Thiazole-2-yl benzoyl hydrazine derivative as well as preparation method and application thereof

Abstract

The invention discloses thiazole-2-yl benzoyl hydrazine derivatives as well as a preparation method and application thereof, and belongs to the field of medicinal chemistry. The thiazole-2-yl benzoyl hydrazine derivative shows an excellent broad-spectrum plant pathogenic bacterium resisting effect, has the advantage of being simple in synthesis method, and has important significance on discovery of novel bactericides and overcoming of drug resistance of plant pathogenic fungi.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a thiazol-2-yl benzohydrazide derivative, a preparation method and application thereof. BACKGROUND

[0002] Plant pathogenic fungi are ubiquitous biological constraints in global agricultural production, causing 16-30% of pre-harvest yield loss of major crops every year. Current plant disease control still highly depends on chemical fungicides, among which succinate dehydrogenase inhibitors (SDHIs) occupy 28% of the global fungicide market due to their potent and broad-spectrum antifungal activity. As early as 1966, the first SDHI-carboxin was launched by AgrEvo (now Syngenta) for seed treatment. Subsequently, although oxycarboxin was developed, its activity against basidiomycetes such as rusts was higher, but its fungicidal spectrum was narrower, thus limiting its use. However, with the continuous deepening of new pesticide research and the continuous improvement of synthesis technology in the 21st century, new SDHIs have emerged, broadening the fungicidal spectrum and being widely used to control various plant fungal diseases. For example, ofurace, boscalid and thifluzamide have made important progress in this field. However, due to long-term unscientific and uncontrolled misuse of SDHIs, plant pathogenic fungi have become increasingly resistant, and SDHIs have limited effect on oomycetes.

[0003] In recent years, the hydrazine structure has been introduced into the design of SDHIs as a key nitrogen-containing skeleton, becoming a substitute for the traditional amide bridge due to its wide range of biological and pharmacological activities. However, current lead compounds containing hydrazine structures mainly use six-membered aromatic ring systems (such as benzene, pyridine, phenyl ether) as the structural framework, and the hydrazine group is mostly used as a terminal substituent. This structural homogenization leads to convergence of molecular lipophilicity, which may increase the risk of developing resistance. Therefore, there is an urgent need to develop the next generation of fungicides with a broader antibacterial spectrum and lower environmental impact. SUMMARY

[0004] The purpose of the present application is to provide a thiazol-2-yl benzohydrazide derivative, a preparation method and application thereof, to solve the problems existing in the prior art and provide a compound with high-efficiency and broad-spectrum antifungal activity against plant pathogenic fungi.

[0005] To achieve the above-mentioned purpose, the present application provides the following solutions.

[0006] The present application provides a thiazol-2-yl benzohydrazide derivative, the structure of which is shown in the general formula as follows:

[0007]

[0008] wherein:

[0009] R 1 is selected from one or more of alkyl, alkoxy, halogen, trifluoromethyl, and the substitution sites include one or more of ortho, meta, and para positions.

[0010] R2is H or wherein * indicates the attachment site to N (not including C), R 3 is selected from one or more of alkyl, alkoxy, halogen, trifluoromethyl, and the substitution sites include one or more of ortho, meta, and para positions.

[0011] Further, R 1 is selected from one or more of methyl, methoxy, halogen, and trifluoromethyl; and R 3 is selected from one or more of methyl, methoxy, halogen, and trifluoromethyl.

[0012] The present application further provides a preparation method of the thiazol-2-yl benzohydrazide derivative described above, comprising the following steps:

[0013] Step 1: using 3-bromo-1,1,1-trifluoropropan-2-one and thiosemicarbazide as raw materials, mixing and reacting in an organic solvent to obtain compound A;

[0014] ;

[0015] Step 2: dissolving compound A, substituted or unsubstituted benzoic acid, and a condensation reagent into an organic solvent to perform a condensation reaction, thereby obtaining a thiazol-2-yl benzohydrazide derivative.

[0016] In step 1, the molar ratio of 3-bromo-1,1,1-trifluoropropan-2-one to thiosemicarbazide is 1.0:1.0-1.1.

[0017] In step 1, the reaction temperature is 80 ℃, and the reaction time is 4-5 h.

[0018] In step 2, the substituted or unsubstituted benzoic acid is selected from one of p-methylbenzoic acid, m-methylbenzoic acid, p-chlorobenzoic acid, m-chlorobenzoic acid, p-bromobenzoic acid, m-bromobenzoic acid, p-fluorobenzoic acid, m-fluorobenzoic acid, p-trifluoromethylbenzoic acid, m-trifluoromethylbenzoic acid, o-methylbenzoic acid, o-chlorobenzoic acid, o-bromobenzoic acid, o-fluorobenzoic acid, o-trifluoromethylbenzoic acid, 3,5-dichlorobenzoic acid, 3,5-dibromobenzoic acid, 3,5-bistrifluoromethylbenzoic acid, and m-methoxybenzoic acid.

[0019] Further, in step 2, when R 2 is H:

[0020] 2a. Compound A, substituted or unsubstituted benzoic acid, and a condensing agent are dissolved in an organic solvent and subjected to a condensation reaction to obtain R. 2 The condensing agent is O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethylurea tetrafluoroborate (TBTU); the molar ratio of compound A, substituted or unsubstituted benzoic acid, and condensing agent is 1.0:1.2:1.2. The condensation reaction is carried out at room temperature for 4-5 h.

[0021] Furthermore, in step 2, when the R of the target product... 2 for And R 3 With R 1 When they are the same:

[0022] 2b. Compound A, substituted or unsubstituted benzoic acid, and a condensing agent are dissolved in an organic solvent and subjected to a condensation reaction to obtain R. 2 for And R 3 With R 1 The same thiazol-2-ylbenzoylhydrazine derivative; the condensing agent is N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (TCFH); the molar ratio of compound A, substituted or unsubstituted benzoic acid, and condensing agent is 1.0:2.2:2.2. After the raw materials are added, the reaction is first carried out in an ice bath for 0.5 h, and then at 40 °C for 4-5 h.

[0023] Furthermore, in step 2, when the R of the target product... 2 for And R 3 With R 1 Not at the same time:

[0024] 2c. The R obtained from 2a 2 A thiazol-2-ylbenzoylhydrazine derivative of H, substituted or unsubstituted benzoic acid, and a condensing agent are dissolved in an organic solvent and subjected to a condensation reaction to obtain R. 2 for And R 3 With R 1 Different thiazol-2-ylbenzoylhydrazine derivatives; the condensing agent is phosphorus oxychloride; R 2 The molar ratio of the thiazol-2-ylbenzoylhydrazine derivative with H, substituted or unsubstituted benzoic acid, and condensing agent is 1.0:1.2:4.0. After the raw materials are added, the reaction is first carried out under ice bath conditions for 0.5 h, and then at 40 °C for 4-5 h.

[0025] The substituted or unsubstituted benzoic acid used in step 2c is different from the substituted or unsubstituted benzoic acid used in step 2a.

[0026] In the preparation process of the present application, the organic solvent used in each step is independently selected from one of ethanol, dichloromethane or pyridine.

[0027] As a further preferred embodiment of the present application, after the condensation reaction is completed, the steps of extraction, drying, suction filtration, vacuum distillation and column chromatography separation are further included.

[0028] More preferably, after the reactions in steps 2a and 2b are completed, the extraction is specifically as follows: the reaction solvent is rotary evaporated, and then saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution are sequentially used as the water phase, and ethyl acetate is used as the organic phase for extraction; the column chromatography separation is specifically as follows: 200-300 mesh column chromatography silica gel powder; the elution reagent for step 2a is a mixture of dichloromethane: petroleum ether = 1:2, the elution reagent for step 2b is a mixture of dichloromethane: petroleum ether = 1:1; and the drying reagent used is anhydrous sodium sulfate.

[0029] More preferably, after the reaction in step 2c is completed, the extraction is specifically as follows: 10% dilute hydrochloric acid solution and saturated sodium chloride solution are sequentially used as the water phase, and ethyl acetate is used as the organic phase for extraction; the column chromatography separation is specifically as follows: 200-300 mesh column chromatography silica gel powder; the elution reagent for step 2c is a mixture of dichloromethane: petroleum ether = 2:1; and the drying reagent used is anhydrous sodium sulfate.

