CN116969954A

CN116969954A - Tricyclic fused heterocyclic compounds containing lactam and application thereof

Info

Publication number: CN116969954A
Application number: CN202311220781.0A
Authority: CN
Inventors: 江薰垣; 万凯; 黄聪灵; 陈炎; 唐雪妹; 黄健祥; 王威利
Original assignee: Institute Of Agricultural Quality Standards And Monitoring Technology Guangdong Academy Of Agricultural Sciences
Current assignee: Institute Of Agricultural Quality Standards And Monitoring Technology Guangdong Academy Of Agricultural Sciences
Priority date: 2023-09-21
Filing date: 2023-09-21
Publication date: 2023-10-31
Anticipated expiration: 2043-09-21
Also published as: CN116969954B

Abstract

The invention belongs to the technical field of heterocyclic compounds, and particularly relates to a tricyclic fused heterocyclic compound containing lactam and application thereof. The invention provides a tricyclic fused heterocyclic compound containing lactam with a novel structure, which has strong killing activity on agricultural and forestry pests, sanitary pests and the like, has high killing activity on culex light at a low concentration of 100 mg/L, has the characteristic of low toxicity on non-target organisms such as earthworms, fishes and the like, and has good application prospect in pest control.

Description

Tricyclic fused heterocyclic compounds containing lactam and application thereof

Technical Field

The invention belongs to the technical field of heterocyclic compounds. More particularly, to a tricyclic fused heterocyclic compound containing lactam and application thereof.

Background

The novel heterocyclic pesticides represented by the nitrogen-containing heterocycle have high activity, broad insecticidal spectrum, low toxicity to mammals and proper field stability, and the nitrogen-containing heterocyclic compounds become important hot spot fields for the creation of novel pesticides. In recent years, none of the newly developed pesticides, including Benzpyrimoxan, flupyrimin, cyclobutrifluram, tyclopyrazoflor, flupyradifurone, isocycloseram, dimpropyridaz, methoxypiperidine ethyl, and hydroprene, is not a nitrogen-containing heterocyclic compound (pesticides, 2022, 61 (3): 157-162,10.16820/j.cnki.1006-0413.2022.03.014; pesticides, 2021,60 (2): 79-82, 10.16820/j.cnki.1006-0413.2021.02.001; pesticides, 2020,59 (4): 292-295, 10.16820/j.cnki.1006-0413.2020.04.014; world pesticides, 2019,41 (3): 57-60, 10.16201/j.cnki.cn31-1827/tq.2019.03.11). Of the 7 pesticides newly published by WHO and ISO in 2022, 5 were all nitrogen-containing heterocycles (world pesticides, 2023, 45 (2): 15-26, 10.16201/j.cnki.cn10-1660/tq.2023.02). These newly developed pesticides each have one or more nitrogen-containing heterocycles (e.g., pyrazole, imidazole, pyridine, pyrimidine, pyridazine, and other nitrogen-containing heterocycles) in their molecular structure. In particular Oxazosulfyl, fluazaindolizine and the like contain a condensed heterocyclic structure such as benzoxazole or benzimidazole (world pesticides, 2022,44 (3): 9-20, 10.16201/j.cnki.cn10-1660/tq.2022.03.02; pesticides, 2019,58 (12): 859-863, 10.16820/j.cnki.1006-0413.2019.12.001).

However, because the single pesticide is used frequently in excess, and the existing pesticide has higher toxicity to the environment while killing pests, serious resistance and interactive resistance problems are caused, the pesticide effect is reduced, the application of the pesticide is greatly limited, and the development of agriculture and forestry is further restricted. To solve the above problems, the applicant has invested a lot of time and effort to develop a new pesticide which is more efficient and environmentally friendly. The invention is further research based on the prior patent CN108003162B, CN108129481B, and aims to provide more novel compounds with better biological activity for the agricultural field so as to relieve the trouble of agricultural drug administration caused by the resistance problem of the existing pesticide.

Disclosure of Invention

The invention aims to overcome the problems of resistance and environmental risk and the defects and defects that the activity of the existing pesticide needs to be further improved, and provides a tricyclic fused heterocyclic compound containing lactam, which has good activity and high safety, and more surprisingly has high killing activity on pests such as culex light in lower concentration and better killing effect.

It is another object of the present invention to provide an agricultural composition.

It is another object of the present invention to provide the use of the agricultural composition in the preparation of an insecticide for killing or preventing agroforestry pests, hygiene pests or pests that are harmful to animal health.

The above object of the present invention is achieved by the following technical scheme:

the invention provides a tricyclic fused heterocyclic compound containing lactam and an agropharmaceutically acceptable salt thereof, wherein the tricyclic fused heterocyclic compound containing lactam has a structure shown in a formula (I):

wherein R is ¹ Is hydrogen, halogen, -NH ₂ 、-CN、-CO ₂ R ⁸ 、C _1~6 Alkyl, C _1~6 Haloalkyl or C _1~6 A heteroalkyl group;

R ² is-SR ⁹ 、-S(O)R ⁹ or-S (O) ₂ R ⁹ ；

R ³ Is hydrogen, -COR ¹⁰ 、C _1~6 Alkyl, C _1~6 Heteroalkyl, C _2~6 Alkenyl or C _2~6 Alkynyl, wherein alkyl, alkenyl or alkynyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution;

R ⁴ 、R ⁵ 、R ⁶ and R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl, C _1~6 Haloalkyl, C _1~6 Heteroalkyl, -OR ¹² 、-COR ¹² 、-CO ₂ R ¹² 、-CONR ¹² R ¹³ or-NR ¹² R ¹³ And R is ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Are not hydrogen at the same time;

R ⁸ is hydrogen, C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution;

R ⁹ is C _1~6 Alkyl, C _1~6 Heteroalkyl, aryl or heteroaryl, wherein alkyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution;

R ¹⁰ is amino, C _1~6 Alkyl or C _1~6 Heteroalkyl, in which the amino or alkyl group is unsubstituted or substituted by one or more substituents R ¹¹ Substitution;

R ¹¹ is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _1~6 Heteroalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, aryl, heteroaryl, -NO ₂ 、-CN、-NH ₂ 、-OH、-COR’、-CO ₂ R ' or-CONR ' R ' ' wherein R ' and R ' ' are independently hydrogen, C _1~6 Alkyl, C _1~6 Haloalkyl or C _1~6 A heteroalkyl group;

R ¹² and R is ¹³ Each independently is hydrogen, C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution;

in the structure shown in the formula (I), the heteroalkyl refers to an alkyl group comprising at least one heteroatom, and the heteroatom is selected from N, O, S or P; the cycloalkyl group means having C _3~6 Saturated monocyclic cycloalkyl; the cycloalkenyl refers to having C _3~6 Unsaturated monocyclic cycloalkyl; the aryl group is C _5~6 Carbocyclic aromatic ring, C _7~12 Bicyclic or C _10~15 Tricyclic, and when bicyclic or tricyclic, at least one of the rings is a carbocyclic aromatic ring; the heteroaryl group is C _5~6 Aromatic monocyclic ring, C _8~12 Bicyclic or C _11~15 Bicyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O or S, the remaining ring atoms being carbon and, in the case of bicyclic or tricyclic ring, at least one of the rings being aromatic and at least one heteroatom being present in the aromatic ring.

