A saturated nitrogen heterocyclic compound containing a pyrimidine structure, and a preparation method and application thereof

Abstract

The application discloses a saturated nitrogen heterocyclic compound containing a pyrimidine structure and a preparation method and application thereof, and the obtained benzimidazole compound containing the pyrimidine structure has good inhibition effect on plant pathogenic bacteria and fungi, and has good inhibition effect on pathogenic bacteria such as Thanatephorus cucumeris (T.c.), Gibberela zeae (G.z.), Sclerotinia sclerotiorum (S.s.), Verticilium dahliae (V.d.), Botryosphaeria dothidea (B.d.), Fusarium oxysporum (F.o.), Xanthomonas axonopodis pv.citri (Xac), Xanthomonas oryzae pv.oryzae (Xoo) and the like, and provides an important scientific basis for research and development and creation of new pesticides.

Description

Technical Field

[0001] This invention belongs to the field of synthetic technology of saturated nitrogen heterocyclic compounds, specifically relating to a saturated nitrogen heterocyclic compound containing a pyrimidine structure, its preparation method, and its application. Background Technology

[0002] Plant diseases have always been a major constraint on high-quality and high-yield crops. Among them, fungal diseases directly cause a decline in crop yield and quality. Many fungal diseases are characterized by their epidemicity, explosiveness, and devastation, making them extremely destructive and difficult to control, seriously impacting the sustainable development of agriculture. Currently, the control of these diseases mainly relies on chemical fungicides, such as carbendazim, benomyl, cymoxanil, azoxystrobin, oxadiazon, and azoxystrobin. However, the high-dose, high-frequency application of pesticides and the selective evolution of harmful organisms have further exacerbated the difficulty of controlling fungal plant diseases.

[0003] Benzimidazole fungicides, developed in the 1960s and 70s, are characterized by systemic absorption, broad spectrum, high efficiency, and safety. They are well-known first-generation anti-tubulin fungicides and the first fungicides to be influenced by the rapid evolution of target resistance. For decades, they have been widely used in China and many parts of the world to control various plant diseases. In particular, the advent of benomyl marked the transition of fungicides from protective fungicides to systemic fungicides.

[0004] Karaburun et al. reported the antibacterial and antifungal bioactivity of novel benzimidazole compounds. The results showed that benzimidazoles 4a and 4c, containing a bisbenzofuran structure, exhibited good activity against Candida albicans. Ahuja et al. synthesized a series of novel benzimidazole derivatives and determined their antibacterial and antifungal activities. Three compounds were screened, and bioassays showed that these compounds inhibited the growth of Verticillium wilt (F. verticilioides), rice blast fungus (D. oryzae), C. lunata, and F. f. fujikuroi. 50 The values ​​ranged from 10 to 50 μg / mL. Among them, the antibacterial activity against *F. verticilioides* and *F. f. f. f. f. f. f. was stronger than that of carbendazim (ED). 50 The values ​​were 250 μg / mL and 130 μg / mL, respectively. Sun et al. designed and synthesized a series of benzimidazole compounds containing pyrimidine and thioether groups, and determined their antibacterial activity. The target compounds 4h, 4i, 4k, 4l, 4m, 4s, 4t, and 4u exhibited significant antifungal activity, with half-maximum effective concentrations (EC50) reaching 130 μg / mL. 50The values ​​ranged from 0.13 to 0.24 μg / mL, meaning their activity was comparable to or higher than that of carbendazim (EC). 50 =0.21 μg / mL); Chandrika et al. reported the synthesis of 18 alkylated mono, bis, and tribenzimidazoles and their antifungal derivatives. Many bisbenzimidazole compounds were found to have moderate to excellent antifungal activity against all tested fungal strains, EC 0.21 μg / mL. 50 The concentration range was 0.975-15.6 μg / mL; Wang et al. synthesized a series of benzimidazole phenylhydrazone derivatives. Antifungal activity tests were performed on all compounds, and compound 4 was found to have significant inhibitory activity against both *Rice blast fungus* and *Rice blast*, with EC50 values ​​of 0.975-15.6 μg / mL. 50 The values ​​were 1.20 and 1.85 μg / mL, respectively.