[0030] In the reaction process of the present application, thin layer chromatography spot plate can be used to determine the end point of the reaction.

[0031] The present application also provides the use of the above-mentioned thiazol-2-yl benzhydrazide derivative in the preparation of a pharmaceutical preparation for resisting plant pathogenic fungi. The plant pathogenic fungi include one or more of Valsa mali, Sclerotinia sclerotiorum, Botrytis cinerea, Rhizoctonia solani, Alternaria alternata, Fusarium graminearum and Phytophthora capsici.

[0032] The present application also provides a pharmaceutical preparation for resisting plant pathogenic fungi, wherein the active ingredient of the pharmaceutical preparation comprises the thiazol-2-yl benzhydrazide derivative. The plant pathogenic fungi include Valsa mali, Sclerotinia sclerotiorum, Botrytis cinerea, Rhizoctonia solani, Alternaria alternata, Fusarium graminearum and Phytophthora capsici.

[0033] The present application has the following technical effects:

[0034] The present application provides a thiazol-2-yl benzhydrazide derivative and a N'-benzoyl-N-thiazol-2-yl benzhydrazide derivative, as well as a synthesis method thereof. The two types of derivatives exhibit excellent broad-spectrum effect of resisting plant pathogenic fungi.

[0035] The present application has the advantage of a simple synthesis method, and is of great significance for overcoming the drug resistance of plant pathogenic fungi. DETAILED DESCRIPTION

[0036] Various exemplary embodiments of the present application will now be described in detail, with reference to the drawings, which are provided as illustrative examples so as to enable those skilled in the art to practice the present application. However, the present application should not be limited to the embodiments described and shown.

[0037] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. Additionally, the use of the term "about" in the present application is intended to mean that quantities, dimensions, and other specified values need not be achieved exactly, but that deviations or variations, including up to ±10%, are acceptable, as long as the desired characteristics and effects of the compositions and methods according to the present application are achieved. It is further to be understood that the use of relational terms, if any, such as "by", "greater than", "less than" and the like, are used herein to describe a preference or merely an upper or lower limit set only by experimental reproducibility. Further, it is to be understood that the use of the singular includes the plural unless otherwise clear from the context.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods and materials are described. All documents mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the documents are cited. In case of conflict, the present specification will control.

[0039] Various modifications and changes can be made to the specific embodiments of the present application described herein without departing from the scope or spirit of the application. Other embodiments of the application will be apparent to those of ordinary skill in the art from the description and examples presented herein. The description and examples are illustrative of the application and are not intended to limit the scope of the application.

[0040] As used herein, the terms "comprise", "comprising", "include", "including", "have", "having" and the like are open-ended and do not exclude additional elements or steps.

[0041] The column chromatography conditions in the embodiments of the present application are: 200-300 mesh column chromatography silica gel powder. The number of moles marked in the embodiments of the present application represents the amount of the substance in the reaction system.

[0042] Example 1: Preparation of compound A1

[0043] The synthetic route of compound A1 is shown below:

[0044]

[0045] The synthetic steps of compound A1 are as follows:

[0046] (1) Amino thiourea (21 mmol) and 3-bromo-l, l, l-trifluoropropan-2-one (20 mmol) were dissolved in ethanol and refluxed at 80 °C for 5 h. After the reaction was completed, ethanol was removed by distillation under reduced pressure, dichloromethane was added to precipitate the solid, and the solid was dried by suction filtration to obtain compound A.

[0047] (2) p-Toluic acid (1.2 mmol), dry compound A (1.0 mmol), and TBTU (1.2 mmol) were dissolved in 4 mL of dichloromethane, 0.16 mL of triethylamine was added, and the reaction was carried out at room temperature for 5 h. After the reaction was completed, the solvent was evaporated, saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution were used as the water phase, and ethyl acetate was used as the organic phase for extraction, dried with anhydrous sodium sulfate, and filtered by suction. The organic phase was removed by distillation under reduced pressure, and column chromatography was performed using dichloromethane: petroleum ether = (1:2 v / v) to obtain the target compound A1.

[0048] Compound A1: 4-methyl-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, the structural formula is as follows:

[0049]

[0050] Compound A1 was a white solid, and the yield was 88%; mp: 193.4-194.4 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.79 (d, J = 8.2 Hz, 2H), 7.52 (s, 1H), 7.28 (d, J = 7.9 Hz, 2H), 4.88 (s, 2H), 2.43 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 170.93, 163.51, 141.51, 137.66 (q, J = 37.4 Hz), 131.89, 130.27, 128.49, 121.41 (q, J = 270.68 Hz), 119.77 (q, J = 4.0 Hz), 21.54. 19 F NMR (376 MHz, Methylene Chloride-d2) δ -64.83.

[0051] Example 2: Preparation of compound A2

[0052] The only difference between Example 1 and this example is that p-toluic acid in step (2) is replaced by m-toluic acid. Compound A2 is obtained as 3-methyl-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0053]

[0054] Compound A2 is a white solid with a yield of 85%; mp: 134.2-135.2 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.63 (s, 2H), 7.53 (s, 1H), 7.35 (d, J = 6.8 Hz, 2H), 4.87 (s, 2H), 2.42 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 170.59, 162.62, 139.22 (q, J = 38.4 Hz), 137.78, 132.70, 132.28, 130.01, 127.75, 126.63, 120.67 (q, J = 271.7 Hz), 117.79 (q, J = 3.0 Hz), 21.42. 19 F NMR (376 MHz, Chloroform-d) δ -64.51.

[0055] Example 3: Preparation of Compound A3

[0056] The only difference between Example 1 and this example is that p-toluic acid in step (2) is replaced by p-chlorobenzoic acid. Compound A3 is obtained as 4-chloro-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0057]

[0058] Compound A3 is a white solid with a yield of 86%; mp: 185.8-186.8 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.85 (d, J = 7.5 Hz, 2H), 7.54 (s, 1H), 7.44 (d, J = 6.2 Hz, 2H), 4.89 (s, 2H). 13C NMR (101 MHz, Chloroform-d) δ 169.11, 162.43, 139.31(q, J = 38.4 Hz), 137.96, 131.41, 130.91, 128.20, 120.61 (q, J = 270.7 Hz),117.96 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.53.

[0059] Example 4: Preparation of compound A4

[0060] The only difference between Example 1 and this example is that p-toluic acid in step (2) is replaced by m-chlorobenzoic acid. Compound A4 is obtained as 3-chloro-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0061]

[0062] Compound A4 is a white solid with a yield of 81%; mp: 105.3-106.3 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.74 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.41(s, 1H), 4.89 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 168.83, 162.29,139.25 (q, J = 38.4 Hz), 134.33, 133.85, 131.50, 129.81, 129.20, 127.86,120.62 (q, J = 270.7 Hz), 118.01 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.45.

[0063] Example 5: Preparation of compound A5

[0064] The only difference between Example 1 and this example is that p-toluic acid in step (2) is replaced by p-bromobenzoic acid. Compound A5 is obtained as 4-bromo-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0065]

[0066] Compound A5 was a white solid with a yield of 84%; mp: 167.8-168.8 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.78 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.54 (s,1H), 4.89 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 169.24, 162.40, 139.29(q, J = 37.4 Hz), 131.50, 131.40, 131.17, 126.45, 120.61 (q, J = 270.7 Hz),117.97 (q, J = 3.0 Hz). F NMR (376 MHz, Chloroform-d) δ -64.51。

[0067] Example 6: Preparation of compound A6

[0068] The only difference between this example and example 1 was that p-toluic acid in step (2) was replaced by m-bromobenzoic acid. Compound A6 was obtained as 3-bromo-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide with the following structure:

[0069]

[0070] Compound A6 was a white solid with a yield of 89%; mp: 123.7-124.7 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.34(s, 1H), 4.89 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 168.70, 162.27, 139.28 (q, J = 38.4 Hz), 134.55, 134.43, 132.65, 129.45, 128.30, 121.81, 120.60 (q, J = 271.7 Hz), 118.02 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.47.

