Pyridino [1, 2-a] pyrimidine mesoion derivative containing sulfoxide structure as well as preparation and application of pyridino [1, 2-a] pyrimidine mesoion derivative

Abstract

The invention relates to a pyrido [1, 2-a] pyrimidine mesoion derivative containing a sulfoxide structure as well as a preparation method and application of the pyrido [1, 2-a] pyrimidine mesoion derivative. The compound disclosed by the invention has a structure as shown in a formula (I), has excellent insecticidal activity on Frankliniella occidentalis, Sogatella furcifera, aphid, Spodoptera frugiperda, Plutella xylostella, Chilo suppressalis, Prodenia litura, armyworm and the like, and can be used for drugs or medicaments for preventing and treating pests such as Frankliniella occidentalis, Sogatella furcifera, aphid, Spodoptera frugiperda, Plutella xylostella, Chilo suppressalis, Prodenia litura, armyworm and the like. The structure and the preparation process are simple, and the production cost is low. (I)

Description

Technical Field

[0001] This invention relates to the fields of chemical engineering and pesticides, and more specifically to pyrido[1,2-]pyrido[]pyridoxine- ... a Pyrimidine mesonotropic derivatives and their preparation methods, and pyrido[1,2-]pyrido[1,2-]pyridylene-containing sulfoxide units. a Application of pyrimidine metronid derivatives in pesticides for controlling pests such as western flower thrips, rice planthoppers, aphids, fall armyworm, diamondback moth, rice stem borer, corn borer, and armyworm. Background Technology

[0002] Crop pests are one of the major agricultural disasters in my country. They are characterized by their wide variety, significant impact, and frequent outbreaks that cause major losses to agricultural production. Among them, hemiptera, thalassoptera, and lepidopteran pests are some of the most important agricultural pests.

[0003] Rice planthoppers are major migratory pests of rice, belonging to the order Hemiptera (Hemiptera). Hemiptera Planthopper family ( Delphacidae Pests, mainly brown planthoppers ( Nilaparvata lugens ), white-backed planthopper ( Sogatella furcifera ) and gray planthoppers ( Laodelphax striatellus There are three categories. They pose a serious threat to rice production by sucking rice sap, laying eggs, and spreading rice viral diseases. Their sudden onset also makes prevention and control very difficult. Rice planthoppers are characterized by rapid reproduction, large population size, and strong migratory ability. Once they occur, they can easily cause devastating damage to rice, leading to reduced yields or even crop failure.

[0004] Thysanoptera ( Thysanoptera Thrips, also known as pests, are a group of tiny but highly damaging agricultural pests, among which the western flower thrips (Thrips spp.) is the most prominent. frankliniella occidentalis (Pergande) Western flower thrips is considered one of the most destructive species. This pest, native to North America, has spread to over 70 countries and regions worldwide, with an astonishingly wide host range, damaging more than 500 kinds of vegetables, flowers, and cash crops, including peppers, cucumbers, eggplants, roses, and chrysanthemums. Besides directly feeding on plant sap, causing yield losses of 30% to 50%, and in severe cases, total crop failure, western flower thrips can also transmit various viruses, causing indirect damage to plants. It is a highly efficient vector for highly harmful plant viruses such as tomato spotted wilt virus, and viral diseases caused by it can spread rapidly between crops, causing devastating losses of up to 80% or more in the yield and commercial value of crops such as tomatoes and peppers. Furthermore, western flower thrips have extremely high reproductive rates, with more than 15 generations per year, and have developed significant resistance to many commonly used insecticides, greatly increasing the difficulty and cost of control. Therefore, it is widely recognized as one of the number one threats to global agriculture, especially agricultural production, that must be strictly controlled.

[0005] Lepidoptera( Lepidoptera Pests include agricultural pests such as the fall armyworm, diamondback moth, and rice stem borer. Among them, the fall armyworm (… Spodoptera frugiperda ) and rice stem borer ( Chilo suppressalis The fall armyworm, a representative pest of the Lepidoptera order, causes serious damage to various grain crops such as rice and corn during their growth period. It belongs to the Noctuidae family of the Lepidoptera order. Noctuidae genus *Greywing noctuid* ( Spodoptera The insect, native to tropical and subtropical regions of the Americas, is widely distributed and has a wide variety of host species. It is characterized by its strong migratory ability, rapid reproduction, and omnivorous diet, and it damages a variety of crops such as corn, rice, and wheat, posing a serious threat to global agriculture.

[0006] Diamondback moth ( Plutella xylostella ), belonging to the family Pyracantha ( Plutellidae The cruciferous insect, also known as the "hanging silkworm," is a globally prevalent and damaging cruciferous pest. It has a short life cycle, strong adaptability and reproductive capacity, a wide host range, is prone to developing pesticide resistance, and has a high migration rate. Its powerful migratory ability exacerbates the severity of its damage and expands its affected area. It occurs in almost all provinces and cities in my country, making control difficult.

[0007] Currently, chemical pesticide control remains the most direct and effective means of controlling the aforementioned pests. However, the problem of pesticide resistance caused by long-term, large-scale, and irrational use is becoming increasingly serious, severely affecting the control effect. According to statistics from the Arthropod Pesticide Resistance Database (APRD), 637 insect species worldwide have developed varying degrees of resistance to various pesticides, with Hemiptera, Lepidoptera, and Diptera accounting for approximately 52.7%. Over-reliance on and increased dosages to enhance effectiveness have significantly increased control costs and led to environmental pollution. Furthermore, most currently used pesticides are conventional pesticides that are highly toxic, difficult to degrade, and unsafe for non-target organisms such as bees; these pesticides are gradually being restricted or banned. Therefore, the green transformation of agriculture places higher demands on pesticide research and development, urgently requiring the creation of novel pesticides with novel chemical structures, significant control effects, low environmental risks, and novel mechanisms of action.

[0008] In response to this situation, in 2016, Corteva (formerly DuPont) registered a novel mesoionic pyrimidinone insecticide, Triflumezopyrim, in my country. This insecticide exhibits highly effective insecticidal activity against rice planthoppers and is the first commercially available product of its class. Subsequently, the company developed another mesoionic insecticide, dicloromezotiaz, which, in addition to controlling rice planthoppers, is also effective against diamondback moths and armyworms. Several insecticides, due to their excellent efficacy and unique mechanisms of action, are becoming an important option for green pest control in rice. However, they still carry the risk of high toxicity to bees and high levels of resistance (acute contact and acute oral LD50 after 72 hours). 50 They are 0.39 and 0.51 respectively. μ g / each, all of which are highly toxic).

[0009] Since Holyoke CW et al. first disclosed a pyrido[1,2-]pyrido[1,2-]pyrido[1,2-]pyrido[2,2-]pyrido[1,2- ...]pyrido[2, a [Preparation methods of pyrimidine metronid compounds and their good application as insecticides, pyrido[1,2-] a Research on pyrimidinone metronidazole compounds in the agricultural field has become a hot topic.

[0010] In recent years, researchers have focused on structural optimization of pyridopyrimidinone insecticidal compounds, primarily at the 1, 3, and 9 positions. DuPont has conducted extensive research on the 1-position substitution, publishing seven patents between 2009 and 2015. Structure-activity relationship results indicate that when pyrido[1,2-...]... a Pyrimidinone mesoionic skeletons containing 2-chlorothiazol-5-ylmethyl, pyrimidin-5-ylmethyl, and 6-chloropyridin-3-ylmethyl at the 1-position exhibit good to excellent insecticidal activity. In 2016, Hasegawa S. et al. of Nippon Kayaku Co., Ltd. disclosed a series of pyrido[1,2-]pyrimidinone compounds in patent publication number WO2016171053A1. a Among pyrimidine metronid compounds, compounds containing a cyanoethyl group at the 1-position were found to exhibit good to excellent insecticidal activity against cotton aphids and brown planthoppers, with some compounds showing activity at 0.1%... μ At a concentration of g / mL, the lethality against aphids was 100%, and some compounds showed even better insecticidal activity against cotton aphids than trifluorophenylpyrimidine and dicloomezotiazine. The results indicate that, for compounds containing the 1-position moiety, cyanoethyl can serve as an excellent substitution group for 2-chlorothiazol-5-ylmethyl, pyrimidin-5-ylmethyl, and 6-chloropyridin-3-ylmethyl.

[0011] p-pyrido[1,2-a Analysis of patents for pyrimidine ketone metronidazole compounds revealed that researchers achieved the most and most successful substitution at the 3-position of the parent structure. In 2012, Holyoke CW et al. disclosed a class of pyridopyrimidine metronidazole compounds containing diaryl groups in patent WO2012106495A1. These compounds exhibited excellent insecticidal activity against Lepidoptera, Homoptera, and Thysanoptera pests such as the diamondback moth and fall armyworm. Some compounds showed activity at 2... μ At a concentration of g / mL, it showed a 100% lethality against diamondback moth and fall armyworm. From 2012 to 2014, BASF disclosed phenyl compounds with oxime, oxime ether, amidine, and hydrazine substituted at the 3-position in patents WO2012136724A1, EP2684879A1, and WO2014033244A2; the insecticidal activity of these compounds was generally moderate. In 2021, Holmes, M et al. disclosed a series of pyridinopyrimidinone metronidazole compounds containing a 3-alkynylphenyl group at the 3-position in patent WO2021151034A1. Bioactivity tests showed that most compounds exhibited excellent insecticidal activity, with some compounds showing activity as low as 0.4 g / mL. μ At a concentration of g / mL, these compounds still exhibit 100% lethality against lepidopterans such as diamondback moth and fall armyworm. Some compounds also show activity against aphids and planthoppers, significantly enhancing their insecticidal spectrum and activity. In the past two years, pyridopyrimidine ionotropic compounds containing a benzo[a]-heterocyclic ring, a diynyl group, a pyrazole group, and a benzo[a]-dioxanone structure at the 3-position have been disclosed in patents CN120441570A, CN120904195A, CN120774912A, CN120774913A, CN120774911A, CN120774912A, and CN120682223A. Some of these compounds demonstrate good control activity against agricultural pests such as lepidopterans, homoptera, and mites. They are broad-spectrum, highly effective, and systemic, effectively controlling resistant pests and possessing considerable commercial value. Among them, the compound "chlorfenapyr" has been granted a provisional name by ISO. It is a novel chemically structured patented insecticide independently developed by Qingyuan, exhibiting no cross-resistance with existing insecticides. It possesses excellent penetration ability and a certain degree of systemic conductivity, effectively controlling lepidopteran pests such as the rice stem borer and rice leaf roller that have developed resistance to traditional pesticides. The creation of chlorfenapyr marks a significant breakthrough for Qingyuan in the field of rice resistant pest control, and it is expected to become a core force in the rice insecticide market in the future.

[0012] Our research team also conducted extensive research and modification on the 3-position of pyridopyrimidine ketone metronidazole compounds. We first disclosed pyridopyrimidine ketone metronidazole compounds with an indole derivative at the 3-position in patent CN113292557A. These compounds exhibited good insecticidal activity against white-backed planthoppers and broad bean aphids, with some compounds showing activity at 10... μ At a concentration of g / mL, the lethality against white-backed planthopper and broad bean aphid was 100%. Subsequently, patent CN113651811A disclosed pyridinidone metronidazole compounds with an isoxazole unit at the 3-position. These compounds exhibit excellent control efficacy against rice planthoppers, and a compound named "isoxamethonium pyrimidine" was created and named by the National Pesticide Standardization Technical Committee. This compound has a 2 g / mL concentration of g / mL. μ At a concentration of g / mL, the mortality rate against white-backed planthoppers remained 100%. To broaden the insecticidal spectrum and enhance the insecticidal activity of the compound, our research team disclosed a pyridopyrimidinone metronidazole compound containing a 1,2,4-oxadiazole structure at position 3 in patent CN117720535A in 2024. The created compound, "oxadiazole pyrimidin," exhibits excellent activity against rice stem borer, reaching 5 g / mL. μ The lethality rate remains at 95% at a concentration of g / mL, and it also exhibits insecticidal activity against both hemiptera and lepidopteran pests.

[0013] For pyrido[1,2- a Studies on the 9-position substitution of pyrimidinone mesoionic skeletons have found that the insecticidal activity of compounds significantly decreases when groups other than the methyl group are introduced. In 2011, Holyoke CW et al. of Corteva disclosed a method for preparing a class of mesoionic compounds and their application as insecticides in patent WO2011017342A2. These compounds exhibit good insecticidal activity; some compounds showed a 100% lethality against diamondback moth, fall armyworm, and cotton aphid at a concentration of 10 mg / L. Structure-activity relationship studies showed that in pyrido[1,2- a The compound exhibits optimal insecticidal activity against diamondback moth and fall armyworm when the 1-position of the pyrimidine ring is substituted with a 2-chlorothiazol-5-ylmethyl group and the 9-position is substituted with a methyl group. This effect is only effective when the 1-position is 2-chlorothiazol-5-yl, a phenomenon DuPont refers to as the "magic methyl effect." Based on this, DuPont developed dichlorothiapyrimidine, which possesses insecticidal activity against both hemiptera and lepidopteran pests.

[0014] In summary, the presence of 6-chloropyridin-3-ylmethyl, 2-chlorothiazol-5-ylmethyl, or pyrimidin-5-ylmethyl groups at the 1-position of pyridopyrimidinone compounds, along with cyanoacetonitrile, is beneficial for their insecticidal activity. A substituted aryl group at the 3-position is also beneficial for their insecticidal activity; by introducing a substituted aryl group at the 3-position, pyridopyrimidinone mesoionic compounds with insecticidal activity against both hemiptera and lepidopteran pests can be obtained. The absence of substitution or a methyl group at the 9-position of pyridopyrimidinone compounds is beneficial for their insecticidal activity; methyl substitution at the 9-position yields compounds with insecticidal activity against both hemiptera and lepidopteran pests.

