Benzopentaheterocyclic compound containing hydrazone structure and application thereof

Abstract

The application discloses a benzopentaheterocyclic compound containing a hydrazine structure and an application thereof. The compound, stereoisomers of the compound, or a salt of the compound, or a solvate of the compound has good inhibiting effects on plant pathogenic bacteria and fungi. The compound has good inhibiting effects on fungi such as Colletotrichum gloeosporioides, Colletotrichum theae-sinensis, Mycosphaerella pachyrrhizi, Alternaria solani, Phytophthora capsici and the like, and pathogenic bacteria such as Xanthomonas oryzae, Xanthomonas citri and the like. Some of the compounds show excellent inhibiting activities on Colletotrichum theae-sinensis, with an EC 50 of 11.85 μg / mL. Some of the compounds show excellent inhibiting activities on Mycosphaerella pachyrrhizi, with an EC 50 of 2.88-16.41 μg / mL. Some of the compounds show excellent inhibiting activities on Xanthomonas citri, with a primary screening activity of 13.69-27.03 μg / mL, which is superior to a commercial drug, copper oxychloride. Some of the compounds show excellent inhibiting activities on Xanthomonas campestris, with a primary screening activity of 25.07-43.78 μg / mL, which is superior to the commercial drug, copper oxychloride. The application provides an important scientific basis for the research and development of new pesticides.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pesticide creation, and particularly relates to a benzopentaheterocyclic compound containing a hydrazine structure and application thereof. BACKGROUND

[0002] Plant diseases are one of the important factors restricting the high quality and high yield of crops. In agricultural production, plant fungal diseases are a common disease, which directly leads to the decrease of crop yield and quality. At the same time, many plant fungal diseases have the characteristics of prevalence, outbreak and destructiveness, which makes this kind of disease extremely destructive and difficult to control, seriously affecting the sustainable development of agriculture. In the prevention and control of plant fungal diseases, traditional methods mainly use fungicides such as carbendazim, benomyl, thiabendazole, azoxystrobin and pyrifenox for prevention and control. However, due to factors such as large dose, high frequency of pesticide application and selective evolution of harmful organisms, the difficulty of preventing and controlling plant fungal diseases is further increased. Therefore, it is urgent to explore efficient, low-toxic and novel mechanism of action pesticides.

[0003] Studies have shown that target-based drug discovery is of great significance in the creation of new pesticides. However, many traditional fungicides have single action sites, which leads to the easy resistance of plant pathogenic fungi. At the same time, due to the difficulty of target discovery, a large amount of time and research and development costs need to be invested, which is one of the biggest challenges in the creation of new pesticides. It is worth noting that in recent years, it has also been found that many target proteins have multiple action targets, and small molecule drugs acting on different targets also show completely different properties in the functional regulation of proteins.

[0004] Benzimidazole fungicides belong to systemic fungicides, which were first developed in the 1960s and 1970s. They have the characteristics of high efficiency and broad spectrum, and are mainly used to prevent and control most pathogenic fungi in Basidiomycota and some pathogenic fungi in Ascomycota. The action target is β-tubulin. However, in recent decades of agricultural use, the resistance of pathogenic fungi has been increasing, and the control effect has gradually decreased. Therefore, it is of great significance to develop new benzimidazole fungicides with high efficiency, broad spectrum, safety and green environmental protection.

[0005] In 2021, Obydennov et al. prepared a series of N-acyl and N-thioacyl derivatives of benzimidazoles, and studied their fungicidal activity against 13 plant pathogenic fungi. Among them, compounds 3a, 4l and compound 4o showed broad-spectrum biological activity against most of the studied strains, with EC 50The values were in the range of 2.5-20 μg / mL. In addition, the authors determined the possible binding mode of the most active compounds to tubulin by molecular docking: the most optimal tautomer form of the benzimidazole derivatives binding to tubulin is the form containing a bicyclic exocyclic carbon-nitrogen bond. The results showed that the binding of benzimidazoles to E. coli β-tubulin can be performed by forming hydrogen bonds with Leu253 and Ser248 amino acid residues.

[0006] In 2021, Sun et al. synthesized a series of benzimidazole derivatives containing pyrimidine and evaluated their fungicidal activities. The results of bioactivity tests showed that most of the compounds exhibited high fungicidal activity against Botrytis cinerea, among which compound 4m had an EC 50 value of 0.13 μg / mL, which was better than the control drug carbendazim (EC 50 = 0.21 μg / mL). Molecular docking showed that the interaction of compound 4m with β-tubulin was stronger than that of carbendazim.

