Pyrido[1,2-a]pyrimidine mesoionic compounds containing 1,2,4-oxadiol structure, and their production method and use

Abstract

Provided are mesoionic pyrido[1,2-a]pyrimidine compounds having a 1,2,4-oxadiazole structure, stereoisomers thereof, salts thereof, or solvates thereof, which have a simple structure and production process and are low in production cost. 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]primidinium-1-one salt (Z1) is shown.

Description

[Technical field]

[0001] The present invention relates to the fields of chemical industry and pesticides, and in particular to a pyrido[1,2-a]pyrimidine mesoionic compound containing a 1,2,4-oxadiol unit, a preparation method thereof, and the use of the pyrido[1,2-a]pyrimidine mesoionic compound containing a 1,2,4-oxadiol unit as a drug for controlling pests such as rice leafhoppers, aphids, diamondback moths, fall armyworms, planthoppers, armyworms, striped armyworms, rice beetles, and corn armyworms. [Background technology]

[0002] Rice leafhoppers and aphids of the Hemiptera (leaf beetles), and diamondback moths, fall armyworms, and armyworms of the Lepidoptera (moths) are some of the important pests in agriculture. Rice leafhoppers are one of the major pests of rice cultivation, and their occurrence is explosive, they are latent, flying, and destructive. They not only damage rice itself, but also transmit viral diseases such as rice stripe disease and southern rice stripe disease, posing a serious threat to stable rice production and food security. The area of ​​rice cultivation that is damaged annually reaches 10 to 20 million hectares, accounting for about 50% of the total cultivated area. In general, damage reduces yields by 10 to 20%, but in severe cases, it can reduce yields by 40 to 60%, or even lead to complete extinction.

[0003] Aphids are one of the most destructive pests of almost all cultivated crops, with a very short life cycle, in the absence of lethality, a single female can produce billions of offspring per year. Aphids not only weaken plants by sucking sap, but also cause leaf deformation and are vectors of many plant viruses. The diamondback moth is one of the most destructive pests of cruciferous crops worldwide, characterized by high fecundity, rapid generational succession, and long growing season.

[0004] The fall armyworm is native to the tropical and subtropical regions of the Americas, and the highly migratory adults have allowed this important agricultural pest to spread rapidly from the United States to over 100 countries. The fall armyworm causes damage to over 270 host crop species and has a high reproductive and dispersal capacity.

[0005] The armyworm, Pseudotsuga moth, is widely distributed throughout rice-growing regions of China and is an important and difficult-to-control rice boring pest. When it is infested, it can reduce rice yields by 30-50%, and is considered one of the major biological disasters.

[0006] Currently, most of the chemicals used to control agricultural pests such as aphids, rice leafhoppers, diamondback moths, fall armyworms, and striped armyworms are conventional pesticides, which are being restricted or banned due to problems such as high toxicity, persistence, high resistance, and low safety for non-target organisms. For this reason, the development of insecticides with novel structures, high efficiency, low risk, and unique mechanisms of action is urgently needed to achieve sustainable development of agriculture and food security.

[0007] Triflormisur, an ionic insecticide registered in China by Corteva (formerly DuPont) in 2016, has features such as high insecticidal activity against rice leafhoppers, no cross-resistance to existing pesticides, and low toxicity to non-target organisms. Another ionic insecticide, dichlormezothiaz, developed by DuPont, has high activity against rice leafhoppers and cotton aphids, which are Hemiptera (leaf beetles), as well as diamondback moths and armyworms, which are Lepidoptera (moths), expanding the insecticidal spectrum of mesoionic compounds. These features have made ionic insecticides a new focus of global research and development.

[0008] In 2009, Holyoke CW et al. of DuPont first disclosed a method for producing mesoionic pyrido[1,2-a]pyrimidine compounds and their application as insecticides in patent WO2009099929A1, and demonstrated that this type of compound has excellent insecticidal activity against diamondback moth, peach aphid, cotton aphid, and rice leafhopper.

[0009] Furthermore, in 2011, Holyoke CW et al., also from DuPont, disclosed 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 of them showed 100% mortality against diamondback moth, armyworm, and cotton aphid at a concentration of 10 mg / L. Among them, dichlormezothiaz has very high activity against aphids and diamondback moth, and has been developed as a commercial agent.

[0010] Structure-activity relationship (SAR) studies revealed that activity against the diamondback moth and fall armyworm was optimal when position 1 of the pyrido[1,2-a]pyrimidine ring was substituted with a 2-chlorothiazole-5-methyl group and position 9 with a methyl group, a phenomenon known as the "methyl magic effect."

[0011] In 2012, Holyoke CW et al. of Corteva (formerly DuPont) published a pyrido[1,2-a]pyrimidine mesoionic compound containing a double aromatic ring in patent WO2012106495A1. This group of compounds exhibits excellent insecticidal activity against lepidopteran, homopteran, and lepidopteran insects, and has a wide insecticidal spectrum. Specifically, some of the compounds showed 100% mortality against diamondback moth and fall armyworm at a concentration of 2 mg / L, and more than 80% mortality against green peach aphids and potato leaf cicadas at a concentration of 10 mg / L.

[0012] In 2016, Hasegawa S. et al. from Nippon Kayaku Co., Ltd. published mesoionic compounds containing a cyanoethyl group at position 1 of the pyrido[1,2-a]pyrimidine ring in patent WO2016171053A1. These compounds with a cyanoethyl group showed good to excellent insecticidal activity against cotton aphids and brown fly flies. Some compounds showed 100% mortality against aphids at 0.1 mg / L concentration and even retained 70% or more mortality against brown fly flies at 0.05 mg / L concentration. Structure-activity relationship (SAR) studies showed that the highest insecticidal activity was observed when the pyrido[1,2-a]pyrimidine ring had a cyanoethyl group at position 1 and unsubstituted at positions 6, 7, 8, and 9. Furthermore, these compounds are similar to trifluorobenzylpyrimidines and dicloromezotiaz, and it was shown that the insecticidal activity of these compounds was improved when they retained a phenyl group at the 3-position of the pyrido[1,2-a]pyrimidine ring and when the 3-position of the phenyl group was further derivatized.

[0013] In 2021, Holmes, M., Holyoke, CW, Jr., Kar, M., Lahm, GP et al. of FMC published pyrido[1,2-a]pyrimidine mesoionic compounds containing alkyne structural units in patent WO2021151034A1. Many of these compounds showed 80%-100% lethality against diamondback moth and fall armyworm at 0.4 mg / L concentrations. They also showed 70%-100% lethality against corn ash fly, potato leaf fly, peach aphid, cotton aphid, and thrips at 50 mg / L concentrations. SAR studies showed that the insecticidal activity against diamondback moth and fall armyworm was highest when the 9th position of the pyrido[1,2-a]pyrimidine ring was substituted with a methyl group.

[0014] In the same year, the research team published a pyrido[1,2-a]pyrimidine mesoionic compound containing a heterooxadiol structural unit in patent CN113651811A. This group of compounds showed good to excellent insecticidal activity against white-backed flies, and some compounds showed 100% lethality against white-backed flies at a concentration of 10 mg / L. In addition, the compound "heterooxadiol pyrimidine", named by the National Pesticide Standardization Technical Committee, showed 100% lethality against white-backed flies even at a concentration of 2 mg / L. SAR studies showed that the insecticidal activity was optimal 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 heterooxadiol ring were substituted with methyl groups.

