A pyrido[1, 2-a]pyrimidine mesoionic derivative containing 1,2,4-oxadiazole structure and its preparation and use

Abstract

The present invention relates to a pyrido[1,2-a]pyrimidine mesoionic derivative containing a 1,2,4-oxadiazole structure and a preparation method and use thereof. The compound has a structure of formula (I), has excellent insecticidal activity against bean aphids, white-backed plant hoppers, diamondback moths, fall armyworms, striped stem borers, armyworms, etc., and can be used to prepare drugs or medicaments for preventing and controlling pests such as aphids, rice plant hoppers, diamondback moths, fall armyworms, striped stem borers, armyworms, etc. The compound has a simple structure and preparation process, and has low production cost.

Description

Technical Field

[0001] The present invention relates to the field of chemical industry and pesticide, and in particular to a pyrido[1,2-a]pyrimidine mesoionic derivative containing a 1,2,4-oxadiazole unit and a preparation method thereof, and application of the pyrido[1,2-a]pyrimidine mesoionic derivative containing a 1,2,4-oxadiazole unit in medicines for preventing and controlling pests such as rice planthoppers, aphids, diamondback moths, fall armyworms, armyworms, Spodoptera litura, striped stem borers, rice leaf rollers and corn borers. Background Art

[0002] Hemiptera planthoppers, aphids and Lepidoptera diamondback moth, fall armyworm and striped stem borer are two important types of agricultural pests. Rice planthoppers are one of the main pests in rice production. They are explosive, hidden, migratory and destructive. In addition to their own damage to rice, they also spread viral diseases such as rice black-streaked dwarf disease and southern rice black-streaked dwarf disease, which seriously threaten my country's rice production safety and food security. Every year, 10 to 20 million hectares of rice are harmed in my country, accounting for about 50% of the total planting area. Rice planthoppers generally cause a loss of 10% to 20% in rice yield, and in severe cases, the loss can reach 40% to 60%, or even a total crop failure. Aphids are one of the most destructive pests of almost all cultivated crops. Due to their short life cycle, if there is no mortality, a female can produce billions of offspring every year. In addition to weakening plants by sucking sap, aphids can also cause leaf deformation. Aphids are also carriers of many plant viruses. The diamondback moth is one of the most destructive pests of cruciferous crops worldwide. It has the characteristics of high reproductive capacity, rapid generation replacement, and long growing season. The fall armyworm is a native species in tropical and subtropical regions of the Americas. Due to the strong migration ability of the fall armyworm adults, this important agricultural pest has spread rapidly from the Americas to more than 100 countries around the world. The fall armyworm is highly polyphagous, has more than 270 hosts, and has a high potential for reproduction and spread. The Chilo suppressalis is distributed in all rice-growing areas in my country. It is a very important and difficult-to-prevent rice-boring pest. A large outbreak can cause a 30-50% reduction in rice production, which is a major biological disaster for rice. At present, most of the pesticides used to control agricultural pests such as aphids, rice planthoppers, diamondback moths, fall armyworms and Chilo suppressalis are conventional pesticides. They have problems such as high toxicity, difficulty in degradation, strong resistance, and unsafety to non-target organisms, and have gradually been restricted or banned. Therefore, the development of pesticides with novel structures, high efficiency, low risks and unique mechanisms of action has become an urgent issue to be addressed for green agricultural development and food security.

[0003] In 2016, the mesoionic insecticide triflurimidine registered in my country by Corteva (formerly DuPont) has highly effective insecticidal activity against rice planthoppers, has no cross-resistance with existing agents, and has low toxicity to non-target organisms, making it an effective control of resistant planthoppers. In addition to being effective against Hemipteran insects rice planthoppers and cotton aphids, another mesoionic insecticide dicloromezotiaz developed by DuPont also has high activity against Lepidoptera insects diamondback moth and fall armyworm, expanding the insecticidal spectrum of mesoionic compounds. These characteristics of mesoionic insecticides have made them a new hotspot in global research and development. Therefore, research on mesoionic insecticides with novel structures, led by triflurimidine and dicloromezotiaz, has become the main direction of pesticide creation at home and abroad.

[0004] Holyoke CW et al. of Corteva (formerly DuPont) first disclosed in patent WO2009099929A1 in 2009 a method for preparing a pyrido[1,2-a]pyrimidine mesoionic compound and its application as an insecticide. The compound has good insecticidal activity against diamondback moth, green peach aphid, cotton aphid and rice brown planthopper. Structure-activity relationship studies have shown that when the mesoionic parent ring is a pyrido[1,2-a]pyrimidine ring, the compound has good insecticidal activity, while when it is a thiazo[3,2-a]pyrimidine ring or an imidazo[1,2-a]pyrimidine ring, the compound has low insecticidal activity; when the 3-position of the pyrido[1,2-a]pyrimidine ring retains a benzene ring and the 3-position of the benzene ring is derivatized, the compound also has high insecticidal activity.

[0005] In 2011, Holyoke CW et al. of Corteva (formerly DuPont) disclosed in patent WO2011017342A2 a method for preparing a class of mesoionic compounds and their application as insecticides. This class of compounds has good insecticidal activity, and some compounds have a 100% lethality against diamondback moth, fall armyworm and cotton aphid at a concentration of 10 mg / L. Among them, dicloromezotiaz has high insecticidal activity against aphids and diamondback moth, and has been developed as a commercial drug. Structure-activity relationship studies have shown that when the 1-position of the pyrido[1,2-a]pyrimidine ring is substituted with 2-chlorothiazol-5-ylmethyl and the 9-position is substituted with methyl, the compound has the best insecticidal activity against diamondback moth and fall armyworm, and there is a "magical methyl" effect; when the 3-position of the pyrido[1,2-a]pyrimidine ring is substituted with a phenyl having a substituent, the compound also has excellent insecticidal activity.

[0006] In 2012, Holyoke CW et al. of Corteva (formerly DuPont) disclosed a class of pyridopyrimidine mesoionic compounds containing biaryl groups in patent Wo2012106495A1. This class of compounds exhibits excellent insecticidal activity against Lepidoptera, Homoptera and Thysanoptera insects, and has a broad insecticidal spectrum. Some compounds have a 100% lethality against Plutella xylostella and Spodoptera frugiperda at a concentration of 2 mg / L, and a lethality of over 80% against green peach aphid and potato leafhopper at a concentration of 10 mg / L.

[0007] Hasegawa S. et al. of Nippon Kayaku Co., Ltd. disclosed a series of mesoionic compounds containing cyanoethyl at the 1-position of the pyrido[1,2-a]pyrimidine ring in patent WO2016171053A1 in 2016. Most of the compounds containing cyanoethyl showed good to excellent insecticidal activity against cotton aphids and brown planthoppers. Some compounds had a 100% lethality against aphids at a concentration of 0.1 mg / L, and still had a lethality of more than 70% against brown planthoppers at a concentration of 0.05 mg / L. The structure-activity relationship shows that the insecticidal activity of the compound is optimal when the 1-position of the pyrido[1,2-a]pyrimidine ring is cyanoethyl and there is no substitution at the 6, 7, 8, and 9-positions of the pyrido[1,2-a]pyrimidine ring; and this type of compound is similar to triflurofen and dicloromezotiaz, and the insecticidal activity of the compound is high when the 3-position of the pyrido[1,2-a]pyrimidine ring retains the phenyl group and the 3-position of the phenyl group is derivatized.

[0008] In 2021, Holmes, M.; Holyoke, CW, Jr.; Kar, M.; Lahm, GP et al. disclosed a series of pyrido[1,2-a]pyrimidine mesoionic compounds containing alkyne structural units in patent WO2021151034Al. Most of the compounds have a mortality rate of 80% to 100% against diamondback moth and fall armyworm at a concentration of 0.4 mg / L, and a mortality rate of 70% to 100% against corn ash planthopper, potato leafhopper, peach aphid, cotton aphid and thrips at a concentration of 50 mg / L. The structure-activity relationship shows that when the 9-position of the pyrido[1,2-a]pyrimidine ring is methyl-substituted, the compound has high insecticidal activity against diamondback moth and fall armyworm.

