English

• 1.   Introduction

  Oxathiapiprolin (trade name ZorvecR) was the first piperidinyl thiazole isoxazoline fungicide developed by DuPont.^[1] It was low in toxicity and high in efficiency (the dosage was 1/5~1/100 of common fungicides), especially for the pathogens of Oomycetes.^[2~6] Besides oxysterol-binding protein (OSBP) was target protein.^[7] Therefore oxathiapiprolin didn't have mutual resistance with other fungicides. Since ZorvecR was sold, sales had increased year by year. DuPont, Bayer, Syngenta and other researchers in the field had derived and reported many structures of oxathiapiprolin derivatives^[8~16] owning fungicidal activities. For example, the fungicidal activity of derivative 1^[17] developed by DuPont against Plasmopara viticola and Phytophthora infestans was 100% at 40 μg/mL, that of derivative 2^[18] developed by Bayer against Pseudoperonos pora cubensis Rostov was 100% at 100 μg/mL, that of derivative 3^[19] developed by the Clemens Lamberth group against Phytophthora infestans and Plasmopara viticola was 100% at 6 μg/mL (Figure 1). The derivative 4^{[20, 21]} developed by the Won-Sik Choi group had both fungicidal and insecticidal activity (Mosquito larvae) with LC₅₀ (Lethal concentration 50)＝0.513 mmol•L^－1. Excitingly, another piperidinylthiazole isoxazoline fungicide was awarded the ISO (International Organization for Standardization) common name fluoxapiprolin in October 2018. The compound was similar with oxathiapiprolin containing five ring structures (benzene, isoxazole, thiazole, piperidine and pyrazole) and highly fungicidal activity. For example, the fungicidal activity of fluoxapiprolin against Phytophthora infestans and Plasmopara viticola was more than 75% at 0.2 μg/mL.^{[22, 23]}

  Figure 1

  

  Figure 1.  Structures of derivatives 1~4

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  Thiazoles^{[24, 25]} had always been a hot spot in the development of new pesticides. A series of compounds were produced with a broad spectrum of biological activity by modifying structures when the thiazole groups were introduced into a variety of different compound structures. Thiazolidine piperidine structure was a novel thiazole- containing structure which had received much attention in recent years, and substituent can be introduced at positions 4 and 5 on the thiazole ring. However the research about 5-substituted compounds was dwarfed compared with 4-substituted compounds. In order to study the influences of substituent to fungicidal activities about 5-substituted compounds, our group designed and synthesized a series of novel oxathiapiprolin derivatives showed in Figure 2. The structures were confirmed by ¹H NMR, ¹³C NMR and HRMS. Then, the preliminary bioactivity tests showed that target compounds had fungicidal activities (Table 1). The synthetic route of the target compounds was shown in the Scheme 1.

  Figure 2

  

  Figure 2.  Design of target compounds

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  Table 1

  

  Table 1.  Fungicidal activity (inhibition rate/%) of the target compounds 9a~9p at 100 μg/mL

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  Compd.	R	F. graminearum	D. mali	R. solani Ktihn	P. infestans	B. cinerea
  9a	H	30	70	0	50	30
  9b	4-CF3	40	70	0	50	70
  9c	4-F	20	70	0	50	70
  9d	4-Cl	30	0	0	0	70
  9e	4-Br	20	70	0	50	70
  9f	4-tBu	30	0	0	0	60
  9g	3-Cl	40	50	0	0	65
  9h	3-CH3	40	70	0	50	75
  9i	3-CF3	40	70	0	40	60
  9j	3-Br	0	0	0	0	10
  9k	2, 3-Cl2	10	60	0	20	40
  9l	2,4-Cl2	30	60	0	30	60
  9m	2, 5-Cl2	20	60	0	30	60
  9n	2-F	0	0	0	0	20
  9o	—	60	50	0	0	50
  9p	—	20	55	0	20	40
  Azoxystrobin	—	80	50	60	100	40
  a Azoxystrobin as a control drug at a concentration of 50 μg/mL.

  Scheme 1

  

  Scheme 1.  Synthetic route of target compounds

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  2.   Results and discussion

  2.1   Synthesis and characterization

  Substituted aniline as a substrate was experienced diazotization, ^[26] chlorination, ^[27] cyclization and deprotection^[28] to intermediate 8, and then reacted with intermediate 3^{[29, 30]} to give the target compounds 9a~9p. However, the synthesis of intermediate 4 and intermediate 5 largely inhibited the diversity of substrates. The synthesis of intermediate 4 was influenced by the mechanism of diazotization, and the synthesis of intermediate 5 had multiple substitutions and competitive reaction. For that, the multiple substitutions could be controlled by adjusting the amount of sulfonyl chloride, but the competitive reaction was failed to control. It was not conducive to form intermediate 5 when ortho substituent or strong electron donating group existed on benzene ring. Besides, the by-product was dominant in the case of ortho-disubstituted structure. Therefore the target compound 9p (No. 4 carbon) was different with 9k, 9l and 9m (No. 5 carbon) on the position of the thiazole ring showed in Scheme 1.