[0015] In the same year, the research team disclosed a series of pyrido[1,2-a]pyrimidine mesoionic compounds containing an indole structural unit in patent CN113292557A, which showed good insecticidal activity against white-backed fly and broad bean aphid, and some compounds had a 100% mortality rate against white-backed fly and broad bean aphid at a concentration of 10 mg / L.

[0016] 1,2,4-Oxadiazole compounds belong to the five-membered heterocyclic compounds and are known to have a wide range of pesticide biological activities. This type of compound exhibits various excellent biological activities such as insecticidal, fungicidal, and herbicidal activities. For example, **Tioxazafen**, a nematicide for seed treatment developed by Bayer (formerly Monsanto), is a representative example of a 1,2,4-oxadiazole compound that has the characteristics of a broad spectrum, high efficiency, and a new mechanism of action, and exhibits high insecticidal and nematicidal activities.

[0017] In 2018, Xu Liangzhong et al. from Qingdao University of Science and Technology disclosed a 1,2,4-oxadiazole compound containing double phenyl ether in patent CN108299409A, which achieved 100% lethality against the sugar beet moth at a concentration of 0.5 mg / L, and outperformed the control drug lorfluamide.

[0018] Also in 2018, Wang Minghui et al. of Qingdao University of Science and Technology disclosed a series of 1,2,4-oxadiazole compounds containing a pyridine structure in patent CN109336879A. This group of compounds exhibited good to excellent insecticidal activity against diamondback moth, cinnabar mite, and two-spotted spider mite, with some compounds reaching 80% mortality for diamondback moth and 100% mortality for two-spotted spider mite at a concentration of 10 mg / L. These performance results surpass those of the control drug Tioxazafen.

[0019] In 2020, Dai Hong et al. of Nantong University disclosed five 1,2,4-oxadiazole compounds containing a 1,2,3-triazole benzyloxypyrazole structure in patent CN111560015A. The compounds showed good insecticidal activity against the European corn borer, with a mortality rate of 100% at a concentration of 500 mg / L.

[0020] Trifluorophenylpyrimidine is an ionic insecticide that is attracting attention as an effective control agent for pests such as resistant planthoppers and leafhoppers. Our research team will develop a new ionic insecticide, "isoxazolonepyrimidine," based on trifluorophenylpyrimidine. This compound is highly effective against planthoppers and overcomes the drawback of trifluorophenylpyrimidine's toxicity to honeybees, but both compounds have limited effectiveness against lepidopteran pests. Meanwhile, another ionic insecticide, dicloromezotiaz, developed by Corteva (formerly DuPont), is highly effective against lepidopteran pests such as diamondback moths and autumn slime moths in addition to being effective against planthoppers. This progress is considered an important evolution in the development of insecticides that can control both hemipteran and lepidopteran pests. This will promote the development of ionic insecticides with low toxicity, high efficiency and unique mechanism of action that can control hemipteran and lepidopteran pests, and reveal the broad potential of mesoionic compounds in agricultural pest control. From the patent analysis, the following conclusions are drawn: (1) When the ionic mother nucleus is a pyrido[1,2-a]pyrimidine ring, the compound has the best insecticidal activity. (2) When the pyrido[1,2-a]pyrimidine ring has an active group at the 1-position, which is common in neonicotinoid insecticides, the compound has high insecticidal activity. (3) When the 1-position is a 2-chlorothiazole-5-methyl group and the 9-position is a methyl group, the compound has high insecticidal activity against lepidopteran pests. (4) When the 3-position is a benzene ring or a five-membered aromatic ring, the compound has strong insecticidal activity. (5) When the 3-position benzene ring is modified at the meta position, the compound has the maximum insecticidal activity.

[0021] The present inventors aim to develop insecticides that control hemipteran and lepidopteran 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 into the meta-position of the 3-benzene ring of a pyrido[1,2-a]pyrimidine ring to design and synthesize a series of pyrido[1,2-a]pyrimidine mesoionic compounds containing the 1,2,4-oxadiazole structure.

[0022] The test results show that these compounds have excellent insecticidal activity and a wide control spectrum. The present invention provides the possibility of new pesticides that can effectively control Hemipteran and Lepidopteran pests. [Prior art documents] [Patent documents]

[0023] [Patent Document 1] International Patent Publication WO2009099929A1 [Patent Document 2] International Patent Publication WO2011017342A2 [Patent Document 3] International Patent Publication WO2012106495A1 [Patent Document 4] International Patent Publication WO2016171053A1 [Patent Document 5] International Patent Publication WO2021151034Al [Patent Document 6] China Patent Publication CN113651811A [Patent Document 7] China Patent Publication CN113292557A [Patent Document 8] China Patent Publication CN108299409A [Patent Document 9] China Patent Publication CN109336879A [Patent Document 10] China Patent Publication CN111560015A Summary of the Invention [Problem to be solved by the invention]

[0024] An object of the present invention is to provide a pyridine-1,2-a-pyrimidine mesoionic compound 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 comprising the above compound, or a salt thereof, or a solvate thereof.

[0026] Yet another object of the present invention is to provide uses of the above compound, or a salt thereof, or a solvate thereof, or the above composition.

[0027] Another object of the present invention is to provide a method for controlling agricultural pests utilizing the above compound or a salt thereof, or a solvate thereof, or the above composition. [Means for solving the problem]

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

[0029] The 1,2,4-oxadiazole-containing pyridine-1,2-a-pyrimidine mesoionic compounds of the present invention have the following general structural formula (I): JPEG0007660866000001.jpg86135R1 independently selects 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 is independently selected from one or more of hydrogen, deuterium, a halogen, a cyano group, a nitro group, an optionally substituted or unsubstituted alkyl, an optionally substituted or unsubstituted alkoxy, an optionally substituted or unsubstituted alkenyl, an optionally substituted or unsubstituted cycloalkyl, and an optionally substituted or unsubstituted aryl.

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

[0032] R5 is independently selected from 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, R1 is 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 heteroaryl.

[0034] 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] R3 and R4 are independently selected from one or more of hydrogen, deuterium, halogen, nitro group, hydroxyl group, amino group, thiol group, cyano group, and C1-C6 alkyl.

[0036] 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, R1 is independently 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, Select one or more of the following: JPEG0007660866000002.jpg68170.

[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 one or more of the following: JPEG0007660866000003.jpg55170.

[0039] Preferred compounds are the following compounds Z1-Z25. JPEG0007660866000004.jpg150170

[0040] Methods for preparing these compounds include the following: JPEG0007660866000005.jpg31170 More preferably, it further includes: JPEG0007660866000006.jpg37170 More preferably, it includes: JPEG0007660866000007.jpg100170

[0041] The present invention provides a composition comprising the above-mentioned compound or its salt or solvate, and an agriculturally usable adjuvant, fungicide, insecticide, or herbicide.Preferably, the formulation form of the composition is selected from emulsifiable concentrate (EC), dust (DP), wettable powder (WP), granule (GR), liquid concentrate (AS), suspension concentrate (SC), ultra-low volume spray (ULV), soluble powder (SP), microcapsule (MC), smoke concentrate (FU), aqueous emulsion (EW), and water-dispersible granule (WG).

