Hydrazide derivative containing 3, 4-dihydroisoquinoline structure, preparation method and application

Abstract

The invention relates to the technical field of pesticides, in particular to a hydrazide derivative containing a 3, 4-dihydroisoquinoline structure, a preparation method and application. The hydrazide derivative containing the 3, 4-dihydroisoquinoline structure is a compound as shown in a formula (I), or a stereoisomer, a tautomer, an isotope derivative and a pesticide acceptable salt thereof. The hydrazide derivative containing the 3, 4-dihydroisoquinoline structure has broad-spectrum inhibitory activity on phytopathogens such as plant pathogenic fungi, especially has excellent inhibitory activity on basidiomycota and ascomycomycota pathogenic fungi such as gaeumannomyces graminis, physalospora piricola, sclerotinia sclerotiorum, botrytis cinerea and rhizoctonia solani, and has broad-spectrum inhibitory activity. The bactericide is expected to be developed into a novel green bactericide which is efficient, safe, economical and environment-friendly.

Description

Technical Field

[0001] The present application relates to the technical field of pesticides, and in particular to hydrazide derivatives containing a 3,4-dihydroisoquinoline structure, preparation methods, and applications. Background Art

[0002] Pesticides are important means of production in the food production process and play a vital role in ensuring high and stable yields of agricultural crops. According to statistics, plant pathogenic fungal infections cause a 20% reduction in global crop yields each year, and a further 10% reduction after harvest. This not only causes huge economic losses to farmers, but also seriously threatens global food production security. The use of fungicides is currently the most effective measure for controlling plant pathogenic fungi, saving a large amount of losses each year. Isoquinoline alkaloids and their derivatives are widely present in nature and have rich and excellent biological activities, such as antibacterial, insecticidal, anti-inflammatory, and anti-cancer activities. In the field of medicinal chemistry technology, isoquinoline alkaloids and their derivatives have attracted extensive research and development attention due to their antibacterial, insecticidal, anti-inflammatory, and anti-cancer biological activities. However, the application of isoquinoline compounds in the pesticide field is limited, and there is a wide range of research and development space.

[0003] Since the first hydrazide compound was reported in 1850, a large number of mono-, di-, and unsubstituted hydrazide derivatives have been commercialized. These compounds can be used as synthetic precursors or intermediates for many important organic molecules. They possess high chemical reactivity and are commonly found in the structures of various pharmaceuticals and pesticides. They play a crucial role in the development of pesticides and are a widely used class of nitrogen heteroatom compounds.

[0004] Because various fungicides are used irrationally after entering the market, fungal resistance to fungicides is becoming increasingly serious. Therefore, developing new fungicides to address the problem of fungal resistance is of great importance to the sustainable development of agriculture. Summary of the Invention

[0005] In order to solve the technical problems existing in the prior art, the present application provides a hydrazide derivative containing a 3,4-dihydroisoquinoline structure, a preparation method and an application. The 3,4-dihydroisoquinoline structure is the advantageous structure of the present invention. The present invention organically combines it with a benzene ring through a hydrazide bond to synthesize a new type of hydrazide derivative containing a 3,4-dihydroisoquinoline structure, which has a highly efficient and broad-spectrum inhibitory effect on plant pathogens, especially plant pathogenic fungi.

[0006] In the first aspect, the present application provides a hydrazide derivative containing a 3,4-dihydroisoquinoline structure, which is a compound represented by formula (I), or its stereoisomers, tautomers, isotopic derivatives and pesticide-acceptable salts.

[0007]

[0008] Each R1 is independently selected from halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino;

[0009] Each R2 independently represents an electron-withdrawing group or an electron-donating group;

[0010] R3 and R4 are each independently selected from H, halogen, amino, hydroxy, nitro, cyano, thiol, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino;

[0011] R5, R6, R7, and R8 are each independently selected from H, optionally substituted alkyl;

[0012] Wherein, "optionally substituted" means unsubstituted, or substituted by one or more selected from halogen, amino, hydroxy, nitro, cyano, and mercapto;

[0013] m is selected from 0, 1, 2, 3, 4 or 5;

[0014] n is selected from 0, 1, 2, 3 or 4.

[0015] In one group of embodiments, the alkyl group is a C1-C8 alkyl group.

[0016] In one group of embodiments, the halogen is selected from fluorine, chlorine, and bromine.

[0017] In one group of embodiments, m=1, and R2 is substituted at the 2-, 3-, or 4-position; preferably, R2 is substituted at the 4-position.

[0018] In one group of embodiments, m=2, R2 is substituted at 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position, 3, 5-position, respectively; preferably, R2 is substituted at 2, 4-position, 3, 4-position, 3, 5-position, respectively.

[0019] In one set of embodiments, the electron-withdrawing group is a halogen, a haloalkyl, a haloalkoxy, a nitro, or a cyano group; and the electron-donating group is an alkyl, an alkoxy, a hydroxyl, an amino, or a thiol group.

[0020] In one embodiment, each R2 independently represents an electron-withdrawing group. Preferably, each R2 independently represents halogen, C1-C8 haloalkyl, C1-8 haloalkoxy, nitro, or cyano; more preferably, each R2 independently represents fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, nitro, or cyano.

[0021] In one group of embodiments, m=1, and R2 is 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, 4-trifluoromethoxy, 4-nitro, or 4-cyano.

[0022] In one group of embodiments, m=2, and R2 is 2, 4-(F)2, 2, 4-(Cl)2, 2-F, 4-Cl, 3, 4-(Cl)2, 3, 5-(Cl)2.

[0023] In one set of embodiments, n=0.

[0024] In one group of embodiments, R3 and R4 are each independently selected from H.

[0025] In one group of embodiments, R5 and R6 are each independently selected from optionally substituted alkyl; preferably, R5 and R6 are each independently selected from methyl.

[0026] In one group of embodiments, R7 and R8 are each independently selected from H.

[0027] In one embodiment, the compound represented by formula (I) is a compound represented by formula I:

[0028]

[0029] In one embodiment, the compound represented by Formula I is one of the following compounds Formula I-1 to Formula I-29:

[0030]

[0031] In a second aspect, the present application provides a method for preparing the hydrazide derivatives containing a 3,4-dihydroisoquinoline structure described in the first aspect, which is prepared according to the following synthetic route:

[0032]

[0033] The groups R1-R8, m, and n are as defined in the first aspect, R9 is an alkyl group, and X is H or a metal. Preferably, R9 is a C1-8 alkyl group, and X is H, an alkali metal, or an alkaline earth metal. More preferably, R9 is a methyl group or an ethyl group, and X is H, lithium, sodium, or potassium.

[0034] Furthermore, the compound of formula (II) is reacted in a first solvent under alkaline conditions to prepare the compound of formula (III). The alkaline conditions refer to the presence of an inorganic base or an organic base, wherein the inorganic base refers to an alkali metal hydroxide or an alkaline earth metal hydroxide, preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide. The first solvent is preferably an alcohol solvent, more preferably ethanol, methanol, or isopropanol. Post-treatment, such as column chromatography, can be performed according to conventional methods.

[0035] Furthermore, the compound of formula (III) and the compound of formula (IV) are reacted in a second solvent under alkaline conditions in the presence of a condensing agent to prepare the compound of formula (I). The alkaline conditions refer to the presence of an organic base or an inorganic base, preferably DIEA, triethylamine, pyridine, or DMAP. The condensing agent is preferably TBTU, HOBt, or DCC. The second solvent is an organic solvent, preferably DMF. Post-treatment, such as column chromatography, can be performed according to conventional methods.

[0036] In one embodiment, the compound of formula (II) is prepared according to the following synthetic route:

[0037]

[0038] Furthermore, the compound of formula (V) and the compound of formula (VI) are reacted in the presence of an acid in a third solvent to prepare the compound of formula (II). Preferably, the acid is an inorganic acid, more preferably concentrated sulfuric acid. The third solvent is an organic solvent, preferably toluene or benzene. Post-processing can be performed according to conventional methods.