[0005] It is evident that benzimidazole compounds have broad application prospects in the field of antifungal treatment. However, how to continue using benzimidazole structures as lead compounds to find highly effective bactericidal target compounds is an urgent problem to be solved. Summary of the Invention

[0006] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0007] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0008] Therefore, the object of the present invention is to overcome the shortcomings of the prior art and provide a saturated nitrogen heterocyclic compound containing a pyrimidine structure.

[0009] To solve the above-mentioned technical problems, the present invention provides the following technical solution: the general structural formula of the saturated nitrogen heterocyclic compound is shown in formula (I):

[0010]

[0011] In the formula, R is selected from one or more of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted amino or heterocyclic amino, substituted or unsubstituted mercapto or heterocyclic mercapto, and substituted or unsubstituted heteroaryl.

[0012] W1, W2, and W3 are selected from carbon and nitrogen, X is selected from nitrogen, oxygen, and sulfur, and A is selected from hydrogen, substituted or unsubstituted phenyl groups.

[0013] As a preferred embodiment of the saturated nitrogen heterocyclic compound containing a pyrimidine structure according to the present invention, wherein: R is selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, wherein the substitution is by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

[0014] As a preferred embodiment of the saturated nitrogen heterocyclic compound containing a pyrimidine structure according to the present invention, wherein: R is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, 1,1-diethanolyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein the substitution is by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

[0015] As a preferred embodiment of the saturated nitrogen heterocyclic compound containing a pyrimidine structure according to the present invention, wherein: R is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, 1,1-diethanolyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluoro Phenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, morpholinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-piperidinylcarboxylate, S-3-piperidinylcarboxylate, 4-piperidinylcarboxylate, pyrrolyl, R-3-hydroxypyrrolyl, S -3-Hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-acetylpiperazinyl, 1-benzylpiperazinyl, 1-(2-methoxybenzyl)piperazinyl, 1-(3-methoxybenzyl)piperazinyl, 1-(4-methoxybenzyl)piperazinyl, 1-(2-methylbenzyl)piperazinyl, 1-(3-methylbenzyl)piperazinyl, 1-(4-methylbenzyl)piperazinyl, 1-(2-chlorobenzyl)piperazinyl, 1-(3-chlorobenzyl)piperazinyl, 1-(4-chlorobenzyl)piperazinyl, 1-(2-fluorobenzyl)piperazinyl, 1-(3-fluorobenzyl)piperazinyl, 1-(4-fluoro ... One of the following: benzyl)piperazinyl, 1-(2-bromobenzyl)piperazinyl, 1-(3-bromobenzyl)piperazinyl, 1-(4-bromobenzyl)piperazinyl, 1-(2-aminobenzyl)piperazinyl, 1-(3-aminobenzyl)piperazinyl, 1-(4-aminobenzyl)piperazinyl, 1-(2-hydroxybenzyl)piperazinyl, 1-(3-hydroxybenzyl)piperazinyl, 1-(4-hydroxybenzyl)piperazinyl, 1-(2-nitrobenzyl)piperazinyl, 1-(3-nitrobenzyl)piperazinyl, 1-(4-nitrobenzyl)piperazinyl, 1-(2-trifluoromethylbenzyl)piperazinyl, 1-(3-trifluoromethylbenzyl)piperazinyl, and 1-(4-trifluoromethylbenzyl)piperazinyl.

[0016] The term "alkyl" as used in this invention refers to branched and straight-chain saturated hydrocarbon groups having a specific number of carbon atoms. For example, "C1-10 alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Additionally, "C1-6 alkyl" refers to alkyl groups 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.

[0017] The term "alkenyl" as used in this invention refers to hydrocarbons that have either straight-chain or branched structures and possess one or more carbon-carbon double bonds present at any stable point in the chain. For example, "C2-6 alkenyl" (or alkenylidene) is intended 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.

[0018] The term "alkynyl" as used in this invention refers to hydrocarbons that have either straight-chain or branched structures and possess one or more carbon-carbon triple bonds that occur at any stable point in the chain. For example, "C2-6 alkynyl" (or ynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, and their analogues.

[0019] In this invention, "substituted" means that any one or more hydrogen atoms on a specified atom or group are substituted with a selected specified group, provided that the valence of the specified atom is not exceeded. 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 point of connection of the substituent to the central structure is in the alkyl moiety. Cyclic double bonds used herein are double bonds formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). When substitution is mentioned, especially polysubstitution, it refers to the substitution of multiple substituents at various positions on a specified group, such as dichlorophenyl referring to 1,2-dichlorophenyl, 1,3-dichlorophenyl, 1,4-dichlorophenyl, and 2,4-dichlorophenyl.

