.7Hz),120.3,120.2(2C),117 .1,117.0,99.7,36.6.

Example 44 Compound I-43

N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((2,4,6-trifluorophenyl)amino)benzamide

The preparation method of compound I-43 in the embodiment is as follows: the method described in Example 2 is adopted, 2,4,6-trifluoroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-43 is a red solid (0.20 g, yield 33%), mp = 138.1-140.8 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.40-7.33 (m, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.78 (t, J = 8.0 Hz, 2H), 6.62 (d, J = 8.4 Hz, 1H), 6.56 (s, 1H), 3.83 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.1,159.7(dt,J＝248.5,14.8Hz),158.5(ddd,J＝250.7,14.9,7.4Hz)(2C),147.3,141.2(q,J＝38.6Hz),136.3,134.3,127.6,121 .1(q,J＝268.6Hz),118.4,114.9,114.5,114.0(td,J＝16.2,5.0Hz),101.1(td,J＝26.2,2.5Hz)(2C),99.7(d,J＝2.1Hz),36.6.

Example 45 Compound I-44

N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((2,4,6-trichlorophenyl)amino)benzamide

The preparation method of compound I-44 in the embodiment is as follows: the method described in Example 2 is adopted, 2,4,6-trichloroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-44 is a white solid (0.21 g, yield 30%), mp = 138.1-140.5 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.05 (s, 1H), 7.97 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.43 (s, 2H), 7.38-7.32 (m, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.62 (s, 1H), 6.45 (d, J = 8.3 Hz, 1H), 3.86 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.7,146.1,141.3(q,J＝38.6Hz),136.3,134.3,134.0,133.8,131.7,129.0(2C),127.9(2C),121.1(q,J＝268.7Hz),119.0,115 .7,115.3,99.6,36.6.

Example 46 Compound I-45

2-((3-chloro-4-fluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-45 in the embodiment is as follows: using the method described in Example 2, 3-chloro-4-fluoroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-45 is a gray solid (0.34 g, yield 55%), mp = 138.8-141.5 ° C; ¹ H NMR (400MHz, Chloroform-d) δ9.16 (s, 1H), 7.99 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.25-7.20 (m, 2H), 7.09 (t, J = 8.7 Hz, 1H), 7.04-7.00 (m, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.54 (s, 1H), 3.82 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,154.6(d,J＝245.4Hz),146.8,141.2(q,J＝38.7Hz),137.7(d,J＝3.2Hz),136.3,134.4,128.1,124.0,121.9(d,J＝6.8Hz),121 .6(d,J＝18.8Hz),121.0(q,J＝268.7Hz),118.9,117.3(d,J＝22.1Hz),115.9,115.3,99.6(d,J＝2.1Hz),36.6.

Example 47 Compound I-46

2-((3-Fluoro-4-chlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-46 in the example is as follows: using the method described in Example 2, replacing aniline with 3-fluoro-4-chloroaniline, and the other steps are the same as in Example 2. The obtained compound I-46 was a white solid (0.22 g, yield 36%), mp = 136.8-138.4 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 7.96 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.48-7.41 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 8.4 Hz, 1H), 6.99 (dd, J = 10.7, 2.5 Hz, 1H), 6.96-6.91 (m, 1H), 6.87 (dd, J = 8.6, 2.0 Hz, 1H), 6.55 (s, 1H), 3.82 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.7,158.6(d,J＝248.2Hz),145.4,141.4(d,J＝9.2Hz),141.3(q,J＝38.9Hz),136.2,134.3,131.2,128.2,121.0(q,J＝269.6Hz),1 19.7, 117.2 (d, J = 3.2Hz), 116.9, 116.6, 114.3 (d, J = 17.9Hz), 108.6 (d, J = 23.7Hz), 99.6 (d, J = 2.0Hz), 36.6.

Example 48 Compound I-47

2-((2-Chloro-4-fluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-47 in the example is as follows: using the method described in Example 2, replacing aniline with 2-chloro-4-fluoroaniline, and the other steps are the same as in Example 2. The obtained compound I-47 was a white solid (0.29 g, yield 47%), mp = 139.4-141.9 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 8.22 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.25-7.21 (m, 1H), 7.17 (dd, J = 8.1, 2.9 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.96-6.86 (m, 2H), 6.53 (s, 1H), 3.76 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.3,158.5(d,J＝246.2Hz),145.7,141.2(q,J＝38.5Hz),136.4,134.2,129.2,128.5,123.0(d,J＝8.6Hz),121.1(q,J＝269.7Hz),1 19.8,117.7,117.5,117.2,117.0,114.7(d,J＝22.2Hz),99.5,36.5.

