Pyrido [1, 2-a] pyrimidone compound containing 1, 3, 4-oxadiazole thioether unit as well as preparation method and application of pyrido [1, 2-a] pyrimidone compound

Abstract

The invention belongs to the technical field of pesticides, and particularly relates to a preparation method and application of a pyrido [1, 2-a] pyrimidone compound containing a 1, 3, 4-oxadiazole thioether unit. The compound is shown as a general formula I, wherein R1 independently represents alkyl, aryl, heterocyclic group and the like; and R2 independently represents hydrogen, alkyl, halogen, or the like. R3 independently represents a methyl group, an ethyl group, an aryl group, a heterocyclic group or the like; the compound has a good prevention and treatment effect on plant hoppers, aphids and the like.

Description

Technical Field

[0001] This invention relates to the fields of chemicals and pesticides, and more specifically to pyrido[1,2-]pyrido[1,3,4-]pyrido[2,4-]pyrido[3 ... a Pyrimidine ketone compounds, their preparation methods, and their application in drugs for controlling planthoppers and aphids. Background Technology

[0002] Pea aphid (scientific name: Acyrthosiphon pisum The aphid (Pterygota spp.), belonging to the genus Pterygota of the family Aphididae in the order Hemiptera, is a significant agricultural pest widely distributed in temperate regions worldwide, particularly rampant in legume-growing areas. It is tiny, with adults measuring approximately 2-4 mm in length. Its body color is mostly pale green or yellowish-green, with distinct black markings on its back. It has slender antennae and a pair of septa at the end of its abdomen—typical characteristics of aphids. Wingless parthenogenetic females are more rounded, while winged parthenogenetic females have transparent wing veins and can disperse to new host plants through migration.

[0003] The pea aphid primarily infests leguminous plants, with core hosts including peas, broad beans, alfalfa, and clover, among which peas are its preferred host crop. Native to Europe, this insect spread worldwide through agricultural trade and is now widely distributed in major pea-producing areas of Northeast, North, and Northwest my country. Warm and humid climates are ideal for its growth and reproduction. The pea aphid exhibits a typical pattern of alternating parthenogenesis and sexual reproduction, completing 10-20 generations per year, demonstrating an extremely high reproductive capacity. The damage caused by pea aphids to agricultural production is mainly manifested in two aspects: First, they directly suck the sap of host plants, causing pea leaves to curl and turn yellow, weakening plant growth, reducing pod setting rate, and resulting in shriveled seeds. In severe cases, this can lead to plant death, generally resulting in a yield reduction of 10%-30%, and in severely affected areas, yield reduction can exceed 50%. Second, they indirectly transmit various plant viral diseases, such as pea mosaic virus and broad bean wilt virus. The damage caused by viral diseases is often more severe than the direct damage caused by aphids, further exacerbating yield losses. In addition, the honeydew secreted by pea aphids can induce sooty mold, affecting the photosynthesis of host plants. At the same time, honeydew can also attract ants to feed on it. Ants protect aphids from predators, forming a "symbiotic relationship" between ants and aphids, further contributing to the damage caused by aphids. As a typical herbivorous insect, the pea aphid is also an important member of the ecosystem. Changes in its population can affect the survival of natural enemies such as ladybugs, lacewings, and aphid wasps, and have a certain impact on the ecological balance of farmland. Currently, pesticide resistance to pea aphids is rapidly evolving, and there are high safety risks to non-target organisms. Therefore, developing green, safe, highly effective, low-risk alternative pesticides with novel mechanisms of action has become an urgent task to support green agricultural development and ensure food security. Mesonotropic insecticides, as a new type of insecticide, are superior to traditional neonicotinoid insecticides in terms of molecular structural innovation and resistance management potential, and have become a key research area in pesticide chemistry and insect toxicology.

[0004] Patent publication number CN120923496A discloses a pyridopyrimidinone mesonotropic derivative containing a dithioacetal unit, its preparation method and uses. Bioactivity test results show that some compounds have good insecticidal activity against aphids.

[0005] Patent publication number CN113292557A discloses a pyridopyrimidinone mesonic derivative containing an indole unit, its preparation method and uses. Bioactivity test results show that some compounds have good insecticidal activity against aphids.

[0006] Patent publication number CN112851665A discloses a novel metronid compound that has excellent control effects on agricultural pests, especially diamondback moth, armyworm, and alfalfa aphid.

[0007] Patent publication number CN118126030A discloses a novel pyrazoline-1,3,4-oxadiazole thioacetamide compound, its preparation method, and its application as an agricultural insecticide. Bioactivity tests show that some compounds have good insecticidal activity against diamondback moth and fall armyworm.

[0008] Patent publication number CN113461630A discloses nocacolone thioether derivatives containing 1,3,4-oxadiazole, their preparation methods, and applications. Bioactivity tests show that some compounds have good control effects against diamondback moth.

[0009] The series of compounds disclosed in the aforementioned patents exhibit excellent control activity against aphids and diamondback moths. Therefore, this patent introduces a biologically active 1,3,4-oxadiazole thioether structural unit based on the methanogenic core ring, and designs and synthesizes a series of methanogenic compounds with novel structures. Compared with previously disclosed methanogenic compounds, the compounds disclosed in this invention have novel structures and excellent control effects against pea aphids, achieving highly efficient control of hemiptera pests. Summary of the Invention

[0010] To address the aforementioned problems in the prior art, the present invention provides a pyrido[1,2-]pyrido[1,3,4-]pyrido[2,4-]pyrido[3 ... a Pyrimidine ketone compounds or their stereoisomers, salts or solvates thereof, which have excellent control effects against pea aphids.

[0011] The technical solution adopted in this invention is as follows: A pyrido[1,2-]pyrido[1,3,4-oxadiazole thioether unit as shown in general formula I a Pyrimidine ketones.

[0012] (I) in R1 is independently selected from one of hydrogen, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl; R2 is independently selected from hydrogen, methyl, halogen, etc. R3 is independently selected from one of hydrogen, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, or any substituted or unsubstituted heteroaryl.

[0013] Preferably, R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; R2 is independently selected from one or more of hydrogen, methyl, and halogen; R3 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, cyano, C1-C6 haloalkyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; The substitution refers to the optional substitution of halogen, nitro, hydroxyl, amino, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, cyano, or C1-C6 haloalkyl.