  Spectral analysis was carried out using the target compound 9a as an example. In ¹H NMR spectrum, 23 hydrogens were assigned. δ 7.47~7.40 (4H) and 7.38~7.33 (1H) were the proton signals of phenyl, δ 6.35 (1H) was the proton signal on the pyrazole ring, δ 5.01 (2H) was the proton signal of methylene linked with pyrazole, δ 2.48 (3H) was the proton signal of the methyl group on the thiazole ring, δ 2.33 (3H) was the proton signal of the methyl group on the pyrazole ring, and the remaining δ 4.62 (1H), 4.06 (1H), 3.37~3.20 (2H), 2.98~2.83 (1H), 2.22 (2H) and 1.87~1.72 (2H) were the proton signals of the piperidine ring. In the ¹³C NMR spectrum, 22 carbons were assigned. There were overlapping carbons due to the symmetry relationship of benzene rings: δ 129.12 (2×C) and 128.64 (2×C), and the pyrazole ring was affected by trifluoromethyl group: δ 121.29 (q, J＝268.4 Hz), 141.74 (q, J＝37.8 Hz) and 104.31~104.04 (m). The molecular ion peak of this compound was calculated as [M+H]⁺ 449.1617, found 449.1615, and the absolute error was within 0.003.

  2.2   Fungicidal activity

  The fungicidal activities of the target compounds 9a~9p were evaluated against Fusarium graminearum (F. graminearum), Diplocarpon mali (D. mali), Rhizoctonia solani Ktihn (R. solani Ktihn), Phytophthora infestans (P. infestans), Botrytis cinerea (B. cinerea) at 100 μg/mL. The results were listed in Table 1. It was found that all the target compounds exhibited certain fungicidal activity against the tested fungi at 100 μg/mL. On the whole, the target compounds showed higher fungicidal activities to azoxystrobin at 50 μg/mL against Diplocarpon mali and Botrytis cinerea. Besides the fungicidal activities of 9b, 9c, 9e and 9h were more than 70%. In addition, it showed that the disubstituted structures (9k, 9l, 9m) could not effectively increase the fungicidal activities comparing with the others (9a~9j). Then there was no significant difference in fungicidal activity between para-substituted structures (9b~9f) and meta-substituted structures (9g~9j). Furthermore, the structure of 9h (3-CH₃) was the best when compared with others (9a~9g, 9i~9p). On the other hand, Major target compounds against Fusarium graminearum were 20~40%, and the fungicidal activities of 9b, 9g, 9h and 9i were 40%. However, 9o (60%) was obviously higher to other target compounds (below 40%) against Fusarium graminearum and the structure of 9o was similar to 9n. Therefore the appearance of cyclopropyl on the thiazole ring might improve fungicidal activity against Fusarium graminearum. In addition the target compounds against Phytophthora infestans were 20~50%, and the fungicidal activities of 9a, 9b, 9c and 9e were 50%. Besides Phytophthora infestans was influenced more by the kinds of substituents when compared with other fungi. Moreover the results of substituted benzene was better to benzene (9a) against in Botrytis cinerea when compared with 9b~9n.

  3.   Conclusions

  Using oxathiapiprolin as a template, sixteen oxathiapiprolin derivatives were designed and synthesized to study the influences of substituent about the fungicidal activities which connected with carbon (No. 5 carbon) near the sulfur on thiazole ring. The structures were confirmed by ¹H NMR, ¹³C NMR and HRMS. From the preliminary bioactivity tests at 100 μg/mL, the target compounds showed universal fungicidal activities and showed higher fungicidal activity against Diplocarpon mal and Botrytis cinereal compared with the azoxystrobin at 50 μg/mL. However, while compared it with the commercial oxathiapiprolin, a significant difference in efficacy was observed. Later, the pyridine structures were prepared to replace the benzene structures in order to study the difference about the position of N on pyridine ring.

  4.   Experimental section

  4.1   Instruments

  Melting points were defined by an X-4 apparatus and uncorrected. ¹H NMR spectra were measured on a Bruker AV-600 instrument using CDCl₃ as the solvent. Mass spectra were determined on a a Bruker Daltonics Bio-TOF-Q Ⅲ mass spectrometer (ESIMS). 1-Cyclopro- pyl-2-(2-fluorophenyl)ethan-1-one (4o) and other reagents purchased were analytical grade or recently prepared before use. The processes of reactions were grasped by TLC, and the silica gel of TLC was GF254.

  4.2   Synthesis

  4.2.1   Preparation of 3-methyl-5-trifluoromethyl-1H- pyrazole (1)

  A mixture of methyl 1,1,1-trifluoropentane-2,4-dione (0.1 mol), hydrazine hydrate (0.1 mol) and EtOH (30 mL) was stirred at reflux for 6 h. The reaction was concentrated in vacuum to give 5-methyl-3-trifluoromethyl-1H-pyra- zole (1) directly used in the next reaction, yield 97.6%, light yellow solid.

