Spirocyclopropane tetronic acid derivative, corresponding agricultural composition and application

Abstract

The invention relates to a novel spirocyclopropane tetronic acid derivative with insecticidal and acaricidal activity as well as preparation and application of the novel spirocyclopropane tetronic acid derivative. Specifically, the invention provides a compound as shown in a formula (I), and an optical isomer, a cis-trans isomer or a pharmaceutically acceptable salt thereof. The compound disclosed by the invention has obvious insecticidal and acaricidal activity, and can be used for developing novel crop insecticidal and acaricidal agents which are low in toxicity, efficient and environment-friendly. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pesticides, and in particular relates to a novel spirocyclopropanetetratonate compound with insecticidal and acaricidal activities, a preparation method and an application thereof. Background Art

[0002] The long-term use of existing pesticides has led to the development of resistance among pests, diseases, and weeds, significantly increasing pesticide usage and causing serious damage to the environment. Therefore, there is a growing demand for the discovery of new pesticides with novel mechanisms of action, such as those with higher activity against insects, mites, or weeds.

[0003] Tetronic acid compounds, with their unique chemical structure, novel mode of action, outstanding control efficacy, and resistance to drug resistance, have distinguished themselves from numerous other insecticides and acaricides, becoming a hot topic in global insecticide and acaricide research and development. The present invention addresses the technical challenges of introducing cyclopropane-containing fragments into the structure of tetronic acid compounds and conducting rational molecular design to produce new and more effective insecticides and acaricides, addressing resistance issues associated with tetronic acid compounds and enabling their application in insecticides and acaricides. Summary of the Invention

[0004] The main purpose of the present invention is to address the above problems and provide a novel spirocyclopropanetetratonate compound with novel structure and excellent insecticidal and acaricidal activity.

[0005] In order to achieve the above-mentioned object, the first aspect of the present invention provides a spirocyclopropanetetradecanate derivative, its optical isomers, cis-trans isomers, or pesticide-acceptable salts thereof, wherein the structural formula of the derivative is shown in formula (I):

[0006]

[0007] Where:

[0008] A and E are each independently selected from: hydrogen, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted benzyl, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; wherein substitution means that one or more H on the group is independently replaced by a group selected from the group consisting of hydrogen, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Halogenated alkenyl, C 2-8 Alkynyl, C 2-8Haloalkynyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Alkylthio, C 1-8 Halogenated alkylthio, C 1-8 Alkyl sulfoxide, C 1-8 Alkylsulfone, nitro, hydroxy, cyano, amino, C 6-10 Aryl or one or more selected from C 1-4 Alkyl, C 1-4 C substituted with haloalkyl, halogen and cyano 6-10 aryl;

[0009] X is O, S or NR 1 , where R 1 Selected from: hydrogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Alkylthio, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S and N, substituted or unsubstituted C 3-6 Cycloalkyl (C 1-4 )alkyl-, substituted or unsubstituted 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N (C 1-4 )alkyl-, substituted or unsubstituted phenyl (C 1-4 ) alkyl-, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S and N (C 1-4 ) alkyl-, substituted or unsubstituted C 1-4 Alkoxy (C 1-4 ) alkyl, substituted or unsubstituted C 1-8 AlkylCO-, substituted or unsubstituted C 1-8 AlkoxyCO-, substituted or unsubstituted C 1-8 AlkylSO-, substituted or unsubstituted C 1-8 AlkylSO2-, substituted or unsubstituted C 1-8 Alkoxy SO-, substituted or unsubstituted C 1-8 Alkoxy SO2-, substituted or unsubstituted C 3-6 CycloalkylCO-, benzoyl; wherein substitution means that one or more H on the group is independently substituted by a group selected from the group consisting of hydrogen, halogen, CN, nitro, hydroxyl, cyano, amino, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0010] n is 1 or 2;

[0011] G is O, S, NR 2 , substituted or unsubstituted C 1-8 Alkyl; wherein the substituted C 1-8 Alkyl refers to a group in which one or more H atoms are independently substituted by a substituent selected from the group consisting of hydrogen, halogen, hydroxy, oxo (=O), =N-OH, =N-OC 1-8 Alkyl, =N-OC 1-8 Halogenated alkyl, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, -OC 3-6 Cycloalkyl; wherein R 2 Selected from the following unsubstituted groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, C 1-8 Alkoxy, C 1-8 Alkylthio, C 6-10 Aryl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N, C 3-6 Cycloalkyl (C 1-4 )alkyl-, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N (C 1-4 )alkyl-, benzyl, C 1-4 Alkoxy (C 1-4 ) alkyl, C 1-8 AlkylCO-, C 1-8 Alkoxy CO-, C 1-8 Alkyl SO-, C 1-8 Alkyl SO2-, C 1-8 Alkoxy SO-, C 1-8 Alkoxy SO2-, C 3-6 CycloalkylCO-, benzoyl.

[0012] Preferably, A and E are each independently selected from: hydrogen, substituted or unsubstituted groups: C 1-8 Alkyl, C 3-8Cycloalkyl, phenyl, benzyl, pyridyl, pyrazolyl, thienyl, furyl or thiazolyl, biphenyl; Substitution means that one or more H atoms on the group are independently substituted by substituents selected from the group consisting of halogen, nitro, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylthio, C 1-4 Halogenated alkylthio, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl.

[0013] Preferably, R 1 Selected from: hydrogen, substituted or unsubstituted groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, C 1-8 Alkoxy, C 1-8 Alkylthio, C 6-10 Aryl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N, C 3-6 Cycloalkyl (C 1-4 )alkyl-, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N (C 1-4 )alkyl-, benzyl, C 1-4 Alkoxy (C 1-4 ) alkyl, C 1-8 AlkylCO-, C 1-8 Alkoxy CO-, C 1-8 Alkyl SO-, C 1-8 Alkyl SO2-, C 1-8 Alkoxy SO-, C 1-8 Alkoxy SO2-, C 3-6 CycloalkylCO-, benzoyl; substitution means that one or more H on the group is independently substituted by a group selected from the following groups: hydrogen, halogen, CN, nitro, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

[0014] Preferably, R 2 Selected from the following unsubstituted groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, C1-8 Alkoxy, C 1-8 Alkylthio, C 6-10 Aryl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N, C 3-6 Cycloalkyl (C 1-4 )alkyl-, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N (C 1-4 )alkyl-, benzyl, C 1-4 Alkoxy (C 1-4 ) alkyl, C 1-8 AlkylCO-, C 1-8 Alkoxy CO-, C 1-8 Alkyl SO-, C 1-8 Alkyl SO2-, C 1-8 Alkoxy SO-, C 1-8 Alkoxy SO2-, C 3-6 CycloalkylCO-, benzoyl.

[0015] Preferably, A and E are each independently selected from:

[0016] and / or,

[0017] X is selected from:

[0018] and / or, G is selected from:

[0019]

[0020] Preferably, the spirocyclopropanetetradecanate derivative is selected from:

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027] And the compounds formed by exchanging the A and E groups in compounds I-1 to VI-14, taking compound I-1 as an example, the compounds formed by replacing A in compound I-1 with H and E with phenyl.

[0028] The second aspect of the present invention provides an agricultural composition, which comprises, based on the total weight of the composition as 100%, (a) 0.001% to 99.99% by weight of the spirocyclopropanetetraonic acid derivative, its optical isomers, cis-trans isomers, or pesticide-acceptable salts, or combinations thereof; and (b) a pesticide-acceptable carrier and / or excipient.

[0029] A third aspect of the present invention provides the use of the spirocyclopropanetetronic acid derivative, its optical isomers, cis-trans isomers, or pesticide-acceptable salts, or the agricultural composition as an insecticide and acaricide for controlling agricultural plant diseases. Preferably, the spirocyclopropanetetronic acid derivative is used to control alfalfa aphids, spider mites, and diamondback moths.

[0030] The fourth aspect of the present invention provides an insecticide and acaricide and / or insecticide prevention and acaricide method, which comprises applying the spirocyclopropanetetronic acid derivative, its optical isomers, cis-trans isomers or their pesticide-acceptable salts, or the agricultural composition of the present invention to animals / plants that are or may be affected by insect pests, the surrounding soil or the environment.

[0031] The present invention also provides a method for controlling pests, comprising applying an effective acaricidal dose (10-1000 mg / L, preferably 100-500 mg / L) of the spirocyclopropanetetronic acid derivative of the present invention, its optical isomers, cis-trans isomers or their pesticide-acceptable salts or the agricultural composition of the present invention to plant seeds and / or plant leaves and / or plant fruits or the location where the plant is growing or expected to grow.

[0032] Preferably, the pests that can be used for control include (but are not limited to): (i) can be used to kill and / or control at least one pest of the order Acarina, Homoptera, Lepidoptera and / or its nymphs and / or its eggs; (ii) can be used for killing insects and / or killing mites; (iii) can be used to prepare a composition or formulation for killing and / or controlling mites, insects and / or their eggs.