[0014] More preferably, R1 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrazolyl, pyrrolyl, furanyl, thiophene, thiazolyl, benzopyrrolyl, pyridazine, pyrimidine, pyrazine, -CN, -CH2CN, -CH2CH2CN, -CCNCH3, -CCNCH2CH3, -CH2F, -CH2CH2F, -CHFCH3, -CH2Cl, -CH2CH2Cl, -CHClCH3, -CH2Br, -CH2CH2Br, -CHBrCH3. , , ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R2 is independently selected from hydrogen, methyl, and halogen; R3 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, methoxy, vinyl, phenyl, benzyl, pyridyl, -CH2F, -CH2CH2F, -CHFCH3, -CH2Cl, -CH2CH2Cl, -CHClCH3, -CH2Br, -CH2CH2Br, -CHBrCH3.

[0015] In the definitions of compounds shown in the above general formulas and in all the following structural formulas, the technical terms used, whether alone or in compound terms, represent the following substituents: alkyl groups having more than two carbon atoms can be straight-chain or branched. For example, the alkyl group in "alkyl" can be -CH2-, -CH2CH2-, -CH(CH3)-, -C(CH3)2-, etc. Alkyl groups are, for example, C1 alkyl-methyl; C2 alkyl-ethyl; C3 alkyl-propyl such as n-propyl or isopropyl; C4 alkyl-butyl such as n-butyl, isobutyl, tert-butyl, or 2-butyl; C5 alkyl-pentyl such as n-pentyl; C6 alkyl-hexyl such as n-hexyl, isohexyl, and 1,3-dimethylbutyl. Similarly, alkenyl groups are, for example, vinyl, allyl, 1-methylprop-2-en-1-yl, 2-methylprop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 1-methylbut-3-en-1-yl, and 1-methylbut-2-en-1-yl. Alkynyl groups are, for example, ethynyl, propynyl, but-2-yn-1-yl, but-3-yn-1-yl, and 1-methylbut-3-yn-1-yl. Multiple bonds can be in any position in each unsaturated group. Cycloalkyl groups are carbocyclic saturated ring systems having, for example, three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Similarly, cycloalkenyl groups are monocyclic alkenyl groups having, for example, three to six carbon ring members, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, wherein double bonds can be in any position. Halogens are fluorine, chlorine, bromine, or iodine.

[0016] Unless otherwise specified, the term "aryl" in this invention includes, but is not limited to, phenyl, naphthyl, and... , The "heterocyclic group" includes, but is not limited to, saturated or unsaturated non-aromatic cyclic groups. , , , , , , , , , , , , , , , , , , , , , , , .

[0017] , , , , , And, including but not limited to, heteroaryl groups, i.e., aromatic cyclic groups containing, for example, 3 to 6 ring atoms and optionally fused with benzo[a] rings, wherein 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms are selected from oxygen, nitrogen, and sulfur, for example , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0018] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes instances where said event or situation occurs and instances where said event or situation does not occur. For example, the term "optionally...substituted" means that the specified atom or group is unsubstituted or substituted by one or more substituents. If a group is substituted by a group, this should be understood to mean that the group is substituted by one or more groups, either the same or different, selected from those groups mentioned. Furthermore, the same or different substitution characters contained in the same or different substituents are chosen independently and may be the same or different. This also applies to ring systems formed from different atoms and units. Meanwhile, the scope of the claims excludes compounds that are chemically unstable under standard conditions, as known to those skilled in the art.

[0019] Furthermore, unless otherwise specified, the phrase "replaced by at least one group" in this invention refers to being replaced by, for example, 1, 2, 3, 4, or 5 groups; groups without specific attachment positions (including heterocyclic groups, aryl groups, etc.) can be attached at any position, including positions attached to C or N; if it is substituted, the substituent can also be substituted at any position, as long as it conforms to the rules of chemical bond attachment. For example, a heteroaryl group substituted by one methyl group. , can represent , , , wait.

[0020] If various functional groups are present, the present invention also includes any ketone and enol tautomer forms, mixtures thereof, and salts thereof.

[0021] Stereoisomers can be obtained from mixtures prepared by optical resolution. Similarly, stereoisomers can be selectively prepared using stereoselective reactions and optically active starting materials and / or auxiliaries. For optical resolution, conventional methods (see Textbooks of Stereochemistry) can generally be used, such as physical methods for resolving mixtures into diastereomers, including crystallization, chromatography, especially column chromatography and high-performance liquid chromatography, distillation under reduced pressure as needed, extraction, and other methods, typically employing chromatographic separation on a chiral solid phase, which can separate the residual mixture of enantiomers. Suitable for preparative or industrial scales are methods such as crystallizing diastereomers, which can be obtained from the compound using optically active acids, and, if acidic groups are present, using optically active bases as needed.

[0022] Pyrido[1,2-]pyrido[1,2-]pyrido[1,3,4-oxadiazole thioether unit aPyrimidine ketones or their stereoisomers, salts or solvates thereof, selected from the following specific compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Preferred compounds are compounds E1-E30 as described below.

[0023] R1, R2, and R3 are independently as described in any one of claims 1-3.

[0024] Preferably, it further includes: , where X is selected from Br or I.

[0025] The present invention also provides a composition comprising the said compound or its stereoisomer, its salt or its solvate, and agriculturally usable adjuvants or fungicides, insecticides or herbicides; preferably, the formulation of the composition is selected from emulsifiable concentrates (EC), powders (DP), wettable powders (WP), granules (GR), aqueous solutions (AS), suspensions (SC), ultra-low volume sprays (ULV), soluble powders (SP), microcapsules (MC), fumigants (FU), emulsions (EW), and water-dispersible granules (WG).

[0026] The application of the compound or its stereoisomer, its salt or its solvate, or the composition thereof in the preparation of pesticides for controlling agricultural pests and diseases, wherein the agricultural pests and diseases are hemiptera; preferably, the hemiptera are planthoppers or aphids.

[0027] This invention provides a method for preventing and controlling agricultural pests and diseases, wherein the compound or its stereoisomer, its salt or its solvate, or the composition thereof acts on a harmful substance or its habitat; preferably, the harmful substance is a hemiptera pest; more preferably, the hemiptera pest is a planthopper or aphid.

[0028] The term "alkyl" as used here refers to both branched and straight-chain saturated hydrocarbon groups having a specific number of carbon atoms. For example, "C 1-10 Alkyl (or alkylene) is intended for C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Alkyl group. Additionally, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted, such that one or more of their hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), 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.