[0020] Combinations of substituents and / or variables are permitted only when these combinations produce stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated from the reaction mixture with useful purity, subsequently formulated to form an effective therapeutic agent. Preferably, the compound does not currently contain N-halogens, S(O)₂H, or S(O)H groups.

[0021] In this invention, "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring moiety, such as phenyl and naphthyl, each of which may be substituted.

[0022] The term "halogen" or "halogen atom" as used in this invention refers to chlorine, bromine, fluorine, and iodine.

[0023] In this invention, "halogenated alkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "halogenated alkyl" includes mono-, di-, and trifluoromethyl groups; even if the halogen in a haloalkyl group is specifically defined as fluorine, chlorine, bromine, or iodine, it still refers to a substituted alkyl group having one or more fluorine, chlorine, bromine, or iodine substituents.

[0024] The term "heteroaryl" as used in this invention 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 the 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 ring completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Nitrogen and sulfur atoms may optionally be oxidized, and nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group 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).

[0025] Exemplary monocyclic heteroaryl groups include pyrrole, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thiophenyl, oxadiazolyl, pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and their analogues.

[0026] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxazolyl, benzoxazolyl, benzothiophenyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoimidazolyl, benzofuranyl, indolazidyl, benzoxazolyl, cronone, coumarinyl, benzothiazolyl, cenolinyl, quinoxalinyl, indazole, pyrrolopyrimidinyl, fluoropyrimidinyl, dihydroisoindolyl, tetrahydroquinolinyl, and their analogues.

[0027] Unless otherwise specified, the compounds of this invention are understood to include both their free state and their salts. The term "salt" means an acidic and / or basic salt formed from an inorganic and / or organic acid and base. Additionally, the term "salt" may include zwitterions (internal salts), such as when a compound of formula I contains a basic segment such as an amine or pyrimidine or imidazole ring, and an acidic segment such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not significantly contribute to toxicity or the biological activity of the salt. However, other salts may be useful, such as those prepared using separation or purification steps, and are therefore also included within the scope of this invention.

[0028] C1-C10 alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and their isomers; C1-C10 alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy and their isomers; C2-C5 alkenyl refers to vinyl, propenyl, allyl, butenyl, pentenyl and their isomers.

[0029] When referring to substituents as alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, mercapto, or phosphinyl, or when these substituents specifically refer to a particular alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, mercapto, or phosphinyl group, it refers to one to three of the aforementioned substituents. For example, methylphenyl refers to a phenyl group with one to three methyl-substituted groups.

[0030] As a preferred embodiment of the saturated nitrogen heterocyclic compound containing a pyrimidine structure according to the present invention, wherein: the structural formula of the saturated nitrogen heterocyclic compound includes compounds with general formula (IA) and compounds with general formula (IB);

[0031]

[0032] In formula (IA), R is selected from one or more of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted amino or heterocyclic amino, substituted or unsubstituted mercapto or heterocyclic mercapto, and substituted or unsubstituted heteroaryl.

[0033] In formula (IB), R1 is selected from one or more of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted amino or heterocyclic amino, substituted or unsubstituted mercapto or heterocyclic mercapto, and substituted or unsubstituted heteroaryl.

[0034] As a preferred embodiment of the saturated nitrogen heterocyclic compound containing a pyrimidine structure according to the present invention, wherein: the structural formula of the benzimidazole compound represented by formula (IA) includes one of the formulas (I-1) to (I-31);

[0035]

[0036] The structural formulas of the saturated nitrogen heterocyclic compounds represented by formula (IB) include one of the formulas (I-32) to (I-34);

[0037]

[0038] As a preferred embodiment of the saturated nitrogen heterocyclic compound containing a pyrimidine structure according to the present invention, the saturated nitrogen heterocyclic compound further includes compounds with the structural formula shown in formula (I-35);

[0039]

[0040] As a preferred embodiment of the saturated nitrogen heterocyclic compound containing a pyrimidine structure according to the present invention, the saturated nitrogen heterocyclic compound further includes stereoisomers, salts, or solvent compounds of the compound with the general structural formula shown in formula (I).

