WO2014036952A1

WO2014036952A1 - Pyridazinone compound and its use

Info

Publication number: WO2014036952A1
Application number: PCT/CN2013/082984
Authority: WO
Inventors: 徐玉芳; 赵振江; 李宝聚; 钱旭红; 朱维平; 石延霞; 韩景龙; 李洪林; 曹贤文; 常康
Original assignee: 华东理工大学
Priority date: 2012-09-06
Filing date: 2013-09-05
Publication date: 2014-03-13
Also published as: CN103664795A; CN103664795B

Abstract

The present invention provides a pyridazinone compound of formula (I) and its use as a plant induced-resistance activator. In the formula, R₁-R₅ are independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, nitro, amino, CN, NCO, NCS, carboxyl, C1-C3 alkoxy formacyl, and C1-C3 amido; X is selected from oxygen, sulfur and nitrogen; R₆ is H, optionally substituted C1-C3 alkyl, optionally substituted phenyl, and 5-10 member heteroaryl; and R₇ is H, optionally substituted C1-C3 alkyl and optionally substituted phenyl.

Description

Pyridazinone compounds and uses thereof

The present invention relates to a pyridazinone compound and use thereof. Background technique

Pesticides are mainly used to prevent various diseases (pests, mites, nematodes, pathogens, weeds and rodents) and to regulate plant growth in the production of agriculture, forestry and animal husbandry. Before the 1980s, pesticides were mainly used for "killing" of harmful substances, but since the 1980s, the concept of pesticides has changed a lot. Today, we don't pay attention to "killing", but we are more focused on regulation. Therefore, the purpose of modern pesticides is to effectively control pests, non-target organisms and environmental safety. China is a big agricultural country. Since the liberation, China's pesticide industry has flourished, and the variety and output of pesticides have doubled. China's pesticide production has been able to meet the needs of agriculture, and there are a certain number of exports, but the varieties are still insufficient. China uses 65 to 700,000 tons of pesticides per year, and the amount of active ingredients is 22 to 250,000 tons. There are very few harmful organisms that can be prevented. About 90% of the pesticides are lost in the farmland, especially the highly toxic pesticides pollute the environment.

Pesticides have a long history of development in the world for about 150 years. In the 1970s and 1980s, the scientific research, development and production of chemical pesticides were unprecedentedly active, and new types of pesticides with high efficiency, low toxicity and novel mechanism of action, such as pyrethroids, pyridinium Azole, pyridine, nicotine, pyrrole, benzoylurea insecticide; carbamate, β-methoxy acrylate, benzimidazole, triazole fungicide; imidazolinone Classes, sulfonylurea herbicides, etc. emerge in an endless stream, prompting chemical pesticides to enter the fast-growing fast lane. However, the negative impacts of large-scale use of traditional pesticides on the environment and the resistance of pathogenic microorganisms and pests have greatly impaired their application ability. If pesticides are used less, pests cannot be effectively prevented, which often leads to agricultural production reduction and direct impact. To the development of the national economy, pesticides in the 21st century are gradually developing into new concepts of bioregulation.

Since 1933, Chester Κ. has published the first article on "Physiological immunity of plants", which has been reviewed by some authors. Among them, tobacco systems have the most research on disease resistance, different scholars Systematic studies on antiviral, antifungal and antibacterial properties, such as tobacco anti-tobacco mosaic virus

(TMV), Cercospora nicotianae, Phytophthora parasitica, Peronospora tabacina, Pseudomonas syrtngae pv.tabaci, and disease-related proteins And the system obtains the disease resistance gene encoding protein. In the early 1960s, Ross studied tobacco mosaic virus to propose a systemic acguired resistance (SA), which is when necrotic pathogens or screened induced bacteria infect or some chemical agents are induced. Some plants can develop resistance to infection by subsequent pathogens. These biological and chemical agents that induce the production of SAR in plants are called plant disease-inducing inducers or activators.

A plant disease activator (elicitor or plant activiator) refers to a substance that has no direct bactericidal activity to the compound itself and its metabolites, but which stimulates the immune system of the plant and the plant produces a system that acquires disease resistance. This resistance has four characteristics, namely: systemic, SAR is expressed in the non-inducing factor treatment site of the plant; persistence, which can last for weeks or even months after SAR production; broad-spectrum, SAR simultaneously for several fungi, bacteria Inhibition of diseases caused by pathogens; Safety, these inducers do not produce a toxic effect on the pathogens, but induce the plant to produce resistance, so there is no side effect on the environment. Therefore, the research and development of such fungicides has broad application prospects.

Pyridazines are a class of heterocyclic compounds with high activity such as herbicidal, insecticidal and acaricidal, and plant growth regulation. Many varieties also have low toxicity and low residue. At present, pyridazine derivatives have become an important class of aromatic heterocyclic compounds, and pyridazinone compounds are an important class of pyridazine derivatives. In 1949, Schoene and Hoffmann first reported that 4-hydroxypyridazinone has a strong inhibitory effect on plant cell division and is used as a plant growth regulator in agricultural production. Pyridazinone pesticides have high activity and environmental friendliness. They play an important role in the integrated pest control and reduce the environmental pollution of pesticides. They are one of the hotspots in research at home and abroad in recent years. They have good biological activity and have become one. Heterocyclic compounds with great development potential and research value. Currently, there are many commercial pyridazinone pesticides, including plant growth regulators, herbicides, fungicides, insecticides, insect growth regulators, and the like.