[0029] "Alkenyl" refers to hydrocarbons that include both straight-chain and branched structures and have one or more carbon-carbon double bonds that appear at any stable point in the chain. For example, "C 2-6 The term "alkenyl" (or "alkenylidene") aims to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups 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 their analogues.

[0030] The term "cycloalkyl" refers to cycloalkyl groups, including mono-, di-, or polycyclic systems. 3-7The purpose of cycloalkyl groups is to include C3, C4, C5, C6, and C7 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and their analogues. As used herein, “carbocyclic” or “carbocyclic remnant” refers to any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic, or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of these carbocyclic rings 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, anthracene, and tetrahydronaphthyl (naphthyl). As mentioned above, bridged rings are also included in the definition of carbocyclic rings (such as [2.2.2]bicyclooctane). Unless otherwise specified, preferred carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocyclic ring" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms are connected to two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always transforms a monocyclic ring into a bicyclic ring. When the rings are bridged, the substituents of the rings are also present on the bridges.

[0031] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group, such as phenyl and naphthyl, having 6 to 12 carbon atoms in the ring moiety, each of which can be substituted.

[0032] The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine, and iodine.

[0033] 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, wherein the heteroatom-containing ring preferably has 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of a heteroatom-containing heteroaryl may contain one or two oxygen or sulfur atoms and / or 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. Nitrogen and sulfur atoms may optionally be oxidized, and nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. Heteroaryl groups may be attached to any available nitrogen or carbon atom in any ring. Where valence permits, if the other ring is a cycloalkyl or heterocyclic ring, it may optionally be substituted with =O (oxygen).

[0034] Beneficial effects: This invention introduces a 1,3,4-oxadiazole thioether unit into pyridine and [1,2- a In the pyrimidinone class, a novel and broad-spectrum insecticidal compound was obtained. This compound exhibits excellent insecticidal activity against pea aphids and can be used as a pesticide to control pea aphids. At the same time, the preparation method of this invention is simple to operate, has low control requirements, requires fewer reagents, and has an ideal yield.

[0035] Example The present invention will be further illustrated below through examples. It should be understood that the methods described in the examples are merely illustrative and not intended to limit the invention. Simple modifications to the preparation methods of the present invention within the framework of the present invention's concept are all within the scope of protection claimed by the present invention. All raw materials and solvents used in the examples are commercially available reagents of the corresponding purity.

[0036] Examples of representative compounds are given below. The synthesis methods of other compounds are similar and will not be described in detail here.

[0037] Example 1: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E1) (1) Preparation of 3-iodobenzoylhydrazide: Methyl m-iodobenzoate (10 g, 38.16 mmol) was dissolved in anhydrous ethanol, and 80% hydrazine hydrate (32.46 mL, 667.82 mmol) was added. The mixture was reacted at room temperature for 3 hours. After the reaction was complete, the solvent in the mixture was evaporated under reduced pressure, and the mixture was then extracted with ethyl acetate to give a white solid in 99.0% yield.

[0038] (2) Preparation of 5-(3-iodophenyl)-1,3,4-oxadiazole-2-thiol: 5 g (19.08 mmol) of 3-iodobenzoylhydrazine was dissolved in anhydrous ethanol, and 1.61 g (28.62 mmol) of potassium hydroxide was added. Then, 1.77 mL (28.62 mmol) of carbon disulfide was gradually added dropwise. After reacting at room temperature for 2 hours, the system was heated to 80 °C and refluxed for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure, and then ice water was added to adjust the pH to 6-7. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography or recrystallization. A white solid was finally obtained in 81.5% yield.

[0039] (3) Preparation of 2-(3-iodophenyl)-5-(methylthio)-1,3,4-oxadiazole: 2.57 g (7.51 mmol) of 5-(3-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 1.25 g (9.01 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Next, 935.10 mmol (15.02 mmol) of iodomethane was added, and the reaction was allowed to proceed at room temperature for 3–4 hours. After the reaction was complete, the system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. Finally, the organic phase was concentrated to give a white solid in 98.1% yield.

[0040] (4) Preparation of diethyl 2-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: (2.56 g, 8.05 mmol) 2-(3-iodophenyl)-5-(methylthio)-1,3,4-oxadiazole, (297.20 mg, 2.41 mmol) 2-pyridinecarboxylic acid, (306.51 mg, 1.61 mmol) cuprous iodide, and (2.33 g, 12.07 mmol) cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, the flask was evacuated to a vacuum, and then purged with nitrogen. Then, (25 mL) 1,4-dioxane and (2.43 mL, 16.09 mmol) diethyl malonate were injected, and the reaction was carried out at 90 °C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography, finally yielding a white solid. Yield: 37.8%.

[0041] (5) 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (150.00 mg, 428.10 µmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in xylene (4 mL), and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography to obtain a yellow solid with a yield of 33.8%.

[0042] Example 2: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-3-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- aPyrimidine-1-onium-2-olate (E2) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 1. (5) 1-((2-chlorothiazo-5-yl)methyl)-9-methyl-3-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (150.00 mg, 428.10 µmol) and 3-methyl-N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in xylene (4 mL), and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography to obtain an orange solid with a yield of 15.6%.

[0043] Example 3: 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onthium-2-olate (E3) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 1. (5) 1-((2-chlorothiazo-5-yl)methyl)-9-methyl-3-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (150.00 mg, 428.10 µmol) was added to a reaction flask with N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine, dissolved in (4 mL) xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 19.8%.

[0044] Example 4: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E4) Steps (1) and (2) are the same as steps (1) and (2) in Example 1. (3) Preparation of 2-(3-iodophenyl)-5-(ethylthio)-1,3,4-oxadiazole: 8.41 g (27.65 mmol) of 5-(3-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in 20 mL of N,N-dimethylformamide, then 4.59 g (33.19 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 2.48 mL (33.19 mmol) of bromoethane was added, and the reaction was allowed to proceed at room temperature for 3–4 hours. After the reaction was complete, the system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, and the organic phase was extracted with ethyl acetate and concentrated to give a white solid in 75.8% yield.

[0045] (4) Preparation of diethyl 2-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: (6.94 g, 20.88 mmol) 2-(3-iodophenyl)-5-(ethylthio)-1,3,4-oxadiazole, (1.29 g, 10.44 mmol) 2-pyridinecarboxylic acid, (1.19 g, 6.26 mmol) cuprous iodide, and (6.04 g, 31.32 mmol) cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum before being purged with nitrogen. Then, (60 mL) 1,4-dioxane and (6.31 mL, 41.76 mmol) diethyl malonate were injected, and the reaction was carried out at 100 °C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography, finally yielding a white solid. Yield: 45.8%.