[0041] Another object of the present invention is to provide a method for preparing a saturated nitrogen heterocyclic compound containing a pyrimidine structure, comprising, wherein the saturated nitrogen heterocyclic compound is synthesized by introducing a pyrimidine fragment as a lead compound using a benzimidazole structure.

[0042] Another object of the present invention is to provide a pharmaceutical composition for the prevention and control of agricultural pests and diseases.

[0043] As a preferred embodiment of the pharmaceutical composition for controlling agricultural pests and diseases according to the present invention, the pharmaceutical composition comprises a saturated nitrogen heterocyclic compound or its stereoisomer, its salt or its solvent compound, and agriculturally acceptable adjuvants, fungicides, insecticides or herbicides.

[0044] As a preferred embodiment of the pharmaceutical composition for preventing and controlling agricultural pests and diseases according to the present invention, the dosage form of the pharmaceutical composition includes one of emulsifiable concentrate, powder, wettable powder, granules, aqueous solution, suspension concentrate, ultra-low volume spray, soluble powder, microcapsule, fumigant, water emulsion or water-dispersible granules.

[0045] Another object of the present invention is to provide an application of a pharmaceutical composition in the prevention and control of agricultural pests and diseases, comprising applying the pharmaceutical composition to the harmful substance or its living environment.

[0046] As a preferred embodiment of the pharmaceutical composition for controlling agricultural pests and diseases according to the present invention, wherein: the agricultural pests and diseases include bacterial or fungal plant diseases, including one of the following: rice sheath blight fungus (Thanatephorus cucumeris, Tc), wheat scab fungus (Gibberelazeae, Gz), rapeseed sclerotinia sclerotiorum (Ss), eggplant verticillium dahliae (Vd), grape bud fungus (Botryosphaeria dothidea, Bd), and pepper wilt fungus (Fusarium oxysporum, Fo).

[0047] As a preferred embodiment of the pharmaceutical composition for preventing and controlling agricultural pests and diseases according to the present invention, wherein the agricultural pests and diseases include plant leaf blight or plant canker.

[0048] As a preferred embodiment of the pharmaceutical composition for controlling agricultural pests and diseases according to the present invention, the agricultural pests and diseases include one of the following: rice bacterial leaf blight, rice bacterial leaf streak, plum bacterial shot-hole disease, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, tobacco bacterial wilt, tobacco red spot disease, tobacco red spot disease, grape canker, tomato canker, kiwifruit canker, apple canker, cucumber gray mold, pepper wilt, rapeseed sclerotinia rot, eggplant verticillium wilt, wheat scab, potato late blight, blueberry root rot, grape spore blight, dragon fruit anthracnose, or rice sheath blight.

[0049] Beneficial effects of this invention:

[0050] This invention synthesizes a class of saturated nitrogen heterocyclic compounds containing pyrimidine structures. These compounds, their stereoisomers, salts, or solvent compounds exhibit good inhibitory effects on plant pathogenic bacteria and fungi. They show excellent inhibitory effects against fungi such as *Thanatephorus cucumeris* (Tc), *Gibberella zeae* (Gz), *Sclerotinia sclerotiorum* (Ss), *Verticillium dahliae* (Vd), *Botryosphaeria dothidea* (Bd), and *Fusarium oxysporum* (Fo), and against pathogenic bacteria such as *Xanthomonas oryzaepv. oryzae* (Xoo) and *Xanthomonas axonopodis pv. citri* (Xac). This provides an important scientific basis for the research and development of new pesticides. Detailed Implementation

[0051] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0052] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0053] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0054] Unless otherwise specified, all raw materials used in this invention are commercially available in the field.

[0055] Example 1: Synthesis of an intermediate for the preparation of benzimidazole compounds containing pyrimidine structures

[0056] A: Synthesize intermediate I, 2-((6-chloropyrimidin-4-yl)thio)-1H-benzimidazole, as shown in formula (II).

[0057]

[0058] In a 50 mL round-bottom flask, add 4,6-dichloropyrimidine (2.0 mmol) and potassium carbonate (3.0 mmol) and 6 mL DMF and stir to dissolve. Then slowly add 2-mercaptobenzimidazole (2.0 mmol) dissolved in 6 mL DMF. Let the reaction proceed overnight at room temperature and monitor the progress of the reaction by TLC.