[0009] In 2021, this research team disclosed a series of pyrido[1,2-a]pyrimidine-type mesoionic compounds containing isoxazole structural units in patent CN113651811A. This type of compound has good to excellent insecticidal activity against white-backed planthoppers. Some compounds have a mortality rate of 100% against white-backed planthoppers at a concentration of 10 mg / L. Among them, the compound "isothiazolidine" named by the National Pesticide Standardization Technical Committee still has a mortality rate of 100% against white-backed planthoppers at a concentration of 2 mg / L. The structure-activity relationship shows that the insecticidal activity of the compound is optimal when the 1-position of the pyrido[1,2-a]pyrimidine ring is substituted with 2-chlorothiazol-5-ylmethyl, the 6, 7, 8, and 9-positions of the pyrido[1,2-a]pyrimidine ring are unsubstituted, and the 3 and 5-positions of the isoxazole ring are substituted with methyl.

[0010] In the same year, our research team disclosed a series of pyrido[1,2-a]pyrimidine mesoionic compounds containing indole structural units in patent CN113292557A. These compounds have good insecticidal activity against white-backed planthoppers and broad bean aphids, and some compounds have a 100% lethality against white-backed planthoppers and broad bean aphids at a concentration of 10 mg / L.

[0011] 1,2,4-oxadiazole compounds belong to the five-membered heterocyclic compounds, have a wide range of pesticide biological activities, and show good biological activities such as insecticide, fungicide, and weed killer. For example, the seed treatment nematicide "Tioxazafen" developed by Bayer (formerly Monsanto) has the characteristics of broad spectrum, high efficiency, and novel mechanism of action. It is a 1,2,4-oxadiazole compound with high insecticidal and nematicidal activity.

[0012] In 2018, Xu Liangzhong and others from Qingdao University of Science and Technology disclosed a 1,2,4-oxadiazole compound containing diphenyl ether in patent CN108299409A. The compound had a mortality rate of 100% against beet armyworm at a concentration of 0.5 mg / L, which was better than the control agent tolfenpyrad.

[0013] In 2018, Wang Minghui and others from Qingdao University of Science and Technology published a series of 1,2,4-oxadiazole compounds containing pyridine structure in patent CN109336879A. These compounds have good to excellent insecticidal activity against Plutella xylostella, Tetranychus cinnabarinus and Tetranychus urticae. Among them, some compounds have a mortality rate of 80% against Plutella xylostella and 100% against Tetranychus urticae at a concentration of 10 mg / L, which is better than the control agent Tioxazafen.

[0014] In 2020, Dai Hong and others from Nantong University announced five 1,2,4-oxadiazole compounds containing 1,2,3-triazolobenzyloxypyrazole structure in patent CN111560015A. The insecticidal activity test results showed that the five 1,2,4-oxadiazole compounds had good insecticidal activity against armyworms, and the mortality rate to armyworms was 100% at a concentration of 500 mg / L.

[0015] Based on the above mesoionic insecticide triflubenzuron, which effectively controls various resistant planthoppers and leafhoppers, this research team developed a new mesoionic insecticide "isothiazide" based on triflubenzuron. In addition to being highly effective against planthoppers, it overcomes the disadvantage of triflubenzuron's toxicity to bees, but both have low efficacy against lepidopteran pests. Another mesoionic insecticide, dicloromezotiaz, developed by Corteva (formerly DuPont), can effectively control lepidopteran pests such as diamondback moth and fall armyworm on the basis of effective control of planthoppers, achieving a leap from controlling hemiptera pests to controlling both hemiptera pests and lepidopteran pests, providing strong support for the development of low-toxic, high-efficiency, novel-mechanism mesoionic insecticides that control both hemiptera and lepidopteran pests, highlighting the broad prospects of mesoionic compounds in controlling crop pests. Through the patent analysis of the above mesoionic insecticides, we know that: 1. When the mesoionic parent ring is a pyrido[1,2-a]pyrimidine ring, the compound has the best insecticidal activity; 2. When the 1-position of the pyrido[1,2-a]pyrimidine ring is an active group commonly found in neonicotinoid insecticides, the compound has high insecticidal activity; 3. When the 1-position of the pyrido[1,2-a]pyrimidine ring is substituted with 2-chlorothiazol-5-ylmethyl and the 9-position is substituted with methyl, the compound has high insecticidal activity against lepidopteran insects; 4. When the 3-position of the pyrido[1,2-a]pyrimidine ring retains a benzene ring or a five-membered aromatic heterocycle, the compound has strong insecticidal activity; 5. The compound has the best insecticidal activity when the meta-position of the phenyl group at the 3-position of the pyrido[1,2-a]pyrimidine ring is derivatized. Therefore, on the basis of retaining the key active structure of the mesoion, the inventors focused on creating insecticides for controlling Hemiptera and Lepidoptera pests, introduced a five-membered heterocyclic 1,2,4-oxadiazole structure with high biological activity into the meta position of the 3-phenyl group of the pyrido[1,2-a]pyrimidine structure, and designed and synthesized a series of pyrido[1,2-a]pyrimidine mesoion derivatives containing 1,2,4-oxadiazole structure. The results of biological activity screening showed that the mesoion derivatives had good insecticidal activity and a broad control spectrum. Summary of the invention

[0016] One of the purposes of the present invention is to provide a class of pyrido[1,2-a]pyrimidine mesoionic derivatives containing 1,2,4-oxadiazole structure and a preparation method thereof.

[0017] Another object of the present invention is to provide a composition containing the above compound or its salt or solvate.

[0018] Another object of the present invention is to provide the use of the above compound or its salt or solvate, or the composition.

[0019] Another object of the present invention is to provide a method for controlling agricultural pests using the above compound or its salt or solvate, or the composition.

[0020] The pyrido[1,2-a]pyrimidine-based ionic derivatives containing a 1,2,4-oxadiazole structure of the present invention have a general structural formula (I) as follows:

[0021] To achieve the above object, the present invention adopts the following technical solutions:

[0022]

[0023] R1 is 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 heteroaryl;

[0024] R2 is 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;

[0025] R3 and R4 are independently selected from one or more of hydrogen, deuterium, halogen, nitro, hydroxyl, amino, thiol, cyano, and any substituted or unsubstituted alkyl;

[0026] 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.

[0027] Preferably, R1 is independently selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C5-C6 heteroaryl;

[0028] R2 is independently selected from one or more of hydrogen, deuterium, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C5-C6 heteroaryl;

[0029] R3 and R4 are independently selected from one or more of hydrogen, deuterium, halogen, nitro, hydroxyl, amino, thiol, cyano, and C1-C6 alkyl;

[0030] R5 is independently selected from one or more of a C1-C6 alkyl group, a C1-C6 alkenyl group, a substituted or unsubstituted C6-C15 aryl group, and a substituted or unsubstituted C5-C6 heteroaryl group.

[0031] More preferably, R1 is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, -CH2CH2CN, -CHCNCH3, -CH2CH2CH2CN, -CH2CHCNCH3, -CHCNCH2CH3, -CH2CH2F, -CHFCH3, -CH2CH2CH2F, -CH2CHFCH3, -CHFCH2CH3, -CH2CH2Cl, -CHClCH3, -CH2CH2CH2Cl, -CH2CHClCH3, -CHClCH2CH3, -CH2CH2Br, -CHBrCH3, -CH2CH2CH2Br, -CH2CHBrCH3, -CHBrCH2CH3,

[0032]

[0033] R5 is independently selected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2Cl, -CH2CH2Br, -CH2CH2F,

[0034]

[0035] Preferred compounds are compounds Z1 to Z25 described below.

