2-substituted-1-H-indole oxadiazole amine derivative compound as well as preparation method and application thereof

Abstract

The invention discloses a chemical preparation method and application of a 2-substituted-1-H-indole oxadiazole amine derivative, a series of compounds which take a urea or thiourea fragment as a linker and are substituted by different phenyl groups are synthesized on the basis of the structure of the 2-substituted-1-H-indole oxadiazole amine derivative, and the compounds have a good inhibition effect on pathogenic bacteria and can be used for preparing a novel compound for treating pathogenic bacteria. The compound has a good inhibition effect on pathogenic bacteria such as xanthomonas oryzae pv. Oryzae, citrus canker pathogen, kiwifruit bacterial canker pathogen and ralstonia solanacearum, and provides an important scientific basis for research, development and creation of new pesticides. The compound has a structure shown in the following general formula.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a class of 2-substitution-1- H -Indoleoxadiazoleamine derivative compounds, their preparation methods, and applications. Background Technology

[0002] Among nitrogen-containing heterocyclic compounds, indole derivatives exhibit diverse biological activities. Indole is a natural product widely found in animals, plants, and microorganisms. Natural products containing indole and synthetic indole derivatives possess a variety of biological activities, such as antitumor, antibacterial, antiviral, and anti-inflammatory pharmacological effects, showing good development potential in the fields of medicine and pesticides.

[0003] In 2017, Wang et al. studied the synthesis and antitumor activity of a series of novel indole derivatives. They evaluated their inhibitory effects on cancer cell lines such as liver cancer, lung cancer, and breast cancer using in vitro cytotoxicity assays. They found that the synthesized compounds showed significant inhibitory activity against cancer cells and have potential value for the development of antitumor drugs.

[0004] In 2019, Li et al. studied the synthesis of indole derivatives and their activity against plant pathogens. They used the mycelial growth rate method to determine their inhibitory effects on *Fusarium graminearum* (wheat scab), *Bacillus oryzae* (rice blast fungus), and *Agropyron cristatum* (tobacco scab). The results showed that the synthesized compounds had significant inhibitory effects on various plant pathogens, demonstrating their potential application value in agricultural disease control.

[0005] In 2020, Chen et al. conducted in-depth research on the antitumor mechanism of indole derivatives. Through in vitro and in vivo experiments, they evaluated the effects of inducing apoptosis in cancer cells and inhibiting tumor growth. They found that these compounds exert antitumor activity by regulating key signaling pathways, providing new ideas for the development of antitumor drugs.

[0006] In 2021, Kumar et al. reviewed the application of indole derivatives in medicinal chemistry, summarizing the research progress on their various biological activities such as antitumor, antibacterial, antiviral and anti-inflammatory effects, and emphasizing the diversity and importance of the indole skeleton as a core structure for drug design.

[0007] In 2018, Zhang et al. studied the synthesis and bioactivity of a series of novel 1,3,4-oxadiazole derivatives. They evaluated their anticancer activity against various cancer cell lines using in vitro cytotoxicity assays and found that the synthesized compounds showed significant inhibitory activity against cancer cells such as breast cancer, lung cancer, and colon cancer, and have potential value for the development of anticancer drugs.

[0008] In 2017, Khan et al. reviewed the synthesis and antiviral activity of 1,3,4-oxadiazole derivatives. They evaluated the effects against HIV, influenza virus, and herpes virus through in vitro antiviral assays and found that these compounds have significant antiviral activity, providing a new direction for the development of antiviral drugs.

[0009] In 2019, Kumar et al. studied the synthesis and antifungal activity of 1,3,4-oxadiazole derivatives. They evaluated the inhibitory activity against various fungi such as Candida albicans, Aspergillus, and Mucor using in vitro antibacterial assays. They found that the synthesized compounds had significant inhibitory effects on fungal pathogens, showing potential value for antifungal drug applications.

[0010] In 2016, Zhang et al. studied the synthesis and insecticidal activity of a series of novel 1,3,4-oxadiazole derivatives. They evaluated the insecticidal effects on agricultural pests such as cotton bollworm and aphid using bioactivity tests and found that the synthesized compounds had significant insecticidal activity against pests, providing a reference for the development of novel insecticides.