  4.2.2   Preparation of ethyl 2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (2)

  A mixture of 3-methyl-5-trifluoromethylpyrazole (1) (0.1 mol), ethylchloroacetate (0.2 mol), potassium carbonate (0.3 mol) and N, N-dimethylformamide (80 mL) was stirred at ambient temperature overnight. The orange mixture was filtered, diluted with ethylacetate, washed with water and brine, dried over with MgSO₄ and concentrated under reduced pressure to give 2-(5-methyl-3-(trifluoro- methyl)-1H-pyrazol-1-yl)acetate (2) directly used in the next reaction, yield 80.6%, light yellow liquid.

  4.2.3   Preparation of 5-methyl-3-trifluoromethyl-1H- pyrazol-1-acetic acid (3)

  2-(5-Methyl-3-trifluoromethyl-1H-pyrazol-1-yl)acetate (2) (0.1 mol), THF (100 mL) and 50% aqueous NaOH solution (30 mL) were mixed and stirred at ambient temperature overnight. When the reaction was over, the THF was removed under reduced pressure and the aqueous solution was washed with ethylacetate. Then the aqueous layer was acidified with 10% HCl solution to pH＝1 to give a precipitate. The precipitate was filtered, washed with water and dried to give 5-methyl-3-trifluoromethyl-1H-pyrazol- 1-acetic acid (3) directly used in the next reaction, yield 85.2%, a white solid.

  4.2.4   Preparation of 1-(substituted-phenyl)propan-2-ones (4a~4n and 4p)

  Synthesis by reference:^[25] A mixture of substituted aniline (0.15 mol), aqueous HCl solution (38 mL) and water (55 mL) was cooled to －5 ℃ in an ice-salt bath, and a cold solution of sodium nitrite (0.15 mol) in water (15 mL) was added over 45 min with stirring. The temperature of the reaction mixture was held at －5~2 ℃. The mixture was stirred for an additional 15 min, and a cold solution boric acid (0.19 mol) in 40% of hydrofluoric acid (39 mL) was slowly added with stirring. The mixture was stirred for an additional 30 min and then stored at about 0 ℃ for 2 h. The mixture was filtered, and the solid was washed with 95% ethanol (30 mL) to give the colorless salt.

  To a stirred mixture of anhydrous CH₃COONa (0.25 mol), cuprous oxide (0.013 mol), and isopropenyl acetate (52.6 mL), the colorless salt was added over 30 min, while the temperature of the reaction mixture was held at 20~25 ℃. The reaction mixture was stirred an additional 6 h at 20~25 ℃. The mixture was filtered and washed with ethylacetate. The solution was collected and distilled under vacuum to give 1-(substituted-phenyl)propan-2-ones (4a~4n, 4p)^[25] as a clear yellow liquid, yields 25%~60%, influenced by the mechanism of diazotization.

  4.2.5   Preparation of 1-chloro-1-(substituted-phenyl)- propan-2-ones (5a~5p)

  In a 50 mL round bottom flask, 1-(substituted-phenyl)propan-2-ones (4a~4p) (0.02 mol) were dissolved in dichloromethane (15 mL). This solution was cooled to 0 ℃, and sulfuryl chloride (0.022 mol) was added slowly over 1 h. The reacting solution was stirred for 7 h at room temperature until TLC revealed complete reaction. Water (20 mL) was added to the solution, the aqueous layer was separated and extracted with dichloromethane (2×10 mL). Then the combined organic layers were washed with saturated NaCl solution, dried over anhydrous MgSO₄ and evaporated to give the crude 1-chloro-1-(substituted-phen- yl)propan-2-ones (5a~5p) directly used in the next reaction.

  4.2.6   Preparation of tert-butyl 4-carbamothioylpiperidine-1-carboxylate (6)

  In a 250 mL round bottom flask, 1-Boc-4-cyanopiperidine (0.04 mol), 70% NaSH (0.18 mol) and NH₄Cl (0.18 mol) were dissolved in DMF (120 mL). The mixture reacted at room temperature with string for 72 h. Ice water 600 g) was added in 1 L beaker, and then the reacted solution was added slowly in beaker with stirring to give a precipitate. The precipitate was filtered, washed with water and dried to give tert-butyl 4-carbamothioylpiperidine-1- carboxylate (6), yield 95.2%, a white solid. m.p. 133~134 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.66 (s, 1H), 7.10 (s, 1H), 4.22 (d, J＝12.5 Hz, 2H), 2.78~2.65 (m, 3H), 1.90 (d, J＝12.6 Hz, 2H), 1.73 (qd, J＝12.9, 4.5 Hz, 2H), 1.46 (s, 9H).

  4.2.7   Preparation of tert-butyl 4-(4-methyl-5-(substituted-phenyl)thiazol-2-yl)piperidine-1-carboxylates (7a~7p)

  In a 250 mL round bottom flask, tert-butyl 4-carbamothioylpiperidine-1-carboxylate (6) (0.05 mol), anhydrous CH₃COONa (0.25 mol) and 1-(substituted-phenyl)propan- 2-ones (4a~4p) (0.05 mol) were dissolved in glacial acetic acid (100 mL). The mixture reacted at 85 ℃ with stirring for 12 h until TLC revealed complete reaction. The glacial acetic acid was removed under reduced pressure, and the remaining liquid was extracted with ethylacetate (100 mL×3). The organic layer was held, washed with saturated NaHCO₃ solution, brine and dried over MgSO₄. Finally the organic solution was concentrated under reduced pressure and separated by column to give 7 directly used in the next reaction.