[0033] In a fifth aspect, the present invention provides a composition comprising (i) a spirocyclopropanetetradecanate derivative, its geometric isomers, stereoisomers, or its pesticide-acceptable salts or prodrugs as an active ingredient; and (ii) a carrier and / or a surfactant.

[0034] Preferably, in the composition, the content of the compound is 0.001-99.999 wt%.

[0035] Preferably, the composition is a pesticide composition; more preferably, it is a mite-killing and insecticide composition.

[0036] In a sixth aspect, the present invention provides a method for killing mites and insects, comprising the steps of: contacting the mites and insects with an effective amount of a spirocyclopropanetetronic acid derivative, its geometric isomers, stereoisomers, or its pesticide-acceptable salts or prodrugs, or a composition as described.

[0037] The seventh aspect of the present invention provides a method for preparing the spirocyclopropanetetradecanate derivative, comprising the steps of:

[0038] (i) Under alkaline conditions, a compound of formula P and a compound of formula Q undergo a Knoevenagel condensation reaction in a corresponding solvent to produce an intermediate compound of formula R, and the obtained compound of formula R undergoes a Corey–Chaykovsky cyclopropanation reaction with Me3SOI in a corresponding solvent under alkaline conditions to produce a compound of formula (I);

[0039] Reaction formula:

[0040]

[0041] Wherein, A, E, G, X, and n are as defined above;

[0042] Alternatively, method 2: (ii) under alkaline conditions, a compound of formula P and a compound of formula S react in a corresponding solvent to form an intermediate compound of formula T; the obtained compound of formula T reacts with a compound of formula U in a corresponding solvent under the catalysis of a rhodium catalyst to form a compound of reaction formula (I).

[0043] Reaction formula:

[0044]

[0045] Wherein, A, E, G, X, and n are as defined above; in the compound of formula S, R 3 = acetyl, trifluoroacetyl, trifluoroacetoxy, etc.

[0046] Alternatively, method 3: (iii) under alkaline conditions, a compound of formula P and a compound of formula V react in a corresponding solvent to form an intermediate compound of formula W; the obtained compound of formula W reacts with a compound of formula U in a corresponding solvent under the catalysis of a rhodium catalyst to form a compound of reaction formula (I).

[0047]

[0048] Wherein, A, E, G, X, and n are as defined above; in the compound of formula V, R 4 = p-methylphenyl, p-aminophenyl, p-acetylamino, 2,4,6-triisopropyl, etc.

[0049] In step (i), the solvent used is selected from one or more of the following solvents having a water content of less than 10 ppm: acetonitrile, tetrahydrofuran, toluene, trifluorotoluene, 1,2-dichloroethane, dichloromethane, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide, or a combination thereof.

[0050] In step (i), the following base is selected: piperidine, sodium carbonate, pyridine, trimethylamine, sodium hydride, calcium hydride, sodium hydroxide, cesium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium ethoxide, triethylamine, aqueous ammonia, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, diisopropylethylamine, lithium bis(trimethylsilyl)amide, DBU, TBD, DMAP, or a combination thereof.

[0051] In step (i), the reaction is carried out at -10-120°C, more preferably 25-110°C.

[0052] In step (i), the reaction time is 1-24 h, more preferably 1-2 h; the solvent used is the same as that in step (i).

[0053] In step (ii), the rhodium catalyst is selected from a common one such as Rh2(esp)2, Rh2(OAC)4, [(CF3COO)2Rh]2, Rh2(TPA)4, RhCl3, Rhodium(II)octanoate dimer, Rhodium(II)trimethylacetate dimer, Rhodiumacetylacetonate, Rhodium(III)chloride hydrate, etc.;

[0054] In step (ii), the molar amount of rhodium catalyst is 2%-5%; the base used is the same as that in step (i);

[0055] In step (ii), the reaction is carried out at 0-50°C, more preferably 25-30°C.

[0056] In step (ii), the reaction time is 1-24 h, more preferably 1-2 h.

[0057] In step (iii), the solvent, rhodium catalyst, reaction time and optimal time used are the same as those in step (ii).

[0058] After extensive and in-depth research, screening, and testing, this invention provides novel spirocyclopropanetetronic acid derivatives with novel structures and insecticidal and acaricidal activity, as well as preparation methods and applications. By structurally modifying existing tetronic acid compounds and introducing a cyclopropane group at the 3-position, this invention has designed and synthesized a series of novel tetronic acid compounds, demonstrating excellent insecticidal and acaricidal activity while broadening the insecticide spectrum. This holds promise for the development of low-toxic, highly effective, and environmentally friendly pesticides. DETAILED DESCRIPTION

[0059] In order to more clearly understand the technical content of the present invention, the following embodiments are given in detail. However, it should be noted that these descriptions are only for further illustrating the features and advantages of the present invention, and are not intended to limit the claims of the invention.

[0060] Unless otherwise specified, the reagents and methods involved in the examples are commonly used in the art.

[0061] the term

[0062] Unless defined otherwise, 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 invention belongs.

[0063] The prefix "C u-v " indicates that the following groups have u to v carbon atoms, such as "C 1-8 ” can be C1, C2, C3, C4, C5, C6, C7 or C8. For example, “C 1-8 "Alkyl" means that the alkyl group has 1 to 8 carbon atoms.

[0064] The term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.

[0065] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0066] The term "alkyl" refers to a straight or branched chain unsubstituted group having 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), preferably a hydrocarbon group of 1 to 6 carbon atoms (i.e., C 1-6 Alkyl), more preferably hydrocarbon group of 1 to 4 carbon atoms (i.e., C 1-4 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl, and the like.

[0067] The term "alkylene" refers to a saturated divalent hydrocarbon radical having 1 to 8 carbon atoms derived by removing two hydrogen atoms from a straight or branched chain saturated hydrocarbon (i.e., C 1-8Alkylene), preferably a hydrocarbon group of 1 to 4 carbon atoms (i.e., C 1-4 alkylene), more preferably 1-3 carbon atoms (i.e., C 1-3 Examples of "alkylene" include, but are not limited to, methylene, ethylene, isopropylene, and the like.

[0068] The term "alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms (ie, C 2-8 alkenyl), preferably 2-6 carbon atoms (ie, C 2-6 alkenyl) or 2-4 carbon atoms (ie, C 2-4 The term "alkenyl" refers to a straight or branched hydrocarbon group having 1 to 2 carbon-carbon double bonds and is not limited to vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0069] The term "alkynyl" refers to a group having 2 to 8 carbon atoms (ie, C 2-8 Alkynyl), preferably 2-6 carbon atoms (ie, C 2-6 Alkynyl) or 2-4 carbon atoms (i.e., C 2-4 alkynyl), and a straight / branched hydrocarbon group having 1 to 2 carbon-carbon triple bonds.

[0070] The term "cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group, which may be substituted with one or more substituents as described herein, and which has 3 to 6 carbon atoms to form a monocyclic ring, or 7 to 12 carbon atoms to form a bicyclic ring. As used herein, a cycloalkyl group has 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl) or 3 to 6 ring carbon atoms (ie C 3-6 Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, cycloheptyl, and cyclooctyl. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.

[0071] The terms "aromatic ring" and "aryl" refer to aromatic carbocyclic groups having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, an aryl group has 6 to 10 ring carbon atoms (i.e., C 6-10 Aryl includes bicyclic groups including an aromatic ring fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring (e.g., benzo[C] 3-6Typically, aryl groups include, but are not limited to, benzene, naphthalene, anthracene, biphenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, and the like. The "aryl" group includes structures in which an aryl ring is fused to a cycloalkyl or heterocycloalkyl group.

[0072] The terms "heterocycle", "heterocyclic", "heterocyclyl" and "heterocycloalkyl" refer to an optionally substituted, fully saturated or partially unsaturated non-aromatic ring group, for example, a 3-7 membered monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic ring system having at least one heteroatom in at least one of the carbon atom-containing rings. Each ring of the heterocyclyl group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. As used herein, the heterocyclyl group has 3 to 10 ring atoms (i.e., 3-10 membered heterocyclyl), 3 to 8 ring atoms (i.e., 3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 3 to 6 ring atoms (i.e., 3-6 membered heterocyclyl) or 5 to 6 ring atoms (i.e., 5-6 membered heterocyclyl). The "heterocyclyl" may be arbitrarily substituted with one or more substituents described herein. Examples of "heterocyclyl" include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, thiomorpholino, piperazinyl, homopiperazinyl, glycidyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, N-pyridylurea, pyrimidinone and 1,1-dioxo-thiomorpholinyl.

