Pyrido[1,2-a] pyrimidine mesoion compound containing 1,2,4-oxadiazole structure as well as preparation and application of the same

Abstract

To provide a pyrido[1,2-a]pyrimidine mesoionic compound having a 1,2,4-oxadiazole structure, a stereoisomer thereof, a salt thereof, or a solvate thereof, which features a simple structure and a preparation process and a low production cost.SOLUTION: Specifically, for example, 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-one salt (Z1) is exemplified.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention belongs to the fields of chemical industry and pesticides, and particularly relates to pyrido[1,2-a]pyrimidine mesoionic compounds containing 1,2,4-oxadiazole units, a method for producing the same, and the use of pyrido[1,2-a]pyrimidine mesoionic compounds containing 1,2,4-oxadiazole units as agents for controlling pests such as Nilaparvata lugens, aphids, Plutella xylostella, Spodoptera litura, leafhoppers, rice stem borers, striped rice borers, rice gall midges, and corn earworms.

Background Art

[0002] Hemiptera (true bugs) such as Nilaparvata lugens and aphids, and Lepidoptera (moths and butterflies) such as Plutella xylostella, Spodoptera litura, and Chilo suppressalis are some of the important pests in agriculture. Nilaparvata lugens is one of the major pests in rice cultivation. Its occurrence is explosive, with latency, flight ability, and destructiveness. It not only damages the rice itself but also transmits viral diseases such as rice stripe disease and southern rice black-streaked dwarf disease, posing a serious threat to the stable production of rice cultivation and food security. The annual damaged rice cultivation area reaches 10 to 20 million hectares, accounting for about 50% of the total cultivated area. In general damage cases, the yield decreases by 10 to 20%, but in severe cases, it can decrease by 40 to 60%, and even lead to complete crop failure.

[0003] Aphids are one of the most destructive pests in almost all cultivated crops. Due to their very short life cycle, if there is no lethality, one female aphid can potentially produce billions of offspring in a year. Aphids not only weaken plants by sucking sap but also cause leaf deformation and are vectors of many plant viruses. Plutella xylostella is one of the most destructive pests globally in cruciferous crops and has characteristics such as high fecundity, rapid generation turnover, and long growth period.

[0004] The fall armyworm, Spodoptera frugiperda, is a pest native to the tropical and subtropical regions of the Americas. It has a high mobility as an adult, and this important agricultural pest has rapidly spread from the Americas to over 100 countries. The fall armyworm damages more than 270 host crops and has high reproductive and dispersal capabilities.

[0005] The striped stem borer, Chilo suppressalis, is widely distributed in rice-growing areas throughout China and is an important and difficult-to-control rice boring pest. During large outbreaks, rice yields can decrease by 30 - 50%, and it is regarded as one of the major biological disasters.

[0006] Currently, many of the pesticides used for controlling agricultural pests such as aphids, planthoppers, diamondback moths, fall armyworms, and striped stem borers are conventional pesticides. Due to problems such as high toxicity, low biodegradability, strong resistance, and low safety to non-target organisms, regulations and bans on their use are advancing. Therefore, the development of insecticides with novel structures, high efficiency, low risk, and unique modes of action is urgently required for the sustainable development of agriculture and the realization of food security.

[0007] In 2016, the ionic insecticide triflumezopyrim registered by Corteva (formerly DuPont) in China has high insecticidal activity against planthoppers, no cross-resistance to existing pesticides, and low toxicity to non-target organisms. Another ionic insecticide, dichloromethothiaz, developed by DuPont, shows high activity not only against planthoppers and cotton aphids of the Hemiptera order but also against diamondback moths and fall armyworms of the Lepidoptera order, expanding the insecticidal spectrum of mesoionic compounds. Due to these characteristics, ionic insecticides have become a new focus of global research and development.

[0008] Holyoke C.W. et al. of DuPont first disclosed the production method of pyrido[1,2-a]pyrimidine mesoionic compounds and their application as insecticides in patent WO2009099929A1 in 2009, showing that this type of compound has excellent insecticidal activity against diamondback moths, peach aphids, cotton aphids, and planthoppers.

[0009] Furthermore, in 2011, Holyoke C.W. et al. of DuPont also published in Patent WO2011017342A2 a method for producing new mesoionic compounds and their application as insecticides. This group of compounds has excellent insecticidal activity, and some compounds showed a 100% lethality rate against Plutella xylostella, Spodoptera litura, and Aphis gossypii at a concentration of 10 mg / L. Among them, dichloromezothiaz has very high activity against aphids and Plutella xylostella and has been developed as a commercial agent.

[0010] Structure-activity relationship (SAR) studies have shown that when the 1-position of the pyrido[1,2-a]pyrimidine ring is substituted with a 2-chlorothiazol-5-methyl group and the 9-position is substituted with a methyl group, the activity against Plutella xylostella and Spodoptera litura is optimal, which is a phenomenon called the "methyl magic effect".

[0011] In 2012, Holyoke C.W. et al. of Corteva (formerly DuPont) published in Patent WO2012106495A1 pyrido[1,2-a]pyrimidine mesoionic compounds containing a double aromatic ring. This group of compounds shows excellent insecticidal activity against Lepidoptera, Homoptera, and Thysanoptera insects and has a broad insecticidal spectrum. Specifically, some compounds showed a 100% lethality rate against Plutella xylostella and Spodoptera litura at a concentration of 2 mg / L, and at a concentration of 10 mg / L, they also showed a lethality rate of over 80% against Myzus persicae and Nephotettix cincticeps.

[0012] In 2016, Hasegawa S. et al. of Nippon Kayaku Co., Ltd. disclosed mesoionic compounds containing a cyanoethyl group at the 1-position of the pyrido[1,2-a]pyrimidine ring in Patent WO2016171053A1. These compounds with a cyanoethyl group showed good to excellent insecticidal activity against Aphis gossypii and Nilaparvata lugens. Some compounds showed 100% lethality against Aphis gossypii at a concentration of 0.1 mg / L, and even maintained a lethality rate of over 70% against Nilaparvata lugens at a concentration of 0.05 mg / L. According to the structure-activity relationship (SAR) study, the highest insecticidal activity was observed when the 1-position of the pyrido[1,2-a]pyrimidine ring was a cyanoethyl group and the 6, 7, 8, and 9 positions were unsubstituted. Also, these compounds are similar to trifluorobenzylpyrimidine and dicloromezotiaz, and it was shown that the insecticidal activity is improved when a phenyl group is retained at the 3-position of the pyrido[1,2-a]pyrimidine ring and further derivatization is carried out at the 3-position of the phenyl group.

[0013] In 2021, Holmes, M., Holyoke, C. W., Jr., Kar, M., Lahm, G. P. et al. of FMC disclosed mesoionic compounds of pyrido[1,2-a]pyrimidines containing an alkyne structural unit in Patent WO2021151034A1. Many of this group of compounds showed a lethality rate of 80% - 100% against Plutella xylostella and Spodoptera litura at a concentration of 0.4 mg / L. Also, at a concentration of 50 mg / L, they showed a lethality rate of 70% - 100% against Laodelphax striatellus, Empoasca onukii, Myzus persicae, Aphis gossypii, and Frankliniella occidentalis. In the SAR study, it was shown that when the 9-position of the pyrido[1,2-a]pyrimidine ring was substituted with a methyl group, the insecticidal activity against Plutella xylostella and Spodoptera litura was the highest.

[0014] In the same year, the research team published a series of mesoionic compounds of pyrido[1,2-a]pyrimidines containing an isoxadione structural unit in Patent CN113651811A. This group of compounds showed good to excellent insecticidal activity against the white-backed planthopper, and some compounds showed a 100% lethality rate against the white-backed planthopper at a concentration of 10 mg / L. In addition, the compound "isoxadione pyrimidine" named by the National Technical Committee for Pesticide Standardization also showed a 100% lethality rate against the white-backed planthopper even at a concentration of 2 mg / L. According to the SAR study, it was shown that the optimal insecticidal activity was achieved when the 1-position of the pyrido[1,2-a]pyrimidine ring was substituted with a 2-chlorothiazol-5-methyl group, the 6, 7, 8, and 9 positions were unsubstituted, and the 3- and 5-positions of the isoxadione ring were substituted with methyl groups.

[0015] In the same year, the research team published a series of compounds of mesoionic compounds of pyrido[1,2-a]pyrimidines containing an indole structural unit in Patent CN113292557A. This group of compounds showed good insecticidal activity against the white-backed planthopper and the cowpea aphid, and for some compounds, the lethality rates of the white-backed planthopper and the cowpea aphid reached 100% at a concentration of 10 mg / L.

[0016] 1,2,4-oxadiazole compounds belong to five-membered heterocyclic compounds and are known for their broad-spectrum pesticidal biological activities. This type of compound exhibits various excellent biological activities such as insecticidal, bactericidal, and herbicidal activities. For example, the nematicide "Tioxazafen" for seed treatment developed by Bayer (formerly Monsanto) is a representative example of 1,2,4-oxadiazole compounds with characteristics of broad-spectrum, high efficiency, and a novel mode of action, showing high insecticidal and nematicidal activities.

[0017] In 2018, Xu Liangzhong et al. from Qingdao University of Science and Technology published 1,2,4-oxadiazole compounds containing a biphenyl ether in Patent CN108299409A. This compound reached a 100% lethality rate against the beet armyworm at a concentration of 0.5 mg / L and exhibited better performance than the control agent, chlorantraniliprole.

[0018] Also in 2018, Wang Minghui et al. from Qingdao University of Science and Technology disclosed a series of compounds of 1,2,4-oxadiazole compounds containing a pyridine structure in Patent CN109336879A. This group of compounds showed good to excellent insecticidal activity against Plutella xylostella, Tetranychus cinnabarinus, and Tetranychus urticae. For some compounds, the lethality rate of Plutella xylostella reached 80% and that of Tetranychus urticae reached 100% at a concentration of 10 mg / L. These performances showed results superior to those of the control agent Tioxazafen.