[0039] In a third aspect, the present application also provides a fungicide composition comprising at least one of the 3,4-dihydroisoquinoline-containing hydrazide derivatives described in the first aspect of the present application as an active ingredient; and an optional pesticide-acceptable carrier and / or adjuvant.

[0040] The fungicide composition of the present application can be applied in the form of a formulation. The hydrazide derivative containing a 3,4-dihydroisoquinoline structure, as the active ingredient, is dissolved or dispersed in a carrier or formulated into a formulation for easier dispersion when used as a fungicide composition. The fungicide composition can be formulated into various liquid formulations, such as soluble powders, dispersible liquids, emulsifiable concentrates, suspensions, aqueous suspensions, microemulsions, emulsions, aqueous emulsions, and water-dispersible granules.

[0041] One or more other insecticides, fungicides, herbicides, plant growth regulators or fertilizers may be added to the fungicidal composition of the present application.

[0042] The present application also discloses the use of the hydrazide derivatives containing a 3,4-dihydroisoquinoline structure described in the first aspect or the fungicide composition described in the third aspect for controlling plant diseases caused by plant pathogens; preferably used in agriculture, forestry, horticulture, and health fields.

[0043] In one group of embodiments, an effective amount of the hydrazide derivative containing a 3,4-dihydroisoquinoline structure as described above, or the fungicidal composition as described above is applied to plants, plant propagation materials, or subsequently grown plant organs and cultivation media, cultivation materials, or cultivation space; or an effective amount of the hydrazide derivative containing a 3,4-dihydroisoquinoline structure as described above, or the fungicidal composition as described above is used to prevent or control pathogenic fungi at the roots of wood.

[0044] Preferably, an effective amount of the hydrazide derivative containing a 3,4-dihydroisoquinoline structure or the fungicide composition described above is applied to leaves, stems, roots, seeds, or soil.

[0045] In one embodiment, the pathogen is preferably a pathogenic fungus, including but not limited to Ascomycota, Basidiomycota, Plasmodiophoromycota, Oomycota, Chytridiomycota, Zygomycota, and Deuteromycota; preferably a Basidiomycota or Ascomycota pathogen. Preferably, the plant pathogen is Gaeumannomyces graminis, Physalospora piricola, Sclerotinia sclerotiorum, Botrytis cinerea, and Rhizoctonia solani.

[0046] In one set of embodiments, the plant diseases are take-all, ring rot, sclerotinia, gray mold and sheath blight, preferably wheat take-all, apple ring rot, rapeseed sclerotinia, grape gray mold and rice sheath blight.

[0047] The hydrazide derivatives containing a 3,4-dihydroisoquinoline structure described in the first aspect of the present application or the fungicidal composition described in the third aspect can be used together with one or more other insecticides, fungicides, herbicides, plant growth regulators or fertilizers.

[0048] The beneficial effects of the present invention are:

[0049] This invention organically combines a 3,4-dihydroisoquinoline structure with a benzene ring fragment via a hydrazide bond to synthesize a novel class of hydrazide derivatives containing a 3,4-dihydroisoquinoline structure. Results show that these compounds exhibit broad-spectrum antifungal activity against plant pathogens, such as fungi, particularly against take-all pathogen of wheat, apple ring rot pathogen, sclerotinia sclerotiorum, grape gray mold, and rice sheath blight pathogen (especially rice sheath blight and take-all pathogen). Structure-activity relationship analysis indicates that substitution of electron-withdrawing groups (F, Br, Cl, CF3, OCF3, etc.) on the benzene ring of the molecular skeleton imparts more efficient and broad-spectrum antifungal activity to these compounds. These compounds possess novel structures, simple synthesis, and structures completely different from existing commercial fungicides. They are expected to be developed into novel, highly effective, safe, economical, and environmentally friendly green fungicides. DETAILED DESCRIPTION

[0050] The alkyl group in the term "alkyloxy", the alkyl group in "alkylthio", the alkyl group in "alkylamino", and "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, preferably containing 1-20, 1-18, 1-16, 1-12, 1-10 carbon atoms, preferably 1-8 carbon atoms (C1-8 alkyl) straight chain or branched chain group (the number of carbon atoms is between 1-8, specifically 1, 2, 3, 4, 5, 6, 7 or 8), more preferably containing 1-6 carbon atoms (i.e. C1-6 alkyl, the number of carbon atoms is between 1-6, specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1 dimethylpropyl, 1,2 dimethylpropyl, 2,2 dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0051] The term "alkyloxy" refers to an alkyl-O-group, "alkylthio" refers to an alkyl-S-group, and "alkylamino" refers to an alkyl-NH- or dialkyl-N-group, wherein the alkyl groups in the dialkyl-N-group may be selected from the same group or from different groups.

[0052] The term "halogen" refers to F, Cl, Br, I.

[0053] The hydrazide derivatives containing a 3,4-dihydroisoquinoline structure described herein are interpreted to include the compound of Formula I and its stereoisomers, tautomers, isotopic derivatives, or pesticide-acceptable salts. The stereoisomers, tautomers, isotopic derivatives, or pesticide-acceptable salts of the compound are obtained by conventional techniques in the art and exhibit the same or similar effects in vivo and in vitro using substantially the same mechanism of action as the compound.

[0054] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers, wherein configurational isomers further include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometric isomers may exist in the present compound. Optical isomers refer to substances with identical molecular structures and similar physical and chemical properties but different optical rotations. The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are defined as in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds with asymmetrically substituted carbon atoms (having equal numbers of R and S configurations) are racemic at those carbon atoms. Atoms having an excess of one configuration (relative to the other) result in that configuration being present in a higher number, preferably in an excess of about 85% to 90%, more preferably in an excess of about 95% to 99%, and even more preferably in an excess of greater than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0055] The term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some of the bonding electrons.

[0056] The term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically-tagged or enriched form containing one or more atoms having an atomic mass or mass number that is different from the atomic mass or mass number of the atom found in the largest amount in nature. Isotopes may 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 125I. Compounds containing other isotopes of these and / or other atoms are within the scope of the present invention. Isotopically labeled compounds of the present invention can be prepared by general methods well known to those skilled in the art.

[0057] The term "pesticide-acceptable salt" refers to a salt obtained by reacting a hydrazide derivative containing a 3,4-dihydroisoquinoline structure of the present application with a chemically acceptable acid, wherein the chemically acceptable acid may 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); the pesticide-acceptable salt may also be a salt obtained by reacting a hydrazide derivative containing a 3,4-dihydroisoquinoline structure of the present application with a chemically acceptable base, wherein the chemically acceptable base may 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.). Furthermore, the pesticide-acceptable salt may be a potassium salt, sodium salt, ammonium salt, calcium salt, pyridinium salt, choline salt, hydrochloride, phosphate, acetate, benzenesulfonate, or oxalate.