[0042] In addition, the above-mentioned compound or its salt or solvate, or the composition can be used to control agricultural pests, such as hemipteran and lepidopteran pests, preferably rice planthoppers, aphids, diamondback moths, fall armyworms, rice armyworms, common cutworms, divoltine moths, rice beetles, and corn stalk moths.

[0043] Furthermore, the present invention provides a method for controlling agricultural pests. The method is characterized by applying the above-mentioned compound or its stereoisomer, or its salt or solvate, or the composition to the pest or its habitat. The agricultural pest is preferably a hemipteran pest or a lepidopteran pest, and more preferably a rice planthopper, aphid, diamondback moth, fall armyworm, rice armyworm, common cutworm, divoltine moth, rice beetle, corn stalk moth, etc. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] <Terminology> The term "alkyl" as used herein is meant to include branched or straight chain saturated hydrocarbon groups having the specified 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 alkyls. 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 replaced with other chemical groups. Examples of alkyl include methyl, ethyl, propyl (including normal propyl and isopropyl), butyl (including normal butyl, isobutyl, tert-butyl), pentyl (including normal pentyl, isopentyl, neopentyl) and the like.

[0045] The term "alkenyl" includes straight or branched hydrocarbon structures in which one or more carbon-carbon double bonds may be present in 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 single, double and polycyclic structures. "C3-7 cycloalkyl" is intended to include C3, C4, C5, C6 and C7 cycloalkyls. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornane groups and the like.

[0047] The term "carbocycle" or "carbocyclic residue" refers to a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic ring, or a 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of these carbocycles include cyclopropyl, cyclobutyl, cyclobutene, cyclopentyl, pentene, cyclohexyl, cyclohexene, cycloheptyl, cycloheptene, adamantane, cyclooctyl, cyclooctene, cyclooctadiene, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, inman, adamantane, anthracene, and tetralin (decalin).

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

[0049] The term "aryl" refers to mono- or bicyclic aromatic hydrocarbon groups containing 6 to 12 carbon atoms (eg, phenyl and naphthyl groups), each of which may be substituted.

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

[0051] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic, 9- or 10-membered bicyclic, or 11- to 14-membered tricyclic groups, at least one of which contains at least one heteroatom (O, S, or N). The heteroatom-containing ring preferably contains one, two, or three heteroatoms selected from O, S, and N. Each heteroatom-containing heteroaryl ring may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. The fused rings constituting the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may be optionally oxidized or the nitrogen atoms may be quaternized. The bicyclic or tricyclic heteroaryl must contain at least one fully aromatic ring, and the remaining fused rings may be aromatic or non-aromatic. Heteroaryl can be attached at any available nitrogen or carbon atom of any ring. If chemical valency permits, the other ring can also be substituted with =O (oxygen) if it is a cycloalkyl or heterocycle.

[0052] Working Example The present invention will be described in more detail through the following examples. However, the methods described in the examples are merely for the purpose of illustrating the present invention and are not intended to limit the present invention. All simple improvements based on the concept of the present invention are intended to be included in the scope of the claims of the present invention. In addition, all raw materials and solvents used in the examples were commercially available reagents of the corresponding purity. EXAMPLES

[0053] 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-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 bicarbonate (5.5 g, 65.5 mmol), absolute ethanol (100 mL) and water (20 mL) were mixed in a 250 mL three-neck flask and reacted under reflux for 6 to 8 hours. After the reaction was completed, the solvent was concentrated and 100 mL of water was added, resulting in the precipitation of a large amount of white solid. This was suction filtered and dried to obtain a white solid (9.8 g) 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 acetic acid chloride (1.2 g, 15.3 mmol) was added dropwise while stirring at room temperature. The temperature was then raised to 100 °C and the reaction was carried out for 8 to 10 hours. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed, and the mixture was mixed with silica gel and separated by column chromatography to obtain a white solid (1.6 g) 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 iodide (106.5 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) were added to a 200 mL Schlenk flask, and malonate (1.8 g, 11.2 mmol) was added under a nitrogen atmosphere, followed by 50 mL of dry 1,4-dioxane as a solvent. After all the materials were added, the reaction system was heated to 90 °C and reacted for 8 to 12 hours. After the reaction was completed, the reaction system was cooled to room temperature and 100 mL of saturated aqueous ammonium chloride solution was added to quench the reaction. Extraction with ethyl acetate (50 mL x 3) was performed, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by column chromatography to obtain a colorless oil (1.2 g) in a yield of 67.4%.

[0058] (4) Preparation of 2-(3-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonate (1.2 g, 3.8 mmol), 50 mL of absolute ethanol, and 50 mL of aqueous sodium hydroxide (0.4 g, 9.4 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add 50 mL of water to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and collect the solvent to obtain 0.8 g of colorless oil. The yield is 80.9%.

[0059] (5) Preparation of 2-(3-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.2 g, 0.8 mmol), 20 mL of methylene dichloride, and 1 drop of N,N-dimethylformamide to a 50 mL round-bottom flask, mix, and add oxalyl chloride (0.4 g, 3.1 mmol) dropwise while stirring at room temperature. After reacting at room temperature for 2-4 hours, remove the solvent under reduced pressure and add 20 mL of methylene dichloride to store.

[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-neck flask, mixed, and reacted at 78 °C for 6 to 10 hours. After the reaction is complete, the mixture is removed of the solvent 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-oxadiol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-basic-2-ol salt (Z1): Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (160.2 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride, and add 3 drops of triethylamine. Allow to react at room temperature for 20 minutes, and add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 125.0 mg of a yellow solid. The yield is 40.1%. EXAMPLES

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

[0063] (1)~(5) The same procedures as steps (1) to (5) in Example 1 are 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 are mixed in a 500 mL three-neck flask and reacted at 78 °C for 6 to 10 hours. After the reaction is completed, the mixture is removed of the solvent under reduced pressure, mixed with silica gel and separated using column chromatography to obtain 13.6 g of a pale yellow solid. The yield is 56.7%.

[0065] (7) Z2 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (150.9 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride, and add 3 drops of triethylamine. After reacting at room temperature for 20 minutes, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate using column chromatography to obtain 110.0 mg of a yellow solid. The yield is 36.4%. EXAMPLES

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

[0067] (1)~(5) The same procedures as steps (1) to (5) in 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 bicarbonate (13.4 g, 159.4 mmol), and 100 mL of water are placed in a 250 mL three-neck flask and stirred at 90°C for 30 minutes. Then, add 50 mL of ethanol solution of 2-chloro-5-chloromethylpyridine (17.2 g, 106.3 mmol). After the addition is complete, increase the temperature to 100°C and react for 4-6 hours. After the reaction is complete, cool to room temperature, add 100 mL of water, and then extract with ethyl acetate (100 mL x 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 tan oil. The yield is 57.4%.