Example 49 Compound I-48

2-((2-Fluoro-4-chlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-48 in the embodiment is as follows: using the method described in Example 2, 2-fluoro-4-chloroaniline replaces aniline, and the other steps are the same as in Example 2. The obtained compound I-48 is a green solid (0.33 g, yield 54%), mp = 128.3-130.3 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.10 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.17-7.13 (m, 2H), 7.08 (d, J = 8.7 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.54 (s, 1H), 3.80 (s, 3H); ¹³ C NMR (101MHz, Chloroform-d) δ 167.5, 155.1 (d, J = 249.3Hz), 145.6, 141.2 (q, J = 38.6Hz), 136.3, 134.2, 128.6 (d, J = 9.5Hz), 128.2, 128.0 (d, J = 11.7Hz), 124.8 (d, J＝3.7Hz), 123.2 (d, J＝2.4Hz), 121.1 (q, J＝269.7Hz), 119.6, 117.3, 117.0, 116.6 (d, J＝3.1Hz), 99.5 (d, J＝2.1Hz), 36.5.

Example 50 Compound I-49

2-((4-Fluoro-3-(trifluoromethyl)phenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-49 in the embodiment is as follows: using the method described in Example 2, 4-fluoro-3-trifluoromethylaniline replaces aniline, and the other steps are the same as in Example 2. The obtained compound I-49 is a white solid (0.40 g, yield 60%), mp = 149.5-151.2 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.32 (s, 1H), 7.85 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.46-7.39 (m, 2H), 7.34 (dt, J = 7.0, 3.4 Hz, 1H), 7.20-7.12 (m, 2H), 6.91 (t, J = 7.5 Hz, 1H), 6.56 (s, 1H), 3.84 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.9,155.8(dd,J＝252.8,1.9Hz),146.7,141.3(q,J＝38.9Hz),137.2(d,J＝3.2Hz),136.2,134.4,128.1,127.2(d,J＝8.0Hz),122.5 (q,J＝273.7Hz),121.05(q,J＝268.7Hz),120.5(dd,J＝4.6,1.4Hz),119.0,118.3,118.0,115.6,115.4,99.7(d,J＝2.1Hz),36.6.

Example 51 Compound I-50

2-((4-chloro-3-(trifluoromethyl)phenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-50 in the embodiment is as follows: using the method described in Example 2, 4-chloro-3-trifluoromethylaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-50 is a red solid (0.35 g, yield 50%), mp = 141.2-143.9 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.35 (s, 1H), 7.85 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.49-7.38 (m, 3H), 7.32 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 6.3 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.54 (s, 1H), 3.82 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,145.5,141.3(q,J＝38.7Hz),140.1,136.1,134.4,132.6,129.4(q,J＝31.4Hz),128.1,125.4(d,J＝1.5Hz),124.6,122.7(q, J＝273.4Hz), 121.0 (q, J＝269.7Hz), 119.8, 119.6 (q, J＝5.4, 4.9Hz), 99.7 (d, J＝2.1Hz) 116.43, 116.37, 36.6.

Example 52 Compound I-51

2-((3,5-difluorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-51 in the embodiment is as follows: using the method described in Example 2, 3,5-difluoroaniline replaces aniline, and the other steps are the same as in Example 2. The obtained compound I-51 is a white solid (0.28g, yield 48%), mp = 174.7-176.8°C; ¹ H NMR (400MHz, Chloroform-d) δ9.18 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 7.9Hz, 1H), 7.47 (d, J = 3.9Hz, 2H), 7.03-6.95 (m, 1H), 6.66 (d, J = 7.7Hz, 2H), 6.56 (s, 1H), 6.45 (t, J = 8.9Hz, 1H), 3.82 (s, 3H); ¹³ CNMR(101MHz,Chloroform-d)δ167.5,164.0(d,J＝246.7Hz),163.9(d,J＝246.8Hz),144.6,144.0(t,J＝12.9Hz),141.3(q,J＝38.4Hz),136.1,134.2,128.2,121.0 (q,J＝268.5Hz),120.4,117.9,117.5,102.6(d,J＝11.8Hz),102.6(d,J＝28.1Hz),99.6(d,J＝2.0Hz),97.9(t,J＝25.9Hz),36.6; ESI-MScalculated for C ₁₈ H ₁₄ F ₅ N ₄ O ⁺ [M+H] ⁺ ,397.1082;found,397.1084.