[0071] Example 7: Preparation of compound A7

[0072] The only difference from Example 1 is that p-toluate in step (2) is replaced by p-fluorobenzoic acid. Compound A7 is obtained as 4-fluoro-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0073]

[0074] Compound A7 is a white solid with a yield of 85%; mp: 174.3-175.3 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (dd, J = 8.8, 5.3 Hz, 2H), 7.54 (s, 1H), 7.15 (t, J =8.7 Hz, 2H), 4.90 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 169.96, 163.95 (d, J =250.5 Hz), 163.39, 137.70 (q, J = 36.4 Hz), 132.93 (d, J = 8.1 Hz), 130.24(d, J = 3.0 Hz), 121.39 (q, J = 270.7 Hz), 119.92 (q, J = 4.0 Hz), 115.04 (d,J = 22.2 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.53, -106.94.

[0075] Example 8: Preparation of compound A8

[0076] The only difference from Example 1 is that p-toluate in step (2) is replaced by m-fluorobenzoic acid. Compound A8 is obtained as 3-fluoro-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0077]

[0078] Compound A8 is a white solid with a yield of 82%; mp: 158.7-159.7 °C; 1H NMR (600 MHz, Chloroform-d) δ 7.66 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.55 (s, 1H), 7.46 - 7.43 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.89 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 168.83, 162.36, 161.88 (d, J = 247.4 Hz), 139.32 (q, J = 38.4 Hz), 134.58 (d, J = 7.1 Hz), 129.56 (d, J = 10.1 Hz), 125.53 (d, J = 3.0 Hz), 120.61 (q, J = 273.7 Hz), 118.58 (d, J = 21.2 Hz), 118.00 (q, J = 3.0 Hz), 117.01 (d, J = 23.2 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.51, -112.43.

[0079] Example 9: Preparation of compound A9

[0080] The only difference between this example and Example 1 is that p-toluate in step (2) is replaced by p-trifluoromethylbenzoic acid. Compound A9 is obtained as 4-(trifluoromethyl)-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0081]

[0082] Compound A9 is a white solid with a yield of 86%; mp: 162.3-163.3 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H), 7.58 (s, 1H), 4.90 (s, 2H). 13C NMR (101 MHz, Chloroform-d) δ 169.12, 162.16, 139.38(q, J = 38.4 Hz), 136.21, 133.00 (q, J = 33.3 Hz), 129.98, 124.88 (q, J = 4.0Hz), 123.62 (q, J = 273.7 Hz) 120.57 (q, J = 271.7 Hz), 118.08 (q, J = 4.0Hz). 19 F NMR (376 MHz, Chloroform-d) δ -63.09, -64.53.

[0083] Example 10: Preparation of compound A10

[0084] The only difference between this example and example 1 is that p-toluic acid in step (2) is replaced by m-trifluoromethylbenzoic acid. Compound A10 is obtained as 3-(trifluoromethyl)-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0085]

[0086] Compound A10 is a white solid with a yield of 84%; mp: 65.6-67.6 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.16 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.55 (s, 1H), 4.93 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 169.12, 162.16, 139.38(q, J = 38.4 Hz), 136.21, 133.00 (q, J = 33.3 Hz), 129.98, 124.88 (q, J = 4.0Hz), 123.62 (q, J = 273.7 Hz) 120.57 (q, J = 271.7 Hz), 118.08 (q, J = 4.0Hz). 19F NMR (376 MHz, Chloroform-d) δ -62.81, -64.55.

[0087] Example 11: Preparation of compound A11

[0088] The only difference between this example and Example 1 is that p-toluic acid in step (2) is replaced by o-toluic acid. Compound A11 is obtained as 2-methyl-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0089]

[0090] Compound A11 is a white solid with a yield of 77%; mp: 84.2-85.2 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.55 (s, 1H), 7.38 (s, 1H), 7.33 – 7.26 (m, 3H), 4.78 (s, 2H), 2.35 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 171.91, 161.91, 139.23 (q, J = 37.4 Hz), 135.03, 134.16, 130.29, 130.01, 126.82, 125.47, 120.65 (q, J = 271.7 Hz), 117.80 (q, J = 3.0 Hz), 19.47. 19 F NMR (376 MHz, Chloroform-d) δ -64.45.

[0091] Example 12: Preparation of compound A12

[0092] The only difference between this example and Example 1 is that p-toluic acid in step (2) is replaced by o-chlorobenzoic acid. Compound A12 is obtained as 2-chloro-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0093]

[0094] Compound A12 is a white solid with a yield of 78%; mp: 124.9-125.9 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.57 (s, 1H), 7.46 – 7.38 (m, 4H), 4.85 (s, 2H).13 C NMR (101 MHz, Chloroform-d) δ 169.31, 161.66, 139.35 (q, J = 37.4 Hz), 134.47, 131.12, 131.04, 129.29, 128.17, 126.93, 120.60 (q, J = 271.7 Hz), 117.90 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.42.

[0095] Example 13: Preparation of compound A13

[0096] The only difference between this example and example 1 is that p-toluic acid in step (2) is replaced by o-bromobenzoic acid. Compound A13, 2-bromo-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, is obtained as shown below:

[0097]

[0098] Compound A13 is a white solid with a yield of 77%; mp: 116.2-117.2 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.63 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 20.1, 7.6 Hz, 2H), 4.85 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 169.88, 161.63, 139.39 (q, J = 38.4 Hz), 136.69, 132.36, 131.13, 128.09, 127.45, 120.6 (q, J = 270.7 Hz), 119.60, 117.97 (q, J = 4.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.42.

[0099] Example 14: Preparation of compound A14

[0100] The only difference between Example 1 and this example is that p-toluic acid in step (2) is replaced by o-fluorobenzoic acid. Compound A14, 2-fluoro-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, is obtained as shown in the following structural formula:

[0101]

[0102] Compound A14 is a white solid with a yield of 73%; mp: 131.2-132.2 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.53 (d, J = 22.6 Hz, 3H), 7.27 (d, J = 3.5 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 4.89 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 168.01, 161.93, 159.05 (d, J = 250.4 Hz), 139.31 (q, J = 37.4 Hz), 132.84 (d, J = 9.1 Hz), 129.60 (d, J = 3.0 Hz), 124.37 (d, J = 3.0 Hz), 122.53 (d, J = 16.1 Hz), 120.6 (q, J = 270.7 Hz), 117.69 (q, J = 3.0 Hz), 115.54 (d, J = 18.1 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.48, -110.64.

[0103] Example 15: Preparation of Compound A15

[0104] The only difference between Example 1 and this example is that p-toluic acid in step (2) is replaced by o-fluorobenzoic acid. Compound A14, 2-fluoro-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, is obtained as shown in the following structural formula:

[0105]

[0106] Compound A15 is a white solid with a yield of 73%; mp: 131.2-132.2 °C; 1H NMR (600 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.66 (d, J = 7.1 Hz, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 4.70 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 169.78, 161.55, 139.33 (q, J = 38.4 Hz), 133.17 (q, J = 2.0 Hz), 131.82, 129.85, 127.29, 126.90 (q, J = 32.3 Hz), 126.40 (q, J = 4.0 Hz), 123.67 (q, J = 273.7 Hz), 120.57 (q, J = 270.7 Hz), 117.99 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -60.16, -64.47.

[0107] Example 16: Preparation of compound A16

[0108] The only difference between this example and example 1 is that p-toluic acid in step (2) is replaced by 3,5-dichlorobenzoic acid. Compound A16 is obtained as 3,5-dichloro-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0109]

[0110] Compound A16 is a white solid with a yield of 85%; mp: 138.6-139.6 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.75 (s, 2H), 7.56 (s, 1H), 7.51 (s, 1H), 4.90 (s, 2H). 13 CNMR (101 MHz, Chloroform-d) δ 167.48, 162.05, 139.49 (q, J = 39.4 Hz), 135.37, 134.70, 131.34, 128.20, 120.54 (q, J = 270.7 Hz), 118.15 (q, J = 3.0 Hz). 19F NMR (376 MHz, Chloroform-d) δ -64.51.

