Quinoline derivatives containing piperazine structure, their preparation methods and applications

Abstract

This invention belongs to the field of pesticide chemistry technology, and relates to quinoline derivatives containing piperazine structures, their preparation methods, and applications. This invention provides a quinoline derivative containing a piperazine structure, which exhibits broad-spectrum inhibitory activity against plant pathogens, such as plant pathogenic fungi, especially showing excellent inhibitory activity against *Pseudomonas aeruginosa*, *Sclerotinia sclerotiorum*, *Botrytis cinerea*, *Tricholoma materia granatum*, and *Bacillus thuringiensis*, and holds promise for development into a novel, efficient, safe, economical, and environmentally friendly green fungicide.

Description

Technical Field

[0001] This invention belongs to the field of pesticide chemistry technology, and relates to quinoline derivatives containing piperazine structures, their preparation methods and applications. Background Technology

[0002] Fungal diseases account for over 70% of all plant diseases, and the resulting crop yield losses pose a serious threat to food security. Currently, chemical control remains the most economical, efficient, and widely used strategy for controlling plant fungal diseases. However, long-term, singular use of fungicides targeting specific pathogens can create directional selective pressure on pathogen populations, accelerating the formation and spread of resistant strains. Therefore, developing novel fungicides with new targets or mechanisms of action has become an urgent need to address the challenge of fungal resistance and achieve sustainable disease management.

[0003] Quinoline alkaloids and their derivatives are widely found in nature, exhibiting rich and excellent biological activities, such as antibacterial, insecticidal, anti-inflammatory, and antitumor effects. In the field of medicinal chemistry, quinoline compounds have attracted considerable attention due to their diverse biological activities. However, their application in pesticides remains relatively limited; currently, only a few varieties, such as isopropylquinoline, fluopyram, and phenoxyquinoline, have been commercialized, indicating a vast potential for research and development.

[0004] With the widespread and often inappropriate use of various fungicides in the market, the problem of fungal resistance is becoming increasingly serious. Therefore, developing new and highly effective fungicides to address fungal resistance is of great significance for ensuring the sustainable development of agriculture. Summary of the Invention

[0005] To address the technical problems existing in the prior art, this invention provides a quinoline derivative containing a piperazine structure, its preparation method, and its application, which has a highly efficient and broad-spectrum inhibitory effect on plant pathogens, especially plant pathogenic fungi.

[0006] This invention addresses the significant harm caused by plant pathogenic fungi to agricultural production in my country and the increasingly serious problem of fungal resistance. Utilizing computer-aided drug design, through a cyclical feedback process of virtual screening, organic synthesis, initial activity screening, structural modification, and comprehensive evaluation of biological activity, it screened out promising compounds with certain antibacterial activities. Furthermore, it structurally derived these compounds, synthesizing a series of quinoline derivatives containing piperazine structures, laying the foundation for the creation of novel fungicides and the control of fungal resistance.

[0007] On the one hand, the present invention provides a quinoline derivative containing a piperazine structure, having a structure as shown in formula (I) or a stereoisomer, tautomer, isotopic derivative or pesticide-acceptable salt thereof;

[0008]

[0009] R 1 Selected from amino, hydroxyl, C1-C8 alkyl, C1-C8 haloalkanes, C1-C8 alkoxy, C1-C8 alkylamino, substituted benzene rings or aromatic heterocycles;

[0010] R 1 The substituents described herein are selected from any one or more of halogen, alkyl, alkoxy, amino, amino, amide, hydroxy, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl, and aryl.

[0011] R 1 The aromatic heterocycles mentioned herein are C1-C10 nitrogen-containing heterocycles, C1-C10 oxygen-containing heterocycles, or C1-C10 sulfur-containing heterocycles;

[0012] R 1 The halogens mentioned are fluorine, chlorine, bromine, or iodine;

[0013] R 2 Selected from hydrogen, halogen, amino, amide, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, C1-C8 alkyl, C1-C8 haloalkane, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkylthio or C1-C8 alkylamino.

[0014] R 2 The halogens mentioned are fluorine, chlorine, bromine, or iodine;

[0015] R 3 Selected from hydrogen, C1-C8 alkyl, substituted benzene rings or aromatic heterocycles;

[0016] R 3 The substituents described herein are selected from any one or more of halogen, alkyl, alkoxy, amino, amino, amide, hydroxy, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl, and aryl.

[0017] R 3 The aromatic heterocycles mentioned herein are C1-C10 nitrogen-containing heterocycles, C1-C10 oxygen-containing heterocycles, or C1-C10 sulfur-containing heterocycles;

[0018] R 3 The halogens mentioned are fluorine, chlorine, bromine, or iodine;

[0019] R 4 Selected from hydrogen, hydroxyl, C1-C8 alkyl, C1-C8 haloalkanes, substituted benzene rings or aromatic heterocycles;

[0020] R 4The substituents described herein are selected from any one or more of halogen, alkyl, alkoxy, amino, amino, amide, hydroxy, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl, and aryl.

[0021] R 4 The aromatic heterocycles mentioned herein are C1-C10 nitrogen-containing heterocycles, C1-C10 oxygen-containing heterocycles, or C1-C10 sulfur-containing heterocycles;

[0022] R 4 The halogens mentioned are fluorine, chlorine, bromine, or iodine;

[0023] n is an integer between 0 and 4;

[0024] X represents nitrogen or oxygen.

[0025] Preferably, the quinoline derivative is selected from the following compounds:

[0026]

[0027]

[0028] .

[0029] On the other hand, a method for preparing the quinoline derivatives described in this invention is provided, comprising:

[0030] Route 1:

[0031] ;

[0032] Route 2:

[0033] ;

[0034] Route 3:

[0035] .

[0036] Preferably, route 1 includes:

[0037] Using 2-aminobenzonitrile A with different substitutions as raw materials, 2-aminobenzophenone C was synthesized by nucleophilic addition of cyano groups to Grignard reagent B; then, using 2-aminobenzophenone C and 4-chloroacetoacetate D as raw materials, compound E containing a quinoline core skeleton was constructed in one pot via Lewis acid-catalyzed [4+2] cyclization-aromatization reaction.

[0038] Compound E, containing a quinoline core skeleton, reacts with piperazine-1-carboxylic acid tert-butyl ester F to obtain intermediate G. Intermediate G is deprotected by Boc under acidic conditions (such as HCl) to obtain intermediate H. Intermediate H is then subjected to SN2 nucleophilic substitution to obtain the target quinoline derivative. The obtained product is purified by column chromatography to obtain a pure product.

[0039] Route 2 includes:

[0040] Using 2-aminobenzonitrile A with different substitutions as raw materials, 2-aminobenzophenone C was synthesized by nucleophilic addition of cyano groups to Grignard reagent B; then, using 2-aminobenzophenone C and 4-chloroacetoacetate D as raw materials, compound E containing a quinoline core skeleton was constructed in one pot via Lewis acid-catalyzed [4+2] cyclization-aromatization reaction.

[0041] Piperazine-1-carboxylic acid tert-butyl ester K reacts with acyl chlorides J with different substitutions to give intermediate L, which is then debonded under acidic conditions (such as HCl) to give intermediate M; compound E containing a quinoline core skeleton reacts with intermediate M to give the target quinoline derivative, and the product is purified by column chromatography to obtain the pure product.

[0042] Route 3 includes:

[0043] Carboxylic acid esters are hydrolyzed under alkaline conditions (such as NaOH) to obtain intermediate acid N, which is then condensed with amines, phenols or alcohols to obtain the target quinoline derivative.

[0044] A bactericidal composition is also provided, wherein the active ingredient of the bactericidal composition includes the quinoline derivatives described in this invention.

[0045] Preferably, the bactericidal composition further includes a pesticide-acceptable carrier and / or adjuvant.

[0046] The invention also provides the application of the quinoline derivatives or the bactericidal compositions described herein in the prevention and control of plant diseases caused by plant pathogens.

[0047] The invention also provides the application of the quinoline derivatives or the bactericidal compositions described herein in the prevention and control of plant diseases caused by plant pathogens in the fields of agriculture, forestry, horticulture or health.