Example 53 Compound I-52

2-((3,5-dichlorophenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-52 in the embodiment is as follows: using the method described in Example 2, 3,5-dichloroaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-52 is a white solid (0.40 g, yield 63%), mp = 141.8-143.6 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 7.94 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.51-7.38 (m, 2H), 7.04 (d, J = 1.5 Hz, 2H), 7.00-6.94 (m, 2H), 6.55 (s, 1H), 3.82 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.6,144.8,143.4,141.3(q,J＝38.7Hz),136.1,135.8(2C),134.3,128.2,122.6,121.0(q,J＝268.7Hz),120.3,118.3(2C),117 .5,117.2,99.6(d,J=2.0Hz),36.6; ESI-MS calculated for C ₁₈ H ₁₄ Cl ₂ F ₃ N ₄ O ⁺ [M+H] ⁺ ,429.0491; found, 429.0497.

Example 54 Compound I-53

2-((3-Fluoro-2-methylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The preparation method of compound I-53 in the embodiment is as follows: using the method described in Example 2, 3-fluoro-2-methylaniline is substituted for aniline, and the other steps are the same as in Example 2. The obtained compound I-53 is a gray solid (0.30 g, yield 52%), mp = 135.5-137.8 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.17-7.03 (m, 3H), 6.89-6.80 (m, 2H), 6.56 (s, 1H), 3.84 (s, 3H), 2.18 (s, 3H); ¹³ C NMR (101MHz, Chloroform-d) δ 167.9, 162.1 (d, J = 244.0Hz), 147.3, 141.2 (q, J = 38.6Hz), 140.9 (d, J = 6.6Hz), 136.3, 134.2, 127.9, 126.9 (d, J = 10.2Hz), 121.1 (q, J＝269.7Hz), 119.2 (d, J＝17.7Hz), 118.2, 117.9 (d, J＝2.9Hz), 116.2, 114.9, 111.0 (d, J＝23.1Hz), 99.7 (d, J＝2.1Hz), 36.6, 9.7.

Example 55 Compound I-54

2-((3-chloro-2-methylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-54 in the example is as follows: using the method described in Example 2, replacing aniline with 3-chloro-2-methylaniline, and the other steps are the same as in Example 2. The obtained compound I-54 was a brown solid (0.32 g, yield 52%), mp = 122.5-124.1 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.17 (s, 1H), 7.86 (s, 1H), 7.61 (dd, J = 8.0, 1.3 Hz, 1H), 7.35 (ddd, J = 8.6, 7.2, 1.4 Hz, 1H), 7.22-7.17 (m, 1H), 7.14-7.08 (m, 1H), 6.99-6.95 (m, 2H), 6.86-6.80 (m, 1H), 6.57 (s, 1H), 3.84 (s, 3H), 2.32 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.9,147.7,141.2(q,J＝38.7Hz),140.4,136.3,135.8,134.3,130.9,127.9,127.1,125.6,121.9,121.1(q,J＝268.7Hz),118.0 ,115.8,114.4,99.7(d,J=2.0Hz),36.6,15.1.

Example 56 Compound I-55

2-((4-Fluoro-2-methylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-55 in the example is as follows: using the method described in Example 2, replacing aniline with 4-fluoro-2-methylaniline, and the other steps are the same as in Example 2. The obtained compound I-55 was a brown solid (0.35 g, yield 59%), mp = 125.6-126.7 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.03 (s, 1H), 7.85 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.19 (dd, J = 8.6, 5.4 Hz, 1H), 6.98 (dd, J = 9.2, 2.6 Hz, 1H), 6.90 (td, J = 8.4, 2.8 Hz, 1H), 6.78 (dd, J = 17.7, 8.2 Hz, 2H), 6.56 (s, 1H), 3.85 (s, 3H), 2.24 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.1,160.1(d,J＝243.8Hz),148.9,141.2(q,J＝38.5Hz),136.5,136.0(d,J＝8.1Hz),134.7(d,J＝2.8Hz),134.4,127.8,126.4(d,J =8.6Hz), 121.1 (q, J = 269.7Hz), 117.7 (d, J = 22.1Hz), 117.1, 115.0, 113.7, 113.4 (d, J = 2.7Hz), 99.6 (d, J = 2.1Hz), 36.6, 18.2.