[0073] The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing one or more heteroatoms selected from oxygen, nitrogen and sulfur, including monocyclic, bicyclic or polycyclic fused systems. The heteroaryl group can be arbitrarily substituted with one or more substituents described herein. As used herein, the heteroaryl group can have 5 to 10 ring atoms (i.e., 5-10 membered heteroaryl), 5 to 8 ring atoms (i.e., 3-8 membered heteroaryl), or 5 to 6 ring atoms (i.e., 5-6 membered heteroaryl). The heteroaryl group can have 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, wherein the ring heteroatoms are independently selected from oxygen, nitrogen and sulfur. Examples of "heteroaryl" include, but are not limited to, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, imidazopyridinyl, benzofuranyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, and the like.

[0074] "Oxy" refers to an -O- group, "acyloxy" refers to a -C(=O)-O- group, "carbonyl" refers to a -C(=O)- group, "nitro" refers to a -NO2 group, "cyano" refers to -CN, "hydroxy" refers to -OH, and "amino" refers to -NH2. The term "oxo" represents a divalent radical =O. "Sulfonamido" refers to a -SO2NH2 group. "Carboxyl" refers to a -COOH group. "Benzoyl" refers to a phenyl-CO- group.

[0075] The term "substituted" means that one or more hydrogen atoms in a specific group are replaced by any substituent mentioned in the present specification, provided that the normal valence of the specified group or atom is not exceeded and the compound produced by the substitution is stable, that is, a compound that can be isolated, characterized and tested for biological activity. Unless otherwise specified, the "substituted" means that one or more (such as 2, 3 or 4) hydrogen atoms on the group are independently replaced by a group selected from the following groups: H, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Alkoxy-C 1-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy-carbonyl, substituted or unsubstituted allyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenoxycarbonyl, substituted or unsubstituted C 2-8 Alkenyl-carbonyl, substituted or unsubstituted C 2-8 Alkynyl-carbonyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl-carbonyl, substituted or unsubstituted benzoyl, substituted or unsubstituted furancarbonyl or substituted or unsubstituted N,N-dimethylcarbonyl, and the substitution means that one or more H atoms on the group are independently substituted by a substituent selected from the group consisting of halogen, halogenated or unsubstituted C 1-4 Alkyl, halogenated or unsubstituted C 2-4 Alkenyl, halogenated or unsubstituted C 2-4 Alkynyl, halogenated or unsubstituted C 1-4 Alkoxy and halogenated or unsubstituted C 1-4 Alkyl-carbonyl.

[0076] The term "active substance of the present invention" or "active compound of the present invention" refers to a compound having a structure represented by general formula (I) or an optical isomer, cis-trans isomer, or a pesticidally acceptable salt thereof.

[0077] The term "pesticidally acceptable salt" refers to a salt whose anion is known and acceptable to form a pesticide-acceptable salt. Preferably, the salt is water-soluble. Suitable acid addition salts formed from compounds of formula (I) include salts formed from inorganic acids, such as hydrochlorides, phosphates, sulfates, and nitrates; and salts formed from organic acids, such as acetates and benzoates.

[0078] Active ingredient

[0079] The present invention provides a compound of formula (I), its optical isomers, cis-trans isomers, or pesticide-acceptable salts thereof:

[0080]

[0081] wherein A, E, G, X, and n are as defined above.

[0082] In another preferred embodiment, the compound is any one of the compounds in the examples.

[0083] The present invention is intended to encompass salts of the compounds. A "pesticide-acceptable salt" may have more than one charged atom, and multiple charged atoms may have multiple counterions. Any salt form, such as a pharmaceutically acceptable salt of the compounds of the present invention, including salts of inorganic or organic acids or salts thereof, is within the scope of the present invention. Also within the scope of the present invention are various crystalline forms of the pharmaceutically acceptable salts of the compounds of the present invention. Also within the scope of the present invention are any prodrugs of the compounds of the present invention.

[0084] As used herein, the term "pesticide-acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pesticide-acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0085] A solvate refers to a combination or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. The compounds of the present invention can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water and ethanol, and thus the present invention encompasses both solvated and unsolvated forms.

[0086] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the equilibrium properties between the tautomers, it is understood by those of ordinary skill in the art that compounds comprise all or each tautomer of the compound. Therefore, amide-containing compounds are understood to comprise their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to comprise their amide tautomers.

[0087] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. The compounds may be chiral, racemic or may exist as compositions comprising one or more stereoisomers. The present invention includes enantiomers, diastereomers, racemic mixtures, enantiomerically enriched mixtures and diastereomerically enriched mixtures. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and hindered isomers, and mixtures thereof such as racemic mixtures, will form part of the present invention. In addition, asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are intended to be included in the present invention. If a specific enantiomer of the compounds of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is split to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group such as an amino group, or an acidic functional group such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatography methods known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers can be achieved using chromatography on chiral stationary phases.

[0088] In this article, when the stereochemistry of any particular chiral atom is not determined, all stereoisomers are considered. In addition, the present invention relates to all geometric and positional isomers. The compounds of this invention can exist in different tautomeric forms, and all of these forms are included within the scope of the present invention. All stereoisomers of the compounds of this invention are expected to include mixtures or pure or substantially pure forms.

[0089] Herein, unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. In addition to therapeutic uses, such compounds are useful, for example, as analytical tools or probes in biological assays. Any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compound. An isotopically labeled compound has a structure described by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S.36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure, for example, incorporating radioactive isotopes such as 3 H and 14 C, which can be used in metabolism studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution analysis or radiotherapy of patients.

[0090] Insecticidal activity of the substances of the present invention

[0091] The active compounds of the present invention are active ingredients of preventive and / or therapeutic value in the field of pest control, have a broad biocidal spectrum, and are well tolerated by warm-blooded species, fish, and plants. These active ingredients act on all or individual developmental stages of animal pests, and their insecticidal or acaricidal activity can manifest itself directly.

[0092] The active compounds of the present invention can be used to combat and control infestations of insect pests (e.g., Lepidoptera, Homoptera) and other invertebrate pests (e.g., mites). Insects and mites are hereinafter collectively referred to as pests. Pests that can be combated and controlled using these compounds include those associated with crop cultivation.

[0093] The compounds provided by the present invention have significant insecticidal activity and can be used to control and eliminate a wide range of pests. In this specification, pests that can be killed or controlled include but are not limited to the following pests: such as Tetranychus cinnabarinus. "Mite control" means having acaricidal activity at each stage of the mite life cycle (eggs, larvae, adults). Therefore, the technical solution of the present invention also includes the use of the spirocyclopropanetetronic acid compounds shown in Formula I as acaricides in agriculture or other fields. The spirocyclopropanetetronic acid derivatives of the present invention are also suitable for controlling at least one pest in the order Homoptera (such as alfalfa aphids) and Lepidoptera (such as diamondback moth) in agriculture or other fields.

[0094] Therefore, the technical solution of the present invention also includes the use of the novel spirocyclopropanetetratonate compound represented by formula (I) as an insecticide in agriculture or other fields.

[0095] Composition

[0096] Insecticide / acaricide compositions containing the active substances of the present invention can be prepared into insecticide compositions using conventional methods. These active compounds can be formulated into conventional formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, natural and synthetic materials impregnated with the active substance, microcapsules in polymers, seed coating compositions, and formulations for use with combustion devices, such as fumigation cartridges and trays, and ULV cold mist and warm mist formulations. These formulations can be produced using known methods, for example, by mixing the active compound with an extender, which is a liquid, liquefied gas, or solid diluent or carrier, and optionally a surfactant, i.e., an emulsifier and / or dispersant and / or foam former. When water is used as the extender, for example, an organic solvent can also be used as an adjuvant.

[0097] When a liquid solvent is used as a diluent or carrier, it is basically suitable, such as: aromatic hydrocarbons, for example xylene, toluene or alkylnaphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons, for example chlorobenzene, vinyl chloride or dichloromethane; aliphatic hydrocarbons, for example cyclohexane or paraffin, for example mineral oil fractions; alcohols, for example ethanol or ethylene glycol and their ethers and lipids; ketones, for example acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; or less commonly used polar solvents, for example dimethylformamide, dimethyl sulfoxide and water.

[0098] A diluent or carrier for liquefied gas refers to a liquid that will become a gas at normal temperature and pressure, such as aerosol propellants, such as halogenated hydrocarbons, butane, propane, nitrogen and carbon dioxide.

[0099] Solid carriers can be ground natural minerals such as kaolin, clay, talc, quartz, attapulgite, montmorillonite, or diatomaceous earth; and ground synthetic minerals such as highly dispersed silicic acid, alumina, and silicates. Solid carriers for particles are ground and classified natural zircons such as calcite, marble, pumice, sepiolite, dolomite, inorganic and organic coarse powders, and organic materials such as sawdust, coconut shells, corn cobs, and tobacco stem particles.

[0100] Nonionic and anionic emulsifiers can be used as emulsifiers and / or foam formers. Examples include polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylaryl polyethylene glycol ethers, alkyl sulfonates / sulfates, aryl sulfonates, and albumin hydrolysates. Dispersants include lignin sulfite wastewater and methylcellulose.