[0058] The term "pesticide-acceptable carrier" includes, but is not limited to, surfactants, including ionic surfactants and nonionic surfactants. Surfactants include emulsifiers, dispersants, or wetting agents. Examples of emulsifiers include polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty amines, and commercially available emulsifiers; dispersants include sodium lignin sulfonate, lignin powder, calcium lignin sulfonate, or methylnaphthalenesulfonic acid formaldehyde condensate; and wetting agents include sodium lauryl sulfate, sodium dodecylbenzenesulfonate, or sodium alkylnaphthalenesulfonate. Pesticide-acceptable carriers include solid carriers and / or liquid carriers. Preferably, solid carriers include natural or synthetic clays and silicates, such as natural silica and diatomaceous earth; magnesium silicates, such as talc; magnesium aluminum silicates, such as kaolinite, kaolin, montmorillonite, and mica; white carbon black, calcium carbonate, light calcium carbonate; calcium sulfate; limestone; sodium sulfate; and amine salts, such as ammonium sulfate and hexamethylenediamine. Preferably, the liquid carrier includes water and an organic solvent; when water is used as a solvent or diluent, the organic solvent can be used as an adjuvant or antifreeze additive. Preferably, the organic solvent includes aromatic hydrocarbons (such as benzene, xylene or toluene), chlorinated hydrocarbons (such as chlorobenzene, vinyl chloride, chloroform or dichloromethane), aliphatic hydrocarbons (such as petroleum fractions, cyclohexane or light mineral oil), alcohol solvents (such as isopropyl alcohol, butanol, ethylene glycol, glycerol or cyclohexanol), ether solvents, ester solvents, ketone solvents (such as acetone, cyclohexanone or N-methylpyrrolidone), or dimethylformamide.

[0059] During the preparation of the fungicide composition, the active component can be mixed with a liquid carrier and / or a solid carrier, and a surfactant (such as an emulsifier, dispersant, stabilizer, wetting agent) can be added at the same time. Other auxiliary agents (such as adhesives, defoaming agents, oxidants, etc.) can also be added.

[0060] According to the present application, the hydrazide derivatives containing a 3,4-dihydroisoquinoline structure can be used together with one or more other insecticides, fungicides, herbicides, plant growth regulators or fertilizers, and the components can be applied simultaneously, sequentially or separately.

[0061] The present invention is further illustrated below with reference to examples; however, these examples are not intended to limit the scope of the present invention. Unless otherwise stated, all reactants used in the examples were commercially available or prepared by methods known in the literature or as described in the detailed descriptions. The instruments and equipment used in the synthesis experiments and product analysis and testing were all conventional instruments and equipment commonly used in organic synthesis.

[0062] Those skilled in the art will appreciate that other synthetic routes may also be utilized to synthesize the compounds of the present invention. Although the specific raw materials and conditions in the synthetic routes have been described below, they can easily be replaced with other similar raw materials and conditions, and these modifications or variations of the preparation method of the present invention and the resulting various isomers of the compounds are within the scope of the present invention. In addition, the preparation method described below may be further modified according to the disclosure of the present invention using conventional chemical methods well known to those skilled in the art. For example, appropriate groups may be protected during the reaction, etc.

[0063] Example 1 Preparation of Compound I-1

[0064]

[0065] At room temperature, compound 1 (0.136 g, 1 mmol) and compound 2 (0.17 g, 1.7 mmol) were dissolved in toluene (10 mL) and stirred. Concentrated sulfuric acid (0.2 mL, 1.7 mmol) was slowly added dropwise under an ice bath. After 3-5 minutes, the mixture was brought to room temperature and stirred for 15 minutes. TLC (EA:PE = 1:5) was used to monitor the reaction completion. After the reaction was complete, ice water was poured into the mixture and the toluene was separated. The aqueous phase was adjusted to pH 8-9 with ammonia water and extracted with EA 2-3 times, dried, and purified to obtain a yellow oil, compound II (0.15 g, 65% yield).

[0066] 1H NMR(400MHz,Chloroform-d)δ7.53(dd,J=7.7,1.3Hz,1H),7.38(td,J=7.5,1.4Hz,1H),7.29(dd,J=7.6,1.3 Hz, 1H), 7.16 (dd, J = 7.6, 1.4Hz, 1H), 4.43 (q, J = 7.1Hz, 2H), 2.75 (s, 2H), 1.40 (t, J = 7.1Hz, 3H), 1.27 (s, 6H).

[0067]

[0068] Compound II (0.231 g, 1 mmol) and LiOH·H2O (0.063 g, 1.5 mmol) were dissolved in ethanol (5 mL) and stirred at 78°C for 30 minutes. TLC monitoring (dichloromethane:methanol = 10:1) was performed. After completion of the reaction, the mixture was cooled to room temperature and most of the ethanol was removed by rotary evaporation. The mixture was then poured into 50 mL of water, the pH was adjusted to acidic with HCl (5%), and then extracted 2-3 times with n-butanol. After extraction, the mixture was dried and the n-butanol was removed by rotary evaporation (45-55°C) (ethanol can be used for azeotroping). Purification afforded a white oil, Compound III (0.18 g, 88% yield).

[0069] 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=7.7Hz,1H),7.63(t,J=7.5Hz,1H),7.43(t,J=7.6Hz,1H),7.37(d,J=7.4Hz,1H),2.98(s,2H),1.27(s,6H).

[0070]

[0071] Under nitrogen, compound III (0.23 g, 1.0 mmol), phenylhydrazine (0.32 g, 3.0 mmol), TBTU (0.96 g, 3.0 mmol), DIEA (0.52 g, 4.0 mmol), and DMF (5 mL) were added sequentially to a 10 mL dry pressure tube. The reaction system was stirred at room temperature for 16 hours and monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 2:1) until the starting material disappeared. After completion of the reaction, the mixture was filtered through celite, the filtrate diluted with 10 mL of water, and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed sequentially with deionized water (3 × 10 mL) and saturated brine (3 × 10 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate gradient) to obtain the target compound I-1 as a purple oil (0.15 g, 51% yield).

[0072] 1 H NMR (400MHz, DMSO-d6) δ10.13(d,J=2.9Hz,1H),7.94(d,J=2.8Hz,1H),7.55(d,J=7.6Hz,1H),7.44(t,J=7.5Hz,1H),7.32(t,J=7 .6Hz,1H),7.27(d,J=7.4Hz,1H),7.18(t,J=7.9Hz,2H),6.80(d,J=7.8Hz,2H),6.74(t,J=7.3Hz,1H),2.75(s,2H),1.20(s,6H); 13 C NMR (101MHz, DMSO-d6) δ165.9,158.0,149.2,136.4,131.5,128.8(2C),128.5,126.9,126.3,124.9,118.7,112.2(2C),54.5,37.4,27.2(2C); ESI-MS calculated forC 18 H 20 N3O[M+H] + ,294.1601;found,294.1599.

[0073] Example 2 Preparation of Compound I-2

[0074] The chemical formula of compound I-2 is as follows:

[0075]

[0076] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 2-methylphenylhydrazine. The other steps were the same as in Example 1. Compound I-2 was obtained as a purple oil (0.06 g, yield 19%).

[0077] 1 H NMR (400MHz, DMSO-d6) δ10.13(d,J=2.4Hz,1H),7.60(d,J=7.6Hz,1H),7.45(t,J=7.4Hz,1H),7.34(t,J=7.5Hz,2H),7.28 (d,J=7.4Hz,1H),7.10–7.00(m,2H),6.76(d,J=7.9Hz,1H),6.69(t,J=7.3Hz,1H),2.76(s,2H),2.20(s,3H),1.20(s,6H); 13C NMR(101MHz,DMSO-d6)δ165.8,158.1,146.5,136.4,131.5,130.1,128.5,12 6.9,126.5,126.4,125.0,121.9,118.7,110.8,54.5,37.4,27.2(2C),17.4.

[0078] Example 3 Preparation of Compound I-3

[0079] The chemical formula of compound I-3 is as follows:

[0080]

[0081] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 3-methylphenylhydrazine. The other steps were the same as in Example 1. Compound I-3 was obtained as a purple oil (0.08 g, yield 25%).

[0082] 1 H NMR (400MHz, DMSO-d6) δ10.09(d,J=2.4Hz,1H),7.86(d,J=2.5Hz,1H),7.53(d,J=7.6Hz,1H),7.44(td,J=7.5,1.3Hz,1H),7. 32(t,J=7.5Hz,1H),7.27(d,J=7.4Hz,1H),7.05(t,J=7.7Hz,1H),6.63–6.54(m,3H),2.75(s,2H),2.22(s,3H),1.19(s,6H); 13 CNMR(101MHz,DMSO-d6)δ165.9,158.1,149.2,137.9,136.4,131.5,128.7,1 28.5,126.9,126.2,124.9,119.6,112.9,109.5,54.5,37.4,27.2(2C),21.4.

