Eflucimide derivatives and their antifungal activity

Abstract

The application discloses a series of afluconazole derivatives or pharmaceutically acceptable inorganic salts, organic salts and solvates thereof. The application also discloses a preparation method of the afluconazole derivatives and application of the afluconazole derivatives in preparation of medicines for treating or preventing fungal infections. Experimental results show that the preliminary in-vitro antifungal activity of the target compounds is obviously better than that of afluconazole and other currently widely used azole antifungal medicines (such as miconazole, fluconazole and oterconazole), the water solubility of the target compounds is better, the antibacterial spectrum is wider, the activity is higher, the pharmacokinetic properties are better, and the target compounds have further development potential.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to an effluconazole derivative with antifungal activity or a pharmaceutically acceptable inorganic salt, organic salt, solvate, or polymorph thereof. Background Technology

[0002] Fungal infections are common and difficult-to-treat conditions. In recent years, the incidence and mortality rates of fungal infections have been increasing year by year, while the availability of antifungal drugs in clinical practice remains relatively limited. Azole antifungal drugs are still the first-line treatment. Although these drugs have some efficacy, their clinical application is restricted due to their toxic side effects, poor efficacy against deep fungal infections, and especially the emergence of azole-resistant fungi in recent years. Therefore, developing highly effective, low-toxicity, and structurally novel antifungal drugs remains a very urgent task. Efinaconazole, jointly developed by Research Pharmaceuticals Co., Ltd. and Valeant, was first approved by Health Canada on October 2, 2013, followed by approval from the U.S. Food and Drug Administration (FDA) on June 6, 2014, and approval from the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on July 4, 2014, for the topical treatment of onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes. Although iefluconazole has good antibacterial efficacy in treating superficial fungal infections, it still suffers from drawbacks such as poor water solubility, unsatisfactory pharmacokinetic properties, limitation to topical application, single dosage form, and narrow antibacterial spectrum. While a few structurally modified derivatives of iefluconazole have been developed in the prior art, they have not yet achieved satisfactory antifungal efficacy and pharmacokinetic properties. Summary of the Invention

[0003] To overcome the shortcomings of existing technologies, this invention, based on the molecular docking research results of the lead compound iefluconazole with the target enzyme (CYP51), modifies the 4-methylenepiperidine in its structure. This is achieved by introducing amides, esters, or selenoesters into the methylene group, or by reducing the methylene group to a methyl group before introducing amides, esters, or selenoesters, thereby increasing the number of hydrogen bond acceptors and hydrogen bond donors in the target molecule. This leads to greater interactions between the target molecule and the amino acid residues of the target enzyme. Simultaneously, by increasing molecular polarity, its water solubility is improved, resulting in the design of a series of iefluconazole derivatives. The in vitro antifungal activity of the designed target compounds was tested using a two-fold dilution method. The preliminary in vitro antifungal activity of several target compounds was found to be significantly better than that of the lead compound iefluconazole and other widely used azole antifungal drugs (such as miconazole and fluconazole), exhibiting better water solubility, a broader antibacterial spectrum, higher activity, better pharmacokinetic properties, and greater potential for further research and development.

[0004] To achieve the above objectives, the present invention discloses the following technical content.

[0005] An iefluconazole derivative as shown in Formula I, or a pharmaceutically acceptable inorganic salt, organic salt, or solvate thereof:

[0006]

[0007] in:

[0008]

[0009] Y = NH; O; Se

[0010] H; OH; NH2; N=CHAr; (CH2) n CH3

[0011] R 1 ,R 2 =H; CH3; CF3; OCH3; OCF3; C2H5; OC2H5; OH; NH2; F; Cl; Br; I; CO2H; CO2CH3; CO2C2H5; NO2; CN

[0012] n = 0 to 7.

[0013] in for Y is NH, O, or Se, preferably NH or O; R is a substituted benzene ring, hydrogen atom, hydroxyl group, or amino group, preferably a substituted ring.

[0014] R 1 ,R 2 H atom, halogen, nitro, trifluoromethyl, alkyl, alkoxy; R 1 R 2 They can be the same or different; the preferred R 1 ,R 2 H atom, halogen, alkyl, trifluoromethyl; R 1 R 2 They can be the same or different; the preferred R 1 ,R 2 Halogen, alkyl; R 1 ,R 2 They can be the same or different. The preferred R... 1 ,R 2 For halogens, R 1 ,R 2 They can be the same or different.

[0015] This invention further discloses a drug with antifungal activity, comprising the active ingredient of an icofol derivative of Formula I or a pharmaceutically acceptable inorganic salt, organic salt, solvate, or polymorph thereof; each unit dose of the drug contains 10-500 mg of the icofol derivative of Formula I or a pharmaceutically acceptable inorganic salt, organic salt, solvate, or polymorph thereof. Preferably, each unit dosage form of the drug contains 50-300 mg of the icofol derivative of Formula I or a pharmaceutically acceptable inorganic salt, organic salt, solvate, or polymorph thereof.

[0016] The present invention further provides a method for preparing iefluconazole derivatives or pharmaceutically acceptable inorganic salts, organic salts, solvates, optical isomers or polymorphs thereof, characterized in that the method for preparing the derivative comprises the following steps:

[0017] Synthesis method 1 of the target compound:

[0018] Starting with N-Boc-4-piperidinone (2) and (2-amino-2-oxoethyl)phosphonate diethyl ester (3), the intermediate 2-(piperidin-4-yl)acetamide (4) was obtained by Wittig-Horner reaction and deprotection of Boc group. 4 was then reacted with commercially available iriconazole intermediate (1) by alkylation reaction to obtain the target compound A01.

[0019] Method 2 for synthesizing the target compound:

[0020] Starting with N-Boc-4-piperidinone (2) and ethyl 2-diethoxyphosphonoethyl acetate (5), N-Boc-2-(piperidin-4-yl)acetic acid (7) was obtained by Wittig-Horner reaction and ester hydrolysis. 7 was reacted with various substituted anilines under HATU-DIPEA catalysis to obtain intermediate 8 (or 9). 8 (or 9) was then reacted with commercially available aniconazole intermediate (1) by alkylation to obtain the target compound A02-A14.

[0021] Synthesis method 3 of the target compound:

[0022] Using ethyl 2-(piperidin-4-yl)ethyl acetate (10) and icorconazole intermediate (1) as raw materials, A28 is obtained by alkylation reaction. A28 is reacted with hydroxylamine hydrochloride or hydrazine hydrate to obtain target compound A15 or A16. Compound A16 is then reacted with various substituted benzaldehydes to form Schiff bases to obtain target compounds A17-A25.