  7g as an example. ¹H NMR (500 MHz, Chloroform-d) δ: 7.44~7.31 (m, 4H), 4.22 (s, 2H), 3.13 (tt, J＝11.7, 3.7 Hz, 1H), 2.88 (s, 2H), 2.46 (s, 3H), 2.20~2.04 (m, 2H), 1.74 (qd, J＝12.2,4.3 Hz, 2H), 1.48 (s, 9H); ¹³C NMR (126 MHz, Chloroform-d) δ: 172.26, 154.71,147.35, 133.73, 130.72, 130.37 (2×C), 129.64, 128.90 (2×C), 79.65, 43.71, 40.81 (2×C), 32.47 (2×C), 28.477(3×C), 16.04. HRMS (ESI) calcd for C₂₀H₂₅ClN₂O₂SNa [M+Na]⁺ 415.1395, found 415.1403.

  4.2.8   Preparation of 4-methyl-5-(substituted-phenyl)- 2-(piperidin-4-yl)thiazole hydrochlorates (8a~8p)

  In a 50 mL round bottom flask, tert-butyl 4-(4-methyl-5-(substituted-phenyl)thiazol-2-yl)piperidine-1-carboxylate (7) (0.05 mol) were dissolved in 4 mol•L^－1 HCl/dioxane (20 mL), The mixture reacted at room temperature with stirring until no more solid produced. The mixture was filtered and washed with ether to give 8 directly used in the next reaction.

  8g as an example. ¹H NMR (500 MHz, DMSO-d₆)δ: 9.38 (d, J＝9.0 Hz, 1H), 9.24 (d, J＝8.8 Hz, 1H), 7.56~7.46 (m, 4H), 3.41~3.25 (m, 3H), 3.07~2.95 (m, 2H), 2.40 (s, 3H), 2.22~2.13 (m, 2H), 2.05~1.90 (m, 2H); ¹³C NMR (126 MHz, DMSO-d₆)δ: 168.23, 151.71,134.32, 134.09, 131.81,131.25, 130.04, 129.72, 128.72,43.17 (2×C), 37.00, 29.00 (2×C), 17.35. HRMS (ESI) calcd for C₁₅H₁₈ClN₂S [M+H]⁺ 293.0874, found 293.0882.

  4.2.9   Preparation of the target compounds 9a~9p

  In a 15 mL seal tube, 4-methyl-5-(substituted-phenyl)-2-(piperidin-4-yl)thiazole hydrochlorates (8a~8p) (1 mmol), N, N-diisopropylethylamine (5 mmol), EDCl (0.15 mmol), HOBT (0.15 mmol) and 5-methyl-3-trifluoromethyl-1H- pyrazol-1-acetic acid (3) (1.1 mmol) were dissolved in dichloromethane (4 mL). The mixture reacted at room temperature with stirring for 24 h. The combined organic layers were washed with saturated NaHCO₃ solution and brine, dried over with MgSO₄ and concentrated under reduced pressure and column separation to give the target compounds 9a~9p.

  2-(5-Methyl-3-trifluoromethyl-1H-pyrazol-1-yl)-1-(4-(4-methyl-5-phenylthiazol-2-yl)piperidin-1-yl)ethan-1-one (9a): White powder, yield 62%. m.p. 113~114 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.47~7.40 (m, 4H), 7.38~7.33 (m, 1H), 6.35 (s, 1H), 5.08~4.93 (m, 2H), 4.62 (d, J＝13.8 Hz, 1H), 4.06 (d, J＝14.2 Hz, 1H), 3.37~3.20 (m, 2H), 2.98~2.83 (m, 1H), 2.48 (s, 3H), 2.33 (s, 3H), 2.22 (dd, J＝24.2, 12.2 Hz, 2H), 1.87~1.72 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 170.45, 163.76, 147.14, 141.82, 141.74 (q, J＝37.8 Hz), 132.03, 131.10, 129.12 (2×C), 128.64 (2×C), 127.72, 121.29 (q, J＝268.4 Hz), 104.31~104.04 (m), 51.50, 45.00, 42.14, 40.21, 32.50, 31.92, 16.02, 11.22. HRMS (ESI) calcd for C₂₂H₂₄F₃N₄OS [M+H]⁺ 449.1617, found 449.1615.