[0019] In 2020, Dai Hong et al. from Nantong University disclosed five 1,2,4-oxadiazole compounds containing a 1,2,3-triazole benzyloxy pyrazole structure in Patent CN111560015A. This compound showed good insecticidal activity against Chilo suppressalis, and the lethality rate reached 100% at a concentration of 500 mg / L.

[0020] Trifluorophenylpyrimidine has attracted attention as an ionic insecticide that effectively controls pests such as resistant planthoppers and leafhoppers. This research team develops a new ionic insecticide, "isoxazolopyrimidine," based on trifluorophenylpyrimidine. This compound shows high efficacy against planthoppers and overcomes the toxicity drawback of trifluorophenylpyrimidine to honeybees. However, both of them have limited efficacy against Lepidoptera pests. On the other hand, another ionic insecticide, dicloromezotiaz, developed by Corteva (formerly DuPont), shows high control efficacy not only against planthoppers but also against Lepidoptera pests such as diamondback moths and fall armyworms. This progress is regarded as an important evolution in the development of insecticides capable of controlling both Hemiptera and Lepidoptera pests from Hemiptera pests. As a result, the development of ionic insecticides with low toxicity, high efficiency, and a unique mode of action that can control Hemiptera and Lepidoptera pests is promoted, and the broad possibilities of mesoionic compounds in controlling agricultural pests are revealed. From patent analysis, the following conclusions are obtained: (1) When the ionic mother nucleus is a pyrido[1,2-a]pyrimidine ring, the insecticidal activity of the compound is the best. (2) When having a common active group in neonicotinoid insecticides at the 1-position of the pyrido[1,2-a]pyrimidine ring, the insecticidal activity is high. (3) When the 1-position is a 2-chlorothiazol-5-methyl group and the 9-position is a methyl group, the insecticidal activity against Lepidoptera pests is high. (4) When the 3-position is a benzene ring or a five-membered aromatic ring, the insecticidal activity is strong. (5) When the benzene ring at the 3-position is modified at the meta-position, the insecticidal activity of the compound is the maximum.

[0021] The inventor develops an insecticide that controls Hemiptera and Lepidoptera pests while maintaining the important active structure of ionic insecticides. A five-membered ring structure with high biological activity, 1,2,4-oxadiazole, is introduced at the meta-position of the benzene ring at the 3-position of the pyrido[1,2-a]pyrimidine ring, and a series of pyrido[1,2-a]pyrimidine mesoionic compounds containing 1,2,4-oxadiazole structures are designed and synthesized.

[0022] The test results show that these compounds have excellent insecticidal activity and a broad control spectrum. The present invention provides the possibility of a new pesticide capable of efficiently controlling Hemiptera and Lepidoptera pests.

Prior Art Documents

Patent Documents

[0023]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Summary of the Invention

Problems to be Solved by the Invention

[0024] One object of the present invention is to provide pyridine-1,2-a-pyrimidine mesoionic compounds containing a 1,2,4-oxadiazole structure and a method for producing the same.

[0025] Another object of the present invention is to provide a composition containing the above compound or a salt thereof, or a solvate thereof.

[0026] Another object of the present invention is to provide the use of the above compound or its salt, or its solvate, or the above composition.

[0027] Another object of the present invention is to provide a method for controlling agricultural pests by using the above compound or its salt, or its solvate, or the above composition.

Means for Solving the Problems

[0028] In order to achieve the above object, the present invention adopts the following technical means.

[0029] The pyridine-1,2-a-pyrimidine mesoionic compound containing a 1,2,4-oxadiazole structure of the present invention has the following general structural formula (I): JPEG2025094925000001.jpg86135R1 independently selects any one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.

[0030] R2 independently selects any one or more of hydrogen, deuterium, halogen, cyano group, nitro group, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, and optionally substituted or unsubstituted aryl.

[0031] R3 and R4 independently select any one or more of hydrogen, deuterium, halogen, nitro group, hydroxy group, amino group, thiol group, cyano group, and optionally substituted or unsubstituted alkyl.

[0032] R5 independently selects any one or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, and optionally substituted or unsubstituted aryl.

[0033] Preferably, each R1 independently selects one or more of hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C5-C6 heteroaryl.

[0034] Each R2 independently selects one or more of hydrogen, deuterium, halogen, cyano group, nitro group, C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C5-C6 heteroaryl.

[0035] Each of R3 and R4 independently selects one or more of hydrogen, deuterium, halogen, nitro group, hydroxy group, amino group, thiol group, cyano group, and C1-C6 alkyl.

[0036] Each R5 independently selects one or more of C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C5-C6 heteroaryl.

[0037] More preferably, each R1 independently selects one or more of hydrogen, deuterium, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, -CH2CH2CN, -CHCNCH3, -CH2CH2CH2CN, -CH2CHCNCH3, -CHCNCH2CH3, -CH2CH2F, -CHFCH3, -CH2CH2CH2F, -CH2CHFCH3, -CHFCH2CH3, -CH2CH2Cl, -CHClCH3, -CH2CH2CH2Cl, -CH2CHClCH3, -CHClCH2CH3, -CH2CH2Br, -CHBrCH3, -CH2CH2CH2Br, -CH2CHBrCH3, -CHBrCH2CH3, JPEG2025094925000002.jpg68170, or any combination thereof.

[0038] R5 is independently methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tetrabutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2Cl, -CH2CH2Br, -CH2CH2F, Select any one or more of JPEG2025094925000003.jpg55170.

[0039] Preferred compounds are the following compounds Z1-Z25. JPEG2025094925000004.jpg150170

[0040] The production methods of these compounds include the following. JPEG2025094925000005.jpg31170 More preferably, the following are further included. JPEG2025094925000006.jpg37170 Even more preferably, the following are included. JPEG2025094925000007.jpg100170

[0041] The present invention provides the above compounds or their salts or solvates, and compositions containing auxiliaries or fungicides, insecticides, herbicides that can be used in agriculture. Preferably, the formulation form of the composition is selected from emulsion (EC), dust (DP), wettable powder (WP), granule (GR), solution (AS), suspension concentrate (SC), ultra-low volume spray (ULV), soluble powder (SP), microcapsule (MC), fumigant (FU), aqueous emulsion (EW), water dispersible granule (WG).

[0042] Also, the above compounds or their salts or solvates, or the composition can be used for controlling agricultural pests. The agricultural pests are hemiptera pests and lepidoptera pests, preferably targeting rice planthoppers, aphids, diamondback moths, common cutworms, rice stem borers, cabbage armyworms, yellow stem borers, rice leaf beetles, corn borers, etc.

[0043] Furthermore, the present invention provides a method for controlling agricultural pests. The method is characterized in that the above-mentioned compound or its stereoisomer, or its salt or solvate, or the composition is allowed to act on the pests or their living environment. Preferably, the agricultural pests are hemiptera pests and lepidoptera pests, and more preferably, the method targets pests such as Nilaparvata lugens, aphids, Plutella xylostella, Spodoptera exigua, Chilo suppressalis, Ostrinia furnacalis, and Helicoverpa armigera.

Modes for Carrying Out the Invention

[0044] <Definition of Terms> As used herein, the term "alkyl" means a branched or straight-chain saturated hydrocarbon group having a specific number of carbon atoms. For example, "C1-C10 alkyl" (or alkylene) is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl. Also, for example, "C1-C6 alkyl" means an alkyl having 1 to 6 carbon atoms. Alkyl may be unsubstituted or substituted, and one or more hydrogen atoms may be substituted with other chemical groups. Examples of alkyl include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), and the like.

[0045] The term "alkenyl" means a straight-chain or branched hydrocarbon structure containing one or more carbon-carbon double bonds at any stable position. For example, "C2-C6 alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.

[0046] As used herein, the term "cycloalkyl" refers to cycloalkyls including monocyclic, bicyclic, and polycyclic structures. "C3-7 cycloalkyl" is intended to include C3, C4, C5, C6 and C7 cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornane group and the like.

[0047] The term "carbocyclic" or "carbocyclic residue" refers to stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered monocyclic or bicyclic, or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered or 13-membered bicyclic or tricyclic rings. They may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of these carbocycles include cyclopropyl, cyclobutyl, cyclobutenyl group, cyclopentyl, pentenyl group, cyclohexyl, cyclohexenyl group, cycloheptyl, cycloheptenyl group, adamantane group, cyclooctyl, cyclooctenyl group, cyclooctadiene, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl group, phenyl group, naphthyl group, indanyl group, adamantane group, anthracene group and tetralin group (decalin).

[0048] As described above, bridge rings are also included in the definition of carbocyclic rings (e.g., [2.2.2]bicyclooctane). Unless otherwise specified, preferred carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. The term "carbocyclic ring" is intended to include "aryl". When one or more carbon atoms connect two non-adjacent carbon atoms, a bridge ring is formed. Preferred bridges consist of one or two carbon atoms. A bridge always changes a monocyclic ring into a bicyclic ring. When rings are connected by a bridge, the substituents may be present on the bridge.

[0049] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group containing 6 to 12 carbon atoms (e.g., phenyl group and naphthyl group), and each group is substitutable.

[0050] The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine and iodine.

[0051] The term "heteroaryl" refers to substituted and unsubstituted aromatic monocyclic groups of 5 or 6 members, bicyclic groups of 9 or 10 members, or tricyclic groups of 11 to 14 members, with at least one heteroatom (O, S, or N) contained in at least one of the rings. The ring containing this heteroatom preferably contains heteroatoms selected from 1, 2, or 3 O, S, and N. Each ring of the heteroaryl containing a heteroatom can contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms. However, the total number of heteroatoms in each ring is 4 or less, and each ring has at least one carbon atom. The fused rings constituting the bicyclic and tricyclic groups contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Nitrogen and sulfur atoms may optionally be oxidized or the nitrogen atom may be quaternized. The bicyclic or tricyclic heteroaryl must contain at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. Heteroaryl can be bonded to any available nitrogen or carbon atom of any ring. When the valence allows, when the other ring is a cycloalkyl or heterocycle, it may be substituted with =O (oxygen).

