3-thiotetronic acid derivative, and preparation method therefor and use thereof

Abstract

A 3-thiotetronic acid derivate, and a preparation method therefor and the use thereof. Specifically, provided is a compound of formula (I), and an optical isomer thereof, a cis-trans isomer thereof, or an agrochemically acceptable salt thereof. The compound has significantly improved insecticidal and acaricidal activities, and can be used in the development of novel crop insecticidal and acaricidal agents having low toxicity, high efficiency, and which are environmentally friendly.

Description

3-thio-ketol acid derivatives, and preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pesticides, and particularly relates to a 3-thio-ketol acid derivative with insecticidal and miticidal activity, and a preparation method and application thereof BACKGROUND

[0002] The long-term use of existing pesticides has resulted in resistance of pests, weeds and diseases to the pesticides, thereby significantly increasing the use amount of the pesticides and causing serious damage to the environment. Therefore, new pesticides with novel action mechanisms, such as new pesticides with higher insecticidal, miticidal or herbicidal activity, are required to be continuously discovered.

[0003] Ketol acid compounds have become a hot spot in the research and development of insecticides and miticides in the world due to their unique chemical structure, novel action mode, excellent control effect and difficulty in developing resistance. The present application aims to introduce a sulfur-containing group into the structure of ketol acid compounds and perform reasonable molecular design to produce new and more effective insecticides and miticides, solve the problem of resistance of ketol acid insecticides and miticides, and make the ketol acid insecticides and miticides applied to insecticides and miticides. SUMMARY

[0004] The present application aims to provide a 3-thio-ketol acid derivative with novel structure and excellent insecticidal and miticidal activity.

[0005] In a first aspect, the present application provides a compound of formula (I), an optical isomer, a cis-trans isomer thereof, or a pesticidally acceptable salt thereof,

[0006] In the formula, A is a substituted or unsubstituted C

[0007] A is a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, a substituted or unsubstituted benzyl, a substituted or unsubstituted C 1-8 alkyl, a substituted or unsubstituted C 3- 8cycloalkyl, a substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; wherein the substitution means that one or more H on the group is independently substituted by a group selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1- 8haloalkoxy, C1-8 alkylthio, C 1-8 haloalkylthio, C 1-8 alkylsulfoxyl, C 1-8 alkylsulfone, nitro, hydroxy, cyano, amino, C 6-10 aryl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which are unsubstituted or substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 haloalkyl, halogen and cyano; 6-10 aryl;

[0008] n is 0, 1 or 2;

[0009] E is hydrogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkylthio, C 1-8 haloalkylthio, unsubstituted or halogenated C 1-4 alkyl-COO-unsubstituted or halogenated C 1-4 alkyl-, unsubstituted or halogenated C 1-4 alkyl-COO-unsubstituted or halogenated C 1-4 alkyl, unsubstituted or halogenated C 1-4 alkyl-PO(unsubstituted or halogenated C 1-4 alkyl)2, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which are unsubstituted or substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 )alkyl-, substituted or unsubstituted C 3-8 cycloalkyl(C 1-4 )alkyl-, wherein the substitution means that one or more H on the group is independently replaced by a member selected from the group consisting of hydrogen, deuterium, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkylthio, C 1-8 haloalkylthio, nitro, hydroxy, cyano, amino, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which are unsubstituted or substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, C 1-4alkyl, C 1-4 haloalkyl, halogen and cyano;

[0010] X is O, S or N-R, wherein R is selected from the group consisting of 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 comprising 1-3 heteroatoms selected from the group consisting of O, S and N, substituted or unsubstituted 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from the group consisting of O, S and N, substituted or unsubstituted C 3-6 cycloalkyl(C 1-4 )alkyl-, substituted or unsubstituted 3-6 membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of O, S and N (C 1-4 )alkyl-, substituted or unsubstituted phenyl(C 1-4 )alkyl-, substituted or unsubstituted 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from the group consisting of 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 alkoxySO-, substituted or unsubstituted C 1-8 alkoxySO2-, substituted or unsubstituted C 3-6 cycloalkylCO-, benzoyl; wherein the substitution means that one or more H on the group is independently replaced by a member selected from the group consisting of hydrogen, halogen, CN, nitro, hydroxy, cyano, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0011] G and L are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2- 8alkynyl, C2-8 Halogenated alkynyl group, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, substituted or unsubstituted C 6- 10 aryl, substituted or unsubstituted 5-6 membered heteroaryl groups containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted phenyl groups (C 1-4 Alkyl group; or G and L together with the carbon atom attached to them to form a substituted or unsubstituted C group. 3-8 Cycloalkyl, substituted or unsubstituted, 3-8 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from nitrogen, oxygen or sulfur; wherein the substitution refers to one or more H atoms on the group being independently substituted by substituents selected from the group consisting of: hydrogen, halogen, hydroxyl, oxo (=O), =N-OH, =N-OC. 1-8 Alkyl, =N-OC 1-8 Haloalkyl, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 alkenyl, C 2-8 Haloalkenyl, C 2-8 alkynyl group, C 2-8 Halogenated alkynyl group, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, -OC 3-8 Cycloalkyl groups, or two substituents of the same or adjacent ring atoms, together with the ring atoms they are attached to, form substituted or unsubstituted C14 groups. 3-8 A cycloalkyl or substituted or unsubstituted 3- to 8-membered heterocyclic alkyl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein the substitution refers to one or more H atoms on the cycloalkyl or heterocyclic alkyl group being independently substituted by a group selected from the group consisting of halogens, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups.

[0012] In another preferred embodiment, ring A is a substituted or unsubstituted group of the following: C 1-8 Alkyl, C 3-8 Cycloalkyl, phenyl, benzyl, pyridyl, pyrazolyl, thiophenyl, furanyl or thiazolyl, biphenyl; preferably, the substituent refers to one or more H atoms on the group being independently replaced by a substituent selected from the group consisting of: halogen, nitro, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C1-4 alkylthio, C 1-4 haloalkylthio, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl.

[0013] In another preferred embodiment, ring A is substituted or unsubstituted phenyl, benzyl, pyridyl, pyrazolyl, thienyl, furanyl or thiazolyl; preferably, the substituents mean that one or more H atoms of the group are independently replaced by a substituent selected from the group consisting of halogen, nitro, hydroxy, cyano, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 haloalkylthio, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl.

[0014] In another preferred embodiment, E is hydrogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkylthio, C 1-8 haloalkylthio, unsubstituted or halogenated C 1-4 alkyl-COO-unsubstituted or halogenated C 1-4 alkyl-, unsubstituted or halogenated C 1-4 alkyl-PO(unsubstituted or halogenated C 1-4 alkyl)2, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted phenyl (C 1-4 )alkyl-, wherein the substitution means that one or more H of the group are independently replaced by a group selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkylthio, C 1-8 haloalkylthio, nitro, hydroxy, cyano, amino, phenyl or phenyl which is substituted by one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halogen and cyano.

[0015] In another preferred embodiment, E is hydrogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkylthio, C 1-8 haloalkylthio, unsubstituted or halo-substituted C 1-4 alkyl-COO-unsubstituted or halo-substituted C 1-4 alkyl-, unsubstituted or halo-substituted C 1-4 alkyl-PO(unsubstituted or halo-substituted C 1-4 alkyl)2, C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, benzyl.

[0016] In another preferred embodiment, X is O, S or N-R, wherein R is selected from the group consisting of: 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 the group consisting of O, S and N, C 3-6 cycloalkyl(C 1-4 )alkyl-, 3-6 membered heterocycloalkyl(C 1-4 )alkyl- containing 1-3 heteroatoms selected from the group consisting of O, S and N, benzyl, C 1-4 alkoxy(C 1-4 )alkyl, C 1-8 alkylCO-, C 1-8 alkoxyCO-, C 1-8 alkylSO-, C 1-8 alkylSO2-, C 1-8 alkoxySO-, C 1-8 alkoxySO2-, C3-6 cycloalkyl CO-, benzoyl.

[0017] In another preferred embodiment, X is O, S or N-R; and the substituent R is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 halogenalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-CH2, C 3-6 halogenalkyl, C 2-4 alkenyl, C 2-4 halogenalkenyl, C 2-4 alkynyl, C 2-4 halogenalkynyl, C 1-4 alkoxy, C 1-4 halogenalkoxy, phenyl, benzyl, C 1-4 alkylcarbonyl.

[0018] In another preferred embodiment, X is N-R; and the substituent R is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 halogenalkyl.

[0019] In another preferred embodiment, E is cyano, C 1-8 alkyl, C 1-8 halogenalkyl, C 2-8 alkenyl, C 2-8 halogenalkenyl, C 2-8 alkynyl, C 2-8 halogenalkynyl, unsubstituted or halogenated C 1-4 alkyl-COO-unsubstituted or halogenated C 1-4 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted phenyl (C 1-4 )alkyl- or substituted or unsubstituted C 3-8 cycloalkyl (C 1-4 )alkyl-, wherein the substitution means that one or more H on the group is independently replaced by a member selected from the group consisting of deuterium, halogen, C 1-8 alkyl, C 1-8 halogenalkyl, C 1-8 alkoxy and C 1-8 halogenalkoxy.

[0020] In another preferred embodiment, E is C 1-6 alkyl, C 1-6 halogenalkyl or cyano, preferably C 1-4 alkyl, C 1-4 halogenalkyl or cyano.

[0021] In another preferred embodiment, when n is 0, the E group is selected from CH3, CF3, CHF2, CH2CF3, CN; when n is 1 or 2, the E group is selected from CH3, CF3.

[0022] In another preferred embodiment, A is selected from:

[0023] In another preferred embodiment, is selected from:

[0024] In another preferred embodiment, G and L are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, substituted or unsubstituted benzyl; or G and L, together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur; wherein the substitution means that one or more H atoms on the group are independently replaced with a substituent selected from the group consisting of hydrogen, halogen, hydroxyl, oxo (=0), =N-OH, =N-OC 1-8 alkyl, =N-OC 1-8 haloalkyl, C 1- 8alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, -O-C 3-6 cycloalkyl; or two substituents of the same or adjacent ring atoms, together with the ring atom(s) to which they are attached, form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur, and the substitution means that one or more H on the cycloalkyl or heterocycloalkyl are independently replaced with a group selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy.

[0025] In another preferred embodiment, G and L are each independently selected from hydrogen, C 1-4Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkoxy group; or G and L together form substituted or unsubstituted -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2- and -CH2-CH2-X-CH2-CH2-, where X is selected from NR. 1 O, S and CR ’ R”, ​​and one or more H atoms in -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-X-CH2-CH2- are optionally substituted with groups selected from the group consisting of: halogens, C 1-4 Alkyl or C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; wherein R 1 Selected from the following groups: H, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R ’ "and R" are independently selected from the following groups: H, C 1-4 Alkyl or C 1-4 Halogenated alkyl, or R ’ Together with R, they form oxometalates (=O), =N-OH, and =N-OC. 1-4 Alkyl, =N-OC 1-4 Haloalkyl, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -O-CH2-CH2-O- and -S-CH2-CH2-S-.

[0026] In another preferred embodiment, X is selected from:

[0027] In another preferred embodiment, Selected from:

[0028] In another preferred embodiment, A is a substituted or unsubstituted phenyl group, wherein the substituent is one or more selected from the group consisting of: hydrogen, halogen, C. 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C1-8 Haloalkoxy. In another preferred embodiment, A is selected from the group consisting of 2,5-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dichlorophenyl and 2,4-dichlorophenyl.

[0029] In another preferred embodiment, G and L are each independently selected from C. 1-8 Alkyl; preferably, G and L are each independently methyl.

[0030] In another preferred embodiment, G and L together with the carbon atom they are attached to form a substituted or unsubstituted C. 3-6 Cycloalkyl (such as cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl) or oxacyclohexyl, wherein the substitution refers to one or more H atoms on the group being independently substituted by a substituent selected from the group consisting of: C 1-4 Alkoxy, oxo (=O), =N-OH and =N-OC 1-4 alkyl;

[0031] In another preferred embodiment, G and L together with the carbon atom attached to them form a substituted or unsubstituted 3-oxetane or 4-oxetane;

[0032] In another preferred embodiment, G and L, together with the carbon atom they are attached to, form 1-(C 1-4 )alkoxy-piperidin-4-yl. In another preferred embodiment, X is NH or -NC 1-4 alkyl.

[0033] In another preferred embodiment, A is a substituted phenyl group, wherein the substitution refers to one or more H atoms on the group being independently substituted by a group selected from the group consisting of halogens, C, and so on. 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups.

[0034] In another preferred example, n is 0. In another preferred example, n is 2.

[0035] In another preferred embodiment, E is C. 1-8 Alkyl, C 1-8 Halogenated alkyl groups, deuterated C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Haloalkenyl, C 2-8 Alkyne group or CN.

[0036] In another preferred embodiment, E is C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0037] In another preferred embodiment, n is 0; and E is C. 1-4 Alkyl or C1-4 haloalkyl.

[0038] In another preferred embodiment, n is 0; and E is CN.

[0039] In another preferred embodiment, halo is Cl. In another preferred embodiment, halo is F.

[0040] In another preferred embodiment, A is In another preferred embodiment, is

[0041] In another preferred embodiment, the compound has the structure of Formula (II):

[0042] wherein n, A, E, X are as defined above, and Y is nothing, -CH2, -CH-O-C 1-3 alkyl, O, S, -CF2, N-O-C 1-3 alkyl, -C(C 1-3 alkyl)2, NC 1-3 alkyl, -CH-OH, C=O, -C=N-O-C 1-3 alkyl, and -C=N-OH.

[0043] In another preferred embodiment, wherein Y is nothing, -CH2, -CH-O-C 1-3 alkyl, O, -CF2, N-O-C 1-3 alkyl, -C(C 1-3 alkyl)2, NC 1-3 alkyl, C=O, and -C=N-O-C 1-3 alkyl.

[0044] In another preferred embodiment, Y is nothing, -CH2, -CH-O-C 1-3 alkyl, or O.

[0045] In another preferred embodiment, the compound has the structure of Formula (III):

[0046] wherein n, A, E, X are as defined above.

[0047] In another preferred embodiment, the compound has the structure of Formula (IV):

[0048] wherein n, A, E, X are as defined above, and Z is an oxygen or sulfur atom, and m is selected from 0, 1, 2, or 3.

[0049] In another preferred embodiment, the compound has the structure of Formula (V):

[0050] wherein n, A, E, X are as defined above, and R 4 is H or C 1-4 alkyl.

[0051] In another preferred embodiment, the group in the compound of formula I is optionally independently as corresponding group in Table 1 of this application.

[0052] In another preferred embodiment, the compound of formula I is a compound shown in Table 1.

[0053] In a second aspect of the present application, there is provided a composition comprising, based on the total weight of the composition being 100%:

[0054] (a) 0.001 to 99.99% by weight of a compound of formula (I), an optical isomer, a geometric isomer, or a pesticidally acceptable salt thereof, as described in the first aspect of the present application; and

[0055] (b) a pesticidally acceptable carrier and / or excipient.

[0056] In a third aspect of the present application, there is provided the use of a compound of formula (I), an optical isomer, a geometric isomer, or a pesticidally acceptable salt thereof, as described in the first aspect of the present application, or a composition as described in the second aspect of the present application, as an insecticide, acaricide for crops.

[0057] In a fourth aspect of the present application, there is provided a method of killing and / or repelling insects and / or acarids, the method comprising applying a compound of the first aspect, an optical isomer, a geometric isomer, or a pesticidally acceptable salt thereof, or a composition of the second aspect of the present application, to a plant, an animal, soil or an environment in the vicinity thereof that is or can be subject to infestation by insects and / or acarids.

[0058] The present application also provides a method of controlling pests, by applying an effective acaricidal amount (10-1000 mg / L, more preferably 100-500 mg / L) of a compound of the first aspect of the present application, an optical isomer, a geometric isomer, or a pesticidally acceptable salt thereof, or a composition of the second aspect of the present application, to a plant seed and / or plant foliage and / or plant fruit or a locus in which the plant is growing or is expected to grow.

[0059] Preferably, the pests to be controlled include, but are not limited to, (i) at least one pest and / or its nymphs and / or its eggs from the orders Acarina, Symphyta, Orthoptera, Dermaptera, Isoptera, Thysanoptera, Lepidoptera, Coleoptera, Hymenoptera, Diptera, Siphonaptera, Chalcidoidea, and plant parasitic nematodes;

[0060] (ii) for use in killing and / or repelling insects and / or acarids;

[0061] (iii) for use in the preparation of a composition or formulation for killing and / or controlling mites and / or eggs thereof;

[0062] (iv) for use in the preparation of a composition or formulation for killing mites and / or insects.

[0063] In another preferred embodiment, the compound of formula I is for use in killing and / or controlling mites and / or for use in the preparation of a composition or formulation for killing insects and / or mites.

[0064] In another preferred embodiment, the compound of formula I is for use in killing and / or controlling harmful mites and / or eggs thereof in agriculture, in pastures, in lawns and / or indoors.

[0065] In another preferred embodiment, the compound of formula I is for use in killing and / or controlling harmful insects in agriculture, in pastures, in lawns and / or indoors.

[0066] In another preferred embodiment, the mites are harmful mites.

[0067] In another preferred embodiment, the mites are selected from the group consisting of Tetranychus urticae Koch, Tetranychus viennensis Zacher, Tetranychus truncatus Ehara, Tetranychus cinnabarinus Boisduval, Panonychus ulmi Koch, Panonychus citri McGregor, Bryobia rubrioculus Scheuten, Petrobia latens Muller, Oligonychus ununguis Jacobi, Brevipalpus obovatus Donnadieu, B. lewisi McGregor, Tenuipalpus taonicas Ma et Yuan, Tenuipalpus zhizhilashviliae Reck, C. vitis Pagenstecher, A. steinwedeni Keifer, A. macrodonis Keifer, Eriophyes pyri Pagenst, Epitrimerus pirifolia Keifer, Polyphagotarsonemus latus Banks, Penthaleus major Duges, Rhizoglyphus callae Oudemans.

[0068] In another preferred embodiment, the pests are selected from the group consisting of Scutigerella immaculat, Acheta domesticus, Gryllotalpa spp., Locusta inigratoria, Melanoplus spp., Schistocer cagregaria, Blatta orientalis, Periplanet ainericana, Leucophae amaderae, Blattella gerrnanica, Reticuliterines spp., Pediculus humanuscorporis, Haematopinus spp., Linognathus spp., Trichodectes spp., Dainalinia spp., Hercinothrips fernoralis, Thrips tabaci, Thrips palmi, Frankliniella occidentalis, Eurygaster spp., Dysdercus interrnedius, Piesrna quadrata, Cimexiectularius, Rhodnius prolixus, Triatoma spp., Aleurodes brassicae, Beinisia tabaci, Trialeurodes vaporariorum, Aphis gossypii, Brevicoryne brassicae, Cryptomyzus ribis, Aphis fabae, Aphis poini, Eriosoma lanigerum, Hyalopterus arundinis, Phylloxera vastatrix, Pernphigus spp., Macrosiphurn avenae, Myzus spp.), Phorodon humuli, Rhopalosiphum padi, Einpoasca spp., Nephotettix cincticeps, Lecanium corni, Saissetia oleae, Laodelphax striatellus, Nilaparvata lugens, Aonidiella aurantii, Aspidiotus hederae, Pseudococcus spp., Psylla spp., Pectinophora gossypiella, Bupalus piniarius, Cheirnantobia brumata, Lithocolletis blancardella, Hyponomeuta padella, Plutella xylostella, Malacosoma neustria, Euproctis chrysorrhoea, Lymantria spp., Bucculatrix thurberiella, Phyllocnistis citrella, Agrotis spp., Euxoa spp., Feltia spp., Earias insulana, Heliothis spp., Mamestra brassicae, Panolis flammea, Spodoptera litura, Spodoptera frugiperda, Spodoptera spp., Trichoplusia ni, Carpocapsa pomifera, Pieris spp., Chilo spp.), corn earworm (Helicoverpa zea), Mediterranean flour moth (Ephestia kuehniella), giant wax moth (Galleria mellonella), webbing clothes moth (Tineola bisselliella), case-bearing clothes moth (Tinea pellionella), brown-headed clothes moth (Hofmannophila pseudospretella), lime aphid moth (Cacoecia podana), eastern tent caterpillar moth (Choristoneura funiferana), grape berry moth (Clysia ambiguella), tea tortrix moth (Homona magnanima), light brown apple moth (Tortrix viridana), rice leaffolder (Cnaphalocerus spp.), rice leafroller (Oulema oryzae), furniture beetle (Anobium punctatum), lesser grain borer (Rhizopertha dominica), bean bruchid (Bruchidius obtectus), bean weevil (Acanthoscelides obtectus), banded elm leaf beetle (Hylotrupes bajulus), alder cone leaf beetle (Agelastica alni), Colorado potato beetle (Leptinotarsa decemlineata), mustard beetle (Phaedon cochleariae), Diabrotica spp., cabbage beetle (Psylliodes chrysocephala), Mexican bean beetle (Epilachna varivestis), sawtoothed grain beetle (Oryzaephilus surinamensis), Anthonomus spp., Sitophilus spp., black vine weevil (Otiorrhynchus sulcatus), banana root borer (Cosmopolites sordidus), cabbage gall midge (Ceuthorrhynchus assimilis), clover leaf weevil (Hypera postica), Dermestes spp., Trogoderrna spp., Anthrenus spp., Attagenus spp., Lyctus spp., rape beetle (Meligethes aeneus), Ptinus spp.), yellow spider mite (Tetranychus urticae), yellow mealworm (Tenebrio molitor), wireworms (Agriotes spp.), Conoderus spp., May / June beetles (Melolontha melolontha), A. sols- titialis, C. zealandica, rice rootworm (Lissorhoptrus oryzophilus), Diprion spp., Hoplocampa spp., Lasius spp., M. pharaonis, Vespula spp., Aedes spp., Anopheles spp., Culex spp., Drosophila melanogaster, Musca spp., Fannia spp., Calliphora vicina, Lucilia spp., Chrysomyia spp., Cuterebra spp., Gastrophilus spp., Hyppobosca spp., Stomoxy spp., Oestrus spp., Hypoderma spp., Tabanus spp., Bibio hortulanus, Oscinella frit, Phorbia spp., Pegomyia hyoscyami, Ceratitis capitata, Dacus oleae, Tipula paludosa, Hylemyia spp., Liriomyza spp., Xenopsylla cheopis, Ceratophyllus spp., Pratylenchus spp.), Radopholus similis, Ditylenchus dipsaci, Tylenchulus sernipenetrans, Heterodera spp., Globodera spp., Meloidogyne spp., Aphelenchoides spp., Longidorus spp., Xiphinema spp., Trichodorus spp., Bursaphelenchus spp.

[0069] In a fourth aspect, the present application provides a composition comprising (i) a compound according to the first aspect, a geometric isomer, a stereoisomer thereof, or a pesticidally acceptable salt or a prodrug thereof, as an active ingredient; and (ii) a carrier and / or a surfactant.

[0070] In another preferred embodiment, the content of the compound in the composition is 0.001 to 99.999 wt%.

[0071] In another preferred embodiment, the composition is a pesticidal composition; preferably, an acaricidal composition, an insecticidal composition.

[0072] In a fifth aspect, the present application provides a method for killing mites and insects, comprising the step of contacting the mites and insects with an effective amount of a compound according to the first aspect, a geometric isomer, a stereoisomer thereof, or a pesticidally acceptable salt or a prodrug thereof or a composition according to the fourth aspect.

[0073] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail below (e.g., in the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they will not be listed one by one here.

[0074] In a sixth aspect, the present application provides a method for preparing the compound according to the first aspect, comprising the steps of:

[0075] (i) a substitution reaction between a compound of formula P and a compound of formula Q in the presence of a base to obtain a compound of formula (I);

[0076] Reaction Scheme (I),

[0077] wherein n = 0; and A, E, G, L are as defined in claim 1.

[0078] or further comprising the following step 2:

[0079] and (ii) oxidizing the compound obtained in step 1 in the presence of an oxidizing agent to obtain the compound of formula (I),

[0080] reaction formula (II),

[0081] wherein n = 1 or 2; and A, E, G, L are as defined above.

[0082] In step (i), the solvent used is selected from one or more of the following having water content less than 10 ppm: benzene, toluene, ethyl acetate, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, PEG400, n-heptane, n-hexane, cyclohexane, petroleum ether, dimethylformamide, dimethyl sulfoxide, or a combination thereof.

[0083] In step (i), an inorganic base or an organic base selected from the group consisting of sodium hydroxide, cesium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium ethoxide, triethylamine, dimethylaminopyridine, aqueous ammonia, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, diisopropylethylamine, lithium bis(trimethylsilyl)amide, DBU, TBD, DMAP, pyridine, or a combination thereof is used.

[0084] In step (i), the reaction is carried out at -20°C to 100°C, more preferably at 15-35°C.

[0085] In step (i), the reaction time is 1-24 h, more preferably 2-4 h.