[0059] After the reaction was complete, 90 mL of redistilled water was added, and the mixture was extracted three times with 30 mL of ethyl acetate. The organic phases were combined and then washed once with 50 mL of saturated NH4Cl solution and once with 50 mL of saturated NaCl solution. The organic phases were dried over anhydrous Na2SO4. Finally, the organic phases were concentrated by rotary evaporation at 45 °C and purified by column chromatography (eluent (V / V): PE / EA = 80 / 1) to obtain intermediate I, 2-((6-chloropyrimidin-4-yl)thio)-1H-benzimidazole, a white solid with a yield of 81.7%.

[0060] B: Synthesize intermediate II, 2-chloro-4-(4-(trifluoromethyl)phenoxy)pyrimidine, as shown in formula (III).

[0061]

[0062] In a 50 mL round-bottom flask, add 2.0 mmol of 4,6-dichloropyrimidine and 3.0 mmol of potassium carbonate and 6 mL of DMF and stir to dissolve. Then slowly add 2.0 mmol of p-trifluoromethylphenol and let it react overnight at room temperature. Monitor the reaction progress by TLC.

[0063] After the reaction was complete, 90 mL of redistilled water was added, and the mixture was extracted three times with 30 mL of ethyl acetate. The organic phases were combined and then washed once with 50 mL of saturated NH4Cl solution and once with 50 mL of saturated NaCl solution. The organic phases were dried over anhydrous Na2SO4. Finally, the organic phases were concentrated by rotary evaporation at 45 °C, and purified by column chromatography (eluent (V / V): PE / EA = 80 / 1) to give intermediate II, 2-chloro-4-(4-(trifluoromethyl)phenoxy)pyrimidine, a white solid with a yield of 62.7%.

[0064] Example 22: Preparation formula of 6-phenylpyrimidine-4-thio)-1H-benzimidazole (I-2)

[0065] Referring to formula (A), this embodiment provides a method for preparing 2-(6-chloropyrimidinyl-4-thio)-1H-benzimidazole, specifically as follows:

[0066] 1) In a 15 mL round-bottom flask, add 2-(6-chloropyrimidinyl-4-thio)-1H-benzimidazole (1.00 mmol) dissolved in 6 mL LDM, then add phenol (1.00 mmol) and potassium carbonate (3.00 mmol), and react at room temperature for 24 h. The reaction progress is monitored by TLC.

[0067] 2) After the reaction was complete, 90 mL of redistilled water was added, and the mixture was extracted three times with 30 mL of ethyl acetate. The organic phases were combined and then washed twice with 50 mL of saturated NaCl solution. The organic phases were dried over anhydrous Na2SO4. Finally, the mixture was concentrated at 45 °C using a rotary evaporator, and purified by column chromatography (eluent (V / V): DCM / MeOH = 100 / 1) to obtain the target compound, with the structural formula shown in formula (I-2). It was a white solid with a yield of 62.3%.

[0068] Example 32: Preparation formula (I-30) of (6-trifluoromethyl)phenyl)thio)pyrimidinyl)-4-thio)-1H-benzimidazole

[0069] Referring to formula (B), this embodiment provides a method for preparing 2-(6-trifluoromethyl)phenyl)thio)pyrimidinyl)-4-thio)-1H-benzimidazole, specifically as follows:

[0070]

[0071] The difference between this embodiment and Example 2 is that the phenol in step 1) is changed to p-trifluoromethylthiophenol, while the remaining steps are the same as in Example 2. The target compound of this embodiment, 2-(6-trifluoromethyl)phenyl)thio)pyrimidinyl)-4-thio)-1H-benzimidazole, with the structural formula shown in formula (I-30), is a white solid with a yield of 50.5%.

[0072] Example 42: Preparation of ((6-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)thio)-benzothiazole (Formula I-32)

[0073] Referring to formula (C), this embodiment provides a method for preparing 2-((4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)thio)-1H-benzimidazole, specifically as follows:

[0074]

[0075] 1) In a 15 mL round-bottom flask, add 4-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidine (1.00 mmol) dissolved in 6 mL LDM, then add 2-mercaptobenzothiazole (1.00 mmol) and potassium carbonate (3.00 mmol), and react at 100 °C for 10 h. The reaction progress is monitored by TLC.