[0048] Preferably, the plant pathogen is a plant pathogenic fungus, which is selected from one or more of the following phyla: clubroot, oomycetes, chytrid, zygomycetes, ascomycetes, basidiomycetes, and deuteromycetes.

[0049] More preferably, the plant pathogenic fungi include apple rot fungus, rapeseed sclerotinia rot fungus, grape gray mold fungus, wheat take-all fungus, and rice blast fungus.

[0050] Preferably, the plant diseases include rot, take-all, ring spot, sclerotinia rot, gray mold, sheath blight, scab, rice blast, late blight, pepper blight, powdery mildew, downy mildew, wilt, and brown spot.

[0051] More preferably, the plant diseases include apple rot, rapeseed sclerotinia stem rot, grape gray mold, wheat take-all disease, and rice blast.

[0052] The bactericidal composition of the present invention can be applied in the form of a formulation, wherein the quinoline derivative is dissolved or dispersed in a carrier or formulated as an active component to facilitate dispersion when used as a bactericidal composition. The bactericidal composition can be formulated into various liquids, such as soluble powders, dispersible liquids, emulsifiable concentrates, suspensions, aqueous suspensions, microemulsions, emulsions, water-in-oil emulsions, and water-dispersible granules.

[0053] One or more other insecticides, fungicides, herbicides, plant growth regulators and fertilizers may be added to the bactericidal composition of the present invention.

[0054] In this invention, a safe and effective amount of the quinoline derivative or bactericidal composition as described herein is applied to plants, plant propagation materials or subsequently grown plant organs and cultivation media, cultivation materials or cultivation space.

[0055] In this invention, safe and effective amounts of quinoline derivatives or fungicidal compositions as described herein are used to prevent or control pathogenic fungi on wood roots. For example, safe and effective amounts of quinoline derivatives or fungicidal compositions as described herein are applied to leaves, stems, roots, seeds, and / or soil.

[0056] Stereoisomers are isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers. Configurational isomers include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometric isomers can exist in the compounds of this invention. Optical isomers are substances with identical molecular structures and similar physicochemical properties, but different optical rotations.

[0057] Tautomers are structural isomers with different energies that can interconvert through low energy barriers. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomers. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0058] Isotope derivatives refer to the quinoline derivatives of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine include, but are not limited to: 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 35 S, 18 F, 36 Cl、 80 Br and 125 I. Compounds containing these and / or other isotopes are within the scope of this invention. The isotopically labeled compounds of this invention can be prepared using general methods well known to those skilled in the art.

[0059] A pesticide-acceptable salt refers to a salt obtained by reacting the quinoline derivatives of this invention with a chemically acceptable acid. The chemically acceptable acid can be an inorganic acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid) or an organic acid (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, or benzoic acid). A pesticide-acceptable salt can also be a salt obtained by reacting the quinoline derivatives of this invention with a chemically acceptable base. The chemically acceptable base can be an inorganic base (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) or an organic base (such as trimethylamine, triethylamine, etc.). Pesticide-acceptable salts can be potassium salts, sodium salts, ammonium salts, calcium salts, pyridine salts, choline salts, hydrochloride salts, phosphates, acetates, benzenesulfonates, or oxalates.

[0060] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0061] This invention utilizes a commercial compound database (Specs: https: / / www.specs.net / ,Enamine Virtual screening was conducted at https: / / enamine.net / to obtain lead compounds, which were then structurally modified to synthesize a novel class of quinoline derivatives containing piperazine structures. Common plant pathogens, such as *Pseudomonas aeruginosa*, *Sclerotinia sclerotiorum*, *Botrytis cinerea*, *Tricholoma materia granatum*, and *Bacillus oryzae*, were selected as targets for antifungal activity assays. The results showed that the compounds of this invention exhibited broad-spectrum antifungal activity against plant pathogens, particularly showing excellent antifungal activity against *Pseudomonas aeruginosa*. Preliminary structure-activity relationship analysis indicated that R... 1The tert-butyl group and halogen substitution on the quinoline ring help these compounds maintain highly efficient and broad-spectrum antibacterial activity.

[0062] These compounds have simple structures and are completely different from existing commercial bactericides, and are expected to be developed into new green bactericides that are efficient, safe, economical and environmentally friendly. Detailed Implementation

[0063] The technical solution of the present invention will be described below with reference to embodiments. However, the present invention is not limited to the following embodiments. Unless otherwise specified, the experimental methods and detection methods described in each embodiment are conventional methods; unless otherwise specified, the reagents and materials can be purchased commercially.

[0064] Example 1

[0065] According to route 1, the preparation route of intermediate H-1 is as follows:

[0066]

[0067] The preparation method of intermediate H-1 includes the following steps:

[0068] S1. At room temperature, compound B-1 (30.0 mL, 1.0 mol / L THF solution, 30 mmol, 3.0 equivalent) and THF (20 mL) were added to a round-bottom flask. The system was stirred at room temperature for 5 minutes under a N2 atmosphere. Separately, compound A-1 (10 mmol, 1.0 equivalent) was dissolved in THF (10 mL), and after the system was cooled to 0°C, this solution was added dropwise to the reaction system. The reaction mixture was then heated to room temperature and stirred for 12 hours, during which the reaction progress was monitored using TLC. After the reaction was complete, the mixture was cooled to 0°C again, and HCl solution (20 mL, 3 mol / L) was slowly added dropwise. After the addition was complete, stirring was continued at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by column chromatography to obtain the intermediate 2-aminobenzophenone C-1.

[0069] S2. 2-Aminobenzophenone C-1 (2.7 g, 20 mmol) and 4-chloroacetoacetate D (3.3 g, 20 mmol) were added to a 100 mL flask and dissolved in DMF (40 mL). Trimethylchlorosilane (TMSCI) (8.7 g, 80 mmol) was added dropwise to the solution, and the system was then heated at 100 °C for 10 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous MgSO4, and the solvent was concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by column chromatography to give intermediate E-1 (yield 85.6%). 1 H NMR (400 MHz, CDCl3) δ 8.17(d, J = 8.4 Hz, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.55 –7.47 (m, 4H), 7.34-7.36 (m, 2H), 5.03 (s, 2H), 3.56 (s, 3H).

[0070] S3. Intermediate E-1 (6.2 g, 20 mmol), potassium iodide (3.5 g, 21 mmol), potassium carbonate (6.6 g, 48 mmol), and piperazine-1-carboxylic acid tert-butyl ester F (3.7 g, 20 mmol) were sequentially added to 50 mL of acetonitrile, and the mixture was stirred at room temperature for 7 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was dissolved in 80 mL of ethyl acetate and washed successively with water and sodium bisulfite solution. After the organic phase was concentrated under reduced pressure, the resulting solid was washed with 40 mL of diethyl ether and filtered to obtain intermediate G-1. This product does not require further purification and can be used directly in subsequent reactions.

[0071] S4. Intermediate G-1 (4.6 g, 10 mmol) was dissolved in 10 mL of hydrochloric acid (6 mol / L), and the resulting mixture was heated under reflux for 1 hour. After confirming the reaction was complete by TLC monitoring, the reaction solution was concentrated to near dryness under reduced pressure. The residue was then adjusted to alkalinity with saturated sodium bicarbonate solution, and the product was extracted with dichloromethane. The organic phase was washed successively with 50 mL of water and concentrated under reduced pressure to obtain intermediate H-1. This product can be used directly in subsequent steps without further purification.

