Quinoline amide derivative as well as preparation method and application thereof

Abstract

The invention discloses a quinoline amide derivative as well as a preparation method and application thereof. The quinoline amide derivative has broad-spectrum and efficient bactericidal activity, and especially has excellent antibacterial activity on agricultural pathogenic bacteria.

Description

Technical Field

[0001] The present invention belongs to the technical field of agricultural bactericides and more specifically relates to a class of quinoline amide derivatives and a preparation method and application thereof. Background Art

[0002] Bacterial diseases of crops are common diseases in my country's agricultural production. They are caused by agricultural pathogenic bacteria. Their degree of harm has surpassed plant viruses and become the second largest pathogen after fungi. The current area of ​​bacterial diseases in my country is 120 million mu, and the market capacity of bacterial disease prevention and control exceeds 2 billion yuan. At present, in agricultural production, the agents for the prevention and control of bacterial diseases mainly include copper preparations (including organic or inorganic copper preparations) and antibiotic products with large dosages. Among them, the prevention effect of copper preparations is low, and a large amount of heavy metals are sprayed into the environment, which pollutes the soil, water and food, causing concerns about environmental and food safety; and the large-scale use of agricultural antibiotics will promote the spread of antimicrobial resistance and may cause human pathogens to develop resistance to medical antibiotics. Zhongshengmycin is a type of natural antibiotic produced by the Hainan variant of Streptomyces lilacinus, and the cost of obtaining it is much higher than that of synthetic antibiotics. However, there are only a few chemical bactericides used for agricultural bacterial control, such as chlorothalonil, which are limited by resistance and efficacy in actual production and are unable to fully deal with the problem of agricultural bacteria invading crops. Therefore, it is an urgent need to develop new low-toxic, low-residue, safe green chemical bactericides.

[0003] In previous studies, quinoline compounds were reported to have a wide range of biological activities, such as oxolinic acid has good preventive effects on rice seedling rot, cucumber bacterial angular spot and tomato bacterial wilt; Patent publications CN109942488A and CN117362227A disclose a class of quinoline carboxylate compounds that show good activity against a variety of bacteria in the agricultural field, among which fluquinometoate obtained the ISO name in July 2024. However, there are still few drugs for agricultural pathogenic bacteria, and exploring more drugs for agricultural pathogenic bacteria has become a technical problem that needs to be solved urgently. Summary of the invention

[0004] Based on the above existing technical problems, the primary purpose of the present invention is to provide a class of quinolineamide derivatives. The quinolineamide derivatives have broad-spectrum and high-efficiency bactericidal activity, especially excellent antibacterial activity against agricultural pathogenic bacteria.

[0005] The second object of the present invention is to provide a method for preparing a class of quinoline amide derivatives.

[0006] The third object of the present invention is to provide an agricultural composition.

[0007] The fourth object of the present invention is to provide the use of the above-mentioned quinoline amide derivatives or the above-mentioned compositions in the preparation of drugs or bactericides for controlling agricultural pathogenic bacteria.

[0008] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0009] The present invention seeks to protect a class of quinoline amide derivatives, the structure of which is shown in formula (I):

[0010]

[0011] R 1 is selected from hydrogen, halogen; R 2 Selected from hydrogen, halogen, C 3-6 Heterocyclic group, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkoxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino; said C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkoxy, C 3-8 The heterocyclic group is unsubstituted or substituted by one or more independently selected from C 1-6 Alkyl, halogen substituents; R 3 Selected from hydrogen, C 1-6 Alkyl; X is selected from N, O, S; R 4 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, mercapto, C 1-6 Alkylthio, aryl, heteroaryl, -SO 2 R 6 , C 1-6 Alkoxy, cyano, amino; the C 1-6 Alkyl, aryl, heteroaryl are unsubstituted or substituted with one or more independently selected from C 1-6 Alkyl, halogen substituents; R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl; R 6 Selected from C 1-6 alkyl.