In order to develop a more efficient and environment-friendly novel pesticide, the applicant has further studied on the basis of the earlier-stage patent CN108003162B, CN108129481B, has paid a lot of time and effort, creatively discovers that the novel synthesized tricyclic fused heterocyclic compound containing the lactam has high killing activity on agricultural and forestry pests, sanitary pests and the like, and the mortality rate of the pests is over 90 percent after the novel fused heterocyclic compound is treated by the novel fused heterocyclic compound, wherein the mortality rate data is mostly concentrated to over 95 percent, and the novel fused heterocyclic compound has very high killing activity on culex light at a lower concentration of 100 mg/L, has further improved insecticidal activity compared with the novel fused heterocyclic compound containing the lactam in CN108003162B, CN108129481B, and has the characteristic of low toxicity on non-target organisms such as earthworms, fishes and the like.

Preferably, R ¹ Is halogen, -CN, -CO ₂ R ⁸ Or C _1~6 A haloalkyl group; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl or C _1~6 A haloalkyl group; r is R ⁸ Is C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ⁹ Is C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹⁰ Is amino or C _1~6 Alkyl, wherein the amino group, alkyl group are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, -NO ₂ 、-CN、-NH ₂ or-OH.

Preferably, R ³ Is hydrogen, C _1~6 Alkyl, C _2~6 Alkenyl or C _2~6 Alkynyl, wherein alkyl or alkenyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl, C _1~6 Haloalkyl or C _1~6 A heteroalkyl group; r is R ⁸ Is C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁹ Is C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, -NO ₂ 、-CN、-NH ₂ or-OH.

Preferably, R ² is-S (O) R ⁹ or-S (O) ₂ R ⁹ ；R ¹ Is halogen, -CN, -CO ₂ R ⁸ 、C _1~6 Alkyl or C _1~6 A haloalkyl group; r is R ³ Is hydrogen, -COR ¹⁰ 、C _1~6 Alkyl, C _2~6 Alkenyl or C _2~6 Alkynyl, wherein alkyl, alkenyl or alkynyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl, C _1~6 Haloalkyl, -OR ¹² 、-COR ¹² 、-CO ₂ R ¹² 、-CONR ¹² R ¹³ or-NR ¹² R ¹³ ；R ⁸ Is C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁹ Is C _1~6 Alkyl, C _1~6 Heteroalkyl, aryl or heteroaryl, wherein alkyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ¹⁰ Is amino or C _1~6 Alkyl, wherein the amino or alkyl groups are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _1~6 Heteroalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, aryl, -NO ₂ 、-CN、-NH ₂ or-OH; r is R ¹² And R is ¹³ Each independently is hydrogen, C _1~6 Alkyl or C _1~6 A heteroalkyl group.

More preferably, R ² is-S (O) R ⁹ or-S (O) ₂ R ⁹ ；R ¹ Is halogen, -CN, C _1~6 Alkyl or C _1~6 A haloalkyl group; r is R ³ Is hydrogen, -COR ¹⁰ 、C _1~6 Alkyl or C _2~6 Alkenyl in which the alkyl or alkenyl groups are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl, C _1~6 Haloalkyl, -OR ¹² 、-COR ¹² or-CO ₂ R ¹² ；R ⁹ Is C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ¹⁰ Is amino or C _1~6 Alkyl, wherein the amino or alkyl groups are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _1~6 Heteroalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, aryl, -NO ₂ 、-CN、-NH ₂ or-OH; r is R ¹² Is hydrogen, C _1~6 Alkyl or C _1~6 A heteroalkyl group.

More preferably, R ² is-S (O) R ⁹ or-S (O) ₂ R ⁹ ；R ¹ Is halogen, -CN or C _1~6 A haloalkyl group; r is R ³ Is hydrogen, -COR ¹⁰ Or C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl or C _1~6 A haloalkyl group; r is R ⁹ Is C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ¹⁰ Is amino or C _1~6 Alkyl, wherein amino or alkyl is unsubstituted orThrough one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, -NO ₂ 、-CN、-NH ₂ or-OH.

More preferably, R ² is-S (O) R ⁹ or-S (O) ₂ R ⁹ ；R ¹ is-CN or C _1~6 A haloalkyl group; r is R ³ Is hydrogen or C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ Or C _1~6 A haloalkyl group; r is R ⁹ Is C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, -NO ₂ 、-CN、-NH ₂ or-OH.

Further, the halogen is fluorine, chlorine, bromine or iodine, and the term "halogen" preceding the name of a group refers to that group being partially or fully halogenated, i.e. substituted in any combination with F, cl, br or I, such as monofluorodichloromethyl, difluoromethyl, trichloromethyl, pentafluoroethyl, heptafluoroisopropyl or other similar groups.

Further, the alkyl group means a hydrocarbon group selected from saturated straight-chain or branched hydrocarbon groups.

Further, the alkenyl group means a hydrocarbon group selected from straight chain or branched chain, and includes at least one c=c double bond therein. Alkenyl groups having 2 to 6 carbon atoms are preferred, such as vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1, 3-dienyl, 2-methyl-1, 3-butadiene, isopentene, hex-1, 3-dienyl or the like.

Further, the alkynyl refers to a hydrocarbon group selected from straight or branched chains, and including at least one c≡c triple bond therein. Alkynyl groups having 2 to 6 carbon atoms are preferred, such as ethynyl, propynyl, but-1, 3-dialkynyl, or the like.

Further, the cycloalkyl group means a monocyclic hydrocarbon group selected from saturated monocyclic hydrocarbon groups. Monocyclic cycloalkyl groups having 3 to 6 carbon atoms are preferred, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or other similar groups.

Further, the cycloalkenyl group refers to a monocyclic hydrocarbon group selected from unsaturated, and which contains at least one c=c double bond, but is not completely conjugated. Cycloalkenyl groups having 3 to 6 carbon atoms are preferred, such as cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, or the like.