[0052] Examples Hereinafter, the present invention will be described in more detail through examples. However, the methods described in the examples of the present invention are merely for explaining the present invention and do not limit the present invention. All simple improvements based on the concept of the present invention shall be included in the claims of the present invention. Note that all raw materials and solvents used in the examples were commercially available reagents of corresponding purity.

Examples

[0053] Production of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-one salt (Z1)

[0054] (1) Preparation of (Z)-N'-hydroxy-3-iodoimidazole: 3-Iodobenzonitrile (10.0 g, 43.7 mmol), hydroxylamine hydrochloride (3.6 g, 52.4 mmol), sodium hydrogen carbonate (5.5 g, 65.5 mmol), absolute ethanol (100 mL) and water (20 mL) were mixed in a 250 mL three-necked flask, heated and reacted under reflux conditions for 6 - 8 hours. After the reaction was completed, the solvent was concentrated, 100 mL of water was added, and a large amount of white solid precipitated. This was suction filtered and dried, and as a result, a white solid (9.8 g) was obtained, with a yield of 85.7%.

[0055] (2) Preparation of 3-(3-iodophenyl)-5-methyl-1,2,4-oxadiazole:

[0056] (Z)-N'-hydroxy-3-iodoimidazole (2.0 g, 7.6 mmol) and pyridine (30 mL) were added to a 100 mL three-necked round-bottom flask, and acetyl chloride (1.2 g, 15.3 mmol) was added dropwise while stirring at room temperature. Then, the temperature was raised to 100 °C and the reaction was carried out for 8 - 10 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed, and it was mixed with silica gel and separated by column chromatography. As a result, a white solid (1.6 g) was obtained, with a yield of 73.3%.

[0057] (3) Preparation of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonate: 3-(3-Iodophenyl)-5-methyl-1,2,4-oxadiazole (1.6 g, 5.6 mmol), pyridine-2-carboxylic acid (137.7 mg, 1.1 mmol), copper(I) iodide (106.5 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) were added to a 200 mL Schlenk flask. Under a nitrogen atmosphere, malonate (1.8 g, 11.2 mmol) was added, followed by 50 mL of dry 1,4-dioxane as the solvent. After all the materials were added, the reaction system was heated to 90 °C and reacted for 8 - 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, and 100 mL of saturated ammonium chloride aqueous solution was added to stop the reaction. It was extracted with ethyl acetate (50 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography. As a result, a colorless oil (1.2 g) was obtained, and the yield was 67.4%.

[0058] (4) Preparation of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.2 g, 3.8 mmol), 50 mL of absolute ethanol, and 50 mL of aqueous sodium hydroxide solution (0.4 g, 9.4 mmol) were added to a 250 mL round-bottom flask and stirred at room temperature. After the hydrolysis was completed, the solvent was concentrated, and 50 mL of water was added to the residue. It was extracted once with ethyl acetate (50 mL) to remove impurities, and the aqueous phase was recovered. The pH was adjusted to acidic with 6 N hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was recovered to obtain 0.8 g of a colorless oil. The yield was 80.9%.

[0059] (5) Preparation of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.8 mmol), 20 mL of methylene dichloride, and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask and mixed. While stirring at room temperature, oxalyl chloride (0.4 g, 3.1 mmol) is added dropwise. After reacting at room temperature for 2 to 4 hours, the solvent is removed under reduced pressure, and 20 mL of methylene dichloride is added and stored.

[0060] (6) Preparation of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine: 2-Amino-3-methylpyridine (10.0 g, 92.5 mmol), 2-chloro-5-chloromethylthiazole (15.5 g, 92.5 mmol), N,N-diisopropylethylamine (14.3 g, 111.0 mmol), potassium iodide (1.5 g, 9.3 mmol), and 150 mL of xylene are added to a 500 mL three-necked flask and mixed, and reacted at 78 °C for 6 to 10 hours. After completion of the reaction, the solvent in the mixture is removed under reduced pressure, mixed with silica gel, and separated by column chromatography to obtain 10.8 g of a pale yellow solid. The yield is 48.72%.

[0061] (7) Preparation of 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z1): A solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (160.2 mg, 0.7 mmol) in 10 mL of methylene chloride was added to a methylene chloride solution of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride, and 3 drops of triethylamine were added. The reaction was carried out at room temperature for 20 minutes. After the reaction was completed, 2 mL of anhydrous methanol was added to stop the reaction. The mixture was mixed with silica gel and separated by column chromatography to obtain 125.0 mg of a yellow solid. The yield was 40.1%.

Example

[0062] Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z2)

[0063] (1)-(5) The same procedures as in steps (1)-(5) of Example 1 were used.

[0064] (6) Preparation of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine: 2-Aminopyridine (10.0 g, 106.3 mmol), 2-chloro-5-chloromethylthiazole (17.9 g, 106.3 mmol), N,N-diisopropylethylamine (16.5 g, 127.5 mmol), potassium iodide (1.8 g, 10.6 mmol), and 150 mL of xylene were placed in a 500 mL three-necked flask and mixed, and the reaction was carried out at 78 °C for 6-10 hours. After the reaction was completed, the solvent was removed from the mixture under reduced pressure, and the mixture was mixed with silica gel and separated using column chromatography to obtain 13.6 g of a pale yellow solid. The yield was 56.7%.

[0065] (7) Preparation of Z2: A solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (150.9 mg, 0.7 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride, and 3 drops of triethylamine are added. After reacting at room temperature for 20 minutes, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 110.0 mg of a yellow solid. The yield is 36.4%.

Example

[0066] Preparation of 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z3)

[0067] (1)~(5) The same procedures as in steps (1) to (5) of Example 1 are used.

[0068] (6) Preparation of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine: 2-Aminopyridine (10.0 g, 106.3 mmol), sodium hydrogen carbonate (13.4 g, 159.4 mmol), and 100 mL of water are placed in a 250 mL three-necked flask and stirred at 90 °C for 30 minutes. Then, 50 mL of an ethanol solution of 2-chloro-5-chloromethylpyridine (17.2 g, 106.3 mmol) is added. After the addition is complete, the temperature is raised to 100 °C and the reaction is carried out for 4 to 6 hours. After the reaction is completed, it is cooled to room temperature, 100 mL of water is added, and then extracted with ethyl acetate (100 mL × 2). The organic layers are combined, dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain 13.4 g of a yellowish-brown oily substance. The yield is 57.4%.

[0069] (7) Preparation of Z3: A solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (146.9 mg, 0.7 mmol) in 10 mL of methylene chloride was added to a methylene chloride solution of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride, and 3 drops of triethylamine were added. After reacting at room temperature for 20 minutes, 2 mL of anhydrous methanol was added to stop the reaction. It was mixed with silica gel and separated by column chromatography to obtain 98.0 mg of a yellow solid. The yield was 32.9%.

Example

[0070] Production of 1-(2-cyanoethyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z4)

[0071] (1)~(5) The same procedures as in (1) to (5) of Example 1 are used.

[0072] (6) Production of 3-(pyridin-2-ylamino)propionitrile: Di-tert-butyl dicarbonate (24.0 g, 110.0 mmol) and 150 mL of tert-butanol were added to a 25 mL three-necked flask, and 2-aminopyridine (9.4 g, 100.0 mmol) was gradually added while stirring at room temperature. Stirring was continued at room temperature for 5 hours after the addition. After completion of the reaction, the solvent was removed from the mixture under reduced pressure, and it was mixed with silica gel and N-tert-butoxycarbonyl-2-aminopyridine was separated by column chromatography.

[0073] Next, DMF (50 mL) and sodium hydride (5.7 g, 143.1 mmol) are added to a 500 mL three-necked flask, and N-tert-butoxycarbonyl-2-aminopyridine (13.9 g, 71.6 mmol) is gradually added while stirring at room temperature. After the addition, the mixture is stirred at 60 °C for 1 hour, then 3-bromopropionitrile (11.5 g, 85.9 mmol) is added, and stirring is continued at 60 °C for another 1 hour. The reaction is stopped, the mixture is poured into 500 mL of water, and extracted with ethyl acetate (200 mL × 2). The organic layers are combined, washed with saturated brine (200 mL × 2), and dried over anhydrous sodium sulfate. After concentrating the solvent, it is mixed with silica gel and separated by column chromatography to obtain tert-butyl (2-cyanoethyl)-(pyridin-2-yl)aminocarbamate.

[0074] Tert-butyl (2-cyanoethyl)-(pyridin-2-yl)aminocarbamate (10.2 g, 41.3 mmol), 40 mL of methylene dichloride, and trifluoroacetic acid (18.8 g, 165.0 mmol) are added to a 100 mL round-bottom flask, and the mixture is stirred at room temperature for 12 hours. Then, the pH of the reaction system is adjusted to weakly alkaline with saturated sodium bicarbonate solution. The separated organic phase is retained, and the aqueous phase is extracted with methylene dichloride (50 mL × 2). The three organic layers are combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain 5.8 g of 3-(pyridin-2-ylamino)propionitrile. The yield is 39.4%.

[0075] (7) Preparation of Z4: A solution of 3-(pyridin-2-ylamino)propionitrile (98.4 mg, 0.7 mmol) in 10 mL of methylene chloride was added to a methylene chloride solution of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride, and 3 drops of triethylamine were added. After reacting at room temperature for 20 minutes, 2 mL of anhydrous methanol was added to stop the reaction. It was mixed with silica gel and separated by column chromatography to obtain 68.0 mg of a yellow solid. The yield was 27.2%.