[0069] (7) Z3 Production: Add 10 mL of a solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (146.9 mg, 0.7 mmol) in methylene dichloride to the solution of 2-(3-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride in methylene dichloride, and add 3 drops of triethylamine. After reacting for 20 minutes at room temperature, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate using column chromatography to obtain 98.0 mg of a yellow solid. The yield is 32.9%. EXAMPLES

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

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

[0072] (6) Preparation of 3-(pyridin-2-ylamino)propionitrile: Add di-tert-butyl dicarbonate (24.0 g, 110.0 mmol) and 150 mL of tert-butanol to a 25 mL three-neck flask, and slowly add 2-aminopyridine (9.4 g, 100.0 mmol) while stirring at room temperature. Continue stirring at room temperature for 5 hours after the addition. After the reaction is complete, remove the solvent from the mixture under reduced pressure, mix with silica gel, and separate N-tert-butoxycarbonyl-2-aminopyridine by column chromatography.

[0073] Next, add DMF (50 mL) and sodium hydride (5.7 g, 143.1 mmol) to a 500 mL three-neck flask, and slowly add N-tert-butoxycarbonyl-2-aminopyridine (13.9 g, 71.6 mmol) while stirring at room temperature. After the addition, stir at 60 °C for 1 hour, then add 3-bromopropionitrile (11.5 g, 85.9 mmol) and continue stirring at 60 °C for another 1 hour. The reaction is stopped, and 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 saline (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 (2-cyanoethyl)-(pyridin-2-yl)aminocarbamate tert-butyl.

[0074] Add 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) to a 100 mL round-bottom flask and stir at room temperature for 12 hours. Then, adjust the pH of the reaction system to slightly alkaline with saturated sodium bicarbonate solution. Keep the separated organic phase and extract the aqueous phase with methylene dichloride (50 mL x 2). Combine the three organic layers, wash with saturated saline (50 mL x 2), dry with anhydrous sodium sulfate, concentrate, mix with silica gel, and separate by column chromatography to obtain 5.8 g of 3-(pyridin-2-ylamino)propionitrile. The yield is 39.4%.

[0075] (7) Z4 Production: Add 10 mL of a solution of 3-(pyridin-2-ylamino)propionitrile (98.4 mg, 0.7 mmol) in methylene dichloride to the solution of 2-(3-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride in methylene dichloride, and add 3 drops of triethylamine. After reacting for 20 minutes at room temperature, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 68.0 mg of a yellow solid. The yield is 27.2%. EXAMPLES

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

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

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

[0079] (Z)-N′-hydroxy-3-iodine imidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) are added to a 100 mL three-necked round-bottom flask, and propionyl 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, and then cooled to room temperature after the reaction is complete. The solvent is removed, and the product is mixed with silica gel and separated by column chromatography to obtain 1.7 g of a white solid. The yield is 74.2%.

[0080] (3) Preparation of diethyl 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonate: 3-(3-iodophenyl)-5-ethyl-1,2,4-oxadiol (1.7 g, 5.7 mmol), 2-pyridinecarboxylic acid (139.5 mg, 1.1 mmol), copper iodide (107.9 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) are added to a 200 mL Schlenk flask, and diethyl malonate (1.8 g, 11.3 mmol) is added under a nitrogen atmosphere. Next, dry 1,4-dioxane (50 mL) is added as a solvent, and the reaction system is heated to 90 °C and reacted for 8 to 12 hours. After the reaction is completed, it is cooled to room temperature and the reaction is stopped by adding saturated aqueous ammonium chloride solution (100 mL). Extraction is performed 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 1.3 g of a colorless oil. The yield was 69.1%.

[0081] (4) Preparation of 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonate (1.3 g, 3.9 mmol), 50 mL of absolute ethanol, and aqueous sodium hydroxide (0.4 g, 9.8 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add 50 mL of water to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the solvent to obtain 0.9 g of a colorless oil. The yield is 83.3%.

[0082] (5) Preparation of 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), methylene dichloride (20 mL), and one drop of N,N-dimethylformamide to a 50 mL round-bottom flask and mix. Add oxalyl chloride (0.4 g, 2.9 mmol) dropwise while stirring at room temperature and react at room temperature for 2-4 hours. After the reaction is complete, remove the solvent under reduced pressure and add methylene dichloride (20 mL) and store.

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

[0084] (7) Z5 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (144.2 mg, 0.6 mmol) to a methylene dichloride solution of 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction is complete, add 2 mL of anhydrous methanol to quench the reaction, mix with silica gel and separate by column chromatography to obtain 109.0 mg of a yellow solid. The yield is 36.6%. EXAMPLES

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

[0086] (1)~(5) The same method as steps (1) to (5) in Example 5 is used.

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

[0088] (7) Z6 Production: Add 10 mL of a methylene dichloride solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (140.3 mg, 0.6 mmol) to a methylene dichloride solution of 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction, mix with silica gel, and separate by column chromatography to obtain 85.0 mg of a yellow solid. The yield is 28.9%. EXAMPLES

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

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

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

[0092] (7) Z7 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (153.1 mg, 0.6 mmol) to a methylene dichloride solution of 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction, mix with silica gel, and separate by column chromatography to obtain 115.0 mg of a yellow solid. The yield is 37.5%. EXAMPLES

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

[0094] (1)~(5) The same method as steps (1) to (5) in Example 5 is used.

[0095] (6) The same method as in step (6) of Example 4 is used.

[0096] (7) Z8 Production: Add 10 mL of a methylene dichloride solution of 3-(pyridin-2-ylamino)propionitrile (94.0 mg, 0.6 mmol) to a methylene dichloride solution of 2-(3-(5-ethyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction, mix with silica gel, and separate by column chromatography to obtain 55.0 mg of a yellow solid. The yield is 22.2%. EXAMPLES

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

[0098] (1) The same method as in procedure (1) of Example 1 is used.

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

[0100] Add (Z)-N′-hydroxy-3-iodoimidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) to a 100 mL three-necked round-bottom flask, and add isobutyryl chloride (1.6 g, 15.3 mmol) dropwise while stirring at room temperature. Heat the reaction system to 100°C and react for 8-10 hours, and cool to room temperature after the reaction is complete. Remove the solvent, mix with silica gel, and separate 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-oxadiol-3-yl)phenyl)malonate: Add 3-(3-iodophenyl)-5-isopropyl-1,2,4-oxadiol (1.6 g, 5.1 mmol), 2-pyridinecarboxylic acid (125.4 mg, 1.0 mmol), copper iodide (97.0 mg, 0.5 mmol), and cesium carbonate (4.2 g, 12.7 mmol) to a 200 mL Schlenk flask. Add diethyl malonate (1.6 g, 10.2 mmol) and dry 1,4-dioxane (50 mL) under a nitrogen atmosphere. After the addition, heat the reaction system to 90°C and react for 8 to 12 hours. After the reaction is complete, cool to room temperature and add saturated aqueous ammonium chloride solution (100 mL) to quench the reaction. Then, extract with ethyl acetate (50 mL x 3) and combine the organic layers. After drying over anhydrous sodium sulfate and concentrating, the mixture was mixed with silica gel and separated by column chromatography to obtain a colorless oil (1.3 g) in a yield of 73.7%.

[0102] (4) Preparation of 2-(3-(5-isopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-(5-isopropyl-1,2,4-oxadiol-3-yl)phenyl)malonate (1.3 g, 3.8 mmol), absolute ethanol (50 mL), and aqueous sodium hydroxide (0.4 g, 9.4 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add water (50 mL) to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Then adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL×3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the solvent to obtain a colorless oil (1.0 g). The yield is 91.8%.