[0015] In recent years, sulfoxide compounds have been widely used in pesticides such as insecticides, fungicides, and herbicides due to their novel chemical structures, unique mechanisms of action, and excellent biological activity. Their broad-spectrum biological activity has made them one of the most efficient lead structures, playing a vital role in the research and development of new pesticides. Since the first article reporting on the synthesis of sulfoxide compounds in 1865, research on sulfoxide compounds has become a new hot topic. Fipronil, an insecticide with a sulfoxide structure developed by Rhône-Plunkett in France, has broad-spectrum and highly effective activity against pests such as aphids, leafhoppers, and lepidopteran larvae. Ethylenetronidazole, also with a sulfoxide structure, is a broad-spectrum insecticide that can effectively kill various piercing-sucking and chewing insects even with small amounts. Studies have shown that introducing functional groups such as furanyl, thiophene, thiazolyl, phenyl, imidazolyl, and amides into the sulfoxide structure can enhance its insecticidal, fungicidal, and herbicidal activities. Therefore, developing sulfoxide compound pesticides with novel structures, new modes of action, and environmental friendliness has become a hot research topic for scientific researchers.

[0016] This invention addresses the problems of severe insect pest outbreaks, insufficient new drug development, increasing resistance to existing pesticides, and safety concerns regarding non-target organisms and the environment in my country. It is based on sulfoxide structures and pyrido[1,2-] a The important role of pyrimidinone metronidazoles in the research and development of insecticides, with pyrido[1,2-] as an example. a Pyrimidinone mesonotropic compounds were used as a lead compound to introduce a sulfoxide structure with excellent biological activity into pyridinium[1,2-]pyridyl[ ... a A series of pyrido[1,2-]pyrimidine structures containing sulfoxide structures were designed and synthesized at the para and meta positions of the 3-phenyl group. a Pyrimidine metronid derivatives. Bioactivity screening results indicate they possess good insecticidal activity, a broad spectrum of control, and low toxicity to bees, laying a solid foundation for the development of highly effective and low-risk sulfoxide metronid insecticides. Summary of the Invention

[0017] To address the aforementioned problems in the prior art, this invention provides a class of pyrido[1,2-]pyridines containing sulfoxide structures. a [A pyrimidine metronid derivative and its preparation method. The compound exhibits excellent control effects against pests such as western flower thrips, white-backed planthopper, aphids, fall armyworm, diamondback moth, rice stem borer, beet armyworm, and armyworm.]

[0018] Another object of the present invention is to provide a composition containing the above-mentioned compound or its stereoisomer or its salt.

[0019] Another object of the present invention is to provide the use of the above-mentioned compound or its stereoisomer, or its salt, or the composition thereof.

[0020] Another object of the present invention is to provide a method for controlling agricultural pests using the above-mentioned compound or its stereoisomer, or its salt, or the composition thereof.

[0021] To achieve the above objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides a pyrido[1,2-]pyrido[1,2-]pyridylene[2 ... a Pyrimidine mesonotropic derivatives, including compounds having the general formula (I) or its stereoisomers, salts or solvates thereof, the structural formula of which is as follows: (I) in R 1 It is independently selected from one or more of hydrogen, deuterium, alkyl (either substituted or unsubstituted), alkoxy (either substituted or unsubstituted), alkenyl (either substituted or unsubstituted), cycloalkyl (either substituted or unsubstituted), aryl (either substituted or unsubstituted), and heteroaryl (either substituted or unsubstituted); R 2 It is independently selected from one or more of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, mercapto, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl, any substituted or unsubstituted cycloalkyl, and any substituted or unsubstituted aryl. R 3 It is independently selected from one or more of any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl, any substituted or unsubstituted alkynyl, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl.

[0022] Preferably, R 1 Independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; R 2 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; R 3 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups.

[0023] The substitution refers to substitution by at least one or more of alkynyl, cyano, halogen, alkyl, and haloalkyl groups.

[0024] More preferably, R1 is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, phenyl, benzyl, pyridyl, pyrazolyl, pyrroleyl, furanyl, thiophene, thiazolyl, benzopyrroleyl, pyridazine, pyrimidine, pyrazine, -CH2CH2CN, -CHCNCH3, -CH2CH2CH2CN, -CH2CHCNCH3, -CHCNCH2CH3, -CH2CH2F, -CHFCH3, -CH2CH2CH2F, -CH2CHFCH3, -CHFCH2CH3, -CH2CH2Cl, -CHClCH3, -CH2CH2CH2Cl, -CH2CHClCH3, -CHClCH2CH3, -CH2CH2Br, -CHBrCH3, -CH2CH2CH2Br, -CH2CHBrCH3, -CHBrCH2CH3. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R3 is independently selected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, propenyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2Cl, -CH2CH2Br, -CH2CH2F-. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0025] Preferred derivative compounds include compounds Z1-Z62 listed below.

[0026] Secondly, the present invention provides the pyrido[1,2-]pyridyl ...a Methods for preparing pyrimidine mesonotropic derivatives include: Preferably, it further includes: Most preferably, it includes: Thirdly, the present invention provides a composition comprising pyrido[1,2-]pyridyl[1,2-]pyridyl[2 ... a The composition comprises pyrimidine mesonotropic derivatives and agricultural adjuvants; 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).

[0027] Fourthly, the present invention provides the pyrido[1,2-]pyridyl ... a The use of pyrimidine metronid derivatives, or the composition thereof, in the preparation of pesticides for the control of agricultural pests and diseases; wherein the agricultural pests and diseases are Thysanoptera, Hemiptera, and Lepidoptera pests.

[0028] Preferably, the agricultural pests and diseases are western flower thrips, white-backed planthopper, aphid, fall armyworm, diamondback moth, rice stem borer, beet armyworm, and armyworm.

[0029] Fifthly, the present invention provides a method for preventing and controlling agricultural pests and diseases, wherein the pyrido[1,2-]pyridyl group containing a sulfoxide structure is used to... a The pyrimidine-based metronid derivatives, or the composition thereof, act on harmful substances or their habitats; preferably, the agricultural pests are Thysanoptera, Hemiptera, and Lepidoptera pests; more preferably, the agricultural pests are western flower thrips, white-backed planthoppers, aphids, fall armyworms, diamondback moths, rice stem borers, beet armyworms, and armyworms.

[0030] In a sixth aspect, the present invention provides a method for protecting plants from agricultural pests and diseases, comprising inducing the pests to react with the sulfoxide-containing pyridine[1,2-] a The method steps of contacting pyrimidine mesonotropic derivatives or the composition described herein.

[0031] The beneficial effects of this invention are: 1) Excellent insecticidal activity. The compounds provided by this invention exhibit excellent insecticidal activity against western flower thrips, white-backed planthopper, pea aphid, fall armyworm, diamondback moth, rice stem borer, beet armyworm, and armyworm. Most of the compounds are effective at low doses (1). μEven under conditions of g / mL, it still exhibits high insecticidal activity. Therefore, the compound provided by this invention can improve the problem of high-dose application and fundamentally reduce the cost of application and pest resistance.

[0032] 2) High safety. The toxicity test results of the compound of this invention on bees show that it has low toxicity and is bee-friendly, and can not affect bee pollination, thus providing a better solution for protecting bees and other beneficial organisms.

[0033] 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) compounds are intended for C1, C2, C3, C4, C5, C6, C7, C8, C9, and C6. 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.

[0034] "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.

[0035] The term "cycloalkyl" refers to cycloalkyl groups, including mono-, di-, or polycyclic systems. 3-7The cycloalkyl group is intended 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.

[0036] 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.

[0037] The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine, and iodine.

[0038] 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, but 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).

[0039] The term "alkoxy group" refers to an alkyl group that is attached to the remainder of a molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. The alkoxy group contains 1-20 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), 1-propoxy (-OCH2CH2CH3), 2-propoxy (-OCH(CH3)2), and 1-butoxy (-OCH2CH2CH2CH3).

[0040] The term "substituted" refers to the substitution of any one or more hydrogen atoms on a specified atom or group with a selected specified group, provided that the substitution does not exceed the general valence of the specified atom. Unless otherwise specified, substituents are named to the central structure. For example, it can be understood that when (cycloalkyl)alkyl is a possible substituent, the connection point of the substituent to the central structure is in the alkyl moiety, and the substituent group includes, but is not limited to, halogen atoms.

[0041] The term "solvent" refers to an association formed by one or more solvent molecules with the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. Specific implementation methods 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.

[0042] Example 1: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z1): (1) Preparation of methyl 2-(4-mercaptophenyl)acetate: 2-(4-mercaptophenyl)acetic acid (5 g, 29.72 mmol) was added to a 250 mL three-necked round-bottom flask and dissolved in 100 mL of solvent. Concentrated sulfuric acid solution (583.03 mg, 5.94 mmol) was added dropwise to the system under stirring at room temperature. After the addition was complete, the system was heated to 70 °C. After the reaction was complete, the system was cooled to room temperature. The solvent in the reaction was evaporated, and 250 mL of water was added. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, and then extracted once more with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography to obtain 4.45 g of a colorless oil, with a yield of 82.15%.

[0043] (2) Preparation of methyl 2-(4-(phenylthio)phenyl)acetate: 1,10-phenanthroline (148.33 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (149.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of phenylboronic acid (838.01 mg, 6.87 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 1.89 g of a pale yellow oil, with a yield of 88.88%.

[0044] (3) Preparation of dimethyl 2-(4-(phenylthio)phenyl)malonate: 1.89 g (7.32 mmol) of methyl 2-(4-(phenylthio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride (526.71 mg, 27.95 mmol) was added in small, repeated additions while stirring in an ice bath. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 2.01 g of a yellow oil, with a yield of 87.27%.

[0045] (4) Preparation of 2-(4-(phenylthio)phenyl)malonic acid: Dimethyl 2-(4-(phenylthio)phenyl)malonate (2 g, 6.32 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (1.06 g, 18.97 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to give 1.43 g of pale yellow oil, with a yield of 78.46%.

[0046] (5) Preparation of 2-(4-(phenylthio)phenyl)malonyl chloride: 2-(4-(phenylthio)phenyl)malonic acid (1.43 g, 4.96 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (1.89 g, 14.88 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0047] (6) N Preparation of -((2-chlorothiazol-5-yl)methyl)pyridine-2-amine: 2-Aminopyridine (10.0 g, 106.3 mmol), 2-chloro-5-chloromethylthiazole (17.9 g, 106.3 mmol), N , N Diisopropylethylamine (16.5 g, 127.5 mmol), potassium iodide (1.8 g, 10.6 mmol), and 150 mL of xylene were mixed in a 500 mL three-necked flask and reacted at 78 °C for 6–10 h. After the reaction was complete, the reaction mixture was desolvated under reduced pressure, stirred with silica gel, and separated by column chromatography to obtain 13.6 g of a pale yellow solid, with a yield of 56.7%.

[0048] (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(phenylthio)phenyl)malonyl chloride (500 mg, 1.54 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (347.00 mg, 1.54 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 210.3 mg of yellow solid, with a yield of 28.62%.

[0049] (8) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z1): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (210.30 mg, 0.44 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (68.33 mg, 0.39 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain a yellow solid of 204.78 mg, with a yield of 94.22%.

[0050] Example 2: 4-oxo-3-(4-(phenyl sulfoxide)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z2): Steps (1) to (5) are the same as steps (1) to (5) in Example 1. (6) N Preparation of -(pyrimidin-5-methyl)pyridine-2-amine: 2-Aminopyridine (10.0 g, 106.25 mmol) and pyrimidine-5-carboxaldehyde (11.49 g, 106.25 mmol) were added to a 500 mL single-necked flask, and 100 mL of chloroform was added as solvent. The mixture was heated under reduced pressure and separated. When about 20 mL of solvent remained, 80 mL of solvent was added, and the reaction was repeated three times to obtain an imine intermediate. 50 mL of anhydrous methanol was added, and sodium borohydride was added in portions under stirring at room temperature. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the solvent was evaporated, 100 mL of water was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, the solvent was concentrated, and the mixture was stirred with silica gel and separated by column chromatography to obtain 7.86 g of a pale yellow solid, with a yield of 39.73%.

[0051] (7) 4-oxo-3-(4-(phenylthio)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(phenylthio)phenyl)malonyl chloride (500 mg, 1.54 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N 286.31 mg (1.54 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 180.5 mg of yellow solid, with a yield of 26.92%.

[0052] (8) 4-oxo-3-(4-(phenyl sulfoxide)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z2): 4-oxo-3-(4-(phenylthio)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- aPyrimidine-1-onthium-2-ol (181.5 mg, 0.41 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (71.43 mg, 0.41 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated and mixed with silica gel. The solution was separated by column chromatography to obtain 180.12 mg of a yellow solid, with a yield of 95.75%.

[0053] Example 3: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z3): Steps (1) to (5) are the same as steps (1) to (5) in Example 1. (6) N Preparation of 3-((2-chlorothiazol-5-yl)methyl)-3-methylpyridine-2-amine: 2-Amino-3-methylpyridine (10.0 g, 92.5 mmol), 2-chloro-5-chloromethylthiazole (15.5 g, 92.5 mmol), N , N Diisopropylethylamine (14.3 g, 111.0 mmol), potassium iodide (1.5 g, 9.3 mmol), and 150 mL of xylene were mixed in a 500 mL three-necked flask and reacted at 78 °C for 6–10 h. After the reaction was complete, the reaction mixture was desolvated under reduced pressure, stirred with silica gel, and separated by column chromatography to obtain 10.8 g of a pale yellow solid, with a yield of 48.72%.

[0054] (7) 1-((2-chlorothiazo-5-yl)methyl)-9-methyl-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(phenylthio)phenyl)malonyl chloride (500 mg, 1.54 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N-((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (368.57 mg, 1.54 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 259.80 mg of yellow solid, with a yield of 34.34%.

[0055] (8) 1-((2-chlorothiazolyl-5-yl)methyl)-9-methyl-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z3): 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (259.8 mg, 0.53 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (91.12 mg, 0.53 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain a yellow solid of 232.89 mg, with a yield of 86.82%.