[0007] In 2022, Yang et al. designed and synthesized a series of benzimidazole derivatives containing thioether and carbamate moieties and evaluated their antifungal activities. Among them, compound E11 had good antifungal activity against Verticillium daliae and Phytophthora infestans at 50 μg / mL, with inhibition rates of 70% and 75%, respectively, which were better than those of the control drug albendazole (38% and 61%, respectively).

[0008] In 2018, Wang et al. designed and synthesized a series of 3-(thiophene-2-yl)-1,5-dihydro-2H-pyrrol-2-one derivatives with hydrazone groups and evaluated their antifungal activities. Bioactivity tests showed that some of the target compounds had obvious antifungal activity against Fusarium graminearum, Rhizoctorzia solani, Botrytis cinerea, and Colletotrichum capsici, among which compound 5e had an EC 50 value of 1.26 μg / mL, which was better than that of the control drug nithiazine (1.77 μg / mL).

[0009] It can be seen that benzimidazole compounds have broad application prospects in the field of antifungal agents, and how to continue to use benzimidazole structures as lead compounds to find highly active target compounds is a problem that needs to be solved at present. SUMMARY

[0010] This section is intended to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the Abstract and the title of the specification in order to avoid obscuring the purpose of the section, the Abstract and the title, which are to present some aspects of the embodiments of the present application in a simplified form, and are not intended to limit the scope of the present application.

[0011] In view of the above and / or problems existing in the prior art, the present application is proposed.

[0012] Therefore, the purpose of the present application is to overcome the deficiencies in the prior art, and to provide a benzopentaheterocyclic compound containing a hydrazone structure.

[0013] To solve the above technical problems, the present application provides the following technical solutions: the structural general formula of the benzopentaheterocyclic compound is as shown in formula (I):

[0014]

[0015] Among them, R and R1 are selected from one or more of hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, any substituted or unsubstituted alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, any substituted or unsubstituted amine or heterocyclic amine, any substituted or unsubstituted sulfhydryl or heterocyclic sulfhydryl, and any substituted or unsubstituted heteroaryl.

[0016] As a preferred scheme of the benzopentaheterocyclic compound containing a hydrazone structure according to the present application, wherein: the benzopentaheterocyclic compound further includes stereoisomers, salts or solvate compounds of the compound with the structural general formula as shown in formula (I).

[0017] As a preferred scheme of the benzopentaheterocyclic compound containing a hydrazone structure according to the present application, wherein: R and R1 are selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C6-C10 heteroaryl, wherein the substitution is substituted with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

[0018] As a preferred aspect of the benzopentaheterocyclic compound containing a hydrazone structure according to the present application, wherein: R and R1are selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, 1,1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein the substitution is by one or more of C1-C6alkyl, C1-C6alkoxy, amino, hydroxyl, halogen, nitro, trifluoromethyl.

[0019] As a preferred aspect of the benzopentaheterocyclic compound containing a hydrazone structure according to the present application, R is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, 1,1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, morpholinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-piperidinecarboxylic acid ethyl ester, S-3-piperidinecarboxylic acid ethyl ester, 4-piperidinecarboxylic acid methyl ester, pyrrolidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-iso-propylpiperazinyl, 1-tert-butylpiperazinyl, 1-acetyl piperazinyl, 1-benzylpiperazinyl, 1-(2-methoxybenzyl)piperazinyl, 1-(3-methoxybenzyl)piperazinyl, 1-(4-methoxybenzyl)piperazinyl, 1-(2-methylbenzyl)piperazinyl, 1-(3-methylbenzyl)piperazinyl, 1-(4-methylbenzyl)piperazinyl, 1-(2-chlorobenzyl)piperazinyl, 1-(3-chlorobenzyl)piperazinyl, 1-(4-chlorobenzyl)piperazinyl, 1-(2-fluorobenzyl)piperazinyl, 1-(3-fluorobenzyl)piperazinyl, 1-(4-fluorobenzyl)piperazinyl, 1-(2-bromobenzyl)piperazinyl, 1-(3-bromobenzyl)piperazinyl, 1-(4-bromobenzyl)piperazinyl, 1-(2-aminobenzyl)piperazinyl, 1-(3-aminobenzyl)piperazinyl, 1-(4-aminobenzyl)piperazinyl, 1-(2-hydroxybenzyl)piperazinyl, 1-(3-hydroxybenzyl)piperazinyl, 1-(4-hydroxybenzyl)piperazinyl, 1-(2-nitrobenzyl)piperazinyl, 1-(3-nitrobenzyl)piperazinyl, 1-(4-nitrobenzyl)piperazinyl, 1-(2-trifluoromethylbenzyl)piperazinyl, 1-(3-trifluoromethylbenzyl)piperazinyl, 1-(4-trifluoromethylbenzyl)piperazinyl.