[0086] In step (ii), the solvent used is selected from one or more of the following: acetonitrile, tetrahydrofuran, toluene, 1,2-dichloroethane, dichloromethane, 1,4-dioxane, N,N-dimethylformamide, acetone, methanol, cyclohexane, chlorobenzene, more preferably tetrahydrofuran, dichloromethane.

[0087] In step (ii), an oxidizing agent selected from one of the following group is used: m-CPBA, hydrogen peroxide, Oxone, t-BuOOH, Ca(OCl)2, NaClO, RuCl3·3H2O.

[0088] In addition, in step (i), the compound Q can be selected from one of the following compounds Q-1 to Q-13 as an electrophilic reagent donor containing the E group.

[0089] It should be understood that, within the scope of the present application, each of the technical features of the present application described above and each of the technical features specifically described hereinafter (e.g., in the examples) can be combined with each other to constitute a new or preferred technical solution. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0090] The present inventors, through extensive and in-depth research, by a large number of screening and testing, provide a 3-thio ketone acid derivative with novel structure and insecticidal and miticidal activity, and a preparation method and application thereof. The present application restructures the existing ketone acid compound, introduces a sulfur-containing group at its 3-position, designs and synthesizes a series of novel ketone acid compounds, achieves excellent insecticidal and miticidal activity, and expands the insecticidal spectrum, which is expected to develop a new type of pesticide with low toxicity, high efficiency and environmental friendliness. On this basis, the present application is completed.

[0091] TERMS

[0092] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0093] As used herein, the term "containing" or "including" can be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0094] The prefix "C u-v " indicates that the following group has 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" indicates that the alkyl group has 1 to 8 carbon atoms.

[0095] The term "plurality" means 2 or more, such as 2, 3, 4, 5 or 6.

[0096] The term "halogen" or "halo" means fluorine, chlorine, bromine, iodine.

[0097] The term "alkyl" means a straight-chain or branched, unsubstituted hydrocarbon group having 1-8 carbon atoms (i.e., C 1-8 alkyl), preferably 1-6 carbon atoms (i.e., C 1-6 alkyl), and more preferably 1-4 carbon atoms (i.e., C 1-4 alkyl). Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl, and the like.

[0098] The term "alkylene" denotes a saturated divalent hydrocarbon radical derived from a straight chain or branched saturated hydrocarbon by the removal of two hydrogen atoms (i.e., C 1-8 alkylene), preferably 1 to 4 carbon atoms (i.e., C 1-4 alkylene), more preferably 1 to 3 carbon atoms (i.e., C 1-3 alkylene). Examples of "alkylene" include, but are not limited to, methylene, ethylene, isopropylidene, and the like.

[0099] The term "alkenyl" refers to a straight chain or branched hydrocarbon radical having 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), preferably 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl), and having 1 to 2 carbon-carbon double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0100] The term "alkynyl" refers to a straight chain or branched hydrocarbon radical having 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), preferably 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl), and having 1 to 2 carbon-carbon triple bonds.

[0101] The term "cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon radical, which can optionally be substituted with one or more substituents described herein, having 3 to 6 carbon atoms as a monocyclic ring, or 7 to 12 carbon atoms as a bicyclic ring. As used herein, cycloalkyl has 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Examples of monocyclic cycloalkyl 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, cyclooctyl. Exemplary bridged bicyclic cycloalkyl include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane.

[0102] The terms "aromatic ring" and "aryl" refer to an aromatic carbocyclic radical having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused ring systems. As used herein, aryl has 6 to 10 ring carbon atoms (i.e., C 6-10 aryl). Aryl includes bicyclic radicals that include an aromatic ring fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring (e.g., benzocyclo 3-6Cycloalkyl or benzo 4-6 membered heterocyclyl). Typically aryl groups include, but are not limited to, the following groups: benzene, naphthalene, anthracene, biphenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, 2,3-dihydrobenzofuranyl, and the like. The "aryl" class includes structures in which the aryl ring is fused to a cycloalkyl, heterocycloalkyl ring.

[0103] The terms "heterocycle," "heterocyclic," "heterocyclyl," and "heterocycloalkyl" refer to an optionally substituted, fully saturated or partially unsaturated non-aromatic ring group, e.g., it can be 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 carbon atom-containing ring. Each ring of the heterocyclyl group containing a heteroatom can have 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. As used herein, a 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" group can be optionally substituted with one or more substituents described herein, examples of "heterocyclyl" groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, thiomorpholino, piperazinyl, homopiperazinyl, oxetanyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, N-piperidinylurea, pyrimidinonyl, and 1,1-dioxo-thiomorpholinyl.

[0104] The terms "heteroaryl" or "heteroaromatic" refer 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 optionally substituted with one or more substituents described herein. As used herein, a 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" groups include, but are not limited to, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, pyrazinyl, imidazopyridinyl, benzofuranyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, and the like.

[0105] "Oxy" refers to the -O- group, "acyloxy" refers to the -C(=O)-O- group, "carbonyl" refers to the -C(=O)- group, "nitro" refers to the -NO2 group, "cyano" refers to -CN, "hydroxy" refers to -OH, "amino" refers to -NH2. The term "oxo" represents a divalent group =O. "Sulfonamide" refers to the -SO2NH2 group. "Carboxy" refers to the -COOH group. "Benzoyl" refers to the phenyl-CO- group.

[0106] The term "substituted" means that one or more hydrogen atoms in a specified group are replaced with any of the substituents mentioned in the present application, provided that the designated group or atom does not exceed the normal valency for the molecule and that the resulting compound is stable, i.e., can be isolated, characterized, and tested for biological activity. Unless otherwise specified, the "substitution" is by 1 or more (e.g., 2, 3, or 4) hydrogens on the group with the group being independently replaced with a group selected from the group consisting of 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 replaced with 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.

[0107] The term "active substance of the present application" or "active compound of the present application" means a compound of the structure shown in general formula (I) or an optical isomer, a cis-trans isomer, or a pesticidally acceptable salt thereof.

[0108] The term "pharmaceutically acceptable salt" means that the anion of the salt is well- understood and accepted in the formation of pharmaceutically acceptable salts. Preferably, the salt is water soluble. Suitable acid addition salts formed from the compounds of Formula (I) include salts of inorganic acids, for example, hydrochloride, phosphate, sulfate, nitrate; and salts of organic acids, such as acetate, benzoate, and the like.

[0109] Active ingredient

[0110] The present application provides a compound of Formula (I), an optical isomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof:

[0111] wherein n, A, E, G, L are defined as above.

[0112] In another preferred embodiment, the compound is any one of the compounds in the Examples.

[0113] The present application is intended to include salts of the compounds. The "pharmaceutically acceptable salts" can have more than one charged atom, and the multiple charged atoms can have multiple counterions. In exemplary embodiments, the salt form of the compounds is produced, which can convert otherwise oily or tacky compounds into more handleable solid substances. In another exemplary embodiment, the conversion of the free base of the compounds of the present application into the corresponding salt can increase the solubility of the compound in aqueous media, while also being able to affect biological properties, such as bioavailability, pharmacokinetics, and pharmacodynamics. Thus, any salt form, such as a pharmaceutically acceptable salt of the compounds of the present application, including a salt of an inorganic acid or a salt of an organic acid, is within the scope of the present application. Also, various crystalline forms of a pharmaceutically acceptable salt of the compounds of the present application are within the scope of the present application. Any prodrugs of the compounds of the present application are also within the scope of the present application.

[0114] As used herein, the term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of this application include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, 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, besylate, 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, tosylate, undecanoate, valerate salts, and the like.

[0115] Solvate refers to the combination or complex of one or more solvent molecules with a compound of the application. Examples of solvents which form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. The compounds of the application can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the application embrace both solvated and unsolvated forms.

[0116] Some compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the equilibrium nature between tautomers, one of ordinary skill in the art understands that a compound includes all tautomers or each tautomer of the compound. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic acid-containing compounds are understood to include their amide tautomers.

[0117] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. Compounds can be in the form of a single stereoisomer, a racemic mixture, or a mixture of one or more stereoisomers. The present application includes enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, and mixtures of diastereomers. All stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomers, enantiomers and atropisomers, as well as, mixtures thereof, such as racemic mixtures, form part of the present application. Additionally, asymmetric carbon atoms can be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included within the present application. If a particular enantiomer of a compound of the present application 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 cleaved to provide the pure desired enantiomer. Alternatively, where 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 resulting diastereomers and subsequent recovery of the pure enantiomer. Additionally, separation of the enantiomers and diastereomers can be achieved by chromatography utilizing chiral stationary phases.

[0118] In this document, unless otherwise indicated, structures depicted are also meant to include all stereochemical isomers. The present application contemplates all geometric and positional isomers. The compounds of the present application can exist in different tautomeric forms and all such forms are encompassed within the scope of the present application. All stereoisomers of the compounds of the present application are contemplated, whether in mixture with other stereoisomers or not.

[0119] In this document, unless otherwise indicated, structures depicted are also meant to include all isotopically enriched atoms. Such compounds, for example, can be used as analytical tools or probes in biological assays. Any formula or structure given herein is also meant to represent the unlabeled form of the compound as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the formulas 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 suitably substituted into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, 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-labelled compounds of the present disclosure, for example, those incorporating a radioactive isotope such as 3 H and 14 C, can be used in metabolic 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 assays, or in radioactive treatment.

[0120] Insecticidal activity of the inventive substances

[0121] The active compounds according to the invention are active ingredients which are of preventive and / or curative value in the field of pest control (even if applied in low application rates), which have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish and plants. The active ingredients act on all or individual developmental stages of normally sensitive and also resistant animal pests, such as insect or acarine representatives, of all kinds. The insecticidal or acaricidal activity of the active ingredients can manifest itself directly, i.e. for example in the destruction of the pests during the molting, which occurs immediately or only after a certain period of time, or indirectly, for example in a reduced oviposition and / or hatching rate, good activity corresponding to a destruction rate (mortality) of at least 50-60%.

[0122] The active compounds according to the invention can be used to combat and control infestations of insect pests (for example Lepidoptera, Diptera, Hemiptera, Thysanoptera, Orthoptera, Netwvora, Coleoptera, Siphonaptera, Hymenoptera and Isoptera) and other invertebrate pests (for example mites, nematodes and mollusc pests). Insect species, mite species, nematode species and mollusc species are hereinafter collectively referred to as pests. Pests which can be combated and controlled using the inventive compounds include those associated with agriculture (which term includes the growing of crops of food and fibre products), horticulture and animal husbandry, pet care, forestry, and the storage of products of plant origin (for example fruit, grain and timber); those associated with the deterioration of man-made structures and the transmission of diseases of humans and animals; and nuisance pests (for example flies).

[0123] The compounds provided by the present invention have significant pesticidal activity and can be used to control and destroy a wide variety of agricultural, forestry, stored grain, animal health or public health pests. In the present specification, pests which can be killed or controlled include, but are not limited to, the following:

[0124] In particular, the 3-thia-substituted ketonic acid derivatives of the present application show excellent acaricidal activity against Arachnida, Acarina, such as Tetranychus urticae Koch, Tetranychus viennensis Zacher, Tetranychus truncatus Ehara, Tetranychus cinnabarinus Boisduval, Panonychus ulmi Koch, Panonychus citri McGregor, Bryobia rubrioculus Scheuten, Petrobia latens Muller, Oligonychus ununguis Jacobi, Brevipalpus obovatus Donnadieu, B. lewisi McGregor, Tenuipalpus taonicas Ma et Yuan, Tenuipalpus zhizhilashviliae Reck, C. vitis Pagenstecher, A. steinwedeni Keifer, A. macrodonis Keifer, Eriophyes pyri Pagenst, Epitrimerus pirifolia Keifer, Polyphagotarsonemus latus Banks, Penthaleus major Duges, Rhizoglyphus callae Oudemans, and the like. The "acaricidal activity" means the killing activity against mites at each stage (egg, larva, adult) of the life cycle of the mites. Therefore, the present application also includes the use of the 3-thia-substituted ketonic acid derivatives of the present application as acaricides in agriculture or other fields.

[0125] The 3-thia-substituted ketonic acid derivatives of the present application are also suitable for controlling at least one pest from the orders of Synthura, Orthoptera, Homoptera, Siphuntera, Anoplura, Thysanoptera, Heteroptera, Homoptera, Lepidoptera, Coleoptera, Hymenoptera, Diptera, Siphonaptera, and plant parasitic nematodes in agriculture or other fields.

[0126] the Syrphidae, for example, Scutigerella immaculata and the like.

[0127] the Orthoptera, for example, Acheta domesticus, Gryllotalpa spp., Locusta migratoria, Melanoplus spp., Schistocerca gregaria and the like;

[0128] the Blattaria, for example, Blatta orientalis, Periplaneta americana, Leucophaea maderae, Blattella germanica and the like.

[0129] the Isoptera, for example, Reticulitermes spp. and the like.

[0130] the Phthiraptera, for example, Pediculus humanus corporis, Haematopinus spp., Linognathus spp., Trichodectes spp., Damalinia spp. and the like.

[0131] the Thysanoptera, for example, Hercinothrips femoralis, Thrips tabaci, Thrips palmi, Frankliniella occidentalis and the like.

[0132] the Heteroptera, for example, Eurygaster spp., Dysdercus intermedius, Piesma quadrata, Cimex lectularius, Rhodnius prolixus, Triatoma spp. and the like.

[0133] the Hoinoptera, for example, Aleurodes brassicae, Beinisia tabaci, Trialeurodes vaporariorum, Aphis gossypii, Brevicoryne brassicae, Cryptomyzus ribis, Aphis fabae, Aphis poini, Eriosoma lanigerum, Hyalopterus arundinis, Phylloxera vastatrix, Pernphigus spp., Macrosiphurn avenae, Myzus spp., Phorodon humuli, Rhopalosiphum padi, Einpoasca spp., Nephotettix cincticeps, Lecanium corni, Saissetia oleae, Laodelphax striatellus, Nilaparvata lugens, Aonidiella aurantii, Aspidiotus hederae, Pseudococcus spp., Psylla spp., etc.

[0134] the Lepidoptera, for example, Pectinophora gossypiella, Bupalus piniarius, Cheirnathobia brumata, Lithocolletis blancardella, Hyponomeuta padella, Plutella xylostella, Malacosoma neustria, Euproctis chrysorrhoea, Lymantria spp., Bucculatrix thurberiella, Phyllocnists citrella, Agrotis spp., Euxoa spp., Feltia spp., Earias insulana, Heliothis spp., Mamestra brassicae, Panolis flammea, Spodoptera litura, Spodoptera frugiperda, Spodoptera spp., Trichoplusia ni, Carpocapsa pomonella, Pieris spp., Chilo spp., Pyrausta nubilalis, Ephestia kuehniella, Galleria mellonella, Tineola bisselliella, Tinea pellionella, Hofmannophila pseudospretella, Cacoecia podana, Choristoneura funiferana, Clysia ambiguella, Homona magnanima, Tortrix viridana, Cnaphalocerus spp., Oulema oryzae, and the like.

[0135] The order Coleoptera, for example, Anobium punctatum, Rhizopertha dominica, Bruchidius obtectus, Acanthoscelides obtectus, Hylotrupes bajulus, Agelastica alni, Leptinotarsa decemlineata, Phaedon cochleariae, Diabrotica spp., Psylliodes chrysocephal, Epilachna varivestis, Oryzaephilus surinamensis, Anthonomus spp., Sitophilus spp., Otiorrhynchus sulcatus, Cosinopolites sordidus, Ceuthorrhynchus assimilis, Hypera postica, Dermestes spp., Trogoderrna spp., Anthrenus spp., Attagenus spp., Lyctus spp., Meligethes aeneus, Ptinus spp., Niptus bololeucus, Gibbium psylloides, Tribolium spp., Tenebrio molitor, Agriotes spp., Conoderus spp., Melolontha melolontha, Amphimallon solstitialis, Costelytra zealandica, Lissorhoptrus oryzophilus and the like.

[0136] the order of the Hymenoptera, for example, Dipnion spp., Hoplocampa spp., Lasius spp., Monornonium pharaonis, Vespa spp., etc.;

[0137] the order of the Diptera, for example, Aedes spp., Anopheles spp., Culex spp., Drosophila melanogaster, Musca spp., Fannia spp., Calliphora vicina, Lucilia spp., Chrysomyia spp., Cuterebra spp., Gastrophilus spp., Hyppobosca spp., Stomoxy spp., Oestrus spp., Hypoderrna spp., Tabanus spp., Bibio hortulanus, Oscinella frit, Phorbia spp., Pegomyia hyoscyami, Ceratitis capitata, Dacus oleae, Tipula paludosa, Hylemyia spp., Liriotnyza spp., etc.

[0138] the order of the Siphonaptera, for example, Xenopsylla cheopis, Ceratophyllus spp., etc.

[0139] The plant-parasitic nematodes include, for example, Pratylenchus spp., Radopholus similis, Ditylenchus dipsaci, Tylenchulus sernipenetrans, Heterodera spp., Globodera spp., Meloidogyne spp., Aphelenchoides spp., Longidorus spp., Xiphinema spp., Trichodorus spp., Bursaphelenchus spp., and the like.

[0140] Therefore, the technical scheme of the present application also includes the use of the 3-thioxo-ketonic acid compound shown in Formula I as an insecticide in agriculture or other fields.

[0141] Composition

[0142] The insecticide / acaricide composition containing the "active substance of the present application" can be prepared into an insecticide composition in a conventional method. These active compounds can be made into conventional formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, natural and synthetic materials impregnated with active substances, microcapsules in polymers, coating compounds for seeds, and formulations for use with combustion devices, such as smoke cartridges, smoke pots and smoke trays, as well as ULV cold mist and warm mist formulations.

[0143] These formulations can be produced in a known manner, for example, by mixing the active compounds with extenders, that is to say liquid or liquefied gaseous or solid diluents or carriers, and if desired surfactants, that is to say emulsifiers and / or dispersants and / or foam formers. It is also possible to use solid extenders or diluents which can be wetted before use, for example, with water or an aqueous solution. The use of a solvent, for example, an organic solvent, is also possible in the extent permitted by the physical properties and the nature of the active compounds.

[0144] When using liquid solvents as diluents or carriers, it is possible to use, for example, aromatic, such as xylene, toluene or alkylnaphthalenes, chlorinated, for example, chlorobenzen or chlorodebenzen, aliphatic, for example, cyclohexane or paraffins, for example, mineral oil fractions, alcoholic, for example, ethanol, or glycol and their ethers or esters, ketonic, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, or polar solvents, for example, dimethylformamide, dimethyl sulphoxide, or also water.

[0145] Diluents or carriers for liquefied gases refer to liquids which become gaseous at normal temperature and pressure, such as aerosol propellants, e.g. halogenated hydrocarbons and butane, propane, nitrogen and carbon dioxide.

[0146] 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 granules are crushed and fractionated natural zirconia, such as calcite, marble, pumice, sepiolite, dolomite, inorganic and organic coarse powder synthetic granules, and granules of organic materials such as sawdust, coconut shells, corn cobs and tobacco stems.

[0147] Nonionic and anionic emulsifiers can be used as emulsifiers and / or foam-forming agents. Examples are polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates and albumin hydrolysate. Dispersants include lignin sulfite waste liquors and methylcellulose.

[0148] Binders can be used in the formulations, 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.

[0149] Colorants such as inorganic pigments, e.g. iron oxide, titanium oxide and Prussian Blue; organic dyes, e.g. azo dyes or metal phthalocyanine dyes; trace nutrients such as salts of iron, manganese, boron, copper, cobalt, aluminum and zinc, etc. can be used.

[0150] The "active compounds according to the invention" can be present in their commercial formulations or the use forms prepared from these formulations in the form of a mixture with other active compounds which are insecticides, bactericides, fungicides, herbicides, growth regulators and so on. Insecticides include, for example, phosphonates, carbamates, chlorinated hydrocarbons and substances produced by microorganisms, such as abamectin and the like, fungicides include strobilurins, amides, triazoles and the like.

[0151] Furthermore, the "active compounds according to the invention" can also be present in their commercial formulations or the use forms prepared from these formulations in the form of a mixture with synergists, i.e. compounds which enhance the action of the active compounds, it also being possible for the active compounds to be active without the addition of synergists.

[0152] These formulations generally contain from 0.001 to 99.99 % by weight, preferably from 0.01 to 99.9 % by weight, more preferably from 0.05 to 90 % by weight, of the "active compound according to the invention" based on the total weight of the composition. The concentration of active compound in the commercial formulations or application forms can vary within a broad range. The concentration of active compound in the application forms can vary from 0.0000001 to 100 % (g / v), preferably between 0.0001 and 1 % (g / v).

[0153] The compound represented by formula (I), the optical isomer thereof, the cis-trans isomer thereof, or the agriculturally acceptable salt thereof has been found to have a good control effect on, in particular, the pea aphid, the two-spotted spider mite and the diamondback moth.

[0154] The main advantages of the present application include:

[0155] (1) The present application provides a novel 3-thio-ketonic acid derivative, a composition, use and preparation method thereof.

[0156] (2) The compound of the present application has significantly improved insecticidal and miticidal activity, and expands the insecticidal spectrum, and is expected to develop a new type of low-toxicity, high-efficiency, environment-friendly insecticide and miticide for crops.

[0157] The present application will be further described in conjunction with specific implementations. It should be understood that these examples are only used to illustrate the present application and are not used to limit the scope of the present application. The experimental methods in the following examples are not specified, and are generally carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0158] Example 1

[0159] The preparation process of 3-(2,5-dimethylphenyl)-8-methoxy-3-((trifluoromethyl)thio)-1-azaspiro[4.5]decane-2,4-dione is shown as follows:

[0160] Method One

[0161] Reaction reagents and conditions: (a) methanol, 0.5M sodium hydroxide aqueous solution, room temperature, 1h; (b) acetonitrile, argon protection, room temperature, 1h; (c) tetrahydrofuran, potassium carbonate, room temperature, 1h.

[0162] Specifically, the following steps are included:

[0163] Intermediate P-1 [3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one]

[0164] 100 mL single-mouth flask, spinetoram (1.87 g, 5.00 mmol) was put in, 20 mL of methanol was added to dissolve, stirring in ice bath; 10 mL of sodium hydroxide (0.20 g, 5.00 mmol) aqueous solution was prepared, and slowly added to the above reaction system, after the dropwise addition was completed, continue to stir at room temperature, TLC tracking, about 1 h after the reaction was completed. The reaction solution was adjusted to PH = 3 with 1M hydrochloric acid solution, and then the methanol in the reaction system was removed under vacuum, the residual aqueous solution was extracted with dichloromethane (3*20 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, white solid was obtained, yield 93.12%.

[0165] Intermediate Q-6-1 [2-((trifluoromethyl)thio)isoindoline-1,3-dione]

[0166] 100 mL two-mouth flask, AgSCF3 (6.25 g, 30.00 mmol) was put in, N-bromosuccinimide (5.20 g, 23.00 mmol) was put in, and dry acetonitrile (40 mL) was added. The mixture was stirred at room temperature for 3 h, and then the solvent was removed under a rotary evaporator. In the preliminary concentrate, dichloromethane (20 mL) was added to dissolve, and filtered with diatomite, washed with dichloromethane, and the solvent was rotary dried to obtain the standard compound (white solid, 5.30 g, 93.23%)

[0167] Compound I-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-((trifluoromethyl)thio)-1-azaspiro[4.5]decane-2,4-dione]

[0168] 25 mL single-mouth round-bottom flask, intermediate P-1 (0.30 g, 1.00 mmol) was put in, intermediate Q-6-1 (0.30 g, 1.20 mmol) was put in, 10 mL of tetrahydrofuran was added to dissolve, potassium carbonate (0.55 g, 4.00 mmol) was added, and the reaction was carried out at room temperature, TLC tracking reaction, 0.5 h after the reaction was completed. The reaction solution was rotary dried, dichloromethane was added, silica gel column chromatography was carried out, petroleum ether: ethyl acetate = 2:1 (V:V), and the solvent was rotary dried to obtain compound I-1 (white solid, 0.23 g, 57.31%).

[0169] Method two

[0170] Reaction reagents and conditions: (a) methanol, 0.5M sodium hydroxide aqueous solution, room temperature, 1h; (b) acetonitrile, nitrogen protection, AgSCF3, room temperature, 10 minutes; (c) tetrahydrofuran, potassium carbonate, room temperature, 1h.

[0171] Specifically, the following steps are included:

[0172] Intermediate P-1 [3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1- azaspiro[4.5]dec-3-en-2-one]

[0173] The preparation of 3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1- azaspiro[4.5]dec-3-en-2-one was carried out in the same way as the synthesis of Intermediate P-1 in Example 1.

[0174] Intermediate Q-7-1 [2-((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1- dioxide]

[0175] In a 100 mL round-bottom flask filled with nitrogen, AgSCF3(6.25 g, 30.00 mmol) was put into N-chlorosulfenylbenzamide (5.0 g, 23.00 mmol) and dry acetonitrile (40 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then the solvent was removed under a rotary evaporator. In the primary concentrate, dichloromethane (20 mL) was added for dissolution and filtered with diatomite, washed with dichloromethane, and the solvent was spun dry to obtain the standard compound (white solid, 5.48 g, 84.23%).