[0056] Example 4: 1-(2-cyanoethyl)-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z4): Steps (1) to (5) are the same as steps (1) to (5) in Example 1. (6) Preparation of 3-(2-pyridylamino)propionitrile: In a 500 mL three-necked flask, sodium hydride (2.29 g, 95.63 mmol) and 120 mL DMF were added. 2-Aminopyridine (10 g, 106.25 mmol) was slowly added with stirring at room temperature. After the addition was complete, the mixture was stirred at 60 °C for 1 hour. 3-Bromopropionitrile (11.39 g, 85.0 mmol) was added, and the mixture was stirred at 60 °C for another hour before the reaction was stopped. The reaction mixture was poured into 400 mL of saturated brine, filtered, and washed with a small amount of ethyl acetate. The filtrate was extracted three times with ethyl acetate (3 × 200 mL). The organic layers were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 7.12 g of a pale yellow oil, with a yield of 45.53%.

[0057] (7) 1-(2-cyanoethyl)-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(phenylthio)phenyl)malonyl chloride (500 mg, 1.54 mmol) was dissolved in 20 mL of dry dichloromethane. Intermediate 3-(2-pyridylamino)propionitrile (226.29 mg, 1.54 mmol) was added to the system, followed by the addition of 6–12 drops of triethylamine with stirring. The reaction was allowed to proceed at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction. The mixture was stirred with silica gel and separated by column chromatography to obtain 179.45 mg of a yellow solid, with a yield of 29.22%.

[0058] (8) 1-(2-cyanoethyl)-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z4): 1-(2-cyanoethyl)-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- aPyrimidine-1-onthium-2-ol (179.45 mg, 0.45 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (69.77 mg, 0.40 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 165.88 mg of a yellow solid, with a yield of 88.88%.

[0059] Example 5: 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z5): Steps (1) to (5) are the same as steps (1) to (5) in Example 1. (6) N Preparation of -((6-chloropyridin-3-yl)methyl)pyridin-2-amine: 10.0 g (106.3 mmol) of 2-aminopyridine, 13.4 g (159.4 mmol) of sodium bicarbonate, and 100 mL of water were mixed in a 250 mL three-necked flask and stirred at 90 °C for half an hour. Then, 50 mL of an ethanol solution of 2-chloro-5-chloromethylpyridine (17.2 g, 106.3 mmol) was added. After the addition was complete, the temperature was raised to 100 °C and the reaction proceeded for 4–6 h. After the reaction was complete, the reaction mixture was cooled to room temperature, 100 mL of water was added, and the mixture was 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 column chromatography to obtain 13.4 g of a yellowish-brown oily substance, with a yield of 57.4%.

[0060] (7) 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(phenylthio)phenyl)malonyl chloride (500 mg, 1.54 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N-((6-chloropyridin-3-yl)methyl)pyridin-2-amine (337.75 mg, 1.54 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 221.30 mg of yellow solid, with a yield of 30.50%.

[0061] (8) 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z5): 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (221.3 mg, 0.47 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (80.91 mg, 0.47 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 198.2 mg of a yellow solid, with a yield of 86.63%.

[0062] Example 6: 1-((6-chloropyridin-3-yl)methyl)-9-methyl-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z6): Steps (1) to (5) are the same as steps (1) to (5) in Example 1. (6) N Preparation of 3-((6-chloropyridin-3-yl)methyl)3-methylpyridin-2-amine: 10.0 g (106.3 mmol) of 2-amino-3-methylpyridine, 13.4 g (159.4 mmol) of sodium bicarbonate, and 100 mL of water were mixed in a 250 mL three-necked flask and stirred at 90 °C for half an hour. Then, 50 mL of an ethanol solution of 17.2 g (106.3 mmol) of 2-chloro-5-chloromethylpyridine was added. After the addition was complete, the temperature was raised to 100 °C and the reaction proceeded for 4–6 h. After the reaction was complete, the reaction mixture was cooled to room temperature, 100 mL of water was added, and the mixture was 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 column chromatography to obtain 14.3 g of a yellowish-brown oily substance, with a yield of 61.27%.

[0063] (7) 1-((6-chloropyridin-3-yl)methyl)-9-methyl-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(phenylthio)phenyl)malonyl chloride (500 mg, 1.54 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)3-methylpyridin-2-amine (359.31 mg, 1.54 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 225.20 mg of yellow solid, with a yield of 30.14%.

[0064] (8) 1-((6-chloropyridin-3-yl)methyl)-9-methyl-4-oxo-3-(4-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z6): 1-((6-chloropyridin-3-yl)methyl)-9-methyl-4-oxo-3-(4-(phenylthio)phenyl)-4 H -pyrido[1,2- aPyrimidine-1-onthium-2-ol (225.2 mg, 0.46 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (71.97 mg, 0.42 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated and mixed with silica gel. The solution was separated by column chromatography to obtain 202.45 mg of a yellow solid, with a yield of 87.03%.

[0065] Example 7: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z7): (1) Preparation of methyl 2-(3-mercaptophenyl)acetate: 2-(3-mercaptophenyl)acetic acid (5 g, 29.72 mmol) was added to a 250 mL three-necked round-bottom flask and dissolved in 100 mL of solvent. Concentrated sulfuric acid solution (583.03 mg, 5.94 mmol) was added dropwise to the system under stirring at room temperature. After the addition was complete, the system was heated to 70 °C. After the reaction was complete, the system was cooled to room temperature, the solvent in the reaction was evaporated, and 250 mL of water was added. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, and then extracted once more with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 4.65 g of a colorless oil, with a yield of 85.84%.

[0066] (2) Preparation of methyl 2-(3-(phenylthio)phenyl)acetate: 1,10-phenanthroline (148.33 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (149.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of phenylboronic acid (838.01 mg, 6.87 mmol) and methyl 2-(3-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 1.65 g of a pale yellow oil, with a yield of 77.6%.

[0067] (3) Preparation of dimethyl 2-(3-(phenylthio)phenyl)malonate: 1.65 g (6.40 mmol) of methyl 2-(3-(phenylthio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride (616.71 mg, 37.25 mmol) was added in small, repeated additions while stirring in an ice bath. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.85 g of a yellow oil, with a yield of 91.55%.

[0068] (4) Preparation of 2-(3-(phenylthio)phenyl)malonic acid: Dimethyl 2-(3-(phenylthio)phenyl)malonate (1.85 g, 5.85 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.98 g, 17.54 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.63 g of pale yellow oil, with a yield of 96.68%.

[0069] (5) Preparation of 2-(3-(phenylthio)phenyl)malonyl chloride: 2-(3-(phenylthio)phenyl)malonic acid (1.63 g, 5.65 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.87 g, 22.61 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0070] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(phenylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(3-(phenylthio)phenyl)malonyl chloride (500 mg, 1.54 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (347.00 mg, 1.54 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 261.6 mg of yellow solid, with a yield of 35.6%.

[0071] (8) 1-((2-chlorothiazolyl-5-yl)methyl)-4-oxo-3-(3-(phenyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z7): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(phenylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (261.6 mg, 0.55 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (94.44 mg, 0.55 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 258.1 mg of a yellow solid, with a yield of 95.45%.

[0072] Example 8: 4-oxo-3-(3-(phenyl sulfoxide)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z8): Steps (1) to (5) are the same as steps (1) to (5) in Example 1. Step (6) is the same as step (6) in Example 2. (7) 4-oxo-3-(3-(phenylthio)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(3-(phenylthio)phenyl)malonyl chloride (500 mg, 1.54 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N 286.31 mg (1.54 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and the sample was separated by column chromatography to obtain 188.72 mg of yellow solid, with a yield of 27.99%.

[0073] (8) 4-O-3-(3-(phenyl sulfoxide)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z8): 4-oxo-3-(3-(phenylthio)phenyl)-1-(pyrimidin-5-ylmethyl)-4H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (188.72 mg, 0.43 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (59.41 mg, 0.34 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 178.20 mg of a yellow solid, with a yield of 91.10%.

[0074] Example 9: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z9): (1) Preparation of methyl 2-(4-(methylthio)phenyl)acetate: 2-(4-(methylthio)phenyl)acetic acid (5 g, 27.44 mmol) was added to a 250 mL three-necked round-bottom flask and dissolved in 100 mL of solvent. Concentrated sulfuric acid solution (538.16 mg, 5.49 mmol) was added dropwise to the system under stirring at room temperature. After the addition was complete, the system was heated to 70 °C. After the reaction was complete, the system was cooled to room temperature, the solvent in the reaction was evaporated, and 250 mL of water was added. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, and then extracted once more with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 5.31 g of a colorless oil, with a yield of 98.61%.

[0075] (2) Preparation of dimethyl 2-(4-(methylthio)phenyl)malonate: Methyl 2-(4-(methylthio)phenyl)acetate (2 g, 10.19 mmol) was added to a 100 mL three-necked round-bottom flask. Using 20 mL of dimethyl carbonate as solvent, 6 mL of tetrahydrofuran was added. Under ice bath conditions, 60% sodium hydride (526.71 mg, 27.95 mmol) was added in small, repeated additions while stirring. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 2.3 g of a yellow oil, with a yield of 88.75%.

[0076] (3) Preparation of 2-(4-(methylthio)phenyl)malonic acid: Dimethyl 2-(4-(methylthio)phenyl)malonate (2.3 g, 9.04 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (1.52 g, 27.13 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.5 g of pale yellow oil, with a yield of 73.3%.

[0077] (4) Preparation of 2-(4-(methylthio)phenyl)malonyl chloride: 2-(4-(methylthio)phenyl)malonic acid (1.5 g, 6.63 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (3.37 g, 26.52 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0078] Step (5) is the same as step (6) in Example 1. (6) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-olate: 2-(4-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (428.86 mg, 1.90 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 280.20 mg of yellow solid, with a yield of 35.45%.

[0079] (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z9): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (280.20 mg, 0.67 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (68.33 mg, 0.61 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 270.12 mg of a yellow solid, with a yield of 92.83%.

[0080] Example 10: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z10): Steps (1) to (4) are the same as steps (1) to (4) in Example 9. Step (5) is the same as step (6) in Example 3. (6) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-olate: 2-(4-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (455.51 mg, 1.90 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 312.3 mg of yellow solid, with a yield of 38.23%.

[0081] (7) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol salt (Z10): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (312.30 mg, 0.73 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (112.8 mg, 0.65 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 298.1 mg of a yellow solid, with a yield of 92.03%.

[0082] Example 11: 4-oxo-3-(4-(methyl sulfoxide)phenyl)-1-(pyrimidin-5-ylmethyl)-4H-pyrido[1,2-a]pyrimidin-1-onthium-2-ol (Z11): Steps (1) to (4) are the same as steps (1) to (4) in Example 9. Step (5) is the same as step (6) in Example 2. (6) 4-oxo-3-(4-(methylthio)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N 353.85 mg (1.90 mmol) of pyrimidin-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and the sample was separated by column chromatography to obtain 219.32 mg of yellow solid, with a yield of 30.66%.

[0083] (7) 4-oxo-3-(4-(methyl sulfoxide)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z11): 4-oxo-3-(4-(methylthio)phenyl)-1-(pyrimidin-5-ylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (219.32 mg, 0.58 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (85.46 mg, 0.50 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 177.2 mg of a yellow solid, with a yield of 77.5%.

[0084] Example 12: 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z12): Steps (1) to (4) are the same as steps (1) to (4) in Example 9. Step (5) is the same as step (6) in Example 5. (6) 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)pyridin-2-amine (417.42 mg, 1.90 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 237.69 mg of yellow solid, with a yield of 30.52%.

[0085] (7) 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z12): 1-((6-chloropyridin-3-yl)methyl)-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (237.69 mg, 0.50 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (86.91 mg, 0.50 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 221.14 mg of a yellow solid, with a yield of 89.99%.

[0086] Example 13: 1-((6-chloropyridin-3-yl)methyl)-9-methyl-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z13): Steps (1) to (4) are the same as steps (1) to (4) in Example 9. Step (5) is the same as step (6) in Example 6. (6) 1-((6-chloropyridin-3-yl)methyl)-9-methyl-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)3-methylpyridin-2-amine (444.07 mg, 1.90 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 237.71 mg of yellow solid, with a yield of 29.51%.

[0087] (7) 1-((6-chloropyridin-3-yl)methyl)-9-methyl-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol salt (Z13): 1-((6-chloropyridin-3-yl)methyl)-9-methyl-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (237.71 mg, 0.56 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (91.93 mg, 0.53 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 201.9 mg of a yellow solid, with a yield of 81.85%.

[0088] Example 14: 1-(2-cyanoethyl)-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z14): Steps (1) to (4) are the same as steps (1) to (4) in Example 9. Step (5) is the same as step (6) in Example 4. (6) 1-(2-cyanoethyl)-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) was dissolved in 20 mL of dry dichloromethane. Intermediate 3-(2-pyridylamino)propionitrile (279.67 mg, 1.90 mmol) was added to the system, followed by the addition of 6–12 drops of triethylamine with stirring. The reaction was allowed to proceed at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction. The mixture was stirred with silica gel and separated by column chromatography to obtain 172.3 mg of a yellow solid, with a yield of 26.87%.

[0089] (7) 1-(2-cyanoethyl)-4-oxo-3-(4-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z14): 1-(2-cyanoethyl)-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (172.3 mg, 0.51 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (88.12 mg, 0.51 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 156.67 mg of a yellow solid, with a yield of 86.81%.

[0090] Example 15: 1-(2-cyanoethyl)-9-methyl-3-(4-(methylenesulfinyl)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z15): Steps (1) to (4) are the same as steps (1) to (4) in Example 9. (5) Preparation of 3-((3-methylpyridin-2-yl)amino)propionitrile: In a 500 mL three-necked flask, sodium hydride (2.37 g, 96.63 mmol) and 120 mL DMF were added. 2-Amino-3-methylpyridine (10 g, 106.25 mmol) was slowly added with stirring at room temperature. After the addition was complete, the mixture was stirred at 60 °C for 1 hour. 3-Bromopropionitrile (11.41 g, 85.2 mmol) was added, and the mixture was stirred at 60 °C for another hour before the reaction was stopped. The reaction mixture was poured into 400 mL of saturated brine, filtered, and washed with a small amount of ethyl acetate. The filtrate was extracted three times with ethyl acetate (3 × 200 mL). The organic layers were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 7.01 g of a pale yellow oil, with a yield of 42.13%.