  2-(5-Methyl-3-trifluoromethyl-1H-pyrazol-1-yl)-1-(4-(4-methyl-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (9b): White powder, yield 55%. m.p. 148~149 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.69 (d, J＝8.2 Hz, 2H), 7.54 (d, J＝8.1 Hz, 2H), 6.35 (s, 1H), 5.09~4.95 (m, 2H), 4.62 (d, J＝13.0 Hz, 1H), 4.07 (d, J＝14.1 Hz, 1H), 3.36~3.21 (m, 2H), 2.89 (td, J＝14.3, 13.0, 3.0 Hz, 1H), 2.50 (s, 3H), 2.34 (s, 3H), 2.29~2.15 (m, 2H), 1.88~1.73 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 171.45, 163.80, 148.31,141.84, 141.74 (q, J＝38.0 Hz), 135.84, 129.64 (q, J＝32.7 Hz), 129.56, 129.30 (2×C), 125.62 (q, J＝3.7 Hz, 2×C), 123.95 (q, J＝272.2 Hz), 121.29 (q, J＝268.6 Hz), 104.22~104.12 (m), 51.47, 44.97, 42.09, 40.24, 32.44, 31.88, 16.12, 11.19. HRMS (ESI) calcd for C₂₃H₂₃F₆N₄OS [M+H]⁺ 539.1311, found 539.1298.

  1-(4-(5-(4-Fluorophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9c): White powder, yield 62%. m.p. 133~134 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.46~7.33 (m, 2H), 7.21~7.03 (m, 2H), 6.35 (s, 1H), 5.11~4.92 (m, 2H), 4.61 (d, J＝13.8 Hz, 1H), 4.10~3.99 (m, 1H), 3.27 (dddt, J＝26.6, 11.3, 7.7, 3.5 Hz, 2H), 2.98~2.79 (m, 1H), 2.44 (s, 3H), 2.33 (s, 3H), 2.29~2.12 (m, 2H), 1.88~1.69 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 170.53, 163.77, 162.28 (d, J＝248.1 Hz), 147.24, 141.83, 141.72 (d, J＝37.9 Hz), 130.86 (d, J＝8.2 Hz, 2×C), 129.97, 128.01 (d, J＝3.3 Hz), 121.28 (q, J＝268.5 Hz), 115.67 (d, J＝21.7 Hz, 2×C), 104.23~104.10 (m), 51.47, 44.98, 42.11, 40.19, 32.47, 31.90, 15.84, 11.19. HRMS (ESI) calcd for C₂₂H₂₂F₄N₄OSNa[M+Na]⁺ 489.1343, found 489.1334.

  1-(4-(5-(4-Chlorophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9d): White powder, yield 66%. m.p. 137~138 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.41 (d, J＝8.1 Hz, 2H), 7.35 (d, J＝8.1 Hz, 2H), 6.35 (s, 1H), 5.11~4.92 (m, 2H), 4.61 (d, J＝13.3 Hz, 1H), 4.13~4.01 (m, 1H), 3.37~3.19 (m, 2H), 2.94~2.82 (m, 1H), 2.46 (s, 3H), 2.33 (s, 3H), 2.29~2.13 (m, 2H), 1.87~1.72 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 170.95, 163.81,147.45, 141.85, 141.77 (d, J＝37.8 Hz), 133.84, 130.45, 130.35 (2×C), 129.93, 128.90 (2×C), 121.29 (q, J＝268.5 Hz), 104.30~104.08 (m), 51.49, 45.01, 42.12,40.19, 32.49, 31.91,15.94, 11.23. HRMS (ESI) calcd for C₂₂H₂₂ClF₃N₄OSNa [M+Na]⁺ 505.1047, found 505.1033.

  1-(4-(5-(4-Bromophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9e): White powder, yield 72%. m.p. 158~159 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.60~7.53 (m, 2H), 7.32~7.26 (m, 2H), 6.35 (s, 1H), 5.08~4.94 (m, 2H), 4.64~4.57 (m, 1H), 4.09~4.02 (m, 1H), 3.35~3.20 (m, 2H), 2.88 (td, J＝14.2, 13.2, 3.1 Hz, 1H), 2.46 (s, 3H), 2.33 (s, 3H), 2.26~2.15 (m, 2H), 1.86~1.72 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 170.95, 163.81,147.52, 141.85, 141.80 (q, J＝37.8 Hz), 131.87 (2×C), 130.97, 130.63 (2×C), 129.94, 121.96, 121.29 (q, J＝268.4 Hz), 104.21 (q, J＝1.9 Hz), 51.51, 45.03, 42.13, 40.21, 32.49, 31.91,15.99, 11.25. HRMS (ESI) calcd for C₂₂H₂₂BrF₃- N₄OSNa [M+Na]⁺ 549.0542, found 549.0523.

  1-(4-(5-(4-(tert-Butyl)phenyl)-4-methylthiazol-2-yl)pi-peridin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9f): White powder, yield 50%. m.p. 137~138 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.45 (d, J＝7.9 Hz, 2H), 7.36 (d, J＝8.0 Hz, 2H), 6.34 (s, 1H), 5.05~4.95 (m, 2H), 4.61 (d, J＝14.2 Hz, 1H), 4.03 (d, J＝14.6 Hz, 1H), 3.36~3.17 (m, 2H), 2.94~2.82 (m, 1H), 2.48 (s, 3H), 2.32 (s, 3H), 2.26~2.15 (m, 2H), 1.88~1.73 (m, 2H), 1.36 (s, 9H); ¹³C NMR (126 MHz, Chloroform-d) δ: 170.17, 163.77, 150.85, 146.85, 141.83, 141.77 (q, J＝38.0 Hz), 131.16, 129.06, 128.79 (2×C), 125.61 (2×C), 121.30 (q, J＝268.6 Hz), 104.26~104.13 (m), 51.53, 45.04, 42.17, 40.23, 34.62, 32.54, 31.96, 31.24 (3×C), 16.06, 11.24. HRMS (ESI) calcd for C₂₆H₃₁F₃N₄OSNa [M+Na]⁺ 527.2063, found 527.206.