[0101] Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, may be used in the formulations.

[0102] Colorants such as inorganic dyes, such as iron oxide, cobalt oxide and Prussian blue; organic dyes, such as azo dyes or metal phthalocyanine dyes; trace nutrients, such as salts of iron, manganese, boron, copper, cobalt, aluminum and zinc, etc. can be used.

[0103] The "active compound of the present invention" may be present in a mixture with other active compounds in their commercial preparations or in dosage forms prepared from these preparations. These other active compounds are insecticides (such as phosphates, carbamates, chlorinated hydrocarbons and substances produced by microorganisms, such as abamectin, etc.), fungicides (strobilurins, amides, triazoles, etc., fungicides, herbicides, growth control agents, etc.).

[0104] Furthermore, the "active compound of the present invention" may be present in commercial formulations or dosage forms prepared from these formulations in admixture with a synergist. These synergists are compounds that enhance the action of the active compound. However, since the active compound itself is active, the addition of a synergist is not necessary. These formulations typically contain 0.001 to 99.99% by weight of the "active compound of the present invention," preferably 0.01 to 99.9% by weight, and more preferably 0.05 to 90% by weight, of the total weight of the composition. The concentration of the active compound in commercial formulations or dosage forms can vary over a wide range. The concentration of the active compound in the dosage form can range from 0.0000001 to 100% (g / v), preferably between 0.0001 and 1% (g / v).

[0105] Tests have shown that the compound represented by formula (I), its optical isomers, cis-trans isomers, or its pesticide-acceptable salts have particularly good control effects on alfalfa aphids, spider mites, and diamondback moths.

[0106] The main advantages of the present invention include:

[0107] (1) The present invention provides a novel spirocyclopropanetetrahydrogen phosphate compound and its composition, use and preparation method.

[0108] (2) The compounds of the present invention have significant insecticidal and acaricidal activity and expand the insecticidal spectrum, and are expected to develop new low-toxic, high-efficiency, and environmentally friendly crop insecticides and acaricides.

[0109] The present invention will be further described below in conjunction with specific implementation. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0110] Example 1

[0111] The preparation process of 1-phenyl-11-azabispiro[2.1.55.23]dodecane-4,12-dione is as follows:

[0112]

Method 1

[0113]

[0114] Reaction reagents and conditions: (a) toluene, glacial acetic acid, piperidine, argon protection, 110°C, 2h; (b) N,N-dimethylformamide, Me3SOI, NaH, room temperature, 1h.

[0115] Specifically, the following steps are included:

[0116] Intermediate P-1: 3-benzylidene-1-azaspiro[4.5]decane-2,4-dione

[0117]

[0118] 1-Azaspiro[4.5]decane-2,4-dione (334.42 mg, 2.00 mmol) was placed in a 25 mL Schlenk tube and dissolved in 15 mL of toluene. The mixture was stirred in an ice bath and slowly added dropwise with glacial acetic acid (57.24 μL, 1 mmol), piperidine (39.10 μL, 0.4 mmol), and benzaldehyde (264.28 μL, 2.6 mmol). After complete addition, the mixture was refluxed in a 110°C oil bath. TLC analysis indicated that the reaction was complete after approximately 2 h. The solvent was then removed on a rotary evaporator, and the reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate solution. The residual aqueous solution was extracted with dichloromethane (3 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness. An appropriate amount of dichloromethane was added, and the filtrate was purified by silica gel column chromatography. The solvent was evaporated to obtain 474.90 mg of a yellow solid (93.00% yield).

[0119] Compound I-1: 1-phenyl-11-azabispiro[2.1.55.23]dodecane-4,12-dione

[0120]

[0121] To a 25 mL single-necked round-bottom flask, 7 mL of N,N-dimethylformamide was added, cooled to 0°C, and sodium hydride (104 mg, 2.60 mmol) and Me3SOI (572.18 mg, 2.60 mmol) were added. Intermediate P-1 (510.64 mg, 2.00 mmol) was added and reacted at room temperature. The reaction was monitored by TLC. The reaction was terminated after 1 h. 15 mL of water and 1 mL of acetic acid were added to remove the sodium hydride. The remaining aqueous solution was extracted with ethyl acetate (3*10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by silica gel column chromatography with petroleum ether:ethyl acetate = 10:1 (v:v). The solvent was evaporated to obtain compound I-1 (white solid, 0.22 g, 40.50%).

[0122] The final test results are as follows: 1 H NMR (400MHz, CDCl3) δ8.09–7.85(m,1H+0.7H,major+minor),7.32–7.18(m,5H+3.5H,major+minor),3.41–3.21(t,J=8.9Hz,1H,major),3.11(t,J=9.1Hz,1H ,minor),2.36–2.06(m,2H+1.4H,major+minor),1.93–1.67(m,5H+3.5H,major+minor),1.42–1.22(m,5H+3.5H,major+minor).HRMS(EI-TOF)m / z:[M]+calcd forC 17 H 19 NO2:269.1410; found:269.1416.

[0123]

Method 2

[0124]

[0125] Reaction reagents and conditions: (a) anhydrous acetonitrile, nitrogen protection, potassium hydroxide, iodophenyldiacetic acid, room temperature, 2h; (b) 1,2-dichloroethane, nitrogen protection, styrene, Rh2(esp)2, room temperature, 4h.

[0126] Specifically, the following steps are included:

[0127] Intermediate P-1: 3-(phenyl-λ 3 -iodidene)-1-azaspiro[4.5]decane-2,4-dione

[0128]

[0129] In a 100 mL round-bottom flask filled with nitrogen, 1-azaspiro[4.5]decane-2,4-dione (1.00 g, 6.00 mmol) and potassium hydroxide (2.02 g, 36.00 mmol) were added, and dry acetonitrile (20 mL) was added in an ice bath (0°C). The mixture was stirred at room temperature for 10 minutes, and compound Y (2.13 g, 6.6 mmol) was added. Stirring was continued at 0°C for 2 hours, and the solvent was removed on a rotary evaporator. Water (10 mL) was added to the preliminary concentrate, and the mixture was filtered and washed with water (3 x 5 mL) and isopropyl ether (10 mL). The filter cake obtained was standard compound P-1 (white solid, 2.2 g, 99.14%).

[0130] Compound I-1: 1-phenyl-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0131]

[0132] Rh2(esp)2 (3.05 mg, 0.004 mmol) and intermediate P-1 (73.90 mg, 0.20 mmol) were placed in a 10 mL Schlenk tube. 2 mL of 1,2-dichloroethane was added for dissolution. Styrene (45.98 μL, 0.40 mmol) was added dropwise. The reaction was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-1 (white solid, 40 mg, 74.26%). The results were the same as above.

[0133]

Method 3

[0134]

[0135] Reaction reagents and conditions: (a) acetonitrile, triethylamine, 4-acetamidobenzenesulfonyl azide, room temperature, 2h; (b) 1,2-dichloroethane, nitrogen protection, styrene, Rh2(esp)2, room temperature, 2h.

[0136] Specifically, the following steps are included:

[0137] Intermediate P-1: 3-diazo-1-azaspiro[4.5]decane-2,4-dione

[0138]

[0139] In a 100 mL round-bottom flask filled with nitrogen, 1-azaspiro[4.5]decane-2,4-dione (1.67 g, 10.00 mmol) was placed in a nitrogen-filled 100 mL round-bottom flask. Dry acetonitrile (40 mL) was added under an ice bath (0°C), followed by the compound of formula Z (2.04 g, 8.50 mmol). Triethylamine (4.2 mL, 30.00 mmol) was then added dropwise. The mixture was stirred at room temperature for 2 h, and the solvent was then removed on a rotary evaporator. A small amount of water (10 mL) was added to the preliminary concentrate, and the residual aqueous solution was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was then purified by silica gel column chromatography with dichloromethane:methanol = 20:1 (v:v). The solvent was then evaporated to obtain compound P-1 (white solid, 1.32 g, 68.32%).

[0140] Compound I-1: 1-phenyl-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0141]

[0142] In a 10mL Schlenk tube, Rh2(esp)2 (3.05mg, 0.004mmol) and intermediate P-1 (38.64mg, 0.20mmol) were placed and dissolved in 2mL of 1,2-dichloroethane. Styrene (45.98μL, 0.40mmol) was added dropwise. The reaction was allowed to react at room temperature and monitored by TLC. The reaction was terminated after 2h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed and the solvent was evaporated to obtain compound I-1 (white solid, 33.21mg, 61.65%). Final analysis results were the same as above.

[0143] Example 2

[0144] 1-(2,4-dichlorophenyl)-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0145]

[0146] Reaction reagents and conditions: (a) toluene, glacial acetic acid, piperidine, argon protection, 110°C, 2h; (b) N,N-dimethylformamide, Me3SOI, NaH, room temperature, 1h.