[0011] In 2020, Patel et al. reviewed the multifunctionality of the 1,3,4-oxadiazole scaffold in drug discovery, summarizing its applications in various drug activities such as anticancer, antiviral, antifungal, anti-inflammatory, and antibacterial effects through a comprehensive literature analysis, emphasizing its broad potential as a core scaffold for drug design.

[0012] In summary, these studies show that derivatives containing indole and pyrazole groups have good application prospects and exhibit good biological activity in both antibacterial and antitumor applications. Summary of the Invention

[0013] To address the technical problems existing in the prior art, the purpose of this invention is to provide a class 1 2-bit substitution-1- H -Indoleoxadiazoleamine derivative compounds, their preparation methods and applications: The synthesis steps are few, the raw materials are readily available, and the synthesis method is simple. At the same time, they have good biological activity against a variety of plant pathogens such as rice bacterial blight, citrus canker, kiwifruit canker, and tobacco bacterial wilt.

[0014] To achieve the above objectives and technical effects, the present invention employs the following technical solution: a class of 2-substituted -1-H-indoleoxadiazoleamine derivative compounds, wherein the class of 2-substituted -1-H-indoleoxadiazoleamine derivative compounds has a structure as shown in general formula (I):

[0015] Wherein, X is an oxygen atom or a sulfur atom; R is hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitro, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester.

[0016] The substitution refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

[0017] Further, R is selected from any one of hydrogen, deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, trifluoromethoxy, nitro, trichloromethyl, trichloromethoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted pyridine, wherein the substitution refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

[0018] Furthermore, R can be selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, trifluoromethoxy, nitro, trichloromethyl, trichloromethoxy, phenyl, benzylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2 The phenyl group can be substituted with any one of the following: -chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, and halogens (F, Cl, and Br) at different positions.

[0019] Furthermore, the aforementioned type of 2-position substitution -1- H -Indoleoxadiazoleamine derivatives are selected from the following compounds:

[0020] DT-1: ; DT-2: ; DT-3: ; DT-4: ; DT-5: ; DT-6: ; DT-7: ; DT-8: ; DT-9: ; DT-10: ; DT-11: ; DT-12: ; DT-13: ; DT-14: ; DT-15: ; Y1: ; Y2: ; Y3: ; Y4: ; Y5: ; Y6: ; Y7: ; Y8: ; Y9: ; Y10: ; Y11: ; Y12: ; Y13: ; Y14: ; Y15: .

[0021] This invention also discloses a class of 2-position substitution -1- H The preparation method of the indoleoxadiazoleamine derivative compound includes the following steps:

[0022] The present invention also discloses a composition comprising the compound or its stereoisomer, or its salt or its solvate as described above, and agriculturally usable adjuvants or fungicides, insecticides or herbicides, wherein the formulation of the composition is selected from emulsifiable concentrates (EC), powders (DP), wettable powders (WP), granules (GR), aqueous solutions (AS), suspensions (SC), ultra-low volume sprays (ULV), soluble powders (SP), microcapsules (MC), fumigants (FU), emulsions (EW), and water-dispersible granules (WG).

[0023] The present invention also discloses the application of the composition described above in the field of preventing and controlling agricultural pests and diseases.

[0024] Furthermore, the agricultural pests and diseases mentioned are bacterial or fungal plant diseases.

[0025] Furthermore, the agricultural diseases and pests mentioned are rice bacterial blight, citrus canker, and kiwifruit canker.

[0026] The present invention also provides a method for preventing and controlling agricultural pests and diseases, wherein the compound or its stereoisomer, its salt or its solvate, or the composition thereof acts on the harmful substance or its living environment.

[0027] The present invention also provides a method for protecting plants from agricultural pests and diseases, comprising the steps of contacting the plant with the compound or its stereoisomer, its salt or its solvate, or the composition thereof.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention synthesizes a series of indole compounds based on the 2-position oxadiazole-substituted indole structure. These compounds have good inhibitory effects on pathogenic bacteria, such as rice bacterial blight, citrus canker, kiwifruit bacterial canker, and tobacco bacterial wilt, providing an important scientific basis for the research and development of new pesticides. Detailed Implementation

[0029] The present invention will now be described in detail so that its advantages and features can be more easily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention.