[0046] (5) 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (400.00 mg, 1.10 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine (272.51 mg, 1.21 mmol) were added to a reaction flask, dissolved in xylene (8 mL), and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. The yield was 11.3%.

[0047] Example 5: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-9-methyl-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E5) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 4. (5) 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-9-methyl-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (400.00 mg, 1.10 mmol) and 3-methyl-N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in xylene (8 mL), and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. The yield was 14.4%.

[0048] Example 6: 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-ol (E6) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 4. (5) 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (400.00 mg, 1.10 mmol) and N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine (265.23 mg, 1.21 mmol) were added to a reaction flask, dissolved in (8 mL) xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 13.7%.

[0049] Example 7: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onthium-2-olate (E7) (1) Preparation of 4-iodobenzoylhydrazide: 10 g (38.16 mmol) of methyl 4-iodobenzoate was dissolved in anhydrous ethanol, and 32.46 mL (667.82 mmol) of 80% hydrazine hydrate was added. The mixture was reacted at room temperature for 3 hours. After the reaction was completed, the solvent of the mixture was evaporated under reduced pressure, and then extracted with ethyl acetate to give a white solid with a yield of 99.0%.

[0050] (2) Preparation of 5-(4-iodophenyl)-1,3,4-oxadiazole-2-thiol: 5 g (19.08 mmol) of 4-iodobenzoylhydrazine was dissolved in anhydrous ethanol, and 1.61 g (28.62 mmol) of potassium hydroxide was added. Then, 1.77 mL (28.62 mmol) of carbon disulfide was gradually added dropwise. After reacting at room temperature for 2 hours, the system was heated to 80 °C and refluxed for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure, and then ice water was added to adjust the pH to 6-7. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography or recrystallization. A white solid was finally obtained in 82.5% yield.

[0051] (3) Preparation of 2-(4-iodophenyl)-5-(methylthio)-1,3,4-oxadiazole: 2.57 g (7.51 mmol) of 5-(4-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 1.25 g (9.01 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Next, 935.10 mmol (15.02 mmol) of iodomethane was added, and the reaction was allowed to proceed at room temperature for 3–4 hours. After the reaction was complete, the system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, and the mixture was extracted with ethyl acetate. Finally, the organic phase was concentrated to give a white solid in 59.4% yield.

[0052] (4) Preparation of diethyl 2-(4-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: (2.56 g, 8.05 mmol) 2-(4-iodophenyl)-5-(methylthio)-1,3,4-oxadiazole (297.20 mg, 2.41 mmol), 2-pyridinecarboxylic acid (306.51 mg, 1.61 mmol), cuprous iodide, and (2.33 g, 12.07 mmol) cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, the flask was evacuated to a vacuum, and then purged with nitrogen. Then, (25 mL) 1,4-dioxane and (2.43 mL, 16.09 mmol) diethyl malonate were injected, and the reaction was carried out at 100 °C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography, finally yielding a white solid. Yield: 38.7%.

[0053] (5) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(4-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (470.00 mg, 1.34 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine (363.29 mg, 1.61 mmol) were added to a reaction flask, dissolved in 10 mL xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. The yield was 15.1%.

[0054] Example 8: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-3-(4-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E8) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 7. (5) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-3-(4-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(4-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (470.00 mg, 1.34 mmol) and 3-methyl-N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine (353.71 mg, 1.48 mmol) were added to a reaction flask, dissolved in 10 mL xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. The yield was 11.5%.

[0055] Example 9: 1-((6-chloropyridin-3-yl)methyl)-3-(4-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E9) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 7. (5) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: The intermediate (470.00 mg, 1.34 mmol) diethyl 2-(4-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate and (324.13 mg, 1.48 mmol) N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in (10 mL) xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 13.8%.

[0056] Example 10: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(5-ethylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E10) Steps (1) and (2) are the same as steps (1) and (2) in Example 7. (3) Preparation of 2-(4-iodophenyl)-5-(ethylthio)-1,3,4-oxadiazole: 8.41 g (27.65 mmol) of 5-(4-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in 20 mL of N,N-dimethylformamide, then 4.59 g (33.19 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 2.48 mL (33.19 mmol) of bromoethane was added, and the reaction was allowed to proceed at room temperature for 3–4 hours. After the reaction was complete, the system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, and the organic phase was extracted with ethyl acetate and concentrated to give a white solid in 76.5% yield.

[0057] (4) Preparation of diethyl 2-(4-(5-(ethio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: (6.94 g, 20.88 mmol) 2-(4-iodophenyl)-5-(ethylthio)-1,3,4-oxadiazole, (1.29 g, 10.44 mmol) 2-pyridinecarboxylic acid, (1.19 g, 6.26 mmol) cuprous iodide, and (6.04 g, 31.32 mmol) cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum, then purged with nitrogen. Then, (60 mL) 1,4-dioxane and (6.31 mL, 41.76 mmol) diethyl malonate were injected, and the reaction was carried out at 100 °C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography, finally yielding a white solid. Yield: 45.8%.

[0058] (5) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(5-ethylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(4-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (600.00 mg, 1.65 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine (445.92 mg, 1.98 mmol) were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 20.3%.

[0059] Example 11: 3-(4-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl)-1-((2-chlorothiazol-5-yl)methyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E11) Steps (1) and (2) are the same as steps (1) and (2) in Example 7. (3) Preparation of 2-benzylthio-5-(4-iodophenyl)-1,3,4-oxadiazole: 7.00 g (23.02 mmol) of 5-(4-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 3.82 g (27.62 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 3.28 mL (27.62 mmol) of benzyl bromide was added, and the reaction was allowed to proceed at room temperature for 4–5 hours. After the reaction was complete, 500 mL of water was added to the system, and the pH was adjusted to 5–6 with hydrochloric acid. The mixture was then extracted with ethyl acetate, and the organic phase was concentrated to give a white solid. Yield: 69.4%.