Further, the aryl group refers to a group selected from the group consisting of: (a) Such as a 5-to 6-membered carbocyclic aromatic monocyclic ring, for example, a furan ring, thiophene ring, benzene ring, pyridine ring, or the like; (b) A 7-to 12-membered bicyclic ring system wherein at least one ring is a carbocyclic aromatic ring, such as naphthalene or 1,2,3, 4-tetrahydroquinoline, and the like; (c) Such as 10-15 membered tricyclic ring systems, wherein at least one ring is a carbocyclic aromatic ring, such as fluorene or acridine, and the like. For example, aryl is selected from 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered cycloalkyl or a heterocyclic ring optionally containing at least one heteroatom selected from N, O or S, provided that the point of attachment is on the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused to the heterocyclic ring, and the point of attachment can be on the carbocyclic aromatic ring or on the cycloalkyl when the carbocyclic aromatic ring is fused to the cycloalkyl. However, aryl groups do not include heterocyclic groups or overlap heteroaryl groups, which are defined below, respectively. Thus, if one or more carbocyclic aromatic rings are fused to a heterocyclic aromatic ring, the resulting ring system is heteroaryl, as defined herein, rather than aryl.

Further, the heteroaryl group refers to a group selected from the group consisting of: (a) A 5-6 membered aromatic monocyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O or S, the remaining ring atoms being carbon; (b) An 8-12 membered bicyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O or S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring; (c) An 11-15 membered bicyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O or S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. For example, heteroaryl groups include 5-7 membered heterocyclic aromatic rings fused to 5-7 membered cycloalkyl rings. For the fused bicyclic heteroaryl ring system, wherein only one ring contains at least one heteroatom, the point of attachment may be on the heteroaromatic ring or the cycloalkyl ring.

Further, the heterocyclic group refers to a ring selected from the group consisting of: 4-16 membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated rings containing at least one carbon atom in addition to 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen. Also referred to are aliphatic spirocyclic rings comprising at least one heteroatom selected from N, O and S, provided that the point of attachment is on the heterocycle. The ring may be saturated or contain at least one double bond. The point of attachment may be a carbon atom or a heteroatom in the heterocycle.

Further, the condensed heterocyclic ring refers to a polycyclic ring system such as a bi-or tri-cyclic ring system in which two rings share only two ring atoms and one bond and in which at least one non-C atom is contained in the ring atoms. Examples of the condensed heterocyclic ring may include (a) a condensed bisheterocycloalkyl group such as a bisheterocyclic ring composed of an arrangement of 7 to 12 ring atoms selected from the above-mentioned [4,4], [4,5], [5,6] and [6,6] ring systems; (b) A fused bicyclic heteroaryl ring, such as the 8-to 12-membered bicyclic heteroaryl ring described above; (c) Fused tricyclic heteroaryl rings such as the 11-15 membered tricyclic heteroaryl rings described above, for example pyrazolo [1,5-a ] quinazoline, pyrazolo [1,5-c ] quinazoline, pyrrolo [1,2-a ] quinazoline, pyrazolo [1,5-a ] pyrido [3,2-e ] pyrimidine, pyrazolo [1,5-a ] pyrido [3,4-e ] pyrimidine, pyrazolo [1,5-a ] pyrido [2,3-e ] pyrimidine, pyrazolo [1,5-a ] pyrido [4,3-e ] pyrimidine, and the like; (d) a fused bicyclic or tricyclic heterocyclyl ring as described above.

Further, the compounds may contain an asymmetric center and thus may exist as enantiomers. When the lactam-containing tricyclic fused heterocyclic compounds have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers are among the broader classes of stereoisomers. All of these possible stereoisomers include substantially pure resolved enantiomers (meaning that the target stereoisomer comprises no more than 10wt% of any other stereoisomer), racemic mixtures and diastereomeric mixtures thereof. Unless otherwise indicated, reference to one isomer applies to any possible isomer. When the isomer composition is not specifically indicated, all possible isomers are included.

When the compound contains olefinic double bonds, these double bonds are meant to contain, unless otherwise specifiedEAndZgeometric isomers.

Some compounds may exist at different hydrogen attachment points, known as tautomers. For example, comprising carbonyl-CH ₂ Compounds of C (O) -groups (keto) may undergo tautomerism to form hydroxy-ch=c (OH) -groups (enol). Individual keto and enol forms, and mixtures thereof, are also included when applicable.

Further, the acceptable salts refer to salts whose cations or anions are known and which are useful in forming purposes in the art, including (a) suitable salts having a base, for example, salts formed from compounds of formula (I) containing a carboxyl group, including salts of alkali metals (such as sodium and potassium), alkaline earth metals (such as calcium and magnesium), ammonium and amines; (b) Suitable salts with acid groups, for example salts formed with compounds of formula (I) containing an amino group, include salts with inorganic acids, for example hydrochloride, sulphate, sulphite, phosphate, hydrogen phosphate or nitrate, and salts with organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, salicylic acid or oxalic acid.

In addition, if the compound is obtained as an acid addition salt, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salt may be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, consistent with conventional procedures for preparing acid addition salts from basic compounds. Those of skill in the art will appreciate the variety of synthetic methods that can be used to prepare pesticidally acceptable addition salts without undue experimentation.

The present invention also provides an insecticide composition comprising:

(a) 0.001 to 99.99wt% of the tricyclic fused heterocyclic compound containing lactam, or an agropharmaceutically acceptable salt thereof, or a combination thereof; and

(b) A pesticidally acceptable carrier and/or excipient.

Further, the lactam-containing tricyclic fused heterocyclic compound of the present invention can be prepared as an active compound in a conventional manner to a pesticidal composition. These active compounds can be combined into conventional formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules or aerosols, natural and synthetic materials impregnated with the active substance, microcapsules in polymers, coating compounds for seeds, and formulations for use with combustion devices, such as smoking cartridges, smoking cans or trays, and Ultra Low Volume (ULV) cold or hot fog formulations.

These formulations can be produced by known methods, for example by mixing the active compound with extenders, which are diluents or carriers, liquid or liquefied gas or solid, and optionally surfactants, i.e. emulsifiers and/or dispersants and/or foam formers. For example, when water is used as the extender, organic solvents may also be used as adjuvants.

Basically, it is suitable to use a liquid solvent as a diluent or carrier, such as: aromatic hydrocarbons such as xylene, toluene or alkyl naphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzene, vinyl chloride or dichloromethane; aliphatic hydrocarbons, such as cyclohexane, paraffin or mineral oil fractions; alcohols, such as ethanol or ethylene glycol, and their ethers and lipids; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; or less commonly polar solvents such as dimethylformamide, dimethylsulfoxide, or water. By diluent or carrier for the liquefied gas is meant a liquid which will become a gas at normal temperature and pressure, for example an aerosol propellant such as halogenated hydrocarbons, butane, propane, nitrogen or carbon dioxide.