Example

[0076] Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z5):

[0077] (1) The same method as in procedure (1) of Example 1 is used.

[0078] (2) Preparation of 3-(3-iodophenyl)-5-ethyl-1,2,4-oxadiazole:

[0079] (Z)-N′-Hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) were added to a 100 mL three-necked round-bottom flask, and propionyl chloride (1.4 g, 15.3 mmol) was added dropwise while stirring at room temperature. The reaction system was heated to 100 °C and reacted for 8 to 10 hours, and after completion of the reaction, it was cooled to room temperature. The solvent was removed, mixed with silica gel and separated by column chromatography to obtain 1.7 g of a white solid. The yield was 74.2%.

[0080] (3) Preparation of diethyl 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonate: 3-(3-Iodophenyl)-5-ethyl-1,2,4-oxadiazole (1.7 g, 5.7 mmol), 2-pyridinecarboxylic acid (139.5 mg, 1.1 mmol), copper(I) iodide (107.9 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) were added to a 200 mL Schlenk flask, and diethyl malonate (1.8 g, 11.3 mmol) was added under a nitrogen atmosphere. Next, dry 1,4-dioxane (50 mL) was added as a solvent, and the reaction system was heated to 90 °C and reacted for 8 - 12 hours. After completion of the reaction, it was cooled to room temperature, and a saturated aqueous ammonium chloride solution (100 mL) was added to stop the reaction. It was extracted with ethyl acetate (50 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain 1.3 g of a colorless oil. The yield was 69.1%.

[0081] (4) Preparation of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.3 g, 3.9 mmol), 50 mL of absolute ethanol, and an aqueous sodium hydroxide solution (0.4 g, 9.8 mmol) were added to a 250 mL round-bottom flask and stirred at room temperature. After completion of hydrolysis, the solvent was concentrated, and 50 mL of water was added to the residue. It was extracted once with ethyl acetate (50 mL) to remove impurities, and the aqueous phase was collected. The pH was adjusted to acidic with 6 N hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain 0.9 g of a colorless oil. The yield was 83.3%.

[0082] (5) Preparation of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-(5-Ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), methylene dichloride (20 mL), and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask and mixed. While stirring at room temperature, oxalyl chloride (0.4 g, 2.9 mmol) is added dropwise, and the reaction is carried out at room temperature for 2 to 4 hours. After completion of the reaction, the solvent is removed under reduced pressure, and methylene dichloride (20 mL) is added and stored.

[0083] (6) The same method as in procedure (6) of Example 2 is used.

[0084] (7) Preparation of Z5: A 10 mL solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (144.2 mg, 0.6 mmol) in methylene dichloride is added to a methylene dichloride solution of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. 3 drops of triethylamine are added, and the reaction is carried out at room temperature for 20 minutes. After completion of the reaction, 2 mL of anhydrous methanol is added to stop the reaction, and it is mixed with silica gel and separated by column chromatography to obtain 109.0 mg of a yellow solid. The yield is 36.6%.

Example

[0085] Preparation of 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z6)

[0086] (1)~(5) The same methods as in procedures (1) to (5) of Example 5 are used.

[0087] (6) The same method as in procedure (6) of Example 3 is used.

[0088] (7) Preparation of Z6: A solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (140.3 mg, 0.6 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction, which is then mixed with silica gel and separated by column chromatography to obtain 85.0 mg of a yellow solid. The yield is 28.9%.

Example

[0089] Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z7)

[0090] (1)-(5) The same method as in steps (1)-(5) of Example 5 is used.

[0091] (6) The same method as in step (6) of Example 1 is used.

[0092] (7) Preparation of Z7: A solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (153.1 mg, 0.6 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction, which is then mixed with silica gel and separated by column chromatography to obtain 115.0 mg of a yellow solid. The yield is 37.5%.

Example

[0093] Production of 1-(2-cyanoethyl)-3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z8)

[0094] (1) to (5) Use the same method as in steps (1) to (5) of Example 5.

[0095] (6) Use the same method as in step (6) of Example 4.

[0096] (7) Production of Z8: A solution of 3-(pyridin-2-ylamino)propionitrile (94.0 mg, 0.6 mmol) in 10 mL of methylene dichloride is added to a methylene dichloride solution of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction, and it is mixed with silica gel and separated by column chromatography to obtain 55.0 mg of a yellow solid. The yield is 22.2%.

Example

[0097] Production of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z9)

[0098] (1) Use the same method as in step (1) of Example 1.

[0099] (2) Production of 3-(3-iodophenyl)-5-isopropyl-1,2,4-oxadiazole:

[0100] (Z)-N'-Hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) are added to a 100 mL three-necked round-bottom flask, and isobutyryl chloride (1.6 g, 15.3 mmol) is added dropwise while stirring at room temperature. The reaction system is heated to 100 °C and reacted for 8 - 10 hours, and after the reaction is completed, it is cooled to room temperature. The solvent is removed, mixed with silica gel and separated by column chromatography to obtain 1.6 g of a white solid. The yield is 66.7%.

[0101] (3) Preparation of diethyl 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonate: 3-(3-Iodophenyl)-5-isopropyl-1,2,4-oxadiazole (1.6 g, 5.1 mmol), 2-pyridinecarboxylic acid (125.4 mg, 1.0 mmol), copper(I) iodide (97.0 mg, 0.5 mmol), and cesium carbonate (4.2 g, 12.7 mmol) are added to a 200 mL Schlenk flask. Under a nitrogen atmosphere, diethyl malonate (1.6 g, 10.2 mmol) and dry 1,4-dioxane (50 mL) are added. After the addition, the reaction system is heated to 90 °C and reacted for 8 - 12 hours. After the reaction is completed, it is cooled to room temperature, and a saturated ammonium chloride aqueous solution (100 mL) is added to stop the reaction. Then, it is extracted with ethyl acetate (50 mL × 3), and the organic layers are combined. Dried over anhydrous sodium sulfate, concentrated, mixed with silica gel and separated by column chromatography to obtain a colorless oil (1.3 g). The yield is 73.7%.

[0102] (4) Preparation of 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.3 g, 3.8 mmol), absolute ethanol (50 mL), and an aqueous sodium hydroxide solution (0.4 g, 9.4 mmol) are added to a 250 mL round-bottom flask and stirred at room temperature. After the hydrolysis is complete, the solvent is concentrated, and water (50 mL) is added to the residue. The impurities are removed by extraction with ethyl acetate (50 mL) once, and the aqueous phase is collected. Then, the pH is adjusted to acidic with 6 N hydrochloric acid, and extraction is performed with ethyl acetate (50 mL × 3). The organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is concentrated to obtain a colorless oil (1.0 g). The yield is 91.8%.

[0103] (5) Preparation of 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), dichloromethane (20 mL), and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask, and oxalyl chloride (0.4 g, 2.8 mmol) is added dropwise while stirring at room temperature. After reacting at room temperature for 2 - 4 hours, the solvent is removed under reduced pressure, and dichloromethane (20 mL) is added and stored.

[0104] (6) The same method as in procedure (6) of Example 2 is used.

[0105] (7) Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-yl-2-ol salt (Z9): A solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (155.5 mg, 0.7 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain a yellow solid (87.0 mg). The yield is 26.3%.

Example

[0106] Example 10: Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z10)

[0107] (1)-(5) The same methods as steps (1)-(5) of Example 9 are used.

[0108] (6) The same method as step (6) of Example 1 is used.

[0109] (7) Preparation of Z10: A solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (165.2 mg, 0.7 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 94.0 mg of a yellow solid. The yield is 27.6%.

Example

[0110] Example 11: Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z11)

[0111] (1) Use the same method as in step (1) of Example 1.

[0112] (2) Preparation of 5-cyclopropyl-3-(3-iodophenyl)-1,2,4-oxadiazole:

[0113] (Z)-N′-Hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) are added to a 100 mL three-necked round-bottom flask, and cyclopropylcarbonyl chloride (1.6 g, 15.3 mmol) is added dropwise while stirring at room temperature. The reaction system is heated to 100 °C and reacted for 8 - 10 hours. After the reaction is completed, it is cooled to room temperature and the solvent is removed. It is mixed with silica gel and separated by column chromatography to obtain a white solid (1.8 g). The yield is 75.6%.

[0114] (3) Preparation of diethyl 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonate: 3-(3-Iodophenyl)-5-cyclopropyl-1,2,4-oxadiazole (1.8 g, 5.7 mmol), 2-pyridinecarboxylic acid (142.0 mg, 1.2 mmol), copper(I) iodide (109.8 mg, 0.6 mmol), and cesium carbonate (4.7 g, 14.4 mmol) are added to a 200 mL Schlenk flask. Diethyl malonate (1.9 g, 11.5 mmol) and dry 1,4-dioxane (50 mL) are added under a nitrogen atmosphere. After the addition, the reaction system is heated to 90 °C and reacted for 8 - 12 hours. After the reaction is completed, it is cooled to room temperature, and a saturated aqueous ammonium chloride solution (100 mL) is added to stop the reaction. Then, it is extracted with ethyl acetate (50 mL × 3), and the organic layers are combined. Dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain a colorless oil (1.4 g). The yield is 70.5%.

[0115] (4) Preparation of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.4 g, 4.1 mmol), absolute ethanol (50 mL), and an aqueous sodium hydroxide solution (0.4 g, 10.2 mmol) are added to a 250 mL round-bottom flask and stirred at room temperature. After the hydrolysis is complete, the solvent is concentrated, and water (50 mL) is added to the residue. It is extracted once with ethyl acetate (50 mL) to remove impurities, and the aqueous phase is collected. Then, the pH is adjusted to acidic with 6 N hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is concentrated to obtain a colorless oil (1.0 g). The yield is 85.3%.