[0023] Synthesis method 4 of the target compound:

[0024] Using the previously prepared A28 as a raw material, its free acid (A26) was obtained by hydrolysis with lithium hydroxide. A26 was then subjected to esterification with various substituted phenols to obtain the target compounds A29-A34. In the presence of isobutyl chloroformate, A26 was subjected to Se-acylation with various alkyl or substituted phenyl diselenyl ethers under sodium borohydride catalysis to obtain the target compounds A35-A37.

[0025] Method 5 for synthesizing the target compound:

[0026] Starting with commercially available methyl 2-(piperidin-4-yl)acetate hydrochloride (12), BO5 was prepared by alkylation reaction with ivermectin intermediate (1). BO5 was hydrolyzed with lithium hydroxide to obtain its free acid BO4. BO4 was then subjected to amidation reaction with various substituted anilines under HATU catalysis to obtain BO2 and BO3. BO4 was then subjected to esterification reaction with various substituted phenols to obtain the target compounds B6-B10.

[0027] Synthesis method 6 for the target compound:

[0028] Using the previously prepared B04 as raw material, in the presence of isobutyl chloroformate, it undergoes a Se-acylation reaction with various alkyl or substituted phenyl diselenyl ethers under sodium borohydride catalysis to obtain the target compounds B11-B13.

[0029] The organic solvents used in the above preparation methods include: acetone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, acetonitrile, dioxane, tetrahydrofuran, diethyl ether, isopropyl ether, petroleum ether, ethyl acetate, cyclohexane, N,N-dimethylamide, dimethyl sulfoxide, and C1-C6 alcohol solvents; the basic catalysts include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate; and the organic bases include pyridines, triethylamine, imidazole heterocyclic amines, N,N-disubstituted aniline, HATU, DIPEA, EDCI, and C1-C6 aliphatic secondary and tertiary amines. The reducing agents include sodium borohydride, potassium borohydride, and lithium aluminum tetrahydrogenate. The catalysts in the acylation reaction include CDI, ethyl chloroformate, isobutyl chloroformate, isopropyl chloroformate, and phenyl chloroformate.

[0030] This invention also discloses the application of iefluconazole derivatives or their pharmaceutically acceptable inorganic salts, organic salts, and solvates in the preparation of drugs for treating or preventing fungal infections. Mouse experimental results showed that the ointment prepared using the iefluconazole derivative B12 of this invention achieved a cure rate of 99%, with an average cure time of 7 days. This indicates that the ointment of this invention has a better curative effect.

[0031] The present invention is described in more detail below:

[0032]

[0033] The technical problem solved by this invention is to provide a novel effluconazole derivative and its preparation method. As an antifungal agent, it has strong antibacterial activity against common pathogenic fungi in clinical practice, and is expected to overcome the shortcomings of currently used effluconazole in clinical practice, such as poor water solubility, unsatisfactory pharmacokinetic properties, only suitable for external use, single dosage form, and narrow antibacterial spectrum.

[0034] This invention provides iefluconazole derivatives of formula I or pharmaceutically acceptable inorganic salts, organic salts, solvates or polymorphs thereof:

[0035]

[0036] in:

[0037]

[0038] Y = NH; O; Se

[0039] H; OH; NH2; N=CHAr; (CH2) n CH3

[0040] R 1 ,R 2 =H; CH3; CF3; OCH3; OCF3; C2H5; OC2H5; OH; NH2; F; Cl; Br; I; CO2H; CO2CH3; CO2C2H5; NO2; CN

[0041] n = 0 to 7;

[0042] According to the present invention, the particularly preferred eloxonazole derivative of Formula I is selected from...

[0043]

[0044]

[0045]

[0046]

[0047] Since the effluconazole derivatives of Formula I according to the present invention, or their pharmaceutically acceptable salts or solvates, have potential antifungal activity, they can be used clinically as antifungal agents.

[0048] The compounds according to the present invention can be used as active ingredients for the treatment or prevention of fungal infections. The present invention also provides methods for treating or preventing the aforementioned diseases, including administering a therapeutically effective amount of the compounds of the present invention to a patient who has or is susceptible to the disease.

[0049] This invention includes pharmaceutical compositions containing an icofonazole derivative of formula I or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The compounds of this invention can be administered on their own or as pharmaceutical compositions comprising the compounds of this invention mixed with pharmaceutically acceptable diluents, adjuvants, and / or carriers, and are particularly preferred to be compositions free from substances that can cause adverse effects such as allergic reactions.

[0050] When the pharmaceutical compositions of the present invention are used clinically, they can be formulated into several dosage forms, which contain some excipients commonly used in the pharmaceutical field; for example, oral preparations (such as tablets, capsules, ointments, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions, or injectable dry powders that can be used immediately after being added to water for injection before injection); and topical preparations (such as ointments or solutions).

[0051] The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavoring agents, etc., for oral formulations; preservatives, solubilizers, stabilizers, etc., for injectable formulations; and matrices, diluents, lubricants, preservatives, etc., for topical formulations. The pharmaceutical formulations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0052] Furthermore, the clinical dosage of the iefluconazole derivative of Formula I or its pharmaceutically acceptable salts, solvates, or polymorphs for patients can be appropriately adjusted based on: the therapeutic efficacy and bioavailability of the active ingredient in vivo, their metabolic and excretion rates, and the patient's age, sex, and disease stage. However, the daily dose for adults should generally be 10-500 mg, preferably 50-300 mg. Therefore, when the pharmaceutical composition of the present invention is formulated into unit dosage forms, considering the above-mentioned effective dosage, each unit dosage form should contain 10-500 mg of the iefluconazole derivative of Formula I or its pharmaceutically acceptable salts or solvates, preferably 50-300 mg. These preparations can be administered at regular intervals (preferably one to six times) under the guidance of a physician or pharmacist.

[0053] The following synthetic routes describe the preparation of compounds of Formula I of the present invention. All starting materials are prepared by the methods described in these synthetic routes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final compounds of the present invention are prepared by the methods described in these synthetic routes or by similar methods well known to those skilled in the art of organic chemistry. All variable factors used in these synthetic routes are defined below or as defined in the claims.

[0054] According to the compound of formula I of the present invention, in the target compound synthetic route described below, the substituents are as defined above.

[0055] Synthetic route 1 for the target compound:

[0056]

[0057] Synthetic route 2 for the target compound:

[0058]

[0059] Synthetic route 3 for the target compound:

[0060]

[0061] Synthetic route 4 for the target compound:

[0062]

[0063] Synthetic route 5 for the target compound:

[0064]

[0065] Synthetic route 6 for the target compound:

[0066]

[0067] Synthetic route of the target compound involved in this invention

[0068] Synthetic route 1 for the target compound:

[0069] Starting with N-Boc-4-piperidinone (2) and (2-amino-2-oxoethyl)phosphonate diethyl ester (3), the intermediate 2-(piperidin-4-yl)acetamide (4) was obtained by Wittig-Horner reaction and deprotection of Boc. 4 was then reacted with commercially available ciprofloxacin intermediate (1) by alkylation to obtain the target compound A01.

