Amide derivative containing trifluoromethylpyridine as well as synthesis method and application of amide derivative

Abstract

The invention relates to the technical field of compound synthesis, in particular to an amide derivative containing trifluoromethylpyridine as well as a synthesis method and application of the amide derivative. The structural general formula of the amide derivative is shown as a formula I, a formula II and a formula III. The amide derivative has a novel molecular skeleton, has excellent anti-fungal disease activity on tomato gray mold, rice sheath blight disease and sclerotinia rot of colza, and also has good protection and treatment activity on tomato crops. The invention also provides a synthesis method and application of the amide derivative containing trifluoromethylpyridine.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and in particular to an amide derivative containing trifluoromethylpyridine, its synthesis method, and its application. Background Technology

[0002] Fungi are a significant threat to agricultural production, causing substantial losses. Fungi infect crop plants, disrupting their physiological structure and metabolic processes, triggering various diseases that spread rapidly. Some fungi even produce toxins harmful to humans and animals, entering the food chain through agricultural products and causing enormous damage and economic losses. Currently, fungicides are the primary means of scientifically controlling fungal diseases and ensuring agricultural production. However, the widespread use of chemical pesticides has led to problems such as pesticide resistance in pathogenic fungi and severe soil and water pollution. Therefore, the development of new, highly efficient, low-risk, and crop-safe green fungicides is urgently needed.

[0003] Amide functional groups are widely present in the biological and synthetic fields, encompassing proteins, polymers, agrochemicals, and pharmaceuticals. In the agrochemical field, amide derivatives exhibit diverse and broad-spectrum biological activities, including antifungal, insecticidal, herbicidal, and antiviral activities. Their synthesis and biological evaluation have long been important topics in pesticide chemistry. To date, numerous carboxylamide-containing fungicides have been commercialized, among which succinate dehydrogenase inhibitors (SDHIs) are one of the fastest-growing and most active broad-spectrum fungicide classes in recent years. Notably, the trifluoromethylpyridine fragment has been incorporated into some SDHIs and other commercially available fungicides: for example, fluopyram, fluopyram, and fluopyram containing this fragment have all shown excellent protective efficacy against various fungal diseases. Trifluoromethylpyridine, as a bioactive fragment with significant application value, plays a crucial role in drug design, particularly in the development of antifungal agents. Due to the strong electronegativity, high stability, and lipophilicity of the trifluoromethyl group, compounds containing -CF3 often exhibit significant biological activity and unique physicochemical properties. Introducing a trifluoromethylpyridine fragment can enhance the antifungal activity of antibiotics and improve their efficacy against resistant strains. Furthermore, this structural unit has been widely used in the design of novel antifungal agents to inhibit fungal growth and reproduction by targeting specific sites on the cell wall or membrane. Therefore, splicing the trifluoromethylpyridine fragment with an amide structure holds promise for generating antifungal candidate compounds with potential applications in crop protection. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides an amide derivative containing trifluoromethylpyridine, its synthesis method, and its application. This amide derivative has a novel molecular skeleton and exhibits excellent antifungal activity against tomato gray mold, rice sheath blight, and rapeseed sclerotinia stem rot, while also demonstrating good protective and curative activity against tomato crops.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] This invention provides an amide derivative containing trifluoromethylpyridine, the general structural formula of which is shown in Formula I, Formula II and Formula III:

[0007] Formula I; Formula II; Formula III;

[0008] Wherein, R is selected from any one of phenyl, halophenyl, phenyl-C1 to C4 alkyl, phenyl-C1 to C4 alkoxy and 5 to 6 membered heterocycles;

[0009] R 1 It is selected from any one of benzyl, methyl, and ethyl.

[0010] R 2 It is selected from any one of phenyl, 5-6 membered heterocycles, 5-6 membered haloheterocycles, 5-6 membered heterocycles-C1-C6 alkyl and 5-6 membered haloheterocycles-C1-C6 alkyl;

[0011] R 3 Selected from 5- to 6-membered halogenated heterocycles.

[0012] Preferably, the amide derivative is any one of the following compounds:

[0013] .

[0014] The present invention also provides a method for synthesizing the amide derivative described in the above technical solution, comprising the following steps:

[0015] 1) Under a nitrogen atmosphere, nitromethane, potassium hydroxide and dimethyl sulfoxide were mixed and stirred, and then mixed with compound 1 and subjected to an arylation reaction to obtain compound 2;

[0016] Compound 2 was mixed with anhydrous ethanol and stannous chloride dihydrate and then subjected to a reduction reaction to obtain compound 3.

[0017] Compound 4 was mixed with selenium dioxide and pyridine and then subjected to an oxidation reaction to obtain compound 5.

[0018] Compound 5 was mixed with dichloromethane, N,N-dimethylformamide and oxalyl chloride and subjected to a substitution reaction to obtain compound 6;

[0019] Compound 3 was mixed with compound 6 and diisopropylethylamine and then subjected to a condensation reaction to obtain compound 7.

[0020] Compound 7 was mixed with methanol, hydroxylamine hydrochloride and potassium carbonate and then subjected to a condensation reaction to obtain compound 8.

[0021] Compound 8 was mixed with sodium hydride, N,N-dimethylformamide and a haloalkane and then subjected to an alkylation reaction to obtain the compound shown in Formula I.

[0022] 2) Compound 7 was mixed with a primary amine and tetraisopropyl titanate and then subjected to a condensation reaction to obtain the compound shown in Formula II;

[0023] 3) The compound shown in Formula II was mixed with sodium borohydride and anhydrous ethanol and then subjected to a reduction reaction to obtain the compound shown in Formula III;

[0024] The structural formulas of compounds 1-8 are as follows:

[0025]

[0026] Compound 1 Compound 2 Compound 3

[0027]

[0028] Compound 4, Compound 5, Compound 6, Compound 7

[0029]

[0030] Compound 8.

[0031] Preferably, in step 1), the volume of nitromethane, the mass of potassium hydroxide, the volume of dimethyl sulfoxide, and the mass of compound 1 are 12.48 mL: 10.39 g: 150 mL: 10 g; the conditions for the arylation reaction include: a temperature of 20~30℃ and a time of 3~5 h;

[0032] The mass ratio of compound 2 to the volume of anhydrous ethanol and the mass of stannous chloride dihydrate is 2.41 g: 70 mL: 45.13 g; the conditions for the reduction reaction include: a temperature of 75-85°C and a time of 4-10 h.

[0033] The molar ratio of compound 4 to the mass of selenium dioxide and the volume ratio of pyridine is 5 mmol: 1.11 g: 20 mL; the oxidation reaction conditions include a temperature of 90~110℃ and a time of 2~8 h.

[0034] The molar ratio of compound 5 to the volume of dichloromethane, the number of drops of N,N-dimethylformamide, and the volume of oxaloyl chloride is 2 mmol: 20 mL: 1-2 drops: 0.18 mL; the conditions for the substitution reaction include: a temperature of 0-30 °C and a time of 0.5-2 h.

[0035] The mass ratio of compound 3 to the molar ratio of compound 6 and the volume ratio of diisopropylethylamine is 505.4 mg: 2 mmol: 0.7 mL, and the condensation reaction conditions include: temperature of 0~40℃ and time of 0.5~4 h.

[0036] The molar ratio of compound 7 to the volume of methanol, the mass of hydroxylamine hydrochloride, and the mass ratio of potassium carbonate are 3 mmol: 25 mL: 625.39 mg: 621.92 mg. The conditions for the condensation reaction are: temperature of 50-70 °C and time of 6-12 h.

[0037] The molar ratio of compound 8 to sodium hydride, N,N-dimethylformamide, and haloalkane is 0.15 mmol:10.8 mg:2 mL:0.23 mmol; the alkylation reaction conditions include: a temperature of 0-30 °C and a time of 1-6 h.

[0038] Preferably, in step 2), the molar ratio of compound 7 to the molar ratio of the primary amine and the volume ratio of tetraisopropyl titanate are 0.15 mmol:0.45 mmol:1~2 mL; the conditions for the condensation reaction include: a temperature of 20~30℃ and a time of 6~24 h.

[0039] Preferably, in step 3), the molar ratio of the compound shown in Formula II to the mass of sodium borohydride and the volume ratio of anhydrous ethanol is 0.15 mmol: 17 mg: 1 mL; the conditions for the reduction reaction include: a temperature of 20~30℃ and a time of 0.5~1 h.

[0040] The present invention also provides the application of the amide derivatives described in the above technical solution in the prevention and control of plant fungal diseases.

[0041] Preferably, the concentration of the amide derivative used is 0.195 to 400 µg / mL.