The solid carrier may be ground natural minerals such as kaolin, clay, talc, quartz, activated clay, montmorillonite or diatom; the solid support may be ground synthesized minerals such as highly dispersed silicic acid, alumina or silicate. The solid support for the particles can be crushed and graded natural zircon, such as calcite, marble, pumice, sepiolite or dolomite; the solid support for the particles may also be particles synthesized from inorganic and organic coarse powders; the solid support for the particles may also be particles of organic material, such as wood dust, coconut husk, corn cobs or tobacco stems.

Nonionic and anionic emulsifiers can be used as emulsifiers and/or foam formers. Such as polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates, and albumin hydrolysates. The dispersant includes substances such as lignin sulfite waste liquor or methylcellulose.

Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions, for example acacia, polyvinyl alcohol and polyvinyl acetate, can be used in the formulation. Colorants such as inorganic dyes, e.g. iron oxide, cobalt oxide or Prussian blue, and organic dyes, e.g. azo dyes or metallic phthalocyanine dyes, may also be used in the formulation; trace nutrients such as salts of iron, manganese, boron, copper, cobalt, aluminum, and zinc may also be used in the formulation.

These active compounds of the present invention may be present in commercial formulations or in dosage forms prepared from these formulations in admixture with other active compounds including, but not limited to: insecticides, bactericides, acaricides, nematicides, fungicides, growth control agents and the like.

In addition, the active compounds according to the invention can also be present in their commercial formulations as a mixture with synergists in the dosage forms used which are prepared from these formulations. Synergists are compounds that enhance the action of an active compound, which may not be necessary because of its own activity.

These formulations generally comprise 0.001 to 99.99wt% of the lactam-containing tricyclic fused heterocyclic compound, preferably 0.01 to 99.9wt%, more preferably 0.05 to 90wt%.

The concentration of the active compound in the dosage form employed from commercial preparations can vary widely. The concentration of active compound in the dosage form may be between 0.0000001 and 100% (g/v), preferably between 0.0001 and 1%.

The invention also provides application of the agricultural composition in preparing pesticides for killing or preventing agricultural and forestry pests, sanitary pests or pests harmful to animal health.

Further, the insecticide is a generic term for a substance having an effect of controlling all the above-mentioned pests.

Preferably, the agroforestry pests, hygiene pests include lepidopteran, hymenoptera, hemipteran, coleoptera, diptera, blattaria, orthoptera or thysanoptera pests.

Preferably, the animal health-damaging pests are animal parasitic fleas and/or acarids;

preferably, the pest is a piercing-sucking or chewing type mouth gag pest.

Still further, examples of such pests include, but are not limited to, coleopteran insects: for example, the maize weevil @Sitophilus zeamais) Radix Et rhizoma Rhei and radix Et rhizoma ValerianaeTribolium castaneum) Chinese ladybug seedHenosepilachna vigintioctomaculata) Baxingjingchuang (a Chinese ladybug)Henosepilachna sparsa) The rater with fine chestAgriotes fusciollis) Radix seu herba Chloranthi HeterophylliAnomala cupripes) "SiwenjiujiujiujiujiujiujiujiujiujiPopillia quadriguttata) Rhizoma Solani Tuber osi leaf squama ManisMonolepta hieroglyphica) Radix seu folium PiniMonochamus alternatus) Root of Oryza sativa LEchinocnemus squameus) Radix seu folium PaulowniaeBasiprionota bisignata) Radix seu folium HeterophyllaeAnoplophora chinensis) Radix seu folium Mori and radix TianchiApripona germari) Bark beetle at umbilical abdomenSoclytus schevy) Flea beetle with curved stripPhyllotreta striolata) Cucumber flea beetleEpitrix cucumeris) Tomato, flea beetle and its production processEpitrix fuscula) Or fine chest flammulina velutipesAgriotes fuscicollis) Etc.; lepidopteran insects: for example, gypsy moth @Lymantria dispar) Curtain caterpillarMalacosoma neustria testacea) Radix seu cortex Buxae JaponicaeDiaphania perspectalis) The big bag moth isClania variegata) The yellow thorn moth isCnidocampa flauescens) Chinese pine caterpillarDendrolimus punctatus) The ancient moth isOrgyia antiqua) Radix et rhizoma Gaultheriae YunnanensisParanthrene tabaniformis) Spodoptera litura (L.) HeimSpodoptera litura) Chilo suppressalisChilo suppressalis) Oryza incertulas (L.) kuntzeOstrinia nubilalis) Pink mothEphestia cautella) Cotton roll mothAdoxophyes orana) Chestnut mothlaspyresia splendana) Radix seu herba Gei aleppiciAgrotis fucosa) Disc of cabbage butterflyPieris rapae) The Chilo suppressalis is Galleria mellonella) Beet armywormSpodoptera exigua) Cowpea pod borerMaruca testulalisGeyer and plutella xylostellaPlutella xylostella) The orange moth is a kind of Chinese characterPhyllocnistis citrella) Oriental myxowormMythimna separata) Or spodoptera frugiperdaSpodoptera frugiperda) Etc.; hemipteran insects: for example, apolygus lucorumStephanitis nashi) Radix seu folium Heterophyllae CryptophannaceaeNephotettix cincticeps) Scale of PaederiaUnaspis yanonensis) Chinese peach aphidMyzus persicae) Cotton aphidAphis gossydii) Bean aphidAphis craccivora) Or whiteflyBemisia tabaci) Etc.; insects of the order orthoptera: such as mole cricket of africaGryllotalpa africana) Or Asia migratory locustLocus migratoria) Etc.; hymenoptera insect: for example, solenopsis invicta @Solenopsis invicta) Or the hornet is a hornetTremex fuscicornis) Etc.; insects of the order blattaria: for example, german cockroach @ isBlattella germanica) Periplaneta americana (Periplaneta americana)Periplaneta american) Or termite in the familyCopotermes formosamus) Etc.; diptera insects: for example, liriomyza sativae @Liriomyza sativaeBlanchard, housefly @Musca domestica) Aedes aegypti mosquitoAedes aegypti) Fly speciesDelia platura) Kuh mosquito with light colorCulex pipiens pallens) Culex tiredCulex pipiens quinquefasciatus) Or anopheles sinensisAnopheles sinensis) Etc.; thysanoptera: for example, thrips oryzaeHaplothrips aculeatus) Or frankliniella occidentalisFrankliniella occidentalis). Plant parasitic nematodes: such as root-knot nematodes, root-rot nematodes, aphelenchus xylophilus or pine nematodes, etc. Pests which harm animal health include cattle and ticksBoophilus microplus) Haemaphysalis longifolia (L.) KummerHaemaphysalis longicornis) Small glazed eye tickHyalomma anatolicum) Fly of cowHypodermaspp.; fasciola hepatica; Fasciola hepatica) Monitz belliana (Fr.) KummerMoniezia blanchard) Oriental eelwormsOstertagiaspp.) and protozoaTrypanosoma enansi) Or Ba Bei Sichong%Babesia bigemina) Etc.