[0072] Example 2

[0073] According to route 1, quinoline derivatives containing piperazine structures, I-1 (R... 1 = Ethyl, R 2 = H, R3 = Ph,R 4 The preparation route for (= methyl, X = O) is as follows:

[0074]

[0075] The preparation method of quinoline derivative I-1 containing a piperazine structure includes the following steps:

[0076] Intermediate H-1 (0.36 g, 1 mmol) prepared in Example 1 was dissolved in 5 mL of dichloromethane with triethylamine (0.5 g, 5 mmol). Propionyl chloride (0.24 g, 3 mmol) was slowly added dropwise under ice bath cooling. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The crude product was dissolved in 80 mL of ethyl acetate and washed successively with water and sodium bicarbonate solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to give compound I-1 as a yellow solid (yield 61.3%). 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 1H), 7.72 -7.76 (m, 1H), 7.61 – 7.64 (m, 1H), 7.46 – 7.52 (m, 4H), 7.32 – 7.36 (m, 2H), 4.01 (s, 2H), 3.54 (brs, 2H), 3.48 (s, 3H), 3.35 (brs, 2H), 2.48 (brs, 4H), 2.30 (q, J = 7.5 Hz, 2H), 1.11 (t, J = 7.5 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ172.4, 168.8, 156.6, 147.6, 147.2, 135.7, 130.6, 129.3 (3C), 128.6, 128.3(2C), 127.2, 126.8, 126.7, 126.3, 63.5, 52.8, 52.6, 51.8, 45.3, 41.5, 26.5,9.6.

[0077] Example 3 Preparation of quinoline derivative I-2 containing piperazine structure

[0078] I-2 (R) is a quinoline derivative containing a piperazine structure. 1 = n-propyl, R 2 = H, R 3= Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0079]

[0080] The preparation method of the piperazine-containing quinoline derivative I-2 includes the following steps: The method described in Example 2 is used, except that propionyl chloride is replaced with butyryl chloride; the other steps are the same as in Example 2. The piperazine-containing quinoline derivative is purified by column chromatography to obtain a yellow liquid (yield 66.1%). 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.5Hz, 1H), 7.71 – 7.78 (m, 1H), 7.61 – 7.64 (m, 1H), 7.45 – 7.52 (m, 4H), 7.33- 7.35 (m, 2H), 4.02 (s, 2H), 3.55 (brs, 2H), 3.48 (s, 3H), 3.37 (brs, 2H), 2.51 (brs, 4H), 2.24 – 2.27 (m, 2H), 1.62 (h, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 171.7, 168.8, 155.6, 147.6, 147.2, 135.7,130.5, 129.3 (3C), 128.6, 128.3 (2C), 127.2, 126.8, 126.7, 126.2, 63.5, 52.8,52.6, 51.8, 45.5, 41.4, 35.3, 18.8, 14.1.

[0081] Example 4 Preparation of quinoline derivative I-3 containing piperazine structure

[0082] Quinoline derivatives containing piperazine structures, I-3 (R 1 = Isopropyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0083]

[0084] The preparation method of quinoline derivative I-3 containing a piperazine structure includes the following steps: The method described in Example 2 is used, except that propionyl chloride is replaced with isobutyryl chloride; the other steps are the same as in Example 2. The quinoline derivative I-3 containing a piperazine structure is purified by column chromatography as a yellow solid (yield 91.3%). 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.8 Hz, 1H), 7.72 – 7.76 (m, 1H), 7.61 – 7.64 (m, 1H), 7.44 – 7.52 (m, 4H), 7.32 – 7.37 (m, 2H), 4.02 (s, 2H), 3.55 (brs, 2H), 3.48 (s, 3H), 3.41 (brs,2H), 2.69 - 2.76 (m, 1H), 2.51 (brs, 4H), 1.09 (d, J = 6.9 Hz, 6H); 13 C NMR (101MHz, CDCl3) δ 175.5, 168.8, 155.7, 147.5, 147.2, 135.7, 130.5, 129.3 (3C), 128.5, 128.3 (2C), 127.2, 126.8, 126.7, 126.2, 63.6, 53.0, 52.7, 51.8, 45.3,41.6, 30.1, 19.4 (2C).

[0085] Example 5 Preparation of quinoline derivative I-4 containing piperazine structure

[0086] I-4 (R), a quinoline derivative containing a piperazine structure 1 = n-Butyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0087]

[0088] The preparation method of quinoline derivative I-4 containing a piperazine structure includes the following steps: using the method described in Example 2, except that propionyl chloride is replaced with valerate chloride, and the other steps are the same as in Example 2. The quinoline derivative I-4 containing a piperazine structure was purified by column chromatography as a yellow liquid (yield 90.6%). 1H NMR (400 MHz, CDCl3) δ 8.06 – 8.17(m, 1H), 7.72 – 7.76 (m, 1H), 7.61 – 7.64 (m, 1H), 7.44 – 7.52 (m, 4H), 7.30– 7.38 (m, 2H), 4.01 (s, 2H), 3.54 (brs, 2H), 3.48 (s, 3H), 3.37 (brs, 2H), 2.50 (brs, 4H), 2.25 – 2.29 (m, 2H), 1.53 – 1.61 (m, 2H), 1.28 – 1.38 (m,2H), 0.90 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 171.8, 168.7, 155.7,147.4, 147.2, 135.6, 130.4, 129.2 (3C), 128.5, 128.2 (2C), 127.1, 126.7,126.6, 126.2, 63.6, 52.8, 52.6, 51.7, 45.5, 41.4, 33.0, 27.5, 22.6, 13.9.

[0089] Example 6 Preparation of quinoline derivative I-5 containing piperazine structure

[0090] Quinoline derivatives containing piperazine structures, I-5 (R 1 = tert-butyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0091]

[0092] The preparation method of quinoline derivative I-5 containing a piperazine structure includes the following steps: The method described in Example 2 is used, except that propionyl chloride is replaced with neopentanoyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-5 containing a piperazine structure is purified by column chromatography as a yellow liquid (yield 78.5%). 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.71 – 7.75 (m, 1H), 7.62 (d, J= 8.4, 1H), 7.44 – 7.51 (m, 4H), 7.31 – 7.37 (m, 2H), 4.01 (s, 2H), 3.57 (brs, 4H), 3.49 (s, 3H), 2.51 (brs, 4H), 1.23 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 176.4, 168.8, 155.9, 147.5,147.2, 135.7, 130.5, 129.3 (3C), 128.5, 128.3 (2C), 127.1, 126.7, 126.7,126.2, 63.7, 52.9 (2C), 51.8, 45.1 (2C), 38.7, 28.5 (3C); HRMS (ESI) m / z [M +H] + : calcd for C 27 H 31 N3O3, 446.2438, found, 446.2442.

[0093] Example 7 Preparation of quinoline derivative I-6 containing piperazine structure

[0094] I-6 (R), a quinoline derivative containing a piperazine structure 1 = n-pentyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0095]

[0096] The preparation method of quinoline derivative I-6 containing a piperazine structure includes the following steps: using the method described in Example 2, except that propionyl chloride is replaced with hexanoyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-6 containing a piperazine structure was purified by column chromatography as a yellow liquid (yield 59.2%). 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.5 Hz, 1H), 7.72 – 7.76 (m, 1H), 7.61 – 7.64 (m, 1H), 7.45 – 7.51 (m, 4H), 7.32 – 7.37 (m, 2H), 4.02 (s, 2H), 3.55 (brs, 2H), 3.48 (s, 3H), 3.37 (brs,2H), 2.50 (brs, 4H), 2.24 – 2.29 (m, 2H), 1.55 – 1.63 (m, 2H), 1.24 – 1.31(m, 4H), 0.85 – 0.89 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 171.9, 168.8, 155.8,147.5, 147.2, 135.7, 130.5, 129.3 (3C), 128.6, 128.3 (2C), 127.2, 126.8,126.7, 126.3, 63.6, 52.8, 52.6, 51.8, 45.6, 41.5, 33.4, 31.7, 25.1, 22.6,14.1; HRMS (ESI) m / z [M + H] + : calcd for C 28 H 33 N3O3, 460.2595, found, 460.2603.