The research on the resistance of plant systems has started late in China. The research on the mechanism of plant-induced disease resistance mainly focuses on the transmission mechanism of disease resistance signals, physiological and biochemical mechanisms and the cloning and application of related disease resistance genes, while new plants The development of disease resistance activators is relatively slow. Only a few plant disease activators have been successfully developed so far, among which NCI, BTH, TDL and other commercially successful plant disease resistance activators can induce plants to produce broad-spectrum resistance to bacteria, fungi and viruses ( Michiko Yasuda., J. Pestic. Sci. 2004, 29: 46-49).

In view of this, the development and creation of plant disease resistance activators is attracting widespread attention. Summary of the invention

The present inventors have designed and synthesized a series of pyridazinone compounds, namely compounds of formula I, using computer drug design, medicinal chemistry and molecular biology methods and techniques, and these compounds inhibit agricultural and horticultural and forest pathogenic fungi. The biological activity and the activity of inducing plant disease resistance and its assay methods, and the application of these compounds in the agricultural and horticultural fields as well as the forestry field.

The compound of the pyridazinone compound I of the present invention:

In the formula I, each is independently selected from the group consisting of: hydrogen, C1-C6 fluorenyl, C1-C6 decyloxy, halogen, halogenated C1-C6 fluorenyl, halogenated C1-C6 decyloxy, nitro, amino, CN , NCO, NCS, carboxy, C1-C3 decyloxycarbonyl, C1-C3 amide; X is selected from the group consisting of oxygen, sulfur and nitrogen; ₁₆ is 11, optionally substituted C1-C3 fluorenyl and optionally substituted Phenyl substituted, 5-10 membered heteroaryl; R ₇ is optionally H, substituted C1-C3 fluorenyl and optionally substituted phenyl.

In a particular embodiment, and ₁₅ are each independently H, halo, halo C1-C6 fluorenyl, and halo C1-C6 decyloxy.

In a particular embodiment, R ₃ and R ₄ are each independently H, halo, halo C1-C6 fluorenyl, and halo C1-C6 decyloxy.

In a particular embodiment, it is selected from the group consisting of H, halogen, C1-C6 decyloxy, halo C1-C6 fluorenyl, nitro, halogenated C1-C6 decyloxy, and C1-C6 fluorenyl.

In a specific embodiment, ₁₆ is 11.

In a particular embodiment, R ₇ is H or a C1-C6 fluorenyl group.

In a specific embodiment, X is zero. In a specific embodiment, R ₂ , R ₄ , R ₅ and R ₆ are H, and R _{3 is} selected from the group consisting of H, halogen, C1-C6 decyloxy, halo C1-C6 fluorenyl, nitro, halo Generation C1-C6 decyloxy and C1-C6 fluorenyl, X is 0.

In a particular embodiment, R ₃ , R ₅ and R ₆ are H, and R ₂ and R _{4 are} selected from the group consisting of H, halogen and C1-C6-decyloxy, and X is 0.

In a particular embodiment, the structure of the compound of Formula I is as shown in Formula II:

In the formula, RrR _{5 is} independently selected from the group consisting of hydrogen, C 1-C6 decyloxy, halogen, nitro and halogenated C1-C6 decyloxy.

In a specific embodiment, the structure of the compound of Formula I is as shown in Formula II.

III

The invention further relates to the use of a compound of formula I as a plant disease resistance activator.

In a specific embodiment, the present invention relates to a compound of formula I and an agriculturally acceptable carrier or adjuvant for the preparation of a plant disease resistance activator, an anti-plant virus agent, an insecticide, a fungicide, a plant growth regulator and a weed control Use in the agent.

In a particular embodiment, the compounds of formula I of the invention inhibit pathogenic fungi and induce plant disease resistance. Plants which can be controlled by the compounds of formula I of the present invention include various agricultural plants, horticultural plants, and forestry plants including, but not limited to, cucumber, tomato, rice, and the like.

In a specific embodiment, the plant diseases which can be controlled by the compound of the general formula I of the present invention include, but are not limited to, cucumber blight, cucumber brown spot, cucumber bacterial leaf spot, tomato late blight, rice stalk Disease, cucumber gray mold and cucumber wilt disease.

In a specific embodiment, the plant diseases which can be controlled by the compound of the general formula I of the present invention are tomato late blight, cucumber brown spot, cucumber blight, and rice sheath blight.

In a specific embodiment, the compound of the formula I of the present invention can be used to control the bacterium

, Corynespora cassiicola, Pseudomonas syringae Cucumber horn 3⁄4E disease to the pathogenic type I Pseudomonas syringae pv. Lachrymans ), Phytophthora infestans (Mont.) De Bary, Thanatephorus cucumeris (Frank) Donk.), Botrytis cinerea (Sotrj^s ciMeretz Pers.ex Fr.) and Fusarium oxysporum (Schl.) F.sp cucumerinum Owen) Plant Diseases The present invention also relates to the preparation of compounds of formula I. Specifically, the preparation method of the present invention comprises: using a substituted aniline (a compound of the formula A) as a starting material, adding hydrochloric acid and sodium nitrite to form a diazonium salt, and then adding the formed diazonium salt to 1,3 - An aqueous solution of dimethyl ketone dicarboxylate and sodium acetate in an aqueous solution of ethanol at room temperature (for example, 20 min) to obtain an intermediate benzoquinone (compound represented by formula B). Intermediate B is heated under reflux in o-dichlorobenzene (for example, about 2 h) to obtain compound II; intermediate B is dissolved in aqueous sodium hydroxide solution (for example, 2 M aqueous sodium hydroxide solution), and concentrated hydrochloric acid is added dropwise to precipitate a solid. Compound III was obtained.