[0070] Synthetic route 2 for the target compound:

[0071] Starting with N-Boc-4-piperidinone (2) and ethyl 2-diethoxyphosphonoethyl acetate (5), N-Boc-2-(piperidin-4-yl)acetic acid (7) was obtained by Wittig-Horner reaction and ester hydrolysis. 7 was then amidated with various substituted anilines under HATU-DIPEA catalysis to obtain intermediate 8 (or 9). 8 (or 9) was then alkylated with commercially available ivermectin intermediate (1) to obtain the target compound A02-A14.

[0072] Synthetic route 3 for the target compound:

[0073] Using ethyl 2-(piperidin-4-yl)acetate (10) and icorconazole intermediate (1) as raw materials, A28 is obtained by alkylation reaction. A28 is reacted with hydroxylamine hydrochloride or hydrazine hydrate to obtain target compound A15 or A16. Compound A16 is then reacted with various substituted benzaldehydes to form Schiff bases to obtain target compounds A17-A25.

[0074] Synthetic route 4 for the target compound:

[0075] Using the previously prepared A28 as a raw material, its free acid (A26) is obtained by hydrolysis with lithium hydroxide. A26 undergoes esterification with various substituted phenols to obtain target compounds A29-A34. In the presence of isobutyl chloroformate, A26 undergoes Se-acylation with various alkyl diselenides or substituted phenyl diselenides under sodium borohydride catalysis to obtain target compounds A35-A37.

[0076] Synthetic route 5 for the target compound:

[0077] Starting with commercially available methyl 2-(piperidin-4-yl)acetate hydrochloride (12), BO5 was prepared by alkylation reaction with ivermectin intermediate (1). BO5 was hydrolyzed with lithium hydroxide to obtain its free acid BO4. BO4 was then amidated with various substituted anilines under HATU catalysis to obtain BO2 and BO3. BO4 was then esterified with various substituted phenols to obtain the target compounds B6-B10.

[0078] Synthetic route 6 for the target compound:

[0079] Using the previously prepared B04 as raw material, in the presence of isobutyl chloroformate, it undergoes a Se-acylation reaction with various alkyl or substituted phenyl diselenyl ethers under sodium borohydride catalysis to obtain the target compounds B11-B13. Detailed Implementation

[0080] The present invention is described below through specific embodiments. Unless otherwise specified, the technical means used in the present invention are all methods known to those skilled in the art. Furthermore, the embodiments should be understood as illustrative, not limiting, of the scope of the invention; the essence and scope of the invention are defined only by the claims. For those skilled in the art, various changes or modifications to the material composition and dosage in these embodiments without departing from the essence and scope of the invention also fall within the scope of protection of the invention. The raw materials used in the present invention, such as di(substituted)phenyldiselen ether and dialkyldiselen ether, are prepared in-house; other intermediates and reagents are commercially available. The following examples will better illustrate the compounds of the present invention and their preparation; these examples are intended to explain, not limit, the scope of the invention.

[0081] The preparation methods of di(substituted)phenyl diselenide and dialkyl diselenide are as follows:

[0082] 1. General method for preparing di(substituted)phenyldiselelenide:

[0083] general formula:

[0084]

[0085] Selenium powder (1.572 g, 2 mmol), (substituted) iodobenzene (1 mmol), copper oxide (0.079 g, 0.1 mmol), and potassium hydroxide (1.12 g, 2 mmol) were added to a round-bottom flask, followed by 10 mL of DMSO. The mixture was stirred at 110 °C for 1 h. After cooling to room temperature, 20 mL of a water-ethyl acetate mixture (v / v = 1:1) was added. The mixture was filtered, and the filtrate was retained. The filtrate was washed with water (10 mL × 5), and the organic layer was collected and washed with saturated brine (5 mL × 3). The mixture was dried over anhydrous sodium sulfate. After filtering off the drying agent, the mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (PE:EA = 100:0) to obtain the target compound.

[0086] 2. General method for preparing dialkyl diselenide:

[0087]

[0088] Under nitrogen protection, sodium borohydride (3.78 g, 10 mmol), selenium powder (1.18 g, 14.9 mmol), and 30 mL of anhydrous ethanol were added to a reaction flask. The reaction was carried out at 80 °C for 2 h, followed by the addition of bromoalkane (10 mmol), and the reaction was continued at 80 °C for 6 h. After cooling to room temperature, the mixture was filtered, and the filtrate was retained. The filtrate was washed with water (10 mL × 5), and the organic layer was collected and washed with saturated brine (5 mL × 3). The mixture was dried over anhydrous sodium sulfate, and after filtering to remove the desiccant, it was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (PE:EA = 100:0) to obtain the target compound.

[0089] Example 1:

[0090] 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl)piperidin-4-ylidene)

[0091] Preparation of acetamide (A01)

[0092] N-Boc-4-piperidinone (2) (0.3 g, 1.2 mmol), (2-amino-2-oxoethyl)phosphonate diethyl ester (3) (0.67 g, 4.8 mmol), and 2 g of 1-ethyl-3-methylimidazolium sulfate were added sequentially to a 25 mL pear-shaped flask. 6 mL of purified water was added, and the mixture was stirred in a 100 °C oil bath for 48 h. The reaction was quenched by slowly adding 20 mL of water to room temperature. The reaction mixture was extracted with dichloromethane (20 mL × 3), and the organic layers were combined and washed once with 60 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography at 200–300 μM (eluent: dichloromethane / anhydrous methanol, 50 / 1, V / V) to give 0.29 g of the white solid target compound A01, with a yield of 62.3%. mp192.1~193.2℃; ESI-MS(m / z): 392.4[M+H] + (calcd.for C 19 H 23 F2N5O2,391.4), 1 H-NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.68(s,1H),7.34(td,J=9.1,6.8Hz,1 H),7.27-7.21(m,1H),7.11(ddd,J=11.9,9.1,2.6Hz,1H),6.91(td,J=8.5,2. 7Hz,1H),6.75(s,1H),5.61(s,1H),5.51(s,1H),4.85(q,J=14.9Hz,2H),3.13 (q,J=6.9Hz,1H),3.04-2.77(m,4H),2.49-2.23(m,4H),0.75(d,J=6.9Hz,3H). 13 C-NMR(101MHz,DMSO-d6)δ168.32,163.36,163.24,160.92,160.80,160.17,160 .04,157.72,157.59,153.53,150.94,145.16,130.81,130.75,130.66,126.26, 126.23,126.14,126.10,117.30,111.30,111.09,104.56,104.30,104.27,104.02,79.02,78.97,63.66,63.62,56.19,56.14,52.64,52.16,37.34,29.63,7.60.