[0103] (5) Preparation of 2-(3-(5-isopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-(5-isopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), methylene dichloride (20 mL), and one drop of N,N-dimethylformamide to a 50 mL round-bottom flask and add oxalyl chloride (0.4 g, 2.8 mmol) dropwise with stirring at room temperature. After reacting at room temperature for 2-4 h, remove the solvent under reduced pressure and add methylene dichloride (20 mL) and store.

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

[0105] (7) Preparation of 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-isopropyl-1,2,4-oxadiol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-basic-2-ol salt (Z9): Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (155.5 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-isopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain a yellow solid (87.0 mg). The yield is 26.3%. EXAMPLES

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

[0107] (1)~(5) The same method as steps (1) to (5) in Example 9 is used.

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

[0109] (7) Z10 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (165.2 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-isopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 94.0 mg of a yellow solid. The yield is 27.6%. EXAMPLES

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

[0111] (1) The same method as in procedure (1) of Example 1 is used.

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

[0113] (Z)-N'-hydroxy-3-iodine imidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) were added to a 100 mL three-necked round bottom flask, and cyclopropylcarbonyl chloride (1.6 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, the mixture was cooled to room temperature and the solvent was removed. The product was mixed with silica gel and separated by column chromatography to obtain a white solid (1.8 g). The yield was 75.6%.

[0114] (3) Preparation of diethyl 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonate: Add 3-(3-iodophenyl)-5-cyclopropyl-1,2,4-oxadiol (1.8 g, 5.7 mmol), 2-pyridinecarboxylic acid (142.0 mg, 1.2 mmol), copper iodide (109.8 mg, 0.6 mmol), and cesium carbonate (4.7 g, 14.4 mmol) to a 200 mL Schlenk flask. Add diethyl malonate (1.9 g, 11.5 mmol) and dry 1,4-dioxane (50 mL) under a nitrogen atmosphere. After the addition, heat the reaction system to 90°C and react for 8 to 12 hours. After the reaction is complete, cool to room temperature and add saturated aqueous ammonium chloride solution (100 mL) to quench the reaction. Then, extract with ethyl acetate (50 mL x 3) and combine the organic layers. After drying over anhydrous sodium sulfate and concentrating, the mixture was mixed with silica gel and separated by column chromatography to obtain a colorless oil (1.4 g) in a 70.5% yield.

[0115] (4) Preparation of 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonate (1.4 g, 4.1 mmol), absolute ethanol (50 mL), and aqueous sodium hydroxide (0.4 g, 10.2 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add water (50 mL) to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Then adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the solvent to obtain a colorless oil (1.0 g). The yield is 85.3%.

[0116] (5) Preparation of 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), methylene dichloride (20 mL), and one drop of N,N-dimethylformamide to a 50 mL round-bottom flask and add oxalyl chloride (0.4 g, 2.8 mmol) dropwise with stirring at room temperature. After reacting at room temperature for 2-4 h, remove the solvent under reduced pressure and add methylene dichloride (20 mL) and store.

[0117] (6) The same method as in step (6) of Example 2 is used.

[0118] (7) Z11 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (156.6 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 56.0 mg of a yellow solid. The yield is 16.9%. EXAMPLES

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

[0120] (1)~(5) The same method as steps (1) to (5) in Example 11 is used.

[0121] (6) The same method as in step (6) of Example 3 is used.

[0122] (7) Z12 Production: Add 10 mL of a methylene dichloride solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (152.4 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 35.0 mg of a yellow solid. The yield is 10.7%. EXAMPLES

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

[0124] (1)~(5) The same method as steps (1) to (5) in Example 11 is used.

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

[0126] (7) Z13 Production: Add 10 mL of a methylene dichloride solution of 3-(pyridin-2-ylamino)propionitrile (70.2 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 59.0 mg of a yellow solid. The yield is 21.3%. EXAMPLES

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

[0128] (1)~(5) The same method as steps (1) to (5) in Example 11 is used.

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

[0130] (7) Z14 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (166.3 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 121.0 mg of a yellow solid. The yield is 35.5%. EXAMPLES

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

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

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

[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, the mixture was cooled to room temperature and the solvent was removed. The product 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-oxadiol-3-yl)phenyl)malonate: Add 3-(3-iodophenyl)-5-cyclobutyl-1,2,4-oxadiol (1.8 g, 5.5 mmol), 2-pyridinecarboxylic acid (135.9 mg, 1.1 mmol), copper iodide (105.1 mg, 0.6 mmol), and cesium carbonate (4.5 g, 13.8 mmol) to a 200 mL Schlenk flask. Add diethyl malonate (1.8 g, 11.0 mmol) and dry 1,4-dioxane (50 mL) under a nitrogen atmosphere. After the addition, heat the reaction system to 90°C and react for 8 to 12 hours. After the reaction is complete, cool to room temperature and add saturated aqueous ammonium chloride solution (100 mL) to quench the reaction. Then, extract with ethyl acetate (50 mL x 3) and combine the organic layers. After drying over anhydrous sodium sulfate and concentrating, the mixture was mixed with silica gel and separated by column chromatography to obtain a colorless oil (1.5 g) in a yield of 75.8%.

[0136] (4) Preparation of 2-(3-(5-cyclobutyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-(5-cyclobutyl-1,2,4-oxadiol-3-yl)phenyl)malonate (1.5 g, 4.2 mmol), absolute ethanol (50 mL), and aqueous sodium hydroxide (0.4 g, 10.5 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add water (50 mL) to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Then adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the solvent to obtain a colorless oil (1.1 g). The yield is 86.9%.

[0137] (5) Preparation of 2-(3-(5-cyclobutyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-(5-cyclobutyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), methylene dichloride (20 mL), and one drop of N,N-dimethylformamide to a 50 mL round-bottom flask and add oxalyl chloride (0.4 g, 2.7 mmol) dropwise with stirring at room temperature. After reacting at room temperature for 2-4 h, remove the solvent under reduced pressure and add methylene dichloride (20 mL) and store.

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

[0139] (7) Z15 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (149.3 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-cyclobutyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 107.0 mg of a yellow solid. The yield is 32.87%. EXAMPLES

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

[0141] (1)~(5) The same method as steps (1) to (5) in Example 15 is used.

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

[0143] (7) Z16 Production: Add 10 mL of a methylene dichloride solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (145.3 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-cyclobutyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 66.0 mg of a yellow solid. The yield is 20.5%. EXAMPLES

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

[0145] (1)~(5) The same method as steps (1) to (5) in Example 15 is used.

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

[0147] (7) Z17 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (158.6 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-(5-cyclobutyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 132.0 mg of a yellow solid. The yield is 39.4%. EXAMPLES

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

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

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

[0151] (Z)-N′-hydroxy-3-iodine imidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) were added to a 100 mL three-necked round-bottom flask, and acryloyl 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 8-10 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed. The product was mixed with silica gel and separated by column chromatography to obtain a white solid (1.1 g). The yield was 48.4%.