[0042] Preferably, the plant fungal diseases include one or more of the following: rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, blueberry gray mold, wheat scab, pseudostem spot, aflatoxin, and pepper anthracnose.

[0043] The present invention also provides an antibacterial agent for resisting plant fungal diseases, comprising the amide derivative described in the above technical solution;

[0044] The plant fungal diseases mentioned include one or more of the following: rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, blueberry gray mold, wheat scab, pseudostem spot, aflatoxin, and pepper anthracnose.

[0045] The beneficial effects of this invention are:

[0046] The amide derivatives provided by this invention have a novel molecular skeleton and exhibit certain antifungal effects against plant fungal diseases such as rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, blueberry gray mold, wheat scab, pseudostem spot, aspergillus flavus, and pepper anthracnose. Among them, compounds 9a-9c, 10a-10ad, and 11a-11c in the examples show certain antifungal effects against rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, pseudostem spot, aspergillus flavus, and pepper anthracnose. In particular, compounds 10o, 10t, and 10x show superior inhibitory activity against rice sheath blight, tomato gray mold, and rapeseed sclerotinia rot compared to the commercial fungicide azoxystrobin. Especially at a concentration of 100 µg / mL, compound 10ad exhibits strong in vitro antibacterial activity against rice sheath blight, tomato gray mold, and rapeseed sclerotinia stem rot, all of which surpass azoxystrobin. Furthermore, the amide derivative of this invention containing trifluoromethylpyridine has good protective and curative activity against tomato crops. Attached Figure Description

[0047] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the embodiments will be briefly described below.

[0048] Figure 1 This is a synthetic route for amide derivatives containing trifluoromethylpyridine. Detailed Implementation

[0049] This invention provides an amide derivative containing trifluoromethylpyridine, the general structural formula of which is shown in Formula I, Formula II and Formula III:

[0050] Formula I; Formula II; Formula III;

[0051] Wherein, R is selected from any one of phenyl, halophenyl, phenyl-C1 to C4 alkyl, phenyl-C1 to C4 alkoxy and 5 to 6 membered heterocycles;

[0052] R 1 It is selected from any one of benzyl, methyl, and ethyl.

[0053] R 2It is selected from any one of phenyl, 5-6 membered heterocycles, 5-6 membered haloheterocycles, 5-6 membered heterocycles-C1-C6 alkyl and 5-6 membered haloheterocycles-C1-C6 alkyl;

[0054] R 3 Selected from 5- to 6-membered halogenated heterocycles.

[0055] In this invention, the amide derivative is any one of the following compounds:

[0056] .

[0057] The present invention also provides a method for synthesizing the amide derivative described in the above technical solution, comprising the following steps:

[0058] 1) Under a nitrogen atmosphere, nitromethane, potassium hydroxide and dimethyl sulfoxide were mixed and stirred, and then mixed with compound 1 and subjected to an arylation reaction to obtain compound 2;

[0059] Compound 2 was mixed with anhydrous ethanol and stannous chloride dihydrate and then subjected to a reduction reaction to obtain compound 3.

[0060] Compound 4 was mixed with selenium dioxide and pyridine and then subjected to an oxidation reaction to obtain compound 5.

[0061] Compound 5 was mixed with dichloromethane, N,N-dimethylformamide and oxalyl chloride and subjected to a substitution reaction to obtain compound 6;

[0062] Compound 3 was mixed with compound 6 and diisopropylethylamine and then subjected to a condensation reaction to obtain compound 7.

[0063] Compound 7 was mixed with methanol, hydroxylamine hydrochloride and potassium carbonate and then subjected to a condensation reaction to obtain compound 8.

[0064] Compound 8 was mixed with sodium hydride, N,N-dimethylformamide and a haloalkane and then subjected to an alkylation reaction to obtain the compound shown in Formula I.

[0065] 2) Compound 7 was mixed with a primary amine and tetraisopropyl titanate and then subjected to a condensation reaction to obtain the compound shown in Formula II;

[0066] 3) The compound shown in Formula II was mixed with sodium borohydride and anhydrous ethanol and then subjected to a reduction reaction to obtain the compound shown in Formula III;

[0067] The structural formulas of compounds 1-8 are as follows:

[0068]

[0069] Compound 1 Compound 2 Compound 3

[0070]

[0071] Compound 4, Compound 5, Compound 6, Compound 7

[0072]

[0073] Compound 8.

[0074] In this invention, the preferred ratio of the volume of nitromethane, the mass of potassium hydroxide, the volume of dimethyl sulfoxide, and the mass of compound 1 in step 1) is 12.48 mL: 10.39 g: 150 mL: 10 g; the preferred conditions for the arylation reaction are: a temperature of 20-30°C and a time of 3-5 h; the preferred ratio of the mass of compound 2 to the volume of anhydrous ethanol and the mass of stannous chloride dihydrate is 2.41 g: 70 mL: 45.13 g; the preferred conditions for the reduction reaction are: a temperature of 75-85°C and a time of 4-10 h; the preferred molar ratio of compound 4 to the mass of selenium dioxide and the volume of pyridine is 5 mmol: 1.11 g: 20 mL; the preferred conditions for the oxidation reaction are: a temperature of 90-110°C and a time of 2-8 h; the preferred molar ratio of compound 5 to the volume of dichloromethane, the number of drops of N,N-dimethylformamide, and the volume of oxaloyl chloride is 2 mmol: 20 mL: 1-2 drops. The substitution reaction conditions include: temperature 0~30℃, time 0.5~2h; the preferred mass ratio of compound 3 to the molar ratio of compound 6 and the volume ratio of diisopropylethylamine is 505.4mg:2mmol:0.7mL; the condensation reaction conditions include: temperature 0~40℃, time 0.5~4h; the preferred molar ratio of compound 7 to the volume ratio of methanol, the mass ratio of hydroxylamine hydrochloride, and the mass ratio of potassium carbonate is 3mmol:25mL:625.39mg:621.92mg; the preferred condensation reaction conditions include: temperature 50~70℃, time 6~12h; the preferred molar ratio of compound 8 to the mass ratio of sodium hydride, the volume ratio of N,N-dimethylformamide, and the molar ratio of haloalkanes is 0.15mmol:10.8mg:2mL:0.23mmol; the preferred alkylation reaction conditions include: temperature 0~30℃, time 1~6h.

[0075] In this invention, the preferred molar ratio of compound 7 to the primary amine and the volume ratio of tetraisopropyl titanate is 0.15 mmol:0.45 mmol:1~2 mL; the preferred conditions for the condensation reaction are: a temperature of 20~30°C and a time of 6~24 h.

[0076] In this invention, the preferred molar ratio of the compound represented by Formula II to the mass of sodium borohydride and the volume ratio of anhydrous ethanol is 0.15 mmol:17 mg:1 mL; the preferred conditions for the reduction reaction are: a temperature of 20~30°C and a time of 0.5~1 h.

[0077] This invention also provides the application of the amide derivatives described in the above-mentioned technical solutions in the control of plant fungal diseases. In this invention, the preferred concentration of the amide derivatives is 0.195–400 µg / mL. In this invention, the plant fungal diseases preferably include one or more of the following: rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, blueberry gray mold, wheat scab, pseudostem spot, aspergillus flavus, and pepper anthracnose.

[0078] This invention also provides an antibacterial agent for resisting plant fungal diseases, containing the amide derivatives described in the above technical solution; the plant fungal diseases include one or more of rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, blueberry gray mold, wheat scab, pseudostem spot, aflatoxin, and pepper anthracnose.

[0079] To further illustrate the present invention, the following detailed description is provided in conjunction with embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0080] Example 1

[0081] This embodiment illustrates the preparation method of the amide derivative containing trifluoromethylpyridine according to the present invention, and its synthetic route is as follows: Figure 1 As shown.

[0082] The preparation methods for representative compounds include the following steps:

[0083] (1) Synthesis of compounds 2 and 3:

[0084]

[0085] Nitromethane (12.48 mL, 231.50 mmol) was added very slowly dropwise to a dry dimethyl sulfoxide (150 mL) solution containing potassium hydroxide (10.39 g, 185.20 mmol). The reaction mixture was stirred at 20 °C for 1 hour. Then, compound 1 (10.0 g, 46.30 mmol) was added dropwise to the reaction system. The mixture was stirred at room temperature for 3 hours until 2,3-dichloro-5-(trifluoromethyl)pyridine was completely converted (TLC analysis). The reaction mixture was quenched with ice water. The aqueous phase was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 100 / 1) to give compound 2.