[0093] Example 2:

[0094] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl)piperidin-4-ylidene)-N-phenylacetamide (A02)

[0095] (1) Preparation of 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylic acid tert-butyl ester (6)

[0096] Add starting material 5 (0.59 g, 2.6 mmol), NaH (0.06 g, 2.5 mmol), and 6 mL THF to a 25 mL pear-shaped flask. Place the reactants in an ice-water bath and stir to dissolve. Bring the mixture to room temperature and stir for 30 min. Then add N-Boc-4-piperidinone (2) (0.42 g, 2.1 mmol) and continue stirring at room temperature for 6 h. Quench the reaction with saturated ammonium chloride solution. Extract the reaction mixture with ethyl acetate (20 mL × 3). Combine the organic layers and wash once with saturated sodium chloride solution. Dry the organic layer with anhydrous sodium sulfate, filter off the drying agent, and concentrate under reduced pressure to obtain intermediate 6, a white oily substance, in a yield of 0.53 g. This intermediate can be used directly in the next reaction without further purification. ESI-MS (m / z): 169.3 [M-Boc+H] + (calcd..for C 14 H 23 NO4,269.3).

[0097] (2) Preparation of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (7)

[0098] Intermediate 7 (0.56 g, 2.1 mmol) and 10 mL of methanol were added to a 25 mL pear-shaped flask. The mixture was placed in an oil bath at 65 °C with stirring, and an aqueous solution of sodium hydroxide (0.25 g, 6.3 mmol dissolved in 5 mL of water) was slowly added dropwise. After the addition was complete, the mixture was refluxed for 1 h. The methanol was removed by distillation under reduced pressure. The residue was adjusted to neutral pH with 2 M hydrochloric acid, and stirring was continued for 3 h. The mixture was then filtered to obtain intermediate 7 as a white solid, with a yield of 0.49 g. The overall yield of the two-step reaction was 95%. ESI-MS (m / z): 140.2 [M-Boc-H] - (calcd..forC 12 H 19 NO4,241.2)

[0099] (3) Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethylidene)piperidine-1-carboxylic acid (8)

[0100] Intermediate 7 (0.49 g, 2.0 mmol) was added to a 25 mL pear-shaped flask, followed by 5 mL of DMF. HATU (0.85 g, 2.2 mmol) and aniline (0.21 g, 2.0 mmol) were added sequentially. The mixture was stirred at room temperature for 30 min, and then DIPEA (0.66 g, 5.1 mmol) was slowly added dropwise. The reaction mixture was heated to 55 °C and stirred for 1 h. The reaction was quenched with 20 mL of water at room temperature. The reaction mixture was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined and washed once with 60 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered off the desiccant, and concentrated under reduced pressure to give 0.40 g of white solid intermediate 8, yield 62%. ESI-MS (m / z): 216.4 [M-Boc+H] + (calcd..for C 13 H 15 Preparation of N2O,315.4)(4)N-phenyl-2-(piperidin-4-yl)acetamide hydrochloride (9)

[0101] Intermediate 8 (0.40 g, 1.3 mmol) was added to a 25 mL round-bottom flask, followed by 2 mL of ethyl acetate. 0.95 mL of 2 M ethyl hydrochloride solution was added dropwise, and the reaction mixture was stirred at room temperature for 3 h. The mixture was then filtered and dried to obtain 0.30 g of white solid intermediate 9, with a yield of 95%.

[0102] (5) Preparation of target compound A02

[0103] To a 50 mL thick-walled, pressure-resistant reaction flask equipped with a magnetic stirrer, intermediate 9 (0.30 g, 1.2 mmol), icofol intermediate 1 (0.20 g, 0.8 mmol), magnesium tert-butoxide (0.20 g, 1.2 mmol), and 3 mL of anhydrous acetonitrile were added sequentially. The reaction mixture was stirred in an oil bath at 100 °C for 6 h. The mixture was cooled to room temperature and quenched with 20 mL of water. The reaction mixture was extracted with dichloromethane (20 mL × 3), and the organic layers were combined and washed once with 60 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography at 200–300 μM (eluent: petroleum ether / ethyl acetate, 3 / 1–1 / 1, V / V) to give 0.32 g of white solid A02, yield 85%. mp192.5~193.8℃; ESI-HRMS(m / z): 490.2045[M+Na] + (calcd.for C 25 H 27 F2N5O 2, 467.2154) 1H-NMR (400MHz, CD3OD) δ8.29(s,1H),7.73(s,1H),7.58-7.52(m,2H),7.42(td,J=9.0,6.6Hz,1H),7.32-7.26(m,2H),7.10-7.04(m,1H),6. 91-6.79(m,2H),5.83(s,1H),4.99-4.95(m,2H),3.22(q,J=7.0Hz,1H),3.11-2.92(m,4H),2.62-2.39(m,4H),0.88(dd,J=7.1,1.4Hz,3H). 13 C-NMR(101MHz,CD3OD)δ166.14,163.97,161.39,157.54,156.03,149.93 ,144.45,138.67,130.36,130.30,130.26,130.20,128.36,125.22,125.1 8,123.61,119.82,116.52,110.66,110.48,103.74,103.46,103.20,78. 75,78.70,63.81,63.77,56.19,56.13,52.45,51.77,37.19,29.76,6.24.

[0104] Example 3:

[0105] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl)piperidin-4-ylidene)-N-(4-methoxyphenyl)acetamide (A03)

[0106] The target compound A03 was prepared according to the synthetic method of compound A02, yielding 0.25 g of white solid, with a yield of 72.3%. mp 192.3–193.6 °C; ESI-MS (m / z): 498.2 [M+H] + (calcd.for C 26 H 29 F2N5O3, 497.5) 1H-NMR(400MHz,CD3OD)δ8.29(s,1H),7.73(s,1H),7.49-7.44(m,2H),7.43-7.38(m,1H),6.91-6.78(m,4H),5.80(s,1H ),4.96(s,2H),3.76(s,3H),3.21(q,J=7.0Hz,1H),3.11-2.89(m,4H),2.61-2.37(m,4H),0.87(dd,J=6.8,1.5Hz,3H). 13 C-NMR (101MHz, CD3OD) δ165.95,163.96,163.84,161.50,161.38,160.09,157.65,157.53,15 6.42,155.47,149.94,144.45,131.63,130.36,130.30,130.27,130.21,125.21,125.18,125. 08,125.05,121.57,116.52,113.57,110.70,110.67,110.49,110.46,103.75,103.50,103.47,103.21,78.73,78.68,63.82,63.78,56.19,56.13,54.47,52.44,51.78,37.18,29.75,6.28.

