L-carvone hydrazone derivative and application thereof

Abstract

The invention discloses an L-carvone hydrazone derivative and an application thereof. The L-carvone hydrazone derivative disclosed by the invention has the advantages of low raw material cost, simple and convenient synthesis route and the like, and the obtained L-carvone hydrazone product has an excellent bacteriostatic effect on rhizoctonia solani, botrytis cinerea, sclerotinia sclerotiorum, fusarium graminearum, valsa mali and phytophthora capsici, and can be used for preventing and treating various plant fungal diseases.

Description

Technical Field

[0001] This invention relates to the field of pesticides, specifically to an L-carvone hydrazone derivative, and also to the application of this derivative in the prevention and control of plant fungal diseases, thus having the use of a pesticide fungicide. Background Technology

[0002] The control and suppression of plant pathogens is an important area of ​​pesticide research. Chemical control remains the primary method for preventing the spread and outbreaks of plant pathogenic fungi in agriculture, and the widespread use of fungicides has effectively controlled most plant pathogens. However, with the continuous expansion of fungicide use, plant pathogens have developed resistance to traditional fungicides. At the same time, the high toxicity of existing fungicides to non-target organisms and their serious environmental pollution have greatly limited their application in production. Therefore, the development of novel fungicides that are highly efficient, specific to target organisms, and environmentally friendly is of great importance and significance for ensuring increased and stable agricultural yields and food security.

[0003] L-Carvone is a natural product mainly found in spearmint, also known as spearmint oil. It has a sweet, slightly cool, minty aroma and is commonly used in food, daily chemical additives, and pharmaceuticals. Chemical modification of the active functional groups of L-carvone can yield novel bioactive compounds, providing valuable insights for the development of new drugs.

[0004] On the other hand, in addition to their good medicinal activity, L-carvone derivatives also have the potential to be developed in the field of pesticide creation due to their broad-spectrum bactericidal effects.

[0005] In summary, L-carvone compounds possess diverse biological activities and hold promise as an important class of novel pesticide lead compounds. This invention chemically modifies the carbonyl group of L-carvone to prepare a series of novel compounds with highly efficient and broad-spectrum inhibitory activity against plant pathogenic fungi. Summary of the Invention

[0006] The purpose of this invention is to provide an L-carvone hydrazone derivative.

[0007] The second object of the present invention is to provide uses for the above-mentioned derivatives.

[0008] The first aspect of the present invention provides an L-carvone hydrazone derivative having the structure shown in general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0009]

[0010] Where A is selected from R 1、 R 2、 R3 is independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, hydroxyl, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one, two or three substituents selected from halogen, hydroxyl or methoxy.

[0011] In a specific embodiment, R1, R2, and R3 are independently selected from hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, and hydroxyl, wherein the C1-C3 alkyl and C1-C3 alkoxy are optionally substituted by one, two, or three halogens.

[0012] In the specific implementation scheme, R1 is selected from hydrogen atom, halogen, trifluoromethyl, methyl, methoxy, hydroxyl; R2 is selected from hydrogen atom, halogen, trifluoromethyl, methyl, methoxy; R3 is selected from hydrogen atom, halogen, trifluoromethyl, methyl, methoxy, tert-butyl.

[0013] In a more specific embodiment, R1 is selected from hydrogen atom, 4-methyl, 2-methyl, 2-fluoro, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-methoxy, 2-methoxy, and 4-hydroxy; R2 is selected from hydrogen atom, 4-methyl, 2-methyl, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-methoxy, 2-methoxy, 4-bromo, 2-chloro, 3-chloro, 3-methoxy, and 3-methyl; and R3 is selected from hydrogen atom, 4-methyl, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-methoxy, 4-bromo, 4-tert-butyl, 2-methyl, 2-chloro, 2-fluoro, 3,5-dimethyl, 3-chloro-4-fluoro, 3-chloro, 2,4-dichloro, 3-methyl, and 2-trifluoromethyl.

[0014] This invention also protects L-carvone hydrazone derivatives or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, as shown below:

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021] Secondly, the present invention protects a bactericide containing any of the L-carvone hydrazone derivatives described in any of the preceding claims, or their tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0022] Thirdly, the present invention also provides a method for preparing L-carvone hydrazone derivatives (I), specifically, when A in L-carvone hydrazone derivatives (I) is The preparation method is as follows: In the presence of triethylamine (Et3N), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU) and dichloromethane (DCM), carboxylic acid (II) reacts with substituted phenylhydrazine at room temperature to generate an L-carvone hydrazone derivative (I):

[0023]

[0024] Among the above structural formulas:

[0025] R 3 It has the definition of the corresponding group as described above.

[0026] Fourthly, the present invention also protects the use of any of the L-carvone hydrazone derivatives described in the preceding claims, or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, or the fungicides described in the preceding claims, in the control of plant fungal diseases.

[0027] In a specific implementation plan, the fungal diseases are rice sheath blight fungus, tomato gray mold fungus, wheat scab fungus, rapeseed sclerotium rot fungus, pepper phytophthora, or apple rot fungus.

[0028] Fifthly, the present invention also protects the use of any of the L-carvone hydrazone derivatives described in the preceding claims, or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, or the fungicides described in the preceding claims, in the preparation of medicaments for the prevention and control of plant fungal diseases.

[0029] In a specific implementation plan, the fungal diseases are rice sheath blight fungus, tomato gray mold fungus, wheat scab fungus, rapeseed sclerotium rot fungus, pepper phytophthora, or apple rot fungus.

[0030] Beneficial effects:

[0031] Compared with existing technologies, this invention has significant advantages: It introduces thiazole, amide, and hydrazide fragments into the structure of L-carvone, designing and synthesizing L-carvone hydrazone derivatives (I), which have novel structures. Research on these compounds against plant pathogenic fungi reveals their outstanding inhibitory activity, demonstrating significant advancements in this technology. Specifically, their inhibitory activity against rice sheath blight, tomato gray mold, wheat scab, rapeseed sclerotium rot, and apple rot exceeds that of the control agents thiamethoxam, carbendazim, and cyprodinil, indicating significant application value. Detailed Implementation

[0032] The essential features of this invention are embodied in the following embodiments, but these should not be construed as limiting the invention in any way. Reagents or instruments used, unless otherwise specified, are considered to be conventional products that can be purchased commercially.

[0033] Example 1: Synthesis of (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)-4-phenylthiazole (I1) (R,E)-2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl-1-thioamide (II) (2.0 mmol) and α-bromoacetophenone (1.0 mmol) were added to an 18 mL test tube, followed by the addition of anhydrous ethanol (5.0 mL). The mixture was stirred overnight at room temperature, and the reaction was stopped. Add 20 mL of water, extract with ethyl acetate (3 × 10 mL), wash with saturated brine (20 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent, and purify by silica gel column chromatography to obtain compound (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-4-phenylthiazole (I1).