[0020] As used herein, "alkyl" is intended to include straight-chain and branched saturated hydrocarbon groups of a specified number of carbon atoms. For example, "Ci-10 alkyl" (or alkylene) is intended to include Ci, C2, C3, C4, C5, C6, C7, C8, C9, and C10alkyl groups. Additionally, for example, "Ci-6 alkyl" is intended to mean an alkyl group having from 1 to 6 carbon atoms. The alkyl group can be unsubstituted or substituted with one or more of its hydrogen atoms being replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0021] As used herein, "alkenyl" is intended to include both straight chain and branched hydrocarbon groups having one or more carbon-carbon double bonds in the chain and occurring at any stable point in the chain. For example, "C2-6 alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[0022] As used herein, "alkynyl" is intended to include both straight chain and branched hydrocarbon groups having one or more carbon-carbon triple bonds in the chain and occurring at any stable point in the chain. For example, "C2-6 alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0023] As used herein, "substituted" means that any one or more hydrogen atoms on the designated atom or group is replaced with a selection of the designated group, provided that the designated atom's normal valence is not exceeded. If not otherwise stated, the substituent designation is to the point of attachment to the core structure. For example, it is understood that when (cycloalkyl)alkyl is a possible substituent, the point of attachment to the core structure is in the alkyl portion. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). When substitution is referred to, especially polysubstitution, it is intended to refer to substitution at each available substitutable position of the designated group, such as dichlorophenyl refers to 1,2-dichlorophenyl, 1,3-dichlorophenyl, 1,4-dichlorophenyl, and 2,4-dichlorophenyl.

[0024] Where combinations of substituents and or variables are referenced, only those combinations of substituents and or variables are permissible which result in stable compounds or useful synthetic intermediates. Stable compounds or stable structure implies that the compound is sufficiently robust to be isolated in useful purity from the reaction mixture in which it is prepared, and thereafter be formulated into an effective therapeutic agent. Preferably, the compounds presently described do not contain N-halo, S(O)2H or S(O)H groups

[0025] As used herein, "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which can be substituted.

[0026] As used herein, "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.

[0027] As used herein, "haloalkyl" refers to substituted alkyl groups having one or more halogen substituents. For example, "haloalkyl" includes mono, di and tri-fluoromethyl; even though the halo in haloalkyl is specified as fluorine, chlorine, bromine, iodine, it also refers to substituted alkyl groups having one or more fluorine, chlorine, bromine, iodine substituents.

[0028] As used herein, "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic, 9- or 10-membered bicyclic, and 11- to 14-membered tricyclic groups having at least one heteroatom (O, S, or N) in at least one ring, with the heteroatom-containing rings preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms can optionally be oxidized and the nitrogen atoms can optionally be quaternized. The bicyclic or tricyclic heteroaryl must include at least one fully aromatic ring, and the other fused rings can be aromatic or nonaromatic. The heteroaryl group can be attached at any available nitrogen or carbon atom of any ring. When valence permits, the other ring is additionally optionally substituted with O (oxygen) if the other ring is a cycloalkyl or heterocycloalkyl.

[0029] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

[0030] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0031] If not otherwise specified, the compounds of the present application are understood to include the free form and salts thereof. The term "salt" denotes an acid and / or a base formed by inorganic and / or organic acids and bases. In addition, the term "salt" can include zwitterions (inner salts) such as when a compound of Formula I contains both a basic fragment such as an amine or pyridine or imidazole ring and an acidic fragment such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as salts of acceptable metals and amines, wherein the cation does not contribute significant toxicity or biological activity to the salt. However, other salts can be useful, e.g., in isolation or purification steps, and are included within the scope of the present application.