[0076] 2) After the reaction was complete, 90 mL of redistilled water was added, and the mixture was extracted three times with 30 mL of ethyl acetate. The organic phases were combined and then washed twice with 50 mL of saturated NaCl solution. The organic phases were dried over anhydrous Na₂SO₄. Finally, the mixture was concentrated at 45 °C using a rotary evaporator, and purified by column chromatography (eluent (V / V): DCM / MeOH = 100 / 1) to obtain the target compound, a white solid with the structural formula shown in formula (I-32), in a yield of 78.5%.

[0077] Example 52: Preparation formula (I-35) of -((4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)thio)-1H-benzimidazole

[0078] Referring to formula (D), this embodiment provides a method for preparing 2-((4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)thio)-1H-benzimidazole, specifically as follows:

[0079]

[0080] 1) In a 15 mL round-bottom flask, add 2-chloro-4-(4-(trifluoromethyl)phenyl)pyrimidine (1.00 mmol) dissolved in 6 mL DMF, then add 2-mercaptobenzimidazole (1.00 mmol) and potassium carbonate (3.00 mmol), and react at 100 °C for 10 h. The reaction progress is monitored by TLC.

[0081] 2) After the reaction was complete, the reactants were concentrated by rotary evaporation at 45°C. 90 mL of redistilled water was added, and the mixture was extracted three times with 30 mL of ethyl acetate. The organic phases were combined and washed twice with 50 mL of saturated NaCl solution. The organic phases were then dried over anhydrous NaSO4. Finally, the mixture was concentrated by rotary evaporation at 45°C, and purified by column chromatography (eluent (V / V): DCM / MeOH = 100 / 1) to obtain the target compound, with the structural formula shown in formula (I-35). It was a white solid with a yield of 56.7%.

[0082] By changing the R group according to the method of Example 2, the target compounds with the structural formulas shown in formulas (I-1) to (I-29) were synthesized, and the synthetic route is shown in formula (A-1);

[0083]

[0084] Referring to the method of Example 3, the oxygen atom was replaced with a sulfur atom and -OCH2- to synthesize the target compound with the structural formulas shown in formulas (I-30) to (I-31), and the synthetic route is shown in formula (B-1).

[0085]

[0086] By replacing the X group according to the method of Example 4, the target compound with the structural formulas shown in formulas (I-32) to (I-34) was synthesized, and the synthetic route is shown in formula (C-1);

[0087]

[0088] By changing the linking group according to the method in Example 5, the target compound with the structural formula shown in formula (I-35) was synthesized.

[0089] The synthesis route is shown in equation (D-1);

[0090]

[0091] All target products are white solids. The structure, molecular formula, 1H and 1C NMR spectra, and physicochemical properties of the target products are shown in Table 1.

[0092] Table 1. Characterization data of the target compounds with structural formulas as shown in formulas (I-1) to (I-35).

[0093]

[0094]

[0095]

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[0103] Example 6

[0104] This embodiment is used to verify the application activity of the compound prepared in this invention in the prevention and control of agricultural pests and diseases, specifically;

[0105] EC 50(median effective concentration) is an important indicator for evaluating the sensitivity of plant pathogens to compounds, and it is also an important parameter for setting the concentration of compounds when studying the mechanism of action of target compounds.

[0106] In the concentration gradient experiment, five suitable concentrations (50, 25, 12.5, 6.25, 3.125 μg / mL) were established using the two-fold dilution method. Finally, the inhibition rate of the agent against the plant pathogen and the agent concentration were converted to logarithmic values. The toxicity curve was obtained through regression analysis using SPSS software, and the EC50 was calculated. 50 .

[0107] The effective medium concentration (EC50) of the target compound against plant pathogens was tested using the mycelial growth inhibition method. The test subjects were Fusarium graminearum (Gz), rice sheath blight fungus (Tc), rapeseed sclerotinia sclerotinia (Ss), eggplant verticillium wilt fungus (Vd), grape bud blight fungus (Bd), pepper wilt fungus (Fo), and tobacco auricularia auricula-judae fungus (Aa). The antibacterial activity of the fungi used was tested on PDA medium. All the fungi used were newly activated young fungi one week in advance.