[0086] Compound 2 (2.41 g, 10 mmol) was added to anhydrous ethanol (70 mL) and stirred. Stannous chloride dihydrate (45.13 g, 200 mmol) was then added to the reaction mixture, and the mixture was refluxed overnight until the reaction was complete (thin-layer chromatography analysis). After evaporating the ethanol, the pH was adjusted to 10 by slowly adding saturated sodium carbonate solution. The aqueous layer was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3.

[0087] (2) Synthesis of compound 5:

[0088]

[0089] Compound 4 (5 mmol), selenium dioxide (1.11 g, 10 mmol), and pyridine (20 mL) were added. The mixture was then purged with nitrogen and stirred at 100 °C for 5 hours. After the reaction, the precipitate was filtered off. The filtrate was adjusted to pH 1–2 with hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (3 × 30 mL). The collected organic phase was treated with 2M sodium hydroxide solution to adjust the pH to 11–12, and then extracted with water (3 × 50 mL). The resulting aqueous phase was acidified to pH 1–2 with hydrochloric acid and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and subjected to reduced pressure to remove all volatiles, yielding compound 5.

[0090] (3) Synthesis of compounds 6 and 7:

[0091]

[0092] Compound 5 (2 mmol), dichloromethane (20 mL), and a catalytic amount of N,N-dimethylformamide (1-2 drops) were added, followed by the slow addition of oxaloyl chloride (0.18 mL, 2 mmol) to the mixture. The reaction mixture was stirred at room temperature until efflux ceased, yielding crude compound 6. The reaction system was then cooled to 0 °C. Compound 3 (505.40 mg, 2.4 mmol) and diisopropylethylamine (0.70 mL, 4 mmol) were slowly added to the mixture. The mixture was stirred at room temperature until the reaction was complete (Thin-layer chromatography analysis). The reaction solution was quenched with water. The aqueous phase was extracted with dichloromethane (3 × 50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give compound 7.

[0093] (4) Synthesis of compound 8:

[0094]

[0095] Compound 7 (3 mmol) was dissolved in methanol (25 mL). Hydroxylamine hydrochloride (625.39 mg, 9 mmol) and potassium carbonate (621.92 mg, 4.5 mmol) were added to the reaction mixture. The mixture was stirred overnight under reflux. The mixture was then concentrated under reduced pressure and purified by flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 8.

[0096] (5) Synthesis of compound 9

[0097]

[0098] Compound 8 (0.15 mmol) and sodium hydride (10.8 mg, 0.45 mmol) were added to a 4 mL oven-dried vial equipped with a magnetic stirrer, and then the vial was purged with nitrogen. The mixture was stirred at 0°C for 30 minutes, and then N,N-dimethylformamide (2 mL) was added. Halogenated R was then added to the reaction mixture. 1 (0.23 mmol), heated to room temperature until the reaction was complete (TLC analysis). The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to give compound 9.

[0099] (6) Synthesis of compound 10:

[0100]

[0101] Compound 7 (0.15 mmol) and R2 NH₂ (0.45 mmol) was added to a 4 mL oven-dried vial equipped with a magnetic stirrer. Tetraisopropyl titanate (1–2 mL) was then added to the mixture with stirring at room temperature until most of compound 7 was converted (TLC analysis). The reaction mixture was quenched with water, filtered, and the filtrate was extracted with dichloromethane (3 × 10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by alkaline alumina flash column chromatography to give compound 10.

[0102] (7) Synthesis of compound 11:

[0103]

[0104] Compound 10 (0.15 mmol) and sodium borohydride (17.0 mg, 0.45 mmol) were added to a 4 mL oven-dried vial equipped with a magnetic stirrer. Anhydrous ethanol (1 mL) was then added to the reaction mixture. The mixture was stirred at room temperature until the reaction was complete (Thin-layer chromatography analysis). The crude product was directly purified by flash column chromatography to give compound 11.

[0105] The target compounds 9a-9c, 10a-10ad and 11a-11c obtained in Example 1 of this invention have the following corresponding structures. Compounds 9, 10 and 11 can be obtained by the above-mentioned synthesis steps (1)-(7).

[0106] The physicochemical properties, NMR data, and mass spectrometry data of target compounds 9a-9c, 10a-10ad, and 11a-11c are as follows:

[0107] 9a: Orange solid, yield: 56%, melting point: 75.1-82.1 °C. 1 H NMR (400 MHz, DMSO-d6)δ 9.34 (t, J = 5.7 Hz, 1H), 8.91 (dd, J = 2.1, 1.0 Hz, 1H), 8.46 (d, J = 2.0Hz, 1H), 7.87 – 7.63 (m, 2H), 7.50 – 7.29 (m, 8H), 5.23 (s, 2H), 4.76 (d, J =5.6 Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 163.0, 158.4, 153.5, 143.8 (q, J =4.2 Hz), 137.5, 134.5 (q, J = 3.5 Hz), 131.2, 130.1, 130.1, 128.7, 128.2,127.8, 127.7, 126.4, 125.3 (q, J = 33.0 Hz), 122.8 (q, J = 273.7 Hz), 75.8,41.8. 19 F NMR (377 MHz, DMSO-d6) δ -60.58. HRMS (ESI-TOF) m / z: [M+Na + Calcdfor C 22 H 17 ClF3N3O2Na + 470.0854; Found 470.0863.

[0108] 9b: White solid, yield: 62%, melting point: 152.8-158.9 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (t, J = 5.4 Hz, 1H), 8.99 (dd, J = 2.0, 1.0 Hz, 1H), 8.49 (dd, J =2.0, 0.8 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.58 – 7.35 (m, 3H), 4.73 (d, J = 5.6Hz, 2H), 3.92 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.0, 158.4, 153.1, 143.9(q, J = 4.1 Hz), 134.5 (q, J = 3.4 Hz), 131.2, 130.1, 130.0, 128.7, 126.4,125.3 (q, J = 33.2 Hz), 112.8 (q, J = 273.7 Hz), 62.1, 41.8. 19 F NMR (377 MHz, DMSO-d6) δ -60.57. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 16 H 13 ClF3N3O2Na +394.0541; Found 394.0538.

[0109] 9c: Gray solid, yield: 68%, melting point: 117.9-126.9 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (t, J = 5.5 Hz, 1H), 8.98 (dd, J = 2.0, 1.0 Hz, 1H), 8.49 (d, J =2.0 Hz, 1H), 7.83 – 7.66 (m, 2H), 7.51 – 7.40 (m, 3H), 4.74 (d, J = 5.6 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.1, 158.5, 152.9, 143.9 (q, J = 4.1 Hz), 134.6 (q, J = 3.4 Hz), 131.5, 130.2, 129.9, 128.7, 126.4, 125.4 (q, J = 33.1 Hz), 122.9 (q, J =274.7 Hz), 69.7, 41.8, 14.5. 19 F NMR (377 MHz, DMSO-d6) δ -60.59. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 17 H 15 ClF3N3O2Na + 408.0697; Found 408.0698.

[0110] 10a: Yellow solid, yield: 54%, melting point: 158.7-164.3 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (t, J = 5.7 Hz, 1H), 8.89 – 8.85 (m, 1H), 8.40 (d, J = 2.0 Hz,1H), 8.08 – 7.98 (m, 2H), 7.62 – 7.52 (m, 3H), 7.30 – 7.21 (m, 2H), 7.08 –7.02 (m, 1H), 7.00 – 6.92 (m, 2H), 4.53 (d, J = 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 165.0, 163.0, 158.2, 149.6, 143.8 (q, J = 4.1 Hz), 134.7, 134.5 (q, J = 3.6 Hz), 131.5, 130.1, 128.7, 128.4, 128.1, 125.2 (q, J = 33.0 Hz), 124.2, 122.9 (q, J = 273.7 Hz), 120.0, 41.5. 19 F NMR (377 MHz, DMSO-d6) δ -60.66. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 21 H 15 ClF3N3ONa + 440.0748; Found 440.0745.

[0111] 10b: Yellow solid, yield: 58%, melting point: 145.9-153.2 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (t, J = 5.7 Hz, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0Hz, 1H), 8.32 – 8.26 (m, 1H), 8.10 – 8.04 (m, 2H), 7.73 (td, J = 7.7, 1.9 Hz,1H), 7.63 – 7.54 (m, 3H), 7.12 – 7.07 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 4.55(d, J = 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.9, 164.3, 160.9, 158.3,148.2, 143.9 (q, J = 4.0 Hz), 137.7, 134.5, 134.5 (q, J = 4.2, 3.5 Hz), 132.0, 130.1, 128.8, 128.6, 125.2 (q, J = 32.9 Hz), 122.9 (q, J = 273.7 Hz), 120.2, 116.2, 41.6. 19 F NMR (377 MHz, DMSO-d6) δ -60.62.HRMS (ESI-TOF) m / z: [M+H + Calcd for C 20 H 14 ClF3N4OH + 419.0881; Found 419.0881.