[0116] (5) Preparation of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), methylene dichloride (20 mL), and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask, and oxalyl chloride (0.4 g, 2.8 mmol) is added dropwise while stirring at room temperature. After reacting at room temperature for 2 to 4 hours, the solvent is removed under reduced pressure, and methylene dichloride (20 mL) is added and stored.

[0117] (6) Use the same method as in step (6) of Example 2.

[0118] (7) Preparation of Z11: A 10 mL solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (156.6 mg, 0.7 mmol) in methylene dichloride is added to a methylene dichloride solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. 3 drops of triethylamine are added, and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 56.0 mg of a yellow solid. The yield is 16.9%.

Example

[0119] Example 12: Preparation of 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z12)

[0120] (1)~(5) Use the same method as in steps (1) to (5) of Example 11.

[0121] (6) Use the same method as in step (6) of Example 3.

[0122] (7) Preparation of Z12: A solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (152.4 mg, 0.7 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 35.0 mg of a yellow solid. The yield is 10.7%.

Example

[0123] Example 13: Preparation of 1-(2-cyanoethyl)-3-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z13)

[0124] (1) - (5) The same methods as steps (1) - (5) of Example 11 are used.

[0125] (6) The same method as step (6) of Example 4 is used.

[0126] (7) Preparation of Z13: A solution of 3-(pyridin-2-ylamino)propionitrile (70.2 mg, 0.7 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 59.0 mg of a yellow solid. The yield is 21.3%.

Example

[0127] Example 14: Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z14)

[0128] (1)-(5) The same method as steps (1)-(5) of Example 11 is used.

[0129] (6) The same method as step (6) of Example 1 is used.

[0130] (7) Preparation of Z14: A 10 mL solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (166.3 mg, 0.7 mmol) in methylene chloride is added to a methylene chloride solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. 3 drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 121.0 mg of a yellow solid. The yield is 35.5%.

Example

[0131] Example 15: Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z15)

[0132] (1) The same method as step (1) of Example 1 is used.

[0133] (2) Preparation of 5-cyclobutyl-3-(3-iodophenyl)-1,2,4-oxadiazole:

[0134] (Z)-N′-Hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) were added to a 100 mL three-necked round-bottom flask, and cyclobutylcarbonyl chloride (1.8 g, 15.3 mmol) was added dropwise while stirring at room temperature. The reaction system was heated to 100 °C and reacted for 8 - 10 hours. After the reaction was completed, it was cooled to room temperature and the solvent was removed. It was mixed with silica gel and separated by column chromatography to obtain a white solid (1.8 g). The yield was 72.3%.

[0135] (3) Preparation of diethyl 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonate: 3-(3-Iodophenyl)-5-cyclobutyl-1,2,4-oxadiazole (1.8 g, 5.5 mmol), 2-pyridinecarboxylic acid (135.9 mg, 1.1 mmol), copper(I) iodide (105.1 mg, 0.6 mmol), and cesium carbonate (4.5 g, 13.8 mmol) were added to a 200 mL Schlenk flask. Diethyl malonate (1.8 g, 11.0 mmol) and dry 1,4-dioxane (50 mL) were added under a nitrogen atmosphere. After the addition, the reaction system was heated to 90 °C and reacted for 8 - 12 hours. After the reaction was completed, it was cooled to room temperature, and a saturated aqueous ammonium chloride solution (100 mL) was added to stop the reaction. Then, it was extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. It was dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain a colorless oil (1.5 g). The yield was 75.8%.

[0136] (4) Preparation of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.5 g, 4.2 mmol), absolute ethanol (50 mL), and an aqueous sodium hydroxide solution (0.4 g, 10.5 mmol) are added to a 250 mL round-bottom flask and stirred at room temperature. After the hydrolysis is complete, the solvent is concentrated, and water (50 mL) is added to the residue. The impurities are removed by extraction once with ethyl acetate (50 mL), and the aqueous phase is collected. Then, the pH is adjusted to acidic with 6 N hydrochloric acid, and the mixture is extracted with ethyl acetate (50 mL × 3). The organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is concentrated to obtain a colorless oil (1.1 g). The yield is 86.9%.

[0137] (5) Preparation of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), dichloromethane (20 mL), and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask, and oxalyl chloride (0.4 g, 2.7 mmol) is added dropwise while stirring at room temperature. After reacting at room temperature for 2 - 4 hours, the solvent is removed under reduced pressure, and dichloromethane (20 mL) is added and stored.

[0138] (6) The same method as in procedure (6) of Example 2 is used.

[0139] (7) Preparation of Z15: A 10 mL solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (149.3 mg, 0.7 mmol) in dichloromethane is added to a dichloromethane solution of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride. 3 drops of triethylamine are added, and the mixture is reacted at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. The mixture is mixed with silica gel and separated by column chromatography to obtain 107.0 mg of a yellow solid. The yield is 32.87%.

Example

[0140] Example 16: Preparation of 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z16)

[0141] (1)-(5) The same methods as steps (1)-(5) of Example 15 are used.

[0142] (6) The same method as step (6) of Example 3 is used.

[0143] (7) Preparation of Z16: A 10 mL solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (145.3 mg, 0.7 mmol) in methylene chloride is added to a methylene chloride solution of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. 3 drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 66.0 mg of a yellow solid. The yield is 20.5%.

Example

[0144] Example 17: Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z17)

[0145] (1)-(5) The same methods as steps (1)-(5) of Example 15 are used.

[0146] (6) The same method as step (6) of Example 1 is used.

[0147] (7) Preparation of Z17: A solution of N - ((2 - chlorothiazol - 5 - yl)methyl)-3 - methylpyridin - 2 - amine (158.6 mg, 0.7 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2 - (3 - (5 - cyclobutyl - 1,2,4 - oxadiazol - 3 - yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 132.0 mg of a yellow solid. The yield is 39.4%.

Example

[0148] Example 18: Preparation of 1 - ((2 - chlorothiazol - 5 - yl)methyl)-4 - oxo - 3 - (3 - (5 - ethenyl - 1,2,4 - oxadiazol - 3 - yl)phenyl)-4H - pyrido[1,2 - a]pyrimidinium - 1 - yl - 2 - ol salt (Z18)

[0149] (1) The same method as in step (1) of Example 1 is used.

[0150] (2) Preparation of 3 - (3 - iodophenyl)-5 - ethenyl - 1,2,4 - oxadiazole:

[0151] (Z)-N′ - hydroxy - 3 - iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) are added to a 100 mL three - necked round - bottom flask, and acryloyl chloride (1.4 g, 15.3 mmol) is added dropwise while stirring at room temperature. The reaction system is heated to 100 °C and reacted for 8 - 10 hours. After the reaction is completed, it is cooled to room temperature and the solvent is removed. It is mixed with silica gel and separated by column chromatography to obtain 1.1 g of a white solid. The yield is 48.4%.

[0152] (3) Preparation of diethyl 2 - (3 - (5 - ethenyl - 1,2,4 - oxadiazol - 3 - yl)phenyl)malonate 3-(3-Iodophenyl)-5-ethenyl-1,2,4-oxadiazole (1.1 g, 3.7 mmol), 2-pyridinecarboxylic acid (90.9 mg, 0.7 mmol), copper(I) iodide (70.3 mg, 0.4 mmol), and cesium carbonate (3.0 g, 9.2 mmol) are added to a 200 mL Schlenk flask. Diethyl malonate (1.2 g, 7.4 mmol) and dry 1,4-dioxane (50 mL) are added under a nitrogen atmosphere. After addition, the reaction system is heated to 90 °C and reacted for 8 - 12 hours. After completion of the reaction, it is cooled to room temperature, and a saturated aqueous ammonium chloride solution (100 mL) is added to stop the reaction. Then, it is extracted with ethyl acetate (50 mL × 3), and the organic layers are combined. Dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain a colorless oil (0.8 g). The yield is 65.6%.

[0153] (4) Preparation of 2-(3-(5-ethenyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-(5-ethenyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (0.8 g, 2.4 mmol), absolute ethanol (50 mL), and an aqueous sodium hydroxide solution (0.2 g, 6.1 mmol) are added to a 250 mL round-bottom flask and stirred at room temperature. After completion of hydrolysis, the solvent is concentrated, and water (50 mL) is added to the residue. It is extracted once with ethyl acetate (50 mL) to remove impurities, and the aqueous phase is collected. Then, the pH is adjusted to acidic with 6 N hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is concentrated to obtain a colorless oil (0.4 g). The yield is 60.2%.

[0154] (5) Preparation of 2-(3-(5-ethenyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-(5-ethenyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.4 g, 1.5 mmol), methylene dichloride (20 mL), and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask, and oxalyl chloride (0.7 g, 5.8 mmol) is added dropwise while stirring at room temperature. After reacting at room temperature for 2 to 4 hours, the solvent is removed under reduced pressure, and methylene dichloride (20 mL) is added and stored.

[0155] (6) Use the same method as in step (6) of Example 2.

[0156] (7) Preparation of Z18: A 10 mL solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (329.2 mg, 1.5 mmol) in methylene dichloride is added to a methylene dichloride solution of 2-(3-(5-ethenyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. 3 drops of triethylamine are added, and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 48.0 mg of a yellow solid. The yield is 7.1%.

Example

[0157] Example 19: Preparation of 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z19)

[0158] (1) Use the same method as in step (1) of Example 1.

[0159] (2) Preparation of 3-(3-iodophenyl)-5-phenyl-1,2,4-oxadiazole:

[0160] (Z)-N'-Hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) are added to a 100 mL three-necked round-bottom flask, and benzoyl chloride (2.2 g, 15.3 mmol) is added dropwise while stirring at room temperature. The reaction system is heated to 100 °C and reacted for 8 - 10 hours. After the reaction is completed, it is cooled to room temperature and the solvent is removed. It is mixed with silica gel and separated by column chromatography to obtain a white solid (2.1 g). The yield is 79.0%.