Wherein -R ^{5 is} as described above. detailed description

In the present application, "mercapto" includes both branched and straight chain fluorenyl groups, usually having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms. Examples of mercapto groups include, but are not limited to, methyl, ethyl, propyl, butyl, t-butyl, isobutyl and the like.

"Alkoxy" means a "mercapto-O-" group, wherein the fluorenyl group may be a C1-C6 straight or branched fluorenyl group, preferably a C1-C4 straight or branched fluorenyl group.

In the present invention, the fluorenyl group in the fluorenyl group or the fluorenyloxy group may be optionally substituted with a halogen, a hydroxyl group or the like. Examples of halodecyl or halodecyloxy include, but are not limited to, one or several? , (: 1 and / or Br-substituted C1 -C6 or C1-C6 alkyl with embankment group, specific examples such as trifluoromethyl, -O-CF ₃ and the like.

"Aryl" means a monocyclic, bicyclic or tricyclic aromatic radical containing from 6 to 14 carbon atoms and includes phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, tetrahydronaphthyl, Hydrogenated fluorenyl and the like.

The aryl group may be optionally substituted with from 1 to 5 (for example, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, _-4- aldehyde group, _-6 straight chain or branched fluorenyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a halogen-substituted fluorenyl group (for example, a trifluoromethyl group), a halogen-substituted decyloxy group (for example, a trifluoromethoxy group), a carboxyl group, a C ₄ decyloxy group, Ethoxycarbonyl, N(CH ₃ ) and C ₄ acyl groups.

For example, an aryl group may be substituted with from 1 to 5 groups selected from the group consisting of: halogen, -OH, d_4 methoxy, C ₄ fluorenyl, -NO ₂ , -NH ₂ , -N(CH ₃ ) ₂ , Carboxyl group, and ethoxylated group.

As used herein, "heteroaryl" means that the ring contains 5-10 atoms and 6, 10 or 14 electrons are shared on the ring system. Further, the ring atom contained is a carbon atom and optionally 1 - 3 hetero atoms from oxygen, nitrogen and sulfur.

Useful heteroaryl groups include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyridyl Azinyl, pyrimidinyl and the like.

The heteroaryl group may be optionally substituted by one to five (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of: halogen, d- ₄ aldehyde group, d- ₆ straight or branched fluorenyl group , cyano, nitro, amino, hydroxy, hydroxymethyl, halogen-substituted fluorenyl (eg trifluoromethyl), halogen-substituted oxirane (eg trifluoromethoxy), carboxyl, CM methoxy, Ethoxycarbonyl, N(CH ₃ ) and CM acyl groups. Optionally, in addition to the fluorine-containing substituent, the aryl group may further contain other substituents as described above, such as Cl, Br, -OH, d_ ₄ decyloxy, d_ ₄ fluorenyl Chain, -NO ₂ , -NH ₂ , -N(CH ₃ ) ₂ , carboxyl group, and ethoxylated group.

The invention also includes a pesticidal composition comprising a compound of the invention.

In a specific embodiment, the pesticidal composition of the present invention further comprises a pesticidally acceptable carrier. And a carrier acceptable for pesticides.

The composition may contain 0.01% to 95% by weight of the compound of the formula I or hydrazine of the present invention as an active ingredient.

The agrochemically acceptable carrier includes a variety of solid carriers, liquid carriers, gas carriers, and the like, which are known in the art. The solid carrier can be, for example, fine powder or granules of clay materials such as kaolin, diatomaceous earth, synthetic hydrated silica, bentonite, Fubasami clay and acid clay; various types of talc, ceramics and other inorganic materials such as sericite, quartz, sulfur Fine powder or granules of activated carbon, calcium carbonate and hydrated silica; and fine powder or granules of chemical fertilizers such as ammonium sulphate, ammonium phosphate, ammonium nitrate, urea and ammonium chloride.

The liquid carrier may include, for example, water; alcohols such as methanol and ethanol; ketones such as acetone and methyl ethyl ketone; hydrocarbons such as hexamethylene, cyclohexanthene, kerosene and light oil; esters such as ethyl acetate and butyl acetate Esters; nitriles such as acetonitrile and isobutyronitrile; ethers such as diisopropyl ether and dioxins; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons Such as methylene chloride, trichloroacetic acid and carbon tetrachloride; dimethyl sulfoxide; and vegetable oils such as soybean oil and cottonseed oil.

The gas carrier or propellant may include, for example, Freon gas, Tween gas, LPG (liquefied petroleum gas), dimethyl ether, and carbon dioxide.

The pesticide composition of the present invention may further contain a surfactant such as a mercaptosulfate, a mercaptosulfonate, a mercaptoarylsulfonate, a mercaptoaryl ether, and a polyepoxyquinone derivative thereof, Polyglycol ethers, polyol esters and sugar alcohol derivatives.

The pesticidal composition of the present invention may further contain an adjuvant such as a fixing agent or a dispersing agent, for example, casein, gelatin, polysaccharides (such as starch, gum arabic, cellulose derivatives, and alginic acid), lignin derivatives, bentonite, and sugar. And synthetic water-soluble polymers such as polyvinyl alcohol, polyvinylpyrrolidone and polyacrylic acid.

The pesticidal composition of the present invention may also include stabilizers such as PAP (isopropyl acid phosphate), BHT (2,6-di-tert-butyl-4-methylphenol), BHA (2-tert- a mixture of butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol), vegetable oils, mineral oils, surfactants, fatty acids and esters thereof.

The agricultural pharmaceutical composition of the present invention can be prepared by mixing various components in the agricultural chemical composition of the present invention with each other.