[0112] 10c: Yellow solid, yield: 40%, melting point: 154.3-161.2 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J = 5.6 Hz, 1H), 8.89 – 8.87 (m, 1H), 8.42 (d, J = 2.0Hz, 1H), 8.14 – 8.09 (m, 2H), 8.04 (dd, J = 5.0, 1.7 Hz, 1H), 7.61 – 7.55 (m,4H), 7.01 (dd, J = 7.5, 4.8 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H), 2.21 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.0, 163.4, 159.4, 158.4, 145.2, 143.8 (q, J =4.4 Hz), 138.1, 134.7, 134.5 (q, J = 3.3 Hz), 131.8, 130.1, 128.7, 128.6,125.5, 125.2 (q, J = 32.8 Hz), 122.9 (q, J = 273.7 Hz), 120.5, 41.6, 17.1. 19 F NMR (377 MHz, DMSO-d6) δ -60.61. HRMS (ESI-TOF) m / z: [M+Na + Calcd forC 21 H 16 ClF3N4ONa + 455.0857; Found 455.0841.

[0113] 10d: Yellow solid, yield: 44%, melting point: 137.5-147.0 ℃. 1 H NMR(400 MHz, DMSO-d6) δ 9.15 (t, J = 5.7 Hz, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.42 (d, J =2.0 Hz, 1H), 8.13 (d, J = 5.1 Hz, 1H), 8.08 – 8.01 (m, 2H), 7.61 – 7.53 (m,3H), 6.91 (dd, J = 5.2, 1.5 Hz, 1H), 6.84 (s, 1H), 4.55 (d, J = 5.6 Hz, 2H), 2.25 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.9, 164.1, 160.9, 158.3, 148.3,147.8, 143.8 (q, J = 4.1 Hz), 134.6, 134.5 (q, J = 3.5 Hz), 131.9, 130.1,128.7, 128.5, 125.2 (q, J = 33.0 Hz), 122.9 (q, J = 274.7 Hz), 121.3, 116.7,41.6, 20.5. 19 F NMR (377 MHz, DMSO-d6) δ -60.65. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 21 H 16 ClF3N4ONa + 455.0857; Found 455.0861.

[0114] 10e: Yellow solid, yield: 61%, melting point: 166.4-173.7 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (t, J = 5.7 Hz, 1H), 8.87 – 8.86 (m, 1H), 8.43 (d, J = 2.0Hz, 1H), 8.11 – 8.02 (m, 3H), 7.62 – 7.51 (m, 4H), 6.96 (d, J = 8.1 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 2.25 (s, 3H). 13 C NMR(101 MHz, DMSO-d6) δ 165.1,163.9, 158.5, 158.4, 148.0, 143.8 (q, J = 4.1 Hz), 138.1, 134.7, 134.5 (q, J= 3.5 Hz), 131.8, 130.2, 129.3, 128.7, 128.5, 125.2 (q, J = 33.0 Hz), 122.9 (q, J = 273.7 Hz), 116.1, 41.6, 17.3. 19 F NMR (377 MHz, DMSO-d6) δ -60.59. HRMS (ESI-TOF) m / z: [M+H + Calcd for C 21 H 16 ClF3N4OH + 433.1038; Found 433.1030.

[0115] 10f: White solid, yield: 67%, melting point: 137.1-141.5 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (t, J = 5.6 Hz, 1H), 8.88 (dd, J = 2.0, 1.0 Hz, 1H), 8.42 (d,J = 2.1 Hz, 1H), 8.15 – 8.06 (m, 3H), 7.71 (ddd, J = 10.0, 8.2, 1.5 Hz, 1H), 7.66 – 7.56 (m, 3H), 7.22 (ddd, J = 8.2, 4.8, 3.6 Hz, 1H), 4.57 (d, J = 5.6Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 166.3, 164.7, 158.3, 150.7 (d, J = 243.8Hz), 149.4 (d, J = 3.6 Hz), 143.9 (q, J = 4.1 Hz), 143.5 (d, J = 5.9 Hz), 134.5 (q, J = 3.5 Hz), 134.4, 132.4, 130.1, 128.9, 128.9, 125.3 (q, J = 33.0Hz), 124.0 (d, J = 17.4 Hz), 122.9 (q, J = 273.7 Hz), 122.3 (d, J = 3.1 Hz), 41.8. 19 F NMR (377 MHz, DMSO-d6) δ -60.63, -128.32. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 13 ClF4N4ONa + 459.0606; Found 459.0600.

[0116] 10g: White solid, yield: 51%, melting point: 133.1-136.4 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (t, J = 5.6 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.43 (d, J =2.0 Hz, 1H), 8.21 (dd, J = 4.8, 1.5 Hz, 1H), 8.18 – 8.12 (m, 2H), 7.93 (dd, J= 7.9, 1.5 Hz, 1H), 7.66 – 7.56 (m, 3H), 7.18 (dd, J = 8.0, 4.7 Hz, 1H), 4.57(d, J = 5.6 Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 165.6, 164.4, 158.4, 157.2,146.4, 143.9 (q, J = 4.1 Hz), 138.0, 134.6 (q, J = 3.5 Hz), 134.3, 132.4,130.1, 129.0, 128.9, 125.3 (q, J = 32.9 Hz), 123.5, 122.9 (q, J = 274.7 Hz), 121.9, 41.8. 19 F NMR (377 MHz, DMSO-d6) δ -60.60. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 13 Cl2F3N4ONa + 475.0311; Found 475.0314.

[0117] 10h: White solid, yield: 60%, melting point: 137.1-140.0 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (t, J = 5.6 Hz, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.44 (d, J =2.1 Hz, 1H), 8.24 (dd, J = 4.7, 1.5 Hz, 1H), 8.16 (dt, J = 6.5, 1.7 Hz, 2H), 8.11 – 8.05 (m, 1H), 7.60 (tdd, J = 8.7, 5.4, 3.6 Hz, 3H), 7.09 (dd, J = 7.9, 4.7 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 165.1,164.3, 158.3, 158.1, 147.0, 143.9 (q, J = 4.0 Hz), 141.1, 134.5 (q, J = 3.4Hz), 134.3, 132.3, 130.1, 129.0, 128.8, 125.2 (q, J = 33.0 Hz), 122.9 (q, J =273.7 Hz), 122.0, 113.7, 41.8. 19 F NMR(377 MHz, DMSO-d6) δ -60.58. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 13 BrClF3N4ONa + 518.9806; Found 518.9804.

[0118] 10i: White solid, yield: 66%, melting point: 127.2-135.6 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (t, J = 5.5 Hz, 1H), 8.97 – 8.88 (m, 1H), 8.45 (d, J = 2.1Hz, 1H), 8.31 – 8.15 (m, 4H), 7.70 – 7.53 (m, 3H), 6.91 (dd, J = 7.7, 4.8 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.3, 160.1,158.4, 147.6, 147.1, 146.8, 143.9 (q, J = 3.5 Hz), 134.5 (q, J = 3.4 Hz),134.4, 132.2, 130.1, 128.9, 128.8, 125.2 (q, J = 32.9 Hz), 122.9 (q, J =274.7 Hz), 122.0, 90.1, 41.8. 19 F NMR (377 MHz, DMSO-d6) δ -60.58. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 13 ClF3IN4ONa + 566.9667; Found 566.9669.

[0119] 10j: White solid, yield: 40%, melting point: 146.4-149.9 ℃. 1 H NMR(400 MHz, DMSO-d6) δ 9.24 (t, J = 5.6 Hz, 1H), 8.95 (s, 1H), 8.52 (dd, J = 5.0, 1.6 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.17 (dt, J = 8.0, 2.0 Hz, 3H), 7.71 – 7.52(m, 3H), 7.36 (dd, J = 7.8, 4.9 Hz, 1H), 4.61 (d, J = 5.5 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 165.7, 164.4, 158.4, 157.5, 151.9, 143.9 (q, J = 4.0Hz), 135.6 (q, J = 4.6 Hz), 134.5 (q, J = 3.6 Hz), 134.4, 132.5, 130.1,129.1, 128.9, 125.3 (q, J = 33.1 Hz), 123.4 (q, J = 273.7 Hz), 122.9 (q, J =274.7 Hz), 120.7, 117.4 (q, J = 31.2 Hz), 41.8. 19 F NMR (377 MHz, DMSO-d6) δ -60.52, -60.61. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 21 H 13 ClF6N4ONa + 509.0574; Found 509.0583.