Example 57 Compound I-56

2-((4-chloro-2-methylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-56 in the example is as follows: using the method described in Example 2, replacing aniline with 4-chloro-2-methylaniline, and the other steps are the same as in Example 2. The obtained compound I-56 was a white solid (0.35 g, yield 58%), mp = 159.1-161.3 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 7.76 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 17.3, 8.7 Hz, 2H), 7.07 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.48 (s, 1H), 3.76 (s, 3H), 2.16 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.9,147.7,141.2(q,J＝38.6Hz),137.7,136.4,134.3,134.1,131.1,129.4,127.9,126.8,124.1,121.1(q,J＝268.5Hz),117.9 ,115.7,114.5,99.7(d,J=2.1Hz),36.6,18.0.

Example 58 Compound I-57

2-((5-Fluoro-2-methylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-57 in the example is as follows: using the method described in Example 2, replacing aniline with 5-fluoro-2-methylaniline, and the other steps are the same as in Example 2. The obtained compound I-57 was a red solid (0.32 g, yield 54%), mp = 119.8-122.7 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 1H), 7.84 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.16 (t, 1H), 7.09 (t, 1H), 6.94 (dd, J = 10.5, 2.5 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.63 (td, J = 8.3, 2.5 Hz, 1H), 6.48 (s, 1H), 3.75 (s, 3H), 2.16 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ167.8,161.7(d,J＝243.0Hz),146.5,141.2(q,J＝38.4Hz),140.6(d,J＝9.9Hz),136.3,134.2,132.0(d,J＝9.2Hz),128.1,126.1(d,J =3.1Hz), 121.1 (q, J = 268.5Hz), 118.8, 116.6, 115.8, 110.2 (d, J = 21.0Hz), 107.8 (d, J = 23.9Hz), 99.7 (d, J = 2.1Hz), 36.6, 17.4.

Example 59 Compound I-58

2-((5-chloro-2-methylphenyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzamide

The specific preparation method of compound I-58 in the example is as follows: using the method described in Example 2, replacing aniline with 5-chloro-2-methylaniline, and the other steps are the same as in Example 2. The obtained compound I-58 was a white solid (0.39 g, yield 64%), mp = 115.3-117.8 ° C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 7.92 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.31-7.27 (m, 1H), 7.16 (dd, J = 8.3, 3.9 Hz, 2H), 7.02-6.96 (m, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.56 (s, 1H), 3.83 (s, 3H), 2.24 (s, 3H); ¹³ CNMR(101MHz,Chloroform-d)δ167.9,146.7,141.2(q,J＝38.6Hz),140.5,136.3,134.3,132.2,131.9,129.5,128.0,123.8,121.2,121.1(q,J＝268.6Hz),118. 6,116.4,115.4,99.7(d,J＝2.0Hz),36.6,17.6.

Example 60 Compound I-59

N-(4-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((3-chlorophenyl)amino)benzamide

The preparation method of compound I-59 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with 3-trifluoromethyl-4-chloropyrazolamine, and the other steps are the same as in Example 1, to obtain the intermediate compound IV-3. Then, using the method described in Example 2, replacing IV-1 with IV-3, replacing aniline with 3-chloroaniline, and the other steps are the same as in Example 2. The obtained compound I-59 was a white solid (0.38 g, yield 59%), mp = 139.7-141.6 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 7.81 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.44 (td, J = 7.7, 7.0, 1.3 Hz, 1H), 7.41-7.37 (m, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 2.0 Hz, 1H), 7.07-7.01 (m, 2H), 6.96-6.90 (m, 1H), 3.83 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.2,146.2,142.3,137.2(q,J＝38.2Hz),135.1,134.6,134.0,130.6,128.5,123.4,121.0,120.3(q,J＝269.5Hz),119.4,119.3 ,116.7,115.4,104.2(d,J=1.2Hz),38.1; ESI-MScalculated for C ₁₈ H ₁₃ Cl ₂ F ₃ N ₄ NaO ⁺ [M+Na] ⁺ ,451.0311; found, 451.0312.