[0083] Example 4 Preparation of Compound I-4

[0084] The chemical formula of compound I-4 is as follows:

[0085]

[0086] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 4-methylphenylhydrazine. The other steps were the same as in Example 1. Compound I-4 was obtained as a purple oil (0.11 g, yield 36%).

[0087] 1H NMR (400MHz, DMSO-d6) δ10.09(d,J=4.8Hz,1H),7.76(d,J=4.3Hz,1H),7.52(t,J=6.4Hz,1H),7.43(d,J=6.9Hz,1H ),7.29(dd,J=13.9,6.7Hz,2H),6.99(d,J=7.7Hz,2H),6.74–6.68(m,2H),2.74(s,2H),2.19(s,3H),1.19(s,6H); 13 C NMR(101MHz,DMSO-d6)δ165.8,158.1,146.9,136.4,131.5,129.2(2C),128.5 ,127.3,126.9,126.2,124.9,112.5(2C),54.5,37.4,27.2(2C),20.2; ESI-MS calculated for C 19 H 22 N3O[M+H] + ,308.1757;found,308.1757.

[0088] Example 5 Preparation of Compound I-5

[0089] The chemical formula of compound I-5 is as follows:

[0090]

[0091] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 2-methoxyphenylhydrazine. The other steps were the same as in Example 1. Compound I-5 was obtained as a red oil (0.15 g, yield 45%).

[0092] 1 H NMR (400MHz, DMSO-d6) δ10.22(d,J=3.4Hz,1H),7.57(d,J=8.4Hz,1H),7.43(td,J=7.5,1.3Hz,1H),7.33–7.29(m,1H),7.27(dd,J=7.4,0. 9Hz,2H),7.22(d,J=3.4Hz,1H),6.91(dd,J=8.2,1.4Hz,1H),6.85–6.80(m,1H),6.79–6.69(m,2H),3.38(s,3H),2.74(s,2H),1.20(s,6H); 13C NMR(101MHz,DMSO-d6)δ165.5,158.0,146.5,137.9,136.4,131.5,128.4,12 6.8,126.5,124.9,120.8,119.1,111.3,110.4,55.4,54.5,37.4,27.2(2C).

[0093] Example 6 Preparation of Compound I-6

[0094] The chemical formula of compound I-6 is as follows:

[0095]

[0096] The method described in Example 1 was adopted, and 3-methoxyphenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-6 was obtained as a purple oil (0.09 g, yield 28%).

[0097] 1 H NMR (400MHz, DMSO-d6) δ10.12(d,J=2.9Hz,1H),7.95(d,J=2.9Hz,1H),7.53(d,J=7.6Hz,1H),7.44(td,J=7.4,1.4Hz,1H),7.33(dd,J=7.6,1.4 Hz,1H),7.30–7.25(m,1H),7.07(t,J=8.0Hz,1H),6.44–6.33(m,2H),6. 32(ddd,J=8.1,2.5,0.9Hz,1H),3.69(s,3H),2.75(s,2H),1.19(s,6H); 13 C NMR(101MHz,DMSO-d6)δ165.9,160.2,158.1,150.7,136.4,131.6,129.7,1 28.5,126.9,126.2,124.9,105.0,104.2,98.0,54.8,54.5,37.4,27.2(2C).

[0098] Example 7 Preparation of Compound I-7

[0099] The chemical formula of compound I-7 is as follows:

[0100]

[0101] The method described in Example 1 was adopted, and 4-methoxyphenylhydrazine was used instead of phenylhydrazine. The other steps were the same as in Example 1. Compound I-7 was obtained as a yellow solid (0.11 g, yield 34%), mp = 148.7-156.5°C.

[0102] 1 H NMR(400MHz,DMSO-d6)δ13.16(s,1H),7.82(s,1H),7.39–7.31(m,1H),7.34–7.22(m,2H), 7.17(dt,J=6.8,2.4Hz,3H),6.89(d,J=9.0Hz,2H),3.71(s,3H),2.96(s,2H),1.16(s,6H); 13 C NMR(101MHz,DMSO-d6)δ163.7,154.4,137.3,137.0,135.6,129.3,128.7, 128.3,127.7,126.9,114.7(2C),114.7(2C),55.3,54.8,44.5,29.6(2C).

[0103] Example 8 Preparation of Compound I-8

[0104] The chemical formula of compound I-8 is as follows:

[0105]

[0106] The method described in Example 1 was adopted, and 2-fluorophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-8 was obtained as a yellow oil (0.05 g, yield 14%).

[0107] 1 H NMR (400MHz, DMSO-d6) δ10.21(d,J=2.3Hz,1H),7.90(s,1H),7.58(d,J=7.6Hz,1H),7.44(t,J=7.2Hz,1H),7.32(t,J=7.4Hz,1H),7.27(d, J=7.4Hz,1H),7.11(dd,J=12.1,8.1Hz,1H),7.04(t,J=7.6Hz,1H),6.86(t,J=8.1Hz,1H),6.75(d,J=6.5Hz,1H),2.75(s,2H),1.20(s,6H); 13C NMR (101MHz, DMSO-d6) δ165.9,158.0,150.2(q,J=238.7Hz),136.7(q,J=10.8Hz),136.4,131.6,128.5,126.9,126.4, 124.9, 124.6 (q, J = 3.0Hz), 118.8 (q, J = 6.6Hz), 115.0 (q, J = 17.6Hz), 113.3 (d, J = 3.3Hz), 54.6, 37.4, 27.2 (2C); ESI-MS calculated for C 18 H 19 FN3O[M+H] + ,312.1507;found,312.1513.

[0108] Example 9 Preparation of Compound I-9

[0109] The chemical formula of compound I-9 is as follows:

[0110]

[0111] The method described in Example 1 was adopted, and 3-fluorophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-9 was obtained as a purple oil (0.03 g, yield 10%).

[0112] 1 H NMR(400MHz,Chloroform-d)δ9.12(s,1H),8.11(d,J=7.5Hz,1H),7.39(td,J=7.5,1.3Hz,1H),7.29(dd,J=7.7,1.3Hz,1H),7.17(d,J =1.5Hz,1H),7.15(d,J=1.8Hz,1H),6.69(dd,J=8.1,2.1Hz,1H),6.63(d,J=10.8Hz,1H),6.60–6.55(m,1H),2.75(s,2H),1.27(s,6H); 13 C NMR(101MHz,Chloroform-d)δ163.9(q,J=244.0Hz),136.9(2C),131.9,130.6,130.5,128.3(2C),127.2( 2C), 124.9, 109.3 (q, J = 2.7Hz), 107.6 (q, J = 21.5Hz), 100.8 (q, J = 25.9Hz), 55.2, 38.6, 27.2 (2C); ESI-MS calculated for C 18 H 19FN3O[M+H] + ,312.1507;found,312.1514.

[0113] Example 10 Preparation of Compound I-10

[0114] The chemical formula of compound I-10 is as follows:

[0115]

[0116] The method described in Example 1 was adopted, and 4-fluorophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-10 was obtained as a purple oil (0.05 g, yield 16%).