[0060] (4) Preparation of diethyl 2-[4-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]malonate: 10.54 g (29.43 mmol) of 2-benzylthio-5-(4-iodophenyl)-1,3,4-oxadiazole, 1.81 g (14.71 mmol) of 2-pyridinecarboxylic acid, 1.68 g (8.83 mmol) of cuprous iodide, and 8.51 g (44.14 mmol) of cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum. Nitrogen gas was then introduced, followed by the addition of 60 mL of 1,4-dioxane and 8.89 mL (58.85 mmol) of diethyl malonate. The reaction was carried out at 100 °C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography. Yield: 39.5%.

[0061] (5) 3-(4-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl)-1-((2-chlorothiazol-5-yl)methyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-[4-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]malonate (860.00 mg, 2.02 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine (455.11 mg, 2.02 mmol) were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 18.9%.

[0062] Example 12: 1-((6-chloropyridin-3-yl)methyl)-3-(4-(5-ethylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E12) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 10. (5) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(5-ethylthio-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(4-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (609.00 mg, 1.67 mmol) and N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine (403.82 mg, 1.84 mmol) were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 17.6%.

[0063] Example 13: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(5-(propylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E13) Steps (1) and (2) are the same as steps (1) and (2) in Example 1. (3) Preparation of 2-(3-iodophenyl)-5-propanethio-1,3,4-oxadiazole: 10.00 g (2.88 mmol) of 5-(3-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 5.45 g (39.46 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 3.32 mL (39.46 mmol) of 1-bromopropane was added, and the reaction was allowed to proceed at room temperature for 3–4 hours. After the reaction was complete, the system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, and the organic phase was extracted with ethyl acetate and concentrated. The organic phase was then purified by column chromatography to give a white solid. Yield: 59.9%.

[0064] (4) Preparation of diethyl 2-(3-(5-(propanethio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: (8.70 g, 25.13 mmol) 2-(3-iodophenyl)-5-propenthio-1,3,4-oxadiazole, (1.55 g, 12.57 mmol) 2-pyridinecarboxylic acid, (1.44 g, 7.54 mmol) cuprous iodide, and (7.27 g, 37.70 mmol) cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum before being purged with nitrogen. Then, (60 mL) 1,4-dioxane and (7.59 mL, 50.26 mmol) diethyl malonate were injected, and the reaction was carried out at 100°C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography. Yield: 37.9%.

[0065] (5) 1-((2-chlorothiazo-5-yl)methyl)-3-(3-(5-(propanethio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(propylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (800.00 mg, 1.88 mmol) was reacted with N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine, dissolved in (24 mL) xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 18.8%.

[0066] Example 14: 3-[4-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-[(6-chloropyridin-3-yl)methyl]-4-oxo-4H-pyrido[1,2-] a Pyrimidine-1-onium-2-ol (E14) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 11. (5) 3-[4-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-[(6-chloropyridin-3-yl)methyl]-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: The intermediate (800.00 mg, 1.88 mmol) of diethyl 2-[4-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]malonate was reacted with (412.06 mg, 1.88 mmol) of N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine, dissolved in (14 mL) xylene, and refluxed at 150 °C for 24 hours. The mixture changed from orange-yellow to brown liquid. After the reaction, the mixture was purified by column chromatography. Yield: 22.5%.

[0067] Example 15: 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(3-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl)-4H-pyrido[1,2- a Pyrimidine-1-onthium-2-olate (E15) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 13. (5) 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(3-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl)-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(propylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (600.00 mg, 1.59 mmol) and N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 19.8%.

[0068] Example 16: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(5-butthio-1,3,4-oxadiazol-2-yl)phenyl)-4H-pyrido[1,2- a Pyrimidine-1-onthium-2-olate (E16) Steps (1) and (2) are the same as steps (1) and (2) in Example 1. (3) Preparation of 2-(3-iodophenyl)-5-butthio-1,3,4-oxadiazole: 10.00 g (32.88 mmol) of 5-(3-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 5.45 g (39.46 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 3.70 mL (39.46 mmol) of 1-bromobutane was added, and the reaction was allowed to proceed at room temperature for 3–4 hours. After the reaction was complete, the system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, and the organic phase was extracted with ethyl acetate and concentrated. The organic phase was then purified by column chromatography to give a white solid. Yield: 65.7%.

[0069] (4) Preparation of diethyl 2-(3-(5-(butthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: (9.56 g, 26.53 mmol) 2-(3-iodophenyl)-5-butylthio-1,3,4-oxadiazole, (1.63 g, 13.27 mmol) 2-pyridinecarboxylic acid, (1.52 g, 7.96 mmol) cuprous iodide, and (7.68 g, 39.80 mmol) cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum before being purged with nitrogen. Then, (60 mL) 1,4-dioxane and (8.02 mL, 53.07 mmol) diethyl malonate were injected, and the reaction was carried out at 100°C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography. Yield: 40.1%.

[0070] (5) 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(butyro)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(butyrothio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (600.00 mg, 1.53 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine (379.54 mg, 1.68 mmol) were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 15.3%.

[0071] Example 17: 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(3-(5-butthio-1,3,4-oxadiazol-2-yl)phenyl)-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E17) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 16. (5) 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(3-(5-butthio-1,3,4-oxadiazol-2-yl)phenyl)-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-(butyrothio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (600.00 mg, 1.53 mmol) and N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine (369.41 mg, 1.68 mmol) were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 16.9%.

[0072] Example 18: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E18) Steps (1) and (2) are the same as steps (1) and (2) in Example 7. (3) Preparation of 2-cyclopropylmethylthio-5-(4-iodophenyl)-1,3,4-oxadiazole: 10.00 g (32.88 mmol) of 5-(4-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 6.82 g (49.32 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 4.79 mL (49.32 mmol) of bromomethylcyclopropane was added, and the reaction was allowed to proceed at room temperature for 4–5 hours. After the reaction was complete, the system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, and the organic phase was extracted with ethyl acetate and concentrated. The organic phase was then purified by column chromatography to give a white solid. Yield: 75.7%.

[0073] (4) Preparation of diethyl 2-[4-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl]malonate: 10.54 g (29.43 mmol) of 2-cyclopropylmethylthio-5-(4-iodophenyl)-1,3,4-oxadiazole, 1.81 g (14.71 mmol) of 2-pyridinecarboxylic acid, 1.68 g (8.83 mmol) of cuprous iodide, and 8.51 g (44.14 mmol) of cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, the flask was evacuated to a vacuum, and then purged with nitrogen. Then, 60 mL of 1,4-dioxane and 8.89 mL (58.85 mmol) of diethyl malonate were injected, and the reaction was carried out at 100 °C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography. Yield: 39.9%.