Preferably, the insecticide is applied directly to the pest or to the locus where it contacts.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a tricyclic fused heterocyclic compound containing lactam with a novel structure, which has high killing activity on agriculture and forestry pests, sanitary pests and the like, particularly high activity on culex lachryma, has the characteristic of low toxicity on non-target organisms such as earthworms, fishes and the like, and has higher safety on the environment; has good application prospect in pest control.

Detailed Description

The present invention is further illustrated below with reference to specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.

Reagents and materials used in the following examples are commercially available unless otherwise specified.

In the examples of activity measurement and toxicity measurement, since the bodies of plutella xylostella, aphid, culex pallidum and the like are small, the activity of zebra fish and the like is strong, and earthworms are not easy to separate because of mollusks and the like, it is difficult to ensure that the numbers of test organisms in each treatment and each repetition are consistent, but the numbers of test organisms fluctuate in a small range as much as possible, so the mortality calculated in table 3 may not be an integer.

In the examples of activity assays and toxicity assays, the control group was set up to evaluate whether this bioassay was effective, and when the mortality rate of the control group exceeded 10%, it was determined that the treatment required retesting.

EXAMPLE 1 Synthesis of target Compound Using procedure A

Method A:

x, Y, Z are each a leaving group, such as halogen, hydroxy, or the like. The base is common potassium carbonate, cesium carbonate, etc. or a stronger organic base. The metal catalyst is a common copper or palladium catalyst, such as cuprous iodide and the like. The shielding gas is a common inert gas such as argon, nitrogen, etc. The solvent is common solvent such as N, N-dimethylformamide, tetrahydrofuran, etc.

Taking compound C6 as an example, the specific synthesis process is as follows:

step 1: ethyl 2, 3-dicyanopropionate (1.0 mmol) was added to 20.0. 20.0 mL ethanol, and the reaction mixture was stirred vigorously, hydrazine hydrate (2.0 mmol) was added to the reaction mixture, and the mixture was refluxed under heating, and after the reaction of ethyl 2, 3-dicyanopropionate was completed, the heating was stopped, and the mixture was cooled to room temperature. After the reaction solution was concentrated in vacuo, extracted with ethyl acetate and water, and ethyl acetate obtained by the extraction was concentrated in vacuo to give intermediate 1 (5-amino-1H-pyrazole-3-cyano) as a white solid, intermediate 1 was used directly in the next step without further purification.

Step 2: the N, N-dimethylformamide mixture of intermediate 1 (1.0 mmol), 2, 6-dichloro-4- (trichloromethyl) -benzoyl chloride (1.0 mmol), and cesium carbonate (0.5 mmol) was vigorously stirred at 140℃for 24 hours under nitrogen. Cooled to room temperature, the mixture was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography to give the title compound 2-cyano-6-chloro-8-trifluoromethyl-4, 5-dihydropyrazolo [1,5- α ] quinazolinone (two step yield: 38%).

Step 3: an anhydrous toluene mixture of 2-cyano-6-chloro-8-trifluoromethyl-4, 5-dihydropyrazolo [1,5- α ] quinazolinone (0.1 mmol), trifluoromethylsulfinyl chloride (0.5 mmol), and dimethylamine p-toluenesulfonate salt was heated at 100deg.C with stirring for 24 hours under nitrogen. Cooling to room temperature, vacuum concentrating, and purifying the residue by flash column chromatography to obtain the target compound 2-cyano-6-chloro-8-trifluoromethyl-3-trifluoromethyl sulfinyl-4, 5-dihydropyrazolo [1, 5-alpha ] quinazolinone, yield: 59%.

Other analogous compounds are prepared by reference to the C6 synthesis (wherein the key ring-forming step is also presentBioorganic&Medicinal Chemistry Letters, 2017, 27, 3201;Tetrahedron Letters, 2015, 56, 1367;Synthetic Communications, 2015, 45, 2426;Russian Journal of Organic ChemistryThe documents 2005, 41, 1071, WO2018213712, WO2015065338, etc. use similar cyclization methods, except that different starting materials are selected for the reaction according to the target compounds or are derived from the synthesized target products by alkylation, hydrolysis, esterification or amidation or reductive oxidation. Wherein the 3-position of the compound is converted from hydrogen to-SR ⁹ 、-S(O)R ⁹ 、-S(O) ₂ R ⁹ The same groups can be referred toEuropean Journal of Organic ChemistrySulfur dichloride, alkyl disulfide compounds, and thioreagents such as trifluoromethylsulfinyl chloride used in the literature such as the 2020, 2020, 3997, jiang Xunyuan doctor paper (2019) are completed.

EXAMPLE 2 Synthesis of target Compound Using procedure B

Method B:

x is hydrogen, alkyl or a common protecting group, Z, Y is a leaving group. The alkali is common sodium acetate, sodium ethoxide, etc. or stronger organic alkali. The shielding gas is a common inert gas such as argon, nitrogen, etc. The solvent is common solvent such as N, N-dimethylformamide, tetrahydrofuran, ethanol, etc.

Taking compound C426 as an example, the specific synthesis process is as follows:

step 1: to 20 ml of concentrated hydrochloric acid at-5℃under nitrogen, 2-amino-4-cyano-6-methylbenzoic acid (3.0 mmol) was added, followed by sodium nitrite (3.0 mmol) to the reaction solution. The temperature was raised to 0℃and the reaction was vigorously stirred for 1 hour. Tin dichloride dihydrate (15 mmol) was weighed and dissolved in 4 mL concentrated hydrochloric acid and then added to the above low temperature reaction solution. The temperature was raised to 20℃and the reaction was vigorously stirred for 1 hour. After the reaction was completed, intermediate 1 (2-hydrazino-4-cyano-6-methylbenzoic acid) was obtained by filtration, and intermediate 1 was used in the next step without further purification.

Step 2: a mixture of intermediate 1 (1.0 mmol) and 4, 4-trifluoro-3-cyanoacetone (1.0 mmol) in acetic acid (3 mL) was reacted in a 150℃microwave reactor for 20 minutes. Cooling to room temperature, vacuum concentrating, purifying the residue by column chromatography to obtain the target compound 8-cyano-6-methyl-2-trifluoromethyl-4, 5-dihydropyrazolo [1, 5-alpha ] quinazolinone, yield: 64%.

Step 3: reference is made to the aboveEuropean Journal of Organic ChemistryReference 2020, 2020, 3997 to diethyl disulfide, ferric bromide and elemental iodine to convert 8-cyano-6-methyl-2-trifluoromethyl-4, 5-dihydropyrazolo [1, 5-alpha ]]Conversion of the hydrogen at the 3-position of the quinazolinone to ethylsulfinyl, the compound 8-cyano-6-methyl-2-trifluoromethyl-3- (ethylsulfinyl) -4, 5-dihydropyrazolo [1, 5-alpha ]]Quinazolinone, yield: 65%.