[0176] Compound I-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0177] In a 25 mL single-neck round-bottom flask, Intermediate P-1 (0.30 g, 1.00 mmol) and Intermediate Q-7-1 (0.34 g, 1.20 mmol) were put in, 10 mL of tetrahydrofuran was added for dissolution, and potassium carbonate (0.55 g, 4.00 mmol) was added. The reaction was carried out at room temperature, and the reaction was tracked by TLC. After 0.5 h, the reaction was completed. The reaction solution was spun dry, an appropriate amount of dichloromethane was added, and silica gel column chromatography was performed with petroleum ether: ethyl acetate = 2:1 (V:V). The solvent was spun dry to obtain Compound I-1 (white solid, 0.15 g, 37.21%).

[0178] Method Three

[0179] Reagents and conditions: (a) methanol, 0.5 M aqueous sodium hydroxide solution, room temperature, 1 h; (b) chlorobenzene, triflic anhydride, 70 °C, 2 h; (c) tetrahydrofuran, potassium carbonate, room temperature, 1 h.

[0180] Specifically, the following steps are included:

[0181] Intermediate P-1 [3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1- azaspiro[4.5]dec-3-en-2-one]

[0182] The preparation of 3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1- azaspiro[4.5]dec-3-en-2-one was carried out in the same way as the synthesis of Intermediate P-1 in Example 1.

[0183] Intermediate Q-4 [S-(trifluoromethyl)trifluoromethanesulfonate] CF3S(O)2SCF3

[0184] In a 500 mL three-necked flask, equipped with a 9 stirrer, a thermometer and a 25 mL constant pressure dropping funnel connected to a CaCl2 drying tube, was charged with high purity dry powdered sodium trifluorosulfinic acid (40.9 g, 262.00 mmol), chlorobenzene (153 mL). In the constant pressure dropping funnel was charged with trifluoromethanesulfonic anhydride (20.3 mL, 122.00 mmol). The reactor was heated in a 70 °C oil bath and then trifluoromethanesulfonic anhydride was added dropwise to the reactor over 30 minutes with stirring. The temperature of the reaction mixture reached a maximum of 82 °C during the addition. The reaction mixture became very viscous as sodium trifluoromethanesulfinate was formed. After the addition, the reaction mixture was stirred at 70 °C oil bath for an additional 1 h. Next, the constant pressure dropping funnel was replaced with a rectifying column and the oil bath was gradually heated to 130 °C to collect the distillate (12.70 g, b.p. 66-69 °C, 62.30%).

[0185] [Method Four]

[0186] Reagents and conditions: (a) methanol, 0.5 M aqueous sodium hydroxide, room temperature, 1 h; (b) dichloromethane, potassium carbonate, room temperature, 1 h.

[0187] In particular, the following steps are included:

[0188] Intermediate P-1 [3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1- azaspiro[4.5]dec-3-en-2-one]

[0189] The preparation of 3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1- azaspiro[4.5]dec-3-en-2-one was carried out in the same way as the synthesis of Intermediate P-1 in Example 1.

[0190] Intermediate Q-9-1 [S-(trifluoromethyl)benzenesulfonyl thioester]

[0191] Into a dry 500 mL round bottom flask, under argon atmosphere, was added sodium benzenesulfinate (12.31 g, 75 mmol), anhydrous dichloromethane (100 mL), N-[(trifluoromethyl)thio]aniline (10.21 g, 50 mmol) and anhydrous p-toluenesulfonic acid monohydrate (10.84 g, 57 mmol) sequentially. The mixture was stirred at room temperature for 12 h (TLC monitoring) in the dark. After the reaction was completed, the mixture was diluted with dichloromethane (3 x 100 mL), and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL), and saturated brine (100 mL) sequentially. The organic phase was dried over anhydrous sodium sulfate (20 g) for 30 min, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 100% petroleum ether) to give S-(trifluoromethyl)benzenesulfonyl thioester.

[0192] Compound I-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0193] Into a 25 mL single necked round bottom flask, was added intermediate P-1 (0.30 g, 1.00 mmol), intermediate Q-4 (0.35 g, 1.50 mmol), 10 mL tetrahydrofuran to dissolve, potassium carbonate (0.55 g, 4.00 mmol), reaction at room temperature, TLC to track the reaction, reaction was completed after 0.5 h. The reaction solution was rotary evaporated to dryness, dichloromethane was added, silica gel column chromatography, petroleum ether: ethyl acetate = 2:1 (V:V), rotary evaporation to dryness to give compound I-1 (white solid, 0.27 g, 68.20%). The final test results are as follows:

[0194] m.p. 198.6-199.3 °C; 1 H NMR (600 MHz, CDC13) δ 7.92 (s, 1H), 7.43 (s, 1H), 7.10-7.07 (m, 2H), 3.32 (s, 3H), 3.27-3.23 (m, 1H), 2.53 (s, 3H), 2.32 (s, 3H), 2.18-2.11 (m, 1H), 2.03-1.98 (m, 1H), 1.92-1.85 (m, 2H), 1.62-1.46 (m, 4H). 13 C NMR (100 MHz, CDC13) δ 203.40, 169.40, 136.89, 135.81, 133.76, 130.99, 130.51, 128.77 (q, C-F, J C-F= 310.1 Hz), 127.43, 76.00, 65.83, 64.43, 55.91, 32.82, 31.85, 27.05, 26.92, 21.69, 21.32. 19 F NMR (565 MHz, CDC13) δ -36.75 (s). HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 22 F3NO3SNa + : 424.1165; found: 424.1172.

[0195] Example 2

[0196] The preparation flow of 3-(2,5-dimethylphenyl)-8-methoxy-l-methyl-3-((trifluoromethyl)thio)-l- azaspiro[4.5]decane-2,4-dione is shown below:

[0197] Reagents and conditions: (a) acetonitrile, methyl iodide, potassium carbonate, 6 h; (b) methanol, 0.5 M aqueous sodium hydroxide, room temperature, 1 h; (c) acetonitrile, argon protection, room temperature, 1 h; (d) tetrahydrofuran, potassium carbonate, room temperature, 1 h.

[0198] Specifically, the following steps are included:

[0199] Intermediate P-2 [3-(2,5-dimethylphenyl)-8-methoxy-l-methyl-2-oxo-l-azaspiro[4.5]dec-3- en-4-yl ethyl carbonate]

[0200] Into a 100 mL single-necked flask, spirotetramat (1.87 g, 5.00 mmol) was dissolved in 20 mL of acetonitrile and stirred at room temperature. Then 1 mL of methyl iodide (0.4 mL, 6.42 mmol) was slowly added dropwise using a 1 mL syringe. After the addition was completed, the reaction was continued to stir at room temperature, and TLC tracking showed that the reaction was completed after about 6 h. Silica gel column chromatography was performed using petroleum ether: ethyl acetate = 1:1 (V:V) to obtain compound intermediate P-2 (white solid, 1.61 g, 83.12%).

[0201] Intermediate P-3 [3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-l-methyl-l-azaspiro[4.5]dec-3- en-2-one]

[0202] 100 mL single-necked flask, the intermediate P-2 (1.61 g, 5.11 mmmol) was added and dissolved in 20 mL of methanol, stirred in ice bath; 10 mL of sodium hydroxide (0.24 g, 6.00 mmol) aqueous solution was prepared, and slowly added to the above reaction system with constant pressure dropping funnel, after the addition was completed, continue to stir at room temperature, TLC tracking, about 1 h after the reaction was completed. The reaction solution was adjusted to PH = 3 with 1M hydrochloric acid solution, then the methanol in the reaction system was removed under vacuum, the residual aqueous solution was extracted with dichloromethane (3*20 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give intermediate P-3 (white solid), yield 86%.

[0203] Compound I-2 [3-(2,5-dimethylphenyl)-8-methoxy-1-methyl-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0204] 25 mL single-necked round-bottom flask, the intermediate P-3 (0.32 g, 1.00 mmol), intermediate Q-6-1-1 (0.30 g, 1.20 mmol) was added, 10 mL of tetrahydrofuran was added to dissolve it, potassium carbonate (0.55 g, 4.00 mmol) was added, and the reaction was carried out at room temperature, TLC tracking reaction, 0.5 h after the reaction was completed. The reaction solution was rotary evaporated, dichloromethane was added, and silica gel column chromatography was carried out, petroleum ether: ethyl acetate = 2:1 (V:V), rotary evaporation of the solvent to give compound I-2 (white solid, 0.29 g, 69.42%). The final test results are as follows:

[0205] m.p. 154.4-155.3 °C; 1 H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.08-7.04 (m, 2H), 3.47-3.45 (m, 1H), 3.28 (s, 3H), 3.05 (s, 3H), 2.48 (s, 3H), 2.30 (s, 3H), 2.24-1.94 (m, 4H), 1.86-1.64 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 203.13, 167.09, 136.65, 135.32, 133.53, 130.66, 130.50, 128.86 (q, C-F, J C-F = 309.9 Hz), 128.30, 72.64, 67.32, 63.82, 55.86, 26.20, 26.09, 25.80, 25.46, 25.38, 21.61, 21.25. 19F NMR (565 MHz, CDC13) δ -36.86 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 20 H 24 F3NO3S: 415.1424; found: 415.1427.

[0206] Example 3

[0207] The preparation of 3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4,8-trione is shown in the following flowchart:

[0208] Reagents and conditions: (a) acetonitrile, trimethylsilyl iodide, sodium iodide, heating reflux, 12 h; (b) Dess-Martin periodinane, dichloromethane, room temperature, 12 h; (c) methanol, 0.5 M aqueous sodium hydroxide, room temperature, 1 h; (d) acetonitrile, argon protection, room temperature, 1 h; (e) tetrahydrofuran, potassium carbonate, room temperature, 1 h.

[0209] Specifically, the following steps are included:

[0210] Intermediate P-4 [3-(2,5-dimethylphenyl)-8-hydroxy-2-oxo-1- azaspiro[4.5]dec-3-en-4-yl ethyl carbonate]

[0211] Into a 100 mL single necked flask, sodium iodide (3.74 g, 25.00 mmol) was added, followed by 20 mL acetonitrile, then trimethylsilyl chloride (3.17 mL, 5.00 mmol) was added slowly by 5 mL syringe, after the addition was completed, heating reflux for 30 min, then spirotetramat (1.87 g, 5.00 mmol) was added, continue to stir overnight at room temperature, TLC tracking, about 12 h later the reaction was completed. Then saturated NaHSO3 solution was added to quench, extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution, dried over Na2SO4, rotary evaporation to give compound intermediate P-4 (white solid, 1.53 g, 85.06%).

[0212] Intermediate P-5 [3-(2,5-dimethylphenyl)-2,8-dioxo-1-azaspiro[4.5]dec-3-en-4- yl ethyl carbonate]

[0213] Into a 100 mL single necked flask, was charged with intermediate P-4 (1.80 g, 5.00 mmol), and added with Dess-Martin Oxidizer (3.18 g, 7.50 mmol) in acetonitrile, and dissolved with 25 mL dichloromethane, and stirred at room temperature overnight, TLC tracking, about 12 h later, the reaction was completed. To the reaction solution was added saturated NaHCO3solution to quench, and filtered the precipitate, and the filtrate was extracted with dichloromethane (3*20 mL), and the combined organic phase was dried over anhydrous sodium sulfate, and filtered and evaporated to dryness, and column chromatography on silica gel was performed with petroleum ether: ethyl acetate = 1:1 (V:V), and the solvent was evaporated to dryness to obtain intermediate P-5 (white solid, 1.11 g, yield 62.03%).

[0214] Intermediate P-6 [3-(2,5-dimethylphenyl)-4-hydroxy-1-azaspiro[4.5]dec-3-ene-2,8-dione]

[0215] Into a 100 mL single necked flask, was charged with intermediate P-5 (1.79 g, 5.00 mmol), and dissolved with 20 mL methanol, and stirred in an ice bath; and a 10 mL aqueous solution of sodium hydroxide (0.20 g, 5.00 mmol) was prepared, and slowly added to the above reaction system with a constant pressure dropping funnel, and after the addition was completed, the stirring was continued at room temperature, and TLC tracking, about 1 h later, the reaction was completed. The reaction solution was adjusted to PH = 3 with 1M hydrochloric acid solution, and then the methanol in the reaction system was removed under vacuum, and the residual aqueous solution was extracted with dichloromethane (3*20 mL), and the combined organic phase was dried over anhydrous sodium sulfate, and filtered and evaporated to dryness to obtain intermediate P-6 (white solid, 1.36 g, yield 95.18%).

[0216] Compound I-3 [3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-1-azaspiro[4.5]decane-2,4,8-trione]

[0217] Into a 25 mL single necked round bottom flask, was charged with intermediate P-6 (0.29 g, 1.00 mmol), and intermediate Q-6-1 (0.30 g, 1.20 mmol), and dissolved with 10 mL tetrahydrofuran, and added with potassium carbonate (0.55 g, 4 mmol), and reacted at room temperature, and TLC tracking, 0.5 h later, the reaction was completed. The reaction solution was evaporated to dryness, and added with dichloromethane, and column chromatography on silica gel was performed with petroleum ether: ethyl acetate = 2:1 (V:V), and the solvent was evaporated to dryness to obtain compound I-3 (white solid, 0.26 g, 66.32%). The final test results were as follows:

[0218] m.p. 123.4-124.1 °C, 1H NMR (400 MHz, CDC13) δ 9.42 (s, 1H), 7.40 (s, 1H), 7.15-7.10 (m, 2H), 2.70-2.62 (m, 2H), 2.57 (s, 3H), 2.52-2.39 (m, 3H), 2.33 (s, 3H), 2.17-2.10 (m, 1H), 2.05-1.98 (m, 1H), 1.87-1.80 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 207.44, 202.30, 170.97, 137.04, 135.90, 134.06, 131.31, 130.04, 128.71 (q, C-F, J C-F = 310.2 Hz), 126.77, 65.12, 64.25, 36.93, 36.71, 35.35, 34.21, 21.59, 21.26. 19 F NMR (565 MHz, CDC13) δ -36.79 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 18 H 18 F3NO3S: 385.0954; found: 385.0957.

[0219] Example 4

[0220] The preparation of 3-(2,5-dimethylphenyl)-8-(methoxyimino)-3-methylsulfanyl-1- azaspiro[4.5]decane-2,4-dione is shown in the following scheme:

[0221] Specifically, the following steps are included:

[0222] Intermediate P-7 [3-(2,5-dimethylphenyl)-8-(methoxyimino)-2-oxo-1-azaspiro[4.5]dec-3- en-4-yl ethyl carbonate]

[0223] Into a 100 mL single necked flask, intermediate P-5 (1.79 g, 5.00 mmol) was added and dissolved in 20 mL of ethanol, methoxyamine hydrochloride (0.84 g, 10.00 mmol) was added, the reaction was carried out at room temperature, TLC was used to track the reaction, which was completed after about 2 h. Then most of the ethanol in the reaction system was removed under vacuum, 10 mL of methanol was added, and the solution was poured into ice water to precipitate white flocculent solid, which was filtered and dried to obtain intermediate P-7 (white solid, 1.40 g, yield 72.65%).

[0224] Intermediate P-8 [3-(2,5-dimethylphenyl)-4-hydroxy-8-(methoxyimino)-1- azaspiro[4.5]dec-3-en-2-one]

[0225] Into a 100 mL single necked flask, was placed intermediate P-7 (1.93 g, 5.00 mmol), dissolved in 20 mL of methanol, stirred in ice bath; prepared 10 mL of sodium hydroxide (0.20 g, 5.00 mmol) aqueous solution, slowly added into the above reaction system by constant pressure dropping funnel, after the addition was completed, continued to stir at room temperature, TLC tracking, about 1 h later the reaction was completed. The reaction solution was adjusted to PH = 3 with 1 M hydrochloric acid solution, then the methanol in the reaction system was removed under vacuum, the residual aqueous solution was extracted with dichloromethane (3 * 20 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to give intermediate P-8 (white solid, 1.45 g, yield 92.36%).

[0226] Compound I-4 [3-(2,5-dimethylphenyl)-8-(methoxyimino)-3-methylsulfanyl-1- azaspiro[4.5]decane-2,4-dione]

[0227] Into a 25 mL single necked flask, was placed intermediate P-8 (0.31 g, 1.00 mmol), intermediate Q-6-1 (0.30 g, 1.20 mmol), dissolved in 10 mL of tetrahydrofuran, added potassium carbonate (0.55 g, 4.00 mmol), reacted at room temperature, TLC tracking reaction, 0.5 h later the reaction was completed. The reaction solution was evaporated, added with appropriate amount of dichloromethane, silica gel column chromatography, petroleum ether: ethyl acetate = 2:1 (V:V), the solvent was evaporated to give compound I-4 (white solid, 0.30 g, 73.48%). The final test results were as follows:

[0228] m.p. 176.8-177.6 °C; Z / E = 1:0.9, 1H NMR (400 MHz, CDC13) δ 8.95 - 8.80 (m, 1H + 0.9H, major + minor), 7.40 (s, 1H + 0.9H, major + minor), 7.14 - 7.08 (m, 2H + 1.8H, major + minor), 3.81 (s, 2.7H, minor), 3.80 (s, 3H, major), 3.12 - 3.04 (m, 0.9H, minor), 2.88 - 2.79 (m, 1H, major), 2.64 - 2.57 (m, 1H, major), 2.55 (s, 3H, major), 2.54 (s, 2.7H, minor), 2.46 - 2.37 (m, 1H + 0.9H, major + minor), 2.33 (s, 3H + 2.7H, major + minor), 2.31 - 2.12 (m, 2H + 1.8H + 0.9H, major + minor), 1.99 - 1.70 (m, 2H + 1.8H, major + minor), 1.65 - 1.52 (1H + 0.9H, major + minor). 13 C NMR (100 MHz, CDC13) δ major peaks at 202.38, 170.81, 155.58, 136.91, 135.90, 133.94, 131.12, 130.09, 128.70 (q, C-F, J C-F = 313.4 Hz), 127.03, 66.15, 64.13, 61.35, 34.34, 32.97, 27.23, 21.59, 21.22, 20.34. C-F = 313.4 Hz), 127.03, 66.15, 64.13, 61.35, 34.34, 32.97, 27.23, 21.59, 21.22, 20.34. 19 F NMR (565 MHz, CDC13) δ -36.78 (s) (minor), -36.80 (s) (major). HRMS (EI-TOF) m / z: [M] + calcd for C 19 H 21 F3N2O3S: 414.1220; found: 414.1228.

[0229] Example 5

[0230] 11-(2,5-dimethylphenyl)-11-((trifluoromethyl)thio)-1,4-dioxa-9-azaspiro[4.2.4 8 .2 5 ]tetradecane-10,12-dione was prepared as shown in the following scheme:

[0231] Specifically, the following steps are included:

[0232] Intermediate P-9 [11-(2,5-dimethylphenyl)-12-hydroxy-1,4-dioxa-9-azaspiro[4.2.4 8 .2 5 ]tetradecan-11-en-10-one]

[0233] Into a 100 mL single necked flask, was placed intermediate P-6 (1.43 g, 5.00 mmol), p-toluenesulfonic acid (0.28 g, 1.50 mmol), 30 mL of toluene was added to dissolve the solid, then ethylene glycol (3.00 mL, 50.00 mmol) was added dropwise into the reaction system, heated to reflux, TLC was used to track the reaction, after about 12 h, the reaction was completed. Then most of the toluene in the reaction system was removed under vacuum, extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution, dried over Na2SO4, rotary evaporation to remove the solvent, silica gel column chromatography, petroleum ether: ethyl acetate = 1:1 (V:V), rotary evaporation to remove the solvent to obtain intermediate P-9 (white solid, 1.03 g, 62.35%)

[0234] Compound I-5 [11-(2,5-dimethylphenyl)-11-((trifluoromethyl)thio)-1,4-dioxa-9-azaspiro[4.2.4 8 .2 5 ]tetradecane-10,12-dione]

[0235] Into a 25 mL single necked round bottom flask, was placed intermediate P-9 (0.33 g, 1.00 mmol), intermediate Q-6-1 (0.30 g, 1.20 mmol), 10 mL of tetrahydrofuran was added to dissolve the solid, potassium carbonate (0.55 g, 4 mmol) was added, the reaction was carried out at room temperature, TLC was used to track the reaction, after 0.5 h, the reaction was completed. The reaction solution was rotary evaporated to dryness, an appropriate amount of dichloromethane was added, silica gel column chromatography, petroleum ether: ethyl acetate = 2:1 (V:V), rotary evaporation to remove the solvent to obtain compound I-5 (white solid, 0.29 g, 69.42%). The final test results are as follows:

[0236] m.p. 169.8-170.7 °C; 1H NMR (400 MHz, CDC13) δ 7.42 (s, 1H), 7.32 (s, 1H), 7.11 - 7.06 (m, 2H), 3.98 - 3.88 (m, 4H), 2.52 (s, 3H), 2.34 - 2.36 (m, 4H), 2.05 - 1.97 (m, 1H), 1.89 - 1.81 (m, 2H), 1.77 - 1.69 (m, 2H), 1.70 - 1.62 (m, 1H), 1.58 - 1.50 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 202.74, 169.49, 136.79, 135.84, 133.71, 130.91, 130.38, 132.08 (q, C-F, J C-F = 280.1 Hz), 127.33, 106.94, 65.48, 64.61, 64.56, 64.39, 33.33, 32.31, 30.90, 30.73, 21.58, 21.21. 19 F NMR (565 MHz, CDC13) δ -36.75 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 20 H 22 F3NO4S: 429.1217; found: 429.1225.

[0237] Example 6

[0238] 11-(2,5-dimethylphenyl)-11-((trifluoromethyl)thio)-1,4-dithia-9-azaspiro[4.2.4 8 .2 5 ]tetradecane-10,12-dione was prepared according to the following scheme:

[0239] Specifically, the following steps are included:

[0240] Intermediate P-10 [11-(2,5-dimethylphenyl)-12-hydroxy-1,4-dithia-9-azaspiro[4.2.4 8 .2 5 ]tetradec-11-en-10-one]

[0241] 100 mL single-necked flask, intermediate P-6 (1.43 g, 5.00 mmmol) was added, p-toluenesulfonic acid (0.28 g, 1.50 mmol) was added, 30 mL of toluene was added to dissolve it, 1,2-dithiol (4.40 mL, 50.00 mmol) was added dropwise to the reaction system, heated to reflux, TLC tracking, about 12 h after the reaction was completed. Then remove most of the toluene in the reaction system under vacuum, extract with ethyl acetate, wash the organic phase with saturated NaCl solution, dry over Na2SO4, spin dry the solvent, silica gel column chromatography, petroleum ether: ethyl acetate = 2:1 (V:V), spin dry the solvent to obtain intermediate P-10 (white solid, 1.25 g, 69.40%)

[0242] Compound I-6 [11-(2,5-dimethylphenyl)-11-((trifluoromethyl)thio)-1,4-dithia-9- azaspiro[4.2.4 8 .2 5 ]tetradecane-10,12-dione]

[0243] 25 mL single-necked round-bottom flask, intermediate P-10 (0.36 g, 1 mmol) was added, intermediate Q-6-1 (0.30 g, 1.2 mmol) was added, 10 mL of tetrahydrofuran was added to dissolve it, potassium carbonate (0.55 g, 4 mmol) was added, the reaction was carried out at room temperature, TLC tracking reaction, 0.5 h after the reaction was completed. The reaction solution was spin dried, an appropriate amount of dichloromethane was added, silica gel column chromatography, petroleum ether: ethyl acetate = 2:1 (V:V), spin dry the solvent to obtain compound I-6 (white solid, 0.29 g, 69.42%). The final test results are as follows:

[0244] m.p. 136.9-137.7 °C; 1 H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.38 (s, 1H), 7.11-7.06 (m, 2H), 3.33- 3.24 (m, 4H), 2.54 (s, 3H), 2.44-2.35 (m, 1H), 2.34-2.26 (m, 4H), 2.16-2.08 (m, 2H), 2.07-2.00 (m, 1H), 1.92-1.80 (m, 2H), 1.62-1.52 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 202.79, 169.68, 136.76, 135.92, 133.77, 130.92, 130.32, 128.68 (q, C-F, J C-F= 310.1 Hz), 127.28, 66.35, 65.14, 64.29, 38.83, 38.64, 38.04, 37.85, 35.32, 34.17, 21.66, 21.21. 19 F NMR (565 MHz, CDC13) δ -36.68 (s). HRMS (EI-TOF) m / z: [M] + C 20 H 22 F3NO4S: 461.0760; found: 461.0763.

[0245] Example 7

[0246] The preparation of 3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione is shown in the following scheme:

[0247] Reagents and conditions: (a) dichloromethane, oxalyl chloride, N,N- dimethylformamide, room temperature, 2 h; (b) methanol, thionyl chloride, 40 °C heating to reflux, 10 h; (c) acetonitrile, potassium carbonate, 0 °C→60 °C, reflux, 6 h; (d) tetrahydrofuran, potassium tert-butoxide, 1 mol / L hydrochloric acid, 0 °C→room temperature, 6 h; (e) acetonitrile, argon protection, room temperature, 3 h; (f) tetrahydrofuran, potassium carbonate, room temperature, 0.5 h.