[0120] 10K: Yellow solid, yield: 53%, melting point: 153.2-161.9 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (t, J = 5.4 Hz, 1H), 8.93 – 8.88 (m, 1H), 8.44 (d, J = 2.1Hz, 1H), 8.19 – 8.09 (m, 2H), 8.04 – 8.00 (m, 1H), 7.96 – 7.91 (m, 1H), 7.65– 7.54 (m, 3H), 4.59 (d, J = 5.6 Hz, 2H), 2.26 (s, 3H). 13 C NMR(101 MHz, DMSO-d6) δ 164.9, 164.7, 158.5, 155.5, 146.9, 143.8 (q, J = 3.9 Hz), 141.4,134.6, 134.5 (q, J = 3.6 Hz), 132.2, 131.9, 130.2, 128.9, 128.8, 125.3 (q, J= 33.0 Hz), 122.9 (q, J = 273.7 Hz), 113.8, 41.8, 16.8. 19 F NMR (377 MHz, DMSO-d6) δ -60.58. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 21 H 15 BrClF3N4ONa + 532.9962; Found 532.9965.

[0121] 10L: White solid, yield: 33%, melting point: 141.6-146.0 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (t, J = 5.7 Hz, 1H), 8.90 (dd, J = 2.1, 1.0 Hz, 1H), 8.44 (d,J = 1.5 Hz, 1H), 8.34 – 8.22 (m, 2H), 8.20 – 8.10 (m, 2H), 7.68 – 7.54 (m,3H), 4.60 (d, J = 5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 165.7, 164.3,158.4, 156.1 (d, J = 255.9 Hz), 154.7 (d, J = 2.8 Hz), 143.8 (q, J = 4.0 Hz), 134.5 (q, J = 3.6 Hz), 134.5, 134.3 (d, J = 7.3 Hz), 132.4, 130.1, 129.0,128.8, 128.7 (d, J = 22.1 Hz), 125.3 (q, J = 33.0 Hz), 122.9 (q, J = 274.7Hz), 113.8 (d, J = 4.6 Hz), 41.7. 19 F NMR(377 MHz, DMSO-d6) δ -60.65, -130.73. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 12 BrClF4N4ONa + 536.9711; Found 536.9712.

[0122] 10m: White solid, yield: 53%, melting point: 155.1-158.5 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (t, J = 5.7 Hz, 1H), 8.96 – 8.81 (m, 1H), 8.43 (d, J = 2.0Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.21 – 8.09 (m,2H), 7.77 – 7.46 (m, 3H), 4.60 (d, J = 5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6)δ 165.9, 164.0, 158.3, 157.0, 145.3, 143.8 (q, J = 4.1 Hz), 140.3, 134.5 (q,J = 3.6 Hz), 134.1, 132.6, 130.2, 129.1, 128.9, 127.1, 125.3 (q, J = 32.9Hz), 122.9 (q, J = 273.7 Hz), 114.1, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.61. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 12 BrCl2F3N4ONa + 552.9416; Found 552.9419.

[0123] 10n: Yellow solid, yield: 37%, melting point: 140.8-146.8 ℃. 1 H NMR(400 MHz, DMSO-d6) δ 9.27 (t, J = 5.6 Hz, 1H), 9.01 – 8.75 (m, 1H), 8.51 – 8.38 (m, 2H), 8.33 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 6.9 Hz, 2H), 7.73 – 7.47 (m, 3H), 4.60(d, J = 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 165.8, 164.0, 158.3, 157.3,147.5, 143.8 (q, J = 3.6 Hz), 142.7, 134.5 (q, J = 3.6 Hz), 134.1, 132.6,130.1, 129.1, 128.9, 125.3 (q, J = 33.0 Hz), 122.9 (q, J = 273.7 Hz), 115.5,114.5, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.56. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 12 Br2ClF3N4ONa + 596.8911; Found 596.8906.

[0124] 10°: Yellow solid, yield: 49%, melting point: 167.6-176.7 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (t, J = 5.7 Hz, 1H), 8.96 – 8.79 (m, 1H), 8.57 – 8.34 (m,3H), 8.24 – 8.04 (m, 2H), 7.68 – 7.52 (m, 3H), 4.60 (d, J = 5.4 Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 165.5, 164.0, 158.3, 157.4, 152.5, 147.7, 143.8 (q,J = 3.4 Hz), 134.5 (q,J = 3.5 Hz), 134.1, 132.6, 130.1, 129.0, 128.9, 125.3(q, J = 33.0 Hz), 122.9 (q, J = 273.7 Hz), 114.8, 88.9, 41.7. 19 F NMR (377MHz, DMSO-d6) δ -60.48. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 12 BrClF3IN4ONa + 644.8772; Found 644.8769.

[0125] 10p: Yellow solid, yield: 68%, melting point: 153.7-159.9 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (t, J = 5.6 Hz, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.45 (d, J =2.0 Hz, 1H), 8.23 ​​– 8.15 (m, 2H), 8.12 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.0Hz, 1H), 7.59 (dt, J = 7.5, 4.7 Hz, 3H), 4.61 (d, J = 5.7 Hz, 2H), 2.23 (s,3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.7, 164.0, 158.5, 157.6, 147.5, 147.3,143.8 (q, J = 3.9 Hz), 134.6, 134.5 (q, J = 3.6 Hz), 132.0, 131.7, 130.2,128.8, 128.8, 125.2 (q, J = 32.9 Hz), 122.9 (q, J = 274.7 Hz), 90.5, 41.8,16.6. 19 F NMR (377 MHz, DMSO-d6) δ -60.58. HRMS(ESI-TOF) m / z: [M+Na + Calcdfor C 21 H 15 ClF3IN4ONa + 580.9823; Found 580.9825.

[0126] 10q: Yellow solid, yield: 36%, melting point: 127.3-133.9 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (t, J = 5.6 Hz, 1H), 8.91 (d, J = 2.1 Hz, 1H), 8.45 (d, J =2.1 Hz, 1H), 8.35 – 8.14 (m, 4H), 7.70 – 7.51 (m, 3H), 4.60 (d, J = 5.5 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.8, 164.3, 158.4, 156.8 (d, J = 2.6 Hz), 155.8 (d, J = 256.5 Hz), 143.8 (q, J = 3.5 Hz), 134.8 (d, J = 24.3 Hz), 134.5(q, J = 3.0 Hz), 134.4, 134.1 (d, J = 20.8 Hz), 132.3, 130.2, 128.9, 128.8,125.3 (q, J = 33.3 Hz), 122.9 (q, J = 274.7 Hz), 90.2 (d, J = 3.2 Hz), 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.62, -131.41. HRMS (ESI-TOF) m / z: [M+Na + Calcdfor C 20 H 12 ClF4IN4ONa + 584.9573; Found 584.9579.

[0127] 10r: Yellow solid, yield: 54%, melting point: 144.8-148.8 ℃. 1 H NMR(400 MHz, DMSO-d6) δ 9.22 (t, J = 5.7 Hz, 1H), 9.00 – 8.83 (m, 1H), 8.43 (dd, J = 6.0,2.2 Hz, 2H), 8.30 – 8.11 (m, 3H), 7.71 – 7.51 (m, 3H), 4.61 (d, J = 5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 165.0, 164.0, 159.2, 158.4, 145.8, 145.8,143.8 (q, J = 3.8 Hz), 134.5 (q, J = 3.5 Hz), 134.2, 132.5, 130.2, 129.0,128.9, 126.8, 125.3 (q, J = 33.0 Hz), 122.9 (q, J = 273.7 Hz), 90.6, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.60. HRMS (ESI-TOF) m / z: [M+Na + Calcd forC 20 H 12 Cl2F3IN4ONa + 600.9277; Found 600.9286.

[0128] 10s: Yellow solid, yield: 31%, melting point: 150.7-157.1 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (t, J = 5.7 Hz, 1H), 8.90 (d, J = 1.8 Hz, 1H), 8.52 (d, J =2.2 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.22 – 8.10 (m, 2H), 7.69 – 7.54 (m, 3H), 4.60 (d, J = 5.7 Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 164.9, 164.0, 159.5, 158.4, 148.2, 148.1, 143.8 (q, J = 3.7 Hz), 134.5 (q, J = 3.5 Hz), 134.1, 132.5, 130.1, 129.0, 128.9, 125.3 (q, J = 33.0Hz), 122.9 (q, J = 274.7 Hz), 115.4, 91.1, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ-60.55. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H 12 BrClF3IN4ONa + 644.8772; Found 644.8769.