[0097] Example 8 Preparation of quinoline derivative I-7 containing piperazine structure

[0098] Quinoline derivatives containing piperazine structures, I-7 (R 1 = Hexobase, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0099]

[0100] The preparation method of quinoline derivative I-7 containing a piperazine structure includes the following steps: using the method described in Example 2, except that propionyl chloride is replaced with heptanyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-7 containing a piperazine structure was purified by column chromatography as a yellow liquid (yield 69.2%). 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 1H), 7.78 – 7.72 (m, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.53 – 7.46 (m,4H), 7.33 – 7.36 (m, 2H), 4.02 (s, 2H), 3.55 (brs, 2H), 3.48 (s, 3H), 3.38(brs, 2H), 2.50 (brs, 4H), 2.30 – 2.24 (m, 2H), 1.55 – 1.62 (m, 2H), 1.33 –1.25 (m, 6H), 0.89 – 0.84 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 171.8, 168.8,155.8, 147.5, 147.2, 135.7, 130.5, 129.3 (2C), 129.3, 128.5, 128.3 (2C),127.1, 126.7 (2C), 126.2, 63.6, 52.8, 52.6, 51.8, 45.6, 41.5, 33.4, 31.7,29.2, 25.4, 22.6, 14.1; HRMS (ESI) m / z [M + H] + : calcd for C 29 H 35 N3O3,474.2751, found, 474.2756.

[0101] Example 9 Preparation of quinoline derivative I-8 containing piperazine structure

[0102] I-8 (R), a quinoline derivative containing a piperazine structure 1 = Heptyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0103]

[0104] The preparation method of quinoline derivative I-8 containing a piperazine structure includes the following steps: using the method described in Example 2, except that propionyl chloride is replaced with octanoyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-8 containing a piperazine structure was purified by column chromatography as a yellow liquid (yield 65.1%). 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 1H), 7.71 - 7.75 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.44 - 7.51 (m,4H), 7.30 - 7.39 (m, 2H), 4.01 (s, 2H), 3.53 (brs, 2H), 3.47 (s, 3H), 3.36(brs, 2H), 2.49 (brs, 4H), 2.27 (t, J = 7.7 Hz, 2H), 1.56 – 1.60 (m, 2H), 1.22 – 1.31 (m, 8H), 0.83 – 0.87 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 171.9, 168.8,155.9, 147.5, 147.2, 135.7, 130.5, 129.3 (3C), 128.6, 128.3 (2C), 127.2,126.8, 126.7, 126.3, 63.6, 52.8, 52.6, 51.8 (2C), 45.6, 41.5, 33.4, 31.9,29.6, 29.5, 29.3, 25.5, 22.7, 14.2.

[0105] Example 10 Preparation of quinoline derivative I-9 containing piperazine structure

[0106] Quinoline derivatives containing piperazine structures, I-9 (R 1 = Cyclobutyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0107]

[0108] The preparation method of quinoline derivative I-9 containing a piperazine structure includes the following steps: The method described in Example 2 is used, except that propionyl chloride is replaced with cyclobutylformyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-9 containing a piperazine structure is purified by column chromatography as a yellow solid (yield 60%). 1 H NMR (400 MHz, CDCl3) δ 8.11(d, J = 7.3 Hz, 1H), 7.71 – 7.77 (m, 1H), 7.62 (d, J= 10.2 Hz, 1H), 7.45 – 7.52(m, 4H), 7.33 – 7.36 (m, 2H), 3.99 (s, 2H), 3.53 (brs, 4H), 3.48 (s, 3H),3.13 – 3.21 (m, 1H), 2.48 (br, 2H), 2.42 (br, 2H), 2.27 – 2.34 (m, 2H), 2.05– 2.15 (m, 2H), 1.80 – 1.96 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 173.2, 168.8,155.7, 147.5, 147.2, 135.7, 130.5, 129.3 (3C), 128.6, 128.3 (2C), 127.2,126.8, 126.7, 126.3, 63.6, 52.8, 52.6, 51.8, 44.8, 41.6, 37.2, 25.2 (2C),18.0.

[0109] Example 11 Preparation of quinoline derivative I-10 containing piperazine structure

[0110] I-10 (R), a quinoline derivative containing a piperazine structure 1 = Cyclopentyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0111]

[0112] The preparation method of quinoline derivative I-10 containing a piperazine structure includes the following steps: using the method described in Example 2, except that propionyl chloride is replaced with cyclopentylformyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-10 containing a piperazine structure was purified by column chromatography as a light yellow solid (yield 71.8%). 1 H NMR (400 MHz, CDCl3) δ8.11 (d, J = 8.5 Hz, 1H), 7.72 – 7.76 (m, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.45 –7.52 (m, 4H), 7.34 – 7.36 (m, 2H), 4.00 (s, 2H), 3.54 (brs, 2H), 3.48 (s,3H), 3.41 (brs, 2H), 2.879 – 2.87 (m, 1H), 2.48 (brs, 4H), 1.68 – 1.81 (m,6H), 1.49 – 1.58 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 174.7, 168.9, 150.2,147.3, 135.8, 135.1, 130.5, 129.3 (3C), 128.6, 128.4 (2C), 127.2, 126.8,126.7, 126.3, 63.9, 53.0, 52.7, 51.8, 45.5, 45.5, 41.1, 30.2 (2C), 26.2 (2C).

[0113] Example 12 Preparation of quinoline derivative I-11 containing piperazine structure

[0114] I-11 (R), a quinoline derivative containing a piperazine structure 1 = Cyclohexyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0115]

[0116] The preparation method of quinoline derivative I-11 containing a piperazine structure includes the following steps: using the method described in Example 2, except that propionyl chloride is replaced with cyclohexylformyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-11 containing a piperazine structure was purified by column chromatography as a yellow solid (yield 71.5%). 1 H NMR (400 MHz, CDCl3) δ8.10 (d, J = 9.2 Hz, 1H), 7.71 – 7.75 (m, 1H), 7.62 (dd, J= 8.5, 1.4 Hz, 1H),7.43 – 7.52 (m, 4H), 7.32 -7.35 (m, 2H), 4.01 (s, 2H), 3.53 (brs, 2H), 3.47(s, 3H), 3.40 (brs, 2H), 2.50 (brs, 4H), 2.36 – 2.43 (m, 1H), 1.63 – 1.80 (m,5H), 1.64 – 1.78 (m, 2H), 1.18 – 1.25 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ174.6, 168.8, 155.8, 147.5, 147.2, 135.7, 130.5, 129.3 (3C), 128.5, 128.3(2C), 127.1, 126.7, 126.7, 126.2, 63.6, 53.1, 52.7, 51.8, 45.3, 41.5, 40.5,29.4 (2C), 25.9 (3C).

[0117] Example 13 Preparation of quinoline derivative I-12 containing piperazine structure

[0118] I-12 (R), a quinoline derivative containing a piperazine structure 1 = 4-morpholino, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0119]

[0120] The preparation method of quinoline derivative I-12 containing a piperazine structure includes the following steps: using the method described in Example 2, except that propionyl chloride is replaced with 4-morpholinoformyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-12 containing a piperazine structure was purified by column chromatography as a yellow solid (yield 67.5%). 1 H NMR (400 MHz, CDCl3) δ8.10 (d, J= 7.6 Hz, 1H), 7.71 – 7.75 (m, 1H), 7.63 – 7.63 (m, 1H), 7.43 – 7.53(m, 4H), 7.29 – 7.39 (m, 2H), 4.01 (s, 2H), 3.60 – 3.67 (m, 4H), 3.47 (s,3H), 3.21 – 3.24 (m, 4H), 3.19 (brs, 4H), 2.51 (brs, 4H); 13 C NMR (101 MHz, CDCl3) δ 168.8, 163.9, 155.9, 147.4, 147.2, 135.7, 130.4, 129.3 (3C), 128.5,128.3 (2C), 127.1, 126.7 (2C), 126.2, 63.8, 66.7 (2C), 52.5 (2C), 51.8, 47.4(2C), 46.7 (2C).