[0032] C1-C10 alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and their isomers; C1-C10 alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy and their isomers; C2-C5 alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and their isomers.

[0033] When referring to a substituent as being alkyl, alkenyl, alkynyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or that a particular substituent is specifically an alkyl, alkenyl, alkynyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, it is meant one to three of the recited substituents. For example, methylphenyl means one to three methyl substituents on a phenyl group.

[0034] As a preferred embodiment of the benzoheterocyclic compounds of the present application containing a hydrazone structure, there is provided a benzoheterocyclic compound of the following formula:

[0035]

[0036] It is another object of the present application to provide a pharmaceutical composition for controlling agricultural pests.

[0037] As a preferred solution of the pharmaceutical composition for preventing and treating agricultural pests and diseases according to the present application, wherein: the pharmaceutical composition comprises a benzopentaheterocyclic compound or a stereoisomer thereof, or a salt or a solvent compound thereof and an agriculturally acceptable adjuvant, a fungicide, an insecticide or a herbicide.

[0038] As a preferred solution of the pharmaceutical composition for preventing and treating agricultural pests and diseases according to the present application, wherein: the dosage form of the pharmaceutical composition comprises one of emulsifiable concentrate, powder, wettable powder, granule, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, smoke agent, emulsion in water or water dispersible granule.

[0039] Another object of the present application is to provide an application of the pharmaceutical composition in preventing and treating agricultural pests and diseases, comprising: applying the pharmaceutical composition to pests or their living environment.

[0040] Among them, Colletotrichum gloeosporioides N, Colletotrichum fructicola S, colletotrichum sublineola B are provided by College of Agriculture Guizhou University and Alternaria solani, Fusarium oxysporum

[0041] As a preferred solution of the pharmaceutical composition for preventing and treating agricultural pests and diseases according to the present application, wherein: the agricultural pests and diseases include plant bacterial or fungal diseases, including one of Colletotrichum gloeosporioides (C.g.), Colletotrichum fructicola (C.f.), Colletotrichum sublineola (C.s.), Alternaria solani (A.s.), Fusarium oxysporum (F.o.).

[0042] As a preferred solution of the pharmaceutical composition for preventing and treating agricultural pests and diseases according to the present application, wherein: the agricultural pests and diseases include plant leaf blight or plant canker.

[0043] As a preferred scheme of the pharmaceutical composition for preventing and treating agricultural pests and diseases, the agricultural pests and diseases include one of rice bacterial leaf blight, rice bacterial leaf streak, plum bacterial boring, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, tobacco bacterial wilt, tobacco bacterial leaf spot, grape bacterial wilt, tomato bacterial wilt, kiwi bacterial wilt, apple bacterial wilt, cucumber gray mold, pepper wilt, rape bacterial wilt, eggplant bacterial wilt, wheat scab, potato late blight, blueberry root rot, grape Colletotrichum, dragon fruit anthracnose, or rice sheath blight.

[0044] As used herein, "comprise", "comprising", "have", "having", "include", "including", "contain", "containing", "provide", "providing", "carry", "carrying", "maintain", "maintaining", "enable", "enabling", "carry" and "carrying" are open-ended transitional phrases that are intended to mean including but not limited to.