Step 4: 8-cyano-6-methyl-2-trifluoromethyl-3- (ethylsulfinyl) -4, 5-dihydropyrazolo [1, 5-alpha ] quinazolinone (0.2 mmol), trifluoropropionyl chloride (0.5 mmol) and anhydrous toluene of potassium carbonate are stirred and heated at 100deg.C for 24 hr under nitrogen. Cooling to room temperature, vacuum concentrating, and purifying the residue by column chromatography to obtain the target compound 8-cyano-6-methyl-2-trifluoromethyl-3- (ethylsulfinyl) -4- (3, 3-trifluoropropionyl) -4, 5-dihydropyrazolo [1, 5-alpha ] quinazolinone, yield: 78%.

Other similar compounds were prepared by reference to the synthetic method of C426 (wherein the key ring-forming step is also presentJournal of Medicinal Chemistry, 2017, 60, 9691;Bioorganic&Medicinal Chemistry Letters, 2014, 24, 2693;Journal of Medicinal Chemistry, 2013, 56, 7458;Bioorganic&Medicinal Chemistry Letters, 2009, 19, 4196;Molecular Diversity, 2003, 7, 161;Journal of Heterocyclic Chemistry, 1989, 26, 713;Journal of Heterocyclic ChemistryThe documents 1969, 6, 947, WO2018213712, WO2015065338, etc. use a similar cyclization process, except that different starting materials are selected for the reaction or are derived from the synthesized target product by alkylation, hydrolysis, esterification or amidation or reductive oxidation, depending on the target compound. R at 4-position ³ The group is obtained by substituting the above target compound with an amino group.

EXAMPLE 3 Synthesis of target Compound Using method C

Method C:

x, Z is a leaving group. The base is a common organic base. The shielding gas is a common inert gas such as argon, nitrogen, etc. The solvent is common solvent such as tetrahydrofuran, ethanol, etc.

Taking compound C316 as an example, the specific synthesis process is as follows:

step 1: to a solution of 2-cyano-methyl-acetimidate (3.0 mmol) and 2-amino-3-methoxy-5-nitrobenzoic acid (3.0 mmol) in mixed acetonitrile under nitrogen protection was added sodium ethoxide (6.0 mmol). The reaction was heated with vigorous stirring for 1 hour. After the reaction was completed, cooled to room temperature, concentrated in vacuo, and the residue was purified by column chromatography to obtain intermediate 1 (2-acetonitrile-4-hydroxy-8-methoxy-6-nitroquinazoline) in 49% yield.

Step 2: to a solution of intermediate 1 (1.0 mmol) and cesium carbonate (2.0 mmol) in acetonitrile was added benzyl bromide (0.8 mmol). The reaction was stirred vigorously at room temperature for 24 hours. After the reaction, the mixture was concentrated in vacuo, and the residue was purified by column chromatography to give intermediate 2 (2-acetonitrile-3-benzyl-8-methoxy-6-nitro-3, 4-dihydroquinazolinone), yield: 46%.

Step 3: hydroxylamine hydrochloride (10 mmol) and sodium bicarbonate (10 mmol) were dissolved in ultrapure water, stirred and dissolved, then added into an ethanol solution of intermediate 2 (1.0 mmol), reacted for 2 hours at 20 ℃, the reaction solution was cooled to 0 ℃ and white solid precipitated, intermediate 3 (2-ethylamine oxime-3-benzyl-8-methoxy-6-nitro-3, 4-dihydroquinazolinone) was obtained by filtration, and intermediate 3 was directly carried out in the next step without purification. Intermediate 3 was dissolved in excess acetic anhydride, heated to 100 ℃ for reaction for 4 hours, cooled to 0 ℃ after the reaction was completed, and white solid precipitated, and intermediate 4 (O-acetyl-2-ethylamino-oxime-3-benzyl-8-methoxy-6-nitro-3, 4-dihydroquinazolinone) was obtained by filtration in a two-step yield of 72%.

Step 4: intermediate 4 (1.0 mmol) was dissolved in excess ethanol and heated to 80 ℃ for 1 hour, after completion of the reaction, concentrated in vacuo and the residue purified by column chromatography to give the title compound in yield: 76%. The 2-amino methylation of the compound by adopting the derivatization method converts the hydrogen at the 3-position into a thio compound, and the thio compound is oxidized into a sulfoxide compound to finally obtain the target end product.

Other analogous compounds are prepared by synthetic methods with reference to compound C316 (wherein the key ring-forming step is also providedJournal of Heterocyclic Chemistry, 1997, 34, 1251;Chemische BerichteThe documents 1962, 95, 3042, etc. use a similar cyclization method), except that different raw materials are selected for reaction according to the target compounds, or the synthesized target products are derived by alkylation, hydrolysis, esterification or amidation or reduction oxidation. Amino in the 2-position can be converted into halogen through diazonium reaction or into heteroalkyl through alkylation, and the like, R in the 4-position ³ The group is obtained by substituting the above target compound with an amino group. Wherein some of the compounds are used in the form of ringsTetrahedron, 2013, 69, 6461;Chemistry and Chemical Engineering, 1994, 36, 45;Journal of Heterocyclic ChemistryMethods reported in the literature, 1984, 21, 1049, etc.

The structures of the partial compounds of the present application are shown in Table 1, and the nuclear magnetic resonance hydrogen spectra and mass spectrum data of the partial compounds are shown in Table 2.

TABLE 1 partial Structure of Compounds

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Table 2 nmr hydrogen spectrum and mass spectrum data of partial compounds

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EXAMPLE 4 determination of insecticidal Activity

(1) Insecticidal activity against plutella xylostella

Plutella xylostella (Plutella xylostella) mothPlutella xylostella) Belongs to lepidoptera pests and is provided with a chewing type mouth gag. The plutella xylostella is evaluated as 'ten plant pests in the world' by the international agricultural and biological science center, is one of the most main pests on special vegetables-vegetable centers with the largest cultivation area in the south China, and can harm the whole growth cycle of the vegetable centers. The plutella xylostella has the characteristics of strong reproductive capacity, short generation period and annual reproduction, and causes more prevention and control times and large dosage. The 2-year larva of plutella xylostella is used as a test object, and a leaf dipping feeding method is adopted for testing.