[0161] (3)-(7) It proceeds in the same process to obtain a yellow solid (90.0 mg). The yield is 28.4%.

Example

[0162] Example 20: Preparation of 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z20)

[0163] (1)-(5) The same method as steps (1)-(5) of Example 19 is used.

[0164] (6) The same method as step (6) of Example 3 is used.

[0165] (7) Preparation of Z20: A 10 mL solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (135.5 mg, 0.6 mmol) in methylene chloride is added to a methylene chloride solution of 2-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. 3 drops of triethylamine are added and reacted at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 52.0 mg of a yellow solid. The yield is 16.6%.

Example

[0166] Example 21: Preparation of 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z21)

[0167] (1) Use the same method as in step (1) of Example 1.

[0168] (2) Preparation of 3-(3-iodophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole:

[0169] Add (Z)-N′-hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol), pyridine (20 mL), and trifluoroacetic anhydride (5 mL) to a 100 mL three-necked round-bottom flask. Heat the reaction system to 100 °C and react for 8 - 10 hours. After the reaction is completed, cool to room temperature and remove the solvent. Mix with silica gel and separate by column chromatography to obtain a white solid (1.9 g). The yield is 73.2%.

[0170] (3) Preparation of diethyl 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate: 3-(3-Iodophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (1.9 g, 5.6 mmol), 2-pyridinecarboxylic acid (137.6 mg, 1.1 mmol), copper(I) iodide (106.4 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) are added to a 200 mL Schlenk flask. Diethyl malonate (1.8 g, 12.2 mmol) and dry 1,4-dioxane (50 mL) are added under a nitrogen atmosphere. After addition, the reaction system is heated to 90 °C and reacted for 8 - 12 hours. After completion of the reaction, it is cooled to room temperature, and a saturated aqueous ammonium chloride solution (100 mL) is added to stop the reaction. Then, it is extracted with ethyl acetate (50 mL × 3), and the organic layers are combined. Dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain a colorless oil (1.5 g). The yield is 72.1%.

[0171] (4) Preparation of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.5 g, 4.0 mmol), absolute ethanol (50 mL), and an aqueous sodium hydroxide solution (0.4 g, 10.1 mmol) are added to a 250 mL round-bottom flask and stirred at room temperature. After completion of hydrolysis, the solvent is concentrated, and water (50 mL) is added to the residue. Extracted once with ethyl acetate (50 mL) to remove impurities, and the aqueous phase is collected. Then, the pH is adjusted to acidic with 6 N hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is concentrated to obtain a colorless oil (0.8 g). The yield is 62.8%.

[0172] (5) Preparation of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.6 mmol), methylene dichloride (20 mL), and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask, and oxalyl chloride (0.3 g, 2.5 mmol) is added dropwise while stirring at room temperature. After reacting at room temperature for 2 to 4 hours, the solvent is removed under reduced pressure, and methylene dichloride (20 mL) is added and stored.

[0173] (6) Use the same method as in step (6) of Example 2.

[0174] (7) Preparation of Z21: A 10 mL solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (142.8 mg, 0.6 mmol) in methylene dichloride is added to a methylene dichloride solution of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. 3 drops of triethylamine are added, and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain 47.0 mg of a yellow solid. The yield is 14.7%.

Example

[0175] Example 22: Preparation of 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z22)

[0176] (1) Use the same method as in step (1) of Example 1.

[0177] (2) Preparation of 5-(dichloromethyl)-3-(3-iodophenyl)-1,2,4-oxadiazole:

[0178] (Z)-N'-Hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) are added to a 100 mL three-necked round-bottom flask, and dichloroacetyl chloride (2.3 g, 15.3 mmol) is added dropwise while stirring at room temperature. The reaction system is heated to 100 °C and reacted for 8 - 10 hours. After the reaction is completed, it is cooled to room temperature and the solvent is removed. It is mixed with silica gel and separated by column chromatography to obtain a white solid (1.6 g). The yield is 59.1%.

[0179] (3) Preparation of diethyl 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate: 5-(Dichloromethyl)-3-(3-iodophenyl)-1,2,4-oxadiazole (1.6 g, 4.5 mmol), 2-pyridinecarboxylic acid (111.0 mg, 0.9 mmol), copper(I) iodide (85.9 mg, 0.5 mmol), and cesium carbonate (3.7 g, 11.3 mmol) are added to a 200 mL Schlenk flask. Under a nitrogen atmosphere, diethyl malonate (1.4 g, 9.0 mmol) and dry 1,4-dioxane (50 mL) are added. After the addition, the reaction system is heated to 90 °C and reacted for 8 - 12 hours. After the reaction is completed, it is cooled to room temperature, and a saturated ammonium chloride aqueous solution (100 mL) is added to stop the reaction. Then, it is extracted with ethyl acetate (50 mL × 3), and the organic layers are combined. It is dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain a colorless oil (0.9 g). The yield is 51.6%.

[0180] (4) Preparation of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate (0.9 g, 2.3 mmol), absolute ethanol (50 mL), and an aqueous sodium hydroxide solution (0.2 g, 5.8 mmol) are added to a 250 mL round-bottom flask and stirred at room temperature. After the hydrolysis is complete, the solvent is concentrated, and water (50 mL) is added to the residue. It is extracted once with ethyl acetate (50 mL) to remove impurities, and the aqueous phase is collected. Then, the pH is adjusted to acidic with 6 N hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is concentrated to obtain a colorless oil (0.5 g). The yield is 65.0%.

[0181] (5) Preparation of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.6 mmol), methylene dichloride (20 mL), and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask, and oxalyl chloride (0.3 g, 2.4 mmol) is added dropwise while stirring at room temperature. After reacting at room temperature for 2 - 4 hours, the solvent is removed under reduced pressure, and methylene dichloride (20 mL) is added and stored.

[0182] (6) The same method as in procedure (6) of Example 3 is used.

[0183] (7) Preparation of Z22: A solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (132.7 mg, 0.6 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is allowed to proceed at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. The mixture is mixed with silica gel and separated by column chromatography to obtain 28.0 mg of a yellow solid. The yield is 9.0%.

Example

[0184] Example 23: Preparation of 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(3-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z23)

[0185] (1) The same method as in procedure (1) of Example 1 is used.

[0186] (2) Preparation of 5-(trichloromethyl)-3-(3-iodophenyl)-1,2,4-oxadiazole:

[0187] (Z)-N′-Hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) are added to a 100 mL three-necked round-bottom flask, and trichloroacetyl chloride (2.8 g, 15.3 mmol) is added dropwise while stirring at room temperature. The reaction system is heated to 100 °C and reacted for 8 - 10 hours. After the reaction is completed, it is cooled to room temperature and the solvent is removed. The mixture is mixed with silica gel and separated by column chromatography to obtain a white solid (1.8 g). The yield is 60.6%.

[0188] (3) - (7) Proceed in the same manner to obtain a yellow solid of Z23 (25.0 mg, yield 8.3%).

Example

[0189] Example 24: Preparation of 3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1-((2-chlorothiazol-5-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z24)

[0190] (1) Preparation of (Z)-3-chloro-N′-hydroxy-3-iodoimidazolidone: 3-chloro-5-iodobenzonitrile (2.0 g, 7.6 mmol), hydroxylamine hydrochloride (0.6 g, 9.1 mmol), sodium hydrogen carbonate (1.0 g, 11.4 mmol), absolute ethanol (20 mL), and water (5 mL) are added to a 100 mL three-necked flask. The reaction system is heated to the reflux temperature and reacted for 6 - 8 hours. After the reaction is completed, the solvent is concentrated, and 30 mL of water is added to precipitate a large amount of white solid. It is filtered and dried to obtain a white solid (2.0 g). The yield is 88.9%.

[0191] (2) Preparation of 3-(3-chloro-5-iodophenyl)-5-methyl-1,2,4-oxadiazole:

[0192] (Z)-3-chloro-N′-hydroxy-3-iodoimidazolidone (2.0 g, 6.8 mmol) and pyridine (30 mL) are added to a 100 mL three-necked round-bottom flask, and acetyl chloride (1.1 g, 13.5 mmol) is added dropwise while stirring at room temperature. The reaction system is heated to 100 °C and reacted for 8 - 10 hours. After the reaction is completed, it is cooled to room temperature and the solvent is removed. It is mixed with silica gel and separated by column chromatography to obtain a white solid (1.5 g). The yield is 69.4%.

[0193] (3) Preparation of diethyl 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonate: 3-(3-chloro-5-iodophenyl)-5-methyl-1,2,4-oxadiazole (1.5 g, 4.7 mmol), 2-pyridinecarboxylic acid (115.2 mg, 0.9 mmol), copper(I) iodide (89.1 mg, 0.5 mmol), and cesium carbonate (3.8 g, 11.7 mmol) are added to a 200 mL Schlenk flask. Diethyl malonate (1.5 g, 9.4 mmol) and dry 1,4-dioxane (50 mL) are added under a nitrogen atmosphere. The reaction system is heated to 90 °C and reacted for 8 - 12 hours. After completion of the reaction, it is cooled to room temperature, and a saturated aqueous ammonium chloride solution (100 mL) is added to stop the reaction. Then, it is extracted with ethyl acetate (50 mL × 3), and the organic layers are combined. Dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain a colorless oil (1.0 g). The yield is 60.6%.

[0194] (4) Preparation of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid: Diethyl 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.0 g, 2.8 mmol), absolute ethanol (50 mL), and an aqueous sodium hydroxide solution (0.3 g, 7.1 mmol) are added to a 250 mL round-bottom flask and stirred at room temperature. After completion of hydrolysis, the solvent is concentrated, and water (50 mL) is added to the residue. It is extracted once with ethyl acetate (50 mL) to remove impurities, and the aqueous phase is collected. Then, the pH is adjusted to acidic with 6 N hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is concentrated to obtain a colorless oil (0.6 g). The yield is 71.4%.