[0091] (6) 1-(2-cyanoethyl)-9-methyl-3-(4-(methylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) was dissolved in 20 mL of dry dichloromethane. Intermediate 3-((3-methylpyridin-2-yl)amino)propionitrile (306.33 mg, 1.90 mmol) was added to the system, followed by the addition of 6–12 drops of triethylamine with stirring. The reaction was allowed to proceed at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction. The mixture was stirred with silica gel and separated by column chromatography to obtain 162.97 g of a yellow solid, with a yield of 24.41%.

[0092] (7) 1-(2-cyanoethyl)-9-methyl-3-(4-(methylenesulfinyl)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z15): 1-(2-cyanoethyl)-9-methyl-3-(4-(methylthio)phenyl)-4-oxo-4 H -pyrido[1,2- aPyrimidine-1-onthium-2-ol (162.97 mg, 0.46 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (80.03 mg, 0.46 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 137.6 mg of a yellow solid, with a yield of 80.76%.

[0093] Example 16: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z16): (1) Preparation of methyl 2-(3-(methylthio)phenyl)acetate: 2-(3-(methylthio)phenyl)acetic acid (5 g, 27.44 mmol) was added to a 250 mL three-necked round-bottom flask and dissolved in 100 mL of solvent. Concentrated sulfuric acid solution (538.16 mg, 5.49 mmol) was added dropwise to the system under stirring at room temperature. After the addition was complete, the system was heated to 70 °C. After the reaction was complete, the system was cooled to room temperature, the solvent in the reaction was evaporated, and 250 mL of water was added. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, and then extracted once more with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 5.22 g of a colorless oil, with a yield of 95.4%.

[0094] (2) Preparation of dimethyl 2-(3-(methylthio)phenyl)malonate: Methyl 2-(3-(methylthio)phenyl)acetate (2 g, 10.19 mmol) was added to a 100 mL three-necked round-bottom flask. Using 20 mL of dimethyl carbonate as solvent, 6 mL of tetrahydrofuran was added. Under ice bath conditions, 60% sodium hydride (526.71 mg, 27.95 mmol) was added in small, repeated additions while stirring. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 2.3 g of a yellow oil, with a yield of 88.75%.

[0095] (3) Preparation of 2-(3-(methylthio)phenyl)malonic acid: Dimethyl 2-(3-(methylthio)phenyl)malonate (2.3 g, 9.04 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (1.52 g, 27.13 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.51 g of pale yellow oil, with a yield of 73.4%.

[0096] (4) Preparation of 2-(3-(methylthio)phenyl)malonyl chloride: 2-(3-(methylthio)phenyl)malonic acid (1.51 g, 6.66 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (3.37 g, 26.52 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0097] Step (5) is the same as step (6) in Example 1. (6) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(methylthio)phenyl)-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-olate: Dissolve 2-(3-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) in 20 mL of dry dichloromethane, and add the intermediate to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (428.86 mg, 1.90 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 270.24 mg of yellow solid, with a yield of 30.3%.

[0098] (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z16): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(methylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (270.20 mg, 0.65 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (62.5 mg, 0.65 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 260.2 mg of a yellow solid, with a yield of 89.5%.

[0099] Example 17: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(3-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z17): Steps (1) to (4) are the same as steps (1) to (4) in Example 16. Step (5) is the same as step (6) in Example 3. (6) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(3-(methylthio)phenyl)-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-olate: Dissolve 2-(3-(methylthio)phenyl)malonyl chloride (500 mg, 1.90 mmol) in 20 mL of dry dichloromethane, and add the intermediate to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (455.51 mg, 1.90 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 212.3 mg of yellow solid, with a yield of 25.5%.

[0100] (7) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(3-(methyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z17): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(3-(methylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (212.3 mg, 0.63 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (62.8 mg, 0.63 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 176.2 mg of a yellow solid, with a yield of 80.5%.

[0101] Example 18: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-chlorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z18): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((4-chlorophenyl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of p-chlorophenylboronic acid (1.07 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 1.92 g of a pale yellow oil, with a yield of 79.67%.

[0102] (3) Preparation of dimethyl 2-(4-((4-chlorophenyl)thio)phenyl)malonate: 1.92 g (6.56 mmol) of methyl 2-(4-((4-chlorophenyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride (526.71 mg, 27.95 mmol) was added in small, repeated additions while stirring in an ice bath. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 2.17 g of a yellow oil, with a yield of 94.32%.

[0103] (4) Preparation of 2-(4-((4-chlorophenyl)thio)phenyl)malonic acid: Dimethyl 2-(4-((4-chlorophenyl)thio)phenyl)malonate (2.17 g, 6.19 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (1.04 g, 18.56 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to give 1.45 g of pale yellow oil, with a yield of 72.63%.

[0104] (5) Preparation of 2-(4-((4-chlorophenyl)thio)phenyl)malonyl chloride: 2-(4-((4-chlorophenyl)thio)phenyl)malonic acid (1.45 g, 4.49 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.28 g, 17.97 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0105] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-chlorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-chlorophenyl)thio)phenyl)malonyl chloride (500 mg, 1.39 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (313.77 mg, 1.39 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 269.5 mg of yellow solid, with a yield of 37.83%.

[0106] (8) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-chlorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-ol (Z18): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-chlorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (269.50 mg, 0.53 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (90.76 mg, 0.53 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 243.75 mg of a yellow solid, with a yield of 87.71%.

[0107] Example 19: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-chlorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z19): Steps (1) to (5) are the same as steps (1) to (5) in Example 18. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-chlorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-chlorophenyl)thio)phenyl)malonyl chloride (500 mg, 1.39 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (333.27 mg, 1.39 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 231.5 mg of yellow solid, with a yield of 31.63%.

[0108] (8) 1-((2-chlorothiazolyl-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-chlorophenyl)sulfoxide)phenyl)-4H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z19): 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-chlorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (231.50 mg, 0.44 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (75.88 mg, 0.44 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 198.85 mg of a yellow solid, with a yield of 83.36%.

[0109] Example 20: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(3-((4-chlorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z20): Step (1) is the same as step (1) in Example 7. (2) Preparation of methyl 2-(3-((4-chlorophenyl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube using a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of p-chlorophenylboronic acid (1.07 g, 6.83 mmol) and methyl 2-(3-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction, the system was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated, mixed, and separated by column chromatography to obtain 1.90 g of a pale yellow oil, with a yield of 78.5%.

[0110] (3) Preparation of dimethyl 2-(3-((4-chlorophenyl)thio)phenyl)malonate: 1.9 g (6.5 mmol) of methyl 2-(3-((4-chlorophenyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride (526.71 mg, 27.95 mmol) was added in small, repeated additions while stirring in an ice bath. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 2.15 g of a yellow oil, with a yield of 94.1%.

[0111] (4) Preparation of 2-(3-((4-chlorophenyl)thio)phenyl)malonic acid: Dimethyl 2-(3-((4-chlorophenyl)thio)phenyl)malonate (2.15 g, 6.15 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (1.02 g, 18.5 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.45 g of pale yellow oil, with a yield of 72.63%.

[0112] (5) Preparation of 2-(3-((4-chlorophenyl)thio)phenyl)malonyl chloride: 2-(3-((4-chlorophenyl)thio)phenyl)malonic acid (1.45 g, 4.49 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.28 g, 17.97 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0113] Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazo-5-yl)methyl)-9-methyl-4-oxo-3-(3-((4-chlorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(3-((4-chlorophenyl)thio)phenyl)malonyl chloride (500 mg, 1.39 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (313.77 mg, 1.39 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 260.5 mg of yellow solid, with a yield of 33.5%.

[0114] (8) 1-((2-chlorothiazolyl-5-yl)methyl)-9-methyl-4-oxo-3-(3-((4-chlorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z20): 1-((2-chlorothiazo-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-chlorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (260.50 mg, 0.52 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (87.5 mg, 0.52 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 230.75 mg of a yellow solid, with a yield of 82.5%.

[0115] Example 21: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-fluorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z21): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((4-fluorophenyl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of p-fluorophenylboronic acid (0.96 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 1.85 g of a pale yellow oil, with a yield of 81.34%.

[0116] (3) Preparation of dimethyl 2-(4-((4-fluorophenyl)thio)phenyl)malonate: 1.85 g (6.7 mmol) of methyl 2-(4-((4-fluorophenyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride (526.71 mg, 27.95 mmol) was added in small, repeated additions while stirring in an ice bath. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.95 g of a yellow oil, with a yield of 87.11%.

[0117] (4) Preparation of 2-(4-((4-fluorophenyl)thio)phenyl)malonic acid: Dimethyl 2-(4-((4-fluorophenyl)thio)phenyl)malonate (1.96 g, 5.83 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.98 g, 17.5 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.49 g of pale yellow oil, with a yield of 83.41%.

[0118] (5) Preparation of 2-(4-((4-fluorophenyl)thio)phenyl)malonyl chloride: 2-(4-((4-fluorophenyl)thio)phenyl)malonic acid (1.49 g, 4.86 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.47 g, 19.46 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0119] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-fluorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-fluorophenyl)thio)phenyl)malonyl chloride (500 mg, 1.46 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (328.81 mg, 1.46 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 245.5 mg of yellow solid, with a yield of 33.98%.

[0120] (8) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-fluorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-ol (Z21): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-fluorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (245.50 mg, 0.50 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (85.42 mg, 0.50 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 212.6 mg of a yellow solid, with a yield of 83.89%.

[0121] Example 22: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-fluorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z22): Steps (1) to (5) are the same as steps (1) to (5) in Example 21. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-fluorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-fluorophenyl)thio)phenyl)malonyl chloride (500 mg, 1.46 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (349.25 mg, 1.46 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 205.58 mg of yellow solid, with a yield of 27.67%.

[0122] (8) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-fluorophenyl)sulfoxide)phenyl)-4H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z22): 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-fluorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (231.50 mg, 0.40 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (69.56 mg, 0.40 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 185.5 mg of a yellow solid, with a yield of 87.49%.

[0123] Example 23: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((3-fluorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z23): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((3-fluorophenyl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of p-fluorophenylboronic acid (0.96 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, stirred, and separated by column chromatography to obtain 1.77 g of a pale yellow oil, with a yield of 77.82%.

[0124] (3) Preparation of dimethyl 2-(4-((3-fluorophenyl)thio)phenyl)malonate: 1.77 g (6.41 mmol) of methyl 2-(4-((3-fluorophenyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.82 g of a yellow oil, with a yield of 84.98%.

[0125] (4) Preparation of 2-(4-((3-fluorophenyl)thio)phenyl)malonic acid: Dimethyl 2-(4-((3-fluorophenyl)thio)phenyl)malonate (1.82 g, 5.44 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.92 g, 16.33 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.35 g of pale yellow oil, with a yield of 80.97%.

[0126] (5) Preparation of 2-(4-((3-fluorophenyl)thio)phenyl)malonyl chloride: 2-(4-((3-fluorophenyl)thio)phenyl)malonic acid (1.35 g, 4.46 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.24 g, 17.63 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0127] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((3-fluorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((3-fluorophenyl)thio)phenyl)malonyl chloride (500 mg, 1.46 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (328.81 mg, 1.46 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 241.96 mg of yellow solid, with a yield of 33.49%.

[0128] (8) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((3-fluorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z23): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((3-fluorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (241.96 mg, 0.49 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (84.19 mg, 0.49 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 195.5 mg of a yellow solid, with a yield of 78.27%.

[0129] Example 24: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((3-fluorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z24): Steps (1) to (5) are the same as steps (1) to (5) in Example 23. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((3-fluorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((3-fluorophenyl)thio)phenyl)malonyl chloride (500 mg, 1.46 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (349.25 mg, 1.46 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 189.7 mg of yellow solid, with a yield of 25.53%.

[0130] (8) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((3-fluorophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z24): 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((3-fluorophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (189.70 mg, 0.37 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (64.19 mg, 0.40 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain a yellow solid of 171.1 mg, with a yield of 87.45%.

[0131] Example 25: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(p-tolylsulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z25): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-(p-Tolylthio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of p-methylphenylboronic acid (0.93 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, stirred, and separated by column chromatography to obtain 1.8 g of a pale yellow oil, with a yield of 80.29%.

[0132] (3) Preparation of dimethyl 2-(4-(p-Tolylthio)phenyl)malonate: 1.8 g (6.51 mmol) of methyl 2-(4-(p-tolylthio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.78 g of a yellow oil, with a yield of 81.72%.

[0133] (4) Preparation of 2-(4-(p-Tolylthio)phenyl)malonic acid: Dimethyl 2-(4-(p-Tolylthio)phenyl)malonate (1.78 g, 5.32 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.90 g, 15.97 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.45 g of pale yellow oil, with a yield of 88.92%.

[0134] (5) Preparation of 2-(4-(p-Tolylthio)phenyl)malonyl chloride: 2-(4-(p-Tolylthio)phenyl)malonic acid (1.45 g, 4.8 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.43 g, 19.18 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0135] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazo-5-yl)methyl)-4-oxo-3-(4-(p-tolylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(p-Tolylthio)phenyl)malonyl chloride (500 mg, 1.47 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (332.66 mg, 1.47 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 225.9 mg of yellow solid, with a yield of 31.15%.

[0136] (8) 1-((2-chlorothiazolyl-5-yl)methyl)-4-oxo-3-(4-(p-tolylsulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z25): 1-((2-chlorothiazo-5-yl)methyl)-4-oxo-3-(4-(p-tolylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (225.9 mg, 0.50 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (79.23 mg, 0.50 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 187.8 mg of a yellow solid, with a yield of 80.52%.

[0137] Example 26: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(p-tolylsulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z26): Steps (1) to (5) are the same as steps (1) to (5) in Example 25. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazo-5-yl)methyl)-9-methyl-4-oxo-3-(4-(p-tolylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(p-Tolylthio)phenyl)malonyl chloride (500 mg, 1.47 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (353.33 mg, 1.47 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 195.5 mg of yellow solid, with a yield of 26.21%.