[0248] Specifically, the following steps are included:

[0249] Preparation of [2-(2,4-dichlorophenyl)acetyl chloride]

[0250] Into a 50 mL single-necked round-bottom flask, 2-(2,5-dimethylphenyl)acetic acid (2.46 g, 15.00 mmol) was added, dichloromethane (15 mL) dried with molecular sieves was added, 7-8 drops of N,N-dimethylformamide were added dropwise, then a rubber plug was covered and a balloon was pierced on the rubber plug, and stirring was performed for 2 min. Then oxalyl chloride (1.5 mL) was taken with a 2.5 mL syringe and slowly added to the dichloromethane reaction solution, and stirring was performed at room temperature, TLC was used to track the reaction, and the reaction was completed after 2 h. Then the solvent and acyl chloride residues were removed under reduced pressure to obtain 2-(2,4-dichlorophenyl)acetyl chloride (light yellow liquid, 81.56%).

[0251] Preparation of [1-aminocyclohexane-1-carboxylic acid methyl ester hydrochloride]

[0252] In a 50 mL single-necked round-bottom flask, 1-aminocyclohexane-1-carboxylic acid (1.43 g, 10.00 mmol) was added, 15 mL of methanol was added to the flask, and the solution was cooled to 5-10 °C. SOCl2(2.38 g, 20.00 mmol) was slowly added dropwise, and the solution became milky white and then clear yellow. After the dropwise addition was completed, the solution was warmed to 40 °C and reacted for 10 h. After cooling, the solvent was removed by rotary evaporation to obtain 1-aminocyclohexane-1-carboxylic acid methyl ester hydrochloride (white solid, 1.78 g, 91.99%).

[0253] Preparation of [1-(2-(2,5-dimethylphenyl)acetylamino)cyclohexane-1-carboxylic acid methyl ester]

[0254] In a 100 mL single-necked round-bottom flask, 1-aminocyclohexane-1-carboxylic acid methyl ester hydrochloride and potassium carbonate (5.52 g, 40 mmol) prepared above were added, and anhydrous acetonitrile (20 mL) was added. After stirring for 20 min, a solution of 2-(2,4-dichlorophenyl)acetyl chloride prepared above in 15 mL of acetonitrile was slowly added dropwise at 5-10 °C. After stirring at room temperature for 3 h, the reaction was tracked by TLC. The reaction solution was extracted with ethyl acetate, and the ethyl acetate phase was collected. The solvent was removed by rotary evaporation to obtain intermediate P-11 (yellow oily liquid).

[0255] Intermediate P-12 [3-(2,5-dimethylphenyl)-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one]

[0256] In a 100 mL single-necked round-bottom flask, intermediate P-11 prepared above was added at 0 °C, and tetrahydrofuran (10 mL) was added. A 1 M solution of potassium tert-butoxide (10 mL, 10.00 mmol) in tetrahydrofuran was slowly added dropwise. The reaction was tracked by TLC, and the reaction was completed after stirring for 4 h. The reaction solution was adjusted to pH 2 with 1 mol / L HCl, and a large amount of yellow solid was precipitated. After standing for 0.5 h, the solid was filtered to obtain intermediate P-12 (white solid, 2.25 g, 83.03%).

[0257] Compound I-7 [3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-1-azaspiro[4.5]decane-2,4-dione]

[0258] Into a 25 mL single-mouth round-bottom flask, was placed intermediate P-12 (0.27 g, 1.00 mmol), intermediate Q-6-1 (0.30 g, 1.20 mmol), 10 mL of tetrahydrofuran was added to dissolve it, potassium carbonate (0.55 g, 4.00 mmol) was added, and the reaction was carried out at room temperature. TLC was used to track the reaction, and the reaction was stopped after 0.5 h. The reaction solution was rotary evaporated, and an appropriate amount of dichloromethane was added. Silica gel column chromatography was performed using petroleum ether: ethyl acetate = 2: 1 (V:V) as the eluent. The solvent was rotary evaporated to obtain compound I-7 (white solid, 0.30 g, 81.02%). The final test results are as follows:

[0259] m.p. 124.3-125.2 °C; 1 H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 7.45 (s, 1H), 7.09-7.06 (m, 2H), 2.56 (s, 3H), 2.32 (s, 3H), 1.99 (m, 1H), 1.85-1.70 (m, 2H), 1.66-1.47 (m, 5H), 1.44-1.26 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 203.44, 170.37, 136.64, 135.89, 133.69, 130.78, 130.32, 128.71 (q, C-F, J C-F = 309.9 Hz), 127.50, 67.00, 64.26, 35.53, 33.96, 24.72, 21.66, 21.63, 21.57, 21.16. 19 F NMR (565 MHz, CDCl3) δ -36.84 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 18 H 20 F3NO2S: 371.1162; found: 371.1165.

[0260] Example 8

[0261] Compound I-8 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0262] The preparation of compound I-8 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] used a similar synthesis method as Example 7, except that:

[0263] The phenylacetic acid starting material in step (a) is 2-(2,4-dimethylphenyl)acetic acid.

[0264] The resulting compound I-8 (white solid, 0.34 g, 60.04 %). The final test results are as follows:

[0265] m.p. 123.4-124.1 °C; 1 H NMR (400 MHz, CDC13) δ 8.84 (s, 1H), 7.50 (d, J = 8.0 Hz,

[0266] 1H), 7.03-7.01 (m, 2H), 2.58 (s, 3H), 2.28 (s, 3H), 2.02-1.94 (m, 1H), 1.84-1.68 (m, 2H), 1.64-1.44 (m, 5H), 1.40-1.26 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 203.51, 170.35, 140.09, 139.00, 134.60, 129.92, 128.73 (q, C-F, J C-F = 309.9 Hz), 127.80, 124.74, 66.93, 64.13, 35.63, 33.84, 24.74, 21.94, 21.68, 21.62, 20.92. 19 F NMR (565 MHz, CDC13) δ -36.90 (s). HRMS (EI-TOF) m / z: [M]+calcd for C 18 H 20 F3NO2S: 371.1162; found: 371.1165.

[0267] Example 9

[0268] Compound I-9 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione]

[0269] Compound I-9 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione] was prepared using a synthetic method similar to Example 7, except that:

[0270] The phenylacetic acid starting material in step (a) is 2-(2,4-dimethylphenyl)acetic acid.

[0271] The starting material in step (b) is 4-aminotetrahydropyran-4-carboxylic acid.

[0272] Compound I-9 (white solid, 0.26 g, 69.21 %) was obtained. The final test results were as follows:

[0273] m.p. 133.7-134.6 °C; 1 H NMR (400 MHz, CDC13) δ 9.14 (s, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.06-7.02 (m, 2H), 4.03-3.97 (m, 1H), 3.82-3.71 (m, 2H), 3.67-3.60 (m, 1H), 2.56 (s, 3H), 2.30 (s, 3H), 2.30-2.21 (m, 1H), 1.88-1.74 (m, 1H), 1.70-1.63 (m, 1H), 1.42-1.35 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 202.13, 170.53, 140.44, 138.94, 134.75, 129.78, 128.73 (q, C-F, J C-F = 309.9 Hz), 127.94, 124.25, 64.11, 64.06, 63.73, 63.28, 35.67, 34.01, 21.89, 20.93. 19 F NMR (565 MHz, CDC13) δ -36.80 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 18 F3NO3S: 373.0954; found: 373.0957.

[0274] Example 10

[0275] Compound I-10 [3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decan-2,4-dione]

[0276] Compound I-10 [3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decan-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0277] The starting material in step (b) was 4-aminotetrahydropyran-4-carboxylic acid.

[0278] Compound I-10 (white solid, 0.21 g, 56.35 %) was obtained. The final test results were as follows:

[0279] m.p. 111.5 - 112.3 °C; 1 H NMR (400 MHz, CDC13) δ 9.18 - 9.13 (m, 1H), 7.42 (s, 1H), 7.13 - 7.09 (m, 2H), 4.04 - 3.98 (m, 1H), 3.82 - 3.74 (m, 2H), 3.68 - 3.63 (m, 1H), 2.54 (s, 3H), 2.33 (s, 3H), 2.28 - 2.24 (m, 1H), 1.88 - 1.81 (m, 1H), 1.73 - 1.69 (m, 1H), 1.44 - 1.40 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 202.02, 170.41, 136.89, 135.78, 133.82, 131.09, 130.21, 128.67 (q, C-F, J C-F = 307.8 Hz), 126.95, 64.23, 64.11, 63.76, 63.31, 35.53, 34.12, 21.56, 21.25. 19 F NMR (565 MHz, CDC13) δ -36.70 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 18 F3NO3S: 373.0954; found: 373.0957.

[0280] Example 11

[0281] Compound 1-11 [3-(2,5-dimethoxyphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0282] Compound 1-11 [3-(2,5-dimethoxyphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0283] The phenylacetic acid starting material in step (a) was 2,5-dimethoxyphenylacetic acid.

[0284] The resulting compound 1-11 (white solid, 0.30 g, 73.23 %). The final test results were as follows:

[0285] m.p. 158.8 - 159.7 °C; 1H NMR (400 MHz, CDC13) δ 8.00 (s, 1H), 7.51 (d, J = 2.9 Hz, 1H), 6.89 (dd, J = 8.9, 3.0 Hz, 1H), 6.81 (d, J = 8.9 Hz, 1H), 3.82 (s, 3H), 3.67 (s, 3H), 2.23 - 2.15 (m, 1H), 2.05 - 1.93 (m, 2H), 1.86 - 1.79 (m, 1H), 1.78 - 1.69 (m, 2H), 1.64 - 1.56 (m, 1H), 1.53 - 1.31 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 203.52, 168.75, 154.09, 149.89, 128.40 (q, C-F, J C-F = 312.7 Hz), 122.47, 118.25, 115.13, 112.58, 67.29, 59.39, 56.15, 55.90, 37.03, 32.97, 24.75, 21.99, 21.94. 19 F NMR (565 MHz, CDC13) δ -35.43 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 18 H 20 F3NO4S: 403.1060; found: 403.1062.

[0286] Example 12

[0287] Compound I-12 [3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.4]nonane-2,4-dione]

[0288] The preparation of compound I-12 [3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.4]nonane-2,4-dione] was carried out using a similar synthetic procedure to that of Example 7, except that:

[0289] The starting material in step (b) was cyclopeptolysine.

[0290] The resulting compound I-12 (white solid, 0.16 g, 45.78 %). The final test results were as follows:

[0291] m.p. 93.4 - 94.3 °C; 1H NMR (400 MHz, CDC13) δ 8.93 (s, 1H), 7.52 (s, 1H), 7.13 - 7.03 (m, 2H), 2.40 (s, 3H), 2.34 (s, 3H), 2.33 - 2.27 (m, 1H), 1.99 - 1.87 (m, 2H), 1.82 - 1.63 (m, 5H). 13 C NMR (100 MHz, CDC13) δ 204.83, 169.68, 136.40, 134.66, 133.08, 130.77, 130.59, 128.66 (q, C-F, J C-F = 310.2 Hz), 127.74, 73.12, 63.53, 39.47, 39.42, 25.25, 25.20, 21.36, 21.19. 19 F NMR (565 MHz, CDC13) δ -36.36 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 14 Cl2F3NO2S: 357.1005; found: 357.1013.

[0292] Example 13

[0293] Compound 1-13 [7-(2,5-dimethylphenyl)-7-((trifluoromethyl)thio)-5- azaspiro[3.4]octane-6,8-dione]

[0294] Compound 1-13 [7-(2,5-dimethylphenyl)-7-((trifluoromethyl)thio)-5- azaspiro[3.4]octane-6,8-dione] was prepared using a synthetic method similar to Example 7, except that:

[0295] The starting material in step (b) was 1-aminocyclobutanecarboxylic acid.

[0296] The resulting compound 1-13 (white solid, 0.21 g, 61.39 %). The final test results were as follows:

[0297] m.p. 93.4 - 94.3 °C; 1H NMR (400 MHz, CDC13) δ 8.98 (s, 1H), 7.56 (s, 1H), 7.11 - 7.05 (m, 2H), 2.77 - 2.69 (m, 1H), 2.46 - 2.38 (m, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.29 - 2.18 (m, 1H), 2.07 - 1.95 (m, 1H), 1.84 - 1.74 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 203.56, 169.64, 136.40, 133.89, 132.76, 130.79, 130.52, 128.75 (q, C-F, J C-F = 310.4 Hz), 128.07, 65.54, 62.70, 34.48, 33.69, 21.18, 21.03, 13.95. 19 F NMR (565 MHz, CDC13) δ -36.26 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 16 F3NO2S: 343.0849; found: 343.0856.

[0298] Example 14

[0299] Compound 1-14 [6-(2,5-dimethylphenyl)-6-((trifluoromethyl)thio)-4- azaspiro[2.4]heptane-5,7-dione]

[0300] Compound 1-14 [6-(2,5-dimethylphenyl)-6-((trifluoromethyl)thio)-4- azaspiro[2.4]heptane-5,7-dione] was prepared using a synthetic method analogous to Example 7, except that:

[0301] The starting material in step (b) was 1-aminocyclopropane carboxylic acid.

[0302] The resulting compound 1-14 (white solid, 0.19 g, 57.35 %). The final test results were as follows:

[0303] m.p. 134.1 - 135.2 °C; 1H NMR (400 MHz, CDC13) δ 8.31 (s, 1H), 7.57 (s, 1H), 7.15 - 7.02 (m, 2H), 2.37 (s, 3H), 2.29 (s, 3H), 1.73 - 1.65 (m, 1H), 1.64 - 1.61 (m, 1H), 1.43 - 1.39 (m, 1H), 1.36 - 1.27 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 202.86, 170.44, 136.44, 133.33, 132.64, 130.67, 130.50, 128.76, 128.63 (q, C-F, J C-F = 310.6 Hz), 62.15, 47.15, 21.28, 21.00, 17.39, 15.77. 19 F NMR (565 MHz, CDC13) δ -36.20 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 15 H 14 F3NO2S: 329.0692; found: 329.0699.

[0304] Example 15

[0305] Compound 1-15 [3-(2,5-dimethylphenyl)-5,5-dimethyl-3-((trifluoromethyl)thio)pyrrolidine- 2,4-dione]

[0306] Compound 1-15 [3-(2,5-dimethylphenyl)-5,5-dimethyl-3-((trifluoromethyl)thio)pyrrolidine- 2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0307] The starting material in step (b) was 2-aminoisobutyric acid.

[0308] The resulting compound 1-15 (white solid, 0.14 g, 41.39 %). The final test results were as follows:

[0309] m.p. 128.9 - 130.1 °C; 1 H NMR (400 MHz, CDC13) δ 8.87 (s, 1H), 7.46 (s, 1H), 7.12 - 7.08 (m, 2H), 2.56 (s, 3H), 2.32 (s, 3H), 1.51 (s, 3H), 1.24 (s, 3H). 13C NMR (100 MHz, CDC13) δ 204.98, 174.99, 135.83, 134.84, 132.74, 132.20, 130.45, 128.32 (q, C-F, J C-F = 313.6 Hz), 128.18, 78.20, 70.19, 24.56, 24.06, 20.97, 20.00. 19 F NMR (565 MHz, CDC13) δ -36.89 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 15 H 16 F3NO2S: 331.0849; found: 331.0850.

[0310] Example 16

[0311] Compound 1-16 [3-(o-Tolyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0312] Compound 1-16 [3-(o-Tolyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a synthetic method similar to Example 7, except that:

[0313] The starting material in Step (a) was o-methylphenylacetic acid.

[0314] The resulting compound 1-16 (white solid, 0.28 g, 78.21 %). The final test results were as follows:

[0315] m.p. 165.6-166.3 °C; 1 H NMR (400 MHz, CDC13) δ 8.84-8.79 (m, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.35-7.15 (m, 3H), 2.62 (s, 3H), 2.03-1.95 (m, 1H), 1.84-1.69 (m, 2H), 1.64-1.24 (m, 7H). 13 C NMR (100 MHz, CDC13) δ 203.41, 170.13, 139.18, 133.77, 130.02, 129.99, 128.71 (q, C-F, J C-F = 310.0 Hz), 127.89, 127.03, 67.04, 64.20, 35.52, 34.01, 24.72, 22.10, 21.70, 21.68. 19F NMR (565 MHz, CDC13) δ -36.78 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 18 F3NO2S: 357.1005; found: 357.1008.

[0316] Example 17

[0317] Compound 1-17 [3-(2,4-dichlorophenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0318] Compound 1-17 [3-(2,4-dichlorophenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0319] The starting material in Step (a) was 2,4-dichlorophenylacetic acid.

[0320] The resulting compound 1-17 (white solid, 0.31 g, 74.35 %). The final test results are as follows:

[0321] m.p. 191.5-192.3 °C; 1 H NMR (400 MHz, CDC13) δ 8.04 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.49-7.38 (m, 2H), 2.40-2.30 (m, 1H), 2.14-1.97 (m, 2H), 1.92-1.76 (m, 3H), 1.70-1.62 (m, 1H), 1.54-1.36 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 202.22, 167.00, 136.42, 134.46, 132.93, 130.23, 129.05, 128.09 (q, C-F, J C-F = 311.6 Hz), 127.62, 68.21, 61.44, 37.87, 33.57, 24.72, 22.17, 21.96. 19 F NMR (565 MHz, CDC13) δ -35.53 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 14 Cl2F3NO2S: 411.0069; found: 411.0075.

[0322] Example 18

[0323] Compound 1-18 [3-(2,4-dichlorophenyl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione]

[0324] The preparation of compound 1-18 [3-(2,4-dichlorophenyl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione] was carried out using a synthetic method analogous to Example 7, except that:

[0325] In step (a), the starting material was 2,4-dichlorophenylacetic acid.

[0326] In step (b), the starting material was 4-aminotetrahydropyran-4-carboxylic acid.

[0327] The resulting compound 1-18 (white solid, 0.22 g, 52.47%) was obtained. The final test results were as follows:

[0328] m.p. 158.8-159.3 °C; 1 H NMR (400 MHz, CDC13) δ 9.00 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.55 - 7.32 (m, 2H), 4.03 - 3.88 (m, 2H), 3.69 - 3.57 (m, 2H), 2.45 - 2.28 (m, 2H), 2.24 - 2.18 (m, 1H), 1.82 - 1.74 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 200.91, 167.49, 136.72, 134.39, 132.63, 130.17, 128.60, 127.95 (q, C-F, J C-F = 311.6 Hz), 127.88, 65.46, 63.60, 63.47, 61.23, 37.92, 33.64. 19 F NMR (565 MHz, CDC13) δ -35.41 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 15 H 12 Cl2F3NO3S: 412.9862; found: 412.9869.

[0329] Example 19

[0330] Compound I-19 [3-(2,4-dichlorophenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.4]nonane-2,4-dione]

[0331] Compound I-19 [3-(2,4-dichlorophenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.4]nonane-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0332] The starting material in step (a) was 2,4-dichlorophenylacetic acid.

[0333] The starting material in step (b) was cycloleucine.

[0334] The resulting compound I-19 (white solid, 0.29 g, 72.43 %). The final test results were as follows:

[0335] m.p. 100.2-101.3 °C; 1 H NMR (400 MHz, CDC13) δ 8.18 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.45-7.40 (m, 2H), 2.54-2.45 (m, 1H), 2.36-2.29 (m, 1H), 2.21-2.12 (m, 1H), 1.88-1.76 (m, 3H), 1.76-1.69 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 203.24, 166.92, 136.40, 134.21, 133.07, 130.13, 129.14, 128.07 (q, C-F, J C-F = 311.6 Hz), 127.67, 74.16, 61.32, 42.45, 38.64, 25.83, 25.02. 19 F NMR (565 MHz, CDC13) δ -35.61 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 15 H 12 Cl2F3NO2S: 396.9913; found: 396.9919.

[0336] Example 20

[0337] Compound I-20 [3-(2,4-dichlorophenyl)-5,5-dimethyl-3-((trifluoromethyl)thio)pyrrolidine- 2,4-dione]

[0338] The preparation of compound I-20 [3-(2,4-dichlorophenyl)-5,5-dimethyl-3- ((trifluoromethyl)thio)pyrrolidine-2,4-dione] was carried out using a similar synthetic procedure to that of Example 7, except that:

[0339] The starting material in step (a) was 2,4-dichlorophenylacetic acid.

[0340] The starting material in step (b) was 2-aminoisobutyric acid.

[0341] The resulting compound I-20 (white solid, 0.24 g, 64.28 %). The final test results are as follows:

[0342] m.p. 153.4-154.2 °C; 1 H NMR (400 MHz, CDC13) δ 8.04 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.46-7.40 (m, 2H), 1.80 (s, 3H), 1.60 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 202.50, 166.43, 136.60, 134.41, 132.90, 130.34, 128.82, 128.03 (q, C-F, J C-F = 312.4 Hz), 127.74, 64.89, 60.94, 29.47, 25.61. 19 F NMR (565 MHz, CDC13) δ -35.63 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 15 H 12 Cl2F3NO3S: 370.9756; found: 370.9760.

[0343] Example 21

[0344] Compound I-21 [3-(thiophen-2-yl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0345] The preparation of compound I-21 [3-(thiophen-2-yl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure to that of Example 7, except that:

[0346] The starting material in step (a) was 2-thiopheneacetic acid.

[0347] The resulting compound I-21 (white solid, 0.34 g, 98.15 %). The final test results are as follows:

[0348] m.p. 128.0 - 129.3 °C; 1 H NMR (400 MHz, CDC13) δ 9.44 (s, 1H), 7.46 (d, J = 5.1 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.04 - 7.00 (m, 1H), 2.06 - 1.95 (m, 1H), 1.90 - 1.81 (m, 1H), 1.77 - 1.64 (m, 5H), 1.63 - 1.52 (m, 1H), 1.50 - 1.35 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 204.65, 169.40, 130.63, 130.20, 129.70, 128.07 (q, C-F, J C-F = 310.1 Hz), 127.66, 67.16, 57.38, 36.54, 33.02, 24.65, 21.39, 21.30. 19 F NMR (565 MHz, CDC13) δ -38.71 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 14 H 14 F3NO2S2: 349.0413; found: 349.0420.

[0349] Example 22

[0350] Compound I-22 [3-benzyl-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0351] Compound I-22 [3-benzyl-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a synthetic method similar to Example 7, except that:

[0352] The starting material in step (a) was hydrogenated cinnamic acid.

[0353] The resulting compound I-22 (white solid, 0.34 g, 96.37 %). The final test results are as follows:

[0354] m.p. 99.6 - 100.1 °C; 1H NMR (400 MHz, CDC13) δ 8.64 (s, 1H), 7.30 - 7.22 (m, 3H), 7.19 - 7.12 (m, 2H), 3.46 (d, J = 13.0 Hz, 1H), 3.32 (d, J = 13.0 Hz, 1H), 1.87 - 1.71 (m, 3H), 1.66 - 1.46 (m, 3H), 1.38 - 1.18 (m, 2H), 1.08 - 0.98 (m, 1H), 0.23 - 0.15 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 206.83, 169.83, 133.40, 131.00 (2C), 129.00 (q, C-F, J C-F = 308.4 Hz), 128.78 (2C), 128.10, 66.88, 57.02, 39.94, 34.88, 32.35, 24.70, 21.49, 21.16. 19 F NMR (565 MHz, CDC13) δ -35.91 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 18 F3NO2S: 357.1005; found: 357.1006.

[0355] Example 23

[0356] Compound 1-23 [3-(2,4-dichlorophenyl)-3-((trifluoromethyl)thio)-1- oxaspiro[4.5]decan-2,4-dione]

[0357] Compound 1-23 [3-(2,4-dichlorophenyl)-3-((trifluoromethyl)thio)-1- oxaspiro[4.5]decan-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0358] The starting material in step (a) was 2,4-dichlorophenylacetic acid.

[0359] The starting material in step (b) was 1-hydroxycyclohexylcarboxylic acid.

[0360] The resulting compound 1-23 (white solid, 0.15 g, 37.58 %). The final test results were as follows:

[0361] m.p. 160.9 - 161.8 °C; 1H NMR (400 MHz, CDC13) δ 8.02 (d, J = 9.2 Hz, 1H), 7.48 - 7.41 (m, 2H), 2.61 - 2.53 (m, 1H), 2.18 - 2.02 (m, 3H), 1.89 - 1.69 (m, 5H), 1.48 - 1.36 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 201.09, 165.58, 137.07, 133.89, 132.61, 130.33, 128.09, 127.86, 127.55 (q, C-F, J C-F = 312.1 Hz), 92.28, 58.19, 37.17, 33.14, 24.52, 21.84, 21.60. 19 F NMR (565 MHz, CDC13) δ -35.47 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 13 Cl2F3O3S: 411.9910; found: 411.9917.

[0362] Example 24

[0363] Compound I-24 [3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-1- oxaspiro[4.5]decane-2,4-dione]

[0364] The preparation of compound I-24 [3-(2,5-dimethylphenyl)-3-((trifluoromethyl)thio)-1- oxaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0365] The starting material in step (b) was 1-hydroxycyclohexylcarboxylic acid.