[0036] The preparation method of the compound comprises:

[0037]

[0038] Preferably, it further comprises:

[0039]

[0040] Most preferably, it includes:

[0041]

[0042] The present invention also provides a composition, which contains the compound or its salt or solvate, and an agriculturally usable adjuvant or fungicide, insecticide or herbicide; preferably, the composition is in the form of emulsifiable concentrate (EC), dust (DP), wettable powder (WP), granule (GR), aqueous solution (AS), suspension (SC), ultra low volume spray (ULV), soluble powder (SP), microcapsule (MC), smoke concentrate (FU), emulsion in water (EW), water dispersible granule (WG).

[0043] The compound or its salt or solvate, or composition can be used for controlling agricultural pests and diseases, and the agricultural pests and diseases are Hemiptera and Lepidoptera pests; preferably, the agricultural pests are rice planthoppers, aphids, diamondback moths, fall armyworms, armyworms, Spodoptera litura, striped stem borer, rice leaf roller and corn borer.

[0044] The present invention provides a method for controlling agricultural pests and diseases, wherein the compound or its stereoisomer, or its salt or solvate, or the composition acts on harmful substances or their living environment; preferably, the agricultural pests and diseases are Hemiptera and Lepidoptera pests; more preferably, the agricultural pests are rice planthoppers, aphids, diamondback moths, fall armyworms, armyworms, Spodoptera litura, Chilo suppressalis, rice leaf rollers and corn borers.

[0045] The term "alkyl" as used herein includes both branched and straight chain saturated hydrocarbon groups having a specified number of carbon atoms. 1-10 "alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, for example, "C 1-6 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl) and the like.

[0046] "Alkenyl" is a hydrocarbon that includes both straight or branched structures and has one or more carbon-carbon double bonds that appear at any stable point in the chain. For example, "C2-6 alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl. Examples of alkenyl include, but are not limited to, 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.

[0047] The term "cycloalkyl" refers to cyclic alkyl groups, including mono-, bi- or polycyclic ring systems.3-7 Cycloalkyl is intended to include C3, C4, C5, C6 and C7 cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like. As used herein, "carbocycle" or "carbocycle residue" refers to any stable 3, 4, 5, 6 or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bi- or tricyclic ring, which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of these carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As described above, bridged rings are also included in the definition of carbocycles (e.g., [2.2.2]bicyclooctane). If not otherwise specified, preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, substituents on the ring may also be present on the bridge.

[0048] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.

[0049] The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine and iodine.

[0050] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11 to 14-membered tricyclic groups, having at least one heteroatom (O, S or N) in at least one ring, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroatom-containing heteroaryl may contain one or two oxygen or sulfur atoms and / or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, but the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom in any ring. If the other ring is a cycloalkyl or heterocycle, it is additionally optionally substituted with =0 (oxygen) when valence permits. Example

[0051] The present invention is further described below by way of examples. It should be understood that the methods described in the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, and simple improvements to the preparation methods of the present invention under the premise of the concept of the present invention belong to the scope of protection claimed in the present invention. All raw materials and solvents used in the examples are commercially available reagents of corresponding purity.

[0052] Example 1: 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]pyrimidin-1-ium-2-olate (Z1):

[0053] (1) Preparation of (Z)-N′-hydroxy-3-iodoimidazole amine:

[0054] 3-iodobenzonitrile (10.0 g, 43.7 mmol), hydroxylamine hydrochloride (3.6 g, 52.4 mmol), sodium bicarbonate (5.5 g, 65.5 mmol), anhydrous ethanol (100 mL) and water (20 mL) were mixed in a 250 mL three-necked flask, heated to reflux, and reacted for 6 to 8 hours. After the reaction was completed, the solvent was concentrated and 100 mL of water was added. A large amount of white solid precipitated, which was filtered and dried to obtain 9.8 g of white solid, with a yield of 85.7%.

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

[0056] (Z)-N′-Hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and acetyl chloride (1.2 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100°C and the reaction was carried out for 8 to 10 h. After the reaction was completed, the mixture was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.6 g of white solid in a yield of 73.3%.

[0057] (3) Preparation of diethyl 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0058] 3-(3-iodophenyl)-5-methyl-1,2,4-oxadiazole (1.6 g, 5.6 mmol), 2-pyridinecarboxylic acid (137.7 mg, 1.1 mmol), cuprous iodide (106.5 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) were added to a 200 mL Schlenk bottle, and diethyl malonate (1.8 g, 11.2 mmol) was added to the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90° C. and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.2 g of a colorless oil with a yield of 67.4%.

[0059] (4) Preparation of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0060] Add diethyl 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.2 g, 3.8 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.4 g, 9.4 mmol) into a 250 mL round-bottom flask and stir at room temperature. After complete hydrolysis, concentrate the solvent, add 50 mL of water to the residue, extract once with ethyl acetate (50 mL) to remove impurities, collect the aqueous phase, adjust the pH to acidic with 6N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the solvent to obtain 0.8 g of colorless oil, and the yield is 80.9%.

[0061] (5) Preparation of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0062] 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.8 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.4 g, 3.1 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0063] (6) Preparation of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine:

[0064] 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 were mixed in a 500 mL three-necked flask and reacted at 78°C for 6 to 10 hours. After the reaction was completed, the reaction mixture was decompressed and desolventized, and the sample was mixed with silica gel. 10.8 g of light yellow solid was separated by chromatography column, and the yield was 48.72%.

[0065] (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]pyrimidin-1-ium-2-olate (Z1):

[0066] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (160.2 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 125.0 mg of a yellow solid with a yield of 40.1%.

[0067] Example 2: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z2):

[0068] Steps (1) to (5) are the same as steps (1) to (5) in Example 1.

[0069] (6) Preparation of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine:

[0070] 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 mixed in a 500 mL three-necked flask and reacted at 78°C for 6 to 10 hours. After the reaction was completed, the reaction mixture was decompressed and desolventized, and the sample was mixed with silica gel and separated by chromatography to obtain 13.6 g of a light yellow solid with a yield of 56.7%.

[0071] (7) 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]pyrimidin-1-ium-2-olate (Z2):

[0072] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (150.9 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The reaction was carried out at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 110.0 mg of a yellow solid with a yield of 36.4%.

[0073] Example 3: 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z3):

[0074] Steps (1) to (5) are the same as steps (1) to (5) in Example 1.

[0075] (6) Preparation of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine:

[0076] 2-Aminopyridine (10.0 g, 106.3 mmol), sodium bicarbonate (13.4 g, 159.4 mmol) and 100 mL of water were mixed in a 250 mL three-necked flask, and stirred at 90°C for half an hour before adding 50 mL of ethanol solution of 2-chloro-5-chloromethylpyridine (17.2 g, 106.3 mmol) to the system. After the addition was completed, the system temperature was raised to 100°C and reacted for 4 to 6 hours. After the reaction was completed, the reaction system was cooled to room temperature, 100 mL of water was added, and then extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated by chromatography to obtain 13.4 g of a yellow-brown oil with a yield of 57.4%.

[0077] (7) 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]pyrimidin-1-ium-2-olate (Z3):

[0078] A 10 mL dichloromethane solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (146.9 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 98.0 mg of a yellow solid with a yield of 32.9%.

[0079] Example 4: 1-(2-cyanoethyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z4):

[0080] Steps (1) to (5) are the same as steps (1) to (5) in Example 1.