[0030] The following provides a brief overview of one or more aspects to offer a basic understanding of them. This overview is not an exhaustive summary of all conceived aspects, nor is it intended to identify key or decisive elements of all aspects, nor to define the scope of any or all aspects. Its sole purpose is to present some concepts of one or more aspects in a simplified form to prepare for the more detailed descriptions that follow.

[0031] A 2-bit substitution -1- H The preparation method of -indoleoxadiazoleamine derivative compounds includes the following steps: Option 1

[0032] First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 0.1 g (7.86 mmol) of isocyanate with different substituents was added dropwise under stirring and reacted at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete. Finally, Lawson's reagent was used to convert the urea group in DT1-15 to thiourea to obtain Y1-Y15.

[0033] Example 1 Synthesis of DT-1 and Y1: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, phenyl isocyanate (7.86 mmol) was added dropwise under stirring and reacted at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-1. Finally, Lawson's reagent was used to convert the urea group in DT-1 to thiourea to obtain Y1.

[0034] Example 2

[0035] Synthesis of DT-2 and Y2: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 2-chlorophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-2. Finally, Lawson's reagent was used to convert the urea group in DT-2 to thiourea to obtain Y2.

[0036] Example 3

[0037] Synthesis of DT-3 and Y3: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 3-chlorophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-3. Finally, Lawson's reagent was used to convert the urea group in DT-3 to thiourea to obtain Y3.

[0038] Example 4

[0039] Synthesis of DT-4 and Y4: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 4-chlorophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-4. Finally, Lawson's reagent was used to convert the urea group in DT-4 to thiourea to obtain Y4.

[0040] Example 5

[0041] Synthesis of DT-5 and Y5: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 3-fluorophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-5. Finally, Lawson's reagent was used to convert the urea group in DT-5 to thiourea to obtain Y5.

[0042] Example 6

[0043] Synthesis of DT-6 and Y6: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 4-fluorophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-6. Finally, Lawson's reagent was used to convert the urea group in DT-6 to thiourea to obtain Y6.

[0044] Example 7

[0045] Synthesis of DT-7 and Y7: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 2-bromophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-7. Finally, Lawson's reagent was used to convert the urea group in DT-7 to thiourea to obtain Y7.

[0046] Example 8

[0047] Synthesis of DT-8 and Y8: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 3-bromophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-8. Finally, Lawson's reagent was used to convert the urea group in DT-8 to thiourea to obtain Y8.

[0048] Example 9

[0049] Synthesis of DT-9 and Y9: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 4-trifluoromethylphenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-9. Finally, Lawson's reagent was used to convert the urea group in DT-9 to thiourea to obtain Y9.

[0050] Example 10

[0051] Synthesis of DT-10 and Y10: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 3-trifluoromethylphenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-10. Finally, Lawson's reagent was used to convert the urea group in DT-10 to thiourea to obtain Y10.

[0053] Synthesis of DT-11 and Y11: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 4-methylphenyl isocyanate (7.86 mmol) was added dropwise with stirring and reacted at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-11. Finally, Lawson's reagent was used to convert the urea group in DT-11 to thiourea to obtain Y11.

[0054] Example 12

[0055] Synthesis of DT-12 and Y12: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 4-cyanophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-12. Finally, Lawson's reagent was used to convert the urea group in DT-12 to thiourea to obtain Y12.

[0056] Example 13

[0057] Synthesis of DT-13 and Y13: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 4-methoxyphenyl isocyanate (7.86 mmol) was added dropwise under stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-13. Finally, Lawson's reagent was used to convert the urea group in DT-13 to thiourea to obtain Y13.

[0058] Example 14

[0059] Synthesis of DT-14 and Y14: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 3-fluoro-2-methylphenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-14. Finally, Lawson's reagent was used to convert the urea group in DT-14 to thiourea to obtain Y14.