[0045] The present application has the following beneficial effects: The present application synthesizes a class of benzopentaheterocyclic compounds containing hydrazone structure, and the compound, stereoisomer thereof, or salt thereof, or solvate thereof has good inhibitory effect on plant pathogenic bacteria and fungi. The compound has good inhibitory effect on fungi such as Colletotrichum gloeosporioides (C.g.), Colletotrichum fructicola (C.f.), Colletotrichum sublineola (C.s.), Alternaria solani (A.s.), and Fusarium oxysporum (F.o.), and pathogenic bacteria such as Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac). For example, the compound numbered 8 has excellent inhibitory activity on Colletotrichum fructicola (C.f.), and the EC 50 50 is 11.85 μg / mL; the compounds numbered 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 15, 17, 25, 26, 27, and 29 have excellent inhibitory activity on Colletotrichum sublineola (C.s.), and the EC 50 50 is 2.88-16.41 μg / mL; the compounds numbered 3, 5, 6, 7, 10, 11, and 12 have good inhibitory activity on Alternaria solani (A.s.), and the EC 50were 10.00 - 26.60 μg / mL; the compounds shown in compound numbers 10, 12 exhibited good inhibitory activity against Fusarium oxysporum (F. o.), and the EC50values thereof were 10.00 - 26.60 μg / mL 50 were 14.39 - 20.33 μg / mL; at a concentration of 50 μg / mL, compounds 1, 2, 7, 9, 11, 26 exhibited excellent inhibitory activity against Xanthomonas oryzae pv. oryzae (Xoo), and the primary screening activity thereof was 76.77 - 98.73 μg / mL, which was superior to the commercial drug CuO (14.46 μg / mL); compounds 1, 2, 7, 9 exhibited excellent inhibitory activity against Xanthomonas axonopodis pv. citri (Xac), and the primary screening activity thereof was 13.69 - 27.03 μg / mL, which was superior to the commercial drug CuO; compounds 1, 7, 9, 11, 15, 26, 30 exhibited excellent inhibitory activity against Pseudomonas syringae pv. Actinidiae (Psa), and the primary screening activity thereof was 25.07 - 43.78 μg / mL, which was superior to the commercial drug CuO, thereby providing an important scientific basis for the research and development of new pesticides. DETAILED DESCRIPTION

[0046] The various illustrative embodiments of the present application will now be described in detail below. This detailed description is merely intended to teach a person skilled in the art further details about the various aspects and features of the present application and is not intended to limit the scope of the application. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and the present application.

[0047] It should be understood that the terms used in the specification of the present application are merely used to describe particular embodiments and are not intended to limit the present application. In addition, for numerical ranges in the present application, it should be understood that each intermediate value between the upper limit and the lower limit of the range is also specifically disclosed. Each smaller range within any stated range or within any stated intermediate value is also encompassed within the present application. The upper and lower limits of these smaller ranges can be independently included or excluded from the range.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods and materials are described. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials in connection with which the documents are cited. In case of conflict between the content of the specification and that of any document incorporated herein by reference, the content of the specification prevails.

[0049] Many modifications and variations of the described implementations of the application can be made without departing from its spirit or scope, as will be apparent to those skilled in the art. Other implementations of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. The specification and examples given are exemplary only. They are intended to illustrate the application, together with the best mode contemplated for its practice.

[0050] As used herein, the terms "comprise", "comprising", "include", "including", "have", "having" and the like are open-ended and do not exclude additional elements or steps.

[0051] In order to make the above objectives, features and advantages of the present application more clear and comprehensible, the specific embodiments of the present application will be described in detail below with reference to the embodiments of the specification.

[0052] The target compounds shown in Table 1, the structural molecular formula, the nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the target compounds are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0053] Table 1: Nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of some compounds

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] Table 2: Physicochemical properties of some target compounds

[0063]

[0064]

[0065] Example 1

[0066] This example is used to verify the application activity of the compound prepared by the present application in the prevention and control of agricultural pests and diseases, specifically;

[0067] EC 50Median effective concentration (EC50) is an important index to evaluate the sensitivity of plant pathogens to compounds, and also an important parameter to set the concentration of compounds when studying the mechanism of action of target compounds.

[0068] In the concentration gradient experiment, the appropriate five concentrations (for example: 50, 25, 12.5, 6.25, 3.125 μg / mL) were set by double dilution method. Finally, the inhibition rate of the fungicide on the plant pathogen and the concentration of the fungicide were converted into logarithmic values, and the toxicity curve was obtained by regression analysis of SPSS software, and the EC 50 .

[0069] The effective concentration EC 50 of the target compound on the plant pathogen was tested by mycelial growth inhibition method. The test objects were Colletotrichum gloeosporioides (C.g.), Colletotrichum fructicola (C.f.), Colletotrichum sublineola (C.s.), Alternaria solani (A.s.) and Fusarium oxysporum (F.o.) in PDA medium. The strains used were young strains activated one week in advance;