[0111] Example 17: Preparation of compound A17

[0112] The only difference between this example and example 1 is that p-toluic acid in step (2) is replaced by 3,5-dibromobenzoic acid. Compound A17 is obtained as 3,5-dibromo-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0113]

[0114] Compound A17 is a white solid with a yield of 87%; mp: 125.4-126.4 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.94 (s, 2H), 7.82 (s, 1H), 7.56 (s, 1H), 4.89 (s, 2H). 13 CNMR (101 MHz, Chloroform-d) δ 167.23, 161.99, 139.43 (q, J = 37.4 Hz), 136.77, 135.78, 131.42, 122.38, 120.52 (q, J = 271.7 Hz), 118.18 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.48.

[0115] Example 18: Preparation of compound A18

[0116] The only difference between this example and example 1 is that p-toluic acid in step (2) is replaced by 3,5-dibromobenzoic acid. Compound A17 is obtained as 3,5-dibromo-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0117]

[0118] Compound A18 is a white solid with a yield of 88%; mp: 94.3-95.3 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.39 (s, 2H), 8.04 (s, 1H), 7.60 (s, 1H), 4.97 (s, 2H). 13H NMR (600 MHz, Chloroform-d) δ 7.53 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.07 (d, J = 7.4 Hz, 1H), 4.88 (s, 2H), 3.85 (s, 3H). 19 F NMR (376 MHz, Chloroform-d) δ -63.04, -64.64.

[0119] Example 19: Preparation of compound A19

[0120] The only difference between this example and Example 1 is that p-toluic acid in step (2) is replaced by 3-methoxybenzoic acid. Compound A19 is obtained as 3-methoxy-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0121]

[0122] Compound A19 is a white solid with a yield of 76%; mp: 154.0-155.0 °C; 1 H NMR (600 MHz, Chloroform-d) δ 7.53 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.07 (d, J = 7.4 Hz, 1H), 4.88 (s, 2H), 3.85 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 170.93, 163.39, 158.76, 137.70 (q, J = 36.4 Hz), 135.25, 129.19, 121.97, 121.40 (q, J = 270.7 Hz), 119.85 (q, J = 3.0 Hz), 116.99, 115.34, 55.76. 19 F NMR (376 MHz, Chloroform-d) δ -64.73.

[0123] Example 20: Preparation of compound A20

[0124] The synthetic route of compound A20 is shown as follows:

[0125]

[0126] The synthetic steps of compound A20 are as follows:

[0127] (1) Reflux the solution of aminothiourea (21 mmol) and 3-bromo-1,1,1- trifluoropropan-2-one (20 mmol) in ethanol at 80 °C for 5 h. After the reaction is completed, remove ethanol by distillation under reduced pressure, add dichloromethane to precipitate the solid, and dry by suction filtration to obtain compound A.

[0128] (2) Dissolve p-toluenic acid (2.2 mmol) and TCFH (2.2 mmol) in 4 mL of dichloromethane, add 0.16 mL of N-methylimidazole, and react for 0.5 h in an ice bath. Add dry compound A (1.0 mmol) to the above reaction solution, and react for 5 h at 40 °C. After the reaction is completed, spin dry the solvent, and extract with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution as the water phase, and ethyl acetate as the organic phase, dry with anhydrous sodium sulfate, and remove the organic phase by suction filtration under reduced pressure. Perform column chromatography separation using dichloromethane: petroleum ether = (1:1 v / v) to obtain the target compound A20.

[0129] Compound A20: 4-methyl-N'-(4-methylbenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, has the following structural formula:

[0130]

[0131] Compound A20 is a white solid with a yield of 85%; mp: 220.5-221.5 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.67 - 7.61 (m, 4H), 7.52 (s, 1H), 7.24 (s, 2H), 7.21 (d, J = 7.7 Hz, 2H), 2.40 (s, 3H), 2.37 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 170.9, 165.7, 161.0, 143.5, 142.6, 137.8 (q, J = 37.4 Hz), 129.8, 129.3, 129.1, 128.8, 128.7, 128.0, 121.1 (q, J = 270.7 Hz), 120.4 (q, J = 3.0 Hz), 21.5. 19 F NMR (376 MHz, Chloroform-d) δ -64.51.

[0132] Example 21: Preparation of compound A21

[0133] The only difference between this example and example 20 is that p-toluic acid is replaced by m-toluic acid in step (2). Compound A21 is obtained as 3-methyl-N'-(3-methylbenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0134]

[0135] Compound A21 is a white solid with a yield of 83%; mp: 57.2-58.2 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.73 (s, 1H), 7.55 - 7.52 (m, 4H), 7.48 (d, J = 7.4 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 9.7 Hz, 3H), 2.35 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 171.1, 166.0, 160.9, 138.7, 138.0, 137.8 (q, J = 38.4 Hz), 133.7, 132.9, 132.2, 131.6, 129.2, 129.1, 128.5, 128.4, 125.6, 125.0, 121.1 (q, J = 270.7 Hz), 120.4 (q, J = 4.0 Hz), 21.3, 21.2. 19 F NMR (376 MHz, Chloroform-d) δ -64.48.

[0136] Example 22: Preparation of compound A22

[0137] The only difference between Example 20 and this example is that p-tollic acid in step (2) is replaced by p-chlorobenzoic acid. Compound A22 is obtained as 4-chloro-N'-(4-chlorobenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0138]

[0139] Compound A22 is a white solid with a yield of 86%; mp: 189.4-190.4 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.73 (s, 1H), 7.69 - 7.67 (m, 4H), 7.56 (s, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 170.0, 165.2, 160.6, 138.3, 137.8 (q, J = 37.4 Hz), 137.3, 130.9, 130.4, 130.0, 129.8, 129.5, 128.9, 121.1 (q, J = 270.7 Hz), 120.7 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.49.

[0140] Example 23: Preparation of Compound A23

[0141] The only difference between Example 20 and this example is that p-tollic acid in step (2) is replaced by m-chlorobenzoic acid. Compound A23 is obtained as 3-chloro-N'-(3-chlorobenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0142]

[0143] Compound A23 is a white solid with a yield of 83%; mp: 110.7-111.7 °C; 1H NMR (600 MHz, Chloroform-d) δ 9.10 (s, 1H), 7.69 - 7.66 (m, 2H), 7.59 - 7.55 (m, 3H), 7.50 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 6.1 Hz, 1H), 7.35 - 7.33 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 169.2, 166.5, 160.1, 139.4 (q, J = 38.4 Hz), 135.1, 134.4, 133.4, 133.0, 132.7, 132.0, 130.2, 129.7, 128.2, 127.8, 126.1, 125.5, 120.3 (q, J = 271.7 Hz), 118.3 (q, J = 4.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.32.

[0144] Example 24: Preparation of compound A24

[0145] The only difference between this example and example 20 is that p-toluate in step (2) is replaced by p-bromobenzoic acid. Compound A24 is obtained as 4-bromo-N'-(4-bromobenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0146]

[0147] Compound A24 is a white solid with a yield of 85%; mp: 219.7-220.7 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.60 (s, 5H), 7.57 (s, 2H), 7.56 (s, 2H). 13 CNMR (101 MHz, Methanol-d4) δ 170.0, 166.8, 160.1, 138.9 (q, J = 38.4 Hz), 131.8, 131.3, 131.2, 130.3, 129.5, 129.0, 127.2, 125.9, 120.7 (q, J = 270.7 Hz), 118.4 (q, J = 3.0 Hz). 19F NMR (376 MHz, Chloroform-d) δ -64.41.

[0148] Example 25: Preparation of compound A25

[0149] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by m-bromobenzoic acid. Compound A25 is obtained as 3-bromo-N'-(3-bromobenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0150]

[0151] Compound A25 is a white solid with a yield of 87%; mp: 153.9-154.9 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.77 (s, 1H), 7.88 - 7.85 (m, 2H), 7.70 (s, 1H), 7.64 (s, 3H), 7.57 (s, 1H), 7.35 - 7.30 (m, 2H). 13 C NMR (101 MHz, Methylene Chloride-d2) δ 170.8, 168.2, 161.8, 141.0 (q, J = 37.4 Hz), 138.0, 136.7, 135.6, 134.9, 132.9, 132.5, 132.5, 131.9, 128.4, 127.9, 124.9, 124.0, 122.4 (q, J = 270.7 Hz), 120.5 (q, J = 4.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.41.