The agricultural chemical composition of the present invention thus formulated can be used as it is or after being diluted with water. This In addition, it can be mixed with other insecticides, nematicides, acaricides, fungicides, fungicides, herbicides, plant growth regulators, synergists, fertilizers, soil conditioners and/or animal feeds. Or don't mix it but use it at the same time.

Accordingly, the present invention also encompasses a method of controlling crop diseases, including, for example, spraying a crop, applying a root of a crop in the soil, and the like.

When the pesticidal composition of the present invention is used in agriculture, an appropriate application amount and concentration can be set according to the conditions including the type, the number of times, the place and the application method, the type of pest, and the degree of damage.

The invention is further illustrated by the following examples, which are intended to illustrate and not to limit the scope of the invention. Example 1

Weigh 4-fluoroaniline (555 mg, 0.5 mmol) in a 25 mL single-mouth eggplant bottle and add 7.5 mL.

4 M hydrochloric acid aqueous solution was stirred under magnetic stirring in an ice bath, and a sodium nitrite aqueous solution (400 mg of sodium nitrite and 4 mL of water) was slowly added dropwise with a constant pressure dropping funnel, and the dropwise addition was completed until the reaction liquid was clarified to obtain a reaction liquid A. Take 870 mg of dimethyl 1,3-acetone dicarboxylate and 3 g of sodium acetate in a 100 mL eggplant-shaped flask, add 10 mL of water and 3 mL of ethanol, and stir magnetically at room temperature to obtain a reaction solution 8. The reaction solution A was slowly added dropwise to the reaction liquid B, and a yellow precipitate was precipitated. After 10 min, the reaction was completed, suction filtration, water washing, and drying. The crude product was purified by silica gel column chromatography (EtOAc /EtOAcEtOAc

Weigh more than 1.2 g of the intermediate in a 100 mL eggplant-shaped flask, add 22 mL of 2 M NaOH aqueous solution, and clarify the reaction solution, slowly add concentrated hydrochloric acid, adjust the pH to 5, precipitate, precipitate, filter, wash, dry Dry. The crude product was recrystallized from methanol to give 4-hydroxy-6-oxo-1-(4-fluorophenyl)-1,6-dihydropyridazin-3-carboxylic acid as a yellow solid 750 mg, yield 75%. Melting point 242~245 °C. 1H NMR (400 MHz, DMSO- ₆ ): δ 7.52 (dd, J; = 5.2 Hz, J ₂ = 8.8 Hz, 2H), 7.27-7.32 (m, 2H), 5.76 (s, 1H) HRMS (ESI) Calcd _{_{_{_{C n H 7 N 2 O 4}}}} F [M + H] + 251.0463, Found 251.0466. Example 2

Preparation of methyl 4-hydroxy-6-oxo-1-(4-fluorophenyl)-1,6-dihydropyridazine-3-carboxylate (Compound D2):

NaN0 ₂ , HCI

H ₂ O, 0. C

D2

Weigh 4-fluoroaniline (555 mg, 0.5 mmol) into a 25 mL single-mouth eggplant-shaped flask, add 7.5 mL of 4 M aqueous hydrochloric acid solution, stir magnetically in an ice bath, and slowly add an aqueous solution of sodium nitrite with a constant pressure dropping funnel. 400 mg of sodium nitrite and 4 mL of water), the addition was completed, and the reaction solution was clarified to obtain a reaction solution A. Take 870 mg of dimethyl 1,3-acetone dicarboxylate and 3 g of sodium acetate in a 100 mL eggplant-shaped flask, add 10 mL of water and 3 mL of ethanol, and stir magnetically at room temperature to obtain a reaction solution 8. The reaction solution A was slowly added dropwise to the reaction liquid B, and a yellow precipitate was precipitated. After 10 minutes, the reaction was completed, suction filtration, water washing, and drying. The crude product was purified by silica gel column chromatography (EtOAc /EtOAcEtOAc

Weigh more than 1.3 g of the intermediate in a 25 mL eggplant-shaped flask, add 8 mL of o-dichlorobenzene, stir with magnetic force, heat to reflux at 180 °C, react for 2 hours, and trace the TLC to complete conversion of the raw materials. After cooling to room temperature, the solvent was removed by rotary evaporation to give a pale yellow solid. The crude product was purified by silica gel column chromatography ( petroleum ether/ethyl acetate = 1/1, v/v) to afford 4-hydroxy-6-oxo-1-(4-fluorophenyl)-1,6-dihydro Methyl pyridazin-3-carboxylate 92 mg, yield 70%, mp 145-146. C. 1H NM ( 400 MHz, CDC1 ₃ ): δ 10.42 (s, 1Η), 7.58 (dd, J; = 5.2 Hz, J ₂ = 8.8 Hz, 2H), 7.17-7.22 (m, 2H), 6.41 (s, 1H), 4.05 (s, 3H). HRMS (ESI) calcd for _{_{_{_{C 12 H 9 N 2 O 4}}}} F [M + H] + 265.0619, Found 265.0622. Example 3

Preparation of 4-hydroxy-6-oxo-1-(4-methoxyphenyl)-1,6-dihydropyridazine-3-carboxylic acid (compound D3)

The conditions and procedures were the same as in Example 1 except that p-methoxyaniline was substituted for p-fluoroaniline in Example 1, to obtain Compound D3 in a yield of 80%. Melting point 232~234 oC:. 1H NM (400 MHz, DMSO- ₆ ): δ 7.41 (d, J = 8.8 Ηζ, ΙΗ), 7.03 (d, J = 8.8 Hz, 1H), 6.18 (s, 1H), 3.81 (s, 3H). H MS (ESI) calcd for _{_{_{_{C 12 H 7 N 2 O 5}}}} [M + H] + 263.0662, Found 263.0666. Example 4