[0121] Example 14 Preparation of quinoline derivative I-13 containing piperazine structure

[0122] I-13 (R), a quinoline derivative containing a piperazine structure 1 = Ph,R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0123]

[0124] The preparation method of quinoline derivative I-13 containing a piperazine structure includes the following steps: using the method described in Example 2, except that propionyl chloride is replaced with benzoyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-13 containing a piperazine structure was purified by column chromatography as a light yellow solid (yield 71.2%). 1 H NMR (400 MHz, CDCl3) δ 8.11(d, J= 8.7 Hz, 1H), 7.72 – 7.76 (m, 1H), 7.61 – 7.63 (m, 1H), 7.44 – 7.52 (m,4H), 7.36 – 7.38 (m, 5H), 7.29 – 7.36 (m, 2H), 4.04 (s, 2H), 3.71 (brs, 2H), 3.49 (s, 3H), 3.34 (brs, 2H), 2.62 (brs, 2H), 2.46 (brs, 2H); 13 C NMR (101 MHz, CDCl3) δ 170.4, 168.8, 155.8, 147.5, 147.2, 135.8, 135.7, 130.5, 129.8, 129.3(3C), 128.5, 128.5 (2C), 128.3 (2C), 127.2, 127.1 (2C), 126.8, 126.7, 126.2,63.7, 52.9, 52.7, 51.8, 47.7, 42.2.

[0125] Example 15 Preparation of quinoline derivative I-14 containing piperazine structure

[0126] I-14 (R), a quinoline derivative containing a piperazine structure 1 = 3-pyridyl, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0127]

[0128] The preparation method of quinoline derivative I-14 containing a piperazine structure includes the following steps: using the method described in Example 2, acetyl chloride is replaced with 3-pyridinecarboxyl chloride, and the other steps are the same as in Example 2. The quinoline derivative I-14 containing a piperazine structure is purified by column chromatography as a yellow solid (yield 55.4%). 1 H NMR (400 MHz, CDCl3) δ8.63 – 8.65 (m, 2H), 8.11 (d, J = 8.4 Hz, 1H), 7.79 – 7.69 (m, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.45 – 7.51 (m, 4H), 7.40 – 7.28 (m, 3H), 4.05 (s, 2H), 3.73(brs, 2H), 3.50 (s, 3H), 3.35 (brs, 2H), 2.64 (brs, 2H), 2.50 (brs, 2H).

[0129] Example 16 Preparation of quinoline derivative I-15 containing a piperazine structure

[0130] I-15 (R), a quinoline derivative containing a piperazine structure 1 = Methylamino, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0131]

[0132] The preparation method of quinoline derivative I-15 containing a piperazine structure includes the following steps: using the method described in Example 2, acetyl chloride is replaced with methylcarbamoyl chloride, and other steps are the same as in Example 2. The quinoline derivative I-15 containing a piperazine structure is purified by column chromatography to obtain a yellow solid (yield 65.5%). 1 H NMR (400 MHz, CDCl3) δ8.10 (d, J = 7.8 Hz, 1H), 7.71 – 7.75 (m, 1H), 7.61 – 7.63 (m, 1H), 7.50 – 7.43(m, 4H), 7.36 – 7.31 (m, 2H), 3.99 (s, 2H), 3.45 (s, 3H), 3.26 (brs, 4H),2.77 (d, J = 4.7 Hz, 3H), 2.48 (brs, 4H); 13 C NMR (101 MHz, CDCl3) δ 168.8,158.5, 156.0, 147.3, 147.2, 135.7, 130.4, 129.3 (2C), 129.2, 128.5, 128.3(2C), 127.1, 126.7, 126.7, 126.2, 63.8, 52.4 (2C), 51.7, 43.7 (2C), 27.6.

[0133] Example 17 Preparation of quinoline derivative I-16 containing piperazine structure

[0134] I-16 (R), a quinoline derivative containing a piperazine structure 1 =Dimethylamino, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0135]

[0136] The preparation method of quinoline derivative I-16 containing a piperazine structure includes the following steps: using the method described in Example 2, acetyl chloride is replaced with dimethylcarbamoyl chloride, and other steps are the same as in Example 2. The quinoline derivative I-16 containing a piperazine structure is purified by column chromatography to obtain a yellow solid (yield 53.4%). 1 H NMR (400 MHz, CDCl3) δ8.10 (d, J = 7.7 Hz, 1H), 7.70 – 7.74 (m, 1H), 7.60 – 7.63 (m, 1H), 7.43 – 7.51(m, 4H), 7.30 – 7.38 (m, 2H), 4.01 (s, 2H), 3.46 (s, 3H), 3.15 (brs, 4H), 2.79 (s, 6H), 2.52 (brs, 4H); 13 C NMR (101 MHz, CDCl3) δ 168.8, 164.8, 156.1,147.3, 147.2, 135.7, 130.3, 129.3 (3C), 128.4, 128.2 (2C), 127.0, 126.7,126.7, 126.2, 63.8, 52.5 (2C), 51.8, 46.7 (2C), 38.5 (2C).

[0137] Example 18 Preparation of quinoline derivative I-17 containing piperazine structure

[0138] I-17 (R), a quinoline derivative containing a piperazine structure 1 = tert-butoxy, R 2 = H, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0139]

[0140] The preparation method of quinoline derivative I-17 containing a piperazine structure includes the following steps: using the method described in Example 2, acetyl chloride is replaced with tert-butyl chloroformate, and the other steps are the same as in Example 2. The quinoline derivative I-17 containing a piperazine structure is purified by column chromatography as a yellow solid (yield 65.4%). 1 H NMR (400 MHz, CDCl3) δ8.10 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.44– 7.51 (m, 4H), 7.38 – 7.32 (m, 2H), 3.98 (s, 2H), 3.47 (s, 3H), 3.32 (brs,4H), 2.43 (brs, 4H), 1.43 (s, 9H).

[0141] Example 19

[0142] According to route 2, quinoline derivatives I-18 (R containing piperazine structures) 1 = tert-butyl, R 2 = 6-F, R 3 = Ph,R 4 The preparation route for (=methyl, X=O) is as follows:

[0143]

[0144] The preparation method of quinoline derivative I-18 containing a piperazine structure includes the following steps:

[0145] S1. At room temperature, magnesium phenyl bromide B-1 (12.0 mL, 1.0 mol / L THF solution, 12 mmol, 3.0 equivalent) and THF (20 mL) were added to a round-bottom flask, and stirred at room temperature for 5 minutes under a N2 atmosphere. Separately, 2-amino-5-fluorobenzonitrile A-2 (4 mmol, 1.0 equivalent) was dissolved in THF (4 mL), and after the reaction system was cooled to 0°C, this solution was slowly added dropwise to the system. After the addition was complete, the reaction mixture was brought back to room temperature and stirred for 12 hours, during which the reaction progress was monitored by TLC. After the reaction was completed, the mixture was cooled to 0°C again, and HCl solution (8 mL, 3 mol / L) was slowly added dropwise, followed by stirring at room temperature for another 30 minutes. The reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by column chromatography to obtain intermediate C-2.

[0146] S2. Intermediate C-2 (0.27 g, 2 mmol) and methyl 4-chloroacetoacetate D (0.33 g, 2 mmol) were added sequentially to a 25 mL flask and dissolved in DMF (4 mL). TMSCI (0.87 g, 8 mmol) was added dropwise to the solution, and the system was then heated at 100 °C for 10 hours. After cooling, the reaction progress was monitored by TLC. The reaction solution was extracted with ethyl acetate, and the organic phases were combined, washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by column chromatography to obtain intermediate E-2.

[0147] S3. Neopentanoyl chloride J-5 (6.2 g, 20 mmol), potassium iodide (3.5 g, 21 mmol), potassium carbonate (6.6 g, 48 mmol), and piperazine-1-carboxylic acid tert-butyl ester K (3.7 g, 20 mmol) were successively added to 50 mL of acetonitrile, and the mixture was stirred at room temperature for 7 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was dissolved in 80 mL of ethyl acetate and washed successively with water and sodium bisulfite solution. After the organic phase was concentrated under reduced pressure, the resulting solid was washed with 40 mL of diethyl ether and filtered to give intermediate L.

[0148] S4. Intermediate L (4.6 g, 10 mmol) was dissolved in 1,4-dioxane solution (15 mL, 4 mol / L) of HCl and stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the reaction solution was concentrated to dryness under reduced pressure. The resulting residue was alkalized with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed with 50 mL of water and concentrated under reduced pressure to obtain intermediate M, which can be used directly in subsequent steps without further purification.