[0081] (6) Preparation of 3-(pyridin-2-ylamino)propionitrile:

[0082] In a 25mL three-necked flask, add di-tert-butyl dicarbonate (24.0g, 110.0mmol) and 150mL of tert-butanol, and slowly add 2-aminopyridine (9.4g, 100.0mmol) under stirring at room temperature. After the addition is completed, continue to stir at room temperature for 5h. After the reaction is completed, the reaction mixture is decompressed and desolventized, mixed with silica gel, and separated by chromatography column to obtain N-tert-butoxycarbonyl-2-aminopyridine. In a 500mL three-necked flask, 50mL of DMF and sodium hydride (5.7g, 143.1mmol) were added successively, and N-tert-butoxycarbonyl-2-aminopyridine (13.9g, 71.6mmol) was slowly added under stirring at room temperature. After the addition was completed, the mixture was stirred at 60°C. After 1 hour, 3-bromopropionitrile (11.5g, 85.9mmol) was added. The reaction was stopped after stirring at 60°C for 1 hour. The reaction mixture was poured into 500mL of water and extracted with ethyl acetate (200mL×2). The organic layers were combined, washed with saturated brine (200mL×2), dried over anhydrous sodium sulfate, concentrated, mixed with silica gel, and separated and purified by chromatography to obtain tert-butyl (2-cyanoethyl)-(pyridin-2-yl)carbamate. In a 100 mL round-bottom flask, add tert-butyl (2-cyanoethyl)-(pyridin-2-yl)carbamate (10.2 g, 41.3 mmol), 40 mL of dichloromethane and trifluoroacetic acid (18.8 g, 165.0 mmol), and stir at room temperature for 12 hours before stopping the reaction. Use saturated sodium bicarbonate aqueous solution to adjust the pH of the reaction system to be alkaline, separate the organic phase, extract the aqueous phase with dichloromethane (50 mL × 2), combine the three organic layers, wash with saturated brine (50 mL × 2), dry with anhydrous sodium sulfate, concentrate, mix with silica gel, separate and purify with a chromatography column to obtain 5.8 g of 3-(pyridin-2-ylamino)propionitrile, with a yield of 39.4%.

[0083] (7) Preparation of 1-(2-cyanoethyl)-3-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z4):

[0084] Add 10 mL of dichloromethane solution of 3-(pyridin-2-ylamino)propionitrile (98.4 mg, 0.7 mmol) to a dichloromethane solution of 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, add 3 drops of triethylamine, and react at room temperature for 20 min. After the reaction is completed, add 2 mL of anhydrous methanol to quench, mix the sample with silica gel, and separate by chromatography to obtain 68.0 mg of a yellow solid with a yield of 27.2%.

[0085] Example 5: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z5):

[0086] Step (1) is the same as step (1) in Example 1

[0087] (2) Preparation of 3-(3-iodophenyl)-5-ethyl-1,2,4-oxadiazole:

[0088] (Z)-N′-Hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and propionyl chloride (1.4 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100°C and the reaction was carried out for 8 to 10 h. After the reaction was completed, the mixture was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.7 g of white solid in a yield of 74.2%.

[0089] (3) Preparation of diethyl 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0090] 3-(3-iodophenyl)-5-ethyl-1,2,4-oxadiazole (1.7 g, 5.7 mmol), 2-pyridinecarboxylic acid (139.5 mg, 1.1 mmol), cuprous iodide (107.9 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) were added to a 200 mL Schlenk bottle, and diethyl malonate (1.8 g, 11.3 mmol) was added to the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90° C. and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.3 g of a colorless oil with a yield of 69.1%.

[0091] (4) Preparation of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0092] Add diethyl 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.3 g, 3.9 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.4 g, 9.8 mmol) into a 250 mL round-bottom flask and stir at room temperature. After complete hydrolysis, concentrate the solvent, add 50 mL of water to the residue, extract once with ethyl acetate (50 mL) to remove impurities, collect the aqueous phase, adjust the pH to acidic with 6N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the solvent to obtain 0.9 g of colorless oil, and the yield is 83.3%.

[0093] (5) Preparation of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0094] 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.4 g, 2.9 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0095] Step (6) is the same as step (6) in Example 2

[0096] (7) 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]pyrimidin-1-ium-2-olate (Z5):

[0097] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (144.2 mg, 0.6 mmol) was added to a dichloromethane solution of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 109.0 mg of a yellow solid with a yield of 36.6%.

[0098] Example 6: 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z6):

[0099] Steps (1) to (5) are the same as steps (1) to (5) of Example 5.

[0100] Step (6) is the same as step (6) in Example 3

[0101] (7) 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]pyrimidin-1-ium-2-olate (Z6):

[0102] A 10 mL dichloromethane solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (140.3 mg, 0.6 mmol) was added to a dichloromethane solution of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 85.0 mg of a yellow solid with a yield of 28.9%.

[0103] Example 7: 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]pyrimidin-1-ium-2-olate (Z7):

[0104] Steps (1) to (5) are the same as steps (1) to (5) of Example 5.

[0105] Step (6) is the same as step (6) in Example 1

[0106] (7) 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]pyrimidin-1-ium-2-olate (Z7):

[0107] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (153.1 mg, 0.6 mmol) was added to a dichloromethane solution of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The reaction was carried out at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 115.0 mg of a yellow solid with a yield of 37.5%.

[0108] Example 8: 1-(2-cyanoethyl)-3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z8):

[0109] Steps (1) to (5) are the same as steps (1) to (5) of Example 5.

[0110] Step (6) is the same as step (6) in Example 4

[0111] (7) Preparation of 1-(2-cyanoethyl)-3-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z8):

[0112] Add 10 mL of dichloromethane solution of 3-(pyridin-2-ylamino)propionitrile (94.0 mg, 0.6 mmol) to a dichloromethane solution of 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, add 3 drops of triethylamine, and react at room temperature for 20 min. After the reaction is completed, add 2 mL of anhydrous methanol to quench, mix the sample with silica gel, and separate by chromatography column to obtain 55.0 mg of yellow solid with a yield of 22.2%.

[0113] Example 9: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z9):

[0114] Step (1) is the same as step (1) in Example 1

[0115] (2) Preparation of 3-(3-iodophenyl)-5-isopropyl-1,2,4-oxadiazole:

[0116] (Z)-N,-hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and isobutyryl chloride (1.6 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100 ° C and reacted for 8 to 10 h. After the reaction was completed, it was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.6 g of white solid with a yield of 66.7%.

[0117] (3) Preparation of diethyl 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0118] 3-(3-iodophenyl)-5-isopropyl-1,2,4-oxadiazole (1.6 g, 5.1 mmol), 2-picolinic acid (125.4 mg, 1.0 mmol), cuprous iodide (97.0 mg, 0.5 mmol), and cesium carbonate (4.2 g, 12.7 mmol) were added into a 200 mL Schlenk bottle, and diethyl malonate (1.6 g, 10.2 mmol) was added into the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90°C and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added into the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.3 g of a colorless oil with a yield of 73.7%.

[0119] (4) Preparation of 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0120] Add diethyl 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.3 g, 3.8 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.4 g, 9.4 mmol) into a 250 mL round-bottom flask and stir at room temperature. After complete hydrolysis, concentrate the solvent, add 50 mL of water to the residue, extract once with ethyl acetate (50 mL) to remove impurities, collect the aqueous phase, adjust the pH to acidic with 6N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the solvent to obtain 1.0 g of colorless oil, and the yield is 91.8%.

[0121] (5) Preparation of 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0122] 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.4 g, 2.8 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0123] Step (6) is the same as step (6) in Example 2

[0124] (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]pyrimidin-1-ium-2-olate (Z9):

[0125] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (155.5 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 87.0 mg of a yellow solid with a yield of 26.3%.

[0126] Example 10: 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]pyrimidin-1-ium-2-olate (Z10):

[0127] Steps (1) to (5) are the same as steps (1) to (5) of Example 9.

[0128] Step (6) is the same as step (6) in Example 1

[0129] (7) 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]pyrimidin-1-ium-2-olate (Z10):

[0130] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (165.2 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 94.0 mg of a yellow solid with a yield of 27.6%.

[0131] Example 11: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z11):

[0132] Step (1) is the same as step (1) in Example 1

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

[0134] (Z)-N,-hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and cyclopropylcarbonyl chloride (1.6 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100 ° C and reacted for 8 to 10 h. After the reaction was completed, it was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.8 g of white solid with a yield of 75.6%.