Preparation of methyl 4-hydroxy-6-oxo-1-(4-methoxyphenyl)-1,6-dihydropyridazine-3-carboxylate (Compound D4):

The conditions and procedures were the same as in Example 2 except that p-methoxyaniline was substituted for p-fluoroaniline in Example 2 to give compound D4), yield 67%, melting point 184·1~184·5 °C. 1H NMR ( 400 MHz, CDC1 ₃ ): δ 10.40 (s, 1Η), 7.50 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.40 (s, 1H), 4.04 (s, 3H), 3.87 (s, 3H). HRMS (ESI) calculated C ₁₃ H ₁₂ N ₂ O ₅ [M+H]+

277.0819, experimental value 277.0822. Example 5

Preparation of 4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid (Compound D5):

D5

The conditions and procedures were the same as in Example 1 except that aniline was used instead of p-fluoroaniline in Example 1. Compound D5 was obtained in a yield of 73% and a melting point of 246.0 to 246.5 °C. 1H NM (400 MHz, DMSO- ₆ ): δ 7.42-7.51 (m, 5 Η), 6.20 (s, 1 Η). HRMS (ESI) Calculated C _n H ₈ N ₂ O ₄ [M+H]+ 233.0557, The experimental value is 233.0577. Example 6

Preparation of 4-hydroxy-6-oxo-l-(4-chlorophenyl (Compound D6):

D6

The conditions and procedures were the same as in Example 1 except that p-chloroaniline was substituted for p-fluoroaniline in Example 1, to give Compound D6, yield 80%, m.p. 1H NMR (400 MHz, DMSO- ₆ ): δ 7.57 (brs, 4H), 6.15 (s, 1H). HRMS (ESI) Calculated C _n H ₇ N ₂ O ₄ Cl

[M+H] ⁺ 267.0167, found 267.0184. Example

Preparation of 4-hydroxy-6-oxo-1-(3, ί. chlorocarboxylic acid (Compound D7)

D7

The conditions and procedures were the same as in Example 1 except that 3,5-dichloroaniline was used instead of p-fluoroaniline in Example 1, to give Compound D7, yield 74%, melting point 263.4 to 263.6 °C. 1H NMR (400 MHz, DMSO- ₆ ): δ 7.71 (s, 1H), 7.7 (s, 2H), 6.14 (s, 1H). HRMS (ESI)

C _n H ₆ N ₂ O ₄ Cl ₂ [M+H]+ 300.9777, found 300.9778. Example 8

Preparation of methyl 4-hydroxy-6-oxo-l-(3,5-dichlorophenyl)-1,6-dihydropyridazine-3-carboxylate (Compound D8):

D8

The conditions and procedures were the same as in Example 2 except that 3,5-dichloroaniline was used instead of p-fluoroaniline in Example 2 to obtain Compound D8 in a yield of 71%. 1HNM (400 MHz, CDC1 ₃ ): δ 10.45 (s, 1H), 7.57 (d, J = 1.6 Hz, 2H), 7.45 (t, J = 1.6 Hz, 1H), 6.41 (s, 1H), 4.08 ( s, 3H). Example 9

Preparation of 4-hydroxy-6-oxo-l-(2,4-dichlorocarboxylic acid (Compound D9):

The conditions and procedures were the same as in Example 1 except that 2,4-dichloroaniline was used instead of p-fluoroaniline in Example 1, to give Compound D9, yield 72%, melting point 236~237 °C. 1H NMR (400 MHz, DMSO- ₆ ): δ 7.87 (s, 1H), 7.61 (s, 2H), 6.13 (s, 1H). H MS (ESI) Calculated C _n H ₆ N ₂ O4Cl ₂ [M +H]+ 300.9777, experimental value 300.9773. Example 10

Preparation of 4-hydroxy-6-oxo-l-(3,4-dichlorocarboxylic acid (Compound D10):

Other conditions and steps and examples except that 3,4-dichloroaniline is substituted for p-fluoroaniline in Example 1. The same as above, the compound D10 was obtained in a yield of 77%, and the melting point was 268.1 to 268.3 °C. 1H NMR (400 MHz DMSO- ₆ ): δ 7.89 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.59 (dd, A = 2.4 Hz, J ₂ = 8.8 Hz, 1H), 6.14 (s, 1H). HRMS (ESI) calcd for _Cn H ₆ N ₂ O ₄ Cl ₂ [M+H]+ 300.9777, calc. 300.9774c Example 11

Preparation of methyl 4-hydroxy-6-oxo-l-(3,4-dichlorophenyl)-1,6-dihydropyridazine-3-carboxylate (Compound D11):

D11

The conditions and procedures were the same as in Example 2 except that 3,4-dichloroaniline was used instead of p-fluoroaniline in Example 2 to give Compound Dll, yield 81%, melting point 179·1 to 179.3 °C. ^l H NM ( 400 MHz, CDC1 ₃ ): δ 10.41 (s, 1Η), 7.76 (s, 1Η), 7.57 (d, J= 8.8 Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H), 6.39 (s, 1H). HRMS (ESI) calcd for C ₁₂ H ₈ N ₂ O ₄ Cl ₂ [M+H]+ 314.9934,

Example 12

Preparation of 4-hydroxy-6-oxo-l-(4-trifluoromethylphenyl)-l,6-dihydropyridazine-3-carboxylic acid (Compound D12):

D12

The conditions and procedures were the same as in Example 1 except that 4-fluorotrifluoroaniline was used instead of p-fluoroaniline in Example 1, to give Compound D12, yield 71%, m.p. 1H NMR (400 MHz, DMSO- ₆ ): δ 7.88 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 6.16 (s, 1H).