[0147] Specifically, the following steps are included:

[0148] Intermediate P-2: 3-(2,4-dichlorobenzylidene)-1-azaspiro[4.5]decane-2,4-dione

[0149]

[0150] In a 25 mL schlenk tube, 1-azaspiro[4.5]decane-2,4-dione (836.05 mg, 5.00 mmol) was placed, and 25 mL of toluene was added to dissolve the mixture. After stirring in an ice bath, glacial acetic acid (143.11 μL, 2.5 mmol), piperidine (98.78 μL, 1 mmol), and 2,4-dichlorobenzaldehyde (1.14 g, 6.5 mmol) were slowly added dropwise. After the addition was complete, the mixture was refluxed in an oil bath at 110°C. The reaction was monitored by TLC. The reaction was complete after about 2 h. The solvent was then removed on a rotary evaporator, and the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution. The residual aqueous solution was extracted with dichloromethane (3*20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. An appropriate amount of dichloromethane was added, and the mixture was purified by silica gel column chromatography. The solvent was dried to obtain 950.10 mg of a yellow solid P-2 with a yield of 58.60%.

[0151] Compound I-2: 1-(2,4-dichlorophenyl)-11-azadispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0152]

[0153] A 50 mL single-necked round-bottom flask was charged with N,N-dimethylformamide (4 mL). The mixture was cooled to 0°C, and sodium hydride (97.60 mg, 2.44 mmol) and Me3SOI (537.00 mg, 2.44 mmol) were added. Intermediate P-2 (610.00 mg, 1.88 mmol) was added and reacted at room temperature. The reaction was monitored by TLC. The reaction was terminated after 1 h. 40 mL of water and 2 mL of acetic acid were added to remove the sodium hydride. The remaining aqueous solution was extracted with ethyl acetate (3*10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by silica gel column chromatography with petroleum ether:ethyl acetate = 2:1 (v:v). The solvent was evaporated to give compound I-2 (white solid, 327.13 mg, 51.45%).

[0154] The final test results are as follows: 1H NMR(400MHz, CDCl3)δ7.87(s,0.25H,minor),7.74(s,0.75H,major),7.35(s,1H+0.3H,major+minor),7.28–7.22 (m,2H+0.6H,major+minor),3.29(t,J=8.8Hz,1H,major),3.10(t,J=8.8Hz,0.3H,minor),2.27(dd,J=8.8,4.2Hz ,0.3H,minor),2.19(dd,J=8.7,4.3Hz,1H,major),2.13(dd,J=8.8,4.3Hz,1H,major),2.09(dd,J=8.9,4.2Hz,0. 3H,minor),1.84–1.60(m,7H+2.1H,major+minor),1.42–1.24(m,3H+0.9H,major+minor).HRMS(EI-TOF)m / z:[M] + calcd for C 17 H 17 Cl2NO2:337.0631; found:337.0636.

[0155] Example 3

[0156] 1-(2,5-dimethylphenyl)-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0157]

[0158] Reaction reagents and conditions: (a) toluene, glacial acetic acid, piperidine, argon protection, 110°C, 2h; (b) N,N-dimethylformamide, Me3SOI, NaH, room temperature, 1h.

[0159] Specifically, the following steps are included:

[0160] Intermediate P-3: 3-(2,5-dimethylbenzylidene)-1-azaspiro[4.5]decane-2,4-dione

[0161]

[0162] In a 25 mL schlenk tube, 1-azaspiro[4.5]decane-2,4-dione (167.21 mg, 1.00 mmol) was added, and 7 mL of toluene was added to dissolve the mixture. The mixture was stirred in an ice bath, and glacial acetic acid (28.62 μL, 0.5 mmol), piperidine (19.76 μL, 0.2 mmol), and 2,5-dimethylbenzaldehyde (183.61 μL, 1.3 mmol) were slowly added dropwise. After the addition was complete, the mixture was refluxed in an oil bath at 110°C. The reaction was monitored by TLC. The reaction was complete after about 2 h. The solvent was then removed on a rotary evaporator, and the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution. The residual aqueous solution was extracted with dichloromethane (3*10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. An appropriate amount of dichloromethane was added, and the mixture was purified by silica gel column chromatography. The solvent was dried to obtain 260.60 mg of yellow solid P-3 with a yield of 92.00%.

[0163] Compound I-3: 1-(2,5-dimethyl)-11-azadispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0164]

[0165] A 50 mL single-necked round-bottom flask was charged with N,N-dimethylformamide (4 mL), cooled to 0°C, and sodium hydride (26.00 mg, 0.65 mmol) and Me3SOI (143.06 mg, 0.65 mmol) were added. Intermediate P-3 (141.69 mg, 0.5 mmol) was added and reacted at room temperature. The reaction was monitored by TLC. The reaction was terminated after 1 h. 10 mL of water and 1 mL of acetic acid were added to remove the sodium hydride. The remaining aqueous solution was extracted with ethyl acetate (3*10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by silica gel column chromatography with petroleum ether:ethyl acetate = 2:1 (v:v). The solvent was evaporated to give compound I-3 (white solid, 42.80 mg, 30.20%).

[0166] The final test results are as follows: 1H NMR (400MHz, CDCl3) δ7.82(s,0.56H,minor),7.64(s,0.8H,major),7.06(s,1H,major),7.04(s,0.7H,minor),7.01–6.96(m,2H+1. 4H,major+minor),3.26(t,J=8.9Hz,0.7H,minor),3.04(t,J=9.0Hz,1H,major),2.38–2.33(m,1.4H,minor),2.32(s,2.1H,minor) ,2.30(s,3H,major),2.24(dd,J=8.9,4.0Hz,1H),2.16(s,2.1H,minor),2.15(s,3H,major),2.06(dd,J=9.0,4.0Hz,1H),1.88–1.7 2(m,3H+2.1H,major+minor),1.67–1.48(m,4H+2.8H,major+minor),1.48–1.23(m,3H+2.1H,major+minor).HRMS(EI-TOF)m / z:[M] + calcd for C 19 H 23 NO2:297.1723; found:297.1729.

[0167] Example 4

[0168] 1-(4-methoxyphenyl)-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0169]

[0170] Reaction reagents and conditions: (a) toluene, glacial acetic acid, piperidine, argon protection, 110°C, 2h; (b) N,N-dimethylformamide, Me3SOI, NaH, room temperature, 1h.

[0171] Specifically, the following steps are included:

[0172] Intermediate P-4: 3-(4-methoxybenzylidene)-1-azaspiro[4.5]decane-2,4-dione

[0173]

[0174] In a 25 mL schlenk tube, 1-azaspiro[4.5]decane-2,4-dione (167.21 mg, 1.00 mmol) was placed, and 7 mL of toluene was added to dissolve the mixture. The mixture was stirred in an ice bath, and glacial acetic acid (28.62 μL, 0.5 mmol), piperidine (19.76 μL, 0.2 mmol), and 4-methoxybenzaldehyde (157.89 μL, 1.3 mmol) were slowly added dropwise. After the addition was complete, the mixture was refluxed in an oil bath at 110°C. The reaction was monitored by TLC. The reaction was complete after about 2 h. The solvent was then removed on a rotary evaporator, and the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution. The residual aqueous solution was extracted with dichloromethane (3*10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. An appropriate amount of dichloromethane was added, and the mixture was purified by silica gel column chromatography. The solvent was dried to obtain 283.02 mg of yellow solid P-4 with a yield of 99.19%.

[0175] Compound I-4: 1-(2,5-dimethyl)-11-azadispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0176]

[0177] A 10 mL Schlenk tube was added with N,N-dimethylformamide (4 mL), cooled to 0°C, and sodium hydride (26.00 mg, 0.65 mmol) and Me3SOI (143.06 mg, 0.65 mmol) were added. Intermediate P-4 (142.67 mg, 0.5 mmol) was added and reacted at room temperature. The reaction was monitored by TLC. The reaction was terminated after 1 h. 10 mL of water and 1 mL of acetic acid were added to remove the sodium hydride. The residual aqueous solution was extracted with ethyl acetate (3*10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by silica gel column chromatography with petroleum ether:ethyl acetate = 2:1 (v:v). The solvent was evaporated to obtain compound I-4 (white solid, 99.11 mg, 66.21%).

[0178] The final test results are as follows: 1H NMR(400MHz, CDCl3)δ7.63(m,0.8H+0.32H,major+minor),7.19(m,2H+0.8H,major+minor),6.82(m,2H+0.8H ,major+minor),3.78(s,3H,major),3.77(s,1.2H,minor),3.32(t,J=8.8Hz,1H,major),3.09(t,J=9.0Hz,0 .4H,minor),2.32(dd,J=8.9,4.3Hz,0.4H,minor),2.24–2.15(m,2H,major),2.11(dd,J=9.2,4.3Hz,0.4H,m inor),1.85–1.49(m,8H+3.2H,major+minor),1.38–1.26(m,2H+0.8H,major+minor).HRMS(EI-TOF)m / z:[M] + calcd for C 18 H 21 NO3:299.1516; found:299.1521.