[0138] (8) 1-((2-chlorothiazo-5-yl)methyl)-9-methyl-4-oxo-3-(4-(p-tolylsulfoxide)phenyl)-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-ol (Z26): 1-((2-chlorothiazo-5-yl)methyl)-9-methyl-4-oxo-3-(4-(p-tolylthio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (195.50 mg, 0.39 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (66.67 mg, 0.39 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 182.3 mg of a yellow solid, with a yield of 90.39%.

[0139] Example 27: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-trifluoromethylphenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z27): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((4-trifluoromethylphenyl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of p-trifluoromethylphenylboronic acid (1.30 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 2.12 g of a pale yellow oil, with a yield of 78.93%.

[0140] (3) Preparation of dimethyl 2-(4-((4-trifluoromethylphenyl)thio)phenyl)malonate: 2.12 g (6.5 mmol) of methyl 2-(4-((4-trifluoromethylphenyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.91 g of a yellow oil, with a yield of 76.49%.

[0141] (4) Preparation of 2-(4-((4-trifluoromethylphenyl)thio)phenyl)malonic acid: Dimethyl 2-(4-((4-trifluoromethylphenyl)thio)phenyl)malonate (1.91 g, 4.97 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.84 g, 14.91 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.42 g of pale yellow oil, with a yield of 80.2%.

[0142] (5) Preparation of 2-(4-((4-trifluoromethylphenyl)thio)phenyl)malonyl chloride: 2-(4-((4-trifluoromethylphenyl)thio)phenyl)malonic acid (1.42 g, 3.99 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.02 g, 15.94 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0143] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-trifluoromethylphenyl)thio)phenyl)-4 H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-trifluoromethylphenyl)thio)phenyl)malonyl chloride (500 mg, 1.27 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (287.0 mg, 1.27 mmol) was added with 6-12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 165.3 mg of yellow solid, with a yield of 23.81%.

[0144] (8) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-trifluoromethylphenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z27): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-trifluoromethylphenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (165.30 mg, 0.30 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (52.15 mg, 0.30 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 139.8 mg of a yellow solid, with a yield of 82.32%.

[0145] Example 28: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-trifluoromethylphenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z28): Steps (1) to (5) are the same as steps (1) to (5) in Example 27. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-trifluoromethylphenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-trifluoromethylphenyl)thio)phenyl)malonyl chloride (500 mg, 1.27 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (304.83 mg, 1.27 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 245 mg of yellow solid, with a yield of 34.40%.

[0146] (8) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-trifluoromethylphenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z28): 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-trifluoromethylphenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (245 mg, 0.44 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (75.5 mg, 0.44 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 211.1 mg of a yellow solid, with a yield of 83.77%.

[0147] Example 29: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-cyanophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z29): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((4-cyanophenyl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of p-cyanoboronic acid (1 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 1.75 g of a pale yellow oil, with a yield of 75.04%.

[0148] (3) Preparation of dimethyl 2-(4-((4-cyanophenyl)thio)phenyl)malonate: 1.75 g (6.18 mmol) of methyl 2-(4-((4-cyanophenyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were extracted again with saturated brine (100 mL × 3), and the mixture was combined once more. After drying with anhydrous sodium sulfate, the solvent was evaporated to dryness to give 1.66 g of a yellow oil, with a yield of 78.73%. (4) Preparation of 2-(4-((4-cyanophenyl)thio)phenyl)malonic acid: Dimethyl 2-(4-((4-cyanophenyl)thio)phenyl)malonate (1.66 g, 4.86 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.82 g, 14.59 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.23 g of pale yellow oil, with a yield of 80.73%.

[0149] (5) Preparation of 2-(4-((4-cyanophenyl)thio)phenyl)malonyl chloride: 2-(4-((4-cyanophenyl)thio)phenyl)malonic acid (1.23 g, 3.93 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (1.99 g, 15.70 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0150] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-cyanophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-cyanophenyl)thio)phenyl)malonyl chloride (500 mg, 1.43 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (322.22 mg, 1.43 mmol) was added with 6-12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 234.8 mg of yellow solid, with a yield of 32.7%.

[0151] (8) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-cyanophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-ol (Z29): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-((4-cyanophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (234.8 mg, 0.47 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (80.55 mg, 0.47 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 217.5 mg of a yellow solid, with a yield of 89.78%.

[0152] Example 30: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-cyanophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z30): Steps (1) to (5) are the same as steps (1) to (5) in Example 29. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-cyanophenyl)thio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-cyanophenyl)thio)phenyl)malonyl chloride (500 mg, 1.43 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (342.25 mg, 1.43 mmol), with 6-12 drops of triethylamine added under stirring, reacted at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 201.6 mg of yellow solid, with a yield of 27.31%.

[0153] (8) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-cyanophenyl)sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol salt (Z30): 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-((4-cyanophenyl)thio)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (201.60 mg, 0.39 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (69.29 mg, 0.39 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 165.5 mg of a yellow solid, with a yield of 79.63%.

[0154] Example 31: 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(cyclopropyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z31): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-(cyclopropylthio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of cyclopropionic acid (586.83 mg, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 1.43 g of a pale yellow oil, with a yield of 78.15%.

[0155] (3) Preparation of dimethyl 2-(4-(cyclopropylthio)phenyl)malonate: 1.43 g (6.43 mmol) of methyl 2-(4-(cyclopropylthio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.55 g of a yellow oil, with a yield of 85.95%.

[0156] (4) Preparation of 2-(4-(cyclopropylthio)phenyl)malonic acid: Dimethyl 2-(4-(cyclopropylthio)phenyl)malonate (1.55 g, 5.53 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.93 g, 16.59 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to approximately 2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.15 g of a pale yellow oily substance, with a yield of 82.44%.

[0157] (5) Preparation of 2-(4-(cyclopropylthio)phenyl)malonyl chloride: 2-(4-(cyclopropylthio)phenyl)malonic acid (1.15 g, 4.56 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.31 g, 18.23 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0158] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(cyclopropylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(cyclopropylthio)phenyl)malonyl chloride (500 mg, 1.73 mmol) was dissolved in 20 mL of dry dichloromethane, and the intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (390.24 mg, 1.73 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 177.2 mg of yellow solid, with a yield of 23.19%.

[0159] (8) 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(cyclopropyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z31): 1-((2-chlorothiazol-5-yl)methyl)-4-oxo-3-(4-(cyclopropylthio)phenyl)-4 H -pyrido[1,2- aPyrimidine-1-onthium-2-ol (177.2 mg, 0.40 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (69.19 mg, 0.40 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 151.5 mg of a yellow solid, with a yield of 82.51%.

[0160] Example 32: 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(cyclopropyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z32): Steps (1) to (5) are the same as steps (1) to (5) in Example 31. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(cyclopropylthio)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(cyclopropylthio)phenyl)malonyl chloride (500 mg, 1.73 mmol) was dissolved in 20 mL of dry dichloromethane, and the intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (414.5 mg, 1.73 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 205.7 mg of yellow solid, with a yield of 26.09%.

[0161] (8) 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(cyclopropyl sulfoxide)phenyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z32): 1-((2-chlorothiazol-5-yl)methyl)-9-methyl-4-oxo-3-(4-(cyclopropylthio)phenyl)-4 H-pyrido[1,2- a Pyrimidine-1-onthium-2-ol (205.5 mg, 0.45 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (77.85 mg, 0.45 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 165.54 mg of a yellow solid, with a yield of 77.75%.

[0162] Example 33: 3-(4-(cyclopropyl sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z33): Steps (1) to (5) are the same as steps (1) to (5) in Example 31. Step (6) is the same as step (6) in Example 2. (7) 3-(4-(cyclopropylthio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(cyclopropylthio)phenyl)malonyl chloride (500 mg, 1.73 mmol) was dissolved in 20 mL of dry dichloromethane, and the intermediate was added to the system. N 321.99 mg (1.73 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and the sample was separated by column chromatography to obtain 121.23 mg of yellow solid, with a yield of 17.42%.

[0163] (8) 3-(4-(cyclopropyl sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate (Z33): 3-(4-(cyclopropylthio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- aPyrimidine-1-onthium-2-ol (121.23 mg, 0.3 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (51.98 mg, 0.3 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 92.1 mg of a yellow solid, with a yield of 73.07%.

[0164] Example 34: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(furan-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z34): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-(furan-2-thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of furan-2-ylboronic acid (0.76 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 1.35 g of a pale yellow oil, with a yield of 66.06%.

[0165] (3) Preparation of dimethyl 2-(4-(furan-2-thio)phenyl)malonate: 1.35 g (5.44 mmol) of methyl 2-(4-(furan-2-thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.04 g of a yellow oil, with a yield of 62.44%.

[0166] (4) Preparation of 2-(4-(furan-2-thio)phenyl)malonic acid: Dimethyl 2-(4-(furan-2-thio)phenyl)malonate (1.04 g, 3.4 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.57 g, 10.19 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to give 880 mg of a pale yellow oil, with a yield of 93.15%.

[0167] (5) Preparation of 2-(4-(furan-2-thio)phenyl)malonyl chloride: 2-(4-(furan-2-thio)phenyl)malonic acid (880 mg, 3.16 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (1.61 g, 12.65 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0168] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-2-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (358.06 mg, 1.59 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 175.6 mg of yellow solid, with a yield of 23.65%.

[0169] (8) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z34): 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (175.60 mg, 0.38 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (64.76 mg, 0.38 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 122.45 mg of a yellow solid, with a yield of 67.43%.

[0170] Example 35: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(furan-2-yl sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z35): Steps (1) to (5) are the same as steps (1) to (5) in Example 34. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-9-methyl-4-oxo-4 H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-2-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (380.31 mg, 1.59 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 180.55 mg of yellow solid, with a yield of 23.61%.

[0171] (8) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(furan-2-yl sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z35): 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (180.55 mg, 0.37 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (64.64 mg, 0.37 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain a yellow solid of 139.98 mg, with a yield of 75.04%.

[0172] Example 36: 3-(4-(furan-2-ylsulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z36): Steps (1) to (5) are the same as steps (1) to (5) in Example 34. Step (6) is the same as step (6) in Example 2. (7) 3-(4-(furan-2-ylthio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-2-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N 295.43 mg (1.59 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was allowed to proceed at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the mixture was stirred with silica gel, and the sample was separated by column chromatography to obtain 151.57 mg of a yellow solid, with a yield of 23.77%.

[0173] (8) 3-(4-(furan-2-ylsulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z36): 3-(4-(furan-2-ylthio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (161.57 mg, 0.38 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (65.07 mg, 0.38 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 126.82 mg of a yellow solid, with a yield of 75.67%.

[0174] Example 37: 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z37): Steps (1) to (5) are the same as steps (1) to (5) in Example 34. Step (6) is the same as step (6) in Example 5. (7) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-4-oxo-4H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-2-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)pyridin-2-amine (348.5 mg, 1.59 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 175.78 mg of yellow solid, with a yield of 23.99%.

[0175] (8) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z37): 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (175.78 mg, 0.56 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (122.52 mg, 0.56 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain a yellow solid of 183.93 mg, with a yield of 71.39%.

[0176] Example 38: 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-yl sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z38): Steps (1) to (5) are the same as steps (1) to (5) in Example 34. Step (6) is the same as step (6) in Example 6. (7) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-2-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)3-methylpyridin-2-amine (370.76 mg, 1.59 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 166.7 mg of yellow solid, with a yield of 22.08%.

[0177] (8) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-yl sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z38): 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (166.7 mg, 0.35 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (60.44 mg, 0.35 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 131.1 mg of a yellow solid, with a yield of 76.09%.

[0178] Example 39: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(thiophen-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z39): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-(thiophene-2-thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube using a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of thiophene-2-ylboronic acid (0.87 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction, the system was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated, mixed, and separated by column chromatography to obtain 1.53 g of a pale yellow oil, with a yield of 70.31%.

[0179] (3) Preparation of dimethyl 2-(4-(thiophene-2-thio)phenyl)malonate: 1.53 g (5.79 mmol) of methyl 2-(4-(thiophene-2-thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were extracted again with saturated brine (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.41 g of a yellow oil, with a yield of 75.57%.

[0180] (4) Preparation of 2-(4-(thiophene-2-thio)phenyl)malonic acid: Dimethyl 2-(4-(thiophene-2-thio)phenyl)malonate (1.41 g, 4.37 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.74 g, 13.12 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to give 1.05 g of pale yellow oil, with a yield of 81.57%.

[0181] (5) Preparation of 2-(4-(thiophene-2-thio)phenyl)malonyl chloride: 2-(4-(thiophene-2-thio)phenyl)malonic acid (1.05 g, 3.57 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (1.81 g, 14.27 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0182] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(thiophen-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(thiophene-2-thio)phenyl)malonyl chloride (500 mg, 1.51 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (340.7 mg, 1.51 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 239.78 mg of yellow solid, with a yield of 34.19%.

[0183] (8) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(thiophen-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-ol (Z39): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(thien-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (239.78 mg, 0.50 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (68.39 mg, 0.50 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 221.7 mg of a yellow solid, with a yield of 89.50%.

[0184] Example 40: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(thiophen-2-yl sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z40): Steps (1) to (5) are the same as steps (1) to (5) in Example 39. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(thiophen-2-ylthio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(thiophene-2-thio)phenyl)malonyl chloride (500 mg, 1.51 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (361.87 mg, 1.51 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 201.45 mg of yellow solid, with a yield of 26.8%.

[0185] (8) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(thiophen-2-yl sulfoxide)phenyl)-9-methyl-4-oxo-4H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z40): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(thiophen-2-ylthio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (201.45 mg, 0.4 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (55.84 mg, 0.4 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated and mixed with silica gel. The solution was separated by column chromatography to obtain 165.25 mg of a yellow solid, with a yield of 79.48%.