HRMS (ESI) calcd for _{_{_{_{C 12 H 7 N 2 O 4}}}} F 3 [M + H] + 301.0431, Found 301.0427. Example 13

Preparation of 4-hydroxy-6-oxo-1-p-nitrophenyl-methyl 1,1-dihydropyridazine-3-carboxylate (Compound D13)

D13

The conditions and procedures were the same as in Example 2 except that p-nitroaniline was used instead of p-fluoroaniline in Example 2. The compound D13 was obtained in a yield of 72%, and the melting point was from 200 to 212 °C. 1H NMR ( 400 MHz, CDC1 ₃ ): δ 10.47 (s, 1 Η), 8.38 (d, J = 9.2 Hz, 2H), 7.90 (d, J = 9.2 Hz, 2H), 6.44 (s, 1H), 4.08 (s, 3H). HRMS (ESI) calcd for C ₁₂ H ₉ N ₃ O ₆ [M+H]+ 292.0564,

Example 14

Preparation of 4-hydroxy-6-oxo-l-(4-trifluoromethylphenyl)-l,6-dihydropyridazine-3-carboxylic acid methyl ester (Compound D14):

D14

The conditions and procedures were the same as in Example 2 except that 4-trifluoromethylaniline was substituted for p-fluoroaniline in Example 2 to give Compound D14 in a yield of 69%. ¹ MR (400 MHz, CDC1 ₃ ): δ 7.57 (dd, J! = 4.8 Hz, J ₂ = 8.8 Hz, 2H), 7.19 (m, 2H), 6.42 (s, 1H), 4.05 (s, 3H). Example 15

Preparation of 4-hydroxy-6-oxo-1-p-bromophenyl- (Compound D15)

D15

Other conditions and steps are the same as in Example 1 except that 4-bromoaniline is substituted for p-fluoroaniline in Example 1. In the same manner, Compound D15 was obtained in a yield of 83%. 1H NM (400 MHz, DMSO- ₆ ): δ 7.70 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 6.17 (s, 1H). Example 16

Preparation of 4-hydroxy-6-oxo-1-p-bromophenyl ester (Compound D16):

D16

The conditions and procedures were the same as in Example 2 except that 4-bromoaniline was used instead of p-fluoroaniline in Example 2 to give Compound D16 in a yield of 69%. 1HNMR (400 MHz, CDC1 ₃ ): δ 10.47 (s, 1H), 8.38 (d, J = 9.2 Hz, 2H), 7.90 (d, J = 9.2 Hz, 2H), 6.44 (s, 1H), 4.08 ( s, 3H). Example 17

Preparation of 4-hydroxy-6-oxo-l-(3-trifluoromethylphenyl)-l,6-dihydropyridazine-3-carboxylic acid (Compound D17):

D17

The conditions and procedures were the same as in Example 1 except that 3-trifluoromethylaniline was used instead of p-fluoroaniline in Example 1, to obtain Compound D17 in a yield of 81%. 1H NM (400 MHz, DMSO- ₆ ): δ 7.95 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 8.0) Hz, 1H), 6.22 (s, 1H). Example 18

Preparation of methyl 4-hydroxy-6-oxo-1-(3-trifluoromethylphenyl)-1,6-dihydropyridazine-3-carboxylate (Compound D18):

The conditions and procedures were the same as in Example 2 except that 3-trifluoromethylaniline was used instead of p-fluoroaniline in Example 2 to give Compound D18 in a yield of 71%. ¹ MN MR (400 MHz, CDC1 ₃ ): δ 10.47 (s, 1Η), 7.88 (s, 1Η), 7.85 (d, J= 8.0 Hz, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.62-7.67 (m, 1H), 6.43 (s, 1H), 4.08 (s, 3H). Example 19

Preparation of 4-hydroxy-6-oxo-l-(4-trifluoromethoxyphenyl)-1,6-dihydropyridazine-3-carboxylic acid (Compound D19):

D19

The conditions and procedures were the same as in Example 1 except that 4-trifluoromethoxyaniline was used instead of p-fluoroaniline in Example 1, to give Compound D19 in a yield of 83%. 1H NM (400 MHz, DMSO- ₆ ): δ 7.67 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 6.17 (s, 1H). Example 20

Preparation of 4-hydroxy-6-oxo-l-(2-trifluoromethylphenyl)-1,6-dihydropyridazine-3-carboxylic acid (Compound D20):

D20

The conditions and procedures were the same as in Example 1 except that 2-trifluoromethylaniline was used instead of p-fluoroaniline in Example 1, to obtain Compound D20 in a yield of 85%. 1H NM (400 MHz, DMSO- ₆ ): δ 7.93 (d, J = 7.6 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.63 ( d, J = 7.6 Hz, 1H), 6.19 (s, 1H). Example 21

Preparation of 4-hydroxy-6-oxo-l-(3-methoxyphenyl)-1,6-dihydropyridazine-3-carboxylic acid (Compound D21)

D21

Except that 3-methoxyaniline was substituted for p-fluoroaniline in Example 1, the other conditions and procedures were the same as in Example 1, to obtain Compound D21, yield 82% ^l R NM (400 MHz, DMSO- ₆ ): δ 7.41 (t, J = 8.0 Hz, 1H), 7.01-7.08 (m, 3H), 6.17 (s, 1H), 3.79 (s, 3H). Example 22