[0107] Example 4:

[0108] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)but-2-yl)piperidin-4-ylidene)-N-(4-methylphenyl)acetamide (A04)

[0109] The compound A04 was prepared according to the synthetic method of compound A02, yielding 0.31 g of a white solid, with a yield of 83.5%. mp 192.1–193.4 °C; ESI-HRMS (m / z): 504.2191 [M+Na] + (calcd.for C 26 H 29 F2N5O2, 481.23O2) 1H-NMR (400MHz, CD3OD) δ8.29(s,1H),7.73(s,1H),7.45-7.38(m,3H),7.10(d,J=8.2Hz,2H),6.87(ddd,J=11.8,8.8,2.6Hz,1H),6.80(td,J=8. 4,2.6Hz,1H),5.81(s,1H),4.96(s,2H),3.21(q,J=7.0Hz,1H),3.10-2. 90(m,4H),2.61-2.38(m,4H),2.28(s,3H),0.87(dd,J=7.0,1.4Hz,3H). 13 C-NMR (101MHz, CD3OD) δ166.05,161.50,161.38,159.98,157.65,157.53,155.69,14 9.94,144.45,136.05,133.34,130.36,130.30,130.27,130.21,128.83,125.21,125. 17,125.05,119.92,116.58,110.70,110.67,110.49,110.46,103.75,103.49,103.21,78.74,78.68,63.82,63.78,56.19,56.13,52.44,51.78,37.18,29.75,19.52,6.27.

[0110] Example 5:

[0111] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)-N-(4-fluorophenyl)acetamide (A05)

[0112] The target compound A05 was prepared according to the synthetic method of compound A02, yielding 0.25 g of white solid, with a yield of 78.2%. mp 194.2–195.1 °C; ESI-MS (m / z): 485.6 [M] + (calcd.for C 25 H 26 F3N5O4,485.5) 1H-NMR(400MHz,CD3OD)δ8.29(s,1H),7.73(s,1H),7.58-7.54(m,2H),7.45-7.39(m,1H),7.05-7.00(m,2H),6.90-6.79(m ,2H),5.81(s,1H),4.97(s,2H),3.22(d,J=7.1Hz,1H),3.08-2.93(m,4H),2.60-2.39(m,4H),0.88(dd,J=7.1,1.5Hz,3H). 13 C-NMR(101MHz,CD3OD)δ166.00,163.97,163.85,161.51,161.38,160.38,160.09,159.97,157.97 ,157.53,156.19,149.95,144.45,134.92,134.89,130.36,130.30,130.27,130.21,125.21,125.1 7,125.08,125.04,121.63,121.55,116.33,114.92,114.70,110.70,110.67,110.50,110.46,103.76,103.50,103.21,78.76,78.70,63.81,63.77,56.19,56.13,52.43,51.76,37.19,29.77,6.26.

[0113] Example 6:

[0114] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)-N-(4-chlorophenyl)acetamide (A06)

[0115] The target compound A06 was prepared according to the synthetic method of compound A02, yielding 0.23 g of white solid, with a yield of 81.5%. mp 194.0–194.6 °C; ESI-MS (m / z): 502.1 [M+H] + (calcd.for C 25 H 26 ClF2N5O2,501.96) 1H-NMR(400MHz,CD3OD)δ8.29(s,1H),7.73(s,1H),7.59-7.55(m,2H),7.42(t d,J=9.0,6.6Hz,1H),7.29-7.26(m,2H),6.88(ddd,J=11.8,8.8,2.6Hz,1H), 6.81(td,J=8.4,2.6Hz,1H),5.81(s,1H),4.97(d,J=1.2Hz,2H),3.21(t,J=7 .0Hz,1H),3.08-2.92(m,4H),2.61-2.39(m,4H),0.87(dd,J=7.1,1.4Hz,3H). 13 C-NMR (101MHz, CD3OD) δ166.02,163.97,163.84,161.50,160.09,159.97,157.64,156. 60,149.94,144.45,137.61,130.35,130.29,130.26,130.20,128.33,125.21,125.17,1 25.08, 125.04, 121.01, 116.29, 110.70, 110.67, 110.50, 110.46, 103.76, 103.50, 103.47, 103.22, 78.76, 78.71, 63.80, 63.76, 56.19, 56.13, 52.43, 51.76, 37.21, 29.78, 6.26.

[0116] Example 7:

[0117] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)-N-(4-bromophenyl)acetamide (A07)

[0118] The target compound A07 was prepared according to the synthetic method of compound A02, yielding 0.22 g of white solid, with a yield of 76.9%. mp 192.3–193.1 °C; ESI-HRMS (m / z): 546.1324 [M+H] + (calcd.ForC 25 H 26 BrF2N5O2, 545.1277) 1H-NMR(400MHz,CD3OD)δ8.29(s,1H),7.73(s,1H),7.54-7.49(m,2H),7.44-7.38(m,3H),6.90-6.78(m,2H),5.8 1(s,1H),4.97(s,2H),3.21(t,J=7.0Hz,1H),3.08-2.92(m,4H),2.61-2.39(m,4H),0.87(dd,J=7.1,1.4Hz,3H). 13 C-NMR (101MHz, CD3OD) δ166.02,163.97,163.85,161.51,161.39,160.09,157.53,156.65 ,149.94,144.45,138.09,131.34,130.35,130.29,130.26,130.20,125.21,125.17,125.0 8,125.04,121.32,116.30,115.79,110.70,110.67,110.49,110.46,103.75,103.50,103.47,103.21,78.77,78.71,63.80,63.76,56.19,56.13,52.42,51.76,37.21,29.78,6.26.

[0119] Example 8:

[0120] Preparation of methyl 4-(2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene))acetamido)benzoate (A08)

[0121] The target compound A08 was prepared according to the synthetic method of compound A02, yielding 0.27 g of a white solid, with a yield of 79.6%. mp 193.5–194.2 °C; ESI-HRMS: 548.2116 [M+Na] + (m / z)(calcd.forC 27 H 29 F2N5O4, 525.2188), 1H-NMR (400MHz, CD3OD) δ8.29 (s, 1H), 7.97-7.92 (m, 2H), 7.74-7.68 (m, 3H), 7.41 (td, J = 9.0, 6.6Hz, 1H), 6.91-6.78 (m, 2H), 5. 85(s,1H),4.97(s,2H),3.87(s,3H),3.22(q,J=7.0Hz,1H),3.15-2.90(m,4H),2.64-2.40(m,4H),0.87(dd,J=7.0,1.3Hz,3H). 13 C-NMR(101MHz,CD3OD)δ166.83,166.11,163.84,161.50,161.38,160.08,159.96 ,157.40,149.95,144.45,143.51,130.35,130.27,130.20,130.12,125.18,125. 05,124.63,118.65,116.26,110.70,110.67,110.49,103.76,103.47,103.22,78.78,78.72,63.78,63.74,56.19,56.13,52.41,51.77,51.06,37.25,29.80,6.25.