[0366] The resulting compound I-24 (white solid, 0.13 g, 33.63 %). The final test results were as follows:

[0367] m.p. 113.3 - 114.4 °C; 1 H NMR (400 MHz, CDC13) δ 7.30 (s, 1H), 7.15 - 7.09 (m, 2H), 2.53 (s, 3H), 2.32 (s, 3H), 2.03 - 1.92 (m, 1H), 1.90 - 1.72 (m, 3H), 1.71 - 1.61 (m, 2H), 1.57 - 1.50 (m, 1H), 1.49 - 1.24 (m, 3H). 13C NMR (100MHz, CDCl3) δ201.68,169.12,137.28,136.07,134.16,131.47,130.08,128.29(q,CF,J C-F =310.4Hz),125.56,90.52,61.96,34.21,33.04,24.46,21.44,21.34,21.26,21.18. 19 F NMR(565MHz,CDCl3)δ-36.70(s).HRMS(EI-TOF)m / z:[M] + calcd for C 16 H 16 F3O2S:372.1002; found:372.1005.

[0368] Example 25

[0369] Compound I-25 [3-(4-fluoro-2-methylphenyl)-3-((trifluoromethyl)thio)-1-azaspiro[4.5]decane-2,4-dione]

[0370] The preparation of compound I-25 [3-(4-fluoro-2-methylphenyl)-3-((trifluoromethyl)thio)-1-azaspiro[4.5]decane-2,4-dione] was carried out using a synthetic method similar to that in Example 7, except that:

[0371] The raw material mentioned in step (a) is 2-methyl-4-fluorophenylacetic acid.

[0372] The raw material mentioned in step (b) is 4-aminotetrahydropyran-4-carboxylic acid.

[0373] The obtained compound I-25 (white solid, 0.29 g, 76.23%). The final detection results are as follows:

[0374] 1 H NMR(400MHz, CDCl3)δ9.37(s,1H),7.68–7.62(m,1H),7.00–6.93(m,2H),4.03–3.96(m,1H),3.87–3.71(m,2H),3.71–3.6 1(m,1H),2.58(s,3H),2.31–2.24(m,1H),1.92–1.85(m,1H),1.75–1.67(m,1H),1.45–1.37(m,1H).HRMS(EI-TOF)m / z:[M] + calcd for C 16 H15 F4NO3S: 377.0704; found: 377.0712.

[0375] Example 26

[0376] Compound I-26 [3-(4-chloro-2-methylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0377] Compound I-26 [3-(4-chloro-2-methylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0378] The starting material in step (a) was 2-methyl-4-fluorobenzoic acid.

[0379] The starting material in step (b) was 4-aminotetrahydropyran-4-carboxylic acid.

[0380] The resulting compound I-26 (white solid, 0.34 g, 86.41 %). The final test results were as follows:

[0381] 1 H NMR (400 MHz, CDC13) δ 9.45 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.26 - 7.22 (m, 2H), 4.01 - 3.96 (m, 1H), 3.86 - 3.71 (m, 2H), 3.68 - 3.62 (m, 1H), 2.54 (s, 3H), 2.31 - 2.24 (m, 1H), 1.94 - 1.86 (m, 1H), 1.78 - 1.68 (m, 1H), 1.45 - 1.39 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 15 ClF3NO3S: 393.0408; found: 393.0413.

[0382] Example 27

[0383] Compound I-27 [3-(4-bromo-2-methylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0384] The preparation of compound I-27 [3-(4-bromo-2-methylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decan-2,4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0385] The starting material in step (a) was 2-methyl-4-bromophenylacetic acid.

[0386] The starting material in step (b) was 4-aminotetrahydropyran-4-carboxylic acid.

[0387] The resulting compound I-27 (white solid, 0.36 g, 83.21%) was obtained. The final test results were as follows:

[0388] 1 H NMR (400 MHz, CDC13) δ 9.26 (s, 1H), 7.56 - 7.50 (m, 1H), 7.42 - 7.35 (m, 2H), 4.04 - 3.95 (m, 1H), 3.86 - 3.80 (m, 1H), 3.78 - 3.70 (m, 1H), 3.70 - 3.60 (m, 1H), 2.54 (s, 3H), 2.25 - 2.20 (m, 1H), 1.95 - 1.85 (m, 1H), 1.80 - 1.70 (m, 1H), 1.46 - 1.39 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 15 BrF3NO3S: 436.9903; found: 436.9907.

[0389] Example 28

[0390] Compound I-28 [3-((trifluoromethyl)thio)-3-(2,4,5-trimethylphenyl)-8-oxa-1- azaspiro[4.5]decan-2,4-dione]

[0391] The preparation of compound I-28 [3-((trifluoromethyl)thio)-3-(2,4,5-trimethylphenyl)-8-oxa-1- azaspiro[4.5]decan-2,4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0392] The starting material in step (a) was 2,4,5-trimethylphenylacetic acid.

[0393] The starting material in step (b) was 4-aminotetrahydropyran-4-carboxylic acid.

[0394] Compound 1-28 (white solid, 0.34 g, 87.18 %) was obtained. The final test results are as follows:

[0395] 1 H NMR (400 MHz, CDC13) δ 9.09 (s, 1H), 7.33 (s, 1H), 6.97 (s, 1H), 4.04 - 3.97 (m, 1H), 3.82 - 3.74 (m, 2H), 3.68 - 3.61 (m, 1H), 2.51 (s, 3H), 2.31 - 2.24 (m, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 1.85 - 1.76 (m, 1H), 1.71 - 1.64 (m, 1H), 1.45 - 1.38 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 18 H 20 F3NO3S: 387.1111; found: 387.1116.

[0396] Example 29

[0397] Compound 1-29 [3-(2-methylphenyl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione]

[0398] Compound 1-29 [3-(2-methylphenyl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione] was prepared using a synthetic method similar to Example 7, except that:

[0399] The starting material in step (a) was o-methylphenylacetic acid.

[0400] The starting material in step (b) was 4-aminotetrahydropyran-4-carboxylic acid.

[0401] Compound 1-29 (white solid, 0.25 g, 71.31 %) was obtained. The final test results are as follows:

[0402] 1H NMR (400 MHz, CDC13) δ 9.35 (s, 1H), 7.66 - 7.62 (m, 1H), 7.35 - 7.18 (m, 3H), 4.03 - 3.96 (m, 1H), 3.82 - 3.73 (m, 2H), 3.68 - 3.61 (m, 1H), 2.60 (s, 3H), 2.32 - 2.24 (m, 1H), 1.88 - 1.81 (m, 1H), 1.74 - 1.65 (m, 1H), 1.43 - 1.37 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 16 F3NO3S; 359.0798; found: 359.0803.

[0403] Example 30

[0404] Compound I-30 [3-(2-chloro-4-fluorophenyl)-3-((trifluoromethyl)thio)-8-oxa- 1-azaspiro[4.5]decane-2,4-dione]

[0405] The preparation of compound I-30 [3-(2-chloro-4-fluorophenyl)-3-((trifluoromethyl)thio)-8-oxa- 1-azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0406] The starting material in step (a) was 2-(2-chloro-4-fluorophenyl)acetic acid.

[0407] The starting material in step (b) was 4-aminotetrahydropyran-4-carboxylic acid.

[0408] The resulting compound I-30 (white solid, 0.36 g, 91.21%) was obtained. The final test results were as follows:

[0409] 1 H NMR (400 MHz, CDC13) δ 9.35 (s, 1H), 7.66 - 7.62 (m, 1H), 7.35 - 7.18 (m, 3H), 4.03 - 3.96 (m, 1H), 3.82 - 3.73 (m, 2H), 3.68 - 3.61 (m, 1H), 2.60 (s, 3H), 2.32 - 2.24 (m, 1H), 1.88 - 1.81 (m, 1H), 1.74 - 1.65 (m, 1H), 1.43 - 1.37 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 15 H 12 ClF4NO3S: 397.0163; found: 397.0158.

[0410] Example 31

[0411] Compound I-31 [3-(2-chloro-4-methylphenyl)-3-((trifluoromethyl)thio)-8-oxa- 1 - azaspiro [4.5] decane-2, 4-dione]

[0412] The preparation of compound I-31 [3-(2-chloro-4-methylphenyl)-3-((trifluoromethyl)thio)-8-oxa- 1 - azaspiro [4.5] decane-2, 4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0413] In Step (a), the starting material was 2-(2-chloro-4-methylphenyl)acetic acid.

[0414] In Step (b), the starting material was 4-aminotetrahydropyran-4-carboxylic acid.

[0415] The resulting compound I-31 (white solid, 0.27 g, 81.68 %) was obtained. The final test results were as follows:

[0416] 1 H NMR (400 MHz, CDC13) δ 9.16 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.24 - 7.18 (m, 2H), 3.89 (m, 2H), 3.68 - 3.53 (m, 2H), 2.43 - 2.27 (m, 5H), 2.24 - 2.18 (m, 1H), 1.82 - 1.75 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 15 ClF3NO3S: 339.0408; found: 339.0413.

[0417] Example 32

[0418] Compound I-32 [3-(3,4'-dimethyl-[1,1'-biphenyl]-4-yl)-3-((trifluoromethyl)thio)-8-oxa- 1 - azaspiro [4.5] decane-2, 4-dione]

[0419] The preparation of compound I-32 [3-(3,4'-dimethyl-[1,1'-biphenyl]-4-yl)-3-((trifluoromethyl)thio)-8-oxa- 1 - azaspiro [4.5] decane-2, 4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0420] The starting material in step (a) was 2-(3,4'-dimethyl-[1,1'-biphenyl]-4-yl)acetic acid.

[0421] The starting material in step (b) was 4-amino-tetrahydropyran-4-carboxylic acid.

[0422] The resulting compound 1-32 (white solid, 0.34 g, 75.61 %). The final test results are as follows:

[0423] 1 H NMR (400 MHz, CDC13) δ 9.58 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.50 - 7.41 (m, 4H), 7.25 - 7.21 (m, 2H), 4.03 - 3.96 (m, 1H), 3.84 - 3.76 (m, 2H), 3.71 - 3.63 (m, 1H), 2.66 (s, 3H), 2.38 (s, 3H), 2.30 - 2.25 (m, 1H), 1.92 - 1.84 (m, 1H), 1.74 - 1.68 (m, 1H), 1.50 - 1.40 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 23 H 22 F3NO3S: 449.1267; found: 449.1271.

[0424] Example 33

[0425] Compound 1-33 [3-(4'-chloro-3'-methyl-[1,1'-biphenyl]-4-yl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decan-2,4-dione]

[0426] Compound 1-33 [3-(4'-chloro-3'-methyl-[1,1'-biphenyl]-4-yl)-3-((trifluoromethyl)thio)-8-oxa-1- azaspiro[4.5]decan-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0427] The starting material in step (a) was 2-(4'-chloro-3'-methyl-[1,1'-biphenyl]-4-yl)acetic acid.

[0428] The starting material in step (b) was 4-amino-tetrahydropyran-4-carboxylic acid.

[0429] The resulting compound 1-33 (white solid, 0.32 g, 68.31 %). The final test results are as follows:

[0430] 1 H NMR (400 MHz, CDC13) δ 9.23 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.45 - 7.38 (m, 4H), 4.05 - 3.98 (m, 1H), 3.86 - 3.74 (m, 2H), 3.70 - 3.64 (m, 1H), 2.65 (s, 3H), 2.34 - 2.26 (m, 1H), 1.96 - 1.88 (m, 1H), 1.77 - 1.72 (m, 1H), 1.50 - 1.44 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 22 H 19 ClF3NO3S: 469.0721; found: 469.0726.

[0431] Example 34

[0432] Compound 1-34 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-8-methoxy-1,8- diazaspiro[4.5]decane-2,4-dione]

[0433] Compound 1-34 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-8-methoxy-1,8- diazaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0434] The phenylacetic acid starting material in step (a) was 2-(2,4-dimethylphenyl)acetic acid.

[0435] The starting material in step (b) was 4-amino-1-methoxypiperidine-4-carboxylic acid.

[0436] The resulting compound 1-34 (white solid, 0.21 g, 52.41 %). The final test results are as follows:

[0437] 1 H NMR (400 MHz, CDC13) δ 8.58 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.06 - 7.00 (m, 2H), 3.48 (s, 3H), 3.40 - 3.07 (m, 2H), 2.73 - 2.60 (m, 1H), 2.54 (s, 3H), 2.45 - 2.13 (m, 5H), 1.87 - 1.60 (m, 2H), 1.57 - 1.38 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C18 H 21 F3N2O3S: 402.1220; found: 402.1225.

[0438] Example 35

[0439] Compound I-35 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-8,8-difluoro-1- azaspiro[4.5]decan-2,4-dione]

[0440] The preparation of compound I-35 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-8,8- difluoro-1-azaspiro[4.5]decan-2,4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0441] The phenylacetic acid starting material in step (a) was 2-(2,4-dimethylphenyl)acetic acid.

[0442] The starting material in step (b) was 1-amino-4,4-difluorocyclohexane-1-carboxylic acid.

[0443] The resulting compound I-35 (white solid, 0.26 g, 63.41 %). The final test results were as follows:

[0444] 1 H NMR (400 MHz, CDC13) δ 9.33 (s, 1H), 7.45 - 7.42 (m, 1H), 7.06 - 7.02 (m, 2H), 2.59 (s, 3H), 2.30 (s, 3H), 2.28 - 2.22 (m, 1H), 2.19 - 1.76 (m, 3H), 1.63 - 1.55 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 18 H 18 F5NO2S: 407.0973; found: 407.0978.

[0445] Example 36

[0446] Compound I-36 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-1-aza-8- thiaspiro[4.5]decan-2,4-dione]

[0447] The preparation of compound I-36 [3-(2,4-dimethylphenyl)-3-((trifluoromethyl)thio)-1- aza-8-thiaspiro[4.5]decan-2,4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0448] The phenylacetic acid starting material in step (a) was 2-(2,4-dimethylphenyl)acetic acid;

[0449] The starting material in step (b) was 4-aminotetrahydrothiopyran-4-carboxylic acid.

[0450] The resulting compound I-36 (white solid, 0.29 g, 74.52%) was obtained. The final test results were as follows:

[0451] 1 H NMR (400 MHz, CDC13) δ 9.52 (s, 1H), 7.50 - 7.45 (m, 1H), 7.05 - 7.01 (m, 2H), 2.91 (m, 1H), 2.83 - 2.68 (m, 2H), 2.60 (s, 3H), 2.53 - 2.44 (m, 1H), 2.38 - 2.32 (m, 1H), 2.29 (s, 3H), 1.98 - 1.83 (m, 2H), 1.70 - 1.63 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 18 F3NO2S2: 389.0726; found: 389.0731.

[0452] Example 37

[0453] Compound I-37 [3-(4-fluoro-2-methylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0454] Compound I-37 [3-(4-fluoro-2-methylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 7, except that:

[0455] The starting material in step (a) was 2-methyl-4-fluorophenylacetic acid.

[0456] The resulting compound I-37 (white solid, 0.29 g, 73.63%) was obtained. The final test results were as follows: 1H NMR (400 MHz, CDC13) δ 8.71 (s, 1H), 7.66 (dd, J = 8.6, 5.6 Hz, 1H), 7.08 - 6.77 (m, 2H), 2.60 (s, 3H), 2.03 - 1.95 (m, 1H), 1.87 - 1.75 (m, 2H), 1.67 - 1.60 (m, 3H), 1.56 - 1.31 (m, 4H). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 14 ClF4NO2S: 375.0911; found: 375.0914.

[0457] Example 38

[0458] Compound 1-38 [3-(4-fluoro-2-methylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0459] The preparation of compound 1-38 [3-(4-fluoro-2-methylphenyl)-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure to Example 7, except that:

[0460] The starting material in step (a) was 2-chloro-4-fluorobenzoic acid.

[0461] The resulting compound 1-38 (white solid, 0.27 g, 68.53 %). The final test results were as follows:

[0462] 1 H NMR (400 MHz, CDC13) δ 8.71 (s, 1H), 7.66 (dd, J = 8.6, 5.6 Hz, 1H), 7.08 - 6.77 (m, 2H), 2.60 (s, 3H), 2.03 - 1.95 (m, 1H), 1.87 - 1.75 (m, 2H), 1.67 - 1.60 (m, 3H), 1.56 - 1.31 (m, 4H). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 14 ClF4NO2S: 395.0365; found: 373.0373.

[0463] Example 39

[0464] Compound I-39 [3-(2,4-dimethylphenyl)-8,8-dimethyl-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0465] The preparation of compound I-39 [3-(2,4-dimethylphenyl)-8,8-dimethyl-3-((trifluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure as in Example 7, except that:

[0466] The phenylacetic acid starting material in step (a) was 2-(2,4-dimethylphenyl)acetic acid.

[0467] The starting material in step (b) was 1-amino-4,4-dimethylcyclohexane-1-carboxylic acid.

[0468] The resulting compound I-39 (white solid, 0.32 g, 80.53%) was obtained. The final test results were as follows:

[0469] 1 H NMR (400 MHz, CDC13) δ 9.11 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.05 - 6.97 (m, 2H), 2.58 (s, 3H), 2.28 (s, 3H), 2.17 - 2.06 (m, 1H), 1.78 - 1.61 (m, 2H), 1.52 - 1.45 (m, 2H), 1.44 - 1.36 (m, 1H), 1.35 - 1.25 (m, 3H), 0.92 (s, 6H). HRMS (EI-TOF) m / z: [M] + calcd for C 20 H 24 F3NO2S: 399.1469; found: 399.1474.

[0470] Example 40

[0471] Compound I-40 [11-(2,4-dimethylphenyl)-11-((trifluoromethyl)thio)-1,4-dioxa-9- azadispiro[4.2.48.2 8 .2 5 ]tetradecane-10,12-dione]

[0472] Compound I-40 [11-(2,4-dimethylphenyl)-11-((trifluoromethyl)thio)-1,4-dioxa-9- azadispiro[4.2.48.2 5The preparation of [tetradecane-10, 12-dione] was carried out using a similar synthetic procedure as in Example 7, except that:

[0473] The phenylacetic acid starting material in step (a) was 2-(2,4-dimethylphenyl)acetic acid;

[0474] The starting material in step (b) was 8-amino-1, 4-dioxaspiro[4.5]decane-8-carboxylic acid.

[0475] The resulting compound I-40 (white solid, 0.31 g, 73.23%) was obtained. The final test results are as follows:

[0476] 1 H NMR (400 MHz, CDC13) δ 8.17 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.04 - 6.99 (m, 2H), 4.01 - 3.86 (m, 4H), 2.55 (s, 3H), 2.32 - 2.23 (m, 4H), 2.00 - 1.92 (m, 1H), 1.86 - 1.79 (m, 3H), 1.78 - 1.68 (m, 2H), 1.55 - 1.46 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 20 H 22 F3NO4S: 429.1212; found: 429.1217.

[0477] Example 41

[0478] The preparation of compound II-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-methylsulfanyl-1- azaspiro[4.5]decane-2,4-dione] is shown in the following scheme:

[0479] Method One

[0480] Reagents and conditions: (a) methanol, 0.5 M aqueous sodium hydroxide, room temperature, 1 h; (b) DCM, sulfonyl chloride, 0 °C, dimethyl disulfide or methyl mercaptan; (c) tetrahydrofuran, potassium carbonate, room temperature, 1 h.

[0481] Specifically, it comprises the following steps:

[0482] The preparation of intermediate P-1 was carried out using the same synthetic procedure as in Example 1 for the synthesis of intermediate P-1.

[0483] Intermediate Q-6-2 [2-(methylthio)isoindoline-1, 3-dione]

[0484] In a 100 mL two-necked flask, 5 mL of sulfonyl chloride (3.37 g, 25.00 mmol) was added dropwise into 25 mmol of methyl mercaptan or dimethyl disulfide (12.50 mmol) and 25 mL of anhydrous DCM at 0 °C. After stirring at this temperature for 0.5 h, the mixture was heated to room temperature and added to 25 mL of anhydrous DCM containing potassium phthalimide salt (3.68 g, 25.00 mmol) through a cannula. After stirring the reaction mixture for 1.5 h, the reaction solution was concentrated by rotary evaporation to remove excess sulfonyl chloride and DCM, and then recrystallized with PE / DCM to obtain intermediate Q-6-2 (white solid, 4.49 g, 93.24%)

[0485] Compound II-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-methylsulfanyl-1- azaspiro[4.5]decane-2,4-dione]

[0486] In a 25 mL single-necked round-bottom flask, intermediate P-1 (0.30 g, 1.00 mmol) and intermediate Q-6-2 (0.23 g, 1.20 mmol) were added and dissolved in 10 mL of tetrahydrofuran, and then potassium carbonate (0.55 g, 4.00 mmol) was added. The reaction was carried out at room temperature, and the reaction was tracked by TLC. After 0.5 h, the reaction was stopped. The reaction solution was rotary evaporated, and then an appropriate amount of dichloromethane was added. The product was purified by silica gel column chromatography using petroleum ether: ethyl acetate = 2:1 (V:V) as the eluent. The solvent was rotary evaporated to obtain compound III-1 (white solid, 0.32 g, 91.24%).

[0487] Method Two

[0488] Reagents and conditions: (a) tetrahydrofuran, potassium carbonate, room temperature, 1 h.

[0489] Specifically, the following steps are included:

[0490] The preparation of intermediate P-1 was carried out in the same way as the synthesis of intermediate P-1 in Example 1.

[0491] Compound II-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-methylsulfanyl-1- azaspiro[4.5]decane-2,4-dione]

[0492] Into a 25 mL single-mouth round-bottom flask, intermediate P-1 (0.30 g, 1.00 mmol) and raw material Q-9-2 (0.15 g, 1.20 mmol) were put, 10 mL of tetrahydrofuran was added to dissolve it, potassium carbonate (0.55 g, 4.00 mmol) was added, and the reaction was carried out at room temperature. TLC was used to track the reaction, and the reaction was stopped after 0.5 h. The reaction solution was rotary dried, an appropriate amount of dichloromethane was added, and silica gel column chromatography was performed with petroleum ether: ethyl acetate = 2:1 (V:V). The solvent was rotary dried to obtain compound II-1 (white solid, 0.19 g, 55.40%). The final test results are as follows:

[0493] m.p. 195.8-196.4 °C; 1 H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.10-7.01 (m, 2H), 6.92 (s, 1H), 3.36 (s, 3H), 3.33-3.25 (m, 1H), 2.55-2.47 (m, 1H), 2.37 (s, 3H), 2.22-2.15 (m, 1H), 2.13 (s, 3H), 2.12-2.09 (m, 1H), 2.08 (s, 1H), 2.07-2.02 (m, 3H), 1.97-1.86 (m, 1H), 1.57-1.35 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 203.74, 170.10, 136.13, 133.14, 132.01, 131.94, 129.70, 128.88, 76.46, 65.40, 60.64, 55.85, 35.61, 31.84, 27.71, 27.46, 21.61, 21.42, 14.06. HRMS (EI-TOF) m / z: [M] + calcd for C 19 H 25 NO3S: 347.1550; found: 347.1557.

[0494] Example 42

[0495] The preparation process of compound II-2 [3-(2,4-dichlorophenyl)-3-(methylthio)-1- azaspiro[4.5]decane-2,4-dione] is shown in the following scheme:

[0496] Reagents and conditions: (a) dichloromethane, oxalyl chloride, N,N- dimethylformamide, room temperature, 2 h; (b) methanol, thionyl chloride, 40 °C heating to reflux, 10 h; (c) acetonitrile, potassium carbonate, 0 °C→60 °C, reflux, 6 h; (d) tetrahydrofuran, potassium tert-butoxide, 1 mol / L hydrochloric acid, 0 °C→room temperature, 6 h; (e) DCM, sulfonyl chloride, 0 °C, dimethyl disulfide or methyl mercaptan; (f) tetrahydrofuran, potassium carbonate, room temperature, 0.5 h.

[0497] The preparation of intermediate P-14 was carried out in the same way as the synthetic method of intermediate P-12 in Example 7, except that:

[0498] The phenylacetic acid raw material described in step (a) used 2-(2,4- dichlorophenyl)acetic acid.

[0499] The preparation of intermediate Q-6-2 was carried out in the same way as the synthetic method in Example 41. Compound II-2 [3-(2,4-dichlorophenyl)-3- (methylthio)-1-azaspiro[4.5]decane-2,4-dione]

[0500] Into a 25 mL single-mouth round-bottom flask, intermediate P-14 (0.31 g, 1.00 mmol) and intermediate Q-6-2 (0.19 g, 1.20 mmol) were placed, 10 mL of tetrahydrofuran was added to dissolve them, and potassium carbonate (0.55 g, 4.00 mmol) was added. The reaction was carried out at room temperature, and the reaction was tracked by TLC. After 0.5 h, the reaction was stopped. The reaction solution was rotary evaporated, dichloromethane was added, and silica gel column chromatography was carried out with petroleum ether: ethyl acetate = 2:1 (V:V). The solvent was rotary evaporated to obtain compound II-2 (white solid, 0.34 g, 94.36%). The final test results are as follows:

[0501] m.p. 199.5-200.3 °C; 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 9.1 Hz, 1H), 7.53 (s, 1H), 7.41-7.38 (m, 2H), 2.42-2.35 (m, 1H), 2.09 (s, 3H), 2.06-1.97 (m, 1H), 1.97-1.88 (m, 2H), 1.84-1.72 (m, 2H), 1.66-1.60 (m, 1H), 1.55-1.30 (m, 3H). 13C NMR (100 MHz, CDC13) δ 203.14, 169.32, 135.71, 134.40, 133.72, 130.25, 129.34, 127.79, 67.30, 59.96, 38.00, 33.62, 24.89, 22.45, 22.11, 14.07. HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 17 Cl2NO2S: 357.0352; found: 357.0359.