Preparation of 4-hydroxy-6-oxo-l-(2-methoxyphenyl)-1,6-dihydropyridazine-3-carboxylic acid (Compound D22)

D22

Except that 2-methoxyaniline was substituted for p-fluoroaniline in Example 1, the other conditions and procedures were the same as in Example 1, to obtain Compound D22, yield 86% 1H NM (400 MHz, DMSO- ₆ ): δ 7.46 ( t, J= 7.6 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.14 (s, 1H), 3.75 (s, 3H). Example 23

Methyl 4-hydroxy-6-oxo-l-(2-methoxyphenyl)-1,6-dihydropyridazine-3-carboxylate (Compound D23)

D23

The conditions and procedures were the same as in Example 2 except that 2-methoxyaniline was used instead of p-fluoroaniline in Example 2 to give Compound D23 in a yield of 66%. 1HNMR (400 MHz, CDC1 ₃ ): δ 10.44 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.05-7.11 (m, 2H), 6.41 (s, 1H), 4.02 (s, 3H), 3.84 (s, 3H). Example 24

Preparation of 4-hydroxy-6-oxo-l-(3,5-dimethoxyphenyl)-l,6-dihydropyridazine-3-carboxylic acid (Compound D24):

D24

The conditions and procedures were the same as in Example 1 except that 3,5-dimethoxyaniline was substituted for p-fluoroaniline in Example 1, to obtain Compound D24 in a yield of 77%. 1H NM (400 MHz, DMSO- ₆ ): δ 6.66 (d, J = 1.0 Hz, 2H), 6.60 (d, J = 1.0 Hz, 1H), 6.17 (s, 1H), 3.78 (s, 6H). Example 25

Preparation of methyl 4-hydroxy-6-oxo-l-(3,5-dimethoxyphenyl)-l,6-dihydropyridazine-3-carboxylate (Compound D25):

D25

The conditions and procedures were the same as in Example 2 except that 3,5-dimethoxyaniline was replaced by p-fluoroaniline in Example 2 to give Compound D25 in a yield of 67%. 1HNMR (400 MHz, CDC1 ₃ ): δ 10.43 (s, 1H), 6.69 (d, J = 2.4 Hz, 2H), 6.54 (d, J = 2.4 Hz, 1H), 6.40 (s, 1H), 4.04 ( s, 3H) 3.83 (s, 6H). Example 26

Preparation of 4-hydroxy-6-oxo-l-(3,4-difluoro-carboxylic acid (Compound D26):

D26

The conditions and procedures were the same as in Example 1 except that 3,4-difluoroaniline was used instead of p-fluoroaniline in Example 1, to obtain Compound D26 in a yield of 78%. 1H NMR (400 MHz, DMSO- ₆ ): δ 7.39-7.46 (m, 3H), 6.17 (s, 1H). Example 27

Preparation of 4-hydroxy-6-oxo-l-(3-fluoro-4-methylphenyl)-1,6-dihydropyridazine-3-carboxylic acid (Compound D27):

D27

Except that 3-fluoro-p-methylaniline was substituted for p-fluoroaniline in Example 1, the other conditions and procedures were the same as in Example 1, to obtain Compound D27, yield 77% 1H NM (400 MHz, DMSO- ₆ ): δ 7.62 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.41 (dd, J _; = 2.0 Hz, J ₂ = 8.0 Hz, 1H) 6.14 (s, 1H), 2, 39 (s, 3H). Example 28

Preparation of 4-hydroxy-6-oxo-l-(3-fluorophenyl)-l,6-dihydropyridazine-3-carboxylic acid methyl ester (Compound D28):

D28

The conditions and procedures were the same as in Example 1 except that 3-fluoroaniline was used instead of p-fluoroaniline in Example 1, to obtain Compound D28 in a yield of 79%. 1H NM (400 MHz, DMSO- ₆ ): δ 7.52-7.59 (m, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31 (dt, J _; = 2.0 Hz, J ₂ = 8.0 Hz, IH), 6.16 (s, 1H). Example 29

Preparation of methyl 4-hydroxy-6-oxo-l-(3-fluorophenyl)-l,6-dihydropyridazine-3-carboxylate (Compound D29):

D29

The conditions and procedures were the same as in Example 2 except that 4-trifluoromethylaniline was substituted for the p-fluoroaniline of Example 2. The compound D29 was obtained in a yield of 66%. ¹ MR (400 MHz, CDC1 ₃ ): δ 10.43 (s, 1Η), 7.42-7.51 (m, 2Η), 7.36-7.39 (m, 1H), 7.13-7.19 (m, 1H), 6.41 (s, 1H), 4.06 (s, 1H). Example 30

Preparation of 4-hydroxy-6-oxo-l-(2-fluorophenyl)-l,6-dihydropyridazine-3-carboxylic acid methyl ester (Compound D30):

D30

The conditions and procedures were the same as in Example 2 except that 2-fluoroaniline was used instead of p-fluoroaniline in Example 2 to obtain Compound D30 in a yield of 59%. 1HNMR (400 MHz, CDC1 ₃ ): δ 10.46 (s, 1H), 7.42 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.43 (s, 1H), 4.05 (s, 1H). Example 31

Preparation of 4-hydroxy-6-oxo-l-(4-fluoro-3-trifluoromethylphenyl)-l,6-dihydropyridazine-3-carboxylic acid (Compound D31):