  1-(4-(5-(3-Chlorophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9g): White powder, yield 54%. m.p. 126~127 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.46~7.29 (m, 4H), 6.35 (s, 1H), 5.08~4.95 (m, 2H), 4.61 (d, J＝14.3 Hz, 1H), 4.06 (d, J＝13.8 Hz, 1H), 3.37~3.20 (m, 1H), 2.89 (td, J＝14.6, 13.5, 3.4 Hz, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 2.27~2.14 (m, 2H), 1.87~1.72 (m, 2H). ¹³C NMR (126 MHz, Chloroform-d) δ: 171.03, 163.79, 147.89, 141.83, 141.75 (d, J＝37.8 Hz), 134.51,133.84, 129.89, 129.57, 129.04, 127.81,127.28, 121.28 (d, J＝268.4 Hz), 104.38~103.99 (m), 51.50, 44.98, 42.10, 40.21, 32.45, 31.88, 16.06, 11.23. HRMS (ESI) calcd for C₂₂H₂₂ClF₃- N₄OSNa [M+Na]⁺ 505.1047, found 505.1032.

  2-(5-Methyl-3-trifluoromethyl-1H-pyrazol-1-yl)-1-(4-(4-methyl-5-(m-tolyl)thiazol-2-yl)piperidin-1-yl)ethan-1- one (9h): White powder, yield 42%. m.p. 109~110 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.37~7.12 (m, 4H), 6.35 (s, 1H), 5.11~4.94 (m, 2H), 4.67~4.55 (m, 1H), 4.05 (dd, J＝15.5, 1.9 Hz, 1H), 3.35~3.21 (m, 2H), 2.89 (td, J＝14.0, 12.9, 3.1 Hz, 1H), 2.48 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.28~2.13 (m, 2H), 1.86~1.73 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 170.35, 163.77, 146.98, 141.82, 141.74 (d, J＝38.0 Hz), 138.37, 131.89, 131.24, 129.83, 128.53 (2×C), 126.19, 122.36 (t, J＝268.5 Hz), 104.33~104.00 (m), 51.49, 45.00, 42.14, 40.18, 32.51, 31.92, 21.34, 16.02, 11.21. HRMS (ESI) calcd for C₂₃H₂₅F₃N₄OSNa[M+Na]⁺ 485.1593, found 485.1574.

  2-(5-Methyl-3-trifluoromethyl-1H-pyrazol-1-yl)-1-(4-(4-methyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (9i): White powder, yield 52%. m.p. 130~131 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.37 (dddd, J＝9.4, 7.7, 5.0, 2.2 Hz, 2H), 7.25~7.16 (m, 2H), 6.35 (s, 1H), 5.11~4.95 (m, 2H), 4.62 (d, J＝14.5 Hz, 1H), 4.06 (d, J＝14.0 Hz, 1H), 3.36~3.23 (m, 2H), 2.95~2.84 (m, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 2.29~2.17 (m, 2H), 1.81 (pd, J＝12.9, 4.2 Hz, 2H); ¹³C NMR (126 MHz, Chloroform-d)δ: 171.33, 163.81,148.13, 141.85, 141.77 (q, J＝38.0 Hz), 132.96, 132.35, 131.17 (q, J＝32.6 Hz), 129.50, 129.24, 125.80 (q, J＝3.6 Hz), 124.44 (q, J＝3.5 Hz), 123.81 (q, J＝272.4 Hz), 121.30 (q, J＝268.5 Hz), 104.58~103.82 (m), 51.50, 44.99, 42.10, 40.22, 32.46, 31.89, 15.97, 11.22. HRMS (ESI) calcd for C₂₃H₂₂F₆N₄OS- Na [M+Na]⁺ 539.1311, found 539.1312.

  1-(4-(5-(3-Bromophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9j): White powder, yield 48%. m.p. 140~141 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.56 (s, 1H), 7.47 (d, J＝7.8 Hz, 1H), 7.34 (d, J＝7.8 Hz, 1H), 7.32~7.26 (m, 1H), 6.34 (s, 1H), 5.05~4.93 (m, 2H), 4.60 (d, J＝14.2 Hz, 1H), 4.03 (d, J＝14.9 Hz, 1H), 3.36~3.17 (m, 2H), 2.94~2.80 (m, 1H), 2.46 (s, 3H), 2.31 (s, 3H), 2.25~2.11 (m, 2H), 1.86~1.70 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 171.06, 163.78, 147.92, 141.82, 141.74 (q, J＝37.8 Hz), 134.12, 131.92, 130.72, 130.13, 129.44, 127.73, 122.63, 121.28 (q, J＝268.5 Hz), 104.32~104.02 (m), 51.49, 44.97, 42.09, 40.20, 32.45, 31.87, 16.04, 11.22. HRMS (ESI) calcd for C₂₂H₂₂BrF₃- N₄OSNa [M+Na]⁺ 549.0542, found 549.0537.