Example 61 Compound I-60

N-(4-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((4-chlorophenyl)amino)benzamide

The preparation method of compound I-60 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with 3-trifluoromethyl-4-chloropyrazolamine, and the other steps are the same as in Example 1, to obtain the intermediate compound IV-3. Then, using the method described in Example 2, replacing IV-1 with IV-3, replacing aniline with 4-chloroaniline, and the other steps are the same as in Example 2. The obtained compound I-60 was a yellow solid (0.33 g, yield 52%), mp = 148.9-151.4 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 7.77 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.33-7.27 (m, 3H), 7.13 (d, J = 8.7 Hz, 2H), 6.89 (t, J = 7.5 Hz, 1H), 3.84 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.3,147.0,139.3,137.2(q,J＝38.1Hz),134.6,134.1,129.6,129.2,128.6,128.4,123.1,120.3(q,J＝269.5Hz),118.7,116.4 ,116.0,114.6,104.2(d,J=1.3Hz),38.1; ESI-MS calculated for C ₁₈ H ₁₄ Cl ₂ F ₃ N ₄ O ⁺ [M+H] ⁺ ,429.0491; found, 429.0497.

Example 62 Compound I-61

N-(4-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((3-trifluoromethylphenyl)amino)benzamide

The preparation method of compound I-61 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with 3-trifluoromethyl-4-chloropyrazolamine, and the other steps are the same as in Example 1, to obtain the intermediate compound IV-3. Then, using the method described in Example 2, replacing IV-1 with IV-3, replacing aniline with 3-trifluoromethylaniline, and the other steps are the same as in Example 2. The obtained compound I-61 was a white solid (0.39 g, yield 56%), mp = 137.2-139.2°C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.32 (s, 1H), 7.78 (s, 1H), 7.74-7.70 (m, 1H), 7.47-7.33 (m, 5H), 7.31 (d, J = 7.6 Hz, 1H), 6.99-6.92 (m, 1H), 3.85 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.3,146.1,141.5,137.3(q,J＝38.2Hz),134.7,134.0,132.0(q,J＝32.3Hz),130.2,128.5,124.3,123.9(q,J＝273.7Hz),120.3( q,J＝270.7Hz),119.9(q,J＝3.8Hz),119.4,117.6(q,J＝3.8Hz),116.4,115.4,104.2(d,J＝1.2Hz),38.1; ESI-MS calculated forC ₁₉ H ₁₃ ClF ₆ N ₄ NaO ⁺ [M+Na] ⁺ ,485.0574;found,485.0580.

Example 63 Compound I-62

N-(4-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((4-trifluoromethylphenyl)amino)benzamide

The preparation method of compound I-62 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with 3-trifluoromethyl-4-chloropyrazolamine, and the other steps are the same as in Example 1, to obtain the intermediate compound IV-3. Then, using the method described in Example 2, replacing IV-1 with IV-3, replacing aniline with 4-trifluoromethylaniline, and the other steps are the same as in Example 2. The obtained compound I-62 was a white solid (0.32 g, yield 47%), mp = 117.4-120.3 ° C; ¹³ C NMR (101 MHz, Chloroform-d) δ 168.3, 145.2, 144.3, 137.2 (qd, J = 38.1, 5.9 Hz), 134.5, 133.6, 131.8, 129.3, 127.7 (2C), 126.8 (q, J = 3.7 Hz), 124.4 (q, J = 272.7 Hz), 120.0, 119.6 (2C), 117.7 (q, J = 263.6 Hz), 117.2, 104.3 (d, J = 9.6 Hz), 38.1; ESI-MS calculated for _{C 19} H ₁₄ ClF ₆ N ₄ O ⁺ [M+H] ⁺ ,463.0755; found,463.0756.

Example 64 Compound I-63

N-(4-Fluoro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((3-chlorophenyl)amino)benzamide

The preparation method of compound I-63 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with 3-trifluoromethyl-4-fluoropyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-4. Then, using the method described in Example 2, replacing IV-1 with IV-4, replacing aniline with 3-chloroaniline, and the other steps are the same as in Example 2. The obtained compound I-63 was a yellow solid (0.35 g, yield 57%), mp = 140.9-142.0°C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 7.84 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.52-7.39 (m, 2H), 7.29 (d, J = 7.5 Hz, 1H), 7.23 (t, J = 1.9 Hz, 1H), 7.11-7.04 (m, 2H), 6.95 (t, J = 7.5 Hz, 1H), 3.81 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.4,146.2,142.3,139.5(d,J＝255.9Hz),135.1,134.6,130.6,128.4,127.3(q,J＝39.4Hz),123.4,122.6(d,J＝22.2Hz),121.0,1 20.1 (q, J=269.7Hz), 119.4, 119.3, 116.7, 115.3, 37.7; ESI-MS calculated for _{C 18} H ₁₃ ClF ₄ N ₄ NaO ⁺ [M+Na] ⁺ , 435.0606; found, 435.0603.