[0108] Weigh the target compound using a 0.01 g / mL balance. Dissolve it in 20 times its weight of DMSO until the concentration of the stock solution is 50 μg / mL. Take the corresponding volume of the stock solution at the desired concentration and transfer it to a 2 mL centrifuge tube. Add DMSO to balance the volume to 1 mL. Transfer the solution to a 15 mL sterile centrifuge tube in a sterile environment. Add 9 mL of Tween-20 water to a final volume of 10 mL. Shake well and pour the solution into the culture medium. Mix thoroughly and aliquot into 9 culture media. Cool the mixture. In a sterile environment, using a sterile 5 mm punch, place the mycelial cake upside down in the center of the culture medium with an inoculation loop. Incubate at 28°C for 3-7 days. When the control group colonies reach a diameter of 5.0-7.0 cm, measure the colony diameter twice using a ruler in a cross-hatching method. Calculate the colony diameter using the average value. Calculate the mycelial growth inhibition rate using the following formula:

[0109] Inhibition rate % = (C1-C2) / (C1-0.5)×100 (In the formula:)

[0110] C1 is the control colony diameter, i.e., the colony diameter of the DMSO treatment (i.e., CK);

[0111] C2 represents the diameter of the treated colonies, i.e., the diameter of the colonies treated with the drug.

[0112] 0.5 is the diameter of the mother mycelium cake;

[0113] The target compounds with structural formulas as shown in formulas (I-1) to (I-36) were tested for EC50 against plant pathogens using the method described above. 50 The results are shown in Table 2.

[0114] Table 2

[0115]

[0116]

[0117] As shown in Table 2, in in vitro experiments, the target compounds exhibited good antibacterial activity against plant pathogens (such as *Fusarium graminearum*, *Rhizoctonia solani*, *Sclerotinia sclerotiorum*, *Verticillium wilt*, and *Aureobasidium acutum*). Among them, compounds with structural formulas (I-7), (I-8), (I-17), (I-18), (I-25), and (I-35) (compounds 7, 8, 17, 18, 25, 29, and 35) showed excellent inhibitory activity against *Sclerotinia sclerotiorum* (Ss), with EC50 values ​​exceeding 100%. 50 The concentration ranged from 0.16 to 7.04 μg / mL.

[0118] Compounds with structural formulas as shown in formulas (I-8), (I-18), (I-25), and (I-33) (compounds 8, 18, 25, and 33) exhibited good inhibitory activity against *Verticillium dahliae* (Vd), the causal agent of eggplant wilt, and their EC50 values ​​were [missing data]. 50 The concentration ranged from 17.14 to 29.99 μg / mL.

[0119] Compounds with structural formulas as shown in formulas (I-8), (I-18), (I-25), and (I-34) (compounds 8, 18, and 25) exhibited good inhibitory activity against *Alternaria alternata* (Aa), the pathogen of *Tobacco Star*. Their EC50 values... 50 The concentrations ranged from 4.52 to 14.04 μg / mL.

[0120] Compounds with structural formulas such as (I-9), (I-18), (I-25), and (I-25) (compounds 9, 18, and 25) showed generally good inhibitory activity against *Gibberella zeae* (Gz), the causal agent of wheat blight. Their EC50 values... 50 The concentration ranged from 12.48 to 23.60 μg / mL.

[0121] Compounds with structural formulas such as (III-18), (III-25), and (III-32) (compounds 18, 25, and 32) showed generally good inhibitory activity against *Thanatephorus cucumeris* (Tc), the causal agent of rice sheath blight. Their EC50 values... 50 The concentration ranges from 3.60 to 11.83 μg / mL. It can be used to prepare pesticides against plant pathogenic bacteria.

[0122] Example 7

[0123] The effective initial concentration of the target compound against plant pathogens was determined using the turbidimetric method. The test subjects were *Xoo* (bacterium oryzae of rice), *Xac* (bacterium canker of citrus), and *Xoc* (bacterial leaf streak of rice). DMSO was dissolved in the culture medium as a blank control. *Xoo* (bacterium oryzae of rice) was placed in NB medium and cultured in a constant temperature shaker at 28℃ and 180 rpm until the logarithmic growth phase. *Xoc* (bacterium canker of citrus) was placed in NB medium. *Xoc* (bacterial leaf streak of rice) was placed in NB medium and cultured in a constant temperature shaker at 28℃ and 180 rpm until the logarithmic growth phase. Prepare different concentrations (e.g., 100, 50, 25, 12.5, 6.25 μg / mL) of the drug (compound) in 5 mL of NB liquid culture medium containing the pathogen and add it to test tubes. Add 40 μL of NB liquid culture medium containing plant pathogen bacteria to each tube. Incubate in a constant temperature shaker at 28-30℃ and 180 rpm for 48 h for rice bacterial blight pathogen, 48 h for citrus canker pathogen, and 36 h for rice bacterial leaf streak pathogen. Measure the OD595 value of each concentration of bacterial suspension using a microplate reader, and also separately measure the OD595 value of the corresponding concentration of sterile NB liquid culture medium containing the pathogen.