[0012] In some embodiments, R 1 is selected from fluorine and chlorine; R 2 Selected from hydrogen, fluorine, chlorine, C 4-6 Heterocyclic group, C 1-4 Alkylthio, C 1-4 Alkylamino, C 1-4 Alkoxy, C 3-6Cycloalkyloxy, C 3-6 Cycloalkylamino; said C 1-4 Alkylthio, C 1-4 Alkylamino, C 1-4 Alkoxy, C 4-6 The heterocyclic group is unsubstituted or substituted by one or more independently selected from C 1-3 Alkyl, fluorine, chlorine substituents; R 3 Selected from hydrogen, C 1-3 Alkyl; R 4 Selected from hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 3-5 Cycloalkyl, mercapto, C 1-3 Alkylthio, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, -SO 2 R 6 , C 1-4 Alkoxy, cyano, amino; the C 1-4 Alkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring are unsubstituted or substituted with one or more independently selected from C 1-3 Alkyl, fluorine, chlorine substituents; R 5 Selected from hydrogen, C 2-4 Alkyl, C 3-5 Cycloalkyl; R 6 Selected from C 1-3 alkyl.

[0013] In some embodiments, R 1 Selected from fluorine;

[0014] R 2 is selected from hydrogen, fluorine, chlorine, and a 6-membered heterocyclic group; the 6-membered heterocyclic group is unsubstituted or substituted by a plurality of independently selected C 1-3 Substitution of alkyl groups;

[0015] R 3 Selected from hydrogen;

[0016] X is selected from N and S;

[0017] R 4 Selected from hydrogen, methyl, ethyl, mercapto, C 1-3 Alkylthio, -SO 2 R 6 ;

[0018] R 5 Selected from C 3-5 Cycloalkyl;

[0019] R 6 Selected from C 1-3 alkyl.

[0020] In some embodiments, R 1 Selected from fluorine;

[0021] R 2 Selected from hydrogen, fluorine, chlorine, -OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-OCH(CH 3 ) 2 、-SCH 3 、-SCH 2 CH 3 、-SCH 2 CH 2 CH 3 、-SCH(CH 3 ) 2 、-NHCH 3 、-NHCH 2 CH 3 、-NHCH 2 CH 2 CH 3 、-NHCH(CH 3 ) 2 、-N(CH 3 ) 2 、-N(CH 2 CH 3 ) 2 、-OCHF 2 、-OCF 3 、-OCH 2 CF 3 、-OCH 2 CH 2 Cl, -SCHF 2 、-SCF 3 、-SCH 2 CF 3 、-SCH 2 CH 2 Cl,

[0022] R 3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl;

[0023] X is selected from N, O, S;

[0024] R 4 Selected from H, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2、-C(CH 3 ) 3 , -CF 3 、-OCH 3 , -CHF 2 , -Ph, pyridyl, methylpyridyl, furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, -Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogenated phenyl, -SCH 3 、-SCH 2 CH 3 、-SCH 2 CH 2 CH 3 、-SCH(CH 3 ) 2 , thiol, -SO 2 R 6 , cyano, amino;

[0025] R 5 are independently selected from hydrogen, -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0026] R 6 Selected from -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-C(CH 3 ) 3 .

[0027] Furthermore, the present invention claims a method for preparing a class of quinoline amide derivatives, comprising reacting a quinolinecarboxylic acid compound (II), an aminodiazole compound (III), a base and a solvent to prepare the quinoline amide derivative; or

[0028] The quinolinecarboxylic acid compound (II), the aminodiazole compound (III), a base and a solvent are mixed for reaction, and then the compound of formula (IV) and the base are added for reaction to prepare the quinoline amide derivative;

[0029] The reaction formula of the preparation method is as follows:

[0030]

[0031] Wherein, L is a leaving group.

[0032] In some embodiments, the leaving group is a halogen, such as fluorine, chlorine, bromine or iodine.

[0033] In some embodiments, the base can be selected from an organic base or an inorganic base; further preferably, the base is selected from one or more of triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, sodium or potassium.

[0034] In some embodiments, the solvent is selected from one or more of aromatic hydrocarbon solvents, halogenated alkane solvents, ether solvents, alkylbenzene solvents, carboxylic acid ester solvents, nitrile solvents, amine solvents, sulfone solvents, and sulfoxide solvents. Further preferably, the solvent is selected from one or more of toluene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, tert-butyl methyl ether, ethyl acetate, chloroform, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, or hexamethylphosphoric triamide.

[0035] In some embodiments, the temperature of the mixed reaction is greater than or equal to room temperature and less than or equal to the boiling point of the reaction solvent. More specifically, the reaction temperature is 30-110° C. For example, 35° C., 40° C., 45° C., 50° C., 60° C., 70° C., 75° C., 80° C., 85° C., 90° C., etc., or the reaction is carried out at the boiling point of the solvent, i.e., under reflux.