  1-(4-(5-(2, 3-Dichlorophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9k): White powder, yield 67%. m.p. 155~156 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.60~7.48 (m, 1H), 7.27 (d, J＝6.8 Hz, 2H), 6.35 (s, 1H), 5.10~4.93 (m, 2H), 4.62 (d, J＝12.6 Hz, 1H), 4.07 (d, J＝13.6 Hz, 1H), 3.39~3.22 (m, 2H), 2.96~2.82 (m, 1H), 2.41~2.13 (m, 8H), 1.80 (td, J＝15.7, 13.9, 7.8 Hz, 2H).¹³C NMR (126 MHz, Chloroform-d) δ: 172.11,163.81,150.03, 141.84, 141.81 (q, J＝38.4, 38.0 Hz), 133.86, 133.21,132.99, 130.88, 130.69, 127.07, 126.88, 121.30 (q, J＝268.5 Hz), 104.31~104.14 (m), 51.54, 45.05, 42.16, 40.25, 32.46, 31.90, 15.78, 11.26. HRMS (ESI) calcd for C₂₂H₂₁Cl₂F₃N₄OSNa[M+Na]⁺ 539.0657, found 539.0655.

  1-(4-(5-(2,4-Dichlorophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9l): White powder, yield 66%. m.p. 150~151 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.53 (d, J＝1.9 Hz, 1H), 7.32~7.27 (m, 2H), 6.35 (s, 1H), 5.09~4.95 (m, 2H), 4.62 (d, J＝14.3 Hz, 1H), 4.06 (d, J＝13.2 Hz, 1H), 3.38~3.22 (m, 2H), 2.98~2.80 (m, 1H), 2.33 (s, 3H), 2.27 (s, 5H), 1.90~1.71 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 172.19, 163.78, 150.10, 141.82, δ 141.77 (q, J＝38.0 Hz), 135.40, 135.17, 133.36, 129.82, 129.32, 127.11,125.98, 121.29 (q, J＝268.4 Hz), 104.18 (q, J＝1.7 Hz), 51.50, 45.01, 42.12,40.23, 32.43, 31.87, 15.76, 11.23. HRMS (ESI) calcd for C₂₂H₂₁Cl₂F₃N₄OSNa [M+Na]⁺ 539.0657, found 539.0651.

  1-(4-(5-(2, 5-Dichlorophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9m): White powder, yield 70%. m.p. 146~147 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.47~7.29 (m, 3H), 6.35 (s, 1H), 5.09~4.93 (m, 2H), 4.60 (dd, J＝21.9, 14.5 Hz, 1H), 4.06 (d, J＝14.6 Hz, 1H), 3.36~3.22 (m, 2H), 2.94~2.84 (m, 1H), 2.40~2.14 (m, 8H), 1.87~1.74 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 172.40, 163.82, 150.25, 141.85, δ 141.88 (q, J＝37.9 Hz), 133.06, 132.52, 132.42, 132.31,131.03, 129.92, 125.89, 122.43 (q, J＝278.3 Hz), 104.30~104.22 (m), 51.59, 45.08, 42.17, 40.26, 32.49, 31.91,15.83, 11.31. HRMS (ESI) calcd for C₂₂H₂₁Cl₂F₃N₄OSNa [M+Na]⁺ 539.0657, found 539.0655.

  1-(4-(5-(2-Fluorophenyl)-4-methylthiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9n): White powder, yield 32%. m.p. 94~95 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.81~7.52 (m, 4H), 6.35 (s, 1H), 5.16~4.91 (m, 2H), 4.62 (d, J＝14.4 Hz, 1H), 4.07 (d, J＝13.8 Hz, 1H), 3.44~3.19 (m, 2H), 2.97~2.80 (m, 1H), 2.49 (s, 3H), 2.34 (s, 3H), 2.29~2.15 (m, 2H), 1.90~1.73 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 172.06, 163.81,159.69 (d, J＝248.9 Hz), 149.63, 141.85, 141.83 (q, J＝37.8 Hz), 132.09, 132.07, 130.17 (d, J＝8.1 Hz), 124.22 (d, J＝3.8 Hz), 121.30 (d, J＝268.5 Hz), 119.61 (d, J＝15.1 Hz), 116.12 (d, J＝22.2 Hz), 104.33~104.07 (m), 51.56, 45.06, 42.18, 40.23, 32.51, 31.91,15.97, 11.28. HRMS (ESI) calcd for C₂₂H₂₂- F₄N₄OSNa [M+Na]⁺ 489.1343, found 489.1344.