[0195] (5) Preparation of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride: 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), methylene dichloride (20 mL), and 1 drop of N,N-dimethylformamide are added to a 50 mL round-bottom flask, and oxalyl chloride (0.3 g, 2.7 mmol) is added dropwise while stirring at room temperature. After reacting at room temperature for 2 to 4 hours, the solvent is removed under reduced pressure, and methylene dichloride (20 mL) is added and stored.

[0196] (6) Use the same method as in step (6) of Example 2.

[0197] (7) Preparation of Z24: A 10 mL solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (152.2 mg, 0.7 mmol) in methylene dichloride is added to a methylene dichloride solution of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. 3 drops of triethylamine are added, and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain a yellow solid (81.0 mg). The yield is 24.7%.

Example

[0198] Example 25: Preparation of 3-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1-((6-chloropyridin-3-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-base-2-ol salt (Z25)

[0199] (1)~(5) Use the same method as in steps (1) to (5) of Example 24.

[0200] (6) Use the same method as in step (6) of Example 3.

[0201] (7) Preparation of Z25: A solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (135.5 mg, 0.6 mmol) in 10 mL of methylene chloride is added to a methylene chloride solution of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid chloride. Three drops of triethylamine are added and the reaction is carried out at room temperature for 20 minutes. After the reaction, 2 mL of anhydrous methanol is added to stop the reaction. It is mixed with silica gel and separated by column chromatography to obtain a yellow solid (39.0 mg). The yield is 12.0%.

[0202] Table 1: Waveform data (1H NMR and 13C NMR) The waveform data of Compounds Z1 to Z25 are described based on the corresponding analysis results. JPEG2025094925000008.jpg221170JPEG2025094925000009.jpg219170JPEG2025094925000010.jpg242170JPEG2025094925000011.jpg239170JPEG2025094925000012.jpg215170

[0203] Test Example 1: Measurement of the control bioactivity of the target compound against the cowpea aphid indoors The target compound is dissolved in a DMSO solution and diluted with TW-80 to prepare a stock solution with a concentration of 1 g / L. Then, it is diluted with TW-80 to prepare test solutions with concentrations of 100.0, 10.0, 1.0 μg / mL and other concentrations.

[0204] Twenty to thirty 3rd-instar cowpea aphids are inoculated into pots planted with cowpea seedlings, and 2 mL of the test solution is sprayed onto each pot. A TW-80 solution containing DMSO is used as a blank control. The test is repeated 3 times for each test condition. The treated cowpea aphids are reared in a greenhouse (temperature: 26 ± 2°C, humidity: 85 ± 5%, light / dark = 14 / 10 hours), and the number of dead insects is recorded after 48 hours.

[0205] The calculation methods for the mortality rate and corrected mortality rate are as follows. The activity data are shown in Table 2. Calculation method Lethality rate = (number of dead insects) / (total number of treated insects) × 100 Corrected lethality rate = (treatment lethality rate - blank lethality rate) / (1 - blank lethality rate) × 100 Table 2: Lethality rates of compounds Z1 - Z25 against cowpea aphids JPEG2025094925000013.jpg180170 Test results From the results of the insecticidal activity, it was confirmed that the compounds of the present invention exhibit good insecticidal activity against cowpea aphids. Many compounds showed a lethality rate of 100% against cowpea aphids at a concentration of 100 μg / mL. For some compounds, the lethality rate remained 100% even at a concentration of 10 μg / mL.

[0206] Test Example 2: Measurement of the control bioactivity of the target compound against the green rice leafhopper indoors Dissolve the target compound in a DMSO solution and dilute it with TW - 80 to prepare a stock solution with a concentration of 1 g / L. Then, dilute it with TW - 80 to prepare test solutions with concentrations of 100.0, 10.0, 1.0 μg / mL and other concentrations.

[0207] Inoculate 20 - 30 third - instar green rice leafhoppers into a pot planted with rice seedlings, and spray 2 mL of the test solution on each pot. Use a TW - 80 solution containing DMSO as a blank control. Conduct a repeated test 3 times for each test condition. Raise the treated green rice leafhoppers in a greenhouse (temperature: 26 ± 2°C, humidity: 85 ± 5%, light / dark = 14 / 10 hours), and record the number of dead insects 48 hours later.

[0208] Calculation method Lethality rate = (number of dead insects) / (total number of treated insects) × 100 Corrected lethality rate = (treatment lethality rate - blank lethality rate) / (1 - blank lethality rate) × 100 Table 3: Lethality rates of compounds Z1 - Z25 against green rice leafhoppers JPEG2025094925000014.jpg173170 Test results From the results of the insecticidal activity, it was confirmed that the compounds of the present invention exhibited good insecticidal activity against the green peach aphid. Many compounds showed a 100% mortality rate against the green peach aphid at a concentration of 100 μg / mL. Among them, compounds Z3 and Z19 had a 100% mortality rate even at a concentration of 10 μg / mL.

[0209] Test Example 3: Measurement of the control bioactivity of the target compound against the diamondback moth indoors Dissolve the target compound in a DMSO solution and dilute it with TW-80 to prepare a stock solution with a concentration of 1 g / L. Then, dilute it with TW-80 to prepare test solutions with concentrations of 100.0, 10.0, 1.0 μg / mL and other concentrations.

[0210] Immerse the leaves of Chinese cabbage in the insecticide solutions with different concentrations for 3 - 5 seconds, and treat the leaves in the control group with a TW-80 solution containing DMSO. After drying the leaves at room temperature for 2 hours, place them in a petri dish with a diameter of 10 cm. Repeat each concentration test 3 times, and use 10 second-instar larvae in each test. Finally, store the petri dishes in an incubator that meets the conditions of 26 °C, 70% RH (relative humidity), and a 14:10 h (light-dark cycle). Observe the results after 48 hours and record the mortality rate.

[0211] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) × 100 Corrected mortality rate = (treatment mortality rate - blank mortality rate) / (1 - blank mortality rate) × 100 Table 4: Mortality rates of compounds Z1 - Z25 against the diamondback moth JPEG2025094925000015.jpg97170 Test results From the results of the insecticidal activity, it was confirmed that the compounds of the present invention exhibited excellent insecticidal activity against the diamondback moth. Many compounds showed a 100% mortality rate against the diamondback moth at a concentration of 100 μg / mL. Among them, compounds Z1, Z7, and Z14 had a 100% mortality rate even at a concentration of 10 μg / mL.

[0212] Test Example 4: Measurement of the Biological Activity of Controlling Maize Pests (Sesamia inferens) Indoors for the Target Compound Use the 3rd instar larvae of Sesamia inferens reared indoors with a uniform physiological state as the test subjects, and select 10 test insects for each petri dish. Place 2 maize leaf pieces with a length of 2 cm in each petri dish. Spray the test chemical solution using a spray tower, and conduct 3 replicate tests for each concentration. Use acetone at the corresponding concentration in the control group. After treatment, transfer the test insects to the breeding conditions for breeding. Observe the results after 48 hours and record the number of dead insects.

[0213] Calculation method Lethality rate = (Number of dead insects) / (Total number of treated insects) × 100 Corrected lethality rate = (Treatment lethality rate - Blank lethality rate) / (1 - Blank lethality rate) × 100 Table 5: Lethality Rate of Compound Z1 against Sesamia inferens JPEG2025094925000016.jpg22170 Test results From the results of the insecticidal activity, it was confirmed that compound Z1 showed excellent insecticidal activity against maize pests (Ostrinia furnacalis). In particular, the lethality rate was 100% even at a concentration of 5 μg / mL.

[0214] Test Example 5: Measurement of the Biological Activity of Controlling Sitophilus zeamais Indoors for the Target Compound Use the 3rd instar larvae of Sitophilus zeamais reared indoors with a uniform physiological state as the test subjects, and select 10 test insects for each petri dish. Place 2 maize leaf pieces with a length of 2 cm in each petri dish. Spray the test chemical solution using a spray tower, and conduct 3 replicate tests for each concentration. Use acetone at the corresponding concentration in the control group. After treatment, transfer the test insects to the breeding conditions for breeding. Observe the results after 48 hours and record the number of dead insects.

[0215] Calculation method Lethality rate = (Number of dead insects) / (Total number of treated insects) × 100 Corrected lethality rate = (Treatment lethality rate - Blank lethality rate) / (1 - Blank lethality rate) × 100 Table 6: Lethality Rate of Compound Z1 against Sitophilus zeamais JPEG2025094925000017.jpg Test Results for 23170 From the results of the insecticidal activity, it was confirmed that Compound Z1 exhibited excellent insecticidal activity against the flour beetle. In particular, even at a concentration of 5 μg / mL, the mortality rate was 100%.

[0216] Test Example 6: Measurement of the Biological Activity of Controlling the Corn Borer by the Target Compound Indoors Using the 3rd instar larvae of the corn borer reared indoors with a uniform physiological state as the test subjects, 10 test insects are selected for each culture dish. Two 2-cm-long corn leaf pieces are placed in the culture dish. The test chemical solution is sprayed using a spray tower, and three replicate tests are conducted for each concentration. Acetone at the corresponding concentration is used in the control group. After treatment, the test insects are transferred to the breeding conditions for breeding. After 48 hours, the results are observed and the number of dead insects is recorded.

[0217] Calculation Method Mortality Rate = (Number of Dead Insects) / (Total Number of Treated Insects) × 100 Corrected Mortality Rate = (Treatment Mortality Rate - Blank Mortality Rate) / (1 - Blank Mortality Rate) × 100 Table 7: Mortality Rate of Compound Z1 against the Corn Borer JPEG2025094925000018.jpg Test Results for 30170 From the results of the insecticidal activity, it was confirmed that Compound Z1 exhibited excellent insecticidal activity against the corn borer. In particular, the mortality rate was 95% at a concentration of 5 μg / mL.