[0152] (3) Preparation of diethyl 2-(3-(5-ethenyl-1,2,4-oxadiol-3-yl)phenyl)malonate: 3-(3-iodophenyl)-5-ethenyl-1,2,4-oxadiol (1.1 g, 3.7 mmol), 2-pyridinecarboxylic acid (90.9 mg, 0.7 mmol), copper 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 the addition, the reaction system is heated to 90°C and reacted for 8 to 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 x 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 (0.8 g). The yield was 65.6%.

[0153] (4) Preparation of 2-(3-(5-ethenyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-(5-ethenyl-1,2,4-oxadiol-3-yl)phenyl)malonate (0.8 g, 2.4 mmol), absolute ethanol (50 mL), and aqueous sodium hydroxide (0.2 g, 6.1 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add water (50 mL) to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Then adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the solvent to obtain a colorless oil (0.4 g). The yield is 60.2%.

[0154] (5) Preparation of 2-(3-(5-ethenyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-(5-ethenyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.4 g, 1.5 mmol), methylene dichloride (20 mL), and one drop of N,N-dimethylformamide to a 50 mL round-bottom flask and add oxalyl chloride (0.7 g, 5.8 mmol) dropwise with stirring at room temperature. After reacting at room temperature for 2-4 h, remove the solvent under reduced pressure and add methylene dichloride (20 mL) and store.

[0155] (6) The same method as in step (6) of Example 2 is used.

[0156] (7) Z18 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (329.2 mg, 1.5 mmol) to a methylene dichloride solution of 2-(3-(5-ethenyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 48.0 mg of a yellow solid. The yield is 7.1%. EXAMPLES

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

[0158] (1) The same method as in procedure (1) of Example 1 is used.

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

[0160] (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 benzoyl chloride (2.2 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, the mixture was cooled to room temperature and the solvent was removed. The product was mixed with silica gel and separated by column chromatography to obtain a white solid (2.1 g). The yield was 79.0%.

[0161] (3)~(7) Proceed in the same manner to obtain a yellow solid (90.0 mg) in 28.4% yield. EXAMPLES

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

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

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

[0165] (7) Z20 Production: Add 10 mL of a methylene dichloride solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (135.5 mg, 0.6 mmol) to a methylene dichloride solution of 2-(3-(5-phenyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 52.0 mg of a yellow solid. The yield is 16.6%. EXAMPLES

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

[0167] (1) The same method as in procedure (1) of Example 1 is used.

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

[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-neck round-bottom flask. Heat the reaction system to 100°C and react for 8-10 hours. After the reaction is complete, 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-oxadiol-3-yl)phenyl)malonate: Add 3-(3-iodophenyl)-5-(trifluoromethyl)-1,2,4-oxadiol (1.9 g, 5.6 mmol), 2-pyridinecarboxylic acid (137.6 mg, 1.1 mmol), copper iodide (106.4 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) to a 200 mL Schlenk flask. Add diethyl malonate (1.8 g, 12.2 mmol) and dry 1,4-dioxane (50 mL) under a nitrogen atmosphere. After the addition, heat the reaction system to 90°C and react for 8 to 12 hours. After the reaction is complete, cool to room temperature and add saturated aqueous ammonium chloride solution (100 mL) to quench the reaction. Then, extract with ethyl acetate (50 mL x 3) and combine the organic layers. After drying over anhydrous sodium sulfate and concentrating, the mixture was mixed with silica gel and separated by column chromatography to obtain a colorless oil (1.5 g) in a yield of 72.1%.

[0171] (4) Preparation of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonate (1.5 g, 4.0 mmol), absolute ethanol (50 mL), and aqueous sodium hydroxide (0.4 g, 10.1 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add water (50 mL) to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Then adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the solvent to give a colorless oil (0.8 g). The yield is 62.8%.

[0172] (5) Preparation of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.2 g, 0.6 mmol), methylene dichloride (20 mL), and one drop of N,N-dimethylformamide to a 50 mL round-bottom flask and add oxalyl chloride (0.3 g, 2.5 mmol) dropwise with stirring at room temperature. After reacting at room temperature for 2-4 h, remove the solvent under reduced pressure and add methylene dichloride (20 mL) and store.

[0173] (6) The same method as in step (6) of Example 2 is used.

[0174] (7) Z21 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (142.8 mg, 0.6 mmol) to a methylene dichloride solution of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 47.0 mg of a yellow solid. The yield is 14.7%. EXAMPLES

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

[0176] (1) The same method as in procedure (1) of Example 1 is used.

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

[0178] (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 dichloroacetyl chloride (2.3 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, the mixture was cooled to room temperature and the solvent was removed. The product was mixed with silica gel and separated by column chromatography to obtain a white solid (1.6 g). The yield was 59.1%.

[0179] (3) Preparation of diethyl 2-(3-(5-(dichloromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonate: Add 5-(dichloromethyl)-3-(3-iodophenyl)-1,2,4-oxadiol (1.6 g, 4.5 mmol), 2-pyridinecarboxylic acid (111.0 mg, 0.9 mmol), copper iodide (85.9 mg, 0.5 mmol), and cesium carbonate (3.7 g, 11.3 mmol) to a 200 mL Schlenk flask. Add diethyl malonate (1.4 g, 9.0 mmol) and dry 1,4-dioxane (50 mL) under a nitrogen atmosphere. After the addition, heat the reaction system to 90°C and react for 8 to 12 hours. After the reaction is complete, cool to room temperature and add saturated aqueous ammonium chloride solution (100 mL) to quench the reaction. Then, extract with ethyl acetate (50 mL x 3) and combine the organic layers. After drying over anhydrous sodium sulfate and concentrating, the mixture was mixed with silica gel and separated by column chromatography to obtain a colorless oil (0.9 g) in a yield of 51.6%.

[0180] (4) Preparation of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-(5-(dichloromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonate (0.9 g, 2.3 mmol), absolute ethanol (50 mL), and aqueous sodium hydroxide (0.2 g, 5.8 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add water (50 mL) to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Then adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the solvent to obtain a colorless oil (0.5 g). The yield is 65.0%.

[0181] (5) Preparation of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-(5-(dichloromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.2 g, 0.6 mmol), methylene dichloride (20 mL), and one drop of N,N-dimethylformamide to a 50 mL round-bottom flask and add oxalyl chloride (0.3 g, 2.4 mmol) dropwise with stirring at room temperature. After reacting at room temperature for 2-4 h, remove the solvent under reduced pressure and add methylene dichloride (20 mL) and store.

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

[0183] (7) Z22 Production: Add 10 mL of a methylene dichloride solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (132.7 mg, 0.6 mmol) to a methylene dichloride solution of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain 28.0 mg of a yellow solid. The yield is 9.0%. EXAMPLES

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

[0187] (Z)-N′-hydroxy-3-iodine imidazolidone (2.0 g, 7.6 mmol) and pyridine (30 mL) were added to a 100 mL three-necked round-bottom flask, and trichloroacetyl chloride (2.8 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, the mixture was cooled to room temperature and the solvent was removed. The product was mixed with silica gel and separated by column chromatography to obtain a white solid (1.8 g). The yield was 60.6%.