[0135] (3) Preparation of diethyl 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0136] 3-(3-iodophenyl)-5-cyclopropyl-1,2,4-oxadiazole (1.8 g, 5.7 mmol), 2-pyridinecarboxylic acid (142.0 mg, 1.2 mmol), cuprous iodide (109.8 mg, 0.6 mmol), and cesium carbonate (4.7 g, 14.4 mmol) were added into a 200 mL Schlenk bottle, and diethyl malonate (1.9 g, 11.5 mmol) was added into the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90 ° C and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.4 g of a colorless oil with a yield of 70.5%.

[0137] (4) Preparation of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0138] Add diethyl 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.4 g, 4.1 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.4 g, 10.2 mmol) into a 250 mL round-bottom flask and stir at room temperature. After complete hydrolysis, concentrate the solvent, add 50 mL of water to the residue, extract once with ethyl acetate (50 mL) to remove impurities, collect the aqueous phase, adjust the pH to acidic with 6N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the solvent to obtain 1.0 g of colorless oil, and the yield is 85.3%.

[0139] (5) Preparation of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0140] 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.4 g, 2.8 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0141] Step (6) is the same as step (6) in Example 2

[0142] (7) 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]pyrimidin-1-ium-2-olate (Z11):

[0143] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (156.6 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 56.0 mg of a yellow solid with a yield of 16.9%.

[0144] Example 12: 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z12):

[0145] Steps (1) to (5) are the same as steps (1) to (5) of Example 11.

[0146] Step (6) is the same as step (6) in Example 3

[0147] (7) 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]pyrimidin-1-ium-2-olate (Z12):

[0148] A 10 mL dichloromethane solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (152.4 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 35.0 mg of a yellow solid with a yield of 10.7%.

[0149] Example 13: 1-(2-cyanoethyl)-3-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z13):

[0150] Steps (1) to (5) are the same as steps (1) to (5) of Example 11.

[0151] Step (6) is the same as step (6) in Example 4

[0152] (7) Preparation of 1-(2-cyanoethyl)-3-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z13):

[0153] Add 10 mL of dichloromethane solution of 3-(pyridin-2-ylamino)propionitrile (70.2 mg, 0.7 mmol) to a dichloromethane solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, add 3 drops of triethylamine, and react at room temperature for 20 min. After the reaction is completed, add 2 mL of anhydrous methanol to quench, mix the sample with silica gel, and separate by chromatography column to obtain 59.0 mg of yellow solid with a yield of 21.3%.

[0154] Example 14: 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]pyrimidin-1-ium-2-olate (Z14):

[0155] Steps (1) to (5) are the same as steps (1) to (5) of Example 11.

[0156] Step (6) is the same as step (6) in Example 1

[0157] (7) 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]pyrimidin-1-ium-2-olate (Z14):

[0158] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (166.3 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The reaction was carried out at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 121.0 mg of a yellow solid with a yield of 35.5%.

[0159] Example 15: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z15):

[0160] Step (1) is the same as step (1) in Example 1

[0161] (2) Preparation of 5-cyclobutyl-3-(3-iodophenyl)-1,2,4-oxadiazole:

[0162] (Z)-N′-Hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and cyclobutylcarbonyl chloride (1.8 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100°C and the reaction was carried out for 8 to 10 h. After the reaction was completed, the mixture was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.8 g of white solid in a yield of 72.3%.

[0163] (3) Preparation of diethyl 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0164] 3-(3-iodophenyl)-5-cyclobutyl-1,2,4-oxadiazole (1.8 g, 5.5 mmol), 2-pyridinecarboxylic acid (135.9 mg, 1.1 mmol), cuprous iodide (105.1 mg, 0.6 mmol), and cesium carbonate (4.5 g, 13.8 mmol) were added into a 200 mL Schlenk bottle, and diethyl malonate (1.8 g, 11.0 mmol) was added into the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90°C and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added into the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.5 g of a colorless oil with a yield of 75.8%.

[0165] (4) Preparation of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0166] Add diethyl 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.5 g, 4.2 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.4 g, 10.5 mmol) into a 250 mL round-bottom flask and stir at room temperature. After complete hydrolysis, concentrate the solvent, add 50 mL of water to the residue, extract once with ethyl acetate (50 mL) to remove impurities, collect the aqueous phase, adjust the pH to acidic with 6N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the solvent to obtain 1.1 g of colorless oil, and the yield is 86.9%.

[0167] (5) Preparation of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0168] 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.4 g, 2.7 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0169] Step (6) is the same as step (6) in Example 2

[0170] (7) 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]pyrimidin-1-ium-2-olate (Z15):

[0171] Add 10 mL of dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (149.3 mg, 0.7 mmol) to a dichloromethane solution of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, add 3 drops of triethylamine, and react at room temperature for 20 min. After the reaction is completed, add 2 mL of anhydrous methanol to quench, mix the sample with silica gel, and separate by chromatography to obtain 107.0 mg of a yellow solid with a yield of 32.87%.

[0172] Example 16: 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z16):

[0173] Steps (1) to (5) are the same as steps (1) to (5) of Example 15.

[0174] Step (6) is the same as step (6) in Example 3

[0175] (7) 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]pyrimidin-1-ium-2-olate (Z16):

[0176] A 10 mL dichloromethane solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (145.3 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 66.0 mg of a yellow solid with a yield of 20.5%.

[0177] Example 17: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)-9-methyl-4-oxo-4HH-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z17):

[0178] Steps (1) to (5) are the same as steps (1) to (5) of Example 15.

[0179] Step (6) is the same as step (6) in Example 1

[0180] (5) 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]pyrimidin-1-ium-2-olate (Z17):

[0181] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (158.6 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 132.0 mg of a yellow solid with a yield of 39.4%.

[0182] Example 18: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(5-vinyl-1,2,4-oxadiazol-3-yl)phenyl)-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z18):

[0183] Step (1) Example 1 Step (1)

[0184] (2) Preparation of 3-(3-iodophenyl)-5-vinyl-1,2,4-oxadiazole:

[0185] (Z)-N′-Hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and acryloyl chloride (1.4 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100°C and the reaction was carried out for 8 to 10 h. After the reaction was completed, the mixture was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.1 g of white solid in a yield of 48.4%.

[0186] (3) Preparation of diethyl 2-(3-(5-vinyl-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0187] 3-(3-iodophenyl)-5-vinyl-1,2,4-oxadiazole (1.1 g, 3.7 mmol), 2-pyridinecarboxylic acid (90.9 mg, 0.7 mmol), cuprous iodide (70.3 mg, 0.4 mmol), and cesium carbonate (3.0 g, 9.2 mmol) were added to a 200 mL Schlenk bottle, and diethyl malonate (1.2 g, 7.4 mmol) was added to the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90° C. and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 0.8 g of a colorless oil with a yield of 65.6%.

[0188] (4) Preparation of 2-(3-(5-vinyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0189] Add diethyl 2-(3-(5-vinyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (0.8 g, 2.4 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.2 g, 6.1 mmol) into a 250 mL round-bottom flask and stir at room temperature. After complete hydrolysis, concentrate the solvent, add 50 mL of water to the residue, extract once with ethyl acetate (50 mL) to remove impurities, collect the aqueous phase, adjust the pH to acidic with 6N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the solvent to obtain 0.4 g of colorless oil, and the yield is 60.2%.

[0190] (5) Preparation of 2-(3-(5-vinyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0191] 2-(3-(5-vinyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.4 g, 1.5 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.7 g, 5.8 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0192] Step (6) is the same as step (6) in Example 2

[0193] (7) Preparation of 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(5-vinyl-1,2,4-oxadiazol-3-yl)phenyl)-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z18):

[0194] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (329.2 mg, 1.5 mmol) was added to a dichloromethane solution of 2-(3-(5-vinyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 48.0 mg of a yellow solid with a yield of 7.1%.

[0195] Example 19: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)-4HH-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z19):

[0196] Step (1) Example 1 Step (1)

[0197] (2) Preparation of 3-(3-iodophenyl)-5-phenyl-1,2,4-oxadiazole:

[0198] (Z)-N′-Hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and benzoyl chloride (2.2 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100°C and the reaction was carried out for 8 to 10 h. After the reaction was completed, the mixture was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 2.1 g of a white solid with a yield of 79.0%.