  1-(4-(4-Cyclopropyl-5-(2-fluorophenyl)thiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan-1-one (9o): White powder, yield 42%. m.p. 109~110 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.50 (td, J＝7.6, 1.9 Hz, 1H), 7.36 (tdd, J＝7.3, 5.1,1.9 Hz, 1H), 7.25~7.14 (m, 2H), 6.34 (s, 1H), 5.08~4.94 (m, 2H), 4.53 (dt, J＝13.4, 4.3 Hz, 1H), 4.00 (dt, J＝13.6, 4.6 Hz, 1H), 3.34~3.16 (m, 2H), 2.93 (ddd, J＝14.0, 11.6, 3.1 Hz, 1H), 2.32 (s, 3H), 2.22~2.11 (m, 2H), 1.94~1.84 (m, 1H), 1.84~1.72 (m, 2H), 1.01 (dt, J＝6.0, 3.0 Hz, 2H), 0.90 (dt, J＝8.2, 3.0 Hz, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 171.74, 163.77, 159.81 (d, J＝248.7 Hz), 154.71,141.84, 141.78 (q, J＝37.8 Hz), 132.35 (d, J＝2.6 Hz), 129.86 (d, J＝8.1 Hz), 124.14 (d, J＝3.7 Hz), 121.31 (q, J＝268.5 Hz) 119.79 (d, J＝15.2 Hz), 116.11,115.93, 104.27~104.13 (m), 51.57, 44.92,42.04, 39.99, 32.32, 31.78, 11.25, 10.99 (d, J＝2.0 Hz), 8.35 (2×C). HRMS (ESI) calcd for C₂₄H₂₄F₄N₄OSNa [M+Na]⁺ 515.1499, found 515.1503.

  1-(4-(4-(2, 6-Dichlorobenzyl)thiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)ethan- 1-one (9p): White powder, yield 64%. m.p. 142~143 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 7.36 (d, J＝8.0 Hz, 2H), 7.22~7.13 (m, 1H), 6.51 (s, 1H), 6.34 (s, 1H), 5.05~4.94 (m, 2H), 4.59~4.49 (m, 1H), 4.46 (d, J＝1.1 Hz, 2H), 4.02 (d, J＝14.5 Hz, 1H), 3.36~3.20 (m, 2H), 2.95~2.81 (m, 1H), 2.32 (s, 3H), 2.26~2.11 (m, 2H), 1.85~1.64 (m, 2H); ¹³C NMR (126 MHz, Chloroform-d) δ: 173.32, 163.83, 152.54, 141.93, 141.73 (q, J＝37.9 Hz). 136.02 (2×C), 134.89, 128.55, 128.33 (2×C), 121.30 (d, J＝268.5 Hz), 113.00, 104.19 (q, J＝1.8 Hz), 51.45, 44.90, 42.04, 39.96, 33.35, 32.46, 31.86, 11.22. HRMS (ESI) calcd for C₂₂H₂₁Cl₂F₃N₄OSNa [M+Na]⁺ 539.0657, found 539.0652.

  4.3   Biological activity test

  The bactericidal activity of the target compounds were tested by the in vitro plate method. Experimental strains were Fusarium graminearum, Diplocarpon mali, Rhizoctonia solani Ktihn, Phytophthora infestans and Botrytis cinerea. The experimental concentration was 100 μg/mL and azoxystrobin was used as a control drug. The quantitative agent of target compound was added at the designed concentration when the melted PDA medium was cooled to 60~70 ℃. After it was sufficiently cooled, the bacteria cake with a diameter of 5 mm was inoculated, and then the culture was carried out in an incubator. The colony diameter was measured and the growth inhibition rate was calculated after 4 days. Besides the results were investigated by the cross method.

  Relative inhibition rate (%)＝(control sample diameter－treated group diameter)/control group expanded diameter×100%.

  Supporting Information The ¹H NMR, ¹³C NMR and HRMS for the synthesized compounds. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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  Figure 1  Structures of derivatives 1~4

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  Figure 2  Design of target compounds

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  Scheme 1  Synthetic route of target compounds

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  Table 1.  Fungicidal activity (inhibition rate/%) of the target compounds 9a~9p at 100 μg/mL

  Compd.	R	F. graminearum	D. mali	R. solani Ktihn	P. infestans	B. cinerea
  9a	H	30	70	0	50	30
  9b	4-CF3	40	70	0	50	70
  9c	4-F	20	70	0	50	70
  9d	4-Cl	30	0	0	0	70
  9e	4-Br	20	70	0	50	70
  9f	4-tBu	30	0	0	0	60
  9g	3-Cl	40	50	0	0	65
  9h	3-CH3	40	70	0	50	75
  9i	3-CF3	40	70	0	40	60
  9j	3-Br	0	0	0	0	10
  9k	2, 3-Cl2	10	60	0	20	40
  9l	2,4-Cl2	30	60	0	30	60
  9m	2, 5-Cl2	20	60	0	30	60
  9n	2-F	0	0	0	0	20
  9o	—	60	50	0	0	50
  9p	—	20	55	0	20	40
  Azoxystrobin	—	80	50	60	100	40
  a Azoxystrobin as a control drug at a concentration of 50 μg/mL.

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