[0152] Example 26: Preparation of compound A26

[0153] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by p-fluorobenzoic acid. Compound A26 is obtained as 4-fluoro-N'-(4-fluorobenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0154]

[0155] Compound A26 is a white solid with a yield of 78%; mp: 201.5-202.5 °C; 1H NMR (600 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.79 - 7.73 (m, 4H), 7.55 (s, 1H), 7.15 - 7.09 (m, 4H). 13 C NMR (101 MHz, Methanol-d4) δ 169.9, 166.7, 165.5 (d, J = 253.5 Hz), 164.6 (d, J = 252.5 Hz), 160.3, 138.9 (q, J = 37.4 Hz), 130.5 (d, J = 9.1 Hz), 130.0 (d, J = 12.1 Hz), 128.5 (d, J = 3.0 Hz), 127.6 (d, J = 3.0 Hz), 120.7 (q, J = 269.7 Hz), 118.4 (q, J = 4.0 Hz), 115.5 (d, J = 22.2 Hz), 114.9 (d, J = 23.2 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.50, -104.68, -106.20.

[0156] Example 27: Preparation of compound A27

[0157] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by m-fluorobenzoic acid. Compound A27 is obtained as 3-fluoro-N'-(3-fluorobenzoyl)-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0158]

[0159] Compound A27 is a white solid with a yield of 81%; mp: 140.6-141.6 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.84 (s, 1H), 7.56 (s, 1H), 7.50 - 7.47 (m, 2H), 7.43 - 7.38 (m, 4H), 7.25 (d, J = 8.8 Hz, 1H), 7.22 - 7.19 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ 169.2, 166.8, 162.6 (d, J = 250.4 Hz), 162.0 (d, J = 249.4 Hz), 159.8, 139.4 (q, J = 38.4 Hz), 133.7 (d, J = 8.1 Hz), 133.0 (d, J = 7.1 Hz), 130.9 (d, J = 8.1 Hz), 130.1 (d, J = 8.1 Hz), 123.7 (d, J = 4.0 Hz), 123.0 (d, J = 3.0 Hz), 120.3 (q, J = 271.7 Hz), 120.2 (d, J = 21.2 Hz), 119.0 (d, J = 21.2 Hz), 118.3 (q, J = 3.0 Hz), 115.2 (d, J = 23.2 Hz), 114.8 (d, J = 23.2 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.47, -110.55, -111.23.

[0160] Example 28: Preparation of compound A28

[0161] The only difference between this example and example 20 is that p-tolylbenzoic acid in step (2) is replaced by p-trifluoromethylbenzoic acid. Compound A28 is obtained as 4-(trifluoromethyl)-N'-[4-(trifluoromethyl)benzoyl]-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0162]

[0163] Compound A28 is a white solid with a yield of 81%; mp: 223.6-224.6 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.78 (s, 1H), 7.85 – 7.82 (m, 4H), 7.74 – 7.70 (m, 4H), 7.60 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.8, 165.3, 160.3, 137.8 (q, J = 37.4 Hz), 136.2, 134.9, 133.0 (q, J = 32.3 Hz), 132.0 (q, J = 32.3 Hz), 129.2, 128.8, 126.4 (q, J = 4.0 Hz), 125.8 (q, J = 4.0 Hz), 124.0 (q, J = 274.72 Hz), 121.0 (q, J = 270.7 Hz), 121.0 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -63.15, -63.28, -64.51.

[0164] Example 29: Preparation of compound A29

[0165] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by m-trifluoromethylbenzoic acid. Compound A29 is obtained as 3-(trifluoromethyl)-N'-[3-(trifluoromethyl)benzoyl]-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0166]

[0167] Compound A29 is a white solid with a yield of 82%; mp: 109.7-110.7 °C; 1 H NMR (600 MHz, Chloroform-d) δ 9.09 (s, 1H), 8.03 (s, 1H), 7.94 (s, 2H), 7.88 (d, J = 7.1 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.8 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 169.0, 166.9, 159.7, 139.5 (q, J = 38.4 Hz), 132.5, 131.7, 131.5, 131.5 (q, J = 33.3 Hz), 130.7 (q, J = 33.3 Hz), 130.7, 129.6, 129.6 (q, J = 4.0 Hz), 129.2, 128.5 (q, J = 4.0 Hz), 125.0 (q, J = 4.0 Hz), 124.4 (q, J = 4.0 Hz), 123.4 (q, J = 273.71 Hz), 123.2 (q, J = 273.7 Hz), 120.3 (q, J = 270.7 Hz), 118.4 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -63.04, -63.28, -64.56.

[0168] Example 30: Preparation of compound A30

[0169] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by o-toluic acid. Compound A30 is obtained as 2-methyl-N'-(2-methylbenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0170]

[0171] Compound A30 is a white solid with a yield of 76%; mp: 174.6-175.6 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.57 (s, 1H), 7.40 - 7.37 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.14 - 7.11 (m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 2.42 (s, 3H), 2.12 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 171.5, 169.2, 159.6, 139.4 (q, J = 38.4 Hz), 137.2, 135.9, 132.4, 132.3, 131.0, 130.7, 130.5, 126.7, 126.6, 125.7, 125.3, 120.5 (q, J = 270.7 Hz), 117.9 (q, J = 3.0 Hz), 19.2, 18.7. 19 FNMR (376 MHz, Chloroform-d) δ -64.51.

[0172] Example 31: Preparation of compound A31

[0173] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by o-chlorobenzoic acid. Compound A31 is obtained as 2-chloro-N'-(2-chlorobenzoyl)-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0174]

[0175] Compound A31 is a white solid with a yield of 78%; mp: 149.3-150.3 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.60 (s, 1H), 7.45 - 7.41 (m, 3H), 7.39 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.32 - 7.29 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 168.7, 166.1, 159.0, 139.5 (q, J = 38.4 Hz), 132.8, 132.4, 131.9, 131.8, 131.3, 130.4, 130.2, 129.5, 129.1, 129.0, 127.2, 127.1, 120.5 (q, J = 271.7 Hz), 118.1 (q, J = 4.0 Hz). 19F NMR (376 MHz, Chloroform-d) δ -64.43.

[0176] Example 32: Preparation of compound A32

[0177] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by o-bromobenzoic acid. Compound A32 is obtained as 2-bromo-N'-(2-bromobenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0178]

[0179] Compound A32 is a white solid with a yield of 78%; mp: 131.2-132.2 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.62 - 7.58 (m, 3H), 7.51 (d, J = 4.8 Hz, 1H), 7.42 - 7.40 (m, 1H), 7.38 - 7.34 (m, 3H), 7.30 (d, J = 4.2 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 169.3, 166.9, 158.9, 139.5 (q, J = 38.4 Hz), 135.0, 134.3, 133.4, 132.3, 132.2, 131.8, 129.3, 129.1, 127.8, 127.6, 120.5 (q, J = 271.7 Hz), 119.4, 119.0, 118.2 (q, J = 4.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.34.

[0180] Example 33: Preparation of compound A33

[0181] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by o-fluorobenzoic acid. Compound A33 is obtained as 2-fluoro-N'-(2-fluorobenzoyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0182]

[0183] Compound A33 was a light yellow solid with a yield of 77%; mp: 125.9-126.9 °C; 1 H NMR (600 MHz, Chloroform-d) δ 9.26 (s, 1H), 7.88 – 7.83 (m, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.23 – 7.21 (m, 2H), 7.16 – 7.10 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 167.6, 163.2, 160.6 (d, J = 251.5 Hz), 158.6 (d, J = 250.5 Hz), 139.5 (q, J = 38.4 Hz), 134.9 (d, J = 9.1 Hz), 133.5 (d, J = 8.1 Hz), 132.0 (d, J = 2.0 Hz), 131.9 (d, J = 3.0 Hz), 130.4 (d, J = 6.1 Hz), 125.0 (d, J = 3.0 Hz), 124.8 (d, J = 3.0 Hz), 120.8 (d, J = 15.1 Hz), 120.4 (q, J = 270.7 Hz), 118.0, 117.9 (q, J = 4.0 Hz), 116.3 (d, J = 23.2 Hz), 115.5 (d, J = 22.2 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.40, -110.62, -112.43.