[0070] The target compound to be tested was weighed with a hundredth balance, and the target compound was dissolved in DMSO with 20 times the volume of the mass of the target compound. The concentration of the mother liquor after complete dissolution was 50 μg / mL. The corresponding volume of the mother liquor was taken in a 2 mL centrifuge tube at the corresponding concentration, and DMSO was added to make up the final volume to 1 mL. It was transferred to a 15 mL sterilized centrifuge tube in a sterile operation table, 9 mL of Tween-20 was added to make up to 10 mL, and it was fully shaken and mixed. After being mixed, it was evenly divided into 9 culture media and cooled for standby. In a sterile operation table, a sterilized puncher (5 mm) was used to pour the fungus cake upside down in the center of the culture medium at 28°C for 4-6 days. When the control group of colonies grew to a diameter of 5.0-7.0 cm, the diameter of the colonies was measured twice by cross method with a ruler, and the average value was calculated. The mycelial growth inhibition rate was calculated according to the following formula:

[0071] Inhibition rate % = (C1-C2) / (C1-0.5) x 100

[0072] C1 is the diameter of the control colony, i.e. the diameter of the colony treated with DMSO (i.e. CK);

[0073] C2 is the treated colony diameter, i.e. the colony diameter after treatment with the test compound;

[0074] 0.5 is the diameter of the mother colony;

[0075] The target compounds of the structural formula shown above were tested for their EC50 values against plant pathogenic fungi according to the above-mentioned method. 50 The results are shown in Table 3.

[0076] Table 3: Antifungal activity of some target compounds against plant pathogenic fungi

[0077]

[0078]

[0079]

[0080] As can be seen from Table 3, in the in vitro test, the target compounds showed good antifungal activity against plant pathogenic fungi such as Colletotrichum gloeosporioides (C.g.), Colletotrichum fructicola (C.f.), Colletotrichum sublineola (C.s.), Alternaria solani (A.s.) and Fusarium oxysporum (F.o.),

[0081] The compound shown in compound No. 8 showed excellent inhibitory activity against Colletotrichum fructicola (C.f.) with an EC50 value of 11.85 μg / mL. 50

[0082] The compounds shown in compound Nos. 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 15, 17, 25, 26, 27 and 29 showed excellent inhibitory activity against Colletotrichum sublineola (C.s.) with an EC50 value of 2.88 - 16.41 μg / mL. 50

[0083] The compounds shown in compound Nos. 3, 5, 6, 7, 10, 11 and 12 showed good inhibitory activity against Alternaria solani (A.s.) with an EC50 value of 10.00 - 26.60 μg / mL. 50

[0084] ​​​The compounds shown in compound numbers 10 and 12 exhibit good inhibitory activity against Fusarium oxysporum (F. o.), and the EC50values thereof are 14.39-20.33 μg / mL; thus, it can be known that such compounds have a great research prospect and can be used for preparing an anti-plant pathogenic bacterial pesticide. 50 595

[0001] The compounds shown in compound numbers 10 and 12 exhibit good inhibitory activity against Fusarium oxysporum (F. o.), and the EC50values thereof are 14.39-20.33 μg / mL; thus, it can be known that such compounds have a great research prospect and can be used for preparing an anti-plant pathogenic bacterial pesticide.

[0085] Example 2

[0086] The effective initial concentration of the target compound on the plant pathogenic bacteria is tested by turbidity method, and the test objects are Xoo, Xac and Psa. DMSO dissolved in the culture medium is used as a blank control. The Xoo (rice bacterial leaf blight pathogen on M210 solid medium) is placed in NB medium, and is cultured in a constant temperature shaker at 28°C and 180 rpm to the logarithmic growth phase for standby; the Xac (on M210 solid medium) is placed in NB medium; the bacterial bacterial leaf spot of rice (on M210 solid medium) is placed in NB medium, and is cultured in a constant temperature shaker at 28°C and 180 rpm to the logarithmic growth phase for standby. The pesticide (compound) is configured into NB liquid medium containing different concentrations (for example: 100, 50, 25, 12.5, 6.25 μg / mL) of poison 5 mL, which is added into a test tube, 40 μL of NB liquid medium containing plant disease bacteria is added, and is oscillated in a constant temperature shaker at 28-30°C and 180 rpm, wherein the Xoo is cultured for 48 h, the Xac is cultured for 48 h, and the Psa is cultured for 36 h. The OD595 value of each concentration of bacterial liquid is measured on an enzyme marker, and the OD595 value of the corresponding concentration of sterile NB liquid medium containing poison is also measured. 595

[0001] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium Inhibition rate % = [(corrected control medium bacterial liquid OD value - corrected poison-containing culture medium OD value) / corrected control medium bacterial liquid OD value] x 100

[0002]

[0003] The technical solutions of the present application are assisted by the examples, but the content of the examples is not limited thereto. The experimental results of the target compounds are shown in Table 4.