The operation process comprises the following steps: each compound to be tested is accurately weighed, and a corresponding volume of dimethyl sulfoxide is added to prepare a mother solution with the concentration of 10 g/L, and the mother solution is gradually diluted to a test liquid with the concentration of 400 mg/L (equivalent to 400 ppm) by using an aqueous solution containing 0.5 Tween-80 per thousandth. Preparing leaf discs from the leaves of the cleaned cabbage seedlings by using a puncher with the diameter of 1.0 cm, immersing the leaf discs in the liquid medicine for 5 seconds, taking out, naturally airing, and transferring into a clean vessel. And (3) inoculating about 35 larvae of plutella xylostella 2 years into the vessel, and raising at a constant temperature of 23 ℃. The experimental results were averaged with 3 replicates per concentration. The control group was an aqueous solution containing 0.5% Tween-80. After 24 hours, the death number of the plutella xylostella is counted, and the death rate is calculated according to a formula: mortality (%) = number of dead insects/total number of insects x 100%. The results are shown in Table 3.

(2) Insecticidal Activity against aphids

Aphids belong to homoptera pests, have piercing-sucking mouthparts, and are common vegetable pests. The aphids have strong fertility, can reproduce 20-30 generations in one year, have prominent generation overlapping phenomenon and have drug resistanceSevere occurrence occurred. By bean aphidAphis craccivora) The aphids are used as test objects and are tested by adopting a dipping method.

The operation process comprises the following steps: each compound to be tested is accurately weighed, and a corresponding volume of dimethyl sulfoxide is added to prepare a mother solution with the concentration of 10 g/L, and the mother solution is gradually diluted to a test liquid with the concentration of 400 mg/L (equivalent to 400 ppm) by using an aqueous solution containing 0.5 Tween-80 per thousandth. After the wingless grown aphids are stably sucked on the bean sprouts, the wingless grown aphids and the bean sprouts are immersed into the test liquid medicine together, taken out after 5 seconds, naturally dried and fed at the constant temperature of 23 ℃. The experimental results were averaged with 3 replicates per concentration. The control group was prepared by taking an equal amount of an aqueous solution containing 0.5% Tween-80 as a blank test solution. After 24 hours, the number of dead aphids was counted and the mortality was calculated according to the formula: mortality (%) = number of dead insects/total number of insects x 100%. The results are shown in Table 3.

(3) Insecticidal activity against culex pallidum

Culex light colorCulex pipiens pallens) Belongs to the subfamily culex and has the capability of transmitting viral diseases such as yellow fever, dengue fever and the like. The culex pallidum 3-instar larvae are used as test objects, and the insect dipping method is adopted for testing.

The operation process comprises the following steps: each compound to be tested is accurately weighed, and a corresponding volume of dimethyl sulfoxide is added to prepare a mother solution with the concentration of 10 g/L, and the mother solution is gradually diluted to a test liquid with the concentration of 100 mg/L (equivalent to 100 ppm) by using an aqueous solution containing 0.1 thousandth of Tween-80. And (3) inoculating 30 heads of 3-year-old culex larvae with the same size into the test liquid medicine, and raising at the constant temperature of 25 ℃. The experimental results were averaged with 3 replicates per concentration. The control group was prepared by taking an equal amount of an aqueous solution containing 0.1% Tween-80 as a blank test solution. After 24 hours, the death rate of the culex larvae is calculated according to the formula: mortality (%) = number of dead insects/total number of insects x 100%. The results are shown in Table 3.

Example 5 non-target biotoxicity example

(1) Acute toxicity to Lumbricus

Soil is an important environmental carrier for pesticides,earthworms are one of the most important representative groups of biomass in soil animal systems, play an irreplaceable role in maintaining the functions of the soil ecosystem, and are widely applied to ecological risk evaluation of chemical pollutants. Selecting Eisenia foetidaEisenia foetida) Adult earthworms are the test objects and are tested according to the operation standard of the 15 th part of the chemical pesticide environmental safety evaluation test rule.

The operation process comprises the following steps: accurately weighing each compound to be tested, respectively adding corresponding volumes of acetone to prepare mother liquor with the concentration of 1.0 g/L, adding the mother liquor into a proper amount of artificial soil, and fully and uniformly stirring to ensure that the concentration of the compound to be tested in the artificial soil is 10 mg/kg. About 10 earthworms are inoculated into the artificial soil, the earthworms are fed at 21 ℃ and with the humidity of 70%, 3 times of repetition are set for each concentration, and the experimental result is taken as the average value of 3 times of results. The control group is that the same amount of acetone without adding medicines is added into artificial soil. After day 7, the death number of earthworms is counted, and the death rate is calculated according to the formula: mortality (%) = number of earthworms dead/total number of earthworms x 100%. The results are shown in Table 3.

(2) Acute toxicity to fish

The fish toxicity test is one of main methods for evaluating the environmental risk of pollutants, zebra fish is taken as a recognized model aquatic organism, the homology with human genes reaches 87%, and the risk evaluation result has strong referenceability. Selecting zebra fishDanio rerio) The juvenile fish is used as a test object, and the test is carried out according to the operation standard of the 12 th part of the chemical pesticide environmental safety evaluation test criterion.

The operation process comprises the following steps: accurately weighing each compound to be tested, adding corresponding volumes of acetone respectively to prepare mother solution with the concentration of 10 g/L, and gradually diluting the mother solution to test liquid medicine with the concentration of 10 mg/L by using an aqueous solution containing 0.1 Tween-80 per thousandth. And (5) inoculating about 10 heads of zebra fish with the same size into the test liquid medicine, and raising the zebra fish at a constant temperature of 25 ℃. The experimental results were averaged with 3 replicates per concentration. The control group was prepared by taking an equal amount of an aqueous solution containing 0.1% Tween-80 as a blank test solution. After 48 hours, the death number of the zebra fish is counted, and the death rate is calculated according to the formula: mortality (%) = number of dead fish/total number of fish x 100%. The results are shown in Table 3.

Table 3 determination of insecticidal Activity of some of the compounds against test pests and toxicity against test non-target organisms

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As shown in the table, the compound has high killing activity on agriculture and forestry pests, animal parasitic pests, sanitary pests and the like, particularly has good activity on lepidoptera, homoptera, diptera and other pests, and after the compound is treated, the mortality rate of the pests is over 90 percent, the mortality rate data is over 95 percent, and the compound has the characteristic of low toxicity on non-target organisms such as Eisenia rubra, zebra fish and the like, and has the safety on the environment.

EXAMPLE 6 preparation of pesticidal compositions containing the Compound of the present invention

(1) Oily suspension

The following components were prepared in proportion: 25% (weight percent, as described below) of any of the above compounds; 5% polyoxyethylene sorbitol hexaoleate; 70% higher aliphatic hydrocarbon oil. The components were milled together in a sand mill until the solid particles fell below 5 microns. The resulting viscous suspension may be used as such, but may also be used after emulsification in water.

(2) Aqueous suspension

The following components were prepared in proportion: 25% of any of the above compounds; 3% hydrated attapulgite; 10% calcium lignosulfonate; 0.5% sodium dihydrogen phosphate; 61.5% water. The components were milled together in a ball mill until the solid particles fell below about 10 microns. The aqueous suspension can be used as such.