[0186] Example 41: 3-(4-(thiophene-2-ylsulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z41): Steps (1) to (5) are the same as steps (1) to (5) in Example 39. Step (6) is the same as step (6) in Example 2. (7) 3-(4-(thiophene-2-ylthio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(thiophene-2-thio)phenyl)malonyl chloride (500 mg, 1.51 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N 281.1 mg (1.51 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and the sample was separated by column chromatography to obtain 147.9 mg of yellow solid, with a yield of 22.04%.

[0187] (8) 3-(4-(thiophene-2-ylsulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z41): 3-(4-(thiophen-2-ylthio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (147.9 mg, 0.45 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (83.15 mg, 0.45 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 125.6 mg of a yellow solid, with a yield of 63.28%.

[0188] Example 42: 1-((6-chloropyridin-3-yl)methyl)-3-(4-(thiophen-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z42): Steps (1) to (5) are the same as steps (1) to (5) in Example 39. Step (6) is the same as step (6) in Example 5. (7) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(thiophen-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(thiophene-2-thio)phenyl)malonyl chloride (500 mg, 1.51 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)pyridin-2-amine (331.61 mg, 1.51 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 181.55 mg of yellow solid, with a yield of 25.16%.

[0189] (8) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(thiophen-2-yl sulfoxide)phenyl)-4-oxo-4H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z42): 1-((6-chloropyridin-3-yl)methyl)-3-(4-(thiophen-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (181.55 mg, 0.55 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (96.32 mg, 0.55 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 158.9 mg of a yellow solid, with a yield of 60.65%.

[0190] Example 43: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(naphthyl-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z43): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-(naphthyl-2-thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube using a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of naphthalene-2-ylboronic acid (1.17 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction, the system was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated, mixed, and separated by column chromatography to obtain 1.15 g of a pale yellow oil, with a yield of 45.3%.

[0191] (3) Preparation of dimethyl 2-(4-(naphthalene-2-thio)phenyl)malonate: 1.15 g (3.73 mmol) of methyl 2-(4-(naphthyl-2-thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 0.98 g of a yellow oil, with a yield of 71.72%.

[0192] (4) Preparation of 2-(4-(naphthalene-2-thio)phenyl)malonic acid: Dimethyl 2-(4-(naphthyl-2-thio)phenyl)malonate (0.98 g, 2.67 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.46 g, 8.02 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to give 775.5 mg of a pale yellow oily substance, with a yield of 85.69%.

[0193] (5) Preparation of 2-(4-(naphthyl-2-thio)phenyl)malonyl chloride: 2-(4-(naphthyl-2-thio)phenyl)malonic acid (775.5 mg, 2.29 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (1.16 g, 9.17 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0194] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(naphthyl-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2-a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-2-thio)phenyl)malonyl chloride (500 mg, 1.34 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (301.52 mg, 1.34 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 91.05 mg of yellow solid, with a yield of 12.91%.

[0195] (8) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(naphthyl-2-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z43): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(naphthyl-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (91.05 mg, 0.17 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (29.76 mg, 0.17 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 54.33 mg of a yellow solid, with a yield of 57.92%.

[0196] Example 44: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(naphthyl-2-yl sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z44): Steps (1) to (5) are the same as steps (1) to (5) in Example 43. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(naphthyl-2-ylthio)phenyl)-9-methyl-4-oxo-4 H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: Dissolve 2-(4-(naphthyl-2-thio)phenyl)malonyl chloride (500 mg, 1.33 mmol) in 20 mL of dry dichloromethane, and add the intermediate to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (319.4 mg, 1.33 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 115.3 mg of yellow solid, with a yield of 15.96%.

[0197] (8) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(naphthyl-2-yl sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z44): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(naphthyl-2-ylthio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (115.3 mg, 0.21 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (36.71 mg, 0.21 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 62.14 mg of a yellow solid, with a yield of 52.35%.

[0198] Example 45: 1-((2-chlorothiazo-5-yl)methyl)-3-(4-((6-chloropyridin-3-yl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z45): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((6-chloropyridin-3-yl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube using a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of 6-chloropyridin-3-ylboronic acid (1.08 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction, the system was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated, mixed, and separated by column chromatography to obtain 1.98 g of a pale yellow oil, with a yield of 81.89%.

[0199] (3) Preparation of dimethyl 2-(4-((6-chloropyridin-3-yl)thio)phenyl)malonate: 1.98 g (6.76 mmol) of methyl 2-(4-((6-chloropyridin-3-yl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 2.01 g of a yellow oil, with a yield of 84.72%.

[0200] (4) Preparation of 2-(4-((6-chloropyridin-3-yl)thio)phenyl)malonic acid: Dimethyl 2-(4-((6-chloropyridin-3-yl)thio)phenyl)malonate (2.01 g, 5.73 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.96 g, 17.19 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to give 1.66 g of pale yellow oil, with a yield of 89.77%.

[0201] (5) Preparation of 2-(4-((6-chloropyridin-3-yl)thio)phenyl)malonyl chloride: 2-(4-((6-chloropyridin-3-yl)thio)phenyl)malonic acid (1.66 g, 5.13 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.6 g, 20.51 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0202] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-((6-chloropyridin-3-yl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((6-chloropyridin-3-yl)thio)phenyl)malonyl chloride (500 mg, 1.39 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (313.77 mg, 1.39 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 195.3 mg of yellow solid, with a yield of 27.41%.

[0203] (8) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-((6-chloropyridin-3-yl)sulfoxide)phenyl)-4-oxo-4 H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z45): 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(((6-chloropyridin-3-yl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (195.3 mg, 0.38 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (59.19 mg, 0.34 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 133.45 mg of a yellow solid, with a yield of 66.26%.

[0204] Example 46: 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(((6-chloropyridin-3-yl)sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z46): Steps (1) to (5) are the same as steps (1) to (5) in Example 45. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-((6-chloropyridin-3-yl)thio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((6-chloropyridin-3-yl)thio)phenyl)malonyl chloride (500 mg, 1.39 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (333.27 mg, 1.39 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 195.65 mg of yellow solid, with a yield of 26.73%.

[0205] (8) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-((6-chloropyridin-3-yl)sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z46): 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(((6-chloropyridin-3-yl)thio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (195.65 mg, 0.37 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (57.61 mg, 0.33 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 155.23 mg of a yellow solid, with a yield of 77.0%.

[0206] Example 47: 3-(4-((6-chloropyridin-3-yl)sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z47): Steps (1) to (5) are the same as steps (1) to (5) in Example 45. Step (6) is the same as step (6) in Example 2. (7) 3-(4-((6-chloropyridin-3-yl)thio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((6-chloropyridin-3-yl)thio)phenyl)malonyl chloride (500 mg, 1.39 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N258.89 mg (1.39 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 122.69 mg of yellow solid, with a yield of 18.66%.

[0207] (8) 3-(4-((6-chloropyridin-3-yl)sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z47): 3-(4-((6-chloropyridin-3-yl)thio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (122.69 mg, 0.26 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (40.21 mg, 0.23 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 86.35 mg of a yellow solid, with a yield of 67.29%.

[0208] Example 48: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((2,2,2-trifluoroethyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (Z48): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)acetate: First, 2-iodo-1,1,1-trifluoroethane (1.89 g, 9 mmol) and 1,8-diazabicycloundec-7-ene (1.37 g, 9 mmol) were weighed into a Shrek reaction tube, followed by methyl p-mercaptophenylacetate (1.64 g, 9 mmol). A Teflon stopper was fitted to the tube, and all openings were sealed with sealing film. The mixture was repeatedly evacuated and purged under nitrogen conditions. Then, 20 mL of ultra-dry DMSO solvent was added to the reaction flask using a syringe, and the mixture was stirred at room temperature for 3–16 hours. After the reaction was complete, the reaction mixture was quenched by stirring in saturated brine. After stirring, 200 mL of 2 mol / L sodium chloride solution was added, and the mixture was stirred thoroughly. The mixture was then extracted with ethyl acetate (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.12 g of a milky white oil, with a yield of 47.1%.

[0209] (3) Preparation of dimethyl 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)malonate: 1.12 g (4.44 mmol) of methyl 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.25 g of a yellow oil, with a yield of 90.74%.

[0210] (4) Preparation of 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)malonic acid: Dimethyl 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)malonate (1.25 g, 3.88 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.65 g, 11.64 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to give 0.95 g of a pale yellow oily substance, with a yield of 83.25%.

[0211] (5) Preparation of 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)malonyl chloride: 0.95 g (3.23 mmol) of 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)malonic acid was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (1.64 g, 12.91 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0212] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-((2,2,2-trifluoroethyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)malonyl chloride (500 mg, 1.51 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (340.79 mg, 1.51 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 98.56 mg of yellow solid, with a yield of 13.49%.

[0213] (8) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-((2,2,2-trifluoroethyl)sulfoxide)phenyl)-4-oxo-4 H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z48): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((2,2,2-trifluoroethyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (98.56 mg, 0.20 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (35.15 mg, 0.20 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 75.2 mg of a yellow solid, with a yield of 73.86%.

[0214] Example 49: 3-(4-((2,2,2-trifluoroethyl)sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (Z49): Steps (1) to (5) are the same as steps (1) to (5) in Example 48. Step (6) is the same as step (6) in Example 2. (7) 3-(4-((2,2,2-trifluoroethyl)thio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((2,2,2-trifluoroethyl)thio)phenyl)malonyl chloride (500 mg, 1.51 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N 281.19 mg (1.51 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and the sample was separated by column chromatography to obtain 73.41 mg of yellow solid, with a yield of 10.94%.

[0215] (8) 3-(4-((2,2,2-trifluoroethyl)sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z49): 3-(4-((2,2,2-trifluoroethyl)thio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (73.41 mg, 0.17 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (28.5 mg, 0.17 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated and mixed with silica gel. The solution was separated by column chromatography to obtain 32.5 mg of a yellow solid, with a yield of 42.73%.

[0216] Example 50: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-bromophenyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (Z50): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((4-bromophenyl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube using a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of 4-bromophenylboronic acid (1.37 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated, mixed, and separated by column chromatography to obtain 2.21 g of a pale yellow oil, with a yield of 79.62%.

[0217] (3) Preparation of dimethyl 2-(4-((4-bromophenyl)thio)phenyl)malonate: 2.21 g (6.55 mmol) of methyl 2-(4-((4-bromophenyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 2.31 g of a yellow oil, with a yield of 89.18%.

[0218] (4) Preparation of 2-(4-((4-bromophenyl)thio)phenyl)malonic acid: Dimethyl 2-(4-((4-bromophenyl)thio)phenyl)malonate (2.31 g, 7.3 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (1.23 g, 21.9 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.85 g of pale yellow oil, with a yield of 87.88%.

[0219] (5) Preparation of 2-(4-((4-bromophenyl)thio)phenyl)malonyl chloride: 2-(4-((4-bromophenyl)thio)phenyl)malonic acid (1.85 g, 5.04 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (2.56 g, 20.15 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0220] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-bromophenyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-bromophenyl)thio)phenyl)malonyl chloride (500 mg, 1.24 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (279.26 mg, 1.24 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 215.62 mg of yellow solid, with a yield of 31.29%.

[0221] (8) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-bromophenyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z50): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-bromophenyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (215.62 mg, 0.39 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (66.82 mg, 0.39 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 159.7 mg of a yellow solid, with a yield of 72%.

[0222] Example 51: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-bromophenyl)sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z51): Steps (1) to (5) are the same as steps (1) to (5) in Example 50. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-bromophenyl)thio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-bromophenyl)thio)phenyl)malonyl chloride (500 mg, 1.24 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (296.61 mg, 1.24 mmol), with 6-12 drops of triethylamine added under stirring, reacted at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 198.5 mg of yellow solid, with a yield of 28.1%.

[0223] (8) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-bromophenyl)sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z51): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-bromophenyl)thio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (198.5 mg, 0.35 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (60.0 mg, 0.35 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 171.21 mg of a yellow solid, with a yield of 83.9%.

[0224] Example 52: 3-(4-((4-bromophenyl)sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z52): Steps (1) to (5) are the same as steps (1) to (5) in Example 50. Step (6) is the same as step (6) in Example 2. (7) 3-(4-((4-bromophenyl)thio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-bromophenyl)thio)phenyl)malonyl chloride (500 mg, 1.24 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N 230.41 mg (1.24 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 154.2 mg of yellow solid, with a yield of 24.09%.

[0225] (8) 3-(4-((4-bromophenyl)sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z52): 3-(4-((4-bromophenyl)thio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onyl-2-ol (154.2 mg, 0.3 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (51.43 mg, 0.3 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 101.56 mg of a yellow solid, with a yield of 63.89%.

[0226] Example 53: 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-bromophenyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z53): Steps (1) to (5) are the same as steps (1) to (5) in Example 50. Step (6) is the same as step (6) in Example 5. (7) 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-bromophenyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-bromophenyl)thio)phenyl)malonyl chloride (500 mg, 1.24 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)pyridin-2-amine (271.8 mg, 1.24 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 185.3 mg of yellow solid, with a yield of 27.19%.

[0227] (8) 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-bromophenyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z53): 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-bromophenyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (185.3 mg, 0.46 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (100.73 mg, 0.46 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain a yellow solid of 192.56 mg, with a yield of 76.23%.

[0228] Example 54: 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-bromophenyl)sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- aPyrimidine-1-onium-2-ol (Z54): Steps (1) to (5) are the same as steps (1) to (5) in Example 50. Step (6) is the same as step (6) in Example 6. (7) 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-bromophenyl)thio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-bromophenyl)thio)phenyl)malonyl chloride (500 mg, 1.24 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)3-methylpyridin-2-amine (289.16 mg, 1.24 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 112.33 mg of yellow solid, with a yield of 16.07%.

[0229] (8) 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-bromophenyl)sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z54): 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-bromophenyl)thio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (112.33 mg, 0.22 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (37.46 mg, 0.22 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 76.2 mg of a yellow solid, with a yield of 65.8%.

[0230] Example 55: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(furan-3-yl sulfoxide)phenyl)-4-oxo-4H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z55): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-(furan-3-thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube using a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of furan-3-ylboronic acid (0.76 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated, mixed, and separated by column chromatography to obtain 1.23 g of a pale yellow oil, with a yield of 60.18%.