[0036] In some embodiments, the reaction temperature is greater than or equal to 0°C and less than or equal to the boiling point of the reaction solvent, for example, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or the reaction is carried out at the boiling point of the solvent, i.e., under reflux.

[0037] In some embodiments, the reaction time is 0.5-48 h, for example 0.5 h, 1 h, 3 h, 5 h, 8 h, 10 h, 12 h, 15 h, 18 h, 20 h, 23 h, 25 h, 28 h, 30 h, 33 h, 35 h, 38 h, 40 h, 44 h or 48 h.

[0038] In some embodiments, when R 2When it is not selected from hydrogen, fluorine or chlorine, those skilled in the art can prepare the quinolinecarboxylic acid compound (II) according to conventional preparation methods in the art. More specifically, in some specific embodiments, the quinolinecarboxylic acid compound (II) can be prepared from the compound represented by formula (II-1) and the compound represented by (V):

[0039]

[0040] Wherein, L is selected from a leaving group. The leaving group is a halogen, such as fluorine, chlorine, bromine or iodine. Specifically, the base is selected from one or more of triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, sodium or potassium. The reaction temperature is greater than or equal to 0°C and less than or equal to the boiling point of the reaction solvent. The reaction time is 0.5-48h.

[0041] Furthermore, the present invention claims an agricultural composition comprising:

[0042] (a) 0.001-99.99 wt % of the quinoline amide derivative, its optical isomers, cis-trans isomers or its pesticide-acceptable salt, or a combination thereof; and

[0043] (b) pesticide-acceptable carriers and / or excipients.

[0044] Furthermore, the present invention seeks to protect the use of the quinoline amide derivatives or the agricultural compositions described above in the preparation of drugs or bactericides for controlling agricultural pathogenic bacteria.

[0045] Preferably, the drug or bactericide is applied directly to the agricultural pathogenic bacteria or the locus where it comes into contact.

[0046] Preferably, the agricultural pathogenic bacteria are selected from:

[0047] Gram-negative bacteria: Erwinia (causing fire blight of apricot, etc.); Pectobacterium (causing soft rot of cruciferous vegetables, potato black leg, etc.); Dickie's genus (causing sweet potato stem rot, corn bacterial stem rot, rice bacterial basal rot, potato black leg, pear rust, etc.); Pantoea (causing corn bacterial wilt, corn Pantoea leaf spot, red bean bacterial leaf blight, stone fruit tree canker, etc.); Pseudomonas (causing peach canker, pea bacterial blight) Bacteria, bacterial black spot of crucifer, bacterial leaf spot of tomato, bacterial spot of tomato, bacterial black spot of rape, bacterial angular spot of sesame, bacterial angular spot of cucumber, wildfire of tobacco, bacterial brown spot of corn, bacterial brown spot of corn, bacterial stem blight of broad bean, bacterial spot of soybean, bacterial leaf spot of beet, bacterial pith necrosis of tomato, soft rot of Pseudomonas aeruginosa of ginseng, etc.); Ralstonia (causing various bacterial wilt diseases, such as tobacco bacterial wilt); Burkholderia The genus Acidovorax (cause bacterial wilt of carnation, onion rot, bacterial ear blight of rice, etc.); the genus Acidovorax (cause fruit spot of melon, brown spot of orchid, brown streak of oat, bacterial leaf spot of konjac, etc.); the genus Xanthomonas (cause bacterial leaf blight of rice, bacterial streak of rice, spot disease of pepper and tomato, scab of pepper and tomato, bacterial black spot of mango, bacterial leaf spot of pepper, bacterial blight of poinsettia, angular spot of cotton, bacterial spot of soybean, black rot of crucifer , cassava bacterial wilt, sugarcane gummosis, anthurium bacterial blight, citrus canker, hyacinth yellow rot, peach bacterial punchhole, strawberry angular leaf spot, poplar bacterial canker, etc.); Agrobacterium (cause root cancer of Rosaceae, etc.); Xylem bacteria (cause Pierce's disease of grapes and citrus variegated chlorosis, etc.); Phloemobacter (cause citrus Huanglongbing, etc.); Enterobacter (cause poplar wilt, etc.); Xylophilus (cause bacterial blight of grapes, etc.).