Example 65 Compound I-64

N-(4-Fluoro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((4-chlorophenyl)amino)benzamide

The preparation method of compound I-64 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with 3-trifluoromethyl-4-fluoropyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-4. Then, using the method described in Example 2, replacing IV-1 with IV-4, replacing aniline with 4-chloroaniline, and the other steps are the same as in Example 2. The obtained compound I-64 was a yellow solid (0.38 g, yield 62%), mp = 132.3-134.6 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 7.72 (s, 1H), 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 (ddd, J = 8.6, 7.1, 1.5 Hz, 1H), 7.33-7.25 (m, 3H), 7.16-7.09 (m, 2H), 6.88 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 3.79 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.4,147.0,139.6(d,J＝256.5Hz),139.3,134.6,129.6(2C),128.7,128.3,127.3(q,J＝40.4Hz),123.2(2C),122.7(d,J＝22.3Hz ), 120.2 (q, J=269.7Hz), 118.6, 116.0, 114.5, 37.8; ESI-MS calculated for C ₁₈ H ₁₄ ClF ₄ N ₄ O ⁺ [M+H] ⁺ , 413.0787; found, 413.0788.

Example 66 Compound I-65

N-(4-Fluoro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((3-trifluoromethylphenyl)amino)benzamide

The preparation method of compound I-65 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with 3-trifluoromethyl-4-fluoropyrazolamine, and the other steps are the same as in Example 1, to obtain the intermediate compound IV-4. Then, using the method described in Example 2, replacing IV-1 with IV-4, replacing aniline with 3-trifluoromethylaniline, and the other steps are the same as in Example 2. The obtained compound I-65 was a brown solid (0.33 g, yield 49%), mp = 121.8-123.6 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.35 (s, 1H), 7.76 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.50-7.41 (m, 3H), 7.40-7.29 (m, 3H), 6.94 (t, J = 7.1 Hz, 1H), 3.80 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.4,146.2,141.5,139.6(d,J＝256.8Hz),134.6,132.0(q,J＝32.3Hz),130.2,128.4,127.4(dd,J＝39.6,6.3Hz),124.3,124.0(q, J＝272.7Hz), 122.6 (d, J＝23.2Hz), 120.2 (q, J＝270.7Hz), 119.9 (q, J＝3.7Hz), 119.4, 117.6 (q, J＝3.7Hz), 116.3, 115.3, 37.8; ESI-MS calculated for C ₁₉ H ₁₃ F ₇ N ₄ NaO ⁺ [ M+Na] ⁺ ,469.0870;found,469.0881.

Example 67 Compound I-66

N-(4-Fluoro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-((4-trifluoromethylphenyl)amino)benzamide

The preparation method of compound I-66 in the embodiment is as follows: using the method described in Example 1, replacing trifluoromethylpyrazolamine with 3-trifluoromethyl-4-fluoropyrazolamine, and the other steps are the same as in Example 1 to obtain the intermediate compound IV-4. Then, using the method described in Example 2, replacing IV-1 with IV-4, replacing aniline with 4-trifluoromethylaniline, and the other steps are the same as in Example 2. The obtained compound I-66 was a brown solid (0.25 g, yield 37%), mp = 123.1-124.8 °C; ¹ H NMR (400 MHz, Chloroform-d) δ 9.33 (s, 1H), 7.83 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.52-7.43 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.97 (ddd, J = 8.1, 6.4, 2.0 Hz, 1H), 3.78 (s, 3H); ¹³ C NMR(101MHz,Chloroform-d)δ168.4,145.3,144.3(d,J＝1.0Hz),139.6(dd,J＝257.0,2.0Hz),134.5,128.5(2C),128.4(d,J＝166.9Hz),126.9(q,J＝3.7Hz),124.5(q,J＝32.8Hz),124.4(q,J＝271.7Hz),122.6(d,J＝22.2Hz),120.1(q,J＝268.6Hz),120.0,119.6(2C),117.2,116.2,37.7；ESI-MS calculatedfor C ₁₉ H ₁₄ F ₇ N ₄ O ⁺ [M+H] ⁺ ,447.1050;found,447.1051.