[0188] (3)~(7) Proceed in a similar manner to give Z23 as a yellow solid (25.0 mg, 8.3% yield). EXAMPLES

[0189] Example 24: Preparation of 3-(3-chloro-5-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)-1-((2-chlorothiazol-5-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidinium-1-basic-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 bicarbonate (1.0 g, 11.4 mmol), absolute ethanol (20 mL), and water (5 mL) are added to a 100 mL three-neck flask. The reaction system is heated to reflux temperature and reacted for 6 to 8 hours. After the reaction is complete, the solvent is concentrated and 30 mL of water is added to precipitate a large amount of white solid. The solid 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-oxadiol:

[0192] (Z)-3-Chloro-N'-hydroxy-3-iodoimidazolidone (2.0 g, 6.8 mmol) and pyridine (30 mL) were added to a 100 mL three-necked round bottom flask, and acetyl chloride (1.1 g, 13.5 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, the mixture was cooled to room temperature and the solvent was removed. The product was mixed with silica gel and separated by column chromatography to obtain a white solid (1.5 g). The yield was 69.4%.

[0193] (3) Preparation of diethyl 2-(3-chloro-5-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonate: Add 3-(3-chloro-5-iodophenyl)-5-methyl-1,2,4-oxadiol (1.5 g, 4.7 mmol), 2-pyridinecarboxylic acid (115.2 mg, 0.9 mmol), copper iodide (89.1 mg, 0.5 mmol), and cesium carbonate (3.8 g, 11.7 mmol) to a 200 mL Schlenk flask. Add diethyl malonate (1.5 g, 9.4 mmol) and dry 1,4-dioxane (50 mL) under a nitrogen atmosphere. Heat the reaction to 90°C and react for 8-12 hours. After the reaction is complete, cool to room temperature and add saturated aqueous ammonium chloride solution (100 mL) to quench the reaction. Then, extract with ethyl acetate (50 mL x 3) and combine the organic layers. After drying over anhydrous sodium sulfate and concentrating, the mixture was mixed with silica gel and separated by column chromatography to obtain a colorless oil (1.0 g) in a yield of 60.6%.

[0194] (4) Preparation of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid: Add diethyl 2-(3-chloro-5-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonate (1.0 g, 2.8 mmol), absolute ethanol (50 mL), and aqueous sodium hydroxide (0.3 g, 7.1 mmol) to a 250 mL round-bottom flask and stir at room temperature. After hydrolysis is complete, concentrate the solvent and add water (50 mL) to the residue. Extract once with ethyl acetate (50 mL) to remove impurities and collect the aqueous phase. Then adjust the pH to acidic with 6 N hydrochloric acid and extract with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the solvent 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-oxadiol-3-yl)phenyl)malonic acid chloride: Add 2-(3-chloro-5-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), methylene dichloride (20 mL), and one drop of N,N-dimethylformamide to a 50 mL round-bottom flask and add oxalyl chloride (0.3 g, 2.7 mmol) dropwise with stirring at room temperature. After reacting at room temperature for 2-4 h, remove the solvent under reduced pressure and add methylene dichloride (20 mL) and store.

[0196] (6) The same method as in step (6) of Example 2 is used.

[0197] (7) Z24 Production: Add 10 mL of a methylene dichloride solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (152.2 mg, 0.7 mmol) to a methylene dichloride solution of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate by column chromatography to obtain a yellow solid (81.0 mg). The yield is 24.7%. EXAMPLES

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

[0199] (1)~(5) The same method as steps (1) to (5) of Example 24 is used.

[0200] (6) The same method as in step (6) of Example 3 is used.

[0201] (7) Z25 Production: Add 10 mL of a methylene dichloride solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (135.5 mg, 0.6 mmol) to a methylene dichloride solution of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiol-3-yl)phenyl)malonic acid chloride. Add 3 drops of triethylamine and react at room temperature for 20 minutes. After the reaction, add 2 mL of anhydrous methanol to quench the reaction. Mix with silica gel and separate 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 analytical results. JPEG0007660866000008.jpg221170JPEG0007660866000009.jpg219170JPEG00076608660 00010.jpg242170JPEG0007660866000011.jpg239170JPEG0007660866000012.jpg215170

[0203] Test Example 1: Measurement of biological activity of target compounds for controlling broad bean aphids indoors The target compound is dissolved in DMSO solution and diluted with TW-80 to prepare a stock solution with a concentration of 1 g / L, which is then diluted with TW-80 to prepare test solutions with concentrations of 100.0, 10.0, 1.0 μg / mL and other concentrations.

[0204] 20-30 3rd instar broad bean aphids are inoculated into pots containing broad bean seedlings, and 2 mL of the test solution is sprayed onto each pot. TW-80 solution containing DMSO is used as a blank control. Each test condition is repeated three times. The broad bean aphids after treatment 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 methods for calculating lethality and calibrated lethality are as follows: Activity data are shown in Table 2. Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 2: Mortality of compounds Z1 to Z25 against broad bean aphids JPEG0007660866000013.jpg180170 Test results The results of the insecticidal activity confirmed that the compounds of the present invention exhibited good insecticidal activity against broad bean aphids. Many of the compounds showed 100% lethality against broad bean aphids at a concentration of 100 μg / mL. Some compounds maintained 100% lethality even at a concentration of 10 μg / mL.

[0206] Test Example 2: Measurement of biological activity of target compounds for controlling green rice leafhoppers indoors The target compound is dissolved in DMSO solution and diluted with TW-80 to prepare a stock solution with a concentration of 1 g / L, which is then diluted with TW-80 to prepare test solutions with concentrations of 100.0, 10.0, 1.0 μg / mL and other concentrations.

[0207] Pots containing rice seedlings are inoculated with 20-30 3rd instar green rice leafhoppers, and 2 mL of the test solution is sprayed on each pot. TW-80 solution containing DMSO is used as a blank control. Each test condition is repeated three times. After treatment, the green rice leafhoppers 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.

[0208] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 3: Mortality of compounds Z1 to Z25 against green rice leafhoppers JPEG0007660866000014.jpg173170Test results From the results of the insecticidal activity, it was confirmed that the compounds of the present invention exhibit good insecticidal activity against the green rice leafhopper. Many of the compounds showed 100% lethality against the green rice leafhopper at a concentration of 100 μg / mL. Among them, compounds Z3 and Z19 showed 100% lethality even at a concentration of 10 μg / mL.

[0209] Test Example 3: Measurement of biological activity of target compounds against diamondback moth indoors The target compound is dissolved in DMSO solution and diluted with TW-80 to prepare a stock solution with a concentration of 1 g / L, which is then diluted with TW-80 to prepare test solutions with concentrations of 100.0, 10.0, 1.0 μg / mL and other concentrations.

[0210] Cabbage leaves are immersed in the insecticide solutions of different concentrations for 3-5 seconds, while control leaves are treated with TW-80 solution containing DMSO. The leaves are dried at room temperature for 2 hours and then placed in a 10 cm diameter culture dish. Each concentration test is repeated three times, with 10 second-instar larvae used for each test. Finally, the culture dish is stored in an incubator that satisfies the following conditions: 26 °C, 70% RH (relative humidity), 14:10 h (light:dark cycle). The results are observed after 48 hours, and the mortality rate is recorded.