[0129] 10t: Yellow solid, yield: 42%, melting point: 187.1-191.0 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (t, J = 5.6 Hz, 1H), 8.90 (d, J = 1.9 Hz, 1H), 8.60 (d, J =2.0 Hz, 1H), 8.42 (dd, J = 24.0, 2.0 Hz, 2H), 8.24 – 8.09 (m, 2H), 7.76 –7.50 (m, 3H), 4.60 (d, J = 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.7,163.9, 159.5, 158.3, 153.2, 153.0, 143.7 (q, J = 4.0 Hz), 134.4 (q, J = 3.4Hz), 134.1, 132.3, 130.1, 128.9, 128.8, 125.2 (q, J = 33.2 Hz), 122.8 (q, J =274.7 Hz), 91.6, 88.9, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.48. HRMS (ESI-TOF) m / z: [M+Na + Calcd for C 20 H12 ClF3I2N4ONa + 692.8633; Found 692.8629.

[0130] 10u: Yellow solid, yield: 39%, melting point: 185.1-189.4 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (t, J = 5.6 Hz, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.58 (d, J =2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.06 (d, J =7.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 4.59 (d, J = 5.7 Hz, 2H), 2.40 (s,3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.6, 164.2, 159.7, 158.4, 153.2, 153.1,143.8 (q, J = 3.6 Hz), 142.8, 134.5 (q, J = 3.4 Hz), 131.6, 130.2, 129.5,129.1, 125.3 (q, J = 33.0 Hz), 122.9 (q, J = 273.7 Hz), 91.9, 88.9, 41.8,21.3. 19 F NMR (377 MHz, DMSO-d6) δ -60.49. HRMS (ESI-TOF) m / z: [M+H + Calcd forC 21 H 14 ClF3I2N4OH + 684.8970; Found 684.8965.

[0131] 10v: Yellow solid, yield: 30%, melting point: 203.2-207.8 ℃. 1 H NMR(400 MHz, DMSO-d6) δ 9.28 (t, J = 5.6 Hz, 1H), 9.09 – 8.82 (m, 1H), 8.60 (d, J = 1.9Hz, 1H), 8.43 (dd, J = 17.9, 2.0 Hz, 2H), 8.33 – 8.20 (m, 2H), 7.47 (t, J =8.8 Hz, 2H), 4.60 (d, J = 5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.7 (d,J = 251.0 Hz), 163.9, 163.5, 159.4, 158.3, 153.3, 153.1, 143.9 (q, J = 3.6Hz), 134.5 (q, J = 3.0 Hz), 131.7 (d, J = 9.3 Hz), 130.8 (d, J = 2.7 Hz), 130.0, 125.3 (q, J = 33.0 Hz), 122.9 (q, J = 273.7 Hz), 116.1 (d, J = 22.1Hz), 91.9, 89.3, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.47, -107.05. HRMS (ESI-TOF) m / z: [M+H + Calcd for C 20 H 11 ClF4I2N4OH + 688.8720; Found 688.8719.

[0132] 10w: Yellow solid, yield: 29%, melting point: 181.3-188.7 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J = 5.7 Hz, 1H), 9.10 – 8.91 (m, 1H), 8.61 (d, J = 1.9Hz, 1H), 8.43 (dd, J = 14.6, 2.2 Hz, 2H), 8.30 – 8.12 (m, 2H), 7.72 (d, J =8.7 Hz, 2H), 4.60 (d, J = 5.7 Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 163.8,163.6, 159.3, 158.3, 153.4, 153.1, 144.0 (q, J = 4.0 Hz), 137.3, 134.5 (q, J= 3.3 Hz), 133.1, 130.7, 130.0, 129.1, 125.3 (q, J = 32.8 Hz), 122.9 (q, J =274.7 Hz), 92.0, 89.5, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.46. HRMS (ESI-TOF) m / z: [M+H + Calcd for C 20 H 11 Cl2F3I2N4OH + 704.8424; Found 704.8433.

[0133] 10x: Yellow solid, yield: 29%, melting point: 186.2-193.2 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J = 5.7 Hz, 1H), 9.08 – 8.90 (m, 1H), 8.61 (d, J = 1.9Hz, 1H), 8.43 (dd, J = 14.4, 2.0 Hz, 2H), 8.15 (dd, J = 8.7, 2.1 Hz, 2H), 7.95 – 7.77 (m, 2H), 4.60 (d, J = 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ163.8, 163.8, 159.3, 158.3, 153.4, 153.1, 144.0 (q, J = 4.7, 3.8 Hz), 134.5(q, J = 3.3 Hz), 133.4, 132.0, 130.9, 130.0, 126.5, 125.3 (q, J = 33.0 Hz), 122.9 (q, J = 273.7 Hz), 92.0, 89.5, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.45. HRMS (ESI-TOF) m / z: [M+H + Calcd for C20 H 11 BrClF3I2N4OH + 748.7919; Found 748.7915.

[0134] 10y: Yellow solid, yield: 40%, melting point: 203.8-208.8 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (t, J = 5.7 Hz, 1H), 8.98 (d, J = 1.9 Hz, 1H), 8.60 (d, J =2.0 Hz, 1H), 8.43 (dd, J = 16.3, 2.0 Hz, 2H), 8.09 – 7.84 (m, 4H), 4.59 (d, J= 5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.2, 163.8, 159.4, 158.3, 153.4,153.1, 144.0 (q, J = 3.6 Hz), 137.9, 134.5 (q, J = 2.7 Hz), 133.7, 130.7,130.0, 125.3 (q, J = 33.2 Hz), 122.9 (q, J = 273.7 Hz), 100.8, 91.9, 89.4,41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.44. HRMS (ESI-TOF) m / z: [M+H + Calcd forC 20 H 11 ClF3I3N4OH + 796.7780; Found 796.7792.

[0135] 10z: Yellow solid, yield: 48%, melting point: 179.5-186.8 ℃. 1 H NMR(400 MHz, DMSO-d6) δ 9.15 (t, J = 5.6 Hz, 1H), 8.93 (d, J = 1.9 Hz, 1H), 8.57 (d, J =2.0 Hz, 1H), 8.41 (dd, J = 27.1, 2.0 Hz, 2H), 8.16 (d, J = 8.6 Hz, 2H), 7.42– 6.93 (m, 2H), 4.59 (d, J = 5.5 Hz, 2H), 3.87 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.3, 164.0, 162.8, 159.7, 158.4, 153.2, 153.1, 143.9 (q, J = 3.5Hz), 134.5 (q, J = 3.6, 2.9 Hz), 131.1, 130.1, 126.8, 125.2 (q, J = 33.1 Hz), 122.9 (q, J = 274.7 Hz), 114.3, 92.1, 88.6, 55.6, 41.7. 19 F NMR (377 MHz, DMSO-d6) δ -60.46. HRMS (ESI-TOF) m / z: [M+H + Calcd for C 21 H 14 ClF3I2N4O2H + 700.8920; Found 700.8923.

[0136] 10aa: Yellow solid, yield: 40%, melting point: 167.6-174.1 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (t, J = 5.6 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.58 (d, J =2.0 Hz, 1H), 8.41 (dd, J = 20.5, 2.0 Hz, 2H), 8.11 (d, J = 8.2 Hz, 2H), 7.47(d, J = 8.1 Hz, 2H), 4.59 (d, J = 5.6 Hz, 2H), 2.98 (p, J = 6.9 Hz, 1H), 1.25(d, J = 6.9 Hz, 6H). 13 C NMR(101 MHz, DMSO-d6) δ 164.6, 164.1, 159.8, 158.4,153.5, 153.2, 153.1, 143.9 (q, J = 3.4 Hz), 134.5 (q, J = 3.3 Hz), 132.0,130.1, 129.3, 126.9, 125.3 (q, J = 33.0 Hz), 122.9 (q, J = 273.7 Hz), 91.7,88.8, 41.8, 33.6, 23.6. 19 F NMR (377 MHz, DMSO-d6) δ -60.49. HRMS (ESI-TOF) m / z: [M+H + Calcd for C 23 H 18 ClF3I2N4OH + 712.9283; Found 712.9292.

[0137] 10ab: Yellow solid, yield: 31%, melting point: 145.6-154.1 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (t, J = 5.6 Hz, 1H), 8.94 (d, J = 1.9 Hz, 1H), 8.57 (d, J =2.0 Hz, 1H), 8.42 (dd, J = 24.2, 2.0 Hz, 2H), 8.10 (d, J = 8.3 Hz, 2H), 7.62(d, J = 8.5 Hz, 2H), 4.58 (d, J = 5.2 Hz, 2H), 1.34 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 164.6, 164.1, 159.9, 158.4, 155.6, 153.2, 153.1, 144.0 (q, J = 2.5Hz), 134.5 (q, J = 2.4 Hz), 131.6, 130.1, 129.0, 125.8, 125.3 (q, J = 33.3Hz), 122.9 (q, J = 273.7 Hz), 91.7, 88.8, 41.8, 34.9, 30.9. 19 F NMR (377 MHz, DMSO-d6) δ -60.44. HRMS(ESI-TOF) m / z: [M+H + Calcd for C 24 H 20 ClF3I2N4OH + 726.9440; Found 726.9435.