[0502] Example 43

[0503] The preparation of compound II-3 [3-(2,4-dimethylphenyl)-3-(methylthio)-1- azaspiro[4.5]decane-2,4-dione] is shown in the following flow chart:

[0504] Reagents and conditions: (a) dichloromethane, oxalyl chloride, N,N- dimethylformamide, room temperature, 2 h; (b) methanol, thionyl chloride, 40 °C heating to reflux, 10 h; (c) acetonitrile, potassium carbonate, 0 °C→60 °C, reflux, 6 h; (d) tetrahydrofuran, potassium tert-butoxide, 1 mol / L hydrochloric acid, 0 °C→room temperature, 6 h; (e) tetrahydrofuran, potassium carbonate, room temperature, 0.5 h.

[0505] The preparation of intermediate P-16 was carried out in the same way as the synthesis of intermediate P-12 in Example 7, except that:

[0506] The phenylacetic acid raw material in step (a) was 2-(2,4-dimethylphenyl)acetic acid.

[0507] Compound II-3 [3-(2,4-dimethylphenyl)-3-(methylthio)-1-azaspiro[4.5]decane- 2,4-dione]

[0508] Into a 25 mL single-mouth round-bottom flask, intermediate P-16 (0.27 g, 1.00 mmol) and raw material Q-9-2 (0.15 g, 1.20 mmol) were put in, 10 mL of tetrahydrofuran was added to dissolve them, and potassium carbonate (0.55 g, 4.00 mmol) was added. The reaction was carried out at room temperature, and the reaction was tracked by TLC. The reaction was completed after 0.5 h. The reaction solution was rotary evaporated to dryness, dichloromethane was added, and silica gel column chromatography was carried out with petroleum ether: ethyl acetate = 2:1 (V:V) to obtain compound II-3 (white solid, 0.23 g, 72.45%). The final test results are as follows:

[0509] 1H NMR (400 MHz, CDC13) δ 7.83 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 2.37 (d, J = 13.0 Hz, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H), 2.05 - 1.93 (m, 2H), 1.88 - 1.72 (m, 3H), 1.69 - 1.62 (m, 1H), 1.53 - 1.30 (m, 3H). HRMS (EI-TOF) m / z: [M] + calcd for C 18 H 23 NO2S: 317.1444; found: 317.1451.

[0510] Example 44

[0511] Compound II-4 [3-(2,4-dimethylphenyl)-3-(methylthio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione]

[0512] The preparation of compound II-4 [3-(2,4-dimethylphenyl)-3-(methylthio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure as in Example 43. The difference is:

[0513] The starting material in step (b) was 4-aminotetrahydropyran-4-carboxylic acid.

[0514] The resulting compound II-4 (white solid, 0.12 g, 37.57%) was obtained. The final test results are as follows:

[0515] 1 H NMR (400 MHz, CDC13) δ 7.83 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 2.37 (d, J = 13.0 Hz, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H), 2.05 - 1.93 (m, 2H), 1.88 - 1.72 (m, 3H), 1.69 - 1.62 (m, 1H), 1.53 - 1.30 (m, 3H). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 21 NO3S: 319.1237; found: 319.1236.

[0516] Example 45

[0517] Compound II-5 [3-(2,4-dimethylphenyl)-8,8-difluoro-3-(methylthio)-1- azaspiro[4.5]decan-2,4-dione]

[0518] The preparation of Compound II-5 [3-(2,4-dimethylphenyl)-8,8-difluoro-3- (methylthio)-1-azaspiro[4.5]decan-2,4-dione] was carried out using a similar synthetic procedure to Example 43, except that:

[0519] The starting material in step (b) was 1-amino-4,4-difluorocyclohexane-1- carboxylic acid.

[0520] The resulting Compound II-5 (white solid, 0.084 g, 23.76%) was obtained. The final test results were as follows:

[0521] 1 H NMR (400 MHz, CDC13) δ 8.19 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 2.48 - 2.35 (m, 2H), 2.32 (s, 3H), 2.30 - 2.21 (m, 2H), 2.16 (s, 3H), 2.06 (s, 3H), 2.04 - 1.85 (m, 3H). HRMS (EI-TOF) m / z: [M] + calcd for C 18 H 21 F2NO2S: 353.1256; found: 353.1208.

[0522] Example 46

[0523] Compound II-6 [3-(2,4-dimethylphenyl)-3-(methylthio)-8-thia-1- azaspiro[4.5]decan-2,4-dione]

[0524] The preparation of Compound II-6 [3-(2,4-dimethylphenyl)-3-(methylthio)-8- thia-1-azaspiro[4.5]decan-2,4-dione] was carried out using a similar synthetic procedure to Example 42, except that:

[0525] The phenylacetic acid starting material in step (a) was 2-(2,4-dimethylphenyl) acetic acid.

[0526] The starting material in step (b) was 4-aminothiophane-4-carboxylic acid

[0527] The resulting compound II-6 (white solid, 0.12 g, 34.77%). The final test results are as follows:

[0528] 1 H NMR (400 MHz, CDC13) δ 8.00 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.01 - 6.96 (s, 1H), 2.85 - 2.65 (m, 4H), 2.62 - 2.54 (m, 1H), 2.50 - 2.41 (m, 1H), 2.39 - 2.32 (m, 1H), 2.31 (s, 3H), 2.18 (s, 3H), 2.07 (s, 3H), 2.05 - 1.97 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 21 NO2S2: 335.1009; found: 335.1010.

[0529] Example 47

[0530] Compound II-7 [3-(4-fluoro-2-methylphenyl)-3-(methylthio)-1-aza-3-cyclodecane-2,4-dione]

[0531] Compound II-7 [3-(4-fluoro-2-methylphenyl)-3-(methylthio)-1-aza-3-cyclodecane-2,4-dione] was prepared using a similar synthetic procedure to Example 42, except that:

[0532] The starting material in step (a) was 4-fluoro-2-methylphenylacetic acid

[0533] The resulting compound II-7 (white solid, 0.20 g, 62.22%). The final test results are as follows:

[0534] 1 H NMR (400 MHz, CDC13) δ 8.00 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.01 - 6.96 (s, 1H), 2.85 - 2.65 (m, 4H), 2.62 - 2.54 (m, 1H), 2.50 - 2.41 (m, 1H), 2.39 - 2.32 (m, 1H), 2.31 (s, 3H), 2.18 (s, 3H), 2.07 (s, 3H), 2.05 - 1.97 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H20 FNO2S: 321.1194; found: 321.1193.

[0535] Example 48

[0536] Compound II-8 [3-(2,4-dimethylphenyl)-8,8-dimethyl-3-(methylthio)-1- azaspiro[4.5]decan-2,4-dione]

[0537] Compound II-8 [3-(2,4-dimethylphenyl)-8,8-dimethyl-3-(methylthio)-1- azaspiro[4.5]decan-2,4-dione] was prepared using a similar synthetic procedure to Example 42, except that:

[0538] The starting material in step (a) was 2-(2,4-dimethylphenyl)acetic acid

[0539] The starting material in step (b) was 1-amino-4,4-dimethylcyclohexanecarboxylic acid

[0540] The resulting compound II-8 (white solid, 0.20 g, 62.22%) was obtained. The final test results were as follows:

[0541] 1 H NMR (400 MHz, CDC13) δ 7.82 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 2.30 (s, 3H), 2.29 - 2.24 (m, 1H), 2.21 - 2.07 (m, 5H), 2.05 (s, 3H), 1.70 - 1.65 (m, 1H), 1.54 - 1.23 (m, 4H), 0.98 (s, 3H), 0.90 (s, 3H). HRMS (EI-TOF) m / z: [M] + calcd for C 20 H 27 NO2S: 345.1757; found: 345.1756.

[0542] Example 49

[0543] Compound II-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-((2,2,2-trifluoroethyl)thio)-1- azaspiro[4.5]decan-2,4-dione]

[0544] Reagents and conditions: (a) anhydrous pyridine, argon, room temperature, 24 h; (b) methanol, 0.5 M aqueous sodium hydroxide, room temperature, 1 h; (c) N,N-dimethylformamide (DMF), potassium carbonate, room temperature, 4 h; (d) dichloroethane (DCE), cesium carbonate or potassium carbonate, room temperature, 12 h.

[0545] Specifically, the following steps are included:

[0546] The preparation of intermediate P-1 was carried out in the same way as the synthesis of intermediate P-1 in Example 1.

[0547] Intermediate Q-9-3 [S-(2,2,2-trifluoroethyl) phenylsulfonyl thioester]

[0548] In a 100 mL single-necked reaction flask, PhSO2SNa (3.92 g, 20.00 mmol), K2CO3 (2.76 g, 20.00 mmol) and 2,2,2-trifluoroethyl triflate (5.57 g, 24.00 mmol) were added to a solution of N,N-dimethylformamide (30 mL) and the reaction was continued to stir at room temperature for 4 h. At the same time, the reaction was monitored by TLC and the reaction was judged to be complete. After dilution with an ice-water mixture, the quenched reaction was transferred to a separatory funnel and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate overnight, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a 5-10% ethyl acetate / hexane mixture as the eluent. The eluent was concentrated to obtain intermediate Q-9-3 (pale yellow oily liquid) in a yield of 75.24%.

[0549] Compound III-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-((2,2,2-trifluoroethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0550] In a 25 mL single-necked round-bottom flask, intermediate P-1 (0.30 g, 1.00 mmol) and intermediate Q-9-3 (0.26 g, 1.00 mmol) were added and dissolved in 10 mL of dichloroethane. Cesium carbonate (0.33 g, 1.00 mmol) or potassium carbonate (0.41 g, 3.00 mmol) was added and the reaction was allowed to proceed at room temperature. The reaction was tracked by TLC and was completed after 12 h. The reaction was rotary evaporated, dichloromethane was added, and the product was purified by silica gel column chromatography using petroleum ether: ethyl acetate = 2:1 (V:V) to obtain compound III-1 (white solid, 0.23 g, 57.31%). The final test results are as follows:

[0551] m.p. 147.3-148.2 °C; 1 H NMR (400 MHz, CDC13) δ 7.71 (s, 1H), 7.43 (s, 1H), 7.18-7.05 (m, 2H), 3.57-3.44 (m, 1H), 3.38 (s, 3H), 3.38-3.18 (m, 2H), 2.51-2.43 (m, 1H), 2.41 (s, 3H), 2.22 (s, 3H), 2.19-2.09 (m, 3H), 2.09-1.99 (m, 1H), 1.89-1.97 (m, 1H), 1.63-1.45 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 204.98, 169.44, 136.38, 133.51, 132.33, 131.82, 130.11, 128.94, 124.98 (q, C-F, 1 J C-F = 274.6 Hz), 76.19, 65.68, 60.02, 55.87, 35.19, 32.68 (q, C-F, 2 J C-F = 32.9 Hz), 31.69, 27.37, 27.27, 21.63, 21.34. 19 F NMR (565 MHz, CDC13) δ -64.64 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 20 H 24 F3NO3S: 415.1424; found: 415.1432.

[0552] Example 50

[0553] Compound III-2 [3-(2,4-dichlorophenyl)-3-((2,2,2-trifluoroethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0554] Compound III-2 [3-(2,4-dichlorophenyl)-3-((2,2,2-trifluoroethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 49, Compound III-2 (white solid, 0.26 g, 62.14 %). The final test results were as follows:

[0555] m.p. 195.3-196.1 °C; 1H NMR (400 MHz, CDC13) δ 8.07 - 7.95 (m, 2H), 7.50 - 7.33 (m, 2H), 3.53 - 3.40 (m, 1H), 3.34 - 3.21 (m, 1H), 2.40 - 2.32 (m, 1H), 2.10 - 1.87 (m, 3H), 1.83 - 1.72 (m, 2H), 1.68 - 1.59 (m, 1H), 1.56 - 1.30 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 204.06, 168.55, 136.23, 134.15, 133.55, 130.45, 129.26, 127.94, 124.75 (q, C-F, 1 J C-F = 274.6 Hz), 67.65, 59.27, 38.19, 33.46, 32.61 (q, C-F, 2 J C-F = 33.2 Hz), 24.79, 22.30, 21.96. 19 F NMR (565 MHz, CDC13) δ -64.57 (s). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 16 Cl2F3NO2S: 425.0226; found: 425.0236.

[0556] Example 51

[0557] Compound III-3 [3-(2,4-dimethylphenyl)-3-((2,2,2-trifluoroethyl)thio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione]

[0558] Compound III-3 [3-(2,4-dimethylphenyl)-3-((2,2,2-trifluoroethyl)thio)-8-oxa-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 49, Compound III-3 (white solid, 0.36 g, 93.14 %). The final test results were as follows:

[0559] 1H NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.01 (s, 1H), 4.01 - 3.88 (m, 2H), 3.68 - 3.61 (m, 2H), 3.50 (m, 1H), 3.56 - 3.44 (m, 1H), 2.41 - 2.25 (m, 5H), 2.21 - 2.14 (m, 4H), 1.7 - 1.63 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 18 H 20 F3NO3S: 387.1111; found: 387.1118.

[0560] Example 52

[0561] Compound IV-1 [(3-((difluoromethyl)thio)-3-(2,5-dimethylphenyl)-8-methoxy-1- azaspiro[4.5]decane-2,4-dione]

[0562] Reagents and conditions: (a) tetrahydrofuran, potassium carbonate, room temperature, 1 h.

[0563] Specifically, the following steps are included:

[0564] The preparation of intermediate P-1 was carried out in the same way as the synthesis of intermediate P-1 in Example 1.

[0565] Compound IV-1 [(3-((difluoromethyl)thio)-3-(2,5-dimethylphenyl)-8-methoxy-1- azaspiro[4.5]decane-2,4-dione]

[0566] Into a 25 mL single-mouth round-bottom flask, intermediate P-1 (0.30 g, 1.00 mmol) and Q-6-3 (0.27 g, 1.20 mmol) were placed, and 10 mL of tetrahydrofuran was added to dissolve them. Potassium carbonate (0.55 g, 4.00 mmol) was added, and the reaction was carried out at room temperature. TLC was used to track the reaction, and the reaction was stopped after 0.5 h. The reaction solution was rotary evaporated, and an appropriate amount of dichloromethane was added. Silica gel column chromatography was performed with petroleum ether: ethyl acetate = 2: 1 (V:V), and the solvent was rotary evaporated to obtain compound IV-1 (white solid, 0.23 g, 57.36%).

[0567] m.p. 152.3-153.4 °C; 1H NMR (400 MHz, CDC13) δ 7.65 (s, 1H), 7.57 - 7.46 (m, 1H), 7.52 (d, J = 23.8 Hz, 1H), 3.34 (s, 3H), 3.32 - 3.25 (m, 1H), 2.36 (s, 3H), 2.27 (s, 3H), 2.14 - 1.99 (m, 3H), 1.96 - 1.73 (m, 3H), 1.61 - 1.42 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 205.51, 169.56, 136.40, 133.75, 132.59, 131.46, 130.29, 129.39, 120.69 (t, C-F, J C-F = 272.9 Hz), 76.04, 65.95, 60.95, 55.84, 34.39, 31.64, 27.05, 27.00, 21.56, 21.26. 19 F NMR (565 MHz, CDC13) δ -91.88 (dd, J = 248.6, 56.1 Hz, IF), -93.60 (dd, J = 248.4, 54.7 Hz, IF). HRMS (EI-TOF) m / z: [M] + calcd for C 19 H 23 F2NO3S: 383.1362; found: 383.1369.

[0568] Example 53

[0569] Compound IV-2 [3-(2,4-dichlorophenyl)-3-((difluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0570] Compound IV-2 [3-(2,4-dichlorophenyl)-3-((difluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 52. Compound IV-2 (white solid, 0.34 g, 86.36%). The final test results are as follows:

[0571] m.p. 144.1 - 145.3 °C; 1H NMR (400 MHz, CDC13) δ 8.05 (d, J = 9.2 Hz, 1H), 8.00 (s, 1H), 7.49 - 7.39 (m, 2H), 7.03 (t, J = 54.6 Hz, 1H), 2.37 - 2.29 (m, 1H), 2.09 - 1.86 (m, 3H), 1.86 - 1.72 (m, 2H), 1.66 - 1.59 (m, 1H), 1.55 - 1.31 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 204.30, 168.12, 136.49, 134.39, 133.21, 130.37, 129.58, 127.93, 120.37 (t, C-F, J C-F = 272.1 Hz), 67.89, 59.98, 38.08, 33.30, 24.73, 22.19, 21.93. 19 F NMR (565 MHz, CDC13) δ -91.38 (dd, J = 248.7, 55.5 Hz, IF), -93.12 (dd, J = 248.5, 54.3 Hz, IF). HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 15 Cl2F2NO2S: 393.0164; found: 393.0167.

[0572] Example 54

[0573] Compound IV-3 [3-(2,4-dichlorophenyl)-3-((difluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0574] Compound IV-3 [3-(2,4-dichlorophenyl)-3-((difluoromethyl)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure as in Example 52. Compound IV-3 (white solid, 0.23 g, 64.21 %). The final test results are as follows:

[0575] 1H NMR (400 MHz, CDC13) δ 9.22 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.19 - 6.87 (m, 3H), 3.94 - 3.87 (m, 2H), 3.69 - 3.59 (m, 2H), 2.32 (s, 3H), 2.30 - 2.22 (m, 4H), 2.20 - 2.12 (m, 1H), 2.08 - 2.00 (m, 1H), 1.64 - 1.57 (m, 1H). HRMS (EI-TOF) m / z: [M] + calcd for C 17 H 19 F2NO3S: 355.1049; found: 355.1052.

[0576] Example 55

[0577] Compound V-1 [3-(2,4-dichlorophenyl)-3-(methylsulfonyl)-1- azaspiro[4.5]decane-2,4-dione]

[0578] Reagents and conditions: (a) CC14 / CH3CN / H20 (1 : 1 :2), NaIO4, RuCl3-3H2O, rt, 3 h.

[0579] In a 25 mL single necked round bottom flask, compound III-2 (0.39 g, 1.000 mmol) was dissolved in 4 mL solution (CC14 / CH3CN / H20 = 1 : 1 :2), after adding RuCl3-3H2O (0.01 mmol) and stirring for several minutes, prepared NaIO4 (2.25 mmol) was added to the mixture. After stirring at room temperature for 3 h, the reaction solution was spin dried, an appropriate amount of dichloromethane was added, and silica gel column chromatography was performed with petroleum ether: ethyl acetate = 2: 1 (V:V), and the solvent was spin dried to obtain compound V-1 (white solid, 0.38 g, 98.35%). The final test results are as follows:

[0580] m.p. 163.5-164.2 °C; 1 H NMR (400 MHz, CDC13) δ 8.57 (d, J = 8.7 Hz, 1H), 8.23 (s, 1H), 7.53 - 7.42 (m, 1H), 2.25 - 2.16 (m, 1H), 1.97 - 1.77 (m, 5H), 1.61 - 1.34 (m, 4H). 13CNMR (101 MHz, CDC13) δ 200.27, 167.01, 136.81, 133.47, 132.19, 131.92, 128.32, 125.97, 78.05, 68.24, 40.06, 33.33, 32.49, 24.77, 21.72, 21.69. HRMS (EI-TOF) m / z: [M] + calcd for C 16 H 17 Cl2NO4S: 389.0250; found: 389.0254.

[0581] Example 56

[0582] Compound VI-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-thiocyanato-1- azaspiro[4.5]decane-2,4-dione]

[0583] The preparation of compound VI-1 [3-(2,5-dimethylphenyl)-8-methoxy-3- thiocyanato-1-azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure as in Example 1, except that:

[0584] Preparation of intermediate Q-6-4 [2-thiocyanatoisoindoline-1,3-dione] described in step (b) of Method One

[0585] Into a 100 mL two-necked flask, was charged with AgSCN 3 (4.98 g, 30.00 mmol), N-bromosuccinimide (5.20 g, 23.00 mmol) and dry acetonitrile (40 mL). The mixture was stirred at room temperature for 3 h, then the solvent was removed under a rotary evaporator. The crude was dissolved in dichloromethane (20 mL) and filtered through celite, washing with dichloromethane, and the solvent was evaporated to dryness to give the standard compound (white solid 4.20 g, 89.42%)

[0586] Intermediate Q-6-4 described in step (b) of Method Two can be replaced by intermediate Q-7-2, which was prepared in a similar manner as intermediate Q-7-1 in Example 1, except that AgSCN reagent was used instead of AgSCF3 reagent.

[0587] Preparation of compound VI-1 [3-(2,5-dimethylphenyl)-8-methoxy-3- thiocyanato-1-azaspiro[4.5]decane-2,4-dione]

[0588] Into a 25 mL single necked round bottom flask, was placed intermediate P-1 (0.30 g, 1.00 mmol), intermediate Q-7-2 (0.24 g, 1.20 mmol), 10 mL tetrahydrofuran was added to dissolve the mixture, triethylamine (0.15 g, 1.50 mmol) was added, the reaction was carried out at room temperature, TLC was used to track the reaction, the reaction was completed after 4 h. The reaction solution was rotary evaporated to dryness, dichloromethane was added, and silica gel column chromatography was performed with petroleum ether: ethyl acetate = 1: 1 (V:V) to obtain compound VI-1 (white solid, 0.29 g, 83.01%). The final test results are as follows:

[0589] 1 H NMR (400 MHz, CDC13) δ 7.76 (s, 1H), 7.38 (s, 1H), 7.11-7.10 (m, 2H), 3.34 (s, 3H), 3.35-3.26 (m, 1H), 2.50 (s, 3H), 2.33 (s, 3H), 2.22-2.12 (m, 1H), 2.06-1.99 (m, 1H), 1.98-1.91 (m, 1H), 1.75-1.50 (m, 5H); 13 C NMR (100 MHz, CDC13) δ 202.79, 167.99, 136.98, 135.11, 133.60, 131.34, 130.44, 127.01, 109.05, 75.69, 65.97, 65.23, 55.96, 32.26, 31.43, 26.86, 26.81, 21.44, 21.23; HRMS (EI-TOF) m / z: [M]+calcd for C 19 H 22 N2O3S: 358.1346; found: 358.1351.

[0590] Example 57

[0591] Compound VI-2 [3-(2,5-dimethylphenyl)-8-methoxy-1-methyl-3-thiocyanate-1- azaspiro[4.5]decane-2,4-dione]

[0592] Compound VI-2 [3-(2,5-dimethylphenyl)-8-methoxy-1-methyl-3-thiocyanate-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic method as in Example 56. The resulting compound VI-2 (white solid, 0.29 g, 78.25%). The final test results are as follows:

[0593] 1H NMR (400 MHz, CDC13) δ 7.33 (s, 1H), 7.12 - 7.07 (m, 2H), 3.51 - 3.45 (m, 1H), 3.30 (s, 3H), 3.08 (s, 3H), 2.46 (s, 3H), 2.32 (s, 3H), 2.18 - 2.07 (m, 3H), 2.06 - 2.00 (m, 1H), 1.91 - 1.81 (m, 2H), 1.80 - 1.70 (m, 1H), 1.30 - 1.26 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 202.47, 166.18, 136.80, 134.79, 133.48, 131.08, 130.40, 127.85, 109.15, 72.43, 67.59, 64.50, 55.88, 25.78, 25.70, 25.59, 25.46, 25.38, 21.34, 21.21; HRMS (EI-TOF) m / z: [M]+calcd for C 20 H 24 N2O3S: 372.1502; found: 372.1510.

[0594] Example 58

[0595] Compound VI-3 [3-(2,5-dimethylphenyl)-8-hydroxy-3-thiocyanato-1- azaspiro[4.5]decane-2,4-dione]

[0596] The preparation of compound VI-3 [3-(2,5-dimethylphenyl)-8-hydroxy-3- thiocyanato-1-azaspiro[4.5]decane-2,4-dione] was similar to Example 56. The resulting compound VI-3 (white solid, 0.21 g, 60.32 %). The final test results were as follows:

[0597] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.39 (s, 1H), 7.21 - 7.16 (m, 2H), 4.75 (s, 1H), 3.62 - 3.43 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.01 - 1.80 (m, 3H), 1.76 - 1.47 (m, 5H); 13C NMR (100 MHz, DMSO-d6) δ 204.74, 166.20, 135.94, 133.74, 132.73, 130.49, 130.26, 128.22, 109.19, 66.19, 65.89, 63.04, 32.97, 31.91, 29.86, 29.69, 20.73, 20.63; HRMS (EI-TOF) m / z: [M]+calcd for C 18 H 20 N2O3S: 344.1189; found: 344.1194.