[0122] Example 9:

[0123] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)-N-hydroxyacetamide (A15)

[0124] To a 50 mL thick-walled, pressure-resistant reaction flask equipped with a magnetic stirrer, intermediate 10 (0.20 g, 1.2 mmol), icofol intermediate 1 (0.20 g, 0.8 mmol), magnesium tert-butoxide (0.20 g, 1.2 mmol), and 3 mL of anhydrous acetonitrile were added sequentially. The reaction mixture was stirred in an oil bath at 100 °C for 6 h. The mixture was cooled to room temperature and quenched with 20 mL of water. The reaction mixture was extracted with dichloromethane (20 mL × 3), and the organic layers were combined and washed once with 60 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography at 200–300 μM (eluent: petroleum ether / ethyl acetate, 75 / 25, V / V) to obtain intermediate 11, a colorless oily substance, which could be used directly in the next reaction without further purification.

[0125] Intermediate 11 (0.5 g, 1.2 mmol), hydroxylamine hydrochloride (2.5 g, 36 mmol), potassium hydroxide (2.0 g), and methanol (20 mL) were added sequentially to a 25 mL pear-shaped flask. The mixture was reacted at 65 °C for 10 h, concentrated under reduced pressure, and the residue was the crude product. This crude product was purified by silica gel column chromatography at 200–300 μM (eluent: dichloromethane / methanol, 97:3, V / V) to give a white solid A15, in a yield of 0.2 g. mp 133.7–134.9 °C; ESI-HRMS (m / z): 406.1655 [M+Na] + (calcd.for C 19 H 23 F2N5O3, 406.1769:). 1 H-NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.69(s,1H),8.31(s,1H),7.67(s,1 H),7.33(td,J=9.1,6.8Hz,1H),7.11(ddd,J=11.9,9.0,2.6Hz,1H),6.91(td ,J=8.5,2.6Hz,1H),5.50(s,1H),5.43(s,1H),4.85(q,J=14.6Hz,2H),3.13( q,J=6.9Hz,1H),3.05–2.75(m,4H),2.49–2.18(m,4H),0.74(d,J=6.8Hz,3H).

[0126] Example 10:

[0127] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)acetylhydrazine (A16)

[0128] Intermediate 11 (0.25 g, 0.6 mmol), hydrazine hydrate (0.1 g, 1.4 mmol), and 20 mL of methanol were added sequentially to a 25 mL pear-shaped flask. The mixture was reacted at 65 °C for 10 h, concentrated under reduced pressure, and the residue was the crude product. This crude product was purified by silica gel column chromatography at 200–300 μM (eluent: dichloromethane / methanol, 97:3, V / V) to give a white solid A16, in a yield of 0.16 g. mp 144.2–146.1 °C; ESI-HRMS (m / z): 429.1813 [M+Na] + (calcd.for C 19 H 24 F2N6O2,429.1929). 1H-NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.27(s,1H),7.65(s,1H),7.31(td,J=9.0,6.7Hz,1H),7. 10(ddd,J=12.0,9.1,2.6Hz,1H),6.90(td,J=8.5,2.6Hz,1H),5.49(s,1H),5.47(s,1H),4.77(s, 2H),4.17(s,2H),3.25(d,J=16.2Hz,1H),3.15(q,J=6.9Hz,1H),3.11–2.88(m,2H),2.72(s,2H), 2.37(ddd,J=11.6,8.7,4.2Hz,1H),2.03–1.94(m,1H),1.74–1.33(m,1H),0.77(d,J=6.8Hz,3H).

[0129] Example 11:

[0130] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)-N'-(2-hydroxybenzyl)acetylhydrazine (A17)

[0131] The target compound A16 (0.4 g, 1 mmol), salicylaldehyde (0.15 g, 1.2 mmol), and 10 mL of methanol were added sequentially to a 25 mL pear-shaped flask. The mixture was reacted at 65 °C for 12 h, concentrated under reduced pressure, and the residue was the crude product. This crude product was purified by silica gel column chromatography at 200–300 μm (eluent: dichloromethane / methanol, 96 / 4, V / V) to give a white solid A17, with a yield of 0.15 g. mp 168.6–170.1 °C; ESI-HRMS (m / z): 511.2263 (calcd. for C 26 H 28 F2N6O3, 511.2191). 1 H-NMR(400MHz,DMSO-d6)δ11.66(s,1H),11.35–11.05(m,1H),8.41–8.22(m, 2H),7.74–7.38(m,2H),7.38–7.17(m,2H),7.14–7.05(m,1H),6.97–6.79(m, 3H),5.57(s,1H),5.49(s,1H),4.78(d,J=5.2Hz,2H),3.29–2.83(m,4H),2.7 3–2.51(m,1H),2.47–1.87(m,3H),1.82–1.57(m,1H),0.77(d,J=7.1Hz,3H).

[0132] Example 12:

[0133] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)acetic acid (A26)

[0134] To a 25 mL pear-shaped flask, add target compound A16 (0.4 g, 1 mmol), 5 mL of water, and 20 mL of methanol sequentially. After thorough mixing, add lithium hydroxide monohydrate (0.629 g, 15 mmol). React at 40 °C for 2 h. Concentrate under reduced pressure to remove methanol. Adjust the pH to neutral with hydrochloric acid. Extract with n-butanol (5 mL × 3), retaining the organic phase. Dry with anhydrous sodium sulfate, filter off the drying agent, and concentrate under reduced pressure to obtain crude A26. Purify by silica gel column chromatography at 200–300 μM (eluent: dichloromethane / methanol, 96 / 4, v / v) to obtain white solid A26, yielding 0.34 g. mp 118.3–120.2 °C; ESI-MS (m / z): 392.1 (calcd.forC 26 H 28 F2N6O3, 392.1).

[0135] Example 13:

[0136] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)-(Se-phenyl)selenoacetate (A35)

[0137] Under nitrogen protection, add A26 (1g, 2.54mmol), isobutyl chloroformate (0.35g, 2.67mmol), N-methylmorpholine (0.3g, 2.67mmol), and 10mL of ethyl acetate to a 50mL reaction flask, and react at 0℃ for 0.5h. The reaction solution is then ready for use.