[0060] Example 15

[0061] Synthesis of DT-15 and Y15: First, methyl 1H-indole-2-carboxylic acid (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (27.44 g, 852.23 mmol) was added. The mixture was heated to 80 °C with stirring. After the reaction was monitored by TLC, the mixture was allowed to cool and stand, and the solid precipitated. The solid was washed with water, filtered, and dried to obtain 1H-indole-2-carbonylhydrazine (8.20 g, yield: 82.00%). Subsequently, 1H-indole-2-carbonylhydrazine (8 g, 45.66 mmol) was weighed and dissolved in 25 mL of methanol, and cyanogen bromide (8.22 g, 77.63 mmol) was added. The mixture was refluxed at 80 °C for 6 h, and the solution was concentrated under reduced pressure. Recrystallization from isopropanol gave the pale yellow product D (yield 60%). Next, 0.1 g of intermediate D (4.62 mmol) was weighed and dissolved in 5 mL of THF. Then, 2,4-dichlorophenyl isocyanate (7.86 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the reaction was complete to obtain DT-15. Finally, Lawson's reagent was used to convert the urea group in DT-15 to thiourea to obtain Y15.

[0062] 2-bit replacement-1- H The physicochemical properties and 1H NMR data of the derivatives of indoleoxadiazole are shown in Table 1, which shows the physicochemical properties and NMR data of the target compounds.

[0063] Table 1 Physicochemical properties and NMR data of the DT series compounds

[0064]

[0065]

[0066] Table 2 Physicochemical properties and NMR data of compound Y series

[0067]

[0068] Pharmacological Example 1: Antibacterial activity test: The inhibition rate of the target compound against plant pathogens was tested using the turbidimetric method. The test subject was *Bacillus thuringiensis*, the causal agent of rice bacterial blight. Xanthomonas oryzae pv. oryzae , Xoo ), Citrus canker pathogen ( Xanthomonas axonopodis pv. citrus , Frozen ), bacterial ulcer pathogen of kiwifruit ( P. syringae pv. Actinidia e, Psa ) and tobacco wilt fungus ( Ralstonia Solanacearum , Rs DMSO was dissolved in the culture medium as a blank control. Rice bacterial blight pathogens (rice bacterial blight pathogens on M210 solid medium) were placed in NB medium and cultured at 28 ℃ and 180 rpm in a constant temperature shaker until the logarithmic growth phase was reached. Citrus canker pathogens (on M210 solid medium) were placed in NB medium and cultured at 28 ℃ and 180 rpm in a constant temperature shaker until the logarithmic growth phase was reached. Kiwi fruit bacterial canker pathogens (on M210 solid medium) were placed in NB medium and cultured at 28 ℃ and 180 rpm in a constant temperature shaker until the logarithmic growth phase was reached.

[0069] Five mL of NB liquid culture medium containing different concentrations of the agent (compound) (e.g., 100, 50 μg / mL) was added to each test tube. Then, 40 µL of NB liquid culture medium containing plant pathogen bacteria was added to each tube. The tubes were incubated at 28-30 ℃ and 180 rpm in a constant temperature shaker for 36 h for rice bacterial blight pathogens, 48 ​​h for citrus canker pathogens, and 36 h for kiwifruit bacterial canker pathogens. The OD values ​​of the bacterial solutions at each concentration were measured using a spectrophotometer. 595 The value was also measured, and the OD of the corresponding concentration of sterile NB liquid culture medium containing the toxin was also determined. 595 value.

[0070] The effective concentration of the target compound against plant pathogens was determined using the turbidimetric method. The test subject was *Bacillus thuringiensis*, the causal agent of rice bacterial blight. Xoo ), Citrus canker pathogen ( Frozen ), bacterial canker of kiwifruit ( Psa ) and tobacco wilt pathogen ( Rs DMSO was dissolved in the culture medium as a blank control. Rice bacterial blight pathogens (rice bacterial blight pathogens on M210 solid medium) were placed in NB medium and cultured at 28 ℃ and 180 rpm in a constant temperature shaker until the logarithmic growth phase was reached. Citrus canker pathogens (on M210 solid medium) were placed in NB medium and cultured at 28 ℃ and 180 rpm in a constant temperature shaker until the logarithmic growth phase was reached. Kiwi fruit bacterial canker pathogens (on M210 solid medium) were placed in NB medium and cultured at 28 ℃ and 180 rpm in a constant temperature shaker until the logarithmic growth phase was reached. Different concentrations (e.g., 100, 50, 25, 12.5, 6.25 μg / mL) of the compound agent containing NB liquid culture medium were prepared and added to test tubes. 40 µL of NB liquid culture medium containing plant pathogen bacteria was added to each tube, and the tubes were incubated at 28-30 ℃ and 180 rpm in a constant temperature shaker for 36 h for rice bacterial blight pathogens, 48 ​​h for citrus canker pathogens, and 36 h for kiwifruit bacterial canker pathogens. The OD values ​​of the bacterial solutions at each concentration were measured using a spectrophotometer. 595 The value was also measured, and the OD of the corresponding concentration of sterile NB liquid culture medium containing the toxin was also determined. 595 value.