[0138] 10ac: Yellow solid, yield: 47%, melting point: 178.1-183.8 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (t, J = 5.7 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.58 (d, J =1.9 Hz, 1H), 8.43 (dd, J = 21.7, 2.0 Hz, 2H), 8.12 (dd, J = 3.8, 1.2 Hz, 1H), 7.97 (dd, J = 5.0, 1.2 Hz, 1H), 7.31 (dd, J = 5.0, 3.8 Hz, 1H), 4.62 (d, J =5.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 163.2, 159.4, 159.0, 158.4, 153.4,153.2, 143.9 (q, J = 4.2 Hz), 141.1, 134.9, 134.5 (q, J = 3.5 Hz), 134.1,130.1, 129.0, 125.3 (q, J = 32.9 Hz), 122.9 (q, J = 273.7 Hz), 92.3, 89.2,41.9. 19 F NMR (377 MHz, DMSO-d6) δ -60.51. HRMS (ESI-TOF) m / z: [M+H + Calcd forC 18 H 10 ClF3I2N4OSH + 676.8378; Found 676.8383.

[0139] 10ad: Yellow solid, yield: 68%, melting point: 130.3-138.9 ℃. 1 H NMR(400 MHz, DMSO-d6) δ 9.35 (t, J = 5.6 Hz, 1H), 8.94 (s, 1H), 8.68 – 8.31 (m, 3H, Zisomer + E isomer), 8.19 – 8.04 (m, 1H), 7.66 (d, J = 3.7 Hz, 1H), 6.81 (dd,J = 3.7, 1.7 Hz, 1H), 4.59 (d,J = 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ162.6, 159.8, 158.4, 154.4, 153.2, 153.1, 149.8, 148.2, 143.9 (q, J = 4.0Hz), 134.5 (q, J = 3.5 Hz), 130.1, 125.2 (q, J = 32.8 Hz), 122.9 (q, J =274.7 Hz), 120.9, 113.2, 91.7, 88.8, 41.8. 19 F NMR (377 MHz, DMSO-d6) δ -60.53. HRMS (ESI-TOF) m / z: [M+H + Calcd for C 18 H 10 ClF3I2N4O2H + 660.8607; Found 660.8608.

[0140] 11a: Yellow solid, yield: 71%, melting point: 150.8-153.8 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 5.6 Hz, 1H), 8.84 (dd, J = 2.0, 1.0 Hz, 1H), 8.42 (d,J = 2.0 Hz, 1H), 7.98 (dd, J = 4.8, 1.5 Hz, 1H), 7.86 – 7.75 (m, 1H), 7.51 (dd, J = 7.0, 1.6 Hz, 2H), 7.42 – 7.16 (m, 3H), 6.56 (dd, J = 7.7, 4.8 Hz,1H), 6.37 (d, J = 7.4 Hz, 1H), 5.82 (d, J = 7.4 Hz, 1H), 4.80 – 4.35 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 170.5, 158.6, 152.7, 146.7, 143.8 (q, J = 4.0Hz), 139.9, 139.3, 134.4 (q, J = 3.5 Hz), 130.1, 128.3, 127.5, 126.9, 125.2(q, J = 33.0 Hz), 122.8 (q, J = 273.7 Hz), 114.4, 105.0, 57.6, 42.2. 19 F NMR (377 MHz, DMSO-d6) δ -60.65. HRMS (ESI-TOF) m / z: [M+Na + Calcd forC 20 H 15 BrClF3N4ONa + 520.9962; Found 520.9959.

[0141] 11b: Yellow solid, yield: 77%, melting point: 147.9-151.5 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 5.6 Hz, 1H), 8.84 (dd, J = 2.0, 1.0 Hz, 1H), 8.43 (d,J = 2.0 Hz, 1H), 8.04 – 7.90 (m, 2H), 7.63 – 7.43 (m, 2H), 7.37 – 7.28 (m,2H), 7.29 – 7.20 (m, 1H), 6.40 (dd, J = 7.4, 5.0 Hz, 1H), 6.28 (d, J = 7.4Hz, 1H), 5.78 (d, J = 7.4 Hz, 1H), 4.75 – 4.42 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 170.6, 158.6, 154.7, 147.3, 146.6, 143.8 (q, J = 3.9 Hz), 139.5,134.5 (q, J = 3.5 Hz), 130.2, 128.3, 127.5, 126.8, 125.2 (q, J = 33.1 Hz), 122.8 (q, J = 273.7 Hz), 114.9, 80.4, 58.1, 42.2. 19 F NMR(377 MHz, DMSO-d6) δ-60.63. HRMS (ESI-TOF) m / z: [M+H + Calcd for C 20 H 15 ClF3IN4OH + 547.0004; Found 547.0006.

[0142] 11c: Yellow solid, yield: 59%, melting point: 108.8-116.7 ℃. 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (t, J = 5.6 Hz, 1H), 8.86 – 8.83 (m, 1H), 8.43 (d, J = 2.0Hz, 1H), 8.22 (d, J = 1.9 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 7.3Hz, 2H), 7.39 – 7.19 (m, 3H), 6.37 (d, J = 7.3 Hz, 1H), 5.70 (d, J = 7.3 Hz, 1H), 4.86 – 4.42 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ170.3, 158.6, 153.9,152.5, 152.1, 143.8 (q, J = 3.9 Hz), 139.0, 134.5 (q, J = 3.6 Hz), 130.2,128.4, 127.6, 126.8, 125.3 (q, J = 33.1 Hz), 122.9 (q, J = 274.7 Hz), 82.2,77.7, 58.1, 42.2. 19 F NMR (377 MHz, DMSO-d6) δ -60.61. HRMS (ESI-TOF) m / z: [M+H + Calcd for C 20 H 14 ClF3I2N4OH + 672.8970; Found 672.8970.

[0143] Example 2

[0144] This embodiment tests the in vitro antifungal activity of the target compound prepared in Example 1. The test results are shown in Table 1.

[0145] The in vitro antifungal activity of the target compound at a concentration of 100 μg / mL against rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, pseudostem mold, aspergillus flavus, and pepper anthracnose was determined using the mycelial growth rate method. Azoxystrobin was selected as a positive control. 2 mg of the target compound was dissolved in 200 μL of dimethyl sulfoxide to obtain a stock solution with a concentration of 10000 μg / mL. The stock solution was added to 20 mL of PDA medium to reach the test concentration of 100 μg / mL, and then poured into 60 mm diameter petri dishes, with three replicates for each concentration. Azoxystrobin was used as a positive control. The fungi in the petri dishes were incubated in a biochemical incubator at 28 ± 1 ℃ for 2–6 days. When the mycelia of the blank control reached 2 / 3 of the petri dish, the colony diameter was measured using the cross-crossing method.

[0146] The formula for calculating the inhibition rate is as follows:

[0147] Inhibition rate = [(C - T) / (C - 0.5)] × 100%

[0148] C-dimethyl sulfoxide treated colony diameter, T-compound treated colony diameter

[0149] The results of the antifungal activity were evaluated and are shown in Table 1.

[0150] Table 1. In vitro antifungal activity of amide derivatives containing trifluoromethylpyridine

[0151] As shown in Table 1, most of the target compounds exhibited certain antifungal activities, particularly against tomato gray mold, rice sheath blight, and rapeseed sclerotinia stem rot. Notably, compounds 10o, 10t, and 10x showed superior inhibitory activity against rice sheath blight, tomato gray mold, and rapeseed sclerotinia stem rot compared to the commercial fungicide azoxystrobin. Especially at a concentration of 100 μg / mL, compound 10ad demonstrated excellent in vitro antifungal activity against rice sheath blight, tomato gray mold, and rapeseed sclerotinia stem rot, with inhibition rates of 85.7%, 75.4%, and 74.9%, respectively, all exceeding those of azoxystrobin.

[0152] Example 3

[0153] This example tested the EC50 response of the highly effective compounds 10t, 10x, and 10ad from Example 2 to tomato gray mold. 50 The values ​​were used to further quantify its antifungal efficacy. The test results are shown in Table 2.

[0154] 50% effective concentration (EC) 50The assay method is the same as the in vitro antifungal activity test in Example 2. The compound is added to the culture medium at gradient concentrations, the inhibition results at each gradient concentration are recorded, and a toxicity regression equation is established by using the logarithm of concentration versus inhibition rate to calculate EC50. 50 Value. EC antifungal activity 50 The results of the activity evaluation are shown in Table 2.