[0231] (3) Preparation of dimethyl 2-(4-(furan-3-thio)phenyl)malonate: 1.02 g (4.95 mmol) of methyl 2-(4-(furan-3-thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. Using 20 mL of dimethyl carbonate as solvent, 6 mL of tetrahydrofuran solvent was added to the system. 60% sodium hydride was added in small amounts several times while stirring under ice bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was completed, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.02 g of a yellow oil, with a yield of 67.22%. (4) Preparation of 2-(4-(furan-3-thio)phenyl)malonic acid: Dimethyl 2-(4-(furan-3-thio)phenyl)malonate (1.02 g, 3.33 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.56 g, 9.99 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to give 810.52 mg of a pale yellow oily substance, with a yield of 87.47%.

[0232] (5) Preparation of 2-(4-(furan-3-thio)phenyl)malonyl chloride: 2-(4-(furan-3-thio)phenyl)malonic acid (810.52 mg, 2.91 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (1.48 g, 11.65 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0233] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-3-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-3-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and the intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (358.06 mg, 1.59 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 125.3 mg of yellow solid, with a yield of 16.88%.

[0234] (8) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-3-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- aPreparation of pyrimidine-1-onium-2-ol (Z55): 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-3-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (125.30 mg, 0.27 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (46.21 mg, 0.27 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched with saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 75.66 mg of a yellow solid, with a yield of 58.39%.

[0235] Example 56: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-(furan-3-yl sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z56): Steps (1) to (5) are the same as steps (1) to (5) in Example 55. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-3-ylthio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-3-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and the intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (380.31 mg, 1.59 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 162.3 mg of yellow solid, with a yield of 21.05%.

[0236] (8) 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-3-yl sulfoxide)phenyl)-9-methyl-4-oxo-4H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z56): 1-((2-chlorothiazo-5-yl)methyl)-3-(4-(furan-3-ylthio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (162.3 mg, 0.27 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (54.5 mg, 0.27 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 110.5 mg of a yellow solid, with a yield of 68.04%.

[0237] Example 57: 3-(4-(furan-3-ylsulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z57): Steps (1) to (5) are the same as steps (1) to (5) in Example 55. Step (6) is the same as step (6) in Example 2. (7) 3-(4-(furan-3-ylthio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-3-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and the intermediate was added to the system. N 295.43 mg (1.59 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 150.5 mg of yellow solid, with a yield of 23.51%.

[0238] (8) 3-(4-(furan-3-ylsulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z57): 3-(4-(furan-3-ylthio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (150.5 mg, 0.28 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (55.5 mg, 0.28 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 106.55 mg of a yellow solid, with a yield of 70.57%.

[0239] Example 58: 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-3-yl sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z58): Steps (1) to (5) are the same as steps (1) to (5) in Example 55. Step (6) is the same as step (6) in Example 5. (7) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-3-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-(furan-3-thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and the intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)pyridin-2-amine (348.5 mg, 1.59 mmol) was added with 6–12 drops of triethylamine under stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 155.38 mg of yellow solid, with a yield of 20.59%.

[0240] (8) 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-3-yl sulfoxide)phenyl)-4-oxo-4 H-pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z58): 1-((6-chloropyridin-3-yl)methyl)-3-(4-(furan-2-ylthio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (155.38 mg, 0.46 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (90.5 mg, 0.46 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 123.03 mg of a yellow solid, with a yield of 61.5%.

[0241] Example 59: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-ethynylphenyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z59): Step (1) is the same as step (1) in Example 1. (2) Preparation of methyl 2-(4-((4-ethynylphenyl)thio)phenyl)acetate: 1,10-phenanthroline (117.39 mg, 0.82 mmol) and Cu(OAc)₂•H₂O (119.50 g, 0.82 mmol) were added separately to 100 mL three-necked round-bottom flasks. The mixture was dissolved in a reaction tube with a mixed solvent of 15 mL DMSO and 15 mL H₂O. The mixture was stirred at room temperature for 10 min, followed by the addition of 4-ethynylphenylboronic acid (1 g, 6.83 mmol) and methyl 2-(4-mercaptophenyl)acetate (1.5 g, 8.23 ​​mmol). The mixture was heated to 65 °C and reacted under reflux for 12 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and extracted once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated, mixed, and separated by column chromatography to obtain 1.56 g of a pale yellow oil, with a yield of 67.12%.

[0242] (3) Preparation of dimethyl 2-(4-((4-ethynylphenyl)thio)phenyl)malonate: 1.56 g (5.52 mmol) of methyl 2-(4-((4-ethynylphenyl)thio)phenyl)acetate was added to a 100 mL three-necked round-bottom flask. 20 mL of dimethyl carbonate was used as the solvent, followed by 6 mL of tetrahydrofuran. 60% sodium hydride was added in small, repeated additions while stirring under ice-bath conditions. After the addition was complete, the temperature was raised to 105 °C, and the reaction was carried out under reflux for 3–4 hours. After the reaction was complete, the system was cooled to room temperature with stirring, quenched with 20 mL of anhydrous methanol, and the solvent was concentrated. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phases were extracted again with saturated brine (100 mL × 3). The organic phases were combined again, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.6 g of a yellow oil, with a yield of 85.08%.

[0243] (4) Preparation of 2-(4-((4-ethynylphenyl)thio)phenyl)malonic acid: Dimethyl 2-(4-((4-ethynylphenyl)thio)phenyl)malonate (1.6 g, 4.7 mmol) was added to a 100 mL round-bottom flask. Using 20 mL of anhydrous ethanol as solvent, 10 mL of sodium hydroxide aqueous solution (0.79 g, 14.10 mmol) was added dropwise to the above system under ice bath conditions. After complete hydrolysis at room temperature, the solvent was concentrated, and 200 mL of water was added to the residue. The residue was extracted once with ethyl acetate (100 mL) to remove impurities. The aqueous phase was collected, and the pH was adjusted to pH≈2 with 6 N hydrochloric acid. After stirring evenly, the aqueous phase was extracted again with ethyl acetate (100 mL × 3). The organic phases were combined, and the organic phase was extracted once with saturated brine. The residue was dried over anhydrous sodium sulfate for 10 minutes, and the solvent was evaporated to dryness to obtain 1.21 g of pale yellow oil, with a yield of 82.42%.

[0244] (5) Preparation of 2-(4-((4-ethynylphenyl)thio)phenyl)malonyl chloride: 2-(4-((4-ethynylphenyl)thio)phenyl)malonic acid (1.21 g, 3.87 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. One drop of N,N-dimethylformamide was added dropwise to the mixture, and oxaloyl chloride (1.97 g, 15.50 mmol) was added dropwise with stirring at room temperature. The flask was immediately sealed with a drying tube after the addition was complete, and the reaction was allowed to proceed at room temperature for 2–4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and 20 mL of dichloromethane was added for later use.

[0245] Step (6) is the same as step (6) in Example 1. (7) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-ethynylphenyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-ethynylphenyl)thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)pyridin-2-amine (323.14 mg, 1.59 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 167.55 mg of yellow solid, with a yield of 23.31%.

[0246] (8) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-ethynylphenyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z59): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-ethynylphenyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (167.55 mg, 0.33 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (57.60 mg, 0.33 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 112.4 mg of a yellow solid, with a yield of 65.01%.

[0247] Example 60: 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-ethynylphenyl)sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z60): Steps (1) to (5) are the same as steps (1) to (5) in Example 59. Step (6) is the same as step (6) in Example 3. (7) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-ethynylphenyl)thio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-ethynylphenyl)thio)phenyl)malonyl chloride (500 mg, 1.59 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (343.22 mg, 1.59 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 110.92 mg of yellow solid, with a yield of 15.01%.

[0248] (8) 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-ethynylphenyl)sulfoxide)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z60): 1-((2-chlorothiazol-5-yl)methyl)-3-(4-((4-ethynylphenyl)thio)phenyl)-9-methyl-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (110.92 mg, 0.21 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (37.09 mg, 0.21 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 63.55 mg of a yellow solid, with a yield of 55.57%.

[0249] Example 61: 3-(4-((4-ethynylphenyl)sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z61): Steps (1) to (5) are the same as steps (1) to (5) in Example 59. Step (6) is the same as step (6) in Example 2. (7) 3-(4-((4-ethynylphenyl)thio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-ethynylphenyl)thio)phenyl)malonyl chloride (500 mg, 1.43 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N 266.62 mg (1.43 mmol) of pyrimidine-5-methylpyridine-2-amine was added with 6–12 drops of triethylamine under stirring, and the mixture was reacted at room temperature for 5 minutes. After the reaction was complete, 1 mL of anhydrous methanol was added to quench the reaction, the mixture was stirred with silica gel, and the sample was separated by column chromatography to obtain 95.33 mg of a yellow solid, with a yield of 14.4%.

[0250] (8) 3-(4-((4-ethynylphenyl)sulfoxide)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z61): 3-(4-((4-ethynylphenyl)thio)phenyl)-4-oxo-1-(5-methylpyrimidinylmethyl)-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (95.33 mg, 0.21 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (35.57 mg, 0.21 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 50.12 mg of a yellow solid, with a yield of 50.82%.

[0251] Example 62: 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-ethynylphenyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onium-2-ol (Z62): Steps (1) to (5) are the same as steps (1) to (5) in Example 59. Step (6) is the same as step (6) in Example 5. (7) 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-ethynylphenyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-olate: 2-(4-((4-ethynylphenyl)thio)phenyl)malonyl chloride (500 mg, 1.43 mmol) was dissolved in 20 mL of dry dichloromethane, and an intermediate was added to the system. N -((6-chloropyridin-3-yl)methyl)pyridin-2-amine (314.51 mg, 1.43 mmol), 6-12 drops of triethylamine were added with stirring, and the reaction was carried out at room temperature for 5 minutes. After the reaction was completed, 1 mL of anhydrous methanol was added to quench the reaction, the sample was stirred with silica gel, and separated by column chromatography to obtain 122.55 mg of yellow solid, with a yield of 17.26%.

[0252] (8) 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-ethynylphenyl)sulfoxide)phenyl)-4-oxo-4 H -pyrido[1,2- a Preparation of pyrimidine-1-onium-2-ol (Z62): 1-((6-chloropyridin-3-yl)methyl)-3-(4-((4-ethynylphenyl)thio)phenyl)-4-oxo-4 H -pyrido[1,2- a Pyrimidine-1-onthium-2-ol (122.55 mg, 0.24 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of dry dichloromethane. Parachloroperoxybenzoic acid (42.64 mg, 0.24 mmol) was added in portions under ice bath conditions. The reaction proceeded for 0.5–1 hour until the starting material was completely converted. The reaction mixture was quenched by adding saturated sodium sulfite solution until the aqueous phase did not turn blue when dropped onto starch-KI paper. After thorough stirring, the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed twice with saturated sodium carbonate solution, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The sample was mixed with silica gel and separated by column chromatography to obtain 81.2 mg of a yellow solid, with a yield of 64.19%.

[0253] The compound's nuclear magnetic resonance hydrogen spectrum ( 1 H NMR and carbon spectroscopy 13 The C NMR data are shown in Table 1.

[0254] Table 1. Spectral data of compounds Z1-Z62 in Examples

[0255] Bioactivity evaluation (1) Insecticidal activity test of compounds Example 1: Determination of the bioactivity of the target compound in controlling white-backed planthoppers indoors.

[0256] 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. Subsequent dilutions with the TW-80 stock solution yielded concentrations of 100.0, 10.0, and 1.0 g / L. μ Test solutions of g / mL and other concentrations.

[0257] Approximately 50 white-backed planthoppers of uniform size (2nd-3rd instar) were collected and transferred to disposable plastic bowls containing 6-7 rice seedlings. The rice seedlings were fixed with clean quartz sand, and a small amount of water was added to keep the quartz sand moist to prevent the rice seedlings from drying out. The bowls were left to stand for 30 minutes to allow the planthoppers to firmly attach to the seedlings. 4 mL of the test solution was sprayed, with a TW-80 solution containing DMSO as a blank control. Each group was tested in triplicate. The treated white-backed planthoppers were placed in a greenhouse (temperature 26±2 ℃, humidity 75±5%, light / dark = 16 / 8h), and the number of dead planthoppers was recorded after 48 h. The lethality rate and corrected lethality 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. Lethality rates of compounds Z1-Z65 against white-backed planthoppers in the examples.

[0258] Insecticidal activity results showed that the compounds exhibited good activity against white-backed planthoppers, with most compounds showing activity at 100... μ g / mL and 10 μ At a concentration of g / mL, the lethality against white-backed planthoppers was 100%, with compounds Z2 and Z52 showing the highest lethality at 1 g / mL. μ Even at a concentration of g / mL, the mortality rate against white-backed planthoppers is still over 70%.

[0259] Example 2: Determination of the bioactivity of the target compound in controlling western flower thrips in the room.

[0260] 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. Subsequent dilutions with the TW-80 stock solution yielded concentrations of 100.0, 10.0, and 1.0 g / L. μ Test solutions of g / mL and other concentrations.

[0261] Fresh kidney beans were selected and cut into uniform strips (approximately 4 cm in diameter). After washing, the surface moisture was absorbed with filter paper. The kidney beans were completely immersed in the corresponding concentration of pesticide solution for 40 seconds. After removal, they were placed in transparent plastic cups with filter paper at the bottom to air dry naturally. Each cup contained one kidney bean and 30-40 healthy western flower thrips (2nd instar nymphs of uniform size). The cups were sealed with 300-mesh nylon mesh and perforated lids, while maintaining ventilation. They were then transferred to a light incubator for cultivation (temperature 26±2 ℃, humidity 75±5%, light / dark = 16 / 8h). Tween-80 aqueous solution without pesticide was used as a blank control, and Tween-80 aqueous solution with DMSO was used as a solvent control. Each experiment was repeated three times, and the number of dead insects was recorded after 48 h. The lethality rate and corrected lethality rate were calculated as follows, and the activity data are shown in Table 3. Mortality rate = (Number of dead insects) / (Total number of insects treated) × 100 Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100 Table 3. Lethality of the compounds in the examples against western flower thrips

[0262] Insecticidal activity results showed that the compounds had good activity against western flower thrips, with most compounds showing activity at 100... μ At a concentration of g / mL, the lethality against western flower thrips was 100%, and some compounds showed a lethality of 10 g / mL. μAt a concentration of g / mL, the lethality against western flower thrips remained 100%, with compounds Z1 and Z39 showing the highest lethality at 1 g / mL. μ Even at a concentration of g / mL, the lethality of western flower thrips is still over 70%.