[0179] Example 5

[0180] 4-(4,12-dioxo-11-azabispiro[2.1.5 5 .2 3 ] dodecane-1-yl) benzonitrile preparation process is as follows:

[0181]

[0182] Reaction reagents and conditions: (a) toluene, glacial acetic acid, piperidine, argon protection, 110°C, 2h; (b) N,N-dimethylformamide, Me3SOI, NaH, room temperature, 1h.

[0183] Specifically, the following steps are included:

[0184] Intermediate P-5: 4-[(2,4-dioxo-1-azaspiro[4.5]dec-3-ylidene)methyl]benzonitrile

[0185]

[0186] In a 50 mL single-necked round-bottom flask, 1-azaspiro[4.5]decane-2,4-dione (501.63 mg, 3.00 mmol) was added, and 15 mL of toluene was added to dissolve the mixture. After stirring under ice bath, glacial acetic acid (85.87 μL, 1.5 mmol), piperidine (59.27 μL, 0.6 mmol), and 4-cyanobenzaldehyde (511.41 mg, 3.9 mmol) were slowly added dropwise. After the addition was complete, the mixture was refluxed in an oil bath at 110 °C and monitored by TLC. The reaction was complete after about 2 h. The solvent was then removed on a rotary evaporator, and the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution. The residual aqueous solution was extracted with dichloromethane (3*20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. An appropriate amount of dichloromethane was added, and the mixture was purified by silica gel column chromatography. The solvent was dried to obtain 665.60 mg of yellow solid P-5 with a yield of 79.14%.

[0187] Compound I-5: 1-(2,5-dimethyl)-11-azadispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0188]

[0189] A 25 mL Schlenk tube was added with N,N-dimethylformamide (4 mL), cooled to 0°C, and sodium hydride (52.00 mg, 1.30 mmol) and Me3SOI (286.12 mg, 1.30 mmol) were added. Intermediate P-5 (280.33 mg, 1.0 mmol) was added and reacted at room temperature. The reaction was monitored by TLC. The reaction was terminated after 1 h. 20 mL of water and 2 mL of acetic acid were added to remove the sodium hydride. The residual aqueous solution was extracted with ethyl acetate (3*20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by silica gel column chromatography with petroleum ether:ethyl acetate = 2:1 (v:v). The solvent was evaporated to obtain compound I-5 (white solid, 151.45 mg, 51.45%).

[0190] The final test results are as follows: 1 H NMR (400MHz, DMSO) δ8.86(s,0.96H),7.74(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),3.09(t,J=8.8Hz,1H),2.26( dd,J=8.7,4.5Hz,1H),1.96(dd,J=9.0,4.5Hz,1H),1.68–1.60(m,4H),1.59–1.46(m,6H).HRMS(EI-TOF)m / z:[M] + calcdfor C 18 H18 N2O2:294.1363; found:294.1368.

[0191] Example 6

[0192] 1-(Thien-3-yl)-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0193]

[0194] Specifically, the following steps are included:

[0195] Intermediate P-6: 3-(phenyl-λ 3 -iodoalkylidene)-1-azaspiro[4.5]decane-2,4-dione

[0196]

[0197] The synthesis method is the same as that of P-1 in Method 2 in Example 1.

[0198] Compound I-6: 1-(thiophen-3-yl)-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0199]

[0200] In a 10 mL Schlenk tube, Rh2(esp)2 (3.05 mg, 0.004 mmol) and intermediate P-6 (73.90 mg, 0.20 mmol) were placed. 2 mL of 1,2-dichloroethane was added for dissolution, and 3-vinylthiophene (41.97 μL, 0.40 mmol) was added dropwise. The mixture was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-6 (white solid, 49.17 mg, 89.28%).

[0201] The final test results are as follows: 1H NMR (400MHz, DMSO) δ9.06 (s, 1H), 7.41 (m, 2H), 7.04 (d, J = 4.9Hz, 1H), 3.08 (t, J = 8.7Hz, 1H), 2.06 (dd, J = 8.5, 4. 2Hz,1H),1.95(dd,J=8.9,4.2Hz,1H),1.60–1.41(m,7H),1.35(m,1H),1.28–1.13(m,2H).HRMS(EI-TOF)m / z:[M] + calcd for C 15 H 17 NO2S:275.0975; found:275.0980.

[0202] Example 7

[0203] 1-Methyl-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0204]

[0205] Specifically, the following steps are included:

[0206] Intermediate P-7: 3-(phenyl-λ 3 -iodoalkylidene)-1-azaspiro[4.5]decane-2,4-dione

[0207]

[0208] The synthesis method is the same as that of P-1 in Method 2 in Example 1.

[0209] Compound I-7: 1-methyl-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0210]

[0211] Rh2(esp)2 (3.05 mg, 0.004 mmol) and intermediate P-7 (73.90 mg, 0.20 mmol) were placed in a 10 mL Schlenk tube. 2 mL of 1,2-dichloroethane was added for dissolution. 2,4,6-trimethylstyrene (64.56 μL, 0.40 mmol) was added dropwise. The mixture was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-7 (white solid, 48.16 mg, 80.97%).

[0212] The final test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.73 (s, 1H), 6.78 (m, 2H), 2.96 (t, J = 9.3Hz, 1H), 2.39 (s, 3H), 2.22 (s,3H),2.19–2.02(m,5H),1.86–1.60(m,6H),1.39–1.19(m,4H).HRMS(EI-TOF)m / z:[M] + calcd for C 18 H 18 N2O2:311.1880; found:311.1885.

[0213] Example 8

[0214] 1-(4-Chlorophenyl)-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0215]

[0216] Specifically, the following steps are included:

[0217] Intermediate P-8: 3-(phenyl-λ 3 -iodoalkylidene)-1-azaspiro[4.5]decane-2,4-dione

[0218]

[0219] The synthesis method is the same as that of P-1 in Method 2 in Example 1.

[0220] Compound I-8: 1-(4-chlorophenyl)-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0221]

[0222] Rh2(esp)2 (3.05 mg, 0.004 mmol) and intermediate P-8 (73.90 mg, 0.20 mmol) were placed in a 10 mL Schlenk tube. 2 mL of 1,2-dichloroethane was added for dissolution. p-Chlorostyrene (48.00 μL, 0.40 mmol) was added dropwise. The reaction was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-8 (white solid, 49.66 mg, 81.73%).

[0223] The final test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.83(s,0.6H),7.53(s,1H),7.30–7.15(m,4H+2.4H,major+minor),3.30(t,J=8.8Hz,1H,major),3.07(t,J=9.0Hz,0.6H,minor) ,2.30(dd,J=8.8,0.6H,minor),2.19(dd,J=8.9,2H,major),2.11(dd,J=9.2,1H,minor),1.78–1.38(m,10H+6H,major+minor).HRMS(EI-TOF)m / z:[M] + calcd for C 17 H 18 ClNO2:303.1021; found:303.1028.

[0224] Example 9

[0225] 1-Butyl-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0226]

[0227] Specifically, the following steps are included:

[0228] Intermediate P-9: 3-(phenyl-λ 3 -iodoalkylidene)-1-azaspiro[4.5]decane-2,4-dione

[0229]

[0230] The synthesis method is the same as that of P-1 in Method 2 in Example 1.

[0231] Compound I-9: 1-butyl-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0232]

[0233] Rh2(esp)2 (3.05 mg, 0.004 mmol) and intermediate P-9 (73.90 mg, 0.20 mmol) were placed in a 10 mL Schlenk tube. 2 mL of 1,2-dichloroethane was added for dissolution. Hexene (49.65 μL, 0.40 mmol) was added dropwise. The mixture was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-9 (white solid, 36.98 mg, 74.15%).

[0234] The final test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.21(s,1H),1.98–1.88(m,1H),1.83–1.74(m,6H),1.72(m,1H),1.66(dd,J=8.4,3.6 Hz,1H),1.62–1.54(m,2H),1.50–1.35(m,3H),1.35–1.23(m,5H),0.92–0.85(m,3H).HRMS(EI-TOF)m / z:[M] + calcd for C 15 H 23 NO2:249.1723; found:249.1727.

[0235] Example 10

[0236] 1-(2,4-dimethylphenyl)-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0237]

[0238] Specifically, the following steps are included:

[0239] Intermediate P-10: 3-(phenyl-λ 3 -iodoalkylidene)-1-azaspiro[4.5]decane-2,4-dione

[0240]

[0241] The synthesis method is the same as that of P-1 in Method 2 in Example 1.