[0124] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium

[0125] Inhibition rate % = [(OD value of bacterial culture in the control medium after correction - OD value of the medium containing the virus after correction) /

[0126] [OD value of bacterial suspension in the control culture medium after correction] × 100

[0127] The experimental results for the target compound are shown in Table 3.

[0128] Table 3

[0129]

[0130] As shown in Table 3, in in vitro experiments, the target compounds exhibited good antibacterial activity against plant pathogenic bacteria (such as *Xanthomonas axonopodis* pv. citri, citrus canker). Compounds 4 and 25 showed excellent inhibitory activity against *Xanthomonas axonopodis* pv. citri, with initial screening activities of 43.07-63.25 μg / mL, superior to commercial drugs such as tebuconazole and thiamethoxam. Compound 25 showed excellent inhibitory activity against *Xanthomonas oryzae* pv. oryzae, citrus canker, with an initial screening activity of 39.95 μg / mL, superior to commercial drug thiamethoxam. The inhibitory effects of compounds 7 and 10 were slightly weaker than those of commercial drug thiamethoxam. These compounds can be used to prepare pesticides against plant pathogenic bacteria.

[0131] In summary, the pyrimidine-containing saturated nitrogen heterocyclic compounds proposed in this invention exhibit good inhibitory effects on both plant pathogenic bacteria and fungi. They demonstrate excellent inhibitory effects against pathogens such as *Thanatephorus cucumeris* (Tc), *Gibberela zeae* (Gz), *Sclerotinia sclerotiorum* (Ss), *Verticilium dahliae* (Vd), *Botryosphaeria dothidea* (Bd), *Fusarium oxysporum* (Fo), *Xanthomonas axonopodis pv. citri* (Xac), and *Xanthomonas oryzae pv. oryzae* (Xoo). This provides an important scientific basis for the research and development of new pesticides.

[0132] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A compound containing a pyrimidine structure, characterized in that: The compound is selected from any one of the compounds shown in Formula (I-2), Formula (I-5), Formula (I-7), Formula (I-8), Formula (I-9), Formula (I-10), Formula (I-12), Formula (I-17), Formula (I-19), Formula (I-20), Formula (I-21), Formula (I-23), Formula (I-24), Formula (I-25), Formula (I-28), Formula (I-29), Formula (I-30), Formula (I-32), Formula (I-33), Formula (I-34), and Formula (I-35); Equation (I-2); Equation (I-5); Equation (I-7); Formula (I-8); Equation (I-9); Formula (I-10); Formula (I-12); Formula (I-17); Formula (I-19); Formula (I-20); Formula (I-21); Formula (I-23); Formula (I-24); Formula (I-25); Formula (I-28); Formula (I-29); Formula (I-30); Formula (I-32); Formula (I-33); Formula (I-34); Formula (I-35).

2. The application of the compound as described in claim 1 in the prevention and control of agricultural pests and diseases.

3. A pharmaceutical composition for controlling agricultural pests and diseases, characterized in that: The pharmaceutical composition comprises a pyrimidine-containing compound or a salt thereof as described in claim 1, as well as an agriculturally acceptable adjuvant, fungicide, insecticide, or herbicide.

4. The pharmaceutical composition for controlling agricultural pests and diseases as described in claim 3, characterized in that: The dosage form of the pharmaceutical composition includes one of the following: emulsifiable concentrate, wettable powder, aqueous solution, suspension concentrate, ultra-low volume spray, soluble powder, microcapsule, fumigant, water emulsion, or water-dispersible granules.

5. The application of the pharmaceutical composition according to any one of claims 3 or 4 in the prevention and control of agricultural pests and diseases, characterized in that: The pharmaceutical composition of claim 3 or 4 is applied to a harmful substance or its living environment, wherein the agricultural pest or disease includes bacterial or fungal plant diseases.

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