[0117] 1 H NMR (400MHz, DMSO-d6) δ10.19(d,J=3.2Hz,1H),7.95(d,J=3.2Hz,1H),7.53(d,J=7.6Hz,1H),7.44(td,J=7.4,1.4Hz ,1H),7.33–7.29(m,1H),7.27(d,J=7.4Hz,1H),7.03(t,J=8.9Hz,2H),6.82–6.76(m,2H),2.74(s,2H),1.19(s,6H); 13 C NMR(101MHz,DMSO-d6)δ165.9,158.0,156.0(q,J=233.4Hz),145.7,136.4,131.6,128.5,126.9,126 .3,124.9,115.3(q,J=22.4Hz,2C),113.4(q,J=7.6Hz,2C),54.5,37.4,27.2(2C); ESI-MScalculated for C 18 H 19 FN3O[M+H] + ,312.1507;found,312.1514.

[0118] Example 11 Preparation of Compound I-11

[0119] The chemical formula of compound I-11 is as follows:

[0120]

[0121] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 2-chlorophenylhydrazine. The other steps were the same as in Example 1. Compound I-11 was obtained as a purple oil (0.14 g, yield 44%).

[0122] 1 H NMR (400MHz, DMSO-d6) δ10.31(d,J=2.2Hz,1H),7.72(d,J=2.3Hz,1H),7.62(d,J=7.6Hz,1H),7.45(t,J=7.4Hz,1H),7.3 1(dt,J=15.8,7.3Hz,3H),7.20(t,J=7.9Hz,1H),6.86(d,J=7.9Hz,1H),6.78(t,J=7.5Hz,1H),2.76(s,2H),1.21(s,6H); 13 CNMR(101MHz,DMSO-d6)δ165.7,158.0,144.6,136.4,131.6,129.3,128.5,12 7.9,126.9,126.5,124.9,119.6,117.2,112.7,54.6,37.4,27.2(2C); ESI-MS calculated forC 18 H 19 ClN3O[M+H] + ,328.1211;found,328.1213.

[0123] Example 12 Preparation of Compound I-12

[0124] The chemical formula of compound I-12 is as follows:

[0125]

[0126] The method described in Example 1 was adopted, and 3-chlorophenylhydrazine was used instead of phenylhydrazine. The other steps were the same as in Example 1. Compound I-12 was obtained as a purple oil (0.15 g, yield 47%).

[0127] 1 H NMR (400MHz, DMSO-d6) δ10.23(d,J=2.5Hz,1H),8.27(d,J=2.6Hz,1H),7.53(d,J=7.6Hz,1H),7.45(t, J=7.3Hz,1H),7.34–7.27(m,2H),7.18(d,J=8.0Hz,1H),6.80–6.71(m,3H),2.76(s,2H),1.20(s,6H); 13C NMR(101MHz,DMSO-d6)δ165.9,157.9,150.8,136.4,133.6,131.6,130.6,12 8.5,126.9,126.2,124.8,118.1,111.4,110.9,54.6,37.4,27.2(2C); ESI-MS calculated for C 18 H 19 ClN3O[M+H] + ,328.1211;found,328.1222.

[0128] Example 13 Preparation of Compound I-13

[0129] The chemical formula of compound I-13 is as follows:

[0130]

[0131] The method described in Example 1 was adopted, and 4-chlorophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-13 was obtained as a purple oil (0.16 g, yield 49%).

[0132] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),8.17–8.08(m,1H),7.53(d,J=7.6Hz,1H),7.44(td,J=7.5,1.3Hz,1H),7.32 (td,J=7.6,1.2Hz,1H),7.27(d,J=7.4Hz,1H),7.25–7.18(m,2H),6.78(d,J=8.9Hz,2H),2.75(s,2H),1.19(s,6H); 13 C NMR (101MHz, DMSO-d6) δ165.8,157.8,148.1,136.4,131.5,128.6(2C),128.5,126.9,126.2,124.8,122.0,113.6(2C),54.5,37.4,27.1(2C); ESI-MS calculated for C 18 H 19 ClN3O[M+H] + ,328.1211;found,328.1213.

[0133] Example 14 Preparation of Compound I-14

[0134] The chemical formula of compound I-14 is as follows:

[0135]

[0136] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 2-bromophenylhydrazine. The other steps were the same as in Example 1. Compound I-14 was obtained as a yellow oil (0.08 g, yield 22%).

[0137] 1 H NMR (400MHz, DMSO-d6) δ10.35(d,J=2.4Hz,1H),7.62(d,J=7.5Hz,1H),7.52(d,J=2.2Hz,1H),7.46(ddd,J=15.3,7.7,1.4Hz,2H) ,7.32(t,J=7.1Hz,1H),7.29–7.24(m,2H),6.83(dd,J=8.1,1.5Hz,1H),6.72(td,J=7.6,1.5Hz,1H),2.76(s,2H),1.20(s,6H).; 13 C NMR (101MHz, DMSO-d6) δ165.7,157.9,145.5,136.3,132.5,131.6,128.4,128.4,126.8,126.5,124.9,120.3,112.9,106.9,54.6,37.4,27.2(2C).

[0138] Example 15 Preparation of Compound I-15

[0139] The chemical formula of compound I-15 is as follows:

[0140]

[0141] The method described in Example 1 was adopted, and 3-bromophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-15 was obtained as a purple oil (0.10 g, yield 27%).

[0142] 1H NMR (400MHz, DMSO-d6) δ10.24(d,J=1.5Hz,1H),8.27(d,J=2.5Hz,1H),7.52(dd ,J=7.8,1.3Hz,1H),7.45(td,J=7.5,1.3Hz,1H),7.32(td,J=7.6,1.3Hz,1H),7 .30–7.27(m,1H),7.13(t,J=8.0Hz,1H),6.93(t,J=2.0Hz,1H),6.89(ddd,J=7. 8,1.9,0.9Hz,1H),6.77(ddd,J=8.2,2.2,0.9Hz,1H),2.76(s,2H),1.20(s,6H); 13 C NMR(101MHz,DMSO-d6)δ165.9,157.9,150.9,136.4,131.6,130.9,128.5,12 6.9,126.1,124.8,122.1,121.0,114.3,111.2,54.6,37.4,27.1(2C); ESI-MS calculated for C 18 H 19 BrN3O[M+H] + ,372.0706;found,372.0712.

[0143] Example 16 Preparation of Compound I-16

[0144] The chemical formula of compound I-16 is as follows:

[0145]

[0146] The method described in Example 1 was adopted, and 4-bromophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-16 was obtained as a purple oil (0.13 g, yield 35%).

[0147] 1 H NMR (400MHz, DMSO-d6) δ10.20(d,J=2.5Hz,1H),8.15(d,J=2.4Hz,1H),7.53(d,J=7.5Hz,1H),7.44(td,J=7 .5,1.2Hz,1H),7.35–7.29(m,3H),7.27(d,J=7.3Hz,1H),6.74(d,J=8.8Hz,2H),2.75(s,2H),1.19(s,6H); 13C NMR (101MHz, DMSO-d6) δ165.8,157.8,148.5,136.4,131.6,131.5(2C),128.5,126.9,126.2,124.8,114.2(2C),109.5,54.5,37.4,27.1(2C); ESI-MS calculated for C 18 H 19 BrN3O[M+H] + ,372.0706;found,372.0707.

[0148] Example 17 Preparation of Compound I-17

[0149] The chemical formula of compound I-17 is as follows:

[0150]

[0151] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 2-trifluoromethylphenylhydrazine. The other steps were the same as in Example 1. Compound I-17 was obtained as a yellow oil (0.10 g, yield 29%).

[0152] 1 H NMR (400MHz, DMSO-d6) δ10.36(d,J=2.0Hz,1H),7.79(d,J=2.0Hz,1H),7.66(d,J=7.6Hz,1H),7.50(dd,J=10.0,7.1Hz,2H),7.46–7.4 3(m,1H),7.33(dt,J=7.7,3.8Hz,1H),7.28(d,J=7.4Hz,1H),7.01(d,J=8.3Hz,1H),6.89(t,J=7.6Hz,1H),2.76(s,2H),1.21(s,6H); 13 C NMR(101MHz,DMSO-d6)δ165.7,157.9,146.1,136.4,133.5,131.6,128.4,126.8,126.6,126.2(q, J=5.6Hz), 124.8, 124.6 (q, J=272.3Hz), 118.2, 112.7, 111.8 (q, J=30.3Hz), 54.6, 37.4, 27.1 (2C).