[0071] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium Inhibition rate % = [(OD value of bacterial suspension in the corrected control medium - OD value of the corrected virus-containing medium) / OD value of bacterial suspension in the corrected control medium] × 100 The embodiments of this invention are provided to illustrate the technical solutions of this invention, but the content of the embodiments is not limited thereto. The experimental results of some target compounds are shown in Table 2, which shows the antibacterial activity of DT and Y series compounds.

[0072] Table 2. Activities of compound Y series against four plant pathogens.

[0073] Note: "-" indicates no activity; "BT" indicates tebuconazole; "TC" indicates thiamethoxam. In in vitro experiments, using marketed drugs BT and TC as positive controls, the activity of some compounds against rice bacterial blight, kiwifruit canker, citrus canker, and tobacco bacterial wilt was tested. Among the target compounds tested, Y15 of the Y series showed better inhibitory activity against citrus canker at a concentration of 50 µg / mL than the control drugs BT and TC, while compound Y1 showed good inhibitory activity against tobacco bacterial wilt at a concentration of 100 µg / mL.

[0074] Any parts or structures not specifically described in this invention can be made using existing technologies or products, and will not be elaborated upon here.

[0075] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made based on the content of the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A class of 2-substituted-1-H-indole oxadiazole amine derivatives, said class of 2-substituted-1-H-indole oxadiazole amine derivatives having a structure as shown in general formula (I): wherein X is an oxygen atom or a sulfur atom; R is hydrogen, deuterium, halogen, cyano, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitro, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester group. wherein The substitution refers to substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, trifluoromethyl.

2. The class of 2-substituted-1-H-indole oxadiazole amine derivative compounds according to claim 1, characterized by, R is selected from any one of hydrogen, deuterium, halogen, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, trifluoromethoxy, nitro, trichloromethyl, trichloromethoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted pyridine, and substitution of halogen (F, Cl and Br) at different positions of the phenyl group.

3. The class of 2-substituted-1-H-indole oxadiazole amine derivatives compounds as claimed in claim-1, wherein, R is selected from any one of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, trifluoromethoxy, nitro, trichloromethyl, trichloromethoxy, phenyl, phenylsulfonyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl.

4. The class of 2-substituted-1-H-indole oxadiazole amine derivatives compounds as claimed in claim 1, wherein, The one indole 2-position oxadiazole ring derivative compound is selected from the following compounds:

5. The type of 2-substituted -1-H-indoleoxadiazoleamine derivative compound according to claim 1, characterized in that, comprising the following steps: DT-1: ; DT-2: ; DT-3: ; DT-4: ; DT-5: ; DT-6: ; DT-7: ; DT-8: ; DT-9: ; DT-10: ; DT-11: ; DT-12: ; DT-13: ; DT-14: ; DT-15: ; Y1： ； Y2： ； Y3： ； Y4： ； Y5： ； Y6： ； Y7： ； Y8： ； Y9： ； Y10： ； Y11： ； Y12： ； Y13： ； Y14： ； Y15： 。 6. A process for the preparation of a 2-substituted-1-H-indole oxadiazole amine derivative compound according to any one of claims 1 to 5, characterized in that, A compound according to any one of claims 1-5, or a stereoisomer thereof, or a salt thereof, or a solvate thereof, and an agriculturally acceptable adjuvant or a fungicide, an insecticide or a herbicide. 。 7. A composition characterized in that, 8. Use of a compound according to any one of claims 1-5, or a composition according to claim 7, in the preparation of a medicine for controlling agricultural pests and diseases. The agricultural pests and diseases are plant bacterial or fungal diseases.

9. Use according to claim 8, characterized in that, The agricultural pests and diseases are rice bacterial leaf blight, citrus canker, kiwifruit canker.

10. Use according to claim 9, characterized in that, ​

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