[0199] (3) Preparation of diethyl 2-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0200] 3-(3-iodophenyl)-5-phenyl-1,2,4-oxadiazole (2.1 g, 6.0 mmol), 2-pyridinecarboxylic acid (148.5 mg, 1.2 mmol), cuprous iodide (114.9 mg, 0.6 mmol), and cesium carbonate (4.9 g, 15.1 mmol) were added to a 200 mL Schlenk bottle, and diethyl malonate (1.9 g, 12.1 mmol) was added to the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90° C. and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.8 g of a colorless oil with a yield of 78.5%.

[0201] (4) Preparation of 2-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0202] Add diethyl 2-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.8 g, 4.7 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.5 g, 11.8 mmol) into a 250 mL round-bottom flask and stir at room temperature. After complete hydrolysis, concentrate the solvent, add 50 mL of water to the residue, extract once with ethyl acetate (50 mL) to remove impurities, collect the aqueous phase, adjust the pH to acidic with 6N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the solvent to obtain 1.2 g of colorless oil, and the yield is 78.2%.

[0203] (5) Preparation of 2-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0204] 2-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.6 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.3 g, 2.5 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0205] Step (6) is the same as step (6) in Example 2

[0206] (7) 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]pyrimidin-1-ium-2-olate (Z19):

[0207] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (139.2 mg, 0.6 mmol) was added to a dichloromethane solution of 2-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 90.0 mg of a yellow solid with a yield of 28.4%.

[0208] Example 20: 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z20):

[0209] Steps (1) to (5) are the same as steps (1) to (5) of Example 19

[0210] Step (6) is the same as step (6) in Example 3

[0211] (7) 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]pyrimidin-1-ium-2-olate (Z20):

[0212] A 10 mL dichloromethane solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (135.5 mg, 0.6 mmol) was added to a dichloromethane solution of 2-(3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 52.0 mg of a yellow solid with a yield of 16.6%.

[0213] Example 21: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z21):

[0214] Step (1) Example 1 Step (1)

[0215] (2) Preparation of 3-(3-iodophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole:

[0216] Add (Z)-N′-hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol), pyridine (20 mL) and trifluoroacetic anhydride (5 mL) into a 100 mL three-necked round-bottom flask, heat to 100 °C and react for 8 to 10 h. After the reaction, cool to room temperature, remove the solvent, mix with silica gel, and separate by column chromatography to obtain 1.9 g of white solid with a yield of 73.2%.

[0217] (3) Preparation of diethyl 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0218] 3-(3-iodophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (1.9 g, 5.6 mmol), 2-pyridinecarboxylic acid (137.6 mg, 1.1 mmol), cuprous iodide (106.4 mg, 0.6 mmol), and cesium carbonate (4.6 g, 14.0 mmol) were added to a 200 mL Schlenk bottle, and diethyl malonate (1.8 g, 12.2 mmol) was added to the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90°C and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.5 g of a colorless oil with a yield of 72.1%.

[0219] (4) Preparation of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0220] Diethyl 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.5 g, 4.0 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.4 g, 10.1 mmol) were added to a 250 mL round-bottom flask and stirred at room temperature. After complete hydrolysis, the solvent was concentrated, 50 mL of water was added to the residue, and ethyl acetate (50 mL) was used for extraction once to remove impurities. The aqueous phase was collected, the pH was adjusted to acidic with 6N hydrochloric acid, and ethyl acetate was used for extraction (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain 0.8 g of colorless oil. The yield was 62.8%.

[0221] (5) Preparation of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0222] 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.6 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.3 g, 2.5 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0223] Step (6) is the same as step (6) in Example 2

[0224] (7) 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]pyrimidin-1-ium-2-olate (Z21):

[0225] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (142.8 mg, 0.6 mmol) was added to a dichloromethane solution of 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 47.0 mg of a yellow solid with a yield of 14.7%.

[0226] Example 22: 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z22):

[0227] Step (1) is the same as step (1) in Example 1

[0228] (2) Preparation of 5-(dichloromethyl)-3-(3-iodophenyl)-1,2,4-oxadiazole:

[0229] (Z)-N′-Hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and dichloroacetyl chloride (2.3 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100°C and reacted for 8 to 10 h. After the reaction was completed, the mixture was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.6 g of a white solid with a yield of 59.1%.

[0230] (3) Preparation of diethyl 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0231] 5-(Dichloromethyl)-3-(3-iodophenyl)-1,2,4-oxadiazole (1.6 g, 4.5 mmol), 2-pyridinecarboxylic acid (111.0 mg, 0.9 mmol), cuprous iodide (85.9 mg, 0.5 mmol), and cesium carbonate (3.7 g, 11.3 mmol) were added to a 200 mL Schlenk bottle, and diethyl malonate (1.4 g, 9.0 mmol) was added to the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90°C and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 0.9 g of a colorless oil with a yield of 51.6%.

[0232] (4) Preparation of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0233] Diethyl 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate (0.9 g, 2.3 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.2 g, 5.8 mmol) were added to a 250 mL round-bottom flask and stirred at room temperature. After complete hydrolysis, the solvent was concentrated, 50 mL of water was added to the residue, and ethyl acetate (50 mL) was used for extraction once to remove impurities. The aqueous phase was collected, the pH was adjusted to acidic with 6N hydrochloric acid, and ethyl acetate was used for extraction (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain 0.5 g of a colorless oil with a yield of 65.0%.

[0234] (5) Preparation of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0235] 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.6 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.3 g, 2.4 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0236] Step (6) is the same as step (6) in Example 3

[0237] (7) 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]pyrimidin-1-ium-2-olate (Z22):

[0238] A 10 mL dichloromethane solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (132.7 mg, 0.6 mmol) was added to a dichloromethane solution of 2-(3-(5-(dichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 28.0 mg of a yellow solid with a yield of 9.0%.

[0239] Example 23: 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(3-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-4HH-pyrido[1,2-a]pyrimidin-1-ium-2-olate (Z23):

[0240] Step (1) is the same as step (1) in Example 1

[0241] (2) Preparation of 5-(trichloromethyl)-3-(3-iodophenyl)-1,2,4-oxadiazole:

[0242] (Z)-N′-Hydroxy-3-iodoimidazoleamine (2.0 g, 7.6 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and trichloroacetyl chloride (2.8 g, 15.3 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100°C and reacted for 8 to 10 h. After the reaction was completed, the mixture was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.8 g of a white solid with a yield of 60.6%.

[0243] (3) Preparation of diethyl 2-(3-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0244] 5-(Trichloromethyl)-3-(3-iodophenyl)-1,2,4-oxadiazole (1.8 g, 4.6 mmol), 2-pyridinecarboxylic acid (113.8 mg, 0.9 mmol), cuprous iodide (88.0 mg, 0.5 mmol), and cesium carbonate (3.8 g, 11.6 mmol) were added to a 200 mL Schlenk bottle, and diethyl malonate (1.5 g, 9.3 mmol) was added to the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90°C and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.1 g of a colorless oil with a yield of 56.4%.

[0245] (4) Preparation of 2-(3-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0246] Diethyl 2-(3-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.1 g, 2.6 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.3 g, 6.5 mmol) were added to a 250 mL round-bottom flask and stirred at room temperature. After complete hydrolysis, the solvent was concentrated, 50 mL of water was added to the residue, and ethyl acetate (50 mL) was used for extraction once to remove impurities. The aqueous phase was collected, the pH was adjusted to acidic with 6N hydrochloric acid, and ethyl acetate was used for extraction (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain 0.7 g of colorless oil. The yield was 73.4%.