[0598] Example 59

[0599] Compound VI-4 [3-(2,5-dimethylphenyl)-3-thiocyanato-1- azaspiro[4.5]decane-2,4,8-trione]

[0600] Compound VI-4 [3-(2,5-dimethylphenyl)-3-thiocyanato-1- azaspiro[4.5]decane-2,4,8-trione] was prepared using a similar synthetic procedure as in Example 56. The resulting compound VI-4 (white solid, 0.18 g, 55.41 %). The final test results are as follows:

[0601] 1 H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.34 (s, 1H), 7.18 - 7.12 (m, 2H), 2.69 - 2.64 (m, 2H), 2.63 - 2.57 (m, 1H), 2.55 (s, 3H), 2.52 - 2.42 (m, 2H), 2.34 (s, 3H), 2.32 - 2.24 (m, 1H), 2.15 - 2.06 (m, 1H), 2.01 - 1.93 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 207.41, 202.20, 169.83, 137.22, 135.19, 133.92, 131.70, 130.02, 126.42, 109.21, 65.43, 65.38, 36.80, 36.64, 34.91, 33.57, 21.40, 21.18; HRMS (EI-TOF) m / z: [M]+calcd for C 18 H 18 N2O3S: 342.1033; found: 342.1041.

[0602] Example 60

[0603] Compound VI-5 [3-(2,5-dimethylphenyl)-8-(hydroxyimino)-3-thiocyanato-1- azaspiro[4.5]decane-2,4-dione]

[0604] Specifically, the following steps are included:

[0605] Intermediate P-14 [3-(2,5-dimethylphenyl)-8-(hydroxyimino)-2-oxo-1- azaspiro[4.5]dec-3-en-4-yl ethyl carbonate]

[0606] Into a 100 mL single necked flask, was placed intermediate P-5 (1.79 g, 5.00 mmol), dissolved in 20 mL of ethanol, and hydroxylamine hydrochloride (0.69 g, 10 mmol) was added. The reaction was stirred at room temperature and followed by TLC. After about 2 h, the reaction was complete. Most of the ethanol was removed by vacuum, 10 mL of methanol was added, and the solution was poured into ice water. A white flocculent solid was precipitated, which was filtered and dried to give intermediate P-14 (white solid, 1.39 g, 74.80% yield).

[0607] Intermediate P-15 [3-(2,5-dimethylphenyl)-4-hydroxy-8-(hydroxyimino)-1- azaspiro[4.5]dec-3-en-2-one]

[0608] Into a 100 mL single necked flask, was placed intermediate P-14 (1.86 g, 5.00 mmol), dissolved in 20 mL of methanol, and stirred in an ice bath. A 10 mL aqueous solution of sodium hydroxide (0.20 g, 5.00 mmol) was prepared and added slowly to the reaction mixture using a constant pressure dropping funnel. After the addition was complete, the reaction was stirred at room temperature and followed by TLC. After about 1 h, the reaction was complete. The reaction was adjusted to pH 3 using 1 M hydrochloric acid solution, and the methanol was removed by vacuum. The residual aqueous solution was extracted with dichloromethane (3 x 20 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give intermediate P-15 (white solid, 1.35 g, 90.18% yield).

[0609] Preparation of compound VI-5 [3-(2,5-dimethylphenyl)-8-(hydroxyimino)-3- thiocyanato-1-azaspiro[4.5]decane-2,4-dione]

[0610] The preparation of compound VI-5 [3-(2,5-dimethylphenyl)-8-(hydroxyimino)-3- thiocyanate-1-azaspiro[4.5]decane-2,4-dione] was similar to Example 56 to give compound VI-5 (white solid, 0.17 g, 47.18 %). The final test results were as follows:

[0611] 1 H NMR (400 MHz, CDC13) δ 9.35 - 9.29 (m, 1H + 0.9H, major + minor), 7.34 (s, 1H + 0.9H, major + minor), 7.16 - 7.08 (m, 2H + 1.9H, major + minor), 3.16 (dt, J = 15.6, 5.5 Hz, 1H, major), 2.97 (dt, J = 15.3, 5.4 Hz, 0.9H, minor), 2.52 (s, 3H + 2.8H, major + minor), 2.48 - 2.38 (m, 2H + 1.9H, major + minor), 2.34 (s, 3H + 2.8H, major + minor), 2.31 - 2.17 (m, 2H + 1.9H, major + minor), 2.10 - 2.00 (m, 1H + 0.9H, major + minor), 1.92 - 1.81 (m, 1H + 0.9H, major + minor), 1.79 - 1.67 (m, 1H + 0.9H, major + minor); 13C NMR (100 MHz, CDC13) δ 202.14 (major), 202.08 (minor), 169.51 (major + minor), 156.37 (major + minor), 137.16 (major + minor), 135.22 (major + minor), 133.84 (major + minor), 131.59 (major + minor), 130.18 (major + minor), 126.64 (major + minor), 109.18 (major + minor), 66.34 (major + minor), 65.39 (major), 65.30 (minor), 35.03 (major), 33.80 (major), 33.73 (minor), 32.44 (minor), 27.22 (major), 27.14 (minor), 21.45 (major), 21.42 (minor), 21.21 (major + minor), 19.95 (major), 19.79 (minor); HRMS (EI-TOF) m / z: [M]+calcd for C 18 H 19 N3O3S: 357.1142; found: 357.1156.

[0612] Example 61

[0613] Compound VI-6 [3-(2,5-dimethylphenyl)-8-(methoxyimino)-3-thiocyanato-1- azaspiro[4.5]decane-2,4-dione]

[0614] Compound VI-6 [3-(2,5-dimethylphenyl)-8-(methoxyimino)-3-thiocyanato-1- azaspiro[4.5]decane-2,4-dione] was prepared using a procedure analogous to Example 56. Compound VI-6 (white solid, 0.19 g, 52.46%) was obtained. The final test results are as follows:

[0615] 1H NMR (400 MHz, CDC13) δ 9.46 (s, 1H + 0.9H, major + minor), 7.34 (s, 1H + 0.9H, major + minor), 7.16 - 7.10 (m, 2H + 1.8H, major + minor), 3.81 (s, 3H, major), 3.80 (s, 2.7H, minor), 3.11 (dt, J = 15.4, 5.5 Hz, 1H, major), 2.92 (dt, J = 15.2, 5.4 Hz, 0.9H, minor), 2.54 (s, 3H, major), 2.54 (s, 2.7H, minor), 2.49 - 2.37 (m, 2H + 1.8H, major + minor), 2.34 (s, 3H + 2.7H, major + minor), 2.32 - 1.99 (m, 3H + 2.7H, major + minor), 1.90 - 1.71 (m, 2H + 1.8H, major + minor); 13 C NMR (100 MHz, CDC13) δ 202.27 (minor), 202.14 (major), 169.66 (major), 169.63 (minor), 155.24 (major), 155.19 (minor), 137.17 (major), 137.12 (minor), 135.28 (major), 135.21 (minor), 133.88 (major), 133.82 (minor), 131.59 (major), 131.54 (minor), 130.18 (minor), 130.13 (major), 126.69 (minor), 126.63 (major), 109.22 (major), 109.16 (minor), 66.46 (minor), 66.43 (major), 65.52 (major), 65.23 (minor), 61.42 (major + minor), 35.28 (major), 34.01 (minor), 33.89 (major), 32.50 (minor), 27.23 (minor), 27.17 (major), 21.47 (minor), 21.42 (major), 21.20 (major + minor), 20.48 (major), 20.32 (minor); HRMS (EI-TOF) m / z: [M]+calcd for C 19 H 21 N3O3S: 371.1298; found: 371.1302.

[0616] Example 62

[0617] Compound VI-7 [11-(2,5-dimethylphenyl)-11-thiocyanato-1,4-dioxa-9- azaspiro[4.2.48.25]tetradecane-10,12-dione]

[0618] The preparation of compound VI-7 [11-(2,5-dimethylphenyl)-11-thiocyanato-1,4- dioxa-9-azaspiro[4.2.48.25]tetradecane-10,12-dione] was carried out similarly to Example 56, to give compound VI-7 (white solid, 0.20 g, 52.69 %). The final test results are as follows:

[0619] 1 H NMR (400 MHz, CDC13) δ 7.61 (s, 1H), 7.36 (s, 1H), 7.14 - 7.08 (m, 2H), 4.01 - 3.88 (m, 4H), 2.51 (s, 3H), 2.33 (s, 3H), 2.06 - 1.89 (m, 4H), 1.83 - 1.65 (m, 4H); 13 C NMR (100 MHz, CDC13) δ 202.24, 168.09, 137.01, 135.31, 133.69, 131.40, 130.38, 127.04, 109.08, 106.84, 65.71, 64.69 (2C), 64.64, 33.06, 32.01, 30.92, 30.82, 21.42, 21.22; HRMS (EI-TOF) m / z: [M]+calcd for C 20 H 22 N2O4S: 386.1295; found: 386.1302.

[0620] Example 63

[0621] Compound VI-8 [11-(2,5-dimethylphenyl)-11-thiocyanato-1,4-dithia-9- azaspiro[4.2.48.25]tetradecane-10,12-dione]

[0622] The preparation of compound VI-8 [11-(2,5-dimethylphenyl)-11-thiocyanato-1,4- dithia-9-azaspiro[4.2.48.25]tetradecane-10,12-dione] was carried out similarly to Example 56, to give compound VI-8 (white solid, 0.34 g, 80.57 %). The final test results are as follows:

[0623] 1 H NMR (400 MHz, CDC13) δ 7.82 (s, 1H), 7.33 (s, 1H), 7.14 - 7.09 (m, 2H), 3.38 - 3.25 (m, 4H), 2.53 (s, 3H), 2.45 - 2.34 (m, 2H), 2.32 (s, 3H), 2.21 - 1.91 (m, 5H), 1.73 - 1.64 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 202.08, 168.12, 136.94, 135.32, 133.68, 131.36, 130.24, 126.87, 108.99, 66.11 (2C), 65.25, 38.80, 38.65, 38.03, 37.79, 34.95, 33.71, 21.39, 21.14; HRMS (EI-TOF) m / z: [M]+calcd for C 20 H 22 N2O2S3: 418.0838; found: 418.0841.

[0624] Example 64

[0625] Compound VI-9 [3-(2,5-dimethylphenyl)-3-thiocyanato-1-azaspiro[4.5]decane-2,4-dione]

[0626] Compound VI-9 [3-(2,5-dimethylphenyl)-3-thiocyanato-1-azaspiro[4.5]decane-2,4-dione] was prepared using a similar method to Example 56, obtaining compound VI-9 (white solid, 0.20 g, 60.89 %). The final test results are as follows:

[0627] 1 H NMR (400 MHz, CDC13) δ 7.82 (s, 1H), 7.33 (s, 1H), 7.14 - 7.09 (m, 2H), 3.38 - 3.25 (m, 4H), 2.53 (s, 3H), 2.45 - 2.34 (m, 2H), 2.32 (s, 3H), 2.21 - 1.91 (m, 5H), 1.73 - 1.64 (m, 1H); 13C NMR (100 MHz, CDC13) δ 202.84, 168.66, 136.91, 135.21, 133.61, 131.27, 130.41, 127.21, 109.04, 67.17, 65.14, 35.00, 33.82, 24.68, 21.78, 21.71, 21.44, 21.22. HRMS (EI-TOF) m / z: [M]+calcd for C 18 H 20 N2O2S: 328.1240; found: 328.1249.

[0628] Example 65

[0629] Compound VI-10 [3-(2,5-dimethylphenyl)-3-thiocyanato-1-azaspiro[4.4]nonane-2,4-dione]

[0630] Compound VI-10 [3-(2,5-dimethylphenyl)-3-thiocyanato-1-azaspiro[4.4]nonane-2,4-dione] was prepared using a similar procedure to Example 56, and the resulting compound VI-10 (white solid, 0.13 g, 41.74 %). The final test results are as follows:

[0631] 1 H NMR (400 MHz, CDC13) δ 7.48 (s, 1H), 7.47 (s, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.18 - 2.09 (m, 1H), 2.07 - 1.97 (m, 1H), 1.90 - 1.76 (m, 6H); 13 C NMR (100 MHz, CDC13) δ 203.89, 167.59, 136.87, 133.92, 132.95, 131.07, 130.80, 127.30, 108.20, 73.25, 67.12, 40.13, 39.20, 25.55, 25.45, 21.30, 21.18. HRMS (EI-TOF) m / z: [M]+calcd for C 17 H 18 N2O2S: 314.1083; found: 314.1093.

[0632] Example 66

[0633] Compound VI-11 [3-(2,5-dimethylphenyl)-5,5-dimethyl-3-thiocyanatopyrrolidine-2,4-dione]

[0634] The preparation of compound VI-11 [3-(2,5-dimethylphenyl)-5,5-dimethyl-3- thiocyanatopyrrolidine-2,4-dione] was carried out using a similar synthetic procedure to Example 56, resulting in compound VI-13 (white solid, 0.16 g, 56.38%). The final test results are as follows:

[0635] 1 H NMR (400 MHz, CDC13) δ 8.03 (s, 1H), 7.41 (s, 1H), 7.17 - 7.07 (m, 2H), 2.51 (s, 3H), 2.34 (s, 3H), 1.59 (s, 3H), 1.35 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 203.18, 168.21, 137.03, 135.11, 133.62, 131.37, 130.35, 127.10, 108.97, 64.79, 64.13, 26.49, 25.54, 21.30, 21.20; HRMS (EI-TOF) m / z: [M]+calcd for C 15 H 16 N2O2S: 288.0927; found: 288.0934.

[0636] Example 67

[0637] Compound VI-12 [3-(2,4-dimethylphenyl)-3-thiocyanato-1- azaspiro[4.5]decane-2,4-dione]

[0638] The preparation of compound VI-12 [3-(2,4-dimethylphenyl)-3-thiocyanato-1- azaspiro[4.5]decane-2,4-dione] was carried out using a similar procedure to Example 56, resulting in compound VI-14 (white solid, 0.19 g, 59.02%). The final test results are as follows:

[0639] 1 H NMR (400 MHz, CDC13) δ 8.36 (s, 1H), 7.49 - 7.43 (m, 1H), 7.09 - 7.02 (m, 2H), 2.55 (s, 3H), 2.30 (s, 3H), 2.04 - 1.95 (m, 1H), 1.89 - 1.81 (m, 2H), 1.70 - 1.59 (m, 3H), 1.58 - 1.44 (m, 3H), 1.42 - 1.30 (m, 1H); 13C NMR (100 MHz, CDC13) δ 202.92, 168.79, 140.69, 138.38, 134.53, 129.98, 127.91, 124.54, 109.08, 67.12, 65.19, 35.13, 33.63, 24.71, 21.77 (2C), 21.69, 21.00; HRMS (EI-TOF) m / z: [M]+calcd for C 18 H 20 N2O2S: 328.1240; found: 328.1248.

[0640] Example 68

[0641] Compound VI-13 [3-(2,4-dichlorophenyl)-3-thiocyanato-1-azaspiro[4.5]decane- 2,4-dione]

[0642] Compound VI-13 [3-(2,4-dichlorophenyl)-3-thiocyanato-1-azaspiro[4.5]decane- 2,4-dione] was prepared using a procedure similar to Example 56, resulting in compound VI-18 (white solid, 0.15 g, 40.14 %). The final test results are as follows:

[0643] 1 H NMR (400 MHz, Methanol-d4) δ 8.00 (d, J = 8.3 Hz, 1H), 7.58 (m, 2H), 2.28 - 2.18 (m, 1H), 2.13 - 2.03 (m, 2H), 1.94 - 1.76 (m, 3H), 1.71 - 1.61 (m, 3H), 1.55 - 1.44 (m, 1H); 13 C NMR (100 MHz, Methanol-d4) δ 203.42, 167.26, 137.76, 135.07, 134.21, 131.34, 129.61, 129.07, 107.92, 69.11, 61.64, 38.90, 34.65, 25.77, 22.86, 22.64; HRMS (EI-TOF) m / z: [M]+calcd for C 16 H 14 Cl2N2O2S: 368.0148; found: 368.0150.

[0644] Example 69

[0645] Compound VI-14 [3-(2-chlorophenyl)-3-thiocyanato-1-azaspiro[4.5]decane-2,4- dione]

[0646] The preparation of compound VI-14 [3-(2-chlorophenyl)-3-thiocyanato-1- azaspiro[4.5]decane-2,4-dione] was carried out using a similar method as in Example 56 to give the compound VI-20 (white solid, 0.20 g, 60.99 %). The final test results are as follows:

[0647] 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.63 - 7.52 (m, 3H), 2.19 - 2.09 (m, 1H), 1.98 - 1.83 (m, 3H), 1.73 - 1.56 (m, 5H), 1.43 - 1.32 (m, 1H); 13 CNMR (100 MHz, DMSO-d6) δ 203.36, 164.90, 132.51, 131.46, 131.40, 130.49, 129.16, 128.03, 107.91, 67.33, 60.40, 37.56, 33.06, 24.30, 21.26, 20.93; HRMS (EI-TOF) m / z: [M]+calcd for C 16 H 15 ClN2O2S: 334.0537; found: 334.0540.

[0648] Example 70

[0649] The preparation of compound VII-1 [3-(2,5-dimethylphenyl)-8-methoxy-3- (phenylthio)-1-azaspiro[4.5]decane-2,4-dione] is shown in the following scheme:

[0650] Reagents and conditions: (a) diphenyl disulfide, iodine, dichloromethane, rt, 3 h; (b) potassium carbonate, tetrahydrofuran, rt. Specifically, it comprises the following steps:

[0651] The preparation of intermediate P-1 was carried out using the same method as in Example 1.

[0652] Intermediate Q-9-4 [phenylsulfonyl thioformate]

[0653] In a 100 mL flask, add sodium benzenesulfinate (2.63 g, 16 mmol) and diphenyl disulfide (1.10 g, 5 mmol) and dissolve with 20 mL of redistilled dichloromethane, add elemental iodine, monitor the reaction with TLC, after 1 h, the raw material is consumed. Then add 20 mL of dichloromethane, followed by an aqueous solution of sodium thiosulfate (1 M, 25 mL), wash the organic phase with water, saturated brine, dry over anhydrous sodium sulfate, filter, rotary evaporate, and pass through a column with PE:EA = 10:1 to obtain intermediate Q-9-4 (colorless oily liquid, 2.33 g, 93.24%)

[0654] Compound VII-1 [3-(2,5-dimethylphenyl)-8-methoxy-3-(phenylthio)-1- azaspiro[4.5]decane-2,4-dione]

[0655] In a 25 mL single-necked round-bottom flask, add intermediate P-1 (0.30 g, 1.00 mmol) and intermediate Q-9-4 (0.30 g, 1.20 mmol), add 10 mL of tetrahydrofuran to dissolve, add potassium carbonate (0.55 g, 4.00 mmol), react at room temperature, track the reaction with TLC, and end the reaction after 0.5 h. Rotary evaporate the reaction solution, add an appropriate amount of dichloromethane, and chromatograph on a silica gel column with petroleum ether: ethyl acetate = 2:1 (V:V), and rotary evaporate the solvent to obtain compound VII-1 (white solid, 0.22 g, 54.45%). The final test results are as follows:

[0656] 1 H NMR (400 MHz, CDC13) δ 7.86 (s, 1H), 7.44 (d, J = 7.0 Hz, 2H), 7.30 (dd, J = 15.2, 8.0 Hz, 2H), 7.24 (d, J = 1.6 Hz, 1H), 7.1-7.04 (m, 2H), 6.99 (s, 1H), 3.31 (s, 3H), 3.24 - 3.16 (m, 1H)), 2.38 (s, 3H), 2.36 (s, 3H), 2.08 - 1.93 (m, 2H), 1.93-1.83 (m, 1H), 1.83-1.67 (m, 3H), 1.45 - 1.32 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C 24 H 27 NO3S: 409.1707; found: 409.1714.

[0657] Example 71

[0658] Compound VII-2 [3-(2,5-dimethylphenyl)-3-(isopentylthio)-8-methoxy-1- azaspiro[4.5]decane-2,4-dione]

[0659] Compound VII-2 [3-(2,5-dimethylphenyl)-3-(isopentylthio)-8-methoxy-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 70, except that:

[0660] The disulfide starting material in step (a) was diisopentyl disulfide;

[0661] The resulting compound VII-2 (white solid, 0.30 g, 73.71 %). The final test results are as follows:

[0662] 1 H NMR (400 MHz, CDC13) δ 7.78 (s, 1H), 7.11 - 7.01 (m, 2H), 6.78 (s, 1H), 3.36 (s, 3H), 3.33 - 3.25 (m, 1H), 2.68 - 2.51 (m, 2H), 2.50 - 2.42 (m, 1H), 2.37 (s, 3H), 2.23 - 2.13 (m, 1H), 2.11 (s, 3H), 2.10 - 2.02 (m, 2H), 1.96 - 1.87 (m, 1H), 1.74 - 1.62 (m, 1H), 1.56 - 1.34 (m, 4H), 0.90 - 0.87 (m, 6H). HRMS (EI-TOF) m / z: [M] + calcd for C 23 H 33 NO3S: 403.2176; found: 403.2183.

[0663] Example 72

[0664] Compound VII-3 [3-(2,5-dimethylphenyl)-3-(isopropylthio)-8-methoxy-1- azaspiro[4.5]decane-2,4-dione]

[0665] Compound VII-3 [3-(2,5-dimethylphenyl)-3-(isopropylthio)-8-methoxy-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 70, except that:

[0666] The disulfide starting material in step (a) was diisopropyl disulfide;

[0667] The base in step (b) was 1 M potassium tert-butoxide solution and heated stirring at 50 °C;

[0668] The resulting compound VII-3 (white solid, 0.12 g, 33.02 %). The final test results are as follows:

[0669] 1 H NMR (400 MHz, CDC13) δ 7.9 (s, 1H), 7.10 - 6.99 (m, 3H), 3.35 (s, 3H), 3.33 - 3.24 (m, 1H), 3.17 - 3.06 (m, 1H), 2.58 - 2.49 (m, 1H), 2.37 (s, 3H), 2.20 - 2.16 (m, 1H), 2.15 (s, 3H), 2.14 - 1.98 (m, H), 1.95 - 1.84 (m, 1H), 1.56 - 1.36 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H). HRMS (EI-TOF) m / z: [M] + calcd for C 21 H 29 NO3S: 375.1863; found: 375.1865.

[0670] Example 73

[0671] Compound VII-4 [3-(2,5-dimethylphenyl)-8-methoxy-3-((4-methoxyphenyl)thio)-1- aza-3-cyclo[4.5]decane-2,4-dione]

[0672] Compound VII-4 [3-(2,5-dimethylphenyl)-8-methoxy-3-((4-methoxyphenyl)thio)-1- aza-3-cyclo[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 70, except that:

[0673] The disulfide starting material in step (a) was 4,4'-dimethoxydibenzyl disulfide;

[0674] The resulting compound VII-4 (white solid, 0.19 g, 44.32 %). The final test results are as follows:

[0675] 1H NMR (400 MHz, CDC13) δ 7.88 (s, 1H), 7.44 - 7.36 (m, 2H), 7.06 (s, 2H), 6.86 (s, 1H), 6.83 - 6.75 (m, 2H), 3.76 (s, 3H), 3.32 (s, 3H), 3.26 - 3.18 (m, 1H), 2.39 (s, 3H), 2.37 (s, 3H), 2.09 - 1.98 (m, 2H), 1.97 - 1.87 (m, 1H), 1.83 - 1.71 (m, 3H), 1.46 - 1.33 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C 25 H 29 NO4S: 439.1812; found: 439.1819.

[0676] Example 74

[0677] Compound VII-5 [methyl 3-((3-(2,5-dimethylphenyl)-8-methoxy-2,4-dioxo-1- azaspiro[4.5]dec-3-yl)thio)propanoate]

[0678] The preparation of compound VII-5 [methyl 3-((3-(2,5-dimethylphenyl)-8-methoxy- 2,4-dioxo-1-azaspiro[4.5]dec-3-yl)thio)propanoate] was carried out using a similar synthetic procedure to Example 70, except that:

[0679] The disulfide starting material in step (a) was dimethyl 3,3'-dithiodipropionate;

[0680] The resulting compound VII-5 (white solid, 0.29 g, 68.84 %). The final test results are as follows:

[0681] 1 H NMR (400 MHz, CDC13) δ 7.88 (s, 1H), 7.44 - 7.36 (m, 2H), 7.06 (s, 2H), 6.86 (s, 1H), 6.83 - 6.75 (m, 2H), 3.76 (s, 3H), 3.32 (s, 3H), 3.26 - 3.18 (m, 1H), 2.39 (s, 3H), 2.37 (s, 3H), 2.09 - 1.98 (m, 2H), 1.97 - 1.87 (m, 1H), 1.83 - 1.71 (m, 3H), 1.46 - 1.33 (m, 2H). HRMS (EI-TOF) m / z: [M] +C 22 H 29 NO5S: 419.1761 ; found: 419.1764.