Embodiment 68

The inhibitory effects of the aromatic aminobenzamide derivatives containing substituted pyrazole structures (compound numbers I-1 to I-66) synthesized in Examples 2 to 67 on the tested plant pathogenic fungi and oomycetes.

1. Experimental subjects

The aromatic aminobenzamide derivatives containing a substituted pyrazole structure synthesized in Examples 2-67, namely compounds I-1 to I-66.

2. Experimental methods

The mycelium linear growth rate method was used to determine the in vitro inhibitory activity of compounds I-1 to I-32 against five tested plant pathogens, including Sclerotinia sclerotiorum, Valsa mali, Botrytis cinerea, Rhizoctonia solani, and Phytophthora capsica. Compounds I-33 to I-66 were further synthesized based on the test results, and the in vitro inhibitory activity of these compounds against Sclerotinia sclerotiorum, Valsa mali, and Botrytis cinerea was determined. The selected fungi and oomycetes were provided by the College of Plant Protection, Northwest Agriculture and Forestry University.

With 20 mg/L fluopyrab and pyraclostrobin solutions as positive controls and 5% DMSO aqueous solution as blank controls, the accurately weighed test compound was completely dissolved in 5% DMSO (v/v) aqueous solution, and the test solution or control solution was quickly mixed with 150 mL sterile PDA medium at 50°C to obtain a drug-containing medium with a mass concentration of 20 mg/L; it was poured into a sterilized culture dish while hot, 10 mL per dish, and cooled for use. The plant pathogens to be tested (bacteria cake diameter = 5 mm) were inoculated into the above culture dishes, and 3 parallels were set for each test group; it was placed in a constant temperature incubator at 25°C for 72 hours, and the colony diameter (mm) was measured by the cross method, and the mycelium growth inhibition rate (IR) was calculated according to formula (1): IR (%) = [(d _c -d ₀ )-(ds-d ₀ )]/(d _c -d ₀ )×100(1);

Where: _d0 is the diameter of the bacterial cake (5 mm), _dc is the average diameter of the colonies in the blank control group (mm), and ds is the average diameter of the colonies in the sample group (mm).

3. The experimental results are shown in Table 1-3

Table 1 Inhibitory effects of the aromatic aminobenzamide derivatives containing substituted pyrazole structures synthesized in Examples 2-33 on plant pathogenic fungi and oomycetes at a concentration of 20 mg/L (inhibition rate, %)

The data in table ^a are the average of three data; Ss ^b S. sclerotiorum; Vm ^c V. mali; Bc ^d B. cinerea; Rs ^e R. solani; Pc ^f P. capsici.

Thirty-two aromatic aminobenzamide derivatives containing substituted pyrazole structures were initially screened at a concentration of 20 mg/L. From Table 1, it can be seen that the inhibition rates of more than half of the compounds I-1 to I-32 against Sclerotinia sclerotiorum, apple rot pathogen and Botrytis cinerea were all above 60%, among which the activity of the compounds against apple rot pathogen was significantly better than that of other fungi, and the inhibition rates of compounds I-1 and I-9 against apple rot pathogen could reach 100%. When R ₁ was CF ₃ and R ₂ was an electron-withdrawing group, the inhibition rates of compounds I-8 to I-16 against Sclerotinia sclerotiorum, apple rot pathogen and Botrytis cinerea could reach above 70%, and the inhibition rates of compounds I-2, I-8, I-10, I-12, I-15, I-16, I-17, I-26, I-31 and I-32 against apple rot pathogen could reach above 90%. Compound I-16 has the best activity against Sclerotinia sclerotiorum of rapeseed, with an inhibition rate of 93.3%. Compound I-13 has an inhibition rate of 84.8% against Botrytis cinerea, which is better than other compounds. This shows that the aromatic aminobenzamide derivatives containing substituted pyrazole structures prepared in this application have the potential to become broad-spectrum antifungal agents.