[0074] (5) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: The intermediate (800.00 mg, 2.05 mmol) of diethyl 2-[4-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl]malonate was dissolved in (24 mL) xylene and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 21.6%.

[0075] Example 19: 1-((6-chloropyridin-3-yl)methyl)-3-(4-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onthium-2-olate (E19) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 18. (5) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-[4-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl]malonate (800.00 mg, 2.05 mmol) was reacted with N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine (405.08 mg, 1.84 mmol), dissolved in xylene (24 mL), and refluxed at 150 °C for 24 hours. After the reaction, the mixture was purified by column chromatography. Yield: 24.8%.

[0076] Example 20: 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-ol (E20) Steps (1) and (2) are the same as steps (1) and (2) in Example 1. (3) Preparation of 2-((cyclopropylmethyl)thio)-5-(3-iodophenyl)-1,3,4-oxadiazole: 10.00 g (32.88 mmol) of 5-(3-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 6.82 g (49.32 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 4.79 mL (49.32 mmol) of bromomethylcyclopropane was added, and the reaction was allowed to proceed at room temperature for 4–5 hours. Post-reaction treatment: The system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to give a white solid. Yield: 72.1%.

[0077] (4) Preparation of diethyl 2-(3-(5-((cyclopropylmethyl)thio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: 10.54 g (29.43 mmol) of 2-((cyclopropylmethyl)thio)-5-(3-iodophenyl)-1,3,4-oxadiazole, 1.81 g (14.71 mmol) of 2-pyridinecarboxylic acid, 1.68 g (8.83 mmol) of cuprous iodide, and 8.51 g (44.14 mmol) of cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum before being purged with nitrogen. Then, 60 mL of 1,4-dioxane and 8.89 mL (58.85 mmol) of diethyl malonate were injected, and the reaction was carried out at 100 °C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography. Yield: 34.2%.

[0078] (5) 1-((2-chlorothiazol-5-yl)methyl)-3-(3-(5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-((cyclopropylmethyl)thio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (600.00 mg, 1.54 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine (381.50 mg, 1.69 mmol) were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 19.6%.

[0079] Example 21: 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-((cyclopropylmethyl)thio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E21) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 20. (5) 1-((6-chloropyridin-3-yl)methyl)-3-(3-(5-((cyclopropylmethyl)thio)-1,3,4-oxadiazol-2-yl)phenyl)-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(3-(5-((cyclopropylmethyl)thio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (600.00 mg, 1.54 mmol) and N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction, the mixture was purified by column chromatography. Yield: 22.5%.

[0080] Example 22: 3-[3-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-(2-chlorothiazol-5-ylmethyl)-4-oxo-4H-pyrido[1,2-] a Pyrimidine-1-onium-2-ol (E22) Steps (1) and (2) are the same as steps (1) and (2) in Example 1. (3) Preparation of 2-benzylthio-5-(3-iodophenyl)-1,3,4-oxadiazole: 10.00 g (32.88 mmol) of 5-(3-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 6.82 g (49.32 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 5.86 mL (49.32 mmol) of benzyl bromide was added, and the reaction was allowed to proceed at room temperature for 4–5 hours. Post-reaction treatment: The system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, the organic phase was extracted with ethyl acetate and concentrated, and purified by column chromatography to give a white solid. Yield: 66.8%.

[0081] (4) Preparation of diethyl 2-[3-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]malonate: 10.54 g (29.43 mmol) of 2-benzylthio-5-(3-iodophenyl)-1,3,4-oxadiazole, 1.81 g (14.71 mmol) of 2-pyridinecarboxylic acid, 1.68 g (8.83 mmol) of cuprous iodide, and 8.51 g (44.14 mmol) of cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum before being purged with nitrogen. Then, 60 mL of 1,4-dioxane and 8.89 mL (58.85 mmol) of diethyl malonate were injected, and the reaction was carried out at 100 °C for 10 hours. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography. Yield: 41.5%.

[0082] (5) 3-[3-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-(2-chlorothiazol-5-ylmethyl)-4-oxo-4H-pyrido[1,2-] a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-[3-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]malonate (860.00 mg, 2.02 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 25.6%.

[0083] Example 23: 3-[3-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-[(6-chloropyridin-3-yl)methyl]-4-oxo-4H-pyrido[1,2-] a Pyrimidine-1-onium-2-olate (E23) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 22. (5) 3-[3-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-[(6-chloropyridin-3-yl)methyl]-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-[3-(5-benzylthio-1,3,4-oxadiazol-2-yl)phenyl]malonate (850.00 mg, 1.99 mmol) and N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine (372.14 mg, 1.69 mmol) were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the solvent was removed, and the mixture was purified by column chromatography. Yield: 18.9%.

[0084] Example 24: 1-[(2-chlorothiazo-5-yl)methyl]-4-oxo-3-[4-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl]-4H-pyrido[1,2- a Pyrimidine-1-onium-2-ol (E24) Steps (1) and (2) are the same as steps (1) and (2) in Example 7. (3) Preparation of 2-(4-iodophenyl)-5-propanethio-1,3,4-oxadiazole: 10.00 g (32.88 mmol) of 5-(4-iodophenyl)-1,3,4-oxadiazol-2-thiol was dissolved in N,N-dimethylformamide, then 5.45 g (39.46 mmol) of anhydrous potassium carbonate was added and stirred at room temperature for 30 minutes. Then, 3.32 mL (39.46 mmol) of 1-bromopropane was added, and the reaction was allowed to proceed at room temperature for 4–5 hours. Post-reaction treatment: The system was poured into ice water, the pH was adjusted to 6–7 with hydrochloric acid, the organic phase was extracted with ethyl acetate and concentrated, and purified by column chromatography to give a white solid. Yield: 60.9%.

[0085] (4) Preparation of diethyl 2-(4-(5-(propanethio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: (9.47 g, 27.36 mmol) 2-(4-iodophenyl)-5-propenthio-1,3,4-oxadiazole, (1.68 g, 13.68 mmol) 2-pyridinecarboxylic acid, (1.56 g, 8.21 mmol) cuprous iodide, and (13.37 g, 41.03 mmol) cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum before being purged with nitrogen. Then, (60 mL) 1,4-dioxane and (8.27 mL, 54.71 mmol) diethyl malonate were injected, and the reaction was carried out at 100°C for 10 hours. The system gradually changed from a grayish-white turbidity to a matcha-green turbidity. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography. Yield: 32.6%.