[0149] S5. Intermediate E-2 (0.066 g, 0.2 mmol), potassium iodide (0.033 g, 0.2 mmol), potassium carbonate (0.11 g, 0.8 mmol), and intermediate M (0.144 g, 0.7 mmol) were sequentially added to 3 mL of dichloromethane, and the mixture was stirred at room temperature for 7 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was redissolved in an appropriate amount of dichloromethane, washed with water, and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by column chromatography to obtain a yellow solid containing a piperazine structure, quinoline derivative I-18 (yield 49.7%). 1 H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 9.1, 5.4 Hz, 1H), 7.48 –7.51 (m, 4H), 7.36 – 7.28 (m, 2H), 7.23 (dd, J= 9.8, 2.5 Hz, 1H), 3.96 (s,2H), 3.54 (brs, 4H), 3.49 (s, 3H), 2.47 (brs, 4H), 1.23 (s, 9H); 13 C NMR (101MHz, CDCl3) δ 176.4, 168.6, 146.8 (d, J = 5.6 Hz), 144.3, 135.3, 131.8 (d, J =9.1 Hz), 129.2(3C), 128.8, 128.5(2C), 127.3, 127.2, 120.5 (d, J = 25.8 Hz), 110.2 (d, J = 23.4 Hz), 63.7, 52.9(2C), 51.9(2C), 45.1, 38.7, 28.5(3C); HRMS(ESI) m / z [M + H] + : calcd for C 27 H 30 FN3O3, 464.2344, found, 464.2352.

[0150] Example 20 Preparation of quinoline derivative I-19 containing piperazine structure

[0151] Quinoline derivatives containing piperazine structures I-19 (R 1 = tert-butyl, R 2 = 6-Cl, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0152]

[0153] The preparation method of quinoline derivative I-19 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-5-chlorobenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-19 containing a piperazine structure is purified by column chromatography to obtain a yellow solid (yield 61.5%). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.9 Hz, 1H), 7.67 (dd, J = 8.9, 2.1 Hz, 1H), 7.58(d, J= 2.2 Hz, 1H), 7.49 – 7.54 (m, 3H), 7.36 – 7.29 (m, 2H), 3.97 (s, 2H), 3.54 (brs, 4H), 3.49 (s, 3H), 2.47 (brs, 4H), 1.24 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 176.4, 168.5, 146.6, 145.7, 135.0, 133.2, 131.4, 131.0, 129.2(3C),128.9, 128.6(2C), 127.5, 127.1, 125.5, 63.7, 52.9(2C), 51.9(2C), 45.1, 38.7,28.5(3C); HRMS (ESI) m / z [M + H] + : calcd for C 27 H 30 ClN3O3, 480.2048, found, 480.2057.

[0154] Example 21 Preparation of quinoline derivative I-20 containing piperazine structure

[0155] Quinoline derivatives containing piperazine structures I-20 (R 1 = tert-butyl, R 2 = 6-Br, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0156]

[0157] The preparation method of quinoline derivative I-20 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-5-bromobenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-20 containing a piperazine structure is purified by column chromatography as a yellow solid (yield 59.5%). 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.9 Hz, 1H), 7.80 (dd, J = 8.8, 2.2 Hz, 1H), 7.75(d, J= 2.0 Hz, 1H), 7.52 – 7.49 (m, 3H), 7.34 – 7.31 (m, 2H), 3.96 (s, 2H), 3.54 (brs, 4H), 3.49 (s, 3H), 2.47 (brs, 4H), 1.24 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 176.4, 168.4, 146.5, 145.9, 135.0, 133.9, 131.1, 129.2(3C), 128.9,128.8, 128.5(2C), 127.5, 127.4, 121.4, 63.7, 52.9(2C), 51.9(2C), 45.5, 38.7,28.5(3C); HRMS (ESI) m / z [M + H] + : calcd for C 27 H 30 BrN3O3, 524.1543, found, 524.1553.

[0158] Example 22 Preparation of quinoline derivative I-21 containing piperazine structure

[0159] Quinoline derivatives containing piperazine structures I-21 (R 1 = tert-butyl, R 2 = 6-CH3, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0160]

[0161] The preparation method of quinoline derivative I-21 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-5-methylbenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-21 containing a piperazine structure is purified by column chromatography as a light yellow solid (yield 89.3%). 1 HNMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.5 Hz, 1H), 7.57 (d, J= 8.5 Hz, 1H), 7.46 –7.53 (m, 3H), 7.38 – 7.31 (m, 3H), 3.97 (s, 2H), 3.54 (brs, 4H), 3.49 (s,3H), 2.47 (brs, 4H), 2.42 (s, 3H), 1.24 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ176.4, 169.0, 155.0, 146.8, 145.8, 137.2, 135.9, 132.7, 129.3(2C), 129.0,128.5, 128.3(2C), 126.7, 126.2, 125.5, 63.8, 52.9(2C), 51.8(2C), 45.2, 38.7,28.5(3C), 21.9; HRMS (ESI) m / z [M + H] + : calcd for C 28 H 33 N3O3, 460.2595, found, 460.2601.

[0162] Example 23 Preparation of quinoline derivative I-22 containing piperazine structure

[0163] Quinoline derivatives containing piperazine structures I-22 (R 1 = tert-butyl, R 2 = 7-F, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0164]

[0165] The preparation method of quinoline derivative I-22 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-4-fluorobenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-22 containing a piperazine structure is purified by column chromatography as a light yellow liquid (yield 95.4%). 1 HNMR (400 MHz, CDCl3) δ 7.73 (dd, J = 9.8, 2.3 Hz, 1H), 7.62 (dd, J= 9.2, 6.1 Hz,1H), 7.52 – 7.46 (m, 3H), 7.35 – 7.30 (m, 2H), 3.97 (s, 2H), 3.54 (brs, 4H), 3.49 (s, 3H), 2.47 (brs, 4H), 1.24 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 176.4,168.6, 163.7 (d, J = 252.1 Hz), 157.5, 148.5 (d, J = 12.8 Hz), 147.5, 135.5,129.2(2C), 129.1, 128.8, 128.4(2C), 126.2 (d, J = 2.5 Hz), 123.3, 117.4 (d, J =24.8 Hz), 113.1 (d, J = 20.4 Hz), 63.8, 52.9(2C), 51.9(2C), 45.1, 38.7, 28.5(3C); HRMS (ESI) m / z [M + H] + : calcd for C 27 H 30 FN3O3, 464.2344, found, 464.2346.

[0166] Example 24 Preparation of quinoline derivative I-23 containing piperazine structure

[0167] Quinoline derivatives containing piperazine structures I-23 (R 1 = tert-butyl, R 2 = 7-Cl, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0168]

[0169] The preparation method of quinoline derivative I-23 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-4-chlorobenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-23 containing a piperazine structure is purified by column chromatography as a white solid (yield 88.7%). 1 H NMR (400 MHz, CDCl3) δ 8.10 (d,J = 2.0 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.52 –7.45 (m, 3H), 7.41 (dd, J = 9.0, 2.1 Hz, 1H), 7.35 – 7.29 (m, 2H), 3.96 (s,2H), 3.54 (brs, 4H), 3.49 (s, 3H), 2.47 (brs, 4H), 1.24 (s, 9H); 13 C NMR (101MHz, CDCl3) δ 176.4, 168.5, 157.5, 147.7, 147.4, 136.5, 135.3, 129.2(2C),128.8, 128.5(2C), 128.4, 128.1(2C), 126.8, 124.7, 63.7, 52.9(2C), 51.9(2C),45.1, 38.7, 28.5(3C).