[0034]

[0035] Compounds I2-I10 were synthesized sequentially according to the method in Example 1. The structures of the synthesized L-carvone hydrazone derivatives (I1-I10) were confirmed by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). The physicochemical parameters and spectral data of the target compounds are shown below:

[0036] (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-4-phenylthiazole (I1): white solid, yield 78.5%, melting point 228.5-230.1℃; 1H NMR (500MHz, CDCl3) δ12.66(s,1H),7.75–7.67(m,2H),7.53–7.42(m,3H),6.72(s,1H),6.31–6.30(m,1H),4.86(d,J=1.8 Hz,2H),3.16(dd,J=16.1,3.9Hz,1H),2.50–2.45(m,1H),2.42–2.34(m,2H),2.22–2.17(m,1H),1.90(s,1H),1.83(s,3H); 13 C NMR (125MHz, CDCl3) δ169.7,157.8,146.2,140.5,137.2,131.5,130.3,129.5, 127.2,125.5,111.0,101.1,40.2,31.2,30.1,21.1,17.4; HRMS(ESI)m / z[M+H] + Calcd.For C 19 H 22 N3S:324.1534, Found:324.1536.

[0037] (R,E)-4-(4-chlorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I2): white solid, yield 62.2%, melting point 237.3-238.3℃; 1 H NMR (500MHz, CDCl3) δ12.57(s,1H),7.67(d,J=8.6Hz,1H),7.47(d,J=8.6Hz,1H),6.72(s,1H),6.35–6.27(m,1H),4 .86(d,J=3.5Hz,1H),3.14(dd,J=16.2,4.0Hz,1H),2.55–2.34(m,3H),2.24–2.14(m,1H),1.90(s,3H),1.83(s,3H); 13 C NMR (125MHz, CDCl3) δ169.8,158.2,146.2,139.7,137.5,136.5,131.6,129.9, 126.9,125.8,111.1,101.4,40.3,31.2,30.2,21.1,17.4; HRMS(ESI)m / z[M+H] + Calcd.For C 19 H 21 ClN3S:358.1145,Found:358.1133.

[0038] (R,E)-4-(4-fluorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I3): white solid, yield 83.1%, melting point 240.4-241.5℃; 1 H NMR (500MHz, CDCl3) δ12.56 (s, 1H), 7.73–7.71 (m, 2H), 7.19 (t, J = 8.5Hz, 2H), 6.66 (s, 1H), 6.32–6.30 (m, 1H), 4.86 (d, J = 2. 8Hz,2H),3.14(dd,J=16.1,4.0Hz,1H),2.50–2.45(m,1H),2.42–2.33(m,2H),2.22–2.16(m,1H),1.90(s,1H),1.83(s,3H); 13 C NMR (125MHz, CDCl3) δ169.8,163.6(d,J=212.5Hz),158.1,146.2,139.6,137.4,131.6(d,J=13.8 Hz)127.7(d,J=8.8Hz),124.2,116.9(d,J=22.3Hz),111.1,100.6,40.3,31.2,30.2,21.1,17.4; 19 F NMR(470MHz, CDCl3)δ-108.7; HRMS(ESI)m / z[M+H] + Calcd.For C 19 H 21 FN3S:342.1440, Found:342.1438.

[0039] (R,E)-4-(4-trifluoromethylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I4): white solid, yield 70.3%, melting point 233.2-233.8℃; 1 H NMR (500MHz, CDCl3) δ12.58(s,1H),7.86(d,J=8.2Hz,2H),7.76(d,J=8.3Hz,2H),6.86(s,1H),6.34–6.32(m,1H),4.86(d,J= 4.1Hz,2H),3.14(dd,J=15.7,3.6Hz,1H),2.51–2.45(m,1H),2.42–2.34(m,2H),2.23–2.17(m,1H),1.90(s,3H),1.83(s,3H); 13C NMR(125MHz, CDCl3)δ169.8,158.4,146.1,139.1,137.7,132.0(q,J=32.5Hz),131.5,130 .5,126.6(q,J=3.8Hz),123.5(q,J=271.3Hz),111.0,103.3,40.2,31.2,30.2,21.0,17.4; 19 F NMR(470MHz, CDCl3)δ-62.9; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 21 F3N3S:392.1408,Found:392.1412.

[0040] (R,E)-4-(4-methylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I5): white solid, yield 78.6%, melting point 235.1-236.4℃; 1 H NMR (500MHz, CDCl3) δ12.63(s,1H),7.60(d,J=8.3Hz,2H),7.28(d,J=8.0Hz,2H),6.64(s,1H),6.36–6.27(m,1H),4.86(d,J= 1.3Hz,2H),3.16(dd,J=16.2,3.9Hz,1H),2.51–2.44(m,1H),2.41–2.34(m,5H),2.21–2.16(m,1H),1.90(s,3H),1.83(s,3H); 13 C NMR (125MHz, CDCl3) δ169.6,157.7,146.2,140.7,140.6,137.1,131.6,130.2,12 5.4,124.5,111.0,100.1,40.2,31.2,30.1,21.3,21.1,17.4; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 24 N3S:338.1691, Found:338.1688.

[0041] (R,E)-4-(2-fluorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I6): white solid, yield 64.7%, melting point 186.3-187.2℃; 1H NMR(500MHz, CDCl3)δ12.70(s,1H),7.90(td,J=7.8,1.7Hz,1H),7.45–7.41( m,1H),7.34(td,J=7.6,1.3Hz,1H),7.23–7.19(m,1H),7.02(d,J=1.3Hz,1H), 6.32–6.30(m,1H),4.86(d,J=1.1Hz,1H),3.16(dd,J=16.7,3.9Hz,1H),2.50– 2.45(m,1H),2.41–2.35(m,2H),2.22–2.16(m,1H),1.90(s,3H),1.83(s,3H); 13 C NMR (125MHz, CDCl3) δ169.2,159.6(d,J=252.6Hz),158.0,146.1,137.3,134.3,131.6(d,J=9.0Hz),131.5,127.6,125 .4(d,J=3.6Hz),116.6(d,J=21.8Hz),115.6(d,J=11.2Hz),110.9,105.7(d,J=14.8Hz),40.2,31.2,30.1,21.0,17.3; 19 F NMR(470MHz, CDCl3)δ-112.2; HRMS(ESI)m / z[M+H] + Calcd.For C 19 H 21 FN3S:342.1440, Found:342.1434.

[0042] (R,E)-4-(4-hydroxyphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I7): white solid, yield 73.7%, melting point 194.1-194.6℃; 1 H NMR (500MHz, CDCl3) δ12.32(s,1H),7.49(d,J=8.7Hz,2H),7.01(d,J=8.7Hz,2H),6.52(s,1H),6.31–6.30(m,1H),4.87(d,J= 1.1Hz,1H),3.13(dd,J=16.1,4.0Hz,1H),2.50–2.42(m,1H),2.38–2.32(m,2H),2.22–2.16(m,1H),1.89(s,3H),1.83(s,3H); 13C NMR (125MHz, CDCl3) δ169.4,158.6,157.6,146.3,140.5,137.1,131.6,126.9 ,119.0,116.6,110.9,99.0,40.2,31.0,30.1,21.0,17.4; HRMS(ESI)m / z[M+H] + Calcd.For C 19 H 22 N3OS:340.1484, Found:340.1475.