[0184] Example 34: Preparation of compound A34

[0185] The only difference between Example 20 and this example is that p-toluic acid in step (2) is replaced by o-trifluoromethylbenzoic acid. Compound A34 is obtained as 2-(trifluoromethyl)-N'-[2-(trifluoromethyl)benzoyl]-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, the structure of which is shown below:

[0186]

[0187] Compound A34 was a white solid with a yield of 75%; mp: 177.4-178.4 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.70 – 7.64 (m, 5H),7.62 – 7.57 (m, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 169.2, 167.4, 158.9, 139.4 (q, J = 38.4 Hz), 132.3, 132.2, 131.5 (q, J = 2.0 Hz), 131.2, 131.1 (q, J = 3.0 Hz), 130.6, 129.0, 128.1 (q, J = 32.3 Hz), 127.8, 126.6 (q, J = 5.0 Hz), 126.0 (q, J = 4.0 Hz), 123.6 (q, J = 273.7 Hz), 122.7 (q, J = 274.7 Hz), 120.5 (q, J = 271.7 Hz), 118.3 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -59.57, -59.91, -64.47.

[0188] Example 35: Preparation of compound A35

[0189] The only difference between Example 20 and this example is that p-toluic acid in step (2) is replaced by 3,5-dichlorobenzoic acid. Compound A35 is obtained as 3,5-dichloro-N'-(3,5-dichlorobenzoyl)-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, the structure of which is shown below:

[0190]

[0191] Compound A35 is a light yellow solid with a yield of 87%; mp: 176.4-177.4°C; 1 H NMR (600 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.62 (s, 2H), 7.60 (s, 3H), 7.58 (s, 1H), 7.51 (s, 1H). 13C NMR (101 MHz, Chloroform-d) δ 167.5, 165.7, 159.5, 139.6 (q, J = 38.4 Hz), 136.1, 135.3, 134.3, 133.6, 133.1, 132.0, 126.4, 126.1, 120.2 (q, J = 271.7 Hz), 118.6 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.43.

[0192] Example 36: Preparation of compound A36

[0193] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by 3,5-dibromobenzoic acid. Compound A36 is obtained as 3,5-dibromo-N'-(3,5-dibromo- benzoyl)-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0194]

[0195] Compound A36 is a white solid with a yield of 86%; mp: 157.1-158.1 °C; 1 H NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 7.86 (s, 1H), 7.80 (s, 5H), 7.59 (s, 1H). 13 CNMR (101 MHz, Chloroform-d) δ 167.2, 165.4, 159.4, 139.6 (q, J = 38.4 Hz), 138.6, 137.4, 134.6, 134.1, 129.8, 129.4, 123.8, 122.9, 120.2 (q, J = 271.7 Hz), 118.5 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.42.

[0196] Example 37: Preparation of compound A37

[0197] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by 3,5-bistrifluoromethylbenzoic acid. Compound A37 is obtained as 3,5-bis(trifluoromethyl)-N'-[3,5-bis(trifluoromethyl)benzoyl]-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0198]

[0199] Compound A37 is a white solid with a yield of 74%; mp: 142.5-143.5 °C; 1 H NMR (600 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.27 (s, 2H), 8.20 (s, 2H), 8.09 (s, 1H), 8.04 (s, 1H), 7.65 (s, 1H). 13 C NMR (101 MHz, Methylene Chloride-d2) δ 167.2, 165.9, 159.4, 139.3 (q, J = 38.4 Hz), 133.7, 132.9, 132.6 (q, J = 34.3 Hz), 131.9 (q, J = 34.3 Hz), 128.6 (q, J = 4.0 Hz), 127.9 (q, J = 4.0 Hz), 126.9 (q, J = 4.0 Hz), 125.7 (q, J = 4.0 Hz), 122.7 (q, J = 273.7 Hz), 122.6 (q, J = 274.7 Hz), 120.3 (q, J = 271.7 Hz), 119.2 (q, J = 4.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -63.10, -63.28, -64.53.

[0200] Example 38: Preparation of compound A38

[0201] The only difference between this example and example 20 is that p-toluic acid in step (2) is replaced by 3,5-bistrifluoromethylbenzoic acid. Compound A37 is obtained as 3,5-bis(trifluoromethyl)-N'-[3,5-bis(trifluoromethyl)benzoyl]-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, with the following structure:

[0202]

[0203] Compound A38 was a light yellow solid with a yield of 80%; mp: 141.0-142.0 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.53 (s, 1H), 7.29 (d, J = 7.9 Hz, 3H), 7.25(s, 1H), 7.22 (s, 2H), 7.06 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 5.3 Hz, 1H),3.77 (d, J = 6.9 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 170.5, 167.7,160.1, 159.8, 159.2, 139.3 (q, J = 38.4 Hz), 133.1, 132.6, 129.9, 129.3,120.4 (q, J = 271.7 Hz), 120.1, 119.4, 119.3, 118.0 (q, J = 3.0 Hz), 118.0,113.0, 112.3, 55.3. 19 F NMR (376 MHz, Chloroform-d) δ -64.39.

[0204] Example 39: Preparation of compound A39

[0205] The synthetic route of compound A39 is shown below:

[0206]

[0207] The synthetic steps of compound A39 are as follows:

[0208] (1) Compound A6 (0.5 mmol) and 3,5-bistrifluoromethylbenzoic acid (0.6 mmol) were dissolved in 2 mL of pyridine, and phosphorus oxychloride (2.0 mmol) was added, and the reaction was carried out under ice bath for 0.5 h. The above reaction solution was transferred to 40 °C for 5 h. After the reaction was completed, 10% dilute hydrochloric acid solution, saturated sodium chloride solution as the water phase, ethyl acetate as the organic phase was used for extraction; dried with anhydrous sodium sulfate, and then filtered under reduced pressure to remove the organic phase, and column chromatography separation was carried out using dichloromethane: petroleum ether = (2:1 v / v) to obtain the target compound A39.

[0209] Compound A39: N'-(3-bromobenzoyl)-3,5-bis(trifluoromethyl)-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, has the following structural formula:

[0210]

[0211] Compound A39 was obtained as a light yellow solid in 58% yield; mp: 147.3-148.3 °C; 1 H NMR (600 MHz, Chloroform-d) δ 9.03 (s, 1H), 8.20 (s, 2H), 8.08 (s, 1H), 7.90 (s, 1H), 7.69 - 7.65 (m, 2H), 7.60 (s, 1H), 7.36 - 7.32 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 169.1, 163.8, 160.4, 137.8 (q, J = 37.4 Hz), 135.1, 134.0, 133.5, 131.5 (q, J = 33.3 Hz), 131.0, 131.0, 128.7 (q, J = 4.0 Hz), 127.5, 126.9 (q, J = 4.0 Hz), 123.2 (q, J = 274.7 Hz), 121.6, 121.0 (q, J = 270.7 Hz), 120.9 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Methylene Chloride-d2) δ -63.51, -64.84.

[0212] Example 40: Preparation of Compound A40

[0213] The only difference between Example 39 and this example is that compound A6 in Step (1) is replaced by compound A10. Compound A40, 3,5-bis(trifluoromethyl)-N'-[3- (trifluoromethyl)benzoyl]-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, has the following structural formula:

[0214]

[0215] Compound A40 was obtained as a white solid in 60% yield; mp: 141.2-142.2 °C; 1H NMR (600 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.16 (s, 2H), 8.07 - 8.04 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.61 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 169.2, 163.7, 160.3, 137.9 (q, J = 37.4 Hz), 133.3, 132.9, 132.7, 131.5 (q, J = 34.3 Hz), 130.2, 129.3 (q, J = 33.3 Hz), 128.8 (q, J = 3.0 Hz), 128.6 (q, J = 4.0 Hz), 126.8 (q, J = 4.0 Hz), 125.1 (q, J = 3.0 Hz), 123.9 (q, J = 273.7 Hz), 123.1 (q, J = 274.7 Hz), 120.9 (q, J = 270.7 Hz), 120.8 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -62.98, -63.24, -64.56.