[0048] Gram-positive bacteria: Corynebacterium (causing potato ring rot, bacterial canker of tomatoes, bacterial wilt of alfalfa, internal wilt of corn, bacterial mosaic of wheat, etc.); Streptomyces (causing potato scab, etc.); Brevibacterium (causing bacterial wilt of beans, yellow blister of tulip, bean wilt, etc.); Arthrobacter (causing American holly leaf blight, etc.); Rhodococcus (causing sweet pea banding, etc.); Bacillus (causing Bacillus leaf spot of corn, white leaf streak of wheat, etc.); Russell's bacillus (causing duckgrass honey ear disease, etc.).

[0049] Further preferably, the agricultural pathogenic bacteria are selected from one or more of Pseudomonas, Ralstonia, and Xanthomonas.

[0050] Compared with the prior art, the present invention has the following beneficial effects:

[0051] The present invention provides a class of quinolineamide derivatives, which have broad-spectrum and highly effective bactericidal activity, especially excellent antibacterial activity against agricultural pathogenic bacteria, and have great application potential and value in the field of plant disease prevention and control. DETAILED DESCRIPTION

[0052] The present invention is further described below in conjunction with specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0053] In the present invention, unless otherwise specified in the context, the words, phrases and symbols used below have the following meanings. The following abbreviations and terms have the following meanings throughout the text:

[0054] The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical, including monocyclic or polycyclic groups. Unless otherwise specified, cycloalkyl has 3-8 carbon atoms. For example, cycloalkyl can be a monocyclic group with 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-3-enyl, cyclohexene, 1-cyclohex-1-enyl, cyclohexadiene, cycloheptene, cyclooctene, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl or similar groups. Cycloalkyl can also be a bicyclic group with 4-8 carbon atoms, such as the bicyclic of [4,5], [5,5], [5,6] and [6,6] ring systems. The cycloalkyl can be saturated or have at least one double bond, but is not completely conjugated, and is not aromatic.

[0055] The term "heterocyclyl" refers to a ring selected from the following: a 3-8 membered monocyclic, bicyclic saturated or partially unsaturated ring, which contains at least one carbon atom in addition to 1, 2, 3 or 4 heteroatoms selected from O, S and N. The heterocyclic ring may be saturated or contain at least one double bond. The heterocyclic ring may be oxo-substituted, i.e. substituted by the group =O. The heterocyclic group may be connected to the rest of the molecule via a carbon atom or a heteroatom. Examples of heterocyclic groups include, but are not limited to, tetrahydrofuranyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, aminopiperidinyl, etc.

[0056] The term "aryl" refers to a 5-6 membered aromatic ring, a 7-12 membered bicyclic ring system, wherein at least one ring in the bicyclic ring system is an aromatic ring. For example, (a) a 5-6 membered aromatic ring includes but is not limited to phenyl; (b) an aryl group of a 7-12 membered bicyclic ring system, such as naphthyl.

[0057] The term "heteroaryl" refers to a 5-6 membered aromatic ring or a 7-12 membered bicyclic ring system, wherein at least one ring in the bicyclic ring system is an aromatic ring, and the aromatic ring contains at least one heteroatom selected from O, S and N. For example, (a) 5-6 membered heteroaryl includes but is not limited to pyridyl, furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, etc.; (b) heteroaryl of a 7-12 membered bicyclic ring system includes but is not limited to benzodioxanyl or quinolyl, etc.

[0058] Example 1

[0059] Referring to the compounds in Table 1, when R 2 The group is selected from hydrogen, fluorine or chlorine, R 3 When the group is selected from hydrogen, the preparation method of quinoline amide derivatives: Taking the synthesis of compound I-1 as an example, the specific synthesis process is as follows:

[0060] The quinolinecarboxylic acid compound 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.056 g, 0.2 mmol) was dissolved in dry N,N-dimethylformamide (2 ml), and N,N-diisopropylethylamine (0.24 mmol, 1.2 equivalents), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.24 mmol, 1.2 equivalents) and aminodiazole compound 2-aminothiadiazole (0.24 mmol, 1.2 equivalents) were added in sequence. The mixture was stirred at room temperature for 4 hours, and the reaction was completed after TLC monitoring. Water (10 mL) was added, and the aqueous layer was extracted with EtOAc (10 mL×3). The organic layers were combined and washed with anhydrous Na 2 SO 4 The residue was dried, concentrated in vacuo, and purified by column chromatography (petroleum ether:ethyl acetate=5:1-3:1) to obtain quinoline amide derivative I-1 with a yield of 0.069 g and a yield of 95%.