[0043] (R,E)-4-(2-methylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I8): white solid, yield 79.8%, melting point 188.5-189.7℃; 1 H NMR (500MHz, CDCl3) δ12.82(s,1H),7.45(dd,J=8.0,1.5Hz,1H),7.37(td,J=7.4,1.5Hz,1H),7.33–7.28(m,2H),6.49(s,1H),6.34–6.25(m,1H),4. 85(d,J=1.8Hz,2H),3.19(dd,J=16.6,3.9Hz,1H),2.50(s,3H),2.47–2.4 4(m,1H),2.42–2.33(m,2H),2.21–2.15(m,1H),1.91(s,3H),1.82(s,3H); 13 CNMR (125MHz, CDCl3) δ169.3,157.9,146.2,140.0,137.1,136.2,131.5,131.4,130.4,12 9.2,127.5,126.7,110.9,104.1,40.2,31.4,30.1,21.0,20.9,17.4; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 24 N3S:338.1691, Found:338.1684.

[0044] (R,E)-4-(2-methoxyphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I9): white solid, yield 85.6%, melting point 223.5-225.1℃; 1H NMR(500MHz, CDCl3)δ13.20(s,1H),7.61(dd,J=7.7,1.7Hz,1H),7.43–7.39(m,1H),7.06–7.02(m,2H),6.84(s,1H),6.29–6.27(m,1H),4.88and 4.85(2s,2H),4.10(s,3H),3.29(dd,J=15.3,3.0Hz,1H),2.46–2.36(m,3H),2.21–2.14(m,1H),1.90(s,3H),1.84(s,3H); 13 CNMR (125MHz, CDCl3) δ169.0,157.6,156.0,146.3,137.8,136.8,131.6,131.5,128.0,12 1.2,115.8,111.7,110.8,103.0,56.1,40.2,31.8,30.1,21.2,17.4; HRMS(ESI)m / z[M+H] + Calcd.ForC 20 H 24 N3OS:354.1640, Found:354.1633.

[0045] (R,E)-4-(4-methoxyphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazole (I10): white solid, yield 81.5%, melting point 231.2-231.8℃; 1 H NMR (500MHz, CDCl3) δ12.56(s,1H),7.65(d,J=8.8Hz,2H),6.99(d,J=8.8Hz,2H),6.56(s,1H),6.30–6.28(m,1H),4.86(d,J=1.2Hz, 2H),3.84(s,3H),3.15(dd,J=15.3,4.0Hz,1H),2.50–2.44(m,1H),2.41–2.33(m,2H),2.22–2.15(m,1H),1.89(s,3H),1.83(s,3H); 13 CNMR (125MHz, CDCl3) δ169.5,161.0,157.5,146.2,140.2,137.0,131.5,127.0,1 19.8,114.8,110.9,99.0,55.3,40.2,31.1,30.1,21.0,17.3; HRMS(ESI)m / z[M+H] + Calcd.For C20 H 24 N3OS:354.1640, Found:354.1632.

[0046] Example 2: Synthesis of (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-N-phenylthiazolyl-4-carboxamide (I11)

[0047] (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazol-4-carboxylic acid (III) (1.0 mmol), triethylamine (2.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.2 mmol) and 1-hydroxybenzotriazole (HOBt, 1.2 mmol) were added to an 18 mL test tube, followed by dichloromethane (5.0 mL) and aniline (1.2 mmol). The mixture was stirred overnight at room temperature, and the reaction was stopped. Add 20 mL of water, extract with ethyl acetate (3 × 10 mL), wash with saturated brine (20 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove solvent, and purify by silica gel column chromatography to obtain compound (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-N-phenylthiazolyl-4-carboxamide (I11).

[0048]

[0049] Compounds I11-I23 were synthesized sequentially according to the method in Example 1. The structures of the synthesized L-carvone hydrazone derivatives (I11-I23) were confirmed by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). The physicochemical parameters and spectral data of the target compounds are shown below:

[0050] (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-N-phenylthiazolyl-4-carboxamide (I11): white solid, yield 64.2%, melting point 210.6-211.2℃; 1H NMR (500MHz, CDCl3) δ8.96 (s, 1H), 8.61 (s, 1H), 7.65 (d, J = 7.9Hz, 2H), 7.58 (s, 1 H),7.33(t,J=7.8Hz,2H),7.10(t,J=7.4Hz,1H),6.10(d,J=6.1Hz,1H),4.83and 4.79(2s,2H),2.70(dd,J=15.7,4.2Hz,1H),2.49–2.44(m,1H),2.33–2.28(m,1H),2.16–2.10(m,2H),1.91(s,3H),1.78(s,3H); 13 C NMR (125MHz, CDCl3) δ168.9,159.4,149.4,147.3,146.0,137.8,132.3,129.0, 124.1,119.6,115.3,110.5,40.6,30.0,28.9,20.6,17.5; HRMS(ESI)m / z[M+H] + Calcd.ForC 20 H 23 N4OS:367.1593, Found:367.1589.

[0051] (R,E)-N-(4-fluorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I12): yellow solid, yield 53.8%, melting point 219.4-220.7℃; 1 H NMR(500MHz, CDCl3)δ8.92(s,1H),8.57(s,1H),7.60–7.58(m,3H),7.01(t,J=8.6Hz,2H),6.10(d,J=6.1Hz,1H),4.83and 4.79(2s,2H),2.69(dd,J=15.5,4.3Hz,1H),2.50–2.46(m,1H),2.34–2.30(m,1H),2.16–2.10(m,2H),1.91(s,3H),1.77(s,3H); 13 C NMR (125MHz, CDCl3) δ168.9, 159.3, 159.2 (d, J = 241.3Hz), 149.5, 147.3, 145.8, 133.9 (d, J = 2.9Hz), 132.5, 132.3, 121.2 (d, J = 7.8Hz), 115.7, 115.4 (d, J = 21.3Hz), 110.5, 40.6, 29.9, 28.9, 20.6, 17.5;19 FNMR(470MHz, CDCl3)δ-118.1; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 22 FN4OS:385.1498,Found:385.1495.

[0052] (R,E)-N-(4-chlorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I13): yellow solid, yield 65.8%, melting point 203.5-204.3℃; 1 H NMR (500MHz, CDCl3) δ8.93(s,1H),8.54(s,1H),7.58–7.56(m,3H),7.26(d,J=8.8Hz,2H),6.10(d,J=6.1Hz,1H),4.82and 4.78(2s,2H),2.68(dd,J=15.5,4.3Hz,1H),2.48–2.44(m,1H),2.32–2.28(m,1H),2.16–2.09(m,2H),1.89(s,3H),1.77(s,3H); 13 C NMR (125MHz, CDCl3) δ168.9,159.3,149.5,147.3,145.7,136.4,132.5,132.3, 129.0,120.7,115.5,110.5,40.6,30.0,28.9,20.6,17.5; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 22 ClN4OS:401.1203,Found:401.1200.

[0053] (R,E)-N-(4-bromophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I14): yellow solid, yield 43.5%, melting point 193.7-195.4℃; 1H NMR (500MHz, CDCl3) δ8.94(s,1H),8.54(s,1H),7.58(s,1H),7.53(d,J=8.4Hz,2H),7.42(d,J=8.3Hz,2H),6.11(d,J=6.1Hz,1H),4.84and 4.80(2s,2H),2.69(dd,J=15.7,4.3Hz,1H),2.50–2.47(m,1H),2.35–2.30(m,1H),2.17–2.11(m,2H),1.91(s,3H),1.78(s,4H); 13 CNMR (125MHz, CDCl3) δ168.9,159.3,149.5,147.3,145.7,136.9,132.5,132.3,13 1.9,121.1,116.6,115.6,110.5,40.6,30.0,28.9,20.6,17.5; HRMS(ESI)m / z[M+H] + Calcd.ForC 20 H 22 BrN4OS:445.0698,Found:445.0693.