[0086] (5) 1-[(2-chlorothiazol-5-yl)methyl]-4-oxo-3-[4-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl]-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(4-(5-(propylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (800.00 mg, 2.11 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in (12 mL) xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 18.9%.

[0087] Example 25: 1-[(6-chloropyridin-3-yl)methyl]-4-oxo-3-[4-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl]-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E25) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 24. (5) 1-[(6-chloropyridin-3-yl)methyl]-4-oxo-3-[4-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl]-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(4-(5-(propylthio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (800.00 mg, 2.20 mmol) and N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine (434.02 mg, 1.98 mmol) were added to a reaction flask, dissolved in 12 mL of xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 22.2%.

[0088] Example 26: 3-[4-(5-Butylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-[(2-chlorothiazol-5-yl)methyl]-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onthium-2-olate (E26) Steps (1) and (2) are the same as steps (1) and (2) in Example 7. (3) Preparation of 2-(4-iodophenyl)-5-butthio-1,3,4-oxadiazole: Dissolve (8.80 g, 28.94 mmol) 5-(4-iodophenyl)-1,3,4-oxadiazol-2-thiol in N,N-dimethylformamide, then add (4.80 g, 34.72 mmol) anhydrous potassium carbonate and stir at room temperature for 30 minutes. Next, add (3.72 mL, 34.72 mmol) 1-bromobutane and react at room temperature for 4-5 hours. Post-reaction treatment: Pour the system into ice water, adjust the pH to 6-7 with hydrochloric acid, extract with ethyl acetate, concentrate the organic phase, and purify by column chromatography to obtain a white solid.

[0089] (4) Preparation of diethyl 2-(4-(5-(butyrothio)-1,3,4-oxadiazol-2-yl)phenyl)malonate: (8.00 g, 22.21 mmol) 2-(4-iodophenyl)-5-butylthio-1,3,4-oxadiazole, (1.37 g, 11.10 mmol) 2-pyridinecarboxylic acid, (1.27 g, 6.66 mmol) cuprous iodide, and (10.85 g, 33.31 mmol) cesium carbonate were added to an anhydrous and oxygen-free reaction flask. A stir bar was added, and the flask was evacuated to a vacuum before being purged with nitrogen. Then, (60 mL) 1,4-dioxane and (8.27 mL, 54.71 mmol) diethyl malonate were injected, and the reaction was carried out at 100°C for 10 hours. The system gradually changed from a grayish-white turbidity to a matcha-green turbidity. After the reaction was complete, a suitable amount of saturated ammonium chloride aqueous solution was added to the system, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by column chromatography. Yield: 39.9%.

[0090] (5) 3-[4-(5-Butylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-[(2-chlorothiazol-5-yl)methyl]-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(4-(5-(butyrothio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (1.00 g, 2.55 mmol) and N-[(2-chlorothiazol-5-yl)methyl]pyridine-2-amine were added to a reaction flask, dissolved in (24 mL) xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 19.0%.

[0091] Example 27: 3-[4-(5-Butylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-[(6-chloropyridin-3-yl)methyl]-4-oxo-4H-pyrido[1,2- a Pyrimidine-1-onium-2-olate (E27) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 26. (5) 3-[4-(5-Butylthio-1,3,4-oxadiazol-2-yl)phenyl]-1-[(6-chloropyridin-3-yl)methyl]-4-oxo-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-(4-(5-(butyrothio)-1,3,4-oxadiazol-2-yl)phenyl)malonate (1.00 g, 2.55 mmol) and N-[(6-chloropyridin-3-yl)methyl]pyridine-2-amine (503.74 mg, 2.29 mmol) were added to a reaction flask, dissolved in 24 mL xylene, and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 23.5%.

[0092] Example 28: 3-[3-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl]-4-oxo-1-(pyrimidin-5-ylmethyl)-4H-pyrido[1,2-] a Pyrimidine-1-onium-2-olate (E28) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 1. (5) 3-[3-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl]-4-oxo-1-(pyrimidin-5-ylmethyl)-4H-pyrido[1,2-] aPreparation of pyrimidine-1-onium-2-olate: Diethyl 2-[3-(5-methylthio-1,3,4-oxadiazol-2-yl)phenyl]malonate (800.00 mg, 2.28 mmol) was dissolved in xylene (24 mL) and refluxed at 150 °C for 24 hours. After the reaction, the mixture was purified by column chromatography. Yield: 20.4%.

[0093] Example 29: 3-[3-(5-ethylthio-1,3,4-oxadiazol-2-yl)phenyl]-4-oxo-1-(pyrimidin-5-ylmethyl)-4H-pyrido[1,2-] a Pyrimidine-1-onthium-2-olate (E29) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 4. (5) 3-[3-(5-ethylthio-1,3,4-oxadiazol-2-yl)phenyl]-4-oxo-1-(pyrimidin-5-ylmethyl)-4H-pyrido[1,2-] a Preparation of pyrimidine-1-onium-2-olate: Diethyl 2-[3-(5-ethylthio-1,3,4-oxadiazol-2-yl)phenyl]malonate (800.00 mg, 2.20 mmol) was dissolved in xylene (24 mL) and refluxed at 150 °C for 24 hours. After the reaction, the product was purified by column chromatography. Yield: 19.5%.

[0094] Example 30: 4-oxo-3-[3-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl]-1-(pyrimidin-5-ylmethyl)-4H-pyrido[1,2-] a Pyrimidine-1-onthium-2-ol inner salt (E30) Steps (1), (2), (3), and (4) are the same as steps (1), (2), (3), and (4) in Example 13. (5) 4-oxo-3-[3-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl]-1-(pyrimidin-5-ylmethyl)-4H-pyrido[1,2- a Preparation of pyrimidine-1-on-2-ol inner salt: The intermediate (800.00 mg, 2.11 mmol) of diethyl 2-[3-(5-propanethio-1,3,4-oxadiazol-2-yl)phenyl]malonate was dissolved in (24 mL) xylene and refluxed at 150 °C for 24 hours. After the reaction was completed, the mixture was purified by column chromatography. Yield: 22%.

[0095] The compound's nuclear magnetic resonance hydrogen spectrum ( 1 H NMR and carbon spectroscopy 13 The C NMR data are shown in Table 1.