[0216] Example 41: Preparation of compound A41

[0217] The only difference between this example and example 39 is that compound A6 in step (1) is replaced by compound A13, and 3,5-bistrifluoromethylbenzoic acid is replaced by m- trifluoromethylbenzoic acid. Compound A41 is obtained as 2-bromo-N'-[3-(trifluoromethyl)benzoyl]-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0218]

[0219] Compound A41 is a white solid with a yield of 55%; mp: 158.3-159.3 °C; 1H NMR (600 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.81 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.76(s, 1H), 7.63 - 7.59 (m, 2H), 7.57 - 7.54 (m, 2H), 7.39 - 7.36 (m, 1H), 7.34- 7.31 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 169.0, 165.9, 159.0, 139.6(q, J = 38.4 Hz), 134.8, 132.2, 132.0, 131.9, 131.5 (q, J = 38.4 Hz), 130.5,129.6, 129.5 (q, J = 4.0 Hz), 129.0, 127.7, 124.5 (q, J = 4.0 Hz), 123.3 (q,J = 273.7 Hz), 120.3 (q, J = 270.7 Hz), 118.7, 118.2 (q, J = 4.0 Hz). 19 F NMR(376 MHz, Chloroform-d) δ -63.03, -64.40.

[0220] Example 42: Preparation of compound A42

[0221] The only difference between this example and example 39 is that compound A6 in step (1) is replaced by compound A13. Compound A42 is obtained as 3,5-bis(trifluoromethyl)-N'-(2-bromobenzoyl)-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0222]

[0223] Compound A42 is a white solid with a yield of 58%; mp: 173.5-174.5 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.81 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.76(s, 1H), 7.63 - 7.59 (m, 2H), 7.57 - 7.54 (m, 2H), 7.39 - 7.36 (m, 1H), 7.34- 7.31 (m, 1H). 13 C NMR (101 MHz, Methylene Chloride-d2) δ 168.9, 164.6, 159.1, 139.2 (q, J = 38.4 Hz), 134.5, 133.3, 132.4, 132.4 (q, J = 34.3 Hz), 132.2, 128.7, 128.0(q, J = 3.0 Hz), 127.7, 126.5 (q, J = 4.0 Hz), 122.7 (q, J = 273.7 Hz), 120.4(q, J = 271.7 Hz), 118.6 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -63.14, -64.42.

[0224] Example 43: Preparation of compound A43

[0225] The only difference between this example and example 39 is that compound A6 in step (1) is replaced by compound A17, and 3,5-bistrifluoromethylbenzoic acid is replaced by m-fluorobenzoic acid. Compound A43 is obtained as 3,5-dibromo-N'-[3-fluorobenzoyl]-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0226]

[0227] Compound A43 is a white solid with a yield of 60%; mp: 112.4-113.4 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.82 (s, 2H), 7.80 (s, 1H), 7.58 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.50 - 7.47 (m, 1H), 7.45 (d, J = 6.6 Hz, 1H), 7.32 - 7.28 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ 167.4, 166.8, 162.7 (d, J = 250.5 Hz), 159.6, 139.5 (q, J = 38.4 Hz), 137.3, 134.9, 132.9 (d, J = 7.1 Hz), 130.9 (d, J = 7.1 Hz), 129.8, 123.0 (d, J = 4.0 Hz), 122.8, 120.4 (d, J = 21.2 Hz), 120.3 (q, J = 271.7 Hz), 118.5 (q, J = 3.0 Hz), 114.9 (d, J = 24.2 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -64.45, -110.27.

[0228] Example 44: Preparation of compound A44

[0229] The only difference between this example and example 39 is that compound A6 in step (1) is replaced by compound A17, and 3,5-bistrifluoromethylbenzoic acid is replaced by m- trifluoromethylbenzoic acid. Compound A44 is obtained as 3,5-dibromo-N'-[3-(trifluoromethyl)benzoyl]-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0230]

[0231] Compound A44 is a white solid with a yield of 55%; mp: 139.0-140.0 °C; 1 H NMR (600 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.03 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.83 (s, 2H), 7.80 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H). 13C NMR (101 MHz, Chloroform-d) δ 167.4, 167.0, 159.5, 139.5 (q, J = 38.4 Hz), 137.4, 134.7, 131.7 (q, J = 4.0 Hz), 130.7, 129.8, 123.2 (q, J = 268.7 Hz), 122.9, 120.2 (q, J = 270.7 Hz), 118.5 (q, J = 4.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -63.02, -64.45.

[0232] Example 45: Preparation of compound A45

[0233] The only difference between this example and example 39 is that compound A6 in step (1) is replaced by compound A17. Compound A45 is obtained as 3,5-dibromo-N'-[3,5-bis(trifluoromethyl)benzoyl]-N-[4- (trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown below:

[0234]

[0235] Compound A45 is a white solid with a yield of 58%; mp: 184.1-185.1 °C; 1 H NMR (600 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.22 (s, 2H), 8.10 (s, 1H), 7.83 (d, J = 6.6 Hz, 3H), 7.61 (s, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 167.2, 165.6, 159.5, 139.6 (q, J = 38.4 Hz), 137.6, 134.5, 133.1, 132.9 (q, J = 34.3 Hz), 129.8, 127.9 (q, J = 3.0 Hz), 126.6 (q, J = 4.0 Hz), 123.0, 122.5 (q, J = 274.7 Hz), 120.2 (q, J = 271.7 Hz), 118.7 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -63.12, -64.53.

[0236] Example 46: Preparation of compound A46

[0237] The only difference between this example and example 39 is that compound A6 in step (1) is replaced by compound A18, and 3,5-bistrifluoromethylbenzoic acid is replaced by m-trifluoromethylbenzoic acid. Compound A46 is obtained as 3,5-bis(trifluoromethyl)-N'-[3-(trifluoromethyl)benzoyl]-N-[4-(trifluoromethyl)thiazol-2-yl]benzohydrazide, whose structure is shown as follows:

[0238]

[0239] Compound A46 is a white solid with a yield of 52%; mp: 153.7-154.7 °C; 1 H NMR (600 MHz, Chloroform-d) δ 9.14 (s, 1H), 8.27 (s, 2H), 8.02 (s, 1H), 7.99 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H). 13 CNMR (101 MHz, Methylene Chloride-d2) δ 167.4, 167.0, 159.6, 139.3 (q, J =38.4 Hz), 133.9, 131.8 (q, J = 34.3 Hz), 131.6, 131.4 (q, J = 33.3 Hz), 130.7, 129.9, 129.8 (q, J = 4.0 Hz), 128.6, 125.5 (q, J = 4.0 Hz), 124.4 (q, J = 4.0 Hz), 123.4 (q, J = 273.7 Hz), 122.8 (q, J = 273.7 Hz), 120.4 (q, J = 270.7 Hz), 119.0 (q, J = 3.0 Hz). 19 F NMR (376 MHz, Chloroform-d) δ -63.15, -63.27, -64.54.

[0240] Effect verification example:

[0241] The thiazol-2-ylbenzohydrazide derivatives and N'-benzoyl-N-thiazol-2-ylbenzohydrazide derivatives prepared in the examples of the present application were subjected to anti-plant pathogenic fungi activity research:

[0242] Test objects: Compounds A1-A46, with Thifluzamide and Tebuconazole as positive controls.

[0243] Experimental method:

[0244] The in vitro inhibitory activities of compounds A1-A46 against Valsa mali, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani, Alternaria alternata, Fusarium graminecola and Phytophthora capsici were determined by mycelial linear growth rate method. The selected fungi were provided by the Plant Disease Control Laboratory of Anhui Agricultural University.