(3) Bait agent

The following components were prepared in proportion: 0.1 to 10% of any one of the above compounds; 80% wheat flour; 19.9 to 10 percent of molasses. These components were thoroughly mixed and formed into a bait shape as required. The edible baits may be dispersed to a locus where sanitary pests infest, for example furniture or industrial sites such as kitchens, hospitals or shops or outdoor areas, to control pests by oral ingestion.

Comparative example 1 comparison of insecticidal Activity

To demonstrate the further improvement in activity of the novel compounds obtained in accordance with the present application, compounds of nearer structure to the selected compounds of the present application were selected from CN108003162B and CN108129481B as representative, synthesized according to the preparation methods described in the prior art, and compared with the insecticidal activity of the selected representative (based on the higher number of compounds synthesized in accordance with the present application, selected part of compounds as representative) compounds of the present application, the procedure and parameters of example 4 were referenced for the determination method. The structure of the selected compounds in CN108003162B and CN108129481B are shown in table 4, and the results of insecticidal activity are shown in table 5.

Table 4 Structure of selected Compounds from CN108003162B and CN108129481B

TABLE 5 comparison of insecticidal Activity

As can be seen from the table, compared with the insecticidal activity of the compound in CN108003162B, CN108129481B, the insecticidal activity of the compound obtained by the invention is further improved, and the death rate of pests is almost 100% after the selected compound is treated, so that the novel synthesized tricyclic fused heterocyclic compound containing the lactam has higher insecticidal activity on agricultural and forestry pests, sanitary pests and the like.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. The tricyclic fused heterocyclic compounds containing the lactam and the pharmaceutically acceptable salts thereof are characterized in that the tricyclic fused heterocyclic compounds containing the lactam have a structure shown in a formula (I):

R ² is-SR ⁹ 、-S(O)R ⁹ or-S (O) ₂ R ⁹ ；

2. The lactam-containing tricyclic fused heterocyclic compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ Is halogen, -CN, -CO ₂ R ⁸ Or C _1~6 A haloalkyl group; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl or C _1~6 A haloalkyl group; r is R ⁸ Is C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ⁹ Is C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹⁰ Is amino or C _1~6 Alkyl, wherein the amino group, alkyl group are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, -NO ₂ 、-CN、-NH ₂ or-OH.

3. The lactam-containing tricyclic fused heterocyclic compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ Is hydrogen, C _1~6 Alkyl, C _2~6 Alkenyl or C _2~6 Alkynyl, wherein alkyl or alkenyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl, C _1~6 Haloalkyl or C _1~6 A heteroalkyl group; r is R ⁸ Is C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁹ Is C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, -NO ₂ 、-CN、-NH ₂ or-OH.

4. The lactam-containing tricyclic fused heterocyclic compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is-S (O) R ⁹ or-S (O) ₂ R ⁹ ；R ¹ Is halogen, -CN, -CO ₂ R ⁸ 、C _1~6 Alkyl or C _1~6 A haloalkyl group; r is R ³ Is hydrogen、-COR ¹⁰ 、C _1~6 Alkyl, C _2~6 Alkenyl or C _2~6 Alkynyl, wherein alkyl, alkenyl or alkynyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl, C _1~6 Haloalkyl, -OR ¹² 、-COR ¹² 、-CO ₂ R ¹² 、-CONR ¹² R ¹³ or-NR ¹² R ¹³ ；R ⁸ Is C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁹ Is C _1~6 Alkyl, C _1~6 Heteroalkyl, aryl or heteroaryl, wherein alkyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ¹⁰ Is amino or C _1~6 Alkyl, wherein the amino or alkyl groups are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _1~6 Heteroalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, aryl, -NO ₂ 、-CN、-NH ₂ or-OH; r is R ¹² And R is ¹³ Each independently is hydrogen, C _1~6 Alkyl or C _1~6 A heteroalkyl group.

5. The lactam-containing tricyclic fused heterocyclic compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is-S (O) R ⁹ or-S (O) ₂ R ⁹ ；R ¹ Is halogen, -CN, C _1~6 Alkyl or C _1~6 A haloalkyl group; r is R ³ Is hydrogen, -COR ¹⁰ 、C _1~6 Alkyl or C _2~6 Alkenyl in which the alkyl or alkenyl groups are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl, C _1~6 Haloalkyl, -OR ¹² 、-COR ¹² or-CO ₂ R ¹² ；R ⁹ Is C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ¹⁰ Is amino or C _1~6 Alkyl, wherein the amino or alkyl groups are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _1~6 Heteroalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, aryl, -NO ₂ 、-CN、-NH ₂ or-OH; r is R ¹² Is hydrogen, C _1~6 Alkyl or C _1~6 A heteroalkyl group.

6. The lactam-containing tricyclic fused heterocyclic compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is-S (O) R ⁹ or-S (O) ₂ R ⁹ ；R ¹ Is halogen, -CN or C _1~6 A haloalkyl group; r is R ³ Is hydrogen, -COR ¹⁰ Or C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ 、-CN、C _1~6 Alkyl or C _1~6 A haloalkyl group; r is R ⁹ Is C _1~6 Alkyl or C _1~6 Heteroalkyl, where alkyl is unsubstituted or substituted with one or more substituents R ¹¹ Substitution; r is R ¹⁰ Is amino or C _1~6 Alkyl, wherein the amino or alkyl groups are unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _1~6 Alkyl, C _1~6 Haloalkyl, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, -NO ₂ 、-CN、-NH ₂ or-OH.

7. The lactam-containing tricyclic fused heterocyclic compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is-S (O) R ⁹ or-S (O) ₂ R ⁹ ；R ¹ is-CN or C _1~6 A haloalkyl group; r is R ³ Is hydrogen or C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is hydrogen, halogen, -NO ₂ Or C _1~6 A haloalkyl group; r is R ⁹ Is C _1~6 Alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents R ¹¹ Substitution; r is R ¹¹ Is halogen, C _3~6 Cycloalkyl, C _3~6 Cycloalkenyl, -NO ₂ 、-CN、-NH ₂ or-OH.

8. An agricultural composition comprising:

(a) 0.001 to 99.99wt% of the lactam-containing tricyclic fused heterocyclic compound of any one of claims 1 to 7, or an agropharmaceutically acceptable salt thereof, or a combination thereof; and

(b) A pesticidally acceptable carrier and/or excipient.

9. Use of the agricultural composition of claim 8 in the manufacture of an insecticide for killing or preventing agroforestry pests, hygiene pests or pests that are harmful to animal health.

10. The use according to claim 9, wherein the pesticidal composition is applied directly to the pest or to the locus where it contacts.