[0242] Compound I-10: 1-(2,4-dimethylphenyl)-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0243]

[0244] Rh2(esp)2 (4.60 mg, 0.006 mmol) and intermediate P-10 (110.80 mg, 0.30 mmol) were placed in a 10 mL Schlenk tube. 5 mL of 1,2-dichloroethane was added for dissolution. 2,4-Dimethylstyrene (87.50 μL, 0.60 mmol) was added dropwise. The mixture was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-10 (white solid, 40.98 mg, 45.93%).

[0245] The final test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.48(s,0.83H,major),7.36(s,0.75H,minor),7.13(t,J=7.2Hz,1H+0.9H,major+minor),6.99(t,J=8.8Hz,1H+0.9H,majo r+minor),6.94(s,1H+0.9H,major+minor),3.27(t,J=9.0Hz,1H,major),3.06(t,J=9.0Hz,0.9H,minor),2.36(dd,J=9.0,4.0Hz,0.9H,minor),2 .29(s,2.7H,minor),2.20–2.27(s,2.7H,minor),2.24(m,2H,major),2.18(s,3H,major),2.17(s,3H,major),2.08(dd,J=9.0,4.0Hz,0.9H,mino r),1.80(m,3H+2.7H,major+minor),1.66(m,6H+5.4H,major+minor),1.60–1.49(m,1H),1.44(m,1H+0.9H,major+minor).HRMS(EI-TOF)m / z:[M] + calcdfor C 19 H 23 NO2:297.1723; found:297.1731.

[0246] Example 11

[0247] 1-(4-chlorophenyl)-8-oxa-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0248]

[0249] Specifically, the following steps are included:

[0250] Intermediate P-11: 3-diazo-8-oxa-1-azaspiro[4.5]decane-2,4-dione

[0251]

[0252] A similar synthesis method to that of Example 1, Method 3, was used, except that:

[0253] The raw material 1-azaspiro[4.5]decane-2,4-dione in the step is replaced by 8-oxa-1-azaspiro[4.5]decane-2,4-dione.

[0254] A white solid P-11 (1.50 g, yield 76.85%) was obtained.

[0255] Compound I-11: 1-(4-chlorophenyl)-8-oxa-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0256]

[0257] Rh2(esp)2 (1.53 mg, 0.002 mmol) and intermediate P-11 (19.52 mg, 0.10 mmol) were placed in a 10 mL Schlenk tube. 1 mL of 1,2-dichloroethane was added for dissolution. p-Chlorostyrene (24.00 μL, 0.20 mmol) was added dropwise. The reaction was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-11 (white solid, 20.41 mg, 66.70%).

[0258] The final test results are as follows: 1H NMR(400MHz, CDCl3)δ8.51(s,0.71H,minor),8.20(s,1H,major),7.31–7.27(m,3.2H,minor),7.20(m,4H,major),3.97(m,2H+ 0.8H,major+minor),3.84–3.76(m,1H,major),3.65–3.53(m,1H+2.4H,major+minor),3.33(t,J=9.0Hz,1H,major),3.12(t,J= 9.0Hz,0.8H,minor),2.36(dd,J=8.8,4.6Hz,0.8H,minor),2.22(m,1H+0.8H,major+minor),2.17(dd,J=9.2,4.6Hz,1H,major ),2.12–1.98(m,2H+0.8H,major+minor),1.71(m,1H,major),1.55(m,2.4H,minor),1.40(m,1H,major).HRMS(EI-TOF)m / z:[M] + calcd for C 16 H 16 ClNO3:305.0819; found:305.0822.

[0259] Example 12

[0260] 1-(2,4-dimethylphenyl)-8-oxa-11-azadispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0261]

[0262] Specifically, the following steps are included:

[0263] Intermediate P-12: 3-diazo-8-oxa-1-azaspiro[4.5]decane-2,4-dione

[0264]

[0265] The synthesis method is the same as that of P-11 in Example 11:

[0266] Compound I-12: 1-(2,4-dimethylphenyl)-8-oxa-11-azadispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0267]

[0268] Rh2(esp)2 (1.53 mg, 0.002 mmol) and intermediate P-11 (19.52 mg, 0.10 mmol) were placed in a 10 mL Schlenk tube. 1 mL of 1,2-dichloroethane was added for dissolution. 2,4-Dimethylstyrene (29.18 μL, 0.20 mmol) was added dropwise. The mixture was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to give compound I-12 (white solid, 18.62 mg, 62.20%).

[0269] The final test results are as follows: 1 H NMR (400MHz, CDCl3) δ8.51 (s, 0.94H, major), 8.40 (s, 0.74H, minor), 7.14 (t, J = 8.4Hz ,1H+0.8H,major+minor),7.05–6.96(m,1H+0.8H,major+minor),6.95(s,1H,major), 6.93(s,1H,minor),3.96(m,1H+0.8H,major+minor),3.85(m,1H+0.8H,major+minor) ,3.57(m,2H+1.6H,major+minor),3.29(t,J=9.0Hz,1H,major),3.10(t,J=9.0Hz,0.8H ,minor),2.41(dd,J=9.0,4.1Hz,0.8H,minor),2.30(s,3H,major),2.28(s,2.4H,min or),2.20(dd,J=9.0,4.0Hz,1H,major),2.16(s,3H,major),2.16(s,2.4H,minor),2.1 5–2.10(m,1H+0.8H,major+minor),2.10–2.04(m,0.8H,minor),2.00–1.93(m,1H,maj or),1.82(m,1H,major),1.60–1.32(m,2H+2.4H,major+minor).HRMS(EI-TOF)m / z:[M] + calcd for C 18 H 21 NO3:299.1521; found:299.1523.

[0270] Example 13

[0271] 1-(4-Fluorophenyl)-8-oxa-11-azabispiro[2.1.5 5 .23] The preparation process of dodecane-4,12-dione is as follows:

[0272]

[0273] Specifically, the following steps are included:

[0274] Intermediate P-13: 3-diazo-8-oxa-1-azaspiro[4.5]decane-2,4-dione

[0275]

[0276] The synthesis method is the same as that of P-11 in Example 11:

[0277] Compound I-13: 1-(4-fluorophenyl)-8-oxa-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0278]

[0279] Rh2(esp)2 (1.53 mg, 0.002 mmol) and intermediate P-13 (19.52 mg, 0.10 mmol) were placed in a 10 mL Schlenk tube. 1 mL of 1,2-dichloroethane was added for dissolution, and p-fluorostyrene (23.86 μL, 0.20 mmol) was added dropwise. The reaction was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-13 (white solid, 17.58 mg, 60.77%).

[0280] The final test results are as follows: 1H NMR(400MHz, CDCl3)δ8.66(s,0.9H,major),8.45(s,0.9H,minor),7.30–7.17(m,4H,major),6.99(m,4H,minor) ,4.04–3.88(m,3H,major),3.79(m,1H,major),3.58(m,4H,minor),3.34(t,J=9.0Hz,1H,major),3.13(t,J=9.0H z,1H,minor),2.35(dd,J=8.8,4.5Hz,1H,minor),2.22(m,2H,major),2.16(dd,J=9.2,4.5Hz,1H,minor),2.05(m ,3H,major),1.69(m,1H+1H,major+minor),1.60–1.46(m,2H,minor),1.39(m,1H,minor).HRMS(EI-TOF)m / z:[M] + calcd for C 16 H 16 FNO3:289.1114; found:289.1112.

[0281] Example 14

[0282] 1-(3-chlorophenyl)-8-oxa-11-azabispiro[2.1.5 5 .2 3 The preparation process of dodecane-4,12-dione is as follows:

[0283]

[0284] Specifically, the following steps are included:

[0285] Intermediate P-14: 3-diazo-8-oxa-1-azaspiro[4.5]decane-2,4-dione

[0286]

[0287] The synthesis method is the same as that of P-11 in Example 11:

[0288] Compound I-14: 1-(3-chlorophenyl)-8-oxa-11-azabispiro[2.1.5 5 .2 3 ]Dodecane-4,12-dione

[0289]

[0290] In a 10 mL Schlenk tube, Rh2(esp)2 (1.53 mg, 0.002 mmol) and intermediate P-14 (19.52 mg, 0.10 mmol) were placed. 1 mL of 1,2-dichloroethane was added to dissolve the mixture, and m-chlorostyrene (25.43 μL, 0.20 mmol) was added dropwise. The reaction was allowed to react at room temperature and monitored by TLC. The reaction was completed after 2 h. Silica gel column chromatography (dichloromethane:methanol = 60:1 (v:v)) was performed, and the solvent was evaporated to obtain compound I-14 (white solid, 18.53 mg, 60.60%).