[0263] Example 3: Determination of the bioactivity of the target compound in controlling the pea aphid in the room.

[0264] 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. Subsequent dilutions with the TW-80 stock solution yielded concentrations of 100.0, 10.0, and 1.0 g / L. μ Test solutions of g / mL and other concentrations.

[0265] Select more than 50 pea aphid nymphs and transfer them to a disposable plastic bowl containing a broad bean seedling. The seedling was fixed with clean quartz sand, and a small amount of water was added to keep the sand moist to prevent the seedling from drying out. Let it stand for 30 minutes to allow the aphids to stabilize and attach to the seedling. Spray with 4 mL of test solution, cover with a homemade breathable plastic cup, and seal the opening with breathable gauze or a perforated lid. A TW-80 solution containing DMSO was used as a blank control. Each group was tested in triplicate. The treated broad bean aphids were placed in a greenhouse (temperature 26±2 ℃, humidity 75±5%, light / dark = 16 / 8h), and the number of dead aphids was recorded after 48 h. The lethality rate and corrected lethality rate were calculated as follows, and the activity data are shown in Table 4. Mortality rate = (Number of dead insects) / (Total number of insects treated) × 100 Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100 Table 4. Mortality rates of the compounds in the examples against the pea pruning aphid

[0266] Insecticidal activity results showed that the compounds exhibited good activity against pea aphids, with most compounds showing activity at 100 μL / min. μ g / mL and 10 μ At a concentration of g / mL, the mortality rate against the pea aphid was 100%, with compounds Z3 and Z24 showing the highest mortality rate. μ Even at a concentration of g / mL, the mortality rate against the pea aphid is still around 70%.

[0267] Example 4: Indoor bioactivity assay of target compound for controlling fall armyworm.

[0268] 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. Subsequent dilutions with the TW-80 stock solution yielded concentrations of 100.0, 10.0, and 1.0 g / L. μ Test solutions of g / mL and other concentrations.

[0269] Third-instar fall armyworms with consistent physiological states, reared indoors, were selected. Half the volume of feed was added to each well of a 24-well plate beforehand. Depending on the test concentration, 100 mg / L of feed was added to each well. μ L's test solution. After the test solution dried, one test worm was picked from each well and tested using the stomach poison method. Each dose was repeated in triplicate, with the corresponding concentration of acetone as a control. The 24-well plate was covered after treatment and placed in a temperature incubator (temperature 26±2 ℃, humidity 75±5%, light / dark = 16 / 8h). The results were checked after 48 h. The lethality and corrected lethality were calculated as follows, and the activity data are shown in Table 5: Mortality rate = (Number of dead insects) / (Total number of insects treated) × 100 Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100 Table 5. Lethality of the compounds in the examples against fall armyworm

[0270] Insecticidal activity results showed that the compounds exhibited good activity against fall armyworm, with most compounds showing activity at 100... μ At a concentration of g / mL, the lethality against fall armyworm was 100%, and some compounds showed a lethality of 10 g / mL. μ At a concentration of g / mL, the lethality against fall armyworm remained 100%, with compound Z51 showing a significant effect. μ Even at a concentration of g / mL, the mortality rate against fall armyworm is still around 75%.

[0271] Example 5: Indoor bioactivity assay of target compound for controlling diamondback moth.

[0272] 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. Subsequent dilutions with the TW-80 stock solution yielded concentrations of 100.0, 10.0, and 1.0 g / L. μ Test solutions of g / mL and other concentrations.

[0273] Cabbage leaves were immersed in solutions with different insecticide concentrations for 30 seconds, while control leaves were treated with a TW-80 solution containing DMSO. After drying at room temperature for 2 hours, the leaves were placed in petri dishes (10 cm in diameter). Each concentration was repeated three times (ten second-instar larvae per repeat). The petri dishes were covered and placed in a temperature incubator (temperature 26±2 ℃, humidity 75±5%, light / dark = 16 / 8h). Results were checked after 48 h. The lethality and corrected lethality were calculated as follows, and the activity data are shown in Table 6. Mortality rate = (Number of dead insects) / (Total number of insects treated) × 100 Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100 Table 6. Lethality of the compounds in the examples against diamondback moth

[0274] Insecticidal activity results showed that the compounds had good activity against diamondback moth, with most compounds showing activity at 100... μ At a concentration of g / mL, the lethality against diamondback moth was 100%, and some compounds showed a lethality of 10 g / mL. μ At a concentration of g / mL, the lethality against diamondback moth remained 100%, with compound Z3 showing a significant improvement. μ Even at a concentration of g / mL, the mortality rate against diamondback moth is still around 78%.

[0275] Example 6: Indoor bioactivity assay of target compound for controlling rice stem borer.

[0276] 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. Subsequent dilutions with TW-80 stock solution yielded concentrations of 50.0, 10.0, and 2.0 g / L. μ Test solutions of g / mL and other concentrations.

[0277] Third-instar rice stem borers of uniform physiological condition were selected for testing. Ten borers were picked from each culture dish. Two 2 cm long corn leaves were placed in each dish, and spraying was performed using a spray tower. Each dose was repeated in triplicate, with acetone at the corresponding concentration as a control. After treatment, the borers were transferred to a temperature incubator (temperature 26±2 ℃, humidity 75±5%, light / dark = 16 / 8h) for rearing. Results were examined after 48 h. The lethality and corrected lethality were calculated as follows, and the activity data are shown in Table 7. Mortality rate = (Number of dead insects) / (Total number of insects treated) × 100 Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100 Table 7. Lethality of compound Z1 against rice stem borer

[0278] Insecticidal activity results showed that compound Z1 had good activity against rice stem borer at 50°C. μ At a concentration of g / mL, the lethality against rice stem borer is 100%, and at 10 μ The lethality rate remains 100% at a concentration of g / mL, at 2 μ The lethality rate at a concentration of g / mL is 45%.

[0279] Example 7: Determination of the bioactivity of the target compound in controlling armyworms 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. Subsequent dilutions with the TW-80 stock solution yielded concentrations of 200.0, 100.0, 25.0, and 10.0 g / L. μ Test solutions of g / mL and other concentrations.

[0281] Third-instar armyworms of uniform physiological condition were selected from indoor rearing, with 10 test worms picked from each petri dish. Two 2 cm long corn leaves were placed in the petri dish, and spraying was performed using a spray tower. Each dose was repeated in triplicate, with the corresponding concentration of acetone serving as a control. After treatment, the worms were transferred to their rearing conditions. Results were examined after 48 hours. The mortality rate and corrected mortality rate were calculated as follows, and the activity data are shown in Table 8. Mortality rate = (Number of dead insects) / (Total number of insects treated) × 100 Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100 Table 8. Lethality of compound Z1 against armyworms

[0282] Insecticidal activity results showed that compound Z1 had good insecticidal activity against armyworms, at 200... μ g / mL and 100 μ At a concentration of g / mL, the lethality against armyworms was 100%, and at 25... μ The lethality rate was still 80% at a concentration of g / mL, and at 10 μ The lethality rate is still 65% even at a concentration of g / mL.

[0283] Example 8: Determination of the bioactivity of the target compound in controlling the beet armyworm indoors.

[0284] 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. Subsequent dilutions with the TW-80 stock solution yielded concentrations of 100.0, 50.0, and 25.0 g / L. μ Test solutions of g / mL and other concentrations.

[0285] Third-instar Spodoptera litura, with consistent physiological state, were selected from indoor rearing. Ten insects were placed in each petri dish. Two 2 cm long corn leaves were placed in each dish, and spraying was performed using a spray tower. Each dosage was repeated in triplicate, with acetone at the corresponding concentration serving as a control. After treatment, the insects were transferred to their rearing conditions. Results were examined after 48 hours. The mortality rate and corrected mortality rate were calculated as follows, and the activity data are shown in Table 9. Mortality rate = (Number of dead insects) / (Total number of insects treated) × 100 Corrected lethality = (treatment lethality - blank lethality) / (1 - blank lethality) × 100 Table 9. Lethality of compound Z1 against Spodoptera litura.

[0286] Insecticidal activity results showed that compound Z1 had good activity against Spodoptera litura at 25°C. μ At a concentration of g / mL, the mortality rate against the beet armyworm is 25%.

[0287] (2) Acute toxicity test of bees Acute toxicity tests on bees were conducted according to the method described in GB / T 31270.10-2014. Symptoms of poisoning and the number of deaths were observed and recorded 48 hours after treatment. The test results showed that the 48-hour-LD50 of compounds Z1 and Z2 of this invention had acute contact toxicity to bees. 50 >11 μ g ai / peak, low toxicity to bees; 48h-LD50 for acute oral toxicity to bees. 50 >11 μ g ai / peak, has low toxicity to bees, while the control drug trifluoropyrimidine has a 48h-LD50 for acute contact and oral toxicity to bees. 50 <1 μ The g ai / peak is highly toxic to bees. Therefore, the compound described in this application shows significantly reduced toxicity to bees and better safety.

[0288] The above bioactivity test results indicate that pyrido[1,2-]pyrido[]pyridoxine containing a sulfoxide structure... a Pyrimidine metronidazole derivatives exhibit good insecticidal activity against insects such as western flower thrips, white-backed planthopper, aphids, fall armyworm, diamondback moth, rice stem borer, beet armyworm, and armyworm, and have low toxicity to bees.

[0289] The above description is only a preferred embodiment of the present invention. It should be noted that those 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-]pyrido[]pyridyl ... a Pyrimidine mesonotropic derivatives, characterized in that, This includes compounds having the structure shown in general formula (I), or their stereoisomers, salts, or solvates, as follows: (I) in R 1 It is independently selected from one or more of hydrogen, deuterium, alkyl (either substituted or unsubstituted), alkoxy (either substituted or unsubstituted), alkenyl (either substituted or unsubstituted), cycloalkyl (either substituted or unsubstituted), aryl (either substituted or unsubstituted), and heteroaryl (either substituted or unsubstituted); R 2 It is independently selected from one or more of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, mercapto, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl, any substituted or unsubstituted cycloalkyl, and any substituted or unsubstituted aryl. R 3 It is independently selected from one or more of any substituted or unsubstituted alkyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted alkenyl, any substituted or unsubstituted alkynyl, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl.

2. The pyrido[1,2-]pyridyl[ ... a Pyrimidine mesonotropic derivatives, characterized in that: R 1 Independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; R 2 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; R 3 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 ynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C 15 One or more of aryl, substituted or unsubstituted C5-C6 heteroaryl groups; The substitution refers to substitution by at least one or more of alkynyl, cyano, halogen, alkyl, and haloalkyl groups.

3. The pyrido[1,2-]pyridyl[ ... a Pyrimidine mesonotropic derivatives, characterized in that: R 1 Independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, phenyl, benzyl, pyridyl, pyrazolyl, pyrrolyl, furanyl, thiophene, thiazolyl, benzopyrrolyl, pyridazine, pyrimidine, pyrazine, -CH2CH2CN, -CHCNCH3, -CH2CH2CH2CN, -CH2CHCNCH3, -CHCNCH2CH3, -CH2CH2F, -CHFCH3, -CH2CH2CH2F, -CH2CHFCH3, -CHFCH2CH3, -CH2CH2Cl, -CHClCH3, -CH2CH2CH2Cl, -CH2CHClCH3, -CHClCH2CH3, -CH2CH2Br, -CHBrCH3, -CH2CH2CH2Br, -CH2CHBrCH3, -CHBrCH2CH3 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R 3 Independently selected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, propenyl, -CH2F, -CHF2, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2Cl, -CH2CH2Br, -CH2CH2F, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ... , , , , , , , , , , , , , , .

4. The pyrido[1,2-]pyridyl[ ... a Pyrimidine mesonotropic derivatives, characterized in that Selected from the following specific compounds:

5. The pyrido[1,2-]pyridyl[ ... a The method for preparing pyrimidine mesonotropic derivatives is characterized by: include: 1） ； 2） 。 6. The pyrido[1,2-]pyridyl group containing a sulfoxide structure as described in claim 5 a A method for preparing pyrimidine mesonotropic derivatives, characterized in that, include: 。 7. A composition, characterized in that... The pyrido[1,2-]pyridyl group containing the sulfoxide structure as described in any one of claims 1-4 a The composition comprises pyrimidine mesonotropic derivatives and agricultural adjuvants; 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).

8. The pyrido[1,2-]pyridyl[ ... a Use of pyrimidine metronid derivatives, or the composition of claim 7, in the preparation of pesticides for controlling agricultural pests and diseases; wherein the agricultural pests and diseases are western flower thrips, white-backed planthopper, aphid, fall armyworm, diamondback moth, rice stem borer, beet armyworm, and armyworm.

9. A method for preventing and controlling agricultural pests and diseases, characterized in that: The pyrido[1,2-] sulfoxide-containing pyridinium benzo[1,2-] of any one of claims 1-4 is used to make the pyrido[1,2-] sulfoxide-containing pyridinium benzo ... a [Pyrimidine metronid derivatives, or the composition of claim 7, acting on harmful substances or their living environment; the agricultural pests and diseases are western flower thrips, white-backed planthopper, aphids, fall armyworm, diamondback moth, rice stem borer, beet armyworm, and armyworm.] 10. A method for protecting plants from agricultural pests and diseases, comprising causing the pest to react with a sulfoxide-containing pyridine[1,2-] according to any one of claims 1-4. a The method steps of contacting the pyrimidine mesonotropic derivative or the composition of claim 7.

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