[0054] (R,E)-N-(4-trifluoromethylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I15): yellow solid, yield 67.7%, melting point 226.1-227.9℃; 1 H NMR (500MHz, CDCl3) δ9.10(s,1H),8.49(s,1H),7.77(d,J=8.3Hz,2H),7.62(s,1H),7.59(d,J=8.4Hz,2H),6.12(d,J=6.2Hz,1H),4.85and 4.80(2s,2H),2.70(dd,J=15.5,4.3Hz,1H),2.52–2.47(m,1H),2.35–2.31(m,1H),2.18–2.12(m,2H),1.91(s,3H),1.79(s,3H); 13 CNMR(125MHz, CDCl3)δ168.9,159.5,149.6,147.2,145.5,141.0,132.6,132.3,126.3(q,J=3.8Hz ),125.8(q,J=33.8Hz),124.1(q,J=270.0Hz),119.1,116.0,110.6,40.6,30.0,28.9,20.6,17.4;19 F NMR(470MHz, CDCl3)δ-61.9; HRMS(ESI)m / z[M+H] + Calcd.ForC 21 H 22 F3N4OS:435.1466,Found:435.1463.

[0055] (R,E)-N-(4-methylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I16): yellow solid, yield 71.6%, melting point 207.0-208.6℃; 1 H NMR (500MHz, CDCl3) δ8.90(s,1H),8.59(s,1H),7.56(s,1H),7.53(d,J=8.0Hz,2H),7.13(d,J=7.9Hz,2H),6.10(d,J=6.0Hz,1H),4.83and 4.79(2s,2H),2.69(dd,J=15.5,4.3Hz,1H),2.50–2.44(m,1H),2.31(s,3H),2.16–2.09(m,2H),1.91(s,3H),1.78(s,3H); 13 C NMR (125MHz, CDCl3) δ168.8,159.3,149.3,147.3,146.1,135.3,133.7,132.4,132.3 ,129.5,119.6,115.0,110.5,40.6,30.0,28.9,20.9,20.6,17.5; HRMS(ESI)m / z[M+H] + Calcd.ForC 21 H 25 N4OS:381.1749, Found:381.1746.

[0056] (R,E)-N-(4-methoxyphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I17): white solid, yield 77.1%, melting point 143.6-145.2℃; 1H NMR (500MHz, CDCl3) δ8.85(s,1H),8.61(s,1H),7.55–7.53(m,3H),6.86(d,J=8.4Hz,2H),6.09(d,J=6.0Hz,1H),4.83and 4.79(2s,2H),3.78(s,3H),2.69(dd,J=15.5,4.3Hz,1H),2.49–2.44(m,1H),2.33–2.28(m,1H),2.16–2.09(m,2H),1.91(s,3H),1.77(s,3H); 13 C NMR (125MHz, CDCl3) δ168.9,159.2,156.2,149.3,147.3,146.1,132.4,132.3,131.0 ,121.2,114.9,114.1,110.5,55.4,40.6,29.9,28.9,20.6,17.5; HRMS(ESI)m / z[M+H] + Calcd.ForC 21 H 25 N4O2S:397.1698,Found:397.1698.

[0057] (R,E)-N-(2-methylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I18): yellow solid, yield 59.2%, melting point 190.2-191.9℃; 1 H NMR (500MHz, CDCl3) δ9.61 (s, 1H), 8.63 (s, 1H), 8.58 (dd, J = 8.3, 1.6Hz, 1H), 7. 62(s,1H),7.37(dd,J=8.0,1.5Hz,1H),7.30–7.27(m,1H),7.05–7.01(m,1H),6 .10(d,J=5.1Hz,1H),4.83and4.79(2s,2H),2.70(dd,J=15.5,4.3Hz,1H),2.50 –2.45(m,1H),2.33–2.28(m,1H),2.17–2.11(m,2H),1.92(s,3H),1.78(s,3H).; 13C NMR (125MHz, CDCl3) δ169.0,159.3,149.3,147.3,146.3,135.9,132.4,132.3,130.3,127.8 ,126.8,124.4,121.5,115.1,110.5,40.7,30.0,29.0,20.5,17.7,17.5; HRMS(ESI)m / z[M+H] + Calcd.For C 21 H 25 N4OS:381.1749, Found:381.1737.

[0058] (R,E)-N-(2-chlorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I19): yellow solid, yield 53.5%, melting point 181.6-182.5℃; 1 H NMR (500MHz, CDCl3) δ9.61 (s, 1H), 8.63 (s, 1H), 8.58 (dd, J = 8.3, 1.6Hz, 1H), 7. 62(s,1H),7.37(dd,J=8.0,1.5Hz,1H),7.30–7.27(m,1H),7.05–7.01(m,1H),6 .10(d,J=5.1Hz,1H),4.83and4.79(2s,2H),2.70(dd,J=15.5,4.3Hz,1H),2.50 –2.45(m,1H),2.36–2.25(m,1H),2.17–2.11(m,2H),1.92(s,3H),1.78(s,3H); 13 C NMR (125MHz, CDCl3) δ168.9,159.3,149.3,147.3,146.0,134.9,132.4,129.0,127.7, 124.3,122.9,121.1,115.7,110.6,40.7,30.0,29.0,20.5,17.5; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 22 ClN4OS:401.1203,Found:401.1188.

[0059] (R,E)-N-(3-chlorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I20): yellow solid, yield 58.4%, melting point 187.1-187.8℃; 1 H NMR (500MHz, CDCl3) δ8.96 (s, 1H), 8.55 (s, 1H), 7.75 (t, J = 2.0Hz, 1H), 7.58 (s ,1H),7.49(dd,J=8.2,2.0Hz,1H),7.24(t,J=8.1Hz,1H),7.08–7.05(m,1H),6. 11(d,J=7.6Hz,1H),4.84and4.80(2s,2H),2.70(dd,J=15.9,3.2Hz,1H),2.52 –2.45(m,1H),2.35–2.29(m,1H),2.17–2.11(m,2H),1.91(s,3H),1.78(s,3H); 13 C NMR (125MHz, CDCl3) δ168.9,159.4,149.5,147.3,145.6,139.0,134.6,132.5,132.3,130 .0,124.1,119.6,117.5,115.6,110.5,40.6,30.0,28.9,20.6,17.5; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 22 ClN4OS:401.1203,Found:401.1194.

[0060] (R,E)-N-(2-methoxyphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I21): yellow solid, yield 78.2%, melting point 173.6-174.7℃; 1H NMR (500MHz, CDCl3) δ9.52 (s, 1H), 9.03 (s, 1H), 8.54 (dd, J = 8.0, 1.7Hz, 1H), 7.60 (s, 1H), 7.0 6–7.02(m,1H),6.99–6.96(m,1H),6.87(dd,J=8.1,1.5Hz,1H),6.07(d,J=5.7Hz,1H),4.80and 4.72(2s,2H),3.82(s,3H),2.62(dd,J=15.6,4.3Hz,1H),2.45–2.40(m,1H),2.29–2.24(m,1H),2.12–2.05(m,2H),1.90(s,3H),1.72(s,3H). 13 C NMR (125MHz, CDCl3) δ169.3,159.1,149.4,148.2,147.2,146.5,132.3,132.3,127.6,123.7 ,121.0,119.6,115.1,110.5,109.8,55.6,40.7,30.0,29.1,20.4,17.5.HRMS(ESI)m / z[M+H] + Calcd.ForC 21 H 25 N4O2S:397.1698,Found:397.1684.