[0061] The reaction formula is as follows:

[0062]

[0063] The compounds I-2 to I-37, I-149 to I-150, and I-153 to I-156 of the present invention were synthesized according to the above method. The structures and data characterizations of the quinoline amide derivatives are shown in Table 1.

[0064] Example 2

[0065] Referring to the compounds in Table 1, when R 2 When the group is not selected from hydrogen, fluorine or chlorine, R 3 When the group is selected from hydrogen, the preparation method of quinoline amide derivatives: Taking the synthesis of compound I-70 as an example, the specific synthesis process is as follows:

[0066] (1) 7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.056 g, 0.2 mmol) was dissolved in dry toluene (2 ml), and piperidine (0.24 mmol, 1.2 equivalents) and potassium hydroxide (0.4 mmol, 2 equivalents) were added in sequence. The mixture was refluxed and stirred for 8 hours. The reaction was monitored by TLC. Water (10 mL) was added, and the pH was adjusted to 3 with dilute hydrochloric acid. The aqueous layer was extracted with EtOAc (10 mL × 3). The organic layers were combined and washed with anhydrous Na 2 SO 4 The residue was dried, concentrated in vacuo, and purified by column chromatography (dichloromethane:methanol=20:1-10:1) to obtain 0.054 g of the product with a yield of 82%. 1 HNMR(500MHz,Chloroform-d)δ9.31(s,1H),8.01(d,J=8.9Hz,1H),7.01(d,J=5.7Hz,1H),3.24(p,J=7.0H z,1H),3.10(t,J=5.2Hz,4H),1.71–1.58(m,6H),0.94(tt,J=7.2,4.3Hz,2H),0.79(tt,J=7.4,4.2Hz,2H).

[0067] (2) Referring to the synthesis method of Example 1, the quinolinecarboxylic acid compound obtained in step 1 was reacted to generate compound I-70 to obtain 0.055 g of the product with a yield of 66%.

[0068] The reaction formula is as follows:

[0069]

[0070] The compounds I-38 to I-69, and I-71 to I-74 of the present invention were synthesized according to the above method. The structures and data characterizations of the quinoline amide derivatives are shown in Table 1.

[0071] Example 3

[0072] Referring to the compounds in Table 1, when R 2 The group is selected from hydrogen, fluorine or chlorine, R 3 When the group is selected from methyl, the preparation method of quinoline amide derivatives: Taking the synthesis of compound I-75 as an example, the specific synthesis process is as follows:

[0073] (1) Prepare quinoline amide derivative I-1 by following the method of Example 1;

[0074] (2) The quinoline amide derivative I-1 (0.073 g, 0.2 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Sodium hydrogen ions (0.24 mmol, 1.2 equivalents) were added at 0°C. After the addition was completed, the mixture was stirred for 10 minutes at room temperature. Then, iodomethane (0.24 mmol, 1.2 equivalents) was added. After the addition was completed, the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. Water (10 mL) was added, and the aqueous layer was extracted with EtOAc (10 mL×3). The organic layers were combined and washed with anhydrous Na 2 SO 4 The product was dried, concentrated in vacuo, and purified by column chromatography (petroleum ether:ethyl acetate=3:1-1:1, v / v) to obtain quinoline amide derivative I-75 with a yield of 0.053 g and a yield of 70%.

[0075] The reaction formula is as follows:

[0076]

[0077] The compounds I-76 to I-111 and I-151 to I-152 of the present invention were synthesized according to the above method, and their structures and data characterizations are shown in Table 1.

[0078] Example 4

[0079] Referring to the compounds in Table 1, when R 2 The group is not selected from hydrogen, fluorine or chlorine, R 3 When the group is selected from methyl, the preparation method of quinoline amide derivatives is:

[0080] (1) This step is carried out by referring to step (1) in Example 2;

[0081] (2) The compound prepared in step (1) was reacted according to the steps of Example 1;

[0082] (3) The compound prepared in step (2) was reacted with the same method as in step (2) of Example 3 to prepare a quinoline amide derivative.