[0153] Example 18 Preparation of Compound I-18

[0154] The chemical formula of compound I-18 is as follows:

[0155]

[0156] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 3-trifluoromethylphenylhydrazine. The other steps were the same as in Example 1. Compound I-18 was obtained as a purple oil (0.11 g, yield 31%).

[0157] 1 H NMR (400MHz, DMSO-d6) δ10.30(d,J=2.5Hz,1H),8.42(d,J=2.5Hz,1H),7.52(dd,J=7.7,1.3Hz,1H),7.47–7.43(m,1H),7.41(d,J=8.8Hz,1H ),7.32(td,J=7.6,1.4Hz,1H),7.28(dd,J=7.6,1.2Hz,1H),6.93(d,J=2.6Hz,1H),6.76(dd,J=8.8,2.7Hz,1H),2.75(s,2H),1.20(s,6H).; 13 C NMR (101MHz, DMSO-d6) δ166.0, 157.9, 149.8, 136.4, 131.6, 130.0, 129.8 (q, J = 31.2Hz), 128.5, 126.8, 126.1, 124. 8,124.4(q,J=272.2Hz),115.8,114.8(q,J=3.7Hz),107.9(q,J=3.9Hz),54.6,37.4,27.1(2C); ESI-MScalculated for C 19 H 19 F3N3O[M+H] + ,362.1475;found,362.1477.

[0158] Example 19 Preparation of Compound I-19

[0159] The chemical formula of compound I-19 is as follows:

[0160]

[0161] The method described in Example 1 was adopted, and 4-trifluoromethylphenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-19 was obtained as a yellow solid (0.13 g, yield 37%), mp = 154.9-158.0 °C.

[0162] 1H NMR (400MHz, DMSO-d6) δ10.31(d,J=2.1Hz,1H),8.59(s,1H),7.56(dd,J=7.8,1.3Hz,1H),7.52(d,J=8.5Hz,2H),7.45(td,J =7.5,1.3Hz,1H),7.33(td,J=7.6,1.4Hz,1H),7.28(dd,J=7.5,1.2Hz,1H),6.89(d,J=8.5Hz,2H),2.76(s,2H),1.21(s,6H); 13 C NMR (101MHz, DMSO-d6) δ165.7,157.8,152.3,136.4,131.6,129.1,128.5,126.9,126.3(q,J=7.1,3.3 Hz, 2C), 125.1 (q, J = 270.3Hz), 124.9, 118.4 (q, J = 31.8Hz), 111.5 (2C), 54.6, 37.4, 27.1 (2C); ESI-MS calculated for C 19 H 19 F3N3O[M+H] + ,362.1475;found,362.1478.

[0163] Example 20 Preparation of Compound I-20

[0164] The chemical formula of compound I-20 is as follows:

[0165]

[0166] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 2-trifluoromethoxyphenylhydrazine. The other steps were the same as in Example 1. Compound I-20 was obtained as a brown solid (0.13 g, yield 34%), mp = 997.4-100.7°C.

[0167] 1 H NMR (400MHz, DMSO-d6) δ10.26(d,J=2.1Hz,1H),8.10(d,J=2.1Hz,1H),7.60(d,J=7.5Hz,1H),7.44(td,J=7.5,1. 3Hz,1H),7.40–7.15(m,6H),6.90(dd,J=8.5,1.6Hz,1H),6.80(td,J=7.7,1.6Hz,1H),2.75(s,2H),1.20(s,6H); 13C NMR(101MHz,DMSO-d6)δ165.9,157.9,141.3,136.3,134.6(q,J=1.6Hz),131.6,128.4,128 .0,126.8,126.4,124.9,121.4,120.5(q,J=256.8Hz),118.5,113.1,54.6,37.4,27.2(2C).

[0168] Example 21 Preparation of Compound I-21

[0169] The chemical formula of compound I-21 is as follows:

[0170]

[0171] The method described in Example 1 was adopted, and 3-trifluoromethoxyphenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-21 was obtained as a purple oil (0.13 g, yield 37%).

[0172] 1 H NMR (400MHz, DMSO-d6) δ10.31–10.17(m,1H),8.38(d,J=1.8Hz,1H),7.51(d,J=7.5Hz,1H),7.44(td,J=7.5,1.3Hz,1H),7. 31(dd,J=6.3,0.9Hz,1H),7.29(t,J=7.0Hz,2H),6.79(dd,J=8.2,1.4Hz,1H),6.71–6.65(m,2H),2.75(s,2H),1.20(s,6H); 13 CNMR(101MHz,DMSO-d6)δ165.9,157.9,151.1,149.5,136.4,131.6,130.6,128.6,126.9,126. 1,124.8,120.2(q,J=255.8Hz),111.0,110.3,103.9,54.6,37.4,27.1(2C); ESI-MScalculated for C 19 H 19 F3N3O2[M+H] + ,378.1424;found,378.1430.

[0173] Example 22 Preparation of Compound I-22

[0174] The chemical formula of compound I-22 is as follows:

[0175]

[0176] The method described in Example 1 was adopted, and 4-trifluoromethoxyphenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-22 was obtained as a purple oil (0.15 g, yield 40%).

[0177] 1 H NMR (400MHz, DMSO-d6) δ10.23(d,J=2.7Hz,1H),8.21(d,J=2.4Hz,1H),7.55(d,J=7.5Hz,1H),7.44(td,J=7.5,1.2Hz,1H ),7.32(t,J=7.1Hz,1H),7.27(d,J=7.4Hz,1H),7.19(d,J=8.6Hz,2H),6.83(d,J=9.0Hz,2H),2.75(s,2H),1.20(s,6H); 13 C NMR (101MHz, DMSO-d6) δ165.8, 157.9, 148.4, 140.5 (q, J = 1.8Hz), 136.4, 131.6, 128.5, 126.9, 126 .3,124.8,122.1(2C),120.4(q,J=254.5Hz),112.8(2C),54.6,37.4,27.1(2C); ESI-MScalculated for C 19 H 19 F3N3O2[M+H] + ,378.1424;found,378.1432.

[0178] Example 23 Preparation of Compound I-23

[0179] The chemical formula of compound I-23 is as follows:

[0180]

[0181] The method described in Example 1 was adopted, and 4-nitrophenylhydrazine was used instead of phenylhydrazine. The other steps were the same as in Example 1. Compound I-23 was obtained as a purple oil (0.09 g, yield 27%).

[0182] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),9.26(s,1H),8.17–8.08(m,2H),7.57(d,J=7.5Hz,1H),7.46(td,J=7.4 ,1.3Hz,1H),7.34(td,J=7.6,1.3Hz,1H),7.29(d,J=7.4Hz,1H),6.91–6.74(m,2H),2.76(s,2H),1.21(s,6H); 13 C NMR (101MHz, DMSO-d6) δ165.6,157.6,154.8,138.2,136.5,131.7,128.5,127.0,126.4,126.1(2C),124.7,110.7(2C),54.7,37.4,27.1(2C); ESI-MS calculated for C 18 H 19 N4O3[M+H] + ,339.1452;found,339.1461.

[0183] Example 24 Preparation of Compound I-24

[0184] The chemical formula of compound I-24 is as follows:

[0185]

[0186] The method described in Example 1 was adopted, and 4-cyanophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-24 was obtained as a purple solid (0.09 g, yield 28%), mp = 85.1-88.8 °C.