[0061] (R,E)-N-(3-methoxyphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I22): yellow solid, yield 66.7%, melting point 179.9-181.2℃; 1 H NMR (500MHz, CDCl3) δ8.95(s,1H),8.62(s,1H),7.56(s,1H),7.45(t,J=2.2Hz,1H),7.21(t,J=8. 1Hz,1H),7.10(dd,J=8.0,1.1Hz,1H),6.65(dd,J=8.2,1.5Hz,1H),6.09(d,J=5.0Hz,1H),4.83and 4.79(2s,2H),3.80(s,3H),2.70(dd,J=16.5,3.8Hz,1H),2.49–2.44(m,1H),2.33–2.28(m,1H),2.16–2.10(m,2H),1.91(s,3H),1.77(s,3H); 13C NMR (125MHz, CDCl3) δ168.9,160.1,159.4,149.4,147.3,146.0,139.1,132.3,129.6,11 5.2,111.8,110.5,110.2,105.1,55.2,40.6,30.0,28.9,20.6,17.5; HRMS(ESI)m / z[M+H] + Calcd.ForC 21 H 25 N4O2S:397.1698,Found:397.1685.

[0062] (R,E)-N-(3-methylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazyl)thiazolyl-4-carboxamide (I23): yellow solid, yield 71.9%, melting point 191.1-191.7℃; 1 H NMR (500MHz, CDCl3) δ8.91(s,1H),8.59(s,1H),7.57(s,1H),7.50(s,1H),7.43(dd,J=6.9,1 .4Hz,1H),7.21(t,J=7.8Hz,1H),6.92(dd,J=8.5,1.1Hz,1H),6.10(d,J=5.0Hz,1H),4.83and 4.80(2s,2H),2.70(dd,J=15.6,3.0Hz,1H),2.50–2.44(m,1H),2.34(s,3H),2.32–2.28(m,1H),2.16–2.10(m,2H),1.91(s,3H),1.78(s,3H); 13 C NMR (125MHz, CDCl3) δ168.8,159.4,149.3,147.3,146.1,138.9,137.7,132.3,132.3,128.8 ,124.9,120.2,116.7,115.2,110.5,40.6,30.0,28.9,21.5,20.6,17.5; HRMS(ESI)m / z[M+H] + Calcd.For C 21 H 25 N4OS:381.1749, Found:381.1747.

[0063] Example 3: Synthesis of (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-N'-phenylthiazolyl-4-carbonylhydrazide (I24)

[0064] (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)thiazol-4-carboxylic acid (III) (1.0 mmol), triethylamine (2.0 mmol), and O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (1.2 mmol) were added to an 18 mL test tube, followed by dichloromethane (5.0 mL) and phenylhydrazine (1.2 mmol). The mixture was stirred overnight at room temperature, and the reaction was stopped. Add 20 mL of water, extract with ethyl acetate (3 × 10 mL), wash with saturated brine (20 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent, and purify by silica gel column chromatography to obtain compound (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-N'-phenylthiazolyl-4-carbonylhydrazide (I24).

[0065]

[0066] Compounds I24-I40 were synthesized sequentially according to the method in Example 3. The structures of the synthesized L-carvone hydrazone derivatives (I24-I40) were confirmed by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). The physicochemical parameters and spectral data of the target compounds are shown below:

[0067] (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-N'-phenylthiazolyl-4-carbonylhydrazide (I24): yellow solid, yield 78.3%, melting point 116.9-117.5℃; 1 H NMR(500MHz, CDCl3)δ9.93(s,1H),9.83(s,1H),7.51(s,1H),7.40(s,1H),7.14–7.10(m,2H),6.90–6.85(m,3H),6.08(d,J=6.1Hz,1H),4.84and 4.80(2s,2H),2.78(dd,J=16.0,4.3Hz,2H),2.45–2.39(m,1H),2.30–2.26(m,1H),2.13–2.07(m,2H),1.90(s,3H),1.76(s,3H); 13CNMR (125MHz, CDCl3) δ170.9,161.7,149.7,147.7,147.5,143.8,132.4,132.2,12 9.1,121.8,116.0,114.7,110.5,40.6,30.0,29.5,20.7,17.6; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 24 N5OS:382.1702, Found:382.1702.

[0068] (R,E)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)-N'-(p-tolyl)thiazolyl-4-carbonylhydrazide (I25): yellow solid, yield 82.4%, melting point 119.3-119.9℃; 1 H NMR (500MHz, CDCl3) δ10.02(s,1H),9.96(s,1H),7.51(s,1H),7.28(s,1H),6.94(d,J=7.7Hz,2H),6.84(d,J=8.0Hz,2H),6.07(d,J=6.1Hz,1H),4.86and 4.82(2s,2H),2.78(dd,J=16.0,4.5Hz,1H),2.46–2.41(m,1H),2.32–2.26(m,1H),2.22(s,3H),2.14–2.08(m,2H),1.89(s,3H),1.78(s,3H); 13 C NMR (125MHz, CDCl3) δ171.0,161.6,149.5,147.5,145.3,143.9,132.4,132.1,131.3 ,129.6,115.9,115.1,110.5,40.7,30.0,29.6,20.7,20.6,17.6; HRMS(ESI)m / z[M+H] + Calcd.For C 21 H 26 N5OS:396.1858, Found:396.1860.

[0069] (R,E)-N'-(4-fluorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I26): yellow solid, yield 62.8%, melting point 172.5-173.2℃; 1H NMR (500MHz, CDCl3) δ9.95(s,1H),9.75(s,1H),7.71(s,1H),7.51(s,1H),6.78(d,J=6.4Hz,4H),6.09(d,J=6.0Hz,1H),4.83and 4.81(2s,2H),2.84(dd,J=16.1,4.2Hz,1H),2.47–2.42(m,1H),2.32–2.27(m,1H),2.17–2.09(m,2H),1.91(s,3H),1.76(s,3H); 13 C NMR (125MHz, CDCl3) δ171.0, 161.8, 158.2 (d, J = 239.7Hz), 150.0, 147.6, 143.9, 143.9, 143.7, 132.4 (d,J=3.8Hz),116.3(d,J=11.3Hz),116.3,115.6(d,J=22.8Hz),110.5,40.7,30.0,29.5,20.7,17.6; 19 F NMR(470MHz, CDCl3)δ-122.2; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 23 FN5OS:400.1607,Found:400.1611.

[0070] (R,E)-N'-(4-chlorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I27): white solid, yield 67.7%, melting point 151.1-151.9℃; 1 H NMR (500MHz, CDCl3)9.64(s,1H),9.35(s,1H),7.51(s,1H),7.47(s,1H),7.04(d,J=8.0Hz,1H),6.73(d,J=8.1Hz,1H),6.10(d,J=6.0Hz,1H),4.81and 4.78(2s,2H),2.76(dd,J=16.1,4.2Hz,1H),2.45–2.39(m,1H),2.32–2.27(m,1H),2.14–2.05(m,2H),1.90(s,3H),1.74(s,3H); 13CNMR (125MHz, CDCl3) δ170.7,161.9,150.0,147.5,146.5,143.6,132.5,132.4,12 9.0,126.4,116.3,115.5,110.5,40.6,30.0,29.3,20.7,17.6; HRMS(ESI)m / z[M+H] + Calcd.ForC 20 H 23 ClN5OS:416.1312,Found:416.1315.