[0245] Thifluzamide and Tebuconazole solutions of 40 mg / L were used as positive controls, and 0.5% DMSO aqueous solution was used as a blank control. The accurately weighed test compounds were completely dissolved in 0.5 mL of DMSO, and 0.5 mL of the test solution or control solution was quickly mixed with 99.5 mL of sterile PDA medium at 50°C to obtain a drug-containing solution with a mass concentration of 40 mg / L. This was poured into a sterilized Petri dish while hot, 10 mL per dish, and cooled for standby. The test plant pathogens (biscuit diameter 9 mm) were inoculated into the above Petri dishes, with 3 parallel samples in each test group. After incubation in a constant temperature incubator at 27°C for 72-120 h, the cross method was used to measure the colony diameter (mm), and the mycelial growth inhibition rate (IR) was calculated according to formula (1):

[0246] .

[0247] The results are shown in Table 1.

[0248]

[0249] Note: a Values are the average standard deviation (SD) of three replicates. V.m b : Valsa mali, S.s c : Sclerotinia scleotiorum, B.c d : Botrytis cinerea, R.se : Rhizoctonia solani, A. a f : Alternaria alternata F. g g : Fusarium graminicola and P. c h : Phytophthora capsici.

[0250] The present application initially screened 46 thiazol-2-yl benzohydrazide derivatives and N'-benzoyl-N-thiazol-2-yl benzohydrazide derivatives (i.e. compounds A1-A46) at a concentration of 40 mg / L for in vitro antifungal activity against seven plant pathogenic fungi. The initial screening results shown in Table 1 indicated that some of the target compounds at a concentration of 40 mg / L had excellent antifungal activity (inhibition rate ≥ 80%) against V. mali, S. sclerotiorum, R. solani and P. capsici. Most of the target compounds also showed moderate to good inhibitory activity against these four plant pathogenic fungi, with inhibition rates ranging from 50% to 80%. These target compounds also showed good antifungal activity against other tested fungi. These preliminary antifungal screening results preliminarily proved the rationality of designing these thiazol-2-yl benzohydrazide derivatives and N'-benzoyl-N-thiazol-2-yl benzohydrazide derivatives.

[0251] Preliminary structure-activity relationship analysis showed that the thiazol-2-yl benzohydrazide skeleton and the N'-benzoyl-N-thiazol-2-yl benzohydrazide skeleton played a crucial role in the activity against plant pathogenic fungi. In general, substitution at position 3 of the benzene ring significantly enhanced the antifungal activity compared to substitution at position 2 or 4; compounds in series B were significantly superior to those in series A in terms of antifungal and antioomycete activity; it is particularly important to note that when the substituent R 2 is 3,5-bis CF3, it plays a key role in maintaining the antioomycete activity of the compound.

[0252] The thiazol-2-yl benzohydrazide derivatives and N'-benzoyl-N-thiazol-2-yl benzohydrazide derivatives prepared by the present application all have activity against plant pathogenic fungi, especially showing particularly significant bacteriostatic activity against V. mali, S. sclerotiorum, R. solani and P. capsici, which lays a foundation for preparing fungicides with thiazol-2-yl benzohydrazide derivatives and N'-benzoyl-N-thiazol-2-yl benzohydrazide derivatives as the main active ingredients against plant pathogenic fungi.

[0253] The above described embodiments are only to illustrate the preferred modes of the present application, and are not intended to limit the scope of the present application. Any modification and improvement made by those skilled in the art to the technical solutions of the present application without departing from the design spirit of the present application shall fall within the protection scope of the present application as defined by the claims.

Claims

1. A thiazol-2-ylbenzoylhydrazine derivative, characterized in that... The structural general formula is as follows: ； Wherein: R 1 one or more of alkyl, alkoxy, halogen, trifluoromethyl, substitution sites include one or more of ortho, meta, para positions; R2is H or , R 3 is selected from one or more of alkyl, alkoxy, halogen, trifluoromethyl, at one or more of the ortho, meta, para positions.

2. A process for the preparation of the thiazol-2-ylbenzohydrazide derivatives according to claim 1, characterized in that The method comprises the following steps: Step 1: 3-bromo-1,1,1-trifluoro-2-propanone and aminothiourea are used as raw materials, mixed and reacted in an organic solvent to obtain compound A; ； Step 2: compound A, substituted or unsubstituted benzoic acid and a condensation reagent are dissolved in an organic solvent to perform a condensation reaction to obtain a thiazol-2-yl benzohydrazide derivative; In step 2, the substituted or unsubstituted benzoic acid is selected from one of p-methylbenzoic acid, m-methylbenzoic acid, p-chlorobenzoic acid, m-chlorobenzoic acid, p-bromobenzoic acid, m-bromobenzoic acid, p-fluorobenzoic acid, m-fluorobenzoic acid, p-trifluoromethylbenzoic acid, m-trifluoromethylbenzoic acid, o-methylbenzoic acid, o-chlorobenzoic acid, o-bromobenzoic acid, o-fluorobenzoic acid, o-trifluoromethylbenzoic acid, 3,5-dichlorobenzoic acid, 3,5-dibromobenzoic acid, 3,5-bistrifluoromethylbenzoic acid and m-methoxybenzoic acid.

3. The preparation method according to claim 2, characterized in that: In step 1, the molar ratio of 3-bromo-1,1,1-trifluoro-2-propanone and aminothiourea is 1.0:1.0-1.

1.

4. The preparation method according to claim 2, characterized in that: In step 1, the reaction temperature is 80℃, and the reaction time is 4-5 h.

5. The preparation method according to claim 2, characterized in that: In Step 2, when R 2 is H: 2a, dissolving compound A, substituted or unsubstituted benzoic acid and condensing reagent into organic solvent, condensing reaction to obtain R 2 thiazol-2-ylbenzohydrazide derivatives wherein R is H; The condensation reagent is O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; The molar ratio of compound A, substituted or unsubstituted benzoic acid and condensation reagent is 1.0:1.2:1.2; The condensation reaction temperature is room temperature, and the reaction time is 4-5 h.

6. The preparation method according to claim 2, characterized in that: In Step 2, when R 2 is and R 3 is the same as R 1 : 2b, dissolving compound A, substituted or unsubstituted benzoic acid and condensing reagent into organic solvent, condensing reaction to obtain R 2 To and R 3 Thiazole-2-yl benzohydrazide derivatives with the same R 1 same thiazole-2-yl benzohydrazide derivatives; The condensation reagent is N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; The molar ratio of compound A, substituted or unsubstituted benzoic acid and condensation reagent is 1.0:2.2:2.2; After the raw materials are added, the reaction is first carried out under ice bath conditions for 0.5 h, and then carried out at 40℃ for 4-5 h.

7. The preparation method according to claim 2 or 5, characterized in that: In Step 2, when R 2 is and R 3 is different from R 1 : 2c, R1of 2a is dissolved in an organic solvent to obtain a thiazol-2-yl benzohydrazide derivative of the formula (I) 2 wherein R1is H, substituted or unsubstituted benzoic acid and condensing reagent are dissolved in an organic solvent to obtain a thiazol-2-yl benzohydrazide derivative of the formula (I) 2 wherein R1is and R1is 3 different from R1 1 a thiazol-2-yl benzohydrazide derivative of the formula (I) The condensation reagent is phosphorus oxychloride. R 2 The molar ratio of thiazole-2-yl benzohydrazide derivative, substituted or unsubstituted benzoic acid and condensing agent, which is H2SO4, is 1.0:1.2:4.

0. After the raw materials are added, the reaction is first carried out under ice bath conditions for 0.5 h, and then at 40°C for 4-5 h.

8. The thiazol-2-yl benzohydrazide derivative according to claim 1 is used for preparing an anti-plant pathogenic fungus pharmaceutical preparation.

9. The use according to claim 8, characterized in that: The plant pathogenic fungi include one or more of Valsa mali, Sclerotinia sclerotiorum, Botrytis cinerea, Rhizoctonia solani, Alternaria alternata, Fusarium graminearum and Phytophthora capsici.

10. An anti-plant pathogenic fungus pharmaceutical preparation, characterized in that: The active ingredient of the pharmaceutical preparation comprises the thiazol-2-yl benzohydrazide derivative according to claim 1.

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