[0682] Example 75

[0683] Compound VII-6 [3-(2,5-dimethylphenyl)-8-methoxy-3-(pyridin-2-ylsulfanyl)-1- azaspiro[4.5]decane-2,4-dione]

[0684] Compound VII-6 [3-(2,5-dimethylphenyl)-8-methoxy-3-(pyridin-2-ylsulfanyl)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 70, except that:

[0685] The disulfide starting material in step (a) was 2,2'-dithiodipyridine;

[0686] The resulting compound VII-6 (white solid, 0.26 g, 64.31 %). The final test results were as follows:

[0687] 1 H NMR (400 MHz, CDC13) δ 8.19 - 8.15 (m, 1H), 7.49 - 7.44 (m, 1H), 7.42 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.98 - 6.93 (m, 1H), 6.78 (s, 1H), 3.32 (s, 3H), 3.27 - 3.16 (m, 1H), 2.63 (s, 3H), 2.30 (s, 3H), 2.26 - 2.08 (m, 3H), 1.87 - 1.77 (m, 1H), 1.51 - 1.24 (m, 4H). HRMS (EI-TOF) m / z: [M] + calcd for C 23 H 26 N2O3S: 410.1659; found: 410.1666.

[0688] Example 76

[0689] Compound VII-7 [3-(2,5-dimethylphenyl)-8-methoxy-3-((4-(trifluoromethyl)phenyl) sulfanyl)-1-azaspiro[4.5]decane-2,4-dione]

[0690] The preparation of compound VII-7 [3-(2,5-dimethylphenyl)-8-methoxy-3-((4- (trifluoromethyl)phenyl)thio)-1-azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure to Example 70, except that:

[0691] The thioether starting material in step (a) was 4-(trifluoromethyl)benzenethiol;

[0692] The resulting compound VII-7 (white solid, 0.28 g, 58.84 %). The final test results are as follows:

[0693] 1 H NMR (400 MHz, CDC13) δ 7.78 (s, 1H), 7.52 - 7.45 (m, 4H), 7.32 (s, 1H), 7.13 - 7.04 (m, 2H), 3.31 (s, 3H), 3.25 - 3.17 (m, 1H), 2.35 (s, 3H), 2.33 (s, 3H), 2.12 - 1.93 (m, 3H), 1.91 - 1.71 (m, 3H), 1.50 - 1.36 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C 25 H 26 F3NO3S: 477.1580; found: 477.1588.

[0694] Example 77

[0695] Compound VII-8 [3-(2,5-dimethylphenyl)-8-methoxy-3-(thiophen-2-ylthio)-1-aza-3- cyclo decane-2,4-dione]

[0696] The preparation of compound VII-8 [3-(2,5-dimethylphenyl)-8-methoxy-3-(thiophen-2-ylthio)-1-aza-3- cyclo decane-2,4-dione] was carried out using a similar synthetic procedure to Example 70, except that:

[0697] The disulfide starting material in step (a) was dithiophene disulfide;

[0698] The resulting compound VII-8 (white solid, 0.18 g, 44.48 %). The final test results are as follows:

[0699] 1H NMR (400 MHz, CDC13) δ 7.91 (s, 1H), 7.44 (dd, J = 5.4, 1.3 Hz, 1H), 7.25 (dd, J = 3.6, 1.3 Hz, 1H), 7.10 - 7.04 (m, 2H), 7.01 - 6.97 (m, 2H), 3.34 (s, 3H), 3.29 - 3.22 (m, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 2.14 - 1.98 (m, 3H), 1.94 - 1.74 (m, 3H), 1.52 - 1.35 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C 22 H 25 NO3S2: 415.1271; found: 415.1274.

[0700] Example 78

[0701] The preparation of compound VII-9 [3-(3-buten-1-ylsulfanyl)-3-(2,5-dimethylphenyl)-8-methoxy-1- azapentacyclododecane-2,4-dione] is shown in the following scheme:

[0702] Reagents and conditions: (a) 4-bromo-1-butene, DMF, N2, rt, 10 h; (b) potassium carbonate, tetrahydrofuran, rt, 10 h.

[0703] Specifically, the following steps are included:

[0704] The preparation of intermediate P-1 was carried out in the same way as the synthesis of intermediate P-1 in Example 1.

[0705] Intermediate Q-9-5 [S-(3-buten-1-yl) benzenesulfonyl thioester]

[0706] In a 100 mL Schlenk flask, sodium benzenethiosulfonate (0.39 g, 2 mmol) was added, replaced with N2, then dissolved with super dry DMF, followed by the addition of 4-bromo-1-butene, and the reaction solution was stirred for 10 h, then ice water was added, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, rotary evaporated, and columned (PE:EA = 9:1) to obtain intermediate Q-9-5 (colorless oily liquid, 0.36 g, 77.74%).

[0707] Compound VII-9 [3-(3-buten-1-ylsulfanyl)-3-(2,5-dimethylphenyl)-8-methoxy-1- azapentacyclododecane-2,4-dione]

[0708] Into a 25 mL single-necked round-bottom flask, was placed intermediate P-1 (0.30 g, 1.00 mmol), intermediate Q-9-5 (0.27 g, 1.20 mmol), and 10 mL of tetrahydrofuran to dissolve the mixture. Potassium carbonate (0.55 g, 4.00 mmol) was added, and the reaction was allowed to proceed at room temperature. TLC was used to track the reaction, and the reaction was stopped after 0.5 h. The reaction solution was rotary evaporated to dryness, and dichloromethane was added. The mixture was purified by silica gel column chromatography using petroleum ether: ethyl acetate = 2: 1 (V:V) as the eluent. The solvent was rotary evaporated to dryness to obtain compound VII-9 (white solid, 0.25 g, 65.37%). The final test results are as follows:

[0709] 1 H NMR (400 MHz, CDC13) δ 7.78 (s, 1H), 7.11 - 7.00 (m, 2H), 6.82 (s, 1H), 5.84 - 5.73 (m, 1H), 5.14 - 5.04 (m, 2H), 3.36 (s, 3H), 3.32 - 3.25 (m, 1H), 2.76 - 2.69 (m 1H), 2.60 - 2.49 (m, 2H), 2.37 (s, 3H), 2.36 - 2.30 (m, 2H), 2.22 - 2.13 (m, 1H), 2.12 (s, 3H), 2.11 - 2.01 (m, 3H), 1.97 - 1.87 (m, 1H), 1.56 - 1.34 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C 22 H 29 NO3S:387.1863; found:387.1874.

[0710] Example 79

[0711] Compound VII-10 [3-(2,5-dimethylphenyl)-8-methoxy-3-(prop-2-yn-1-ylthio)-1- azaspiro[4.5]decane-2,4-dione]

[0712] Compound VII-10 [3-(2,5-dimethylphenyl)-8-methoxy-3-(prop-2-yn-1-ylthio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic method as in Example 78, except that:

[0713] The halogenated hydrocarbon raw material in step (a) was 3-bromopropynyl;

[0714] The obtained compound VII-10 (white solid, 0.19 g, 51.45%). The final test results are as follows:

[0715] 1H NMR (400 MHz, CDC13) δ 7.78 (s, 1H), 7.10 - 7.01 (m, 3H), 3.46 (dd, J = 16.1, 2.7 Hz, 1H), 3.36 (s, 3H), 3.33 - 3.24 (m, 2H), 2.56 - 2.47 (m, 1H), 2.38 (s, 3H), 2.27 (t, J = 2.7 Hz, 1H), 2.2 - 2.16 (m, 1H), 2.15 (s, 3H), 2.13 - 1.99 (m, 3H), 1.94 - 1.86 (m, 1H), 1.57 - 1.37 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C 21 H 25 NO3S:371.1550; found:371.1561.

[0716] Example 80

[0717] Compound VII-11 [3-((cyclopropylmethyl)thio)-3-(2,5-dimethylphenyl)-8- methoxy-1-azaspiro[4.5]decane-2,4-dione]

[0718] The preparation of compound VII-11 [3-((cyclopropylmethyl)thio)-3-(2,5- dimethylphenyl)-8-methoxy-1-azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic procedure to Example 78, except that:

[0719] The halogenated hydrocarbon starting material in step (a) was bromomethylcyclopropane;

[0720] The resulting compound VII-11 (white solid, 0.28 g, 77.83 %). The final test results were as follows:

[0721] 1 H NMR (400 MHz, CDC13) δ 7.78 (s, 1H), 7.10 - 7.01 (m, 3H), 3.46 (dd, J = 16.1, 2.7 Hz, 1H), 3.36 (s, 3H), 3.33 - 3.24 (m, 2H), 2.56 - 2.47 (m, 1H), 2.38 (s, 3H), 2.27 (t, J = 2.7 Hz, 1H), 2.2 - 2.16 (m, 1H), 2.15 (s, 3H), 2.13 - 1.99 (m, 3H), 1.94 - 1.86 (m, 1H), 1.57 - 1.37 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C22 H 29 NO3S: 387.1863; found: 387.1872.

[0722] Example 81

[0723] Compound VII-12 [3-(2,5-dimethylphenyl)-8-methoxy-3-((methyl-d3)thio)-1- azaspiro[4.5]decane-2,4-dione]

[0724] Compound VII-12 [3-(2,5-dimethylphenyl)-8-methoxy-3-((methyl-d3)thio)-1- azaspiro[4.5]decane-2,4-dione] was prepared using a similar synthetic procedure to Example 78, except that:

[0725] The starting material in step (a) was p-toluenesulfonic acid tri-deuteromethyl ester;

[0726] The resulting compound VII-12 (white solid, 0.23 g, 66.10 %). The final test results are as follows:

[0727] 1 H NMR (400 MHz, CDC13) δ 7.75 (s, 1H), 7.10 - 7.01 (m, 2H), 6.97 (s, 1H), 3.35 (s, 2H), 3.33 - 3.24 (m, 1H), 2.57 - 2.46 (m, 1H), 2.37 (s, 3H), 2.21 - 2.13 (m, 1H), 2.12 (s, 3H), 2.11 - 2.01 (m, 3H), 1.97 - 1.87 (m, 1H), 1.57 - 1.35 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C 19 H 22 D3NO3S: 350.1738; found: 350.1742.

[0728] Example 82

[0729] Compound VII-13 [3-(2,5-dimethylphenyl)-8-methoxy-3-((3,4,4-trifluorobut-3-en-1- yl)thio)-1-azaspiro[4.5]decane-2,4-dione]

[0730] The preparation of compound VII-13 [3-(2,5-dimethylphenyl)-8-methoxy-3-((3,4,4- trifluorobut-3-en-1-yl)thio)-1-azaspiro[4.5]decane-2,4-dione] was carried out using a similar synthetic method as in Example 78, except that:

[0731] The halogenated hydrocarbon raw material in step (a) was 4-bromo-1,1,2-trifluoro-1- butene;

[0732] The obtained compound VII-13 (white solid, 0.27 g, 61.53 %). The final test results are as follows:

[0733] 1 H NMR (400 MHz, CDC13) δ 7.73 (s, 1H), 7.09 - 7.01, (m, 3H), 3.35 (s, 3H), 3.33 - 3.25 (m, 1H), 2.93 - 2.84 (m, 1H), 2.78 - 2.81 (m, 1H), 2.62 - 2.43 (m, 3H), 2.37 (s, 3H), 2.20 - 2.15 (m, 1H), 2.14 (s, 3H), 2.13 - 1.99 (m, 3H), 1.96 - 1.85 (m, 1H), 1.59 - 1.37 (m, 2H). HRMS (EI-TOF) m / z: [M] + calcd for C 22 H 26 F3NO3S: 441.1585; found: 441.1583.

[0734] Test Example: Insecticidal activity test of the present application

[0735] All bioassays were performed on standard laboratory-reared organisms. All experiments were run with spirotetramat or spirodiclofen as positive controls. Experiments were conducted at 25 ± 1 °C, and all compounds were dissolved in N,N-dimethylformamide. The stock solutions were diluted with distilled water containing 0.1 mg / L Triton X-100 to obtain a test concentration of 100.0 mg / L. Mortality was assessed on a scale from 0% (no activity) to 100% (complete kill). The number of surviving and dead insects was recorded after each experiment. Each experiment was repeated three times, and the results were averaged. Corrected mortality was calculated according to the formula:

[0736] The mortality data obtained were subjected to probability analysis using IBM SPSS Statistics 25 software.

[0737] Test Example 1 Insecticidal activity against 2-day-old Plutella xylostella

[0738] The diamondback moth is a common crop pest belonging to the order Lepidoptera. As an example, the diamondback moth (Plutella xylostella) was tested using the leaf-dipping method.

[0739] Procedure: The sample was accurately weighed, added to N,N-dimethylformamide to prepare a 10 g / L stock solution, and diluted to 100 mg / L with 0.2 mL / L Triton X-100 aqueous solution. A 1 cm leaf disc was immersed in the solution for 10 s, removed and air-dried, and placed in a culture dish. Four leaf discs were placed in each dish. Two or three instar diamondback moth larvae were introduced into each dish, 10 per dish, and the culture dish was placed on a moistened filter paper to maintain humidity. The dishes were placed in a light incubator. Five days after application, the insects were determined to be dead if they were immobile or unable to move in coordination upon light touch with a brush, and the number of dead insects was recorded. The mortality rate (%) = (number of live insects in the control - number of live insects in the treatment) / number of live insects in the control x 100%. The results are shown in the table below.

[0740] Test Example 2: Insecticidal activity against Tetranychus cinnabarinus

[0741] The Tetranychus cinnabarinus is a common crop pest belonging to the family Tetranychidae in the order Acarina. As an example, the Tetranychus cinnabarinus was tested using the immersion method.

[0742] Procedure: The sample was accurately weighed, added to N,N-dimethylformamide to prepare a 10 g / L stock solution, and diluted to 100 mg / L with 0.2 mL / L Triton X-100 aqueous solution. First, a single leaf of a cowpea with more than 20 mites was immersed in the solution for 10 s, removed and air-dried, and placed in a culture dish containing water for observation. The culture dish was placed in an observation room for incubation. Three replicates were performed. Five days after application, the insects were determined to be dead if they were immobile or unable to move in coordination upon light touch with a brush, and the number of dead insects was recorded. The mortality rate (%) = (number of live mites in the control - number of live mites in the treatment) / number of live mites in the control x 100%. The results are shown in the table below.

[0743] Test Example 3: Insecticidal activity against 2-day-old alfalfa aphids

[0744] The aphid is a common crop pest belonging to the order Homoptera and having a piercing-sucking mouthpart. As an example, the alfalfa aphid (Acyrthosiphon pisum) was tested using the immersion method.

[0745] Operation process: accurately weigh the sample, add N, N-dimethylformamide to prepare 10 g / L of mother liquor, dilute to 100 mg / L with 0.2 mL / L Triton X-100 aqueous solution. First choose 2-day-old aphids more than 15 on a single leaf of Vicia faba, immerse in pesticide solution for 10 s, take out and dry, place on the observation room culture rack, cover with a plastic cup with holes, repeat 3 times for each treatment, and place in the observation room for culture. Five days after application, gently touch with a brush, and determine death if the insect does not move or cannot move coordinately. Record the number of deaths. Calculate the mortality rate (%): mortality rate (%) = (number of live insects in control-number of live insects in treatment) / number of live insects in control x 100%. The results can be seen in the table below.

[0746] LC of test example 4 on pests mites 50 Data test

[0747] Select some compounds with better activity for biological determination at appropriate concentration gradient. The mortality data obtained are analyzed by IBM SPSS Statistics 25 software, and the LC 50 values are calculated.

[0748] The list of compounds of formula and their insecticidal and miticidal activity [mortality rate at 100 ppm concentration on Diamondback moth, Tetranychus cinnabarinus and Alfalfa Aphid] results are shown in Table 1 below; the LC 50 data results of compounds of formula on Diamondback moth, Tetranychus cinnabarinus and Alfalfa Aphid are shown in Table 2 below.

[0749] Table 1 Biological activity of compounds on Alfalfa Aphid, Tetranychus cinnabarinus, Diamondback moth

[0750] Table 2 LC data of compounds on Tetranychus cinnabarinus, Alfalfa Aphid, Diamondback moth 50

[0751] ​From the above experimental results, it can be seen that the compound of the present application exhibits significantly more excellent insecticidal and miticidal activity compared to the quinone acid precursor compounds (VII-1, VII-2, VII-3 and VII-4) without S atom; and the compound of the present application also has more excellent or equivalent insecticidal and miticidal activity compared to the commercial agents Spiromesifen and Spirodiclofen. Therefore, the introduction of the sulfur-containing group at the 3-position of the spiro quinone acid active intermediate can improve the insecticidal and miticidal activity of the compound, which embodies the rationality and innovation of the molecular design, and the application value of the 3-sulfur-substituted quinone acid derivative in the field of pest control.

[0752] All documents referred to in this application are incorporated herein by reference as if each individual document were incorporated by reference. In addition, it should be understood that various modifications and / or alterations can be made to the application herein disclosed by those skilled in the art, without departing from the scope of the application as defined in the following claims.

Claims

1. A compound of formula (I), its optical isomer, cis-trans isomer, or a pesticide-acceptable salt thereof, wherein: A is substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of 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 the group consisting of nitrogen, oxygen, and sulfur; wherein, The substitution refers to the independent substitution of one or more H atoms on a group by a group selected from the group consisting of hydrogen, halogen, C, and H+. 1- 8-alkyl, C 1-8 Haloalkyl, C 2-8 alkenyl, C 2-8 Haloalkenyl, C 2-8 alkynyl group, C 2-8 Halogenated alkynyl group, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Alkylthio, C 1-8 Haloalkylthio group, C 1-8 Alkyl sulfoxide group, C 1-8 Alkyl sulfone, nitro, hydroxyl, cyano, amino, C 6-10 aryl or one or more selected from C 1-4 Alkyl, C 1-4 The C-substituents of alkyl halogens, halogens, and cyano groups 6-10 Aryl; n is 0, 1 or 2; E is hydrogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkylthio, C 1-8 haloalkylthio, unsubstituted or halogenated C 1-4 alkyl-COO-unsubstituted or halogenated C 1-4 alkyl-, unsubstituted or halogenated C 1-4 alkyl-COO-unsubstituted or halogenated C 1-4 alkyl, unsubstituted or halogenated C 1-4 alkyl-PO(unsubstituted or halogenated C 1-4 alkyl)2, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted phenyl (C 1-4 )alkyl-, substituted or unsubstituted C 3-8 cycloalkyl(C 1-4 )alkyl-, wherein the substitution means that one or more H on the radical is independently replaced by a radical selected from the group consisting of hydrogen, deuterium, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 alkylthio, C 1-8 haloalkylthio, nitro, hydroxy, cyano, amino, phenyl or phenyl substituted by one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halogen and cyano; X is O, S or N-R, wherein R is selected from the group consisting of: 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 comprising 1-3 heteroatoms selected from the group consisting of O, S and N, substituted or unsubstituted 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from the group consisting of O, S and N, substituted or unsubstituted C 3-6 cycloalkyl(C 1-4 )alkyl-, substituted or unsubstituted 3-6 membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of O, S and N (C 1-4 )alkyl-, substituted or unsubstituted phenyl(C 1-4 )alkyl-, substituted or unsubstituted 5-6 membered heteroaryl comprising 1-3 heteroatoms selected from the group consisting of 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 alkoxySO-, substituted or unsubstituted C 1-8 alkoxySO2-, substituted or unsubstituted C 3-6 cycloalkylCO-, benzoyl; wherein the substitution means that one or more H on the group is independently replaced by a member selected from the group consisting of: hydrogen, halogen, CN, nitro, hydroxy, cyano, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; G and L are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2- 8alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1-8 haloalkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, 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 phenyl (C 1-4 )alkyl-; or G and L, together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein the substitution 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 (=0), =N-OH, =N-OC 1-8 alkyl, =N-OC 1-8 haloalkyl, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, C 1-8 alkoxy, C 1-8 haloalkoxy, -O-C 3-8 cycloalkyl, or two substituents of the same or adjacent ring atoms, together with the ring atom to which they are attached, form a substituted or unsubstituted C 3-8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, and the substitution means that one or more H on the cycloalkyl or heterocycloalkyl group are independently replaced by a group selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy.

2. The compound of claim 1, wherein A is a substituted or unsubstituted C 1-8 alkyl, C 3-8 cycloalkyl, phenyl, benzyl, pyridyl, pyrazolyl, thienyl, furanyl or thiazolyl, biphenyl; preferably, said substituents mean that one or more H atoms of the radical are independently replaced by a substituent selected from the group consisting of halogen, nitro, hydroxy, cyano, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 haloalkylthio, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl.

3. The compound of claim 1, wherein E is cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl, C 2-8 haloalkynyl, unsubstituted or halogenated C 1-4 alkyl-COO-unsubstituted or halogenated C 1-4 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, substituted or unsubstituted phenyl (C 1- 4) alkyl- or substituted or unsubstituted C 3-8 cycloalkyl (C 1-4 )alkyl-, wherein the substitution means that one or more H on the radical is independently replaced by a member selected from the group consisting of deuterium, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy and C 1-8 haloalkoxy.

4. The compound of claim 1, wherein X is O, S or N-R, wherein R is selected from the group consisting of: 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 the group consisting of O, S and N, C 3-6 cycloalkyl(C 1-4 )alkyl-, 3-6 membered heterocycloalkyl(C 1-4 )alkyl- containing 1-3 heteroatoms selected from the group consisting of O, S and N, benzyl, C 1-4 alkoxy(C 1-4 )alkyl, C 1-8 alkylCO-, C 1-8 alkoxyCO-, C 1-8 alkylSO-, C 1-8 alkylSO2-, C 1-8 alkoxySO-, C 1-8 alkoxySO2-, C 3-6 cycloalkylCO-, benzoyl.

5. The compound of claim 1, wherein G and L are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, substituted or unsubstituted benzyl; or G and L, together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the substitution 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 (=0), =N-OH, =N-OC 1-8 alkyl, =N-OC 1-8 haloalkyl, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, -O-C 3-6 cycloalkyl; or two substituents of the same or adjacent ring atoms, together with the ring atom to which they are attached, form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the substitution means that one or more H on the cycloalkyl or heterocycloalkyl are independently replaced by a group selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy.

6. The compound of claim 1, wherein, wherein A is selected from: and / or selected from the group consisting of: and / or X is selected from the group consisting of: and / or selected from the group consisting of:

7. The compound of claim 1, wherein A is substituted phenyl, said substitution means that one or more H on the group is independently replaced with a member selected from the group consisting of: halo, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy.

8. The compound of claim 1, wherein E is C 1-8 alkyl, C 1-8 haloalkyl, deuterated C 1-8 alkyl, C 2-8 alkenyl, C 2-8 haloalkenyl, C 2-8 alkynyl or CN.

9. The compound of claim 1, wherein The compound has a structure shown in general formula (II): wherein n, A, E, X are as defined in claim 1, wherein Y is none, -CH2, -CH-O-C 1-3 alkyl, O, S, -CF2, N-O-C 1-3 alkyl, -C(C 1-3 alkyl)2, NC 1-3 alkyl, -CH-OH, C=O, -C=N-O-C 1-3 alkyl and -C=N-OH.

10. The compound of claim 1, wherein The compound has a structure shown in general formula (IV): wherein n, A, E, X are as defined in claim 1, wherein Z is an oxygen or sulfur atom, and m is selected from 0, 1, 2 or 3.

11. The compound of claim 1, wherein The compound is selected from the group consisting of:

12. An agricultural composition comprising: (a) from 0.001% to 99.99% by weight of a compound, optical isomer, geometric isomer, or a pesticidally acceptable salt thereof, or a combination thereof, according to any one of claims 1 to 11; and (b) a pesticidally acceptable carrier and / or excipient.

13. Use of a compound, optical isomer, geometric isomer, or a pesticidally acceptable salt thereof, according to any one of claims 1 to 11 or an agricultural composition according to claim 12 for controlling the agricultural plant diseases caused by insects and / or mites, or for the preparation of an insecticidal, miticidal, or insect- and / or mite- controlling agent composition for controlling the agricultural plant diseases.

14. A method of insecticidal, miticidal, and / or insect- and / or mite- controlling, which comprises applying a compound, optical isomer, geometric isomer, or a pesticidally acceptable salt thereof, according to any one of claims 1 to 11 or an agricultural composition according to claim 12 to a plant, to the soil or environment in the vicinity of the plant, which is infested or is likely to be infested by insects and / or mites.

15. A process for the preparation of a compound according to claim 1 selected from the group consisting of: Method 1 : Step (i) is a substitution reaction between the compound of formula P and the compound of formula Q in the presence of a base to give the compound of formula (I); wherein n = 0; and A, E, G, L are as defined in claim 1; wherein Compound Q can be selected from one of the following Q-1 to Q-13 as an electrophile donor of E-containing group: or Method 2: On the basis of step (i) of Method 1, further comprising step (ii): the compound obtained in step 1 is subjected to oxidation reaction in the presence of an oxidizing agent to obtain the compound of formula (I), wherein n = 1 or 2; and A, E, G, L are as defined in claim 1.

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