[0071] (R,E)-N'-(4-trifluoromethylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I28): yellow solid, yield 57.9%, melting point 145.7-146.4℃; 1 H NMR (500MHz, CDCl3) δ9.47(s,1H),9.10(s,1H),7.59(s,1H),7.52(s,1H),7.32(d,J=8.2Hz,2H),6.79(d,J=8.2Hz,2H),6.10(d,J=6.0Hz,1H),4.78and 4.73(2s,2H),2.68(dd,J=16.0,4.2Hz,1H),2.39–2.27(m,2H),2.11–2.00(m,2H),1.89(s,3H),1.71(s,3H); 13 CNMR(125MHz, CDCl3)δ170.8,162.1,150.8,150.4,147.5,143.5,132.8,132.4,126.6(q,J=3.8Hz ),124.5(q,J=268.8Hz),123.1(q,J=31.3Hz),116.7,113.2,110.5,40.6,30.1,29.3,20.7,17.6; 19 F NMR(470MHz, CDCl3)δ-61.5; HRMS(ESI)m / z[M+H] + Calcd.ForC 21 H 23 F3N5OS:450.1575,Found:450.1579.

[0072] (R,E)-N'-(4-bromophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I29): yellow solid, yield 67.5%, melting point 162.4-163.7℃; 1 H NMR (500MHz, CDCl3) δ10.30(s,1H),10.19(s,1H),7.53(s,1H),7.48(s,1H),7.16(d,J=8.2Hz,2H),6.92(d,J=8.2Hz,2H),6.08(d,J=6.0Hz,1H),4.89and 4.85(2s,2H),2.83(dd,J=15.9,4.2Hz,1H),2.49–2.42(m,1H),2.32–2.27(m,1H),2.19–2.10(m,2H),1.90(s,3H),1.80(s,3H),1.25(s,9H); 13 C NMR (125MHz, CDCl3) δ171.2,161.5,149.5,147.6,145.2,145.0,143.9,132.4,132.1,12 5.9,116.02,115.3,110.6,40.7,34.1,31.4,30.0,29.7,20.8,17.6; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 32 N5OS:438.2328, Found:438.2326.

[0073] (R,E)-N'-(4-methoxyphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazino)thiazolyl-4-carbonylhydrazide (I30): yellow solid, yield 76.9%, melting point 118.1-119.6℃; 1 H NMR (500MHz, CDCl3) δ10.22(s,1H),10.15(s,1H),7.51(s,1H),7.40(s,1H),6.88(d,J=9.0Hz,2H),6.67(d,J=9.0Hz,2H),6.07(d,J=6.0Hz,1H),4.86and 4.83(2s,2H),3.69(s,3H),2.83(d,J=15.0Hz,1H),2.48–2.41(m,1H),2.32–2.26(m,1H),2.17–2.09(m,2H),1.89(s,3H),1.78(s,3H); 13C NMR (125MHz, CDCl3) δ171.1,161.5,155.2,149.6,147.6,143.9,141.1,132.4,132.1 ,117.2,115.9,114.4,110.6,55.5,40.7,30.0,29.7,20.7,17.6; HRMS(ESI)m / z[M+H] + Calcd.For C 21 H 26 N5O2S:412.1807,Found:412.1807.

[0074] (R,E)-N'-(2-methylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I31): yellow solid, yield 50.2%, melting point 190.3-191.3℃; 1 H NMR (500MHz, CDCl3) δ9.77(s,1H),9.72(s,1H),7.48(s,1H),7.26(s,1H),7.04(d,J=7 .3Hz,1H),6.93(t,J=7.7Hz,1H),6.80(t,J=7.2Hz,2H),6.09(d,J=6.0Hz,1H),4.82and 4.80(2s,2H),2.86(dd,J=16.1,4.2Hz,1H),2.48–2.41(m,1H),2.33–2.26(m,1H),2.25(s,3H),2.18–2.13(m,2H),1.91(s,3H),1.76(s,3H); 13 C NMR (125MHz, CDCl3) δ170.7,161.7,149.9,147.5,145.5,144.1,132.4,132.2,130.3,126.8 ,123.7,121.3,115.7,113.5,110.4,40.6,30.0,29.4,20.8,17.6,17.1; HRMS(ESI)m / z[M+H] + Calcd.For C 21 H 26 N5OS:396.1858, Found:396.1861.

[0075] (R,E)-N'-(2-chlorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I32): yellow solid, yield 47.8%, melting point 211.7-212.5℃; 1 H NMR (500MHz, DMSO-d6) δ11.26(s,1H),9.92(s,1H),7.68(s,1H),7.67(s,1H),7.36(d,J=7.8Hz,1H),7.21(t,J=7.8Hz,1H),6.85–6.80(m,2 H),6.18–6.16(m,1H),4.86(d,J=8.5Hz,2H),3.03(dd,J=16.6,4.1Hz,1H),2.44–2.30(m,2H),2.23–2.12(m,2H),1.91(s,3H),1.82(s,3H); 13 C NMR(125MHz,DMSO-d6)δ170.3,161.2,149.7,147.6,145.0,144.7,132.2,131.7,129.2,12 7.8,119.6,117.2,114.7,113.0,110.0,39.9,29.9,29.5,20.9,17.5; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 23 ClN5OS:416.1312,Found:416.1309.

[0076] (R,E)-N'-(2-fluorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I33): yellow solid, yield 50.2%, melting point 231.6-232.1℃; 1 H NMR(500MHz, CDCl3)δ9.68(s,1H),9.59(s,1H),7.50(s,1H),7.40(s,1H) ,7.02–6.93(m,2H),6.88(d,J=7.9Hz,1H),6.83–6.77(m,1H),6.08(d,J=6 .0Hz,1H),4.79(d,J=11.8Hz,2H),2.79(dd,J=16.0,4.2Hz,1H),2.46–2.3 9(m,1H),2.32–2.26(m,1H),2.14–2.09(m,2H),1.88(s,3H),1.74(s,3H); 13C NMR (125MHz, CDCl3) δ170.8, 161.9, 151.8 (d, J = 241.4Hz), 149.8, 147.4, 143.7, 135.7 (d, J = 10.7Hz), 132.4, 132.2, 124. 5(d,J=3.4Hz),121.7(d,J=6.9Hz),116.1,115.6(d,J=1.3Hz),115.0(d,J=18.1Hz),110.3,40.6,30.0,29.3,20.6,17.6; 19 FNMR(470MHz, CDCl3)δ-132.6; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 23 FN5OS:400.1607,Found:400.1611.