[0096] Table 1. Spectral data of compounds E1-E21 in Examples

[0097] Example 1: Determination of the bioactivity of the target compound in controlling brown planthoppers and pea aphids indoors.

[0098] The target compound was dissolved in DMSO solution and diluted with distilled water to obtain a stock solution with a concentration of 1 g / L. Then, it was diluted with Tween 80 (0.1%) to obtain test solutions with concentrations of 200, 100 μg / mL and other concentrations.

[0099] 30-40 brown planthoppers (2nd-5th instar) were used to infect rice seedlings in flowerpots, and 2 mL of test solution was sprayed on each seedling. A Tween 80 solution containing DMSO (0.1%) was used as a blank control. Each group was replicated in triplicate. The treated brown planthoppers were reared in a greenhouse (temperature 26±2℃, humidity 85±5%, light / dark ratio = 16 / 8h). The number of dead planthoppers was recorded after 48 hours. The mortality rate and corrected mortality rate were calculated as follows, and the activity data are shown in Table 2. 30-40 adult pea aphids were used to infect broad bean seedlings in flowerpots, and 2 mL of test solution was sprayed on each seedling. A Tween 80 solution containing 0.1% DMSO was used as a blank control. Each group was replicated in triplicate. The treated pea aphids were reared in a greenhouse (temperature 26±2℃, humidity 85±5%, light / dark ratio = 16 / 8h). The number of dead aphids was recorded after 48 hours. The mortality rate and corrected mortality rate were calculated as follows, and the activity data are shown in Table 2. Mortality rate = (Number of dead insects) / (Total number of insects treated) × 100 Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100 Table 2. Mortality rates of the compounds obtained in Examples E1-E30 against pea aphids.

[0100] Insecticidal activity results showed that the compounds exhibited good activity against pea aphids. Most compounds showed a certain mortality rate against pea aphids at a concentration of 200 μg / mL, while compounds E1 and E2 maintained a 100% mortality rate at a concentration of 100 μg / mL. The insecticidal activity of E1 and E2 was comparable to that of the control agent, trifluralin. Furthermore, compounds E1 and E2 showed a 100% mortality rate against brown planthoppers at a concentration of 100 μg / mL.

Claims

1. A pyrido[1,2-]pyrido[1,3,4-] ... a Pyrimidine ketone compounds or their stereoisomers, salts, or solvates thereof, characterized in that, The general formula is as shown in Formula I: （I）； R1 is independently selected from one of hydrogen, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl. R2 is independently selected from hydrogen, alkyl, halogen, etc.; R3 is independently selected from one of hydrogen, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, or any substituted or unsubstituted heteroaryl.

2. The pyrido[1,2-]pyrido[1,3,4-oxadiazole sulfide unit according to claim 1 a Pyrimidine ketone compounds or their stereoisomers, their salts, or their solvates, characterized in that: R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; R2 is independently selected from one or more of hydrogen, alkyl, and halogen; R3 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, cyano, C1-C6 haloalkyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; The substitution refers to the optional substitution of halogen, nitro, hydroxyl, amino, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, cyano, or C1-C6 haloalkyl.

3. The pyrido[1,2]pyrido[1,2]pyrido[2]pyrido[3,4]pyridoxine thioether unit according to claim 1. a Pyrimidine ketone compounds or their stereoisomers, their salts, or their solvates, characterized in that: R1 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrazolyl, pyrrolyl, furanyl, thiophene, thiazolyl, benzopyrrolyl, pyridazine, pyrimidine, pyrazine, -CN, -CH2CN, -CH2CH2CN, -CCNCH3, -CCNCH2CH3, -CH2F, -CH2CH2F, -CHFCH3, -CH2Cl, -CH2CH2Cl, -CHClCH3, -CH2Br, -CH2CH2Br, -CHBrCH3. , , ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R2 is independently selected from hydrogen, methyl, and halogen; R3 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, methoxy, vinyl, phenyl, benzyl, pyridyl, -CH2F, -CH2CH2F, -CHFCH3, -CH2Cl, -CH2CH2Cl, -CHClCH3, -CH2Br, -CH2CH2Br, -CHBrCH3.

4. The pyrido[1,2-]pyrido[1,3,4-oxadiazole sulfide unit according to claim 1 a Pyrimidine ketone compounds or their stereoisomers, their salts, or their solvates, characterized in that: Selected from the following specific compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 5. The pyrido[1,2-]pyrido[1,3,4-oxadiazole thioether unit as described in any one of claims 1-4 a A method for preparing pyrimidinone compounds or their stereoisomers, their salts, or their solvates, characterized in that: Includes the following steps: (1) ； (2) ; (3) ; (4) 。 6. The pyrido[1,2-]pyrido[ ... a A method for preparing pyrimidinone compounds or their stereoisomers, their salts, or their solvates, characterized in that: Step (2) is as follows: , where X is Br or I.

7. A composition, characterized in that... Pyrido[1,2-]pyrido[3,4-]pyrido[4,4-]pyrido[3 ... a The composition may be a pyrimidinone compound or its stereoisomer, its salt or its solvate, and an adjuvant, fungicide, insecticide or herbicide available in agriculture; the formulation of the composition may be selected from emulsifiable concentrates (EC), powders (DP), wettable powders (WP), granules (GR), aqueous solutions (AS), suspensions (SC), ultra-low volume sprays (ULV), soluble powders (SP), microcapsules (MC), fumigants (FU), emulsions (EW), and water-dispersible granules (WG).

8. The pyrido[1,2-]pyrido[ ... a The use of pyrimidinone compounds or their stereoisomers, their salts or their solvates, or the composition of claim 7 in the preparation of pesticides for controlling agricultural pests and diseases, wherein the agricultural pests and diseases are hemiptera pests; wherein the hemiptera pests are planthoppers and aphids.

9. A method for preventing and controlling agricultural pests and diseases, characterized in that: The pyrido[1,2-]pyrido[3,4-oxadiazole thioether unit of any one of claims 1-4 a The pyrimidinone compound or its stereoisomer, its salt or its solvate, or the composition of claim 7 is applied to a harmful substance or its living environment; the harmful substance is a hemiptera pest; the hemiptera pest is a planthopper or aphid.

10. A method for protecting plants from agricultural pests and diseases, comprising causing the pests to react with a pyrido[1,2-]pyrido[ ... a The method steps of contacting a pyrimidinone compound or its stereoisomer, its salt or its solvate, or the composition of claim 7.

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