[0083] Compounds I-112 to I-148 of the present invention were synthesized according to the above method, and their structures and data characterizations are shown in Table 1.

[0084] Table 1 Structure and characterization data of quinoline amide derivatives (I)

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103] Test Case

[0104] The antibacterial activity of the quinolineamide derivatives provided by the present invention was initially screened using the pathogen of rice bacterial blight (Xanthomonas oryzae), and the antibacterial activity of the best compounds in the initial screening was further determined using the pathogen of tobacco bacterial wilt (Ralstonia solanacearum), the pathogen of cucumber bacterial angular spot (Pseudomonas syringaepv.lachrymans), and the pathogen of citrus canker (Xanthomonas citrisubsp.citri). The specific test method is as follows:

[0105] The quinoline amide derivatives prepared in the above examples were prepared and diluted with dimethyl sulfoxide to a series of concentrations: 100 mg / L, 50 mg / L, 25 mg / L, 12.5 mg / L, 6.25 mg / L, 3.125 mg / L, 1.5 mg / L, 0.75 mg / L, 0.3 mg / L, 0.15 mg / L, 0.75 mg / L, 0.325 mg / L, 0.15 mg / L, 0.075 mg / L, 0.0325 mg / L, 0.015 mg / L, 0.0075 mg / L, 0.00325 mg / L. Under aseptic operation conditions, NB culture solution was dispensed into test tubes in equal amounts, and the drug solution was quantitatively drawn from low concentration to high concentration, added to the above test tubes respectively, and fully shaken, and then the bacterial suspension in the logarithmic growth phase was added in equal amounts, and each treatment was repeated 4 times. After mixing, place in a 25°C shaking incubator for dark culture, and measure the OD value during the logarithmic growth phase, as shown in Table 2 below.

[0106] Table 2 EC of quinolineamide derivatives against pathogenic bacteria 50 value

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] From the test results in Table 2, it can be seen that the quinoline amide derivatives provided by the present invention have better antibacterial effects on agricultural pathogenic bacteria than the existing chemical bactericide chlorothalonil. In particular, compounds I-1, I-2, I-3, I-14, I-15, I-16, I-17, I-35, I-37, I-71, I-72, I-73, and I-74 have better antibacterial effects on rice bacterial blight pathogens. Their EC 50 The value is less than 1 mg / L. More preferably, the antibacterial effect of compounds I-1, I-2, I-72, I-73, and I-74 is better than that of the existing biocide Zhongshengmycin.

[0113] The antibacterial activity of compounds I-1, I-2, I-3, I-14, I-15, I-16, I-17, I-35, I-37, I-71, I-72, I-73, and I-74 against tobacco bacterial wilt pathogens, cucumber bacterial angular spot pathogens, and citrus canker pathogens was further evaluated, and it was found that these compounds all had broad-spectrum antibacterial activity and were significantly superior to the chemical bactericide chlorothalonil.

[0114] The antibacterial activity of compounds I-1, I-2, I-3, I-14, I-15, I-16, I-73, and I-74 against tobacco bacterial wilt pathogens is better than that of the existing biofungicide Zhongshengmycin. The antibacterial activity of compounds I-1, I-2, I-14, I-15, I-16, I-17, I-37, I-72, I-73, and I-74 against cucumber bacterial angular spot pathogens is better than that of the existing biofungicide Zhongshengmycin. The antibacterial activity of compounds I-1, I-2, I-3, I-14, I-15, I-37, I-71, I-72, I-73, and I-74 against citrus canker pathogens is better than that of the existing biofungicide Zhongshengmycin.

[0115] It can be seen that the quinoline amide compounds designed and prepared by the present invention have broad-spectrum and high-efficiency fungicidal activity and have great application potential and value in the field of plant disease prevention and control.

[0116] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A quinoline amide derivative, characterized in that: The structure of the quinoline amide derivative is shown in formula (I): R 1 is selected from hydrogen and halogen; R 2 Selected from hydrogen, halogen, C 3-6 Heterocyclic group, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkoxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkylamino; said C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkoxy, C 3-8 The heterocyclic group is unsubstituted or substituted by one or more independently selected from C 1-6 Alkyl, halogen substitution; R 3 Selected from hydrogen, C 1-6 alkyl; X is selected from N, O, S; R 4 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, mercapto, C 1-6 Alkylthio, aryl, heteroaryl, -SO2R 6 , C 1-6 Alkoxy, cyano, amino; the C 1-6 Alkyl, aryl, heteroaryl are unsubstituted or substituted with one or more independently selected from C 1-6 Alkyl, halogen substitution; R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl; R 6 Selected from C 1-6 alkyl.