D31

The conditions and procedures were the same as in Example 1 except that 4-fluoro-3-trifluoromethylaniline was used instead of p-fluoroaniline in Example 1, to obtain Compound D31, yield 78%. 1H NMR (400 MHz, DMSO-): δ 7.65-8.02 (m, 3H), 6.18 (s, 1H). Example 32

Preparation of 4-hydroxy-6-oxo-l-(4-chloro-3-trifluoromethylphenyl)-l,6-dihydropyridazine-3-carboxylic acid (Compound D32):

D32

The conditions and procedures were the same as in Example 1 except that 4-chloro-3-trifluoromethylaniline was used instead of p-fluoroaniline in Example 1, to obtain Compound D32 in a yield of 78%. 1H NM (400 MHz, DMSO- ₆ ): δ 8.09 (d, J = 2.0 Ηζ, ΙΗ), 7.87-7.93 (m, 2H), 6.17 (s, 1H). Example 33

Preparation of 4-hydroxy-6-oxo-l-(4-chloro-3-trifluoromethylphenyl)-l,6-dihydropyridazine-3-carboxylic acid (Compound D33):

D33

The conditions and procedures were the same as in Example 1 except that 4-bromo-3-trifluoromethylaniline was used instead of p-fluoroaniline in Example 1, to obtain Compound D33 in a yield of 81%. 1H NMR (400 MHz, DMSO- ₆ ): δ 8.07 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.81 (dd, J! = 2.4 Hz, J ₂ = 8.8 Hz, 1H), 6.19 (s, 1H). Example 34: Activity test

The inhibitory effect of the compound provided by the invention as a plant disease resistance activator on pathogens:

1. Subjects: Resistance to cucumber blight, cucumber leaf spot resistance, cucumber leaf spot resistance, tomato late blight, rice sheath blight, cucumber gray mold, cucumber blight.

2. Test concentration: This test uses 100 mg/L test concentration.

3. Test method: Seed various crops in advance, and weigh the sample quantitatively, dissolve it with DMF and add appropriate amount of surfactant, and dilute to the set concentration with water. The drug treatment was carried out in four steps, 7 days, 5 days, 3 days, and 1 day before the inoculation, and then the pathogens were simultaneously inoculated at one time. The experiment was carried out by potting and repeated 3 times. The disease index and disease prevention effect are calculated as follows: Disease index = [∑ (number of relative leaves of all levels X relative level) xl OO] / (reported total number of leaves X representative value of the highest level of incidence), control effect (% ) = [(Control area disease index - treatment area disease index) x lOO] / control area disease index.

4, the experimental results

The present invention uses 11 methods for the induction of disease resistance of five diseases by the method described above for the 11 4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid derivatives. The activity was tested and the pre-compound test activity data is shown in Table 1 below: Table 1

The in vivo and ex vivo inhibitory activities of the preferred compounds against several pathogens are shown in Table 2 below. Note: The data in the upper column of each row is in vitro activity and the activity in the lower column is in vivo.

Table 2

Claims

1. Compounds represented by the general formula:

I

In the formula,

R-R ₅ is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkyloxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkyloxy, nitro, amino, CN, NCO , NCS, carboxyl group, C1-C3 alkyloxyformyl group, C1-C3 amide group;

X is selected from oxygen, sulfur and nitrogen;

1 ₆ is 11, optionally substituted C1-C3 alkyl and optionally substituted phenyl substituted, 5-10 membered heteroaryl; and

R ₇ is optionally H, substituted C1-C3 alkyl and optionally substituted phenyl.

2. The compound of claim 1, characterized in that the compound has a structure described in general formula II or III:

In the formula, R _r R ₅ is independently preferably selected from: hydrogen, C1-C6 alkyl group, C1-C6 alkyloxy group, halogen, nitro and halogenated C1-C6 alkyloxy group.

3. The compound according to claim 1 or 2, characterized in that, R ₂ , R ₄ , R ₅ and R ₆ are H, R ₃ is selected from H, halogen, C1-C6 alkyloxy, halogenated C1 -C6 alkyl, nitro, halogenated C1-C6 alkyloxy and C1-C6 alkyl, X is 0.

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4. The compound according to claim 1 or 2, characterized in that, R ₃ , R ₅ and 1 ₆ are R ₂ and R ₄ selected from H, halogen and C1-C.6 alkyloxy group, X is 0 .

5 in The compound is selected from:

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6. Application of the compound described in any one of claims 1 to 5 as a plant disease resistance activator, insecticide, fungicide, plant growth regulator or herbicide.

7. Application of the compound according to any one of claims 1 to 5, characterized in that it is used to prevent and treat Mycosphaerella melonis, Corynespora cassiicola, and Pseudomonas syringae. Cucumber angular spot to disease typei Pseudomonas syringae pv. Lachrymans), Phytophthora infestans (Mont.) De Bary), Thanatephorus cucumeris (Frank) Donk.), Botrytis cinereai Plant diseases caused by Botrytis cinerea Pers.ex Fr.) or F. oxysporum (Schl.)F.sp cucumerinum Owen).

8. Application as claimed in claim 7, characterized in that the compound is used to prevent and treat cucumber vine blight, cucumber brown spot, cucumber bacterial angular leaf spot, tomato late blight, rice sheath blight, and cucumber gray mold. disease or cucumber wilt.

9. A pesticide composition, characterized in that the pesticide composition contains the compound described in any one of claims 1 to 5 and a pesticide acceptable carrier.

10. A method for preventing and treating plant diseases, characterized in that the method includes: administering the compound of any one of claims 1 to 5 or the pesticide composition of claim 9 to the plant, thereby preventing and treating plant diseases. its disease.

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