[0138] Under nitrogen protection, diphenyldiselenes (0.48 g, 1.53 mmol), sodium borohydride (0.12 g, 3.05 mmol), and 10 mL of ethyl acetate were added to another 50 mL reaction flask. The mixture was heated to 50 °C and stirred for 1 h. Then, 0.50 mL of glacial acetic acid was added, and the reaction was continued for another 1 h. The reaction solution was reserved. The two reaction solutions were mixed and reacted at room temperature for 8 h. 10 mL of water was added to the reaction mixture, the organic layer was separated, and washed with saturated brine (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15, v / v) to give the target compound A35 as a yellow oil, with a yield of 0.75 g and a yield of 55%. ESI-MS (m / z): 533.13 [M+H] + (calcd.for C 25 H 26 F2N4O2Se, 532.12). 1 H-NMR (400MHz, Methanol-d4) δ8.27(s,1H),7.72(s,1H),7.56–7.44(m,2H),7.42–7.35(m,4H),6.93–6.75(m,2H),6.13(d,J=1.1Hz,1H),4.95(d ,J=1.0Hz,2H),3.23(q,J=7.0Hz,1H),3.10–2.85(m,4H),2.58(ddt,J=27.7,10.5,5.3Hz,2H),2.36(t,J=5.6Hz,2H),0.86(dd,J=7.1,1.3Hz,3H).

[0139] Example 14:

[0140] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)-(Se-(4-trifluoromethoxy)phenyl)selenoacetate (A36)

[0141] Under nitrogen protection, add A26 (1g, 2.54mmol), isobutyl chloroformate (0.35g, 2.67mmol), N-methylmorpholine (0.3g, 2.67mmol), and 10mL of ethyl acetate to a 50mL reaction flask, and react at 0℃ for 0.5h. The reaction solution is then ready for use.

[0142] Under nitrogen protection, bis(4-trifluoromethoxy)phenyldiselenes (0.73 g, 1.53 mmol), sodium borohydride (0.12 g, 3.05 mmol), and 10 mL of ethyl acetate were added to another 50 mL reaction flask. The mixture was heated to 50 °C and stirred for 1 h. Then, 0.50 mL of glacial acetic acid was added, and the reaction was continued for another 1 h. The reaction solution was reserved. The two reaction solutions were mixed and reacted at room temperature for 8 h. 10 mL of water was added to the reaction mixture, the organic layer was separated, and washed with saturated brine (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15, v / v) to give the target compound A36 as a yellow oil, with a yield of 0.95 g and a yield of 65%. ESI-MS (m / z): 617.1 [M+H] + (calcd.forC 26 H 25 F5N4O3Se, 616.1). 1 H-NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.68(s,1H),7.65–7.58(m,2H),7.42(dt,J=7 .7,1.1Hz,2H),7.33(td,J=9.1,6.8Hz,1H),7.11(ddd,J=11.9,9.1,2.6Hz,1H),6.91( td,J=8.5,2.6Hz,1H),6.28(s,1H),4.93–4.79(m,2H),3.17(q,J=6.9Hz,1H),3.02–2. 74(m,4H),2.57(dd,J=10.8,5.8Hz,2H),2.37(t,J=5.7Hz,2H),0.74(d,J=6.9Hz,3H).

[0143] Example 15:

[0144] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)-(Se-methyl)selenoacetate (A37)

[0145] Under nitrogen protection, add A26 (1g, 2.54mmol), isobutyl chloroformate (0.35g, 2.67mmol), N-methylmorpholine (0.3g, 2.67mmol), and 10mL of ethyl acetate to a 50mL reaction flask, and react at 0℃ for 0.5h. The reaction solution is then ready for use.

[0146] Under nitrogen protection, dimethyl diselenide (0.29 g, 1.53 mmol), sodium borohydride (0.12 g, 3.05 mmol), and 10 mL of ethyl acetate were added to another 50 mL reaction flask. The mixture was heated to 50 °C and stirred for 1 h. Then, 0.50 mL of glacial acetic acid was added, and the reaction was continued for another 1 h. The reaction solution was reserved. The two reaction solutions were mixed and reacted at room temperature for 8 h. 10 mL of water was added to the reaction mixture, the organic layer was separated, and washed with saturated brine (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15, v / v) to obtain the target compound A37 as a yellow oil, with a yield of 0.75 g and a yield of 63%. ESI-MS (m / z): 671.1 [M+H] + (calcd.for C 20 H 24 F2N4O2Se, 670.1).

[0147] Example 16:

[0148] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)-N-(4-fluorophenyl)acetamide (BO2)

[0149] BO4 (0.25 g, 0.63 mmol), CDI (0.15 g, 0.9 mmol), and 10 mL of dichloromethane were added to a 25 mL flask. The mixture was reacted for 30 min, followed by the addition of p-chloroaniline (0.1 g, 0.9 mmol). The mixture was stirred at room temperature for 4 h, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 97 / 3, v / v) to obtain BO2 as a pale yellow oil, with a yield of 0.17 g (56%). ESI-HRMS (m / z): 510.2096 [M+Na] + (calcd.for C 25 H 28 F3N5O2,510.2195). 1H-NMR(400MHz, Methanol-d4)δ8.29(s,1H),7.73(s,1H),7.60–7.50(m,2H),7.42(td,J=9.0,6.6Hz,1H),7.08–6.98(m,2H),6 .87(ddd,J=11.9,8.8,2.6Hz,1H),6.81(td,J=8.4,2.6Hz,1H),4.89(d,J=3.5Hz,2H),3.12(q,J=7.0Hz,1H),3.07–3.00(m,1H ),2.73(dt,J=11.2,2.1Hz,1H),2.63(td,J=11.4,2.4Hz,1H),2.29(d,J=7.0Hz,2H),2.20(td,J=11.6,2.4Hz,1H),1.85–1.72 (m,2H),1.68(dt,J=12.8,3.1Hz,1H),1.47(qd,J=12.2,4.3Hz,1H),1.36(td,J=11.6,8.0Hz,1H),0.91(dd,J=7.1,1.8Hz,3H).

[0150] Example 17:

[0151] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)-N-(4-chlorophenyl)acetamide (BO3)

[0152] BO4 (0.25 g, 0.63 mmol), CDI (0.15 g, 0.9 mmol), and 10 mL of dichloromethane were added to a 25 mL flask. The mixture was reacted for 30 min, followed by the addition of p-chloroaniline (0.11 g, 0.9 mmol). The mixture was stirred at room temperature for 4 h, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 97 / 3, v / v) to obtain BO2 as a yellow oily substance, with a yield of 0.21 g (67%). ESI-HRMS (m / z): 526.1801 [M+Na] + (calcd.for C 25 H 28 ClF2N5O2, 526.1900). 1H-NMR(400MHz, Methanol-d4)δ8.28(s,1H),7.73(s,1H),7.60–7.50(m,2H),7.42(td,J=9.0,6.6Hz,1H),7.32–7.22(m,2 H),6.87(ddd,J=11.9,8.8,2.6Hz,1H),6.80(td,J=8.6,2.8Hz,1H),4.88(d,J=3.3Hz,2H),3.11(q,J=7.0Hz,1H),3.07–3. 00(m,1H),2.78–2.68(m,1H),2.62(td,J=11.4,2.4Hz,1H),2.29(d,J=7.0Hz,2H),2.20(td,J=11.6,2.4Hz,1H),1.86–1.7 2(m,2H),1.68(d,J=12.5Hz,1H),1.47(qd,J=12.2,4.3Hz,1H),1.35(td,J=11.8,8.1Hz,1H),0.91(dd,J=7.0,1.8Hz,3H).