[0170] Example 25 Preparation of quinoline derivative I-24 containing piperazine structure

[0171] Quinoline derivative I-24 (R) containing piperazine structure 1 = tert-butyl, R 2 = 7-Br, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0172]

[0173] The preparation method of quinoline derivative I-24 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-4-bromobenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-24 containing a piperazine structure is purified by column chromatography as a light yellow solid (yield 95.2%). 1 HNMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.58 – 7.45 (m, 5H), 7.31 – 7.33 (m,2H), 3.96 (s, 2H), 3.54 (brs, 4H), 3.49 (s, 3H), 2.47 (brs, 4H), 1.24 (s,9H); 13 C NMR (101 MHz, Chloroform- d) δ 176.4, 168.5, 157.4, 147.9, 147.5,135.2, 131.7, 130.6, 129.2(2C), 128.8, 128.5(2C), 128.2, 127.0, 125.0, 124.9,63.8, 52.9 (2C), 51.9(2C), 45.1, 38.7, 28.5(3C).

[0174] Example 26 Preparation of quinoline derivative I-25 containing piperazine structure

[0175] Quinoline derivatives containing piperazine structures I-25 (R 1 = tert-butyl, R 2 = 7-CF3, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0176]

[0177] The preparation method of quinoline derivative I-25 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-4-trifluoromethylbenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-25 containing a piperazine structure is purified by column chromatography as a light yellow solid (yield 83.2%). 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.63(d, J = 8.7 Hz, 1H), 7.50 – 7.54 (m, 3H), 7.32 – 7.35 (m, 2H), 4.00 (s, 2H), 3.54 (brs, 4H), 3.51 (s, 3H), 2.48 (brs, 4H), 1.24 (s, 9H) 13 C NMR (101 MHz, CDCl3) δ 176.5, 168.3, 157.8, 147.4, 146.4, 135.0, 132.1 (q, J = 33.4 Hz),129.3(2C), 129.0, 128.6(2C), 128.3, 128.1, 127.2 (q, J = 4.2 Hz), 123.9 (q, J=272.7 Hz), 122.7, 63.7, 52.9(2C), 52.0(2C), 45.1, 38.7, 28.5(3C).

[0178] Example 27 Preparation of quinoline derivative I-26 containing piperazine structure

[0179] Quinoline derivative I-26 (R) containing piperazine structure 1 = tert-butyl, R 2 = 7-CH3, R 3 = Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0180]

[0181] The preparation method of quinoline derivative I-26 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-4-methylbenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-26 containing a piperazine structure is purified by column chromatography as a light yellow liquid (yield 78.2%). 1 HNMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.46 – 7.52 (dd, J = 11.0, 7.8 Hz, 4H),7.28 – 7.34 (m, 3H), 3.98 (s, 2H), 3.55 (brs, 4H), 3.49 (s, 3H), 2.55 (s,3H), 2.49 (brs, 4H), 1.23 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 176.4, 169.0,147.5, 147.3, 141.1, 135.9, 129.4, 129.3(3C), 128.5, 128.4, 128.3(2C), 126.4,125.9, 124.2, 63.8, 52.9(2C), 51.8(2C), 45.1, 38.7, 28.5(3C), 21.9.

[0182] Example 28 Preparation of quinoline derivative I-27 containing piperazine structure

[0183] Quinoline derivatives containing piperazine structures I-27 (R 1 = tert-butyl, R 2 = 7-MeO,R 3= Ph,R 4 The chemical formula of (= methyl, X = O) is as follows:

[0184]

[0185] The preparation method of quinoline derivative I-27 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-4-methoxybenzonitrile; the other steps are the same as in Example 19. The quinoline derivative I-27 containing a piperazine structure is purified by column chromatography as a light yellow solid (yield 77.3%). 1 H NMR (400 MHz, CDCl3) δ 7.52 – 7.41 (m, 5H), 7.31 – 7.33 (m, 2H), 7.10 (dd, J = 9.2, 2.5 Hz, 1H), 3.95 (s, 5H), 3.54 (brs, 4H), 3.48 (s, 3H), 2.47 (brs,4H), 1.23 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 176.4, 169.0, 161.5, 156.3,149.2, 147.4, 135.9, 129.2(2C), 128.5, 128.3(2C), 127.9, 124.8, 121.1, 120.2,107.3, 63.8, 55.8, 52.9(2C), 51.8(2C), 45.1, 38.7, 28.5(3C).

[0186] Example 29 Preparation of quinoline derivative I-28 containing piperazine structure

[0187] Quinoline derivative I-28 (R) containing piperazine structure 1 = tert-butyl, R 2 = 6-Cl, R 3 = H, R 4 The chemical formula of (= methyl, X = O) is as follows:

[0188]

[0189] The preparation method of quinoline derivative I-28 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that C-2 is replaced with 2-amino-5-chlorobenzaldehyde in step S1, and the other steps are the same as in Example 19. The quinoline derivative I-28 containing a piperazine structure is purified by column chromatography as a white solid (yield 65.3%).1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.70(dd, J = 9.0, 2.3 Hz, 1H), 4.04 (s, 2H), 3.96 (s, 3H), 3.57 (brs, 4H), 2.45(brs, 4H), 1.24 (s, 9H).

[0190] Example 30 Preparation of quinoline derivative I-29 containing piperazine structure

[0191] Quinoline derivatives containing piperazine structures I-29 (R 1 = tert-butyl, R 2 = 6-Cl, R 3 = CH3, R 4 The chemical formula of (= methyl, X = O) is as follows:

[0192]

[0193] The preparation method of quinoline derivative I-29 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-5-chlorobenzonitrile, and phenyl magnesium bromide is replaced with methyl magnesium bromide; the other steps are the same as in Example 19. The quinoline derivative I-29 containing a piperazine structure is purified by column chromatography as a light yellow solid (yield 75.3%). 1 H NMR (400 MHz, CDCl3) δ 8.06 – 7.89 (m, 2H), 7.66(dd, J = 8.9, 1.9 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 2H), 3.58 (brs, 4H), 2.63 (s,3H), 2.42 (brs, 4H), 1.24 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 176.4, 169.0,156.3, 145.1, 142.3, 133.0, 131.3, 131.1, 127.8, 127.5, 123.4, 63.9, 52.9(2C), 52.4(2C), 44.9, 38.7, 28.5(3C), 15.7.

[0194] Example 31 Preparation of quinoline derivative I-30 containing piperazine structure

[0195] Quinoline derivatives containing piperazine structures I-30 (R 1 = tert-butyl, R 2 = 6-Cl, R 3 = 4-Cl-Ph, R 4 The chemical formula of (= methyl, X = O) is as follows:

[0196]

[0197] The preparation method of quinoline derivative I-30 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-5-chlorobenzonitrile, and magnesium phenyl bromide is replaced with 4-chlorophenyl magnesium bromide. Other steps are the same as in Example 19. The quinoline derivative I-30 containing a piperazine structure is purified by column chromatography as a light yellow solid (yield 73.5%). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 3H), 7.28 (s, 2H), 3.96 (s,2H), 3.55 (s, 3H), 2.54 (brs, 4H), 2.46 (brs, 4H), 1.24 (s, 9H); 13 C NMR (101MHz, CDCl3) δ 176.4, 168.2, 156.5, 145.6, 145.3, 135.1, 133.4(2C), 131.5,131.1, 130.6(2C), 128.9(2C), 127.4, 126.8, 125.1, 63.7, 52.9(2C), 52.1(2C),45.1, 38.7, 28.5(3C); HRMS (ESI) m / z [M + H] + : calcd for C 27 H 29 Cl2N3O3,514.1659, found, 514.1667.