[0155] Table 2. EC50 of some highly effective compounds and commercial fungicides, including azoxystrobin, iprodione, and pyraclostrobin, against tomato gray mold. 50 value

[0156]

[0157] As shown in Table 2, the EC50 of 10t (6.60 μg / mL) and 10x (7.12 μg / mL) 50 The values ​​were all lower than those of azoxystrobin (12.84 μg / mL). Notably, the EC50 values ​​of compound 10ad were lower than those of azoxystrobin. 50 The value was 1.22 μg / mL, which is much lower than that of the commercial fungicides iprodione (4.87 μg / mL) and pyrimethanil (3.52 μg / mL) used to control gray mold in tomatoes.

[0158] Example 4

[0159] This embodiment evaluates the in vitro antifungal activity of the highly effective compound 10ad from detached fruit, based on in vitro antifungal activity tests. 20 mg of compound 10ad was weighed and dissolved in 1 mL of dimethyl sulfoxide solvent, followed by the addition of a certain amount of 0.1% Tween-80 aqueous solution to prepare a stock solution with a concentration of 20000 μg / mL.

[0160] Select ripe, uniform, and healthy tomatoes and wash them with a 75% ethanol solution. Then rinse the surface of the tomatoes with sterile water to remove the 75% ethanol solution, and wipe the surface dry with a paper towel. In the protective activity evaluation experiment, the target compound 10ad was sprayed onto the tomato surface at concentrations of 400 and 200 μg / mL, respectively. Twenty-four hours later, a puncture was made in the center of the tomato using a syringe, and the fungal harvested mushroom was applied to the puncture wound. In the therapeutic activity evaluation experiment, the wound was punctured first, and the fungal harvested mushroom was attached to the tomato. Twenty-four hours later, the target compound 10ad was sprayed at concentrations of 400 and 200 μg / mL.

[0161] Infected tomatoes were placed in an incubator with 80% light and 83% humidity, and a 12 / 12-hour light / dark cycle, and cultured for 5-6 days. The diameter of the rotten patches was then measured. The calculation formula is as follows:

[0162] Inhibition rate = [(C - T) / (C - 0.5)] × 100%

[0163] C-dimethyl sulfoxide treated colony diameter, T-compound treated colony diameter

[0164] The protective and therapeutic activities of the isolated fruit were evaluated, and the results are shown in Table 3.

[0165] Table 3. Protective and curative activities of compound 10ad and commercial fungicides pyraclostrobin, iprodione, and pyraclostrobin on detached fruits.

[0166]

[0167] As shown in Table 3, at a concentration of 400 μg / mL, compound 10ad exhibited superior protective and curative activity compared to azoxystrobin (45.6%, 45.9%), iprodione (46.4%, 45.5%), and pyrimethanil (47.9%, 49.9%). Even at a concentration reduced to 200 μg / mL, the control efficacy of 10ad remained comparable to that of commercial fungicides. These results indicate that compound 10ad is a promising lead compound for the development of novel fungicides.

[0168] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An amide derivative containing trifluoromethylpyridine, characterized in that, The general structural formulas of the amide derivatives are shown in Formula I, Formula II and Formula III: Equation I; Formula II; Formula III; Wherein, R is selected from any one of phenyl, halophenyl, phenyl-C1 to C4 alkyl, phenyl-C1 to C4 alkoxy and 5 to 6-membered heterocycles; R 1 Selected from any one of benzyl, methyl, and ethyl; R 2 It is selected from any one of phenyl, 5-6 membered heterocycles, 5-6 membered haloheterocycles, 5-6 membered heterocycles-C1-C6 alkyl and 5-6 membered haloheterocycles-C1-C6 alkyl; R 3 Selected from 5- to 6-membered halogenated heterocycles.

2. The amide derivative according to claim 1, characterized in that, The amide derivative is any one of the following compounds: 。 3. A method for synthesizing the amide derivative according to claim 1 or 2, characterized in that, Includes the following steps: 1) Under a nitrogen atmosphere, nitromethane, potassium hydroxide and dimethyl sulfoxide were mixed and stirred, and then mixed with compound 1 and subjected to an arylation reaction to obtain compound 2; Compound 2 was mixed with anhydrous ethanol and stannous chloride dihydrate and then subjected to a reduction reaction to obtain compound 3. Compound 4 was mixed with selenium dioxide and pyridine and then subjected to an oxidation reaction to obtain compound 5. Compound 5 was reacted with dichloromethane, N,N -Dimethylformamide and oxalyl chloride were mixed and then subjected to a substitution reaction to give compound 6; Compound 3 was mixed with compound 6 and diisopropylethylamine and then subjected to a condensation reaction to obtain compound 7. Compound 7 was mixed with methanol, hydroxylamine hydrochloride and potassium carbonate and then subjected to a condensation reaction to obtain compound 8. Compound 8 was combined with sodium hydride, N,N - Dimethylformamide and haloalkanes are mixed and then subjected to alkylation to obtain the compound shown in Formula I; 2) Compound 7 was mixed with a primary amine and tetraisopropyl titanate and then subjected to a condensation reaction to obtain the compound shown in Formula II; 3) The compound shown in Formula II was mixed with sodium borohydride and anhydrous ethanol and then subjected to a reduction reaction to obtain the compound shown in Formula III; The structural formulas of compounds 1-8 are as follows: 。 4. The synthesis method according to claim 3, characterized in that, In step 1), the volume of nitromethane, the mass of potassium hydroxide, the volume of dimethyl sulfoxide, and the mass of compound 1 are 12.48 mL: 10.39 g: 150 mL: 10 g; the conditions for the arylation reaction include: a temperature of 20~30℃ and a time of 3~5 h. The mass ratio of compound 2 to the volume of anhydrous ethanol and the mass of stannous chloride dihydrate is 2.41 g: 70 mL: 45.13 g; the conditions for the reduction reaction include: a temperature of 75-85°C and a time of 4-10 h. The molar ratio of compound 4 to the mass of selenium dioxide and the volume ratio of pyridine is 5 mmol: 1.11 g: 20 mL; the oxidation reaction conditions include a temperature of 90~110℃ and a time of 2~8 h. The molar ratio of compound 5 to the volume of dichloromethane, N,N The volume ratio of dimethylformamide drops to oxaloyl chloride was 2 mmol: 20 mL: 1-2 drops: 0.18 mL; the conditions for the substitution reaction included a temperature of 0-30 °C and a time of 0.5-2 h. The mass ratio of compound 3 to the molar ratio of compound 6 and the volume ratio of diisopropylethylamine is 505.4 mg: 2 mmol: 0.7 mL, and the condensation reaction conditions include: temperature of 0~40℃ and time of 0.5~4 h. The molar ratio of compound 7 to the volume of methanol, the mass of hydroxylamine hydrochloride, and the mass ratio of potassium carbonate are 3 mmol: 25 mL: 625.39 mg: 621.92 mg. The conditions for the condensation reaction are: temperature of 50-70 °C and time of 6-12 h. The molar ratio of compound 8 to sodium hydride, N,N-dimethylformamide, and haloalkane is 0.15 mmol:10.8 mg:2 mL:0.23 mmol; the alkylation reaction conditions include: a temperature of 0-30 °C and a time of 1-6 h.

5. The synthesis method according to claim 3, characterized in that, Step 2) The molar ratio of compound 7 to the primary amine and the volume ratio of tetraisopropyl titanate are 0.15 mmol: 0.45 mmol: 1~2 mL; the conditions for the condensation reaction include: temperature of 20~30℃ and time of 6~24 h.

6. The synthesis method according to claim 3, characterized in that, Step 3) The molar ratio of the compound shown in Formula II to the mass of sodium borohydride and the volume ratio of anhydrous ethanol is 0.15 mmol: 17 mg: 1 mL; the conditions for the reduction reaction include: a temperature of 20~30℃ and a time of 0.5~1 h.

7. The use of the amide derivative according to claim 1 or 2 in the prevention and control of plant fungal diseases.

8. The application according to claim 7, characterized in that, The concentration of the amide derivative used is 0.195–400 µg / mL.

9. The application according to claim 7, characterized in that, The plant fungal diseases mentioned include one or more of the following: rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, blueberry gray mold, wheat scab, pseudostem spot, aflatoxin, and pepper anthracnose.

10. An antifungal agent for plant fungal diseases, characterized in that, Contains the amide derivative as described in claim 1 or 2; The plant fungal diseases mentioned include one or more of the following: rice sheath blight, rapeseed sclerotinia rot, cucumber wilt, pepper wilt, tomato gray mold, blueberry gray mold, wheat scab, pseudostem spot, aflatoxin, and pepper anthracnose.

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