[0077] (R,E)-N'-(3,5-dimethylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I34): yellow solid, yield 66.3%, melting point 138.6-140.4℃; 1 H NMR (500MHz, CDCl3) δ9.98(s,1H),9.94(s,1H),7.50(s,1H),7.21(s,1H),6.51(d,J=9.2Hz,3H),6.07(d,J=6.1Hz,1H),4.84and 4.81(2s,2H),2.80(dd,J=16.0,4.2Hz,1H),2.45–2.39(m,1H),2.32–2.26(m,1H),2.13–2.07(m,8H),1.89(s,3H),1.77(s,3H); 13 C NMR (125MHz, CDCl3) δ170.9,161.7,149.6,147.7,147.5,144.0,138.8,132.4,132.0 ,123.7,115.8,112.7,110.4,40.7,30.0,29.5,21.2,20.7,17.6; HRMS(ESI)m / z[M+H] + Calcd.ForC 22 H 28 N5OS:410.2015, Found:410.2014.

[0078] (R,E)-N'-(3-chloro-4-fluorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazine (I35): yellow solid, yield 58.6%, melting point 203.3-203.7℃; 1 H NMR (500MHz, CDCl3) δ9.76 (s, 1H), 9.36 (s, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 6.84 (t, J = 8.7Hz, 1H),6.78(dd,J=6.1,2.7Hz,1H),6.62(dt,J=8.9,3.3Hz,1H),6.10(d,J=6.5Hz,1H),4.80and 4.77(2s,2H),2.77(dd,J=16.0,4.2Hz,1H),2.44–2.38(m,1H),2.32–2.26(m,1H),2.13–2.06(m,1H),1.90(s,3H),1.73(s,3H); 13 C NMR (125MHz, CDCl3) δ171.0,162.1,153.3(d,J=242.1Hz),150.2,147.5,144.6(d,J=2.7Hz),143.3,132.6, 132.3, 121.3 (d, J = 18.7Hz), 116.8, 116.6, 115.9, 113.7 (d, J = 6.6Hz), 110.5, 40.6, 30.0, 29.4, 20.6, 17.6; 19 F NMR(470MHz, CDCl3)δ-125.3; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 23 FN5OS:434.1218,Found:434.1217.

[0079] (R,E)-N'-(3-chlorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I36): yellow solid, yield 60.9%, melting point 160.7-162.3℃; 1H NMR(500MHz, CDCl3)δ9.68(s,1H),9.32(s,1H),7.51(s,1H),7.42(s,1H),7.00(t ,J=8.2Hz,1H),6.79(s,1H),6.67(d,J=8.1Hz,1H),6.08(d,J=5.9Hz,1H),4.79and 4.76(2s,2H),2.73(dd,J=16.0,4.1Hz,1H),2.40(dd,J=14.6,9.3Hz,1H),2.32–2.23(m,1H),2.15–1.99(m,2H),1.89(s,3H),1.72(s,3H); 13 C NMR (125MHz, CDCl3) δ170.8,162.0,150.0,149.1,147.4,143.5,134.9,132.4,132.4,130 .1,121.4,116.4,114.0,112.2,110.4,40.6,30.0,29.3,20.6,17.6; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 23 ClN5OS:416.1312,Found:416.1316.

[0080] (R,E)-N'-(2,4-dichlorophenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazine (I37): yellow solid, yield 54.5%, melting point 156.2-157.1℃; 1 H NMR (500MHz, DMSO-d6) δ11.23(s,1H),9.95(s,1H),7.87(s,1H),7.67(s,1H),7.49(d,J=2.5Hz,1H),7.28(dd,J=8.8,2.4Hz,1H),6.82(d,J=8.8Hz ,1H),6.17(d,J=5.9Hz,1H),4.86(d,J=8.3Hz,2H),3.03(dd,J=16.6,4.1 Hz,1H),2.44–2.30(m,2H),2.23–2.12(m,2H),1.91(s,3H),1.82(s,3H); 13C NMR (125MHz, DMSO-d6) δ170.3,161.1,149.7,147.6,144.8,143.9,132.2,131.7,128.4,12 7.7,122.0,117.6,114.8,114.0,110.0,39.9,29.8,29.4,20.8,17.4; HRMS(ESI)m / z[M+H] + Calcd.For C 20 H 22 Cl2N5OS:450.0922,Found:450.0926.

[0081] (R,E)-N'-(3-methylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I38): yellow solid, yield 67.8%, melting point 129.5-130.2℃; 1 H NMR(500MHz, CDCl3)δ9.91(s,1H),9.87(s,1H),7.51(s,1H),7.25(s,1H),7.02(t,J=7.7Hz,1H),6.75–6.68(m,3H),6.08(d,J=5.1Hz,1H),4.85and 4.81(2s,2H),2.78(dd,J=16.2,3.9Hz,1H),2.46–2.40(m,1H),2.32–2.26(m,1H),2.16(s,3H),2.14–2.08(m,2H),1.90(s,3H),1.77(s,3H); 13 C NMR (125MHz, CDCl3) δ170.9,161.7,149.6,147.7,147.5,144.0,139.0,132.4,132.1,128.9 ,122.7,115.9,115.5,111.9,110.5,40.7,30.0,29.5,21.4,20.7,17.6; HRMS(ESI)m / z[M+H] + Calcd.For C 21 H 26 N5OS:396.1858, Found:396.1857.

[0082] (R,E)-N'-(2-trifluoromethylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I39): yellow solid, yield 53.2%, melting point 188.9-190.5℃;1 H NMR(500MHz,DMSO-d6)δ11.25(s,1H),9.99(s,1H),7.72(s,1H),7.67(s,1H) ,7.57(d,J=7.8Hz,1H),7.51(t,J=7.9Hz,1H),7.01(d,J=8.4Hz,1H),6.94(t, J=7.6Hz,1H),6.17(d,J=5.9Hz,1H),4.87(d,J=9.1Hz,2H),3.04(dd,J=16.6 ,4.1Hz,1H),2.44–2.31(m,2H),2.23–2.12(m,2H),1.92(s,3H),1.82(s,3H); 13 C NMR (125MHz, DMSO-d6) δ170.3,161.2,149.7,147.6,146.3,144.9,133.4,132.1,131.7,126.1(q,J=5Hz ),124.6(q,J=271.3Hz),118.2,114.7,113.1,111.8(q,J=30.0Hz),109.9,39.9,29.9,29.5,20.8,17.4; 19 F NMR(470MHz,DMSO-d6)δ-60.5; HRMS(ESI)m / z[M+H] + Calcd.For C 21 H 23 F3N5OS:450.1575,Found:450.1572.

[0083] (R,E)-N'-(4-tert-butylphenyl)-2-(2-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-methylene)hydrazinoyl)thiazolyl-4-carbonylhydrazide (I40): yellow solid, yield 67.5%, melting point 162.4-163.7℃; 1 H NMR (500MHz, CDCl3) δ10.30(s,1H),10.19(s,1H),7.53(s,1H),7.48(s,1H),7.16(d,J=8.2Hz,2H),6.92(d,J=8.2Hz,2H),6.08(d,J=6.0Hz,1H),4.89and 4.85(2s,2H),2.83(dd,J=15.9,4.2Hz,1H),2.49–2.42(m,1H),2.32–2.27(m,1H),2.19–2.10(m,2H),1.90(s,3H),1.80(s,3H),1.25(s,9H); 13C NMR (125MHz, CDCl3) δ171.2,161.5,149.5,147.6,145.2,145.0,143.9,132.4,132.1,12 5.9,116.02,115.3,110.6,40.7,34.1,31.4,30.0,29.7,20.8,17.6; HRMS(ESI)m / z[M+H] + Calcd.For C 24 H 32 N5OS:438.2328, Found:438.2326.