[0247] (5) Preparation of 2-(3-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0248] 2-(3-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.5 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.3 g, 2.2 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0249] Step (6) is the same as step (6) in Example 3

[0250] (7) 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]pyrimidin-1-ium-2-olate (Z23):

[0251] A 10 mL dichloromethane solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (120.2 mg, 0.5 mmol) was added to a dichloromethane solution of 2-(3-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 25.0 mg of a yellow solid with a yield of 8.3%.

[0252] Example 24: 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]pyrimidin-1-ium-2-olate (Z24):

[0253] (1) Preparation of (Z)-3-chloro-N′-hydroxy-3-iodoimidazole amine:

[0254] 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), anhydrous ethanol (20 mL) and water (5 mL) were mixed in a 100 mL three-necked flask, heated to reflux, and reacted for 6 to 8 hours. After the reaction was completed, the solvent was concentrated and 30 mL of water was added. A large amount of white solid precipitated, which was filtered and dried to obtain 2.0 g of white solid, with a yield of 88.9%.

[0255] (2) Preparation of 3-(3-chloro-5-iodophenyl)-5-methyl-1,2,4-oxadiazole:

[0256] (Z)-3-Chloro-N′-hydroxy-3-iodoimidazoleamine (2.0 g, 6.8 mmol) and pyridine (30 mL) were added into a 100 mL three-necked round-bottom flask, and acetyl chloride (1.1 g, 13.5 mmol) was added dropwise into the above system under stirring at room temperature. The temperature was raised to 100°C and the reaction was carried out for 8 to 10 h. After the reaction was completed, the mixture was cooled to room temperature, desolventized, mixed with silica gel, and separated by column chromatography to obtain 1.5 g of a white solid with a yield of 69.4%.

[0257] (3) Preparation of diethyl 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonate:

[0258] 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), cuprous iodide (89.1 mg, 0.5 mmol), and cesium carbonate (3.8 g, 11.7 mmol) were added to a 200 mL Schlenk bottle, and diethyl malonate (1.5 g, 9.4 mmol) was added to the system under a nitrogen atmosphere, and 50 mL of dry 1,4-dioxane was added as a solvent. After the addition was completed, the system was heated to 90°C and reacted for 8 to 12 h. After the reaction was completed, the system temperature was lowered to room temperature, 100 mL of saturated aqueous ammonium chloride was added to the system to quench the reaction, and ethyl acetate (50 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 1.0 g of a colorless oil with a yield of 60.6%.

[0259] (4) Preparation of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid:

[0260] Add diethyl 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonate (1.0 g, 2.8 mmol), 50 mL of anhydrous ethanol and 50 mL of aqueous sodium hydroxide solution (0.3 g, 7.1 mmol) into a 250 mL round-bottom flask and stir at room temperature. After complete hydrolysis, concentrate the solvent, add 50 mL of water to the residue, extract once with ethyl acetate (50 mL) to remove impurities, collect the aqueous phase, adjust the pH to acidic with 6N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the solvent to obtain 0.6 g of colorless oil, and the yield is 71.4%.

[0261] (5) Preparation of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride:

[0262] 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonic acid (0.2 g, 0.7 mmol), 20 mL of dichloromethane and 1 drop of N,N-dimethylformamide were added into a 50 mL single-necked round-bottom flask and mixed. Oxalyl chloride (0.3 g, 2.7 mmol) was added dropwise under stirring at room temperature. The mixture was reacted at room temperature for 2 to 4 hours. After the reaction was completed, the solvent was removed under reduced pressure and 20 mL of dichloromethane was added for later use.

[0263] Step (6) is the same as step (6) in Example 2

[0264] (7) 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]pyrimidin-1-ium-2-olate (Z24):

[0265] A 10 mL dichloromethane solution of N-((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (152.2 mg, 0.7 mmol) was added to a dichloromethane solution of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The mixture was reacted at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography to obtain 81.0 mg of a yellow solid with a yield of 24.7%.

[0266] Example 25: 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]pyrimidin-1-ium-2-olate (Z25):

[0267] Steps (1) to (5) are the same as steps (1) to (5) of Example 24.

[0268] Step (6) is the same as step (6) in Example 3

[0269] (7) 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]pyrimidin-1-ium-2-olate (Z25):

[0270] A 10 mL dichloromethane solution of N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (135.5 mg, 0.6 mmol) was added to a dichloromethane solution of 2-(3-chloro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)malonyl chloride, and 3 drops of triethylamine were added. The reaction was carried out at room temperature for 20 min. After the reaction was completed, 2 mL of anhydrous methanol was added to quench the reaction. The sample was mixed with silica gel and separated by chromatography column to obtain 39.0 mg of a yellow solid with a yield of 12.0%.

[0271] The compound has a hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) and carbon spectroscopy ( 13 C NMR) data are shown in Table 1.

[0272] Table 1 Spectral data of compounds Z1-Z25

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279] Bioassay Example 1: Determination of the bioactivity of the target compound against broad bean aphids indoors.

[0280] The target compound was dissolved in DMSO solution and diluted with TW-80 to obtain a stock solution with a concentration of 1 g / L, and then diluted with TW-80 to obtain test solutions of 100.0, 10.0 and 1.0 μg / mL and other concentrations.

[0281] 20-30 broad bean aphids (3rd instar) were used to infect broad bean seedlings in pots, and 2 mL of the test night was sprayed, with TW-80 solution containing DMSO as a blank control, and three replicates were used in each group. The treated broad bean aphids were raised in a greenhouse (temperature 26±2°C, humidity 85±5%, light / darkness = 14 / 10h), and the number of dead insects was recorded after 48h. The calculation method of the lethality and corrected lethality is as follows, and the activity data is shown in Table 2:

[0282] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0283] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0284] Table 2 The mortality of compounds Z1-Z25 to broad bean aphids

[0285]

[0286]

[0287] The insecticidal activity results showed that the compounds had good insecticidal activity against broad bean aphids, most of the compounds had a 100% lethality against broad bean aphids at a concentration of 100 μg / mL, and some of the compounds still had a 100% lethality against broad bean aphids at a concentration of 10 μg / mL.

[0288] Bioassay Example 2: Determination of the biological activity of the target compound for controlling white-backed planthoppers indoors.

[0289] The target compound was dissolved in DMSO solution and diluted with TW-80 to obtain a stock solution with a concentration of 1 g / L, and then diluted with TW-80 to obtain test solutions of 100.0, 10.0 and 1.0 μg / mL and other concentrations.

[0290] 20-30 white-backed planthoppers (3rd instar) were used to infect rice seedlings in pots, and 2 mL of the test night was sprayed, with TW-80 solution containing DMSO as a blank control, and three replicates were used in each group. The treated white-backed planthoppers were placed in a greenhouse (temperature 26±2°C, humidity 85±5%, light / darkness = 14 / 10h) and the number of dead insects was recorded after 48h. The calculation method of the lethality and corrected lethality is as follows, and the activity data is shown in Table 3:

[0291] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0292] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0293] Table 3 Mortality of compounds Z1-Z25 to white-backed planthopper

[0294]

[0295]

[0296] The insecticidal activity results showed that the compounds had good insecticidal activity against white-backed planthoppers. Most of the compounds had a 100% lethality to white-backed planthoppers at a concentration of 100 μg / mL, and the lethality of compounds Z3 and Z19 to white-backed planthoppers at a concentration of 10 μg / mL was still 100%.

[0297] Bio-test Example 3: Determination of the biological activity of the target compound for controlling Plutella xylostella indoors.

[0298] The target compound was dissolved in DMSO solution and diluted with TW-80 to obtain a stock solution with a concentration of 1 g / L, and then diluted with TW-80 to obtain test solutions of 100.0, 10.0 and 1.0 μg / mL and other concentrations.