2. The quinoline amide derivative according to claim 1, characterized in that: R 1 Selected from fluorine and chlorine; R 2 Selected from hydrogen, fluorine, chlorine, C 4-6 Heterocyclic group, C 1-4 Alkylthio, C 1-4 Alkylamino, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 3-6 Cycloalkylamino; said C 1-4 Alkylthio, C 1-4 Alkylamino, C 1-4 Alkoxy, C 4-6 The heterocyclic group is unsubstituted or substituted by one or more independently selected from C 1-3 Alkyl, fluorine, chlorine substituents substitution; R 3 Selected from hydrogen, C 1-3 alkyl; R 4 Selected from hydrogen, fluorine, chlorine, C 1-4 Alkyl, C 3-5 Cycloalkyl, mercapto, C 1-3 Alkylthio, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, -SO2R 6 , C 1-4 Alkoxy, cyano, amino; the C 1-4 Alkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring are unsubstituted or substituted with one or more independently selected from C 1-3 Alkyl, fluorine, chlorine substituents substitution; R 5 Selected from hydrogen, C 2-4 Alkyl, C 3-5 Cycloalkyl; R 6 Selected from C 1-3 alkyl.

3. The quinoline amide derivative according to claim 2, characterized in that: R 1 Selected from fluorine; R 2 is selected from hydrogen, fluorine, chlorine, and a 6-membered heterocyclic group; the 6-membered heterocyclic group is unsubstituted or substituted by a plurality of independently selected C 1-3 Substitution of alkyl groups; R 3 Selected from hydrogen; X is selected from N and S; R 4 Selected from hydrogen, methyl, ethyl, mercapto, C 1-3 Alkylthio, -SO2R 6 ; R 5 Selected from C 3-5 Cycloalkyl; R 6 Selected from C 1-3 alkyl.

4. The method for preparing the quinoline amide derivatives according to any one of claims 1 to 3, characterized in that: The quinolinecarboxylic acid compound (II), the aminodiazole compound (III), a base and a solvent are mixed for reaction to prepare the quinolineamide derivative; or The quinolinecarboxylic acid compound (II), the aminodiazole compound (III), a base and a solvent are mixed for reaction, and then the compound of formula (IV) and the base are added for reaction to prepare the quinoline amide derivative; The reaction formula of the preparation method is as follows: Wherein, L is selected from a leaving group.

5. The preparation method according to claim 4, characterized in that: The base is selected from one or more of triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, sodium or potassium.

6. The preparation method according to claim 4, characterized in that: The solvent is selected from one or more of aromatic hydrocarbon solvents, halogenated alkane solvents, ether solvents, alkylbenzene solvents, carboxylic acid ester solvents, nitrile solvents, amine solvents, sulfone solvents, and sulfoxide solvents.

7. An agricultural composition, characterized in that Include: (a) 0.001-99.99 wt % of the quinoline amide derivative according to any one of claims 1 to 3, its optical isomers, cis-trans isomers or its pesticide-acceptable salt, or a combination thereof; and (b) pesticide-acceptable carriers and / or excipients.

8. Use of the quinolineamide derivative according to any one of claims 1 to 3 or the agricultural composition according to claim 7 in the preparation of a medicament or bactericide for controlling agricultural pathogenic bacteria.

9. The use according to claim 8, characterized in that: The drug or bactericide is applied directly to the agricultural pathogenic bacteria or the locus where it comes into contact.

10. The use according to claim 8, characterized in that: The agricultural pathogenic bacteria are selected from one or more of the genera Erwinia, Pectobacterium, Dickie's, Pantoea, Pseudomonas, Ralstonia, Burkholderia, Acidovorax, Xanthomonas, Agrobacterium, Xylella, Bacillus, Enterobacter, Xylophilus, Corynebacterium, Streptomyces, Brevibacterium, Arthrobacter, Rhodococcus, Bacillus, and Russell's.

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