[0084] Example 4: Bactericidal activity of L-carvone hydrazone derivatives I1-I40 of formula (I) of the present invention

[0085] The bioactivity of a series of L-carvone hydrazone derivatives I1-I40 against six plant pathogens tested—Rhizoctoriza solani (rice sheath blight), Botrytis cinerea (tomato gray mold), Sclerotinias clerotiorum (rapeseed sclerotiorum), Gibberella zeae (wheat scab), Valsa mali (apple rot), and Phytophthora capsici (pepper rot)—was determined using the mycelial growth method. The specific operational steps are as follows:

[0086] 1. Weigh 15 mg of the original drug and dissolve it in 0.6 mL of DMF to prepare a stock solution;

[0087] 2. Take 0.1 mL of the stock solution and add it to 50 mL of sterile potato dextrose agar medium (PDA medium). Shake well to obtain a drug-containing medium of 50 mg / L.

[0088] 3. While the above-mentioned drug-containing culture medium is still hot, pour equal amounts into three sterile petri dishes with a diameter of 9 cm. After cooling and solidification, inoculate a 0.5 cm diameter mycelium cake in the center of the culture medium.

[0089] 4. Include a blank control without the test reagent, and replicate each treatment three times;

[0090] 5. Place the above-mentioned petri dishes in a constant temperature incubator at 25±1℃ and incubate in the dark until the colony diameter is about 7.0 to 7.5 cm. Then, measure the colony diameter and calculate the inhibition rate of each drug.

[0091] 6. The formula for calculating the inhibition rate of the compound against fungi is as follows: Inhibition rate = (Coronavirus diameter of blank control - Coronavirus diameter of test agent) ÷ (Coronavirus diameter of blank control - 5mm) × 100%.

[0092] The inhibitory activities of compounds I1-I40 against rice sheath blight, tomato gray mold, rapeseed sclerotium rot, wheat scab, apple rot, and pepper blight pathogens are shown in Table 1.

[0093] Table 1. Inhibition results of compounds I1-I40 against six pathogens.

[0094]

[0095]

[0096] a The commercial fungicides carbendazim, thiamethoxam and cyazofamid were used as control fungicides.

[0097] Table 1 shows that target compound I has a certain degree of antibacterial activity against all six pathogens, especially against rice sheath blight, tomato gray mold, and rapeseed sclerotium rot. Four compounds showed a 100% inhibition rate against rice sheath blight pathogens: I26, I34, I36, and I38. Five compounds showed an inhibition rate exceeding 90% against tomato gray mold pathogens: I8, I26, I36, I38, and I40. Four compounds showed an inhibition rate exceeding 90% against rapeseed sclerotium wilt pathogens: I24, I26, I34, and I37. Four compounds showed an inhibition rate exceeding 80% against wheat scab pathogens: I26, I27, I33, I36, and I38. Four compounds showed an inhibition rate exceeding 80% against apple rot pathogens: I19, I24, I26, I27, I28, and I33. Eight compounds showed an inhibition rate exceeding 50% against pepper phytophthora.

[0098] Analysis of the inhibition rate data obtained from the initial screening revealed that compounds with inhibition rates greater than 70% underwent further EC testing against the corresponding pathogens. 50 The specific methods for toxicity testing are as follows:

[0099] Weigh the test compound to prepare a stock solution, and gradually dilute it to prepare solutions of varying concentrations. Prepare drug-containing plates, using carbendazim, thiamethoxam, and boscalid as control drugs. The remaining operations follow the activity screening method, calculating the inhibition rate at each concentration. Using DPS statistical software, the effective inhibition at intermediate concentrations (EC50-90%) is determined. 50 ).

[0100] EC of some compounds 50 The results of the toxicity test are shown in Table 2:

[0101] Table 2 shows the EC values ​​of some compounds. 50 Toxicity testing a

[0102]

[0103]

[0104] a Repeat three times and take the average.

[0105] Table 2 shows that compounds I26, I34, and I36 have EC50-95% seropotency against rice sheath blight pathogens. 50 Less than 1 μg / mL, superior to the control drug boscalid; compounds I26 and I36 showed EC50 against tomato gray mold. 50 The concentrations were 0.98 and 0.64 μg / mL, respectively, which were superior to the control drug thiafuran. Compounds I26 and I27 showed good antibacterial activity against five plant pathogens tested, including rice sheath blight, tomato gray mold, rapeseed sclerotium rot, wheat scab, and apple rot.

[0106] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, equivalent changes, and alterations made to the above embodiments without departing from the technical essence of the present invention shall fall within the scope of the present invention.

Claims

1. The L-carvone hydrazone derivative of formula (I) or its tautomers, meso, racemic, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof; in, A is selected from R 1、 R 2、 R3 is independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, hydroxyl, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one, two or three substituents selected from halogen, hydroxyl or methoxy.

2. The L-carvone hydrazone derivative of formula (I) according to claim 1, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that, R1, R2, and R3 are independently selected from hydrogen, halogens, substituted or unsubstituted C1-C3 alkyl groups, substituted or unsubstituted C1-C3 alkoxy groups, and hydroxyl groups, wherein the C1-C3 alkyl groups and C1-C3 alkoxy groups are optionally substituted with one, two, or three halogens.

3. The L-carvone hydrazone derivative of formula (I) according to claim 2, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that, R1 is selected from hydrogen atom, halogen, trifluoromethyl, methyl, methoxy, hydroxyl; R2 is selected from hydrogen atom, halogen, trifluoromethyl, methyl, methoxy; R3 is selected from hydrogen atom, halogen, trifluoromethyl, methyl, methoxy, tert-butyl.

4. The L-carvone hydrazone derivative of formula (I) according to claim 3, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that, R1 is selected from hydrogen atom, 4-methyl, 2-methyl, 2-fluoro, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-methoxy, 2-methoxy, and 4-hydroxy. R2 is selected from hydrogen atom, 4-methyl, 2-methyl, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-methoxy, 2-methoxy, 4-bromo, 2-chloro, 3-chloro, 3-methoxy, and 3-methyl. R3 is selected from hydrogen atom, 4-methyl, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-methoxy, 4-bromo, 4-tert-butyl, 2-methyl, 2-chloro, 2-fluoro, 3,5-dimethyl, 3-chloro-4-fluoro, 3-chloro, 2,4-dichloro, 3-methyl, and 2-trifluoromethyl.

5. The following L-carvone hydrazone derivatives or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof:

6. A bactericide, characterized in that, The bactericide contains an L-carvone hydrazone derivative as described in any one of claims 1-5, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

7. The use of the L-carvone hydrazone derivative or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-5, or the fungicide of claim 6, in the control of plant fungal diseases.

8. The application according to claim 7, characterized in that, The fungal diseases mentioned are rice sheath blight fungus, tomato gray mold fungus, wheat scab fungus, rapeseed sclerotium rot fungus, pepper phytophthora fungus, or apple rot fungus.

9. The use of the L-carvone hydrazone derivative or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-5, or the fungicide of claim 6, in the preparation of a medicament for the prevention and control of plant fungal diseases.

10. The application according to claim 9, characterized in that, The fungal diseases mentioned are rice sheath blight fungus, tomato gray mold fungus, wheat scab fungus, rapeseed sclerotium rot fungus, pepper phytophthora fungus, or apple rot fungus.

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