[0299] Cabbage leaves were immersed in solutions with different insecticide concentrations for 3-5 seconds, and control leaves were treated with TW-80 solution containing DMSO. The leaves were dried at room temperature for 2 hours and then placed in a culture dish (10 cm in diameter). Each group of concentrations was repeated three times (ten second-instar larvae were repeated each time). Finally, the culture dish was stored in an incubator at 26°C, 70% RH (relative humidity) and 14:10h (light:dark photoperiod). The results were checked after 48h. The methods for calculating the lethality and corrected lethality are as follows, and the activity data are shown in Table 4:

[0300] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0301] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0302] Table 4 The lethality of the compounds in the examples to Plutella xylostella

[0303]

[0304] The insecticidal activity results showed that the compounds had good activity in killing Plutella xylostella, and most of the compounds had a 100% lethality to white-backed planthoppers at a concentration of 100 μg / mL, among which compounds Z1, Z7 and Z14 still had a 100% lethality to Plutella xylostella at a concentration of 10 μg / mL.

[0305] Bio-test Example 4: Determination of the biological activity of the target compound against fall armyworm indoors.

[0306] Select 3-year-old fall armyworm test insects with the same physiological state reared indoors, and pick 10 test insects in each culture dish. Put 2 2cm long corn leaves in the culture dish, use a spray tower to spray, and repeat 3 times for each dose, with the corresponding concentration of acetone as the control. After spraying, transfer to the rearing conditions for rearing. Check the results after 48 hours. The calculation method of lethality and corrected lethality is as follows, and the activity data is shown in Table 5:

[0307] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0308] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0309] Table 5 Mortality of compound Z1 to fall armyworm

[0310]

[0311] The insecticidal activity results showed that the compound Z1 had good activity in killing fall armyworm, and the lethality to fall armyworm was still 100% at a concentration of 5 μg / mL.

[0312] Bioassay Example 5: Determination of the biological activity of the target compound for controlling armyworms indoors.

[0313] Select 3rd-instar armyworms with the same physiological state in indoor rearing, and pick 10 test insects in each culture dish. Put 2 2cm long corn leaves in the culture dish, use the spray tower to spray, and repeat 3 times for each dose, with the corresponding concentration of acetone as the control. After application, transfer to the rearing conditions for rearing. Check the results after 48h. The calculation method of mortality rate and corrected mortality rate is as follows, and the activity data is shown in Table 6:

[0314] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0315] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0316] Table 6 The lethality of compound Z1 to armyworm

[0317]

[0318] The insecticidal activity results showed that the compound Z1 had good insecticidal activity, and the lethality to the armyworm was still 100% at a concentration of 5 μg / mL.

[0319] Bio-test Example 6: Determination of the biological activity of the target compound against Spodoptera litura indoors.

[0320] Select 3rd-instar Spodoptera litura with the same physiological state in indoor rearing, and pick 10 test insects in each culture dish. Put 2 2cm long corn leaves in the culture dish, use the spray tower to spray, and repeat 3 times for each dose, with the corresponding concentration of acetone as the control. After application, transfer to the rearing conditions for rearing. Check the results after 48h. The calculation method of lethality and corrected lethality is as follows, and the activity data is shown in Table 7:

[0321] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0322] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0323] Table 7 Mortality of compound Z1 to Spodoptera litura

[0324]

[0325] The insecticidal activity results showed that the compound Z1 had good insecticidal activity against Spodoptera litura, and the lethality against Spodoptera litura was still 95% at a concentration of 5 μg / mL.

[0326] Bio-test Example 7: Determination of the biological activity of the target compound for controlling Chilo suppressalis indoors.

[0327] Select 3rd-instar Chilo suppressalis test insects with the same physiological state in indoor rearing, and pick 10 test insects in each culture dish. Put 2 2cm long corn leaves in the culture dish, use the spray tower to spray, and repeat 3 times for each dose, with the corresponding concentration of acetone as the control. After spraying, transfer to the rearing conditions for rearing. Check the results after 48h. The calculation method of lethality and corrected lethality is as follows, and the activity data is shown in Table 8:

[0328] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0329] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0330] Table 8 Mortality of compound Z1 to Chilo suppressalis

[0331]

[0332] The insecticidal activity results showed that the compound Z1 had good insecticidal activity against the Chilo suppressalis, and the lethality against the Chilo suppressalis was still 95% at a concentration of 5 μg / mL.

[0333] Bio-test Example 8: Indoor bioactivity determination of the target compound against rice leaf folder.

[0334] Select 4-year-old rice leaf roller test insects with the same physiological state in indoor rearing, and pick 10 test insects in each culture dish. Put 2 2cm long corn leaves in the culture dish, use the spray tower to spray, and repeat 3 times for each dose. Use the corresponding concentration of acetone as the control. After spraying, transfer to the rearing conditions for rearing. Check the results after 48h. The calculation method of lethality and corrected lethality is as follows, and the activity data is shown in Table 9:

[0335] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0336] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0337] Table 9 Mortality of compound Z1 to rice leaf folder

[0338]

[0339]

[0340] The insecticidal activity results showed that the compound Z1 had good insecticidal activity against rice leaf folder, and the lethality against rice leaf folder was still 90% at a concentration of 5 μg / mL.

[0341] Bio-test Example 9: Determination of the biological activity of the target compound against corn borer indoors.

[0342] Select 2-year-old corn borer test insects with the same physiological state in indoor rearing, and pick 10 test insects in each culture dish. Put 2 2cm long corn leaves in the culture dish, use the spray tower to spray, and repeat 3 times for each dose, with the corresponding concentration of acetone as the control. After spraying, transfer to the rearing conditions for rearing. Check the results after 48 hours. The calculation method of lethality and corrected lethality is as follows, and the activity data is shown in Table 10:

[0343] Mortality rate = (number of dead insects) / (total number of insects treated) × 100

[0344] Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100

[0345] Table 10 Mortality of compound Z1 to corn borer

[0346]

[0347] The results of biological activity tests showed that the compound Z1 had good activity in killing corn borers, and the lethality rate against rice leaf folders was still 95% at a concentration of 5 μg / mL.

[0348] The above biological activity test results show that the pyrido[1,2-a]pyrimidine mesoionic derivative Z1 containing a 1,2,4-oxadiazole structure has good insecticidal activity against Hemiptera and Lepidoptera insects, such as bean aphids, white-backed planthoppers, diamondback moths, fall armyworms, armyworms, Spodoptera litura, striped stem borer, rice leaf folder and corn borer.

[0349] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several changes and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A pyrido[1, 2- a ] pyrimidine mesoionic compound or its salt, characterized in that Selected from the following specific compounds: 。 2. A composition, characterized in that The composition comprises the compound or salt thereof according to claim 1, and an agriculturally usable adjuvant or fungicide, insecticide or herbicide; the dosage form of the composition is selected from emulsifiable concentrate (EC), dust (DP), granule (GR), aqueous solution (AS), suspension (SC), ultra low volume spray (ULV), microcapsule (MC), smoke agent (FU), water emulsion (EW), water dispersible granule (WG).

3. The composition according to claim 2, characterized in that The powders are soluble powders (SP) and wettable powders (WP).

4. Use of the compound or salt thereof according to claim 1, or the composition according to claim 2, in preventing and controlling agricultural pests and diseases, wherein the agricultural pests and diseases are Hemiptera and Lepidoptera pests; the Hemiptera pests are broad bean aphids and white-backed planthoppers; the Lepidoptera pests are Plutella xylostella.

5. A method for preventing and controlling agricultural pests and diseases, characterized in that: The compound or salt thereof according to claim 1, or the composition according to claim 2, is allowed to act on a pest or its living environment; the pest is a Hemiptera and Lepidoptera pest; the Hemiptera pest is aphid and white-backed planthopper; the Lepidoptera pest is diamondback moth.

6. A method for protecting plants from agricultural pests, comprising a method step in which the pests are contacted with the compound or salt thereof according to claim 1, or the composition according to claim 2.

7. Compound Z1 Used in preventing and controlling the Chilo suppressalis, Rice leaf folder, White-backed planthopper, Fall armyworm, Broad bean aphid and Diamondback moth.

8. Compound Z14 Used in preventing and controlling white-backed planthoppers, broad bean aphids and diamondback moths.

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