[0187] 1 H NMR (400MHz, DMSO-d6) δ10.36(d,J=1.8Hz,1H),8.82(d,J=1.8Hz,1H),7.60(d,J=8.5Hz,2H),7.56(d,J=7.7Hz,1H),7.4 5(td,J=7.4,1.4Hz,1H),7.33(t,J=7.7Hz,1H),7.28(d,J=7.4Hz,1H),6.83(d,J=8.5Hz,2H),2.76(s,2H),1.20(s,6H); 13C NMR(101MHz,DMSO-d6)δ165.6,157.6,152.7,136.4,133.5(2C),131.6,128.5 ,126.9,126.3,124.7,120.1,111.7(2C),99.1,54.6,37.4,27.1(2C); ESI-MS calculated for C 19 H 19 N4O[M+H] + ,319.1553;found,319.1556.

[0188] Example 25 Preparation of Compound I-25

[0189] The chemical formula of compound I-25 is as follows:

[0190]

[0191] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 2,4-difluorophenylhydrazine. The other steps were the same as in Example 1. Compound I-25 was obtained as a purple oil (0.10 g, yield 30%).

[0192] 1 H NMR (400MHz, DMSO-d6) δ10.22(d,J=2.5Hz,1H),7.85(s,1H),7.57(d,J=7.1Hz,1H),7.44(td,J=7.4,1.4Hz,1H),7.32(td,J=7.6,1.3Hz,1H),7.27( dd,J=7.5,1.2Hz,1H),7.18(dd,J=11.7,8.9,2.8Hz,1H),6.96(tdd,J=8. 6,2.8,1.3Hz,1H),6.84(td,J=9.4,5.7Hz,1H),2.75(s,2H),1.19(s,6H); 13 C NMR (101MHz, DMSO-d6) δ165.8, 157.9, 152.2 (q, J = 290.7Hz), 152.1 (q, J = 292.0Hz), 136.3, 133.5 (dd, J = 11.0, 2.7Hz), 131.5, 128. 4,126.8,126.3,124.8,113.8(q,J=4.6Hz),111.0(dd,J=21.4,2.4Hz),103.8(dd,J=26.9,22.4Hz),54.5,37.4,27.1(2C); ESI-MS calculated for C 18 H 18F2N3O[M+H] + ,330.1412;found,330.1418.

[0193] Example 26 Preparation of Compound I-26

[0194] The chemical formula of compound I-26 is as follows:

[0195]

[0196] The method described in Example 1 was adopted, and 2-fluoro-4-chlorophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-26 was obtained as a purple solid (0.09 g, yield 26%), mp = 121.9-124.5 °C.

[0197] 1 H NMR (400MHz, DMSO-d6) δ10.25(d,J=2.2Hz,1H),8.09(s,1H),7.57(d,J=7.5Hz,1H),7.44(td,J=7.5,1.3Hz,1H),7 .34–7.29(m,2H),7.27(dd,J=7.4,1.2Hz,1H),7.15–7.12(m,1H),6.82(t,J=9.0Hz,1H),2.75(s,2H),1.19(s,6H); 13 C NMR (101MHz, DMSO-d6) δ165.8,157.8,149.7(q,J=243.3Hz),136.4,136.0(q,J=10.8Hz),131.6,128.5,126.9,126.4, 124.8, 124.7 (q, J = 3.4Hz), 121.4 (q, J = 9.2Hz), 115.6 (q, J = 21.6Hz), 114.2 (q, J = 4.2Hz), 54.6, 37.4, 27.1 (2C); ESI-MS calculated for C 18 H 18 ClFN3O[M+H] + ,346.1117;found,346.1122.

[0198] Example 27 Preparation of Compound I-27

[0199] The chemical formula of compound I-27 is as follows:

[0200]

[0201] The method described in Example 1 was adopted, and phenylhydrazine was replaced by 2,4-dichlorophenylhydrazine. The other steps were the same as in Example 1. Compound I-27 was obtained as a brown oil (0.09 g, yield 25%).

[0202] 1 H NMR (400MHz, DMSO-d6) δ10.34(d,J=2.1Hz,1H),7.92(d,J=1.4Hz,1H),7.61(d,J=7.4Hz,1 H),7.48–7.42(m,2H),7.35–7.26(m,3H),6.82(d,J=8.8Hz,1H),2.76(s,2H),1.20(s,6H); 13 C NMR(101MHz,DMSO-d6)δ165.7,157.8,143.8,136.3,131.6,128.5,128.4,127.9,1 26.8,126.5,124.8,122.0,117.6,113.6,54.6,37.4,27.1(2C); ESI-MScalculated for C 18 H 18 Cl2N3O[M+H] + ,362.0821;found,362.0823.

[0203] Example 28 Preparation of Compound I-28

[0204] The chemical formula of compound I-28 is as follows:

[0205]

[0206] The method described in Example 1 was adopted, and 3,4-dichlorophenylhydrazine was used instead of phenylhydrazine. The other steps were the same as in Example 1. Compound I-28 was obtained as a brown oil (0.09 g, yield 25%).

[0207] 1 H NMR (400MHz, DMSO-d6) δ10.34(d,J=2.1Hz,1H),7.92(d,J=1.4Hz,1H),7.61(d,J=7.4Hz,1 H),7.48–7.42(m,2H),7.35–7.26(m,3H),6.82(d,J=8.8Hz,1H),2.76(s,2H),1.20(s,6H); 13C NMR(101MHz,DMSO-d6)δ165.7,157.8,143.8,136.3,131.6,128.5,128.4,127.9,1 26.8,126.5,124.8,122.0,117.6,113.6,54.6,37.4,27.1(2C); ESI-MScalculated for C 18 H 18 Cl2N3O[M+H] + ,362.0821;found,362.0826.

[0208] Example 29 Preparation of Compound I-29

[0209] The chemical formula of compound I-29 is as follows:

[0210]

[0211] The method described in Example 1 was adopted, and 3,5-dichlorophenylhydrazine was used to replace phenylhydrazine. The other steps were the same as in Example 1. Compound I-29 was obtained as a red oil (0.07 g, yield 19%).

[0212] 1 H NMR (400MHz, DMSO-d6) δ10.31(d,J=1.7Hz,1H),8.55(d,J=1.7Hz,1H),7.52(d,J=7.5Hz,1H),7.45(td,J=7.5,1.3Hz, 1H),7.35–7.31(m,1H),7.28(t,J=7.4Hz,1H),6.87(t,J=1.8Hz,1H),6.74(d,J=1.8Hz,2H),2.76(s,2H),1.20(s,6H); 13 C NMR (101MHz, DMSO-d6) δ165.8,157.7,151.6,136.4,134.5(2C),131.7,128.6,126.9,126.1,124.7,117.4,110.3(2C),54.6,37.4,27.1(2C).

[0213] Example 30 Testing the Inhibitory Effects of 3,4-Dihydroisoquinoline Hydrazide Derivatives I-1 to I-29 on Test Plant Pathogenic Fungi

[0214] 1. Experimental subjects

[0215] The hydrazide derivatives containing a 3,4-dihydroisoquinoline structure synthesized in Examples 1-29 are compounds I-1 to I-29.

[0216] 2. Experimental methods

[0217] Compounds I-1 to I-29 were tested for their in vitro inhibitory activity against five plant pathogens, including Gaeumannomyces graminis (wheat take-all pathogen), Physalospora piricola (apple ring rot pathogen), Sclerotinia sclerotiorum (oilseed rape), Botrytis cinerea (grape gray mold pathogen), and Rhizoctonia solani (rice sheath blight pathogen), using a mycelial linear growth rate assay. The fungi were provided by the College of Plant Protection, Northwest Agriculture and Forestry University.