[0218] Test Example 7: Measurement of the Biological Activity of Controlling the Leafhopper by the Target Compound Indoors Using the 3rd instar larvae of the leafhopper reared indoors with a uniform physiological state as the test subjects, 10 test insects are selected for each culture dish. Two 2-cm-long corn leaf pieces are placed in the culture dish. The test chemical solution is sprayed using a spray tower, and three replicate tests are conducted for each concentration. Acetone at the corresponding concentration is used in the control group. After treatment, the test insects are transferred to the breeding conditions for breeding. After 48 hours, the results are observed and the number of dead insects is recorded.

[0219] Calculation Method Mortality rate = (Number of dead insects) / (Total number of treated insects) × 100 Corrected mortality rate = (Treatment mortality rate - Control mortality rate) / (1 - Control mortality rate) × 100 Table 8: Mortality rate of compound Z1 against leafhoppers JPEG2025094925000019.jpg 29170 Test results From the results of insecticidal activity, it was confirmed that compound Z1 showed excellent insecticidal activity against leafhoppers (Nephotettix cincticeps). In particular, the mortality rate was 95% at a concentration of 5 μg / mL.

[0220] Test Example 8: Measurement of the biological activity of controlling rice leaf beetles indoors for the target compound Use the 4th instar larvae of rice leaf beetles reared indoors with a uniform physiological state as the test subjects, and select 10 test insects for each culture dish. Place 2 corn leaf pieces with a length of 2 cm in each culture dish. The test chemical solution is sprayed using a spray tower, and three replicate tests are conducted for each concentration. Acetone with the corresponding concentration is used in the control group. After treatment, transfer the test insects to the breeding conditions for breeding. Observe the results after 48 hours and record the number of dead insects.

[0221] Calculation method Mortality rate = (Number of dead insects) / (Total number of treated insects) × 100 Corrected mortality rate = (Treatment mortality rate - Control mortality rate) / (1 - Control mortality rate) × 100 Table 9: Mortality rate of compound Z1 against rice leaf beetles JPEG2025094925000020.jpg 29170 Test results From the results of insecticidal activity, it was confirmed that compound Z1 showed excellent insecticidal activity against rice leaf beetles. In particular, the mortality rate was 90% at a concentration of 5 μg / mL.

[0222] Test Example 9: Measurement of the biological activity of controlling corn leaf aphids indoors for the target compound Indoor-reared second-instar corn borer larvae with a uniform physiological state are used as the test subjects, and 10 test insects are selected for each petri dish. Two 2-cm-long corn leaf pieces are placed in each petri dish. The test chemical solution is sprayed using a spray tower, and three replicate tests are conducted for each concentration. Acetone at the corresponding concentration is used in the control group. After treatment, the test insects are transferred to the breeding conditions for rearing. The results are observed 48 hours later, and the number of dead insects is recorded.

[0223] Calculation method Lethality rate = (number of dead insects) / (total number of treated insects) × 100 Corrected lethality rate = (treatment lethality rate - blank lethality rate) / (1 - blank lethality rate) × 100 Table 10: Lethality rate of compound Z1 against corn borer JPEG2025094925000021.jpg27170 Biological activity test results As a result of the biological activity test, it was confirmed that compound Z1 has excellent insecticidal activity against corn borer. In particular, at a concentration of 5 μg / mL, the lethality rate against rice leaf beetle was 95%.

[0224] From the results of these biological activity tests, it was confirmed that the mesoionic compound Z1 of pyrido[1,2-a]pyrimidine containing a 1,2,4-oxadione structure exhibits excellent insecticidal activity against the following Hemiptera and Lepidoptera insects: aphids (Aphis glycines), leafhoppers (Nephotettix cincticeps), green leafhoppers (Nephotettix virescens), corn pests (Ostrinia furnacalis), Spodoptera litura, planthoppers (Laodelphax striatellus), rice leaf beetles, and corn pests (Ostrinia furnacalis).

[0225] The above-described content is only the preferred embodiment of the present invention. For those of ordinary skill in the art, without departing from the creative concept of the present invention, some changes and improvements can be made. All of these changes and improvements shall be included within the protection scope of the present invention.

Claims

1. A mesoionic pyrido[1,2-a]pyrimidine compound having a 1,2,4-oxadiol structure represented by the following general formula (I), a salt thereof, or a solvate thereof: R １ are independently selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaromatic groups; R ２ are independently selected from one or more of hydrogen, deuterium, halogen, cyano, nitro, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, and optionally substituted or unsubstituted aryl. R ３ , R ４ are independently selected from one or more of hydrogen, deuterium, halogen, nitro, hydroxy, amino, thiol, cyano, and optionally substituted or unsubstituted alkyl; R ５ is independently selected from one or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy group, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, and optionally substituted or unsubstituted aryl; A mesoionic pyrido[1,2-a]pyrimidine compound containing a 1,2,4-oxadiol structure, a salt thereof, or a solvate thereof.

2. R １ are independently selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C5-C6 heteroaromatic groups; R ２ are independently selected from one or more of hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C5-C6 heteroaromatic groups; R ３ , R ４ are independently selected from one or more of hydrogen, deuterium, halogen, nitro group, hydroxy group, amino group, thiol group, cyano group, and C1-C6 alkyl; R ５ is independently selected from one or more of C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C5-C6 heteroaromatic groups; The mesoionic pyrido[1,2-a]pyrimidine compound containing a 1,2,4-oxadiol structure according to claim 1, a salt thereof, or a solvate thereof.

3. R １ are independently hydrogen, deuterium, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, -CH ２ CH ２ CN, -CHCNCH ３ , -CH ２ CH ２ CH ２ CN, -CH ２ CHCNCH ３ , -CHCNCH ２ CH ３ , -CH ２ CH ２ F, -CHFCH ３ , -CH ２ CH ２ CH ２ F, -CH ２ CHFCH ３ , -CHFCH ２ CH ３ , -CH ２ CH ２ Cl, -CHClCH ３ , -CH ２ CH ２ CH ２ Cl, -CH ２ CHClCH ３ , -CHClCH ２ CH ３ , -CH ２ CH ２ Br, -CHBrCH ３ , -CH ２ CH ２ CH ２ Br, -CH ２ CHBrCH ３ , -CHBrCH ２ CH ３ , Selected from R ２ is selected from hydrogen, methyl, ethyl, fluorine, chlorine, and bromine; R ３ and R ４ are independently selected from hydrogen, methyl, ethyl, fluorine, chlorine and bromine; R ５ is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -CH ２ F, -CHF2, -CF ３ , -CH ２ Cl, -CHCl ２ , -CCl ３ Selected from The mesoionic pyrido[1,2-a]pyrimidine compound containing a 1,2,4-oxadiol structure according to claim 1, and its salts. また is its solvate.

4. A compound selected from the above compounds, The mesoionic pyrido[1,2-a]pyrimidine compound containing a 1,2,4-oxadiol structure according to claim 1, a salt thereof, or a solvate thereof.

5. As shown in the above formula, R ３ , R ４ , R ５ are independently defined in any one of claims 1 to 3, 2. An intermediate compound for producing the mesoionic pyrido[1,2-a]pyrimidine compound having a 1,2,4-oxadiazole structure according to claim 1, a stereoisomer thereof, a salt thereof, or a solvate thereof.

6. A method for producing the mesoionic pyrido[1,2-a]pyrimidine compound having a 1,2,4-oxadiazole structure according to claim 1, its stereoisomer, its salt, or its solvate, comprising the steps of: This includes: More preferably, it further comprises: More preferably, the following are included: A method comprising:

7. A composition comprising the mesoionic pyrido[1,2-a]pyrimidine compound having a 1,2,4-oxadiazole structure according to any one of claims 1 to 4, a stereoisomer thereof, a salt thereof, or a solvate thereof, and an agriculturally usable adjuvant, fungicide, insecticide, or herbicide, Preferably, the formulation of the composition is selected from among emulsifiable concentrate (EC), dust (DP), wettable powder (WP), granule (GR), liquid (AS), suspension (SC), ultra-low volume spray (ULV), soluble powder (SP), microcapsule (MC), fumigation agent (FU), aqueous emulsion (EW), water-dispersible granule (WG); A composition comprising:

8. Use of the mesoionic pyrido[1,2-a]pyrimidine compound having a 1,2,4-oxadiazole structure according to any one of claims 1 to 4, a stereoisomer thereof, a salt thereof, or a solvate thereof, or the composition according to claim 7, in controlling agricultural pests, comprising: The agricultural pests are hemipteran and lepidopteran pests, Preferred are rice planthoppers, aphids, diamondback moth, fall armyworm, rice armyworm, common cutworm, dimorphophora, rice beetle, and corn stag beetle.

23. The method of claim 22,

9. A method for treating a pest or its habitat by applying a pyrido[1,2-a]pyrimidine mesoionic compound having a 1,2,4-oxadiazole structure according to any one of claims 1 to 4, a stereoisomer thereof, a salt thereof, or a solvate thereof, or a composition according to claim 7, The agricultural pests are hemipteran and lepidopteran pests, Preferred are rice planthoppers, aphids, diamondback moth, fall armyworm, rice armyworm, common cutworm, dimorphophora, rice beetle, and corn stag beetle.

1. A method for controlling agricultural pests, comprising:

10. The method includes a step of contacting a pest with a pyrido[1,2-a]pyrimidine mesoionic compound having a 1,2,4-oxadiazole structure according to any one of claims 1 to 4, a stereoisomer thereof, a salt thereof, or a solvate thereof, or the composition according to claim 7.

1. A method for protecting a plant from an agricultural pest, comprising:

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