Table 2 Inhibitory effect of the aromatic aminobenzamide derivatives containing substituted pyrazole structure synthesized in Example 2-59 on plant pathogenic fungi at a concentration of 10 mg/L (inhibition rate, %)

After analyzing the structures of the excellent active compounds, it was found that when R ₁ is CF ₃ and R ₃ is replaced by electron-withdrawing groups F, Cl and CF ₃ , the activities of the compounds I-9 to I-16 series are significantly better than those of the compounds I-1 to I-8 series. Therefore, the applicant further introduced multiple substituted electron-withdrawing or electron-donating groups at different positions into the terminal benzene of the compounds for structural optimization, and the antifungal activities of the synthesized 26 compounds against Sclerotinia sclerotiorum, apple rot pathogen and Botrytis cinerea were determined at a concentration of 10 mg/L. The results are shown in Table 2. The inhibition rate of compound I-46 against Sclerotinia sclerotiorum can reach 79.2% at 10 mg/L; the inhibition effect of compound I-41 against apple rot pathogen is the best, reaching 86.3%; the inhibition rate of compound I-40 against Botrytis cinerea is 78.2%.

In order to further improve the antifungal activity of the target compound, the structure of the compound is further optimized based on the above results, R ₁ is fixed as CF ₃ , positions 3 and 4 on the terminal benzene ring are Cl and CF ₃ with the best activity, halogen atoms F and Cl are introduced into R ₂ , and the antifungal activities of the synthesized 8 compounds against rapeseed sclerotinia, apple rot pathogen and grape gray mold at a concentration of 10 mg/L are measured. The results are shown in Table 3, and the activity of the compound is further improved, and it has inhibitory activity against these three fungi. The inhibition rates against rapeseed sclerotinia and apple rot pathogen are mostly above 70%, and the highest can reach 83.6% and 92.6% respectively. The antifungal activity of the compound can be further improved through this structural optimization.

Table 3 Inhibitory effect of the aromatic aminobenzamide derivatives containing substituted pyrazole structure synthesized in Examples 60-67 on plant pathogenic fungi at a concentration of 10 mg/L (inhibition rate, %)

In summary, the aromatic aminobenzamide derivatives containing a substituted pyrazole structure prepared by chemical synthesis in the present invention have excellent antifungal activity, especially against apple rot pathogen and rapeseed sclerotinia pathogen, which lays a foundation for the preparation of fungicides with aromatic aminobenzamide derivatives containing a substituted pyrazole structure as the main antifungal active ingredients.

The above description only describes the specific implementation mode of the present invention. Various examples do not limit the essential content of the present invention. After reading the description, ordinary technicians in the relevant technical field can modify or deform the specific implementation modes described above without departing from the essence and scope of the invention.

Claims (7)

1. an arylaminobenzamide derivative containing a substituted pyrazole structure, characterized in that its general structural formula (I) is as follows: Wherein, R ₁ is trifluoromethyl or difluoromethyl; R ₂ is hydrogen, fluorine or chlorine; R ₃ is hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluorine, Chlorine or its multiple substitution combinations. 2. the arylaminobenzamide derivatives containing substituted pyrazole structure according to claim 1, characterized in that: the arylaminobenzamide derivatives containing substituted pyrazole structure are preferably the following compounds: 3. A method for preparing the arylaminobenzamide derivatives containing a substituted pyrazole structure according to any one of claims 1 to 2, characterized in that: the preparation method comprises the following synthetic route: 4. the preparation method of the arylaminobenzamide derivative containing substituted pyrazole structure according to claim 3, is characterized in that: described preparation method specifically comprises the following steps: Step S1, using o-iodobenzoyl chloride (II) and substituted pyrazolamide (III) as raw materials, using an acid-binding agent to undergo a condensation reaction in the first solvent to generate a substituted pyrazole structure corresponding to the general formula (IV) O-iodobenzamide compounds, the resulting product is purified by column chromatography to obtain pure product Step S2, using the o-iodobenzamide compound (IV) containing a substituted pyrazole structure and a substituted aniline (V) as raw materials, using a copper catalyst to undergo a Ullmann coupling reaction in a second solvent and alkaline conditions to generate a substituted The arylaminobenzamide derivatives of the pyrazole structure, that is, the general formula (I), the obtained product is purified by column chromatography to obtain a pure product. 5. the preparation method of the arylaminobenzamide derivatives containing substituted pyrazole structure according to claim 4, characterized in that: the first solvent in the step S1 is 1,2-dichloroethane or dichloromethane. 6. The preparation method of arylaminobenzamide derivatives containing substituted pyrazole structure according to claim 4, characterized in that: the second solvent in the step S2 is dimethylsulfoxide or 1,4 - Dioxane. 7. The application of the arylaminobenzamide derivatives containing substituted pyrazole structure according to any one of claims 1 to 2, characterized in that: the arylamino group containing substituted pyrazole structure Benzamide derivatives are used in agricultural fungicides.