[0198] Example 32 Preparation of quinoline derivative I-31 containing piperazine structure

[0199] Quinoline derivatives containing piperazine structures I-31 (R 1 = tert-butyl, R 2 = 6-Cl, R 3 = 4-CH3-Ph, R 4 The chemical formula of (= methyl, X = O) is as follows:

[0200]

[0201] The preparation method of quinoline derivative I-31 containing a piperazine structure includes the following steps: The method described in Example 19 is used, except that in step S1, 2-amino-5-fluorobenzonitrile is replaced with 2-amino-5-chlorobenzonitrile, and magnesium phenyl bromide is replaced with 4-methylphenyl magnesium bromide. Other steps are the same as in Example 19. The quinoline derivative I-31 containing a piperazine structure is purified by column chromatography as a pale yellow solid (yield 58.5%). 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.9 Hz,1H), 7.71 – 7.57 (m, 2H), 7.31 (d, J = 7.7 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H),3.95 (s, 2H), 3.54 (brs, 4H), 3.53 (s, 3H), 2.47 (brs, 4H), 2.46 (s, 3H),1.23 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 176.4, 168.6, 156.4, 146.8, 145.7,138.8, 133.0, 132.0, 131.3, 130.9, 129.3(2C), 129.1(2C), 127.5, 127.3, 125.6,63.8, 52.9(2C), 52.0(2C), 45.1, 38.7, 28.5(3C), 21.5; HRMS (ESI) m / z [M + H] + : calcd for C 28 H 32 ClN3O3, 494.2205, found, 494.2213.

[0202] Example 33

[0203] According to route 3, quinoline derivatives containing piperazine structures, such as I-32 (R... 1 = tert-butyl, R 2= 6-Cl, R 3 = Ph,R 4 The preparation route for (=ethyl, X = O) is as follows:

[0204]

[0205] The preparation method of quinoline derivative I-32 containing a piperazine structure includes the following steps:

[0206] S1. Dissolve the target compound I-19 in an appropriate amount of ethanol, add sodium hydroxide solution, and carry out a hydrolysis reaction by stirring at 60°C. After the reaction is complete, post-treatment yields intermediate N, which can be directly used in the next reaction.

[0207] S2. In a 10 mL pressure-resistant tube, intermediate N (93.0 mg, 0.2 mmol), ethanol (1.2 mmol), 4-dimethylaminopyridine (DMAP) (5.0 mg, 0.04 mmol), and anhydrous dichloromethane (2.0 mL) were added sequentially. The mixture was stirred in an ice bath for 10 minutes, followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (46.0 mg, 0.24 mmol) in portions. After the addition was complete, the reaction system was slowly brought to room temperature and stirred at room temperature for approximately 10 hours, during which the reaction progress was monitored using TLC. After the reaction was completed, water (10 mL) was added to the system, and the mixture was extracted with dichloromethane (3 × 5 mL). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a pale yellow solid containing a piperazine structure, quinoline derivative I-32 (yield 83.3%). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.57 (s, 1H), 7.55 – 7.45 (m, 3H), 7.38 – 7.28 (m,2H), 3.97 (q, J = 7.2 Hz, 4H), 3.54 (brs, 4H), 2.48 (brs, 4H), 1.24 (s, 9H), 0.85 (t, J = 7.1 Hz, 3H).

[0208] Example 34 Preparation of quinoline derivative I-33 containing piperazine structure

[0209] Quinoline derivatives containing piperazine structures I-33 (R 1 = tert-butyl, R 2= 6-Cl, R 3 = Ph,R 4 The chemical formulas of (= Ph, X = N) are as follows:

[0210]

[0211] The preparation method of quinoline derivative I-33 containing a piperazine structure includes the following steps: the method described in Example 32 is used, except that ethanol is replaced with aniline in step S1, and the other steps are the same as in Example 32. The quinoline derivative I-33 containing a piperazine structure is purified by column chromatography as a pale yellow solid (yield 69.4%). 1 H NMR (400 MHz, CDCl3) δ8.07 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 10.7 Hz, 1H), 7.62 (s, 1H), 7.55 – 7.40(m, 5H), 7.24 (d, J = 6.6 Hz, 4H), 7.08 (t, J = 6.1 Hz, 1H), 4.01 (s, 2H), 3.49(brs, 4H), 2.56 (brs, 4H), 1.21 (s, 9H).

[0212] Effect verification

[0213] The inhibitory effects of the quinoline derivatives containing piperazine structures synthesized in Examples 2-34 on pathogenic fungi of the tested plants.

[0214] 1. Experimental subjects: Quinoline derivatives containing piperazine structures synthesized in Examples 2-34.

[0215] 2. Experimental Methods

[0216] Using quinofumelin as a positive control and 5% DMSO aqueous solution as a blank control, the accurately weighed test compound was completely dissolved in 5% DMSO (v / v) aqueous solution. The test solution or control solution was rapidly mixed with sterile PDA medium at 50℃ to obtain a drug-containing medium with a mass concentration of 50 mg / L or 20 mg / L. The medium was poured into sterilized petri dishes while hot, 10 mL per dish, and cooled for later use. The tested plant pathogens (cup diameter = 5 mm) were inoculated into the above petri dishes, with 3 replicates for each test group. After incubation in a constant temperature incubator at 25℃ for 72 h, the colony diameter (mm) was measured using the cross-cross method, and the mycelial growth inhibition rate (IR) was calculated according to formula (1):

[0217] Equation (1): IR(%) = [(d c -d0)-(ds-d0)] / (d c -d0)×100

[0218] In formula (1): d0 is the diameter of the mushroom cake (5 mm), d c ds represents the average colony diameter (mm) of the blank control group, and ds represents the average colony diameter (mm) of the sample group.

[0219] 3. Experimental results: as shown in Table 1 and Table 2.

[0220] Table 1. Inhibitory effect of quinoline derivatives containing piperazine structure synthesized in Examples 2-18 (50 mg / L) on plant pathogenic fungi (inhibition rate, %)

[0221]

[0222] Note: The data in the table is the average of three data points; Vm b express The waltz of evil (Apple rot bacteria); Bc c express Botrytis cinerea (Gray mold); Ss d express Sclerotinia sclerotiorum (Sclerotinia sclerotiorum var. sclerotiorum); Gg e express Gaeumannomyces graminis (Wheat take-all pathogen); Mo f express Magnaporthe rice (Rice blast fungus).

[0223] Table 1 shows that the quinoline derivatives containing piperazine structures synthesized in Examples 2-18 all exhibited certain antifungal activity against five common plant pathogens at a concentration of 50 mg / L, with the best activity against *Pseudomonas aeruginosa*. When R... 1 When the tert-butyl group is used, it was found that quinoline derivatives I-5 containing piperazine structures have excellent antifungal activity and broad spectrum.

[0224] Table 2. Inhibitory effects of piperazine-containing quinoline derivatives synthesized in Examples 19-34 (20 mg / L) on plant pathogenic fungi (inhibition rate, %)

[0225]

[0226] Note: The data in the table is the average of three data points.

[0227] Table 2 shows that, using quinoline derivative I-5 containing a piperazine structure as the lead compound, the R on the quinoline ring... 2Substitution was performed, and it was found that when R... 2 When the electron-withdrawing group is used, the activity is better. In particular, the 6-position of the quinoline ring is replaced by a chlorine atom to obtain quinoline derivative I-19 containing a piperazine structure. At a concentration of 20 mg / L, its inhibition rate against five pathogens exceeds 80%, and its activity and broad spectrum are greatly improved. It is expected to be developed into a new type of bactericide.

[0228] In summary, the quinoline derivatives containing piperazine structures prepared by chemical synthesis in this invention exhibit significant antifungal activity, especially against apple rot pathogens, which lays the foundation for the preparation of bactericides with quinoline derivatives containing piperazine structures as the main antibacterial active ingredients.

[0229] The embodiments described above are some, but not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art through related deductions and substitutions based on the inventive concept, without inventive effort, are within the scope of protection of the present invention.

Claims

1. A quinoline derivative containing a piperazine structure, characterized by, The quinoline derivatives containing piperazine structures are selected from the following compounds:

2. A fungicidal composition, characterized by, The active ingredient of the bactericidal composition includes the quinoline derivative containing a piperazine structure as described in claim 1.

3. The application of the quinoline derivative containing a piperazine structure as described in claim 1 or the bactericidal composition as described in claim 2 in the prevention and control of plant diseases caused by plant pathogens, characterized in that, The plant pathogens mentioned are apple rot fungus, gray mold fungus, rapeseed sclerotinia rot fungus, wheat take-all fungus, and rice blast fungus.

4. The application according to claim 3, characterized in that, The plant diseases mentioned are rot, take-all disease, sclerotinia rot, gray mold, and rice blast.

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