[0211] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 4: Mortality of compounds Z1 to Z25 against diamondback moth JPEG0007660866000015.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 diamondback moth. Many of the compounds showed 100% lethality against diamondback moth at a concentration of 100 μg / mL. Among them, compounds Z1, Z7, and Z14 showed 100% lethality even at a concentration of 10 μg / mL.

[0212] Test Example 4: Measurement of biological activity of target compounds against corn pests (European corn borer) indoors The test subjects are third-instar European corn borer larvae reared indoors with uniform physiological status, and 10 test larvae are selected for each culture dish. Two corn leaf pieces, each 2 cm long, are placed in the culture dish. The test solution is sprayed using a spray tower, and each concentration is replicated three times. The corresponding concentration of acetone is used as a control. After treatment, the test larvae are transferred to rearing conditions and reared. The results are observed after 48 hours, and the number of dead larvae is recorded.

[0213] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 5: Mortality of compound Z1 against the European corn borer JPEG0007660866000016.jpg22170 Test results The insecticidal activity of compound Z1 was confirmed to have excellent insecticidal activity against corn pests (green rice leafhopper). In particular, the mortality rate was 100% even at a concentration of 5 μg / mL.

[0214] Test Example 5: Measurement of biological activity of target compounds against gypsy moths indoors The test subjects are third-instar gypsy moth larvae reared indoors with uniform physiological conditions, and 10 test insects are selected for each culture dish. Two corn leaf pieces, each 2 cm long, are placed in the culture dish. The test solution is sprayed using a spray tower, and each concentration is replicated three times. The corresponding concentration of acetone is used as a control. After treatment, the test insects are transferred to rearing conditions and reared. The results are observed after 48 hours, and the number of dead insects is recorded.

[0215] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 6: Mortality of compound Z1 to gypsy moth JPEG0007660866000017.jpg23170 Test results The insecticidal activity of compound Z1 was confirmed to be excellent against gypsy moth, with a mortality rate of 100% even at a concentration of 5 μg / mL.

[0216] Test Example 6: Measurement of biological activity of target compounds for controlling armyworm in the room The test subjects are third-instar armyworm moth larvae reared indoors with uniform physiological conditions, and 10 test worms are selected for each culture dish. Two corn leaf pieces, each 2 cm long, are placed in the culture dish. The test solution is sprayed using a spray tower, and each concentration is replicated three times. The corresponding concentration of acetone is used as a control. After treatment, the test worms are transferred to rearing conditions and reared. The results are observed after 48 hours, and the number of dead worms is recorded.

[0217] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 7: Mortality of compound Z1 against armyworm moth JPEG0007660866000018.jpg30170 Test results The insecticidal activity results confirmed that compound Z1 exhibited excellent insecticidal activity against the armyworm moth, with a mortality rate of 95% at a concentration of 5 μg / mL.

[0218] Test Example 7: Measurement of biological activity of target compounds for planthopper control indoors The test subjects are third-instar planthopper larvae reared indoors with uniform physiological conditions, and 10 test insects are selected for each culture dish. Two corn leaf pieces, each 2 cm long, are placed in the culture dish. The test solution is sprayed using a spray tower, and each concentration is replicated three times. The corresponding concentration of acetone is used as a control. After treatment, the test insects are transferred to rearing conditions and reared. The results are observed after 48 hours, and the number of dead insects is recorded.

[0219] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 8: Mortality of compound Z1 against planthoppers JPEG0007660866000019.jpg29170 Test results The insecticidal activity results confirmed that compound Z1 exhibited excellent insecticidal activity against planthoppers (Rice Stem Borer). In particular, the lethality rate was 95% at a concentration of 5 μg / mL.

[0220] Test Example 8: Measurement of biological activity of target compounds for controlling rice beetles indoors Fourth instar rice beetle larvae reared indoors with uniform physiological status are used as test subjects, and 10 test insects are selected for each culture dish. Two corn leaf pieces, each 2 cm long, are placed in the culture dish. The test solution is sprayed using a spray tower, and each concentration is replicated three times. The corresponding concentration of acetone is used as a control. After treatment, the test insects are transferred to rearing conditions and reared. The results are observed after 48 hours, and the number of dead insects is recorded.

[0221] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 9: Mortality of compound Z1 against rice beetles JPEG0007660866000020.jpg29170 Test results The insecticidal activity results confirmed that compound Z1 exhibited excellent insecticidal activity against rice beetles, especially at a concentration of 5 μg / mL, the mortality rate was 90%.

[0222] Test Example 9: Measurement of biological activity of target compounds for corn moth control indoors The test subjects are second-instar corn moth larvae reared indoors with uniform physiological conditions, and 10 test insects are selected for each culture dish. Two corn leaf pieces, each 2 cm long, are placed in the culture dish. The test solution is sprayed using a spray tower, and each concentration is replicated three times. The corresponding concentration of acetone is used as a control. After treatment, the test insects are transferred to rearing conditions and reared. The results are observed after 48 hours, and the number of dead insects is recorded.

[0223] Calculation method Mortality rate = (number of dead insects) / (total number of treated insects) x 100 Calibrated lethality = (treatment lethality - blank lethality) / (1 - blank lethality) x 100 Table 10: Mortality of compound Z1 to corn moth JPEG0007660866000021.jpg27170Bioactivity test results The biological activity test confirmed that compound Z1 had excellent insecticidal activity against corn moths, and in particular, the mortality rate against rice beetles was 95% at a concentration of 5 μg / mL.

[0224] The results of these biological activity tests confirmed that the pyrido[1,2-a]pyrimidine mesoionic compound Z1 containing a 1,2,4-oxadiol structure exhibited excellent insecticidal activity against the following hemipteran and lepidopteran insects: aphids (broad bean aphid), scarabs (green rice leafhopper), caterpillars (diamond moth), corn pests (corn moth), armyworms, planthoppers (rice stem borer), rice beetles, and corn pests (corn moth).

[0225] The above-mentioned contents are only preferred embodiments of the present invention. Those skilled in the art can make some modifications and improvements without departing from the creative concept of the present invention. All such modifications and improvements shall fall within the protection scope of the present invention.

Claims

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

2. The present invention relates to a 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, and an agriculturally usable adjuvant, fungicide, insecticide, or herbicide. A composition comprising:

3. A use of 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, or the composition according to claim 2, in controlling agricultural pests, comprising: The agricultural pest is a rice planthopper, an aphid, a diamondback moth, a rice armyworm, a rice cutworm, a common cutworm, or a rice beetle.

23. The method of claim 22,

4. A method for treating an agricultural pest or its habitat by applying a pyrido[1,2-a]pyrimidine mesoionic compound having a 1,2,4-oxadiazole structure according to claim 1, a stereoisomer thereof, a salt thereof, or a solvate thereof, or a composition according to claim 2, The agricultural pest is a rice planthopper, an aphid, a diamondback moth, a rice armyworm, a rice cutworm, a common cutworm, or a rice beetle.

1. A method for controlling agricultural pests, comprising:

5. A method for preventing agricultural pests comprising the step of contacting an agricultural pest with the pyrido[1,2-a]pyrimidine mesoionic compound having a 1,2,4-oxadiazole structure according to claim 1, a stereoisomer thereof, a salt thereof, or a solvate thereof, or the composition according to claim 2, 1. A method for protecting a plant from an agricultural pest, comprising:

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