[0004] Table 4: Bacteriostatic effect of some target compounds on plant pathogenic bacteria

[0005]

[0006]

[0007] As can be seen from Table 4, in the in vitro test, the target compounds showed good bacteriostatic activity against plant pathogenic bacteria such as Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri. At a concentration of 50 μg / mL, compounds 1, 2, 7, 9, 11 and 26 showed excellent inhibitory activity against Xanthomonas oryzae pv. oryzae (Xoo), with a primary screening activity of 76.77-98.73 μg / mL, which is better than that of the commercial drug CuO (14.46 μg / mL); compounds 1, 2, 7 and 9 showed excellent inhibitory activity against Xanthomonas axonopodis pv. citri (Xac), with a primary screening activity of 13.69-27.03 μg / mL, which is better than that of the commercial drug CuO; compounds 1, 7, 9, 11, 15, 26 and 30 showed excellent inhibitory activity against Pseudomonas syringae pv. Actinidiae (Psa), with a primary screening activity of 25.07-43.78 μg / mL, which is better than that of the commercial drug CuO, and can be used for preparing an antibacterial pesticide against plant pathogenic bacteria.

[0094] In summary, the benzopentaheterocyclic compound containing a hydrazone structure provided by the present application has good inhibitory effect on plant pathogenic bacteria and fungi, and has good inhibitory effect on pathogenic bacteria such as Colletotrichum gloeosporioides (C.g.), Colletotrichum fructicola (C.f.), Colletotrichum sublineola (C.s.), Alternaria solani (A.s.) and Fusarium oxysporum (F.o.), Xanthomonas axonopodis pv. citri (Xac) and Xanthomonas oryzae pv. oryzae (Xoo), which provides an important scientific basis for the research and development of new pesticides.

[0095] It should be noted that the above examples are only used to illustrate the technical solutions of the present application and are not limiting. Although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present application, and all should be covered in the scope of the claims of the present application.

[0096] The application discloses a benzopentaheterocyclic compound containing a hydrazine structure and an application thereof, and the obtained benzopentaheterocyclic compound containing the hydrazine structure has good inhibiting effects on plant pathogenic bacteria and fungi, and has good inhibiting effects on plant pathogenic bacteria and fungi such as Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas axonopodis pv. citri (Xac), Pseudomonas syringae pv. Actinidiae (Psa), Colletotrichum gloeosporioides (C.g.), Colletotrichum fructicola (C.f.), Colletotrichum sublineola (C.s.), Alternaria solani (A.s.) and Fusarium oxysporum (F.o.), and the like, and provides an important scientific basis for research and development of new pesticides.

[0097] The above is only a preferred specific embodiment of the application, but the protection scope of the application is not limited to this, any person skilled in the art can easily think of changes or replacements within the technical range disclosed in the application, which should be covered in the protection scope of the application. Therefore, the protection scope of the application should be subject to the protection scope of the claims.

Claims

1. A benzo[a]five-membered heterocyclic compound containing a hydrazone structure, characterized in that: The benzo-five-membered heterocyclic compound is selected from one of the following compounds: 。 2. A pharmaceutical composition for controlling agricultural pests and diseases, characterized in that: The pharmaceutical composition comprises the benzo[a]pentacyclic heterocyclic compound as described in claim 1 and an agriculturally acceptable fungicide.

3. The pharmaceutical composition for controlling agricultural pests and diseases as described in claim 2, characterized in that: The dosage form of the pharmaceutical composition includes one of the following: emulsifiable concentrate, powder, wettable powder, granules, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, fumigant, water emulsion, or water-dispersible granules.

4. The application of the pharmaceutical composition according to claim 2 or 3 in the prevention and control of agricultural pests and diseases, characterized in that: The pharmaceutical composition described herein acts on harmful substances or their living environment.

5. The application of the pharmaceutical composition as described in claim 4 in the prevention and control of agricultural pests and diseases, characterized in that: The fungal disease of agricultural pests and diseases is: sorghum thorny spores.

6. The application of the pharmaceutical composition as described in claim 4 in the prevention and control of agricultural pests and diseases, characterized in that: Agricultural pests and diseases include bacterial diseases of plants such as rice bacterial blight, citrus canker, and kiwifruit canker.

Images