[0291] The final test results are as follows: 1 H NMR(400MHz, CDCl3)δ8.76(s,0.81H,minor),8.44(s,0.9H,major),7.30–7.21(m,2H+3.6H,major+minor),7.23–7.14(m,1H, major),7.16–7.09(m,1H,major),3.95(m,3H,major),3.81(m,1H,major),3.59(m,4H,minor),3.32(t,J=8.8Hz,1H,major),3 .11(t,J=9.0Hz,0.9H,minor),2.35(dd,J=8.8,4.5Hz,0.9H,minor),2.27–2.17(m,2H,major),2.19–2.12(m,0.9H,minor),2. 08(m,1H+0.9H,major+minor),1.73(m,1H+0.9H,major+minor),1.61–1.42(m,2H+1.8H,major+minor).HRMS(EI-TOF)m / z:[M] + calcdfor C 16 H 16 ClNO3:305.0819; found:305.0821.

[0292] Test Example: Insecticidal Activity Test of the Compounds of the Invention

[0293] Test Example 1 Insecticidal activity against 2-day-old diamondback moth

[0294] Diamondback moth, a common crop pest belonging to the order Lepidoptera, was used as an example for testing using the leaf dip method.

[0295] Operation process: Accurately weigh the sample, add N,N-dimethylformamide to prepare a 10g / L mother solution, and dilute it to 100mg / L with 0.2mL / L Triton X-100 aqueous solution. Immerse a 1cm leaf disc in the solution for 10s, take it out and dry it, and place it in a culture dish, with 4 leaves per dish. Inoculate 2nd or 3rd instar diamondback moth larvae into the dish, 10 per dish, and place moistened filter paper in the culture dish to keep it moist. Repeat 3 times for each treatment and place it in a light incubator. Five days after application, touch the insect with a brush lightly. If the insect body does not move or cannot coordinate its movements, it is considered dead and the number of deaths is recorded. Mortality rate (%) = (number of live insects in the control - number of live insects in the treatment) / number of live insects in the control × 100%. The results can be seen in Table 1 below.

[0296] Test Example 2 Insecticidal activity against Tetranychus cinnabarinus

[0297] The cinnabarinus spider mite belongs to the family Tetranychidae in the order Acariformes and is a common crop pest. Using Tetranychus cinnabarinus as an example, the insect immersion method was used to test the cinnabarinus spider mite.

[0298] Procedure: Accurately weigh the sample, add N,N-dimethylformamide to make a 10g / L stock solution, and dilute to 100mg / L with 0.2mL / L of Triton X-100 aqueous solution. First, insert a single broad bean leaf with 20 or more mites into the solution for 10 seconds. Remove and air dry, then place in a petri dish filled with water for observation. Repeat this three times and incubate in an observation room. Five days after application, gently touch with a brush. If the insects are motionless or unable to coordinate movement, they are considered dead and the number of deaths is recorded. Mortality (%) = (number of live mites in the control group - number of live mites in the treatment group) / number of live mites in the control group × 100%. Results can be found in Table 1 below.

[0299] Test Example 3 Insecticidal activity against 2-day-old alfalfa aphids

[0300] Aphids belong to the order Homoptera, have piercing-sucking mouthparts, and are common crop pests. Taking alfalfa aphid as an example, the insect immersion method was used for testing.

[0301] Operation process: Accurately weigh the sample, add N,N-dimethylformamide to prepare a 10g / L mother solution, and dilute it to 100mg / L with 0.2mL / L Triton X-100 aqueous solution. First, select a single broad bean leaf with more than 15 2-day-old nymphs, immerse it in the solution for 10s, take it out and dry it, place it on the culture rack in the observation room, cover it with a plastic cup with holes, repeat 3 times for each treatment, and place it in the observation room for culture. Five days after application, touch it lightly with a brush. If the insect body does not move or cannot coordinate its movements, it is considered dead and the number of deaths is recorded. And calculate the mortality rate (%): mortality rate (%) = (number of live insects in the control - number of live insects in the treatment) / number of live insects in the control × 100%. The results can be seen in Table 1 below. Table 1 Biological activity of compounds against alfalfa aphid (Alfalfa Aphid), Tetranychus cinnabarinus (Tetranychus cinnabarinus), and Diamondback moth (Diamondback moth)

[0302]

[0303]

[0304] The above experimental results demonstrate that the compounds of the present invention exhibit excellent insecticidal and acaricidal activity against alfalfa aphids, spider mites, and diamondback moths at 500 ppm. Therefore, the introduction of a cyclopropane group at the 3-position of the active spirocyclotetratonate intermediate demonstrates the rationality and innovation of the molecular design, as well as the application value of spirocyclopropanetetratonate derivatives in pest control.

[0305] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

[0306] In this specification, the present invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations may be made without departing from the spirit and scope of the present invention. Therefore, the description is to be regarded as illustrative rather than restrictive.

Claims

1. A spirocyclopropanetetradecanate derivative, its optical isomers, cis-trans isomers, or its pesticide-acceptable salt, characterized in that: The structural formula of the derivative is shown in formula (I): Where: A and E are each independently selected from hydrogen, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted benzyl, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; wherein substitution means that one or more H on the group is independently replaced by a group selected from the group consisting of hydrogen, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkenyl, C 2-8 Halogenated alkenyl, C 2-8 Alkynyl, C 2-8 Haloalkynyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Alkylthio, C 1-8 Halogenated alkylthio, C 1-8 Alkyl sulfoxide, C 1-8 Alkylsulfone, nitro, hydroxy, cyano, amino, C 6-10 Aryl or one or more selected from C 1-4 Alkyl, C 1-4 C substituted with haloalkyl, halogen and cyano 6-10 aryl; X is O, S or NR 1 , where R 1 Selected from: hydrogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Alkylthio, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S and N, substituted or unsubstituted C 3-6 Cycloalkyl (C 1-4 )alkyl-, substituted or unsubstituted 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N (C 1-4 )alkyl-, substituted or unsubstituted phenyl (C 1-4 ) alkyl-, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S and N (C 1-4 ) alkyl-, substituted or unsubstituted C 1-4 Alkoxy (C 1-4 ) alkyl, substituted or unsubstituted C 1-8 AlkylCO-, substituted or unsubstituted C 1-8 AlkoxyCO-, substituted or unsubstituted C 1-8 AlkylSO-, substituted or unsubstituted C 1-8 AlkylSO2-, substituted or unsubstituted C 1-8 Alkoxy SO-, substituted or unsubstituted C 1-8 Alkoxy SO2-, substituted or unsubstituted C 3-6 CycloalkylCO-, benzoyl; wherein substitution means that one or more H on the group is independently substituted by a group selected from the group consisting of hydrogen, halogen, CN, nitro, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; n is 1 or 2; G is O, S, NR 2 , substituted or unsubstituted C 1-8 Alkyl; wherein, substituted means that one or more H atoms on the group are independently replaced by a substituent selected from the group consisting of hydrogen, halogen, hydroxyl, oxo (=O), =N-OH, =N-OC 1-8 Alkyl, =N-OC 1-8 Halogenated alkyl, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, -OC 3-6 Cycloalkyl; wherein R 2 Selected from the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, C 1-8 Alkoxy, C 1-8 Alkylthio, C 6-10 Aryl, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N, C 3-6 Cycloalkyl (C 1-4 )alkyl-, 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, S and N (C 1-4 )alkyl-, benzyl, C 1-4 Alkoxy (C 1-4 ) alkyl, C 1-8 AlkylCO-, C 1-8 Alkoxy CO-, C 1-8 Alkyl SO-, C 1-8 Alkyl SO2-, C 1-8 Alkoxy SO-, C 1-8 Alkoxy SO2-, C 3-6 CycloalkylCO-, benzoyl.

2. The spirocyclopropanetetradecanate derivative according to claim 1, characterized in that A and E are each independently selected from: hydrogen, substituted or unsubstituted groups: C 1-8 Alkyl, C 3-8 Cycloalkyl, phenyl, benzyl, pyridyl, pyrazolyl, thienyl, furyl or thiazolyl, biphenyl; Substitution means that one or more H atoms on the group are independently substituted by substituents selected from the group consisting of halogen, nitro, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylthio, C 1-4 Halogenated alkylthio, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl.

3. The spirocyclopropanetetradecanate derivative according to claim 1, characterized in that A and E are each independently selected from: and / or, X is selected from: and / or G is selected from:

4. The spirocyclopropanetetradecanate derivative according to claim 1, characterized in that The spirocyclopropanetetradecanate derivative is selected from: And compounds obtained by exchanging the A and E groups in compounds I-1 to VI-14.

5. An agricultural composition, characterized in that include (a) 0.001% to 99.99% by weight of the spirocyclopropanetetraonic acid derivative according to any one of claims 1 to 4, its optical isomers, cis-trans isomers, or pesticidally acceptable salts, or a combination thereof; and (b) pesticide-acceptable carriers and / or excipients.

6. Use of the spirocyclopropanetetronic acid derivative, its optical isomers, cis-trans isomers, or pesticide-acceptable salts according to any one of claims 1 to 4, or the agricultural composition according to claim 5 as an insecticide and acaricide for preventing and controlling agricultural plant diseases.

7. The use according to claim 6, characterized in that Used to control alfalfa aphids, spider mites and diamondback moths.

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