[0218] With 20 mg / L quinofumelin as the positive control and 5% DMSO aqueous solution as the blank control, the accurately weighed test compound was completely dissolved in 5% DMSO (v / v) aqueous solution. The test solution or control solution was quickly mixed with 150 mL of sterile PDA medium at 50°C to obtain a drug-containing medium with a mass concentration of 20 mg / L; the medium was poured into sterilized culture dishes while hot, 10 mL per dish, and cooled for later use. The test plant pathogen (bacteria cake diameter = 5 mm) was inoculated into the above-mentioned culture dishes, with 3 parallels for each test group; after being placed in a constant temperature incubator at 25°C for 72 hours, the colony diameter (mm) was measured using the cross-cross method, and the mycelial growth inhibition rate (IR) was calculated according to formula (1): IR (%) = [(d c -d0)-(ds-d0)] / (d c -d0)×100(1);

[0219] Where: d0 is the diameter of the mushroom cake (5mm), d c is the average diameter of the colonies in the blank control group (mm), and ds is the average diameter of the colonies in the sample group (mm).

[0220] 3. Experimental results

[0221] Table 1 below shows the inhibitory effects (inhibition rate, %) of the hydrazide derivatives containing 3,4-dihydroisoquinoline structure, Formulas I-1 to I-29, synthesized in Examples 1-29, on plant pathogenic fungi at a concentration of 20 mg / L.

[0222]

[0223]

[0224] The data in table a are the average of three measurements; Gg: Gaeumannomyces graminis, Pp: Physalospora piricola, Ss: Sclerotinia sclerotiorum, Bc: Botrytis cinerea, Rs: Rhizoctonia solani.

[0225] A preliminary screening of 29 3,4-dihydroisoquinoline hydrazide derivatives at a concentration of 20 mg / L revealed that, as shown in Table 1, more than half of compounds I-1 to I-29 exhibited inhibition rates exceeding 60% against Pseudomonas aeruginosa, Rhizoctonia solani, and Botrytis cinerea. Compounds I-10, I-11, I-12, I-13, I-19, I-22, I-25, and I-26 exhibited significantly better activity against Pseudomonas aeruginosa than other fungi, with compounds I-10, I-11, I-12, I-13, I-19, I-22, I-25, and I-26 achieving 100% inhibition against Pseudomonas aeruginosa. When R is an electron-withdrawing group, compounds I-10, I-13, I-16, and I-19 all exhibited inhibition rates of 70% against Pseudomonas aeruginosa, Rhizoctonia solani, and Botrytis cinerea. Compounds I-16, I-19, and I-22 all achieved inhibition rates exceeding 90% against Pseudomonas aeruginosa and Rhizoctonia solani. Compound I-22 exhibited the best activity against wheat take-all pathogen, apple ring rot pathogen, rapeseed sclerotinia, grape gray mold pathogen, and rice sheath blight pathogen, with inhibition rates exceeding 80%. Its broad-spectrum activity surpassed that of other compounds. This suggests that the compounds prepared in this application have the potential to become broad-spectrum antifungal agents.

[0226] After analyzing the structures of the highly active compounds, it was found that when R is an electron-withdrawing group, the activity of compounds I-8 to I-22 series was significantly superior to that of compounds I-1 to I-7. Therefore, the applicants further analyzed the activity of compounds with multiple electron-withdrawing groups substituted at different positions on the terminal benzene. When R is an electron-withdrawing group substituted at position 4, compounds I-10, I-13, I-16, and I-19 showed significantly better antifungal activity against wheat take-all pathogen, apple ring rot pathogen, grape gray mold pathogen, and rice sheath blight pathogen than compounds with substitutions at other positions.

[0227] In summary, the present invention shows that a class of hydrazide derivatives containing a 3,4-dihydroisoquinoline structure prepared by chemical synthesis has antifungal activity, especially showing significant antifungal activity against wheat take-all pathogen and rice sheath blight pathogen. This lays the foundation for the preparation of fungicides containing hydrazide derivatives containing a 3,4-dihydroisoquinoline structure as the main antifungal active ingredient.

[0228] In addition, any combination of the various embodiments of the present invention may be performed, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention. The above-mentioned embodiment only expresses one embodiment of the present application, and its description is relatively specific and detailed, but it should not be understood as limiting the scope of the patent application. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present application, several variations and improvements can be made, and these all fall within the scope of protection of the present application.

Claims

1. A hydrazide derivative containing a 3,4-dihydroisoquinoline structure, characterized in that: It is a compound represented by formula (I), or its stereoisomers, tautomers, isotopic derivatives and pesticide-acceptable salts; Each R1 is independently selected from halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino; Each R2 independently represents an electron-withdrawing group or an electron-donating group; R3 and R4 are each independently selected from H, halogen, amino, hydroxy, nitro, cyano, thiol, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino; R5, R6, R7, and R8 are each independently selected from H, optionally substituted alkyl; Wherein, "optionally substituted" means unsubstituted, or substituted by one or more selected from halogen, amino, hydroxy, nitro, cyano, and mercapto; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3 or 4.

2. The hydrazide derivative according to claim 1, characterized in that The alkyl group is a C1-C8 alkyl group, and the halogen group is selected from fluorine, chlorine, and bromine.

3. The hydrazide derivative according to any one of claims 1-2, characterized in that m=1, R2 is substituted at the 4-position; or m=2, R2 is substituted at the 2-, 4-position, 3-, 4-position, 3-, 5-position, respectively.

4. The hydrazide derivative according to any one of claims 1 to 3, characterized in that The electron-withdrawing group is halogen, haloalkyl, haloalkoxy, nitro, or cyano; the electron-donating group is alkyl, alkoxy, hydroxyl, amino, or thiol; Preferably, each R2 independently represents halogen, C1-C8 haloalkyl, C1-8 haloalkoxy, nitro, cyano; More preferably, each R2 independently represents fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy.

5. The hydrazide derivative according to claim 4, characterized in that m=1, R2 is 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, 4-trifluoromethoxy, 4-nitro, or 4-cyano; Or m=2, R2 is 2,4-(F)2, 2,4-(Cl)2, 2-F,4-Cl, 3,4-(Cl)2, 3,5-(Cl)2.

6. The hydrazide derivative according to any one of claims 1 to 5, characterized in that R5 and R6 are each independently selected from methyl.

7. The hydrazide derivative according to claim 6, characterized in that The compound represented by formula (I) is a compound represented by formula I: Preferably, the compound represented by formula I is one of the following compounds of formula I-1 to formula I-29:

8. The method for preparing a hydrazide derivative according to any one of claims 1 to 7, wherein: Prepared according to the following synthetic route: The groups of R1-R8, m, and n are defined as described in claims 1-7, R9 is an alkyl group, and X is H or a metal; preferably, R9 is a C1-8 alkyl group, and X is H, an alkali metal, or an alkaline earth metal; more preferably, R9 is a methyl group or an ethyl group, and X is H, lithium, sodium, or potassium.

9. The preparation method according to claim 8, characterized in that The compound of formula (II) was prepared according to the following synthetic route:

10. A bactericidal composition, characterized in that Contains at least one of the 3,4-dihydroisoquinoline structure-containing hydrazide derivatives according to any one of claims 1 to 7 as an active ingredient, and optionally an agriculturally acceptable carrier and / or adjuvant.

11. Use of the hydrazide derivative containing a 3,4-dihydroisoquinoline structure according to any one of claims 1 to 7 or the bactericidal composition according to claim 10, characterized in that: Used to control plant diseases caused by plant pathogens.

12. The use according to claim 11, characterized in that The plant pathogen is a plant pathogenic fungus. Preferably, the plant pathogenic fungus is selected from the phylum Plasmodium, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycetes; more preferably, the plant pathogenic fungus is selected from the phylum Gram-negative, Apple ring rot, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani.

13. The use according to any one of claims 11-12, characterized in that: The plant diseases are take-all disease, ring rot, sclerotinia rot, gray mold and sheath blight, preferably wheat take-all disease, apple ring rot, rapeseed sclerotinia rot, grape gray mold and rice sheath blight.

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