[0153] Example 18:

[0154] Preparation of methyl 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)acetate (BO5)

[0155] Add 2 g (8 mmol) of icofonazole intermediate 1, 1.9 g (10 mmol) of 4-piperidine acetate methyl hydrochloride, 1.7 g (16 mmol) of magnesium tert-butoxide, and 18 mL of anhydrous acetonitrile to a pressure-resistant reaction flask. Seal the flask at 100 °C and react for 10 h. Cool to room temperature, adjust pH to neutral, add 20 mL of water, and extract the reaction solution with dichloromethane (30 mL × 3). Combine the organic phases and wash with saturated brine (30 mL × 2). Dry overnight with anhydrous sodium sulfate. After filtering off the desiccant, concentrate to dryness under reduced pressure. Purify the residue by column chromatography (PE:EA = 4:1) to obtain B05 as a colorless oil, yield 1.8 g, yield 53%, ESI-HRMS (m / z): 422.1822 (calcd..for C 21 H 28 F2N4O3, 422.2129).

[0156] Example 19:

[0157] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)acetic acid (BO4)

[0158] The target compound BO5 (0.4 g, 1 mmol), 5 mL of water, and 20 mL of methanol were added sequentially to a 50 mL pear-shaped flask. After thorough mixing, lithium hydroxide monohydrate (0.629 g, 15 mmol) was added, and the mixture was reacted at 40 °C for 2 h. The methanol was removed by concentration under reduced pressure, and the pH was adjusted to neutral by adding hydrochloric acid. The mixture was extracted with n-butanol (5 mL × 3), and the organic phase was retained. The organic phase was dried with anhydrous sodium sulfate, and the drying agent was filtered off. The crude product BO4 was concentrated under reduced pressure. The crude product BO4 was purified by silica gel column chromatography at 200–300 μM (eluent: dichloromethane / methanol, 96 / 4, V / V) to give a white solid A26, with a yield of 0.34 g. mp 118.3–120.2 °C; ESI-HRMS (m / z): 394.1832 (calcd. for C 26 H 28 F2N6O3, 394.1816).

[0159] Example 20:

[0160] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)-(Se-phenyl)selenoacetate (B11)

[0161] Under nitrogen protection, add BO4 (1g, 2.54mmol), isobutyl chloroformate (0.35g, 2.67mmol), N-methylmorpholine (0.3g, 2.67mmol), and 10mL of ethyl acetate to a 50mL reaction flask, and react at 0℃ for 0.5h. The reaction solution is then ready for use.

[0162] Under nitrogen protection, diphenyldiselenes (0.48 g, 1.53 mmol), sodium borohydride (0.12 g, 3.05 mmol), and 10 mL of ethyl acetate were added to another 50 mL reaction flask. The mixture was heated to 50 °C and stirred for 1 h. Then, 0.50 mL of glacial acetic acid was added, and the reaction was continued for another 1 h. The reaction solution was reserved. The two reaction solutions were mixed and reacted at room temperature for 8 h. 10 mL of water was added to the reaction mixture, the organic layer was separated, and washed with saturated brine (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15, v / v) to give the target compound B11 as a white solid, with a yield of 0.66 g and a yield of 69%. ESI-MS (m / z): 535.1 [M+H] +(calcd.for C 25 H 28 F2N4O2Se, 534.1).

[0163] Example 21:

[0164] Preparation of 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)-(Se-methyl)selenoacetate (B12)

[0165] Under nitrogen protection, add BO4 (1g, 2.54mmol), isobutyl chloroformate (0.35g, 2.67mmol), N-methylmorpholine (0.3g, 2.67mmol), and 10mL of ethyl acetate to a 50mL reaction flask, and react at 0℃ for 0.5h. The reaction solution is then ready for use.

[0166] Under nitrogen protection, dimethyl diselenide (0.29 g, 1.53 mmol), sodium borohydride (0.12 g, 3.05 mmol), and 10 mL of ethyl acetate were added to another 50 mL reaction flask. The mixture was heated to 50 °C and stirred for 1 h. Then, 0.50 mL of glacial acetic acid was added, and the reaction was continued for another 1 h. The reaction solution was reserved. The two reaction solutions were mixed and reacted at room temperature for 8 h. 10 mL of water was added to the reaction mixture, the organic layer was separated, and washed with saturated brine (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15, v / v) to give the target compound B12 as a white solid, with a yield of 0.68 g and a yield of 57%. ESI-MS (m / z): 473.1 [M+H] + (calcd.for C 20 H 26 F2N4O2Se, 472.1). 1H-NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.67(s,1H),7.32(td,J=9.0,6.8Hz,1H),7.10(d dd,J=12.0,9.1,2.6Hz,1H),6.90(td,J=8.5,2.6Hz,1H),5.46(s,1H),4.84–4.72(m,2H) ,3.06(q,J=4.9,3.9Hz,2H),2.64(dd,J=13.6,8.6Hz,3H),2.57–2.50(m,1H),2.17(s,3H ),2.08(dd,J=11.5,2.4Hz,1H),1.75–1.56(m,3H),1.43–1.21(m,2H),0.79–0.73(m,3H).

[0167] Example 22

[0168] Each tablet is prepared containing 100 mg of compound A5:

[0169]

[0170] The active ingredients, lactose, starch, and microcrystalline cellulose, are passed through a 100-mesh sieve and thoroughly mixed. A 2% aqueous solution of hydroxymethyl cellulose is added to the above mixed powder and mixed. The mixture is then passed through a 20-mesh sieve to form a soft mass. The resulting wet granules are dried at 45-55°C. Sodium carboxymethyl starch and magnesium stearate are added to the dried granules and compressed into tablets.

[0171] Example 23

[0172] The preparation of capsules containing 100 mg of compound A6 per capsule is as follows:

[0173]

[0174]

[0175] Example 24

[0176] Preparation of coating containing compound B12

[0177] Compound B12, 4g, potassium soap, 7.5g, camphor, 5g, distilled water added to 100ml.

[0178] Preparation method:

[0179] Dissolve camphor in a 95% (v / v) ethanol solution and set aside; heat potassium soap until it melts and set aside.

[0180] Compound B12 was added to a potassium soap and camphor ethanol solution with constant stirring, followed by the gradual addition of distilled water. After complete emulsification, distilled water was added to the final volume to obtain the final product.

[0181] Pharmacological studies of the product of this invention

[0182] The two-fold dilution method is one of the most common methods for screening the antifungal activity of drugs in vitro. Below, the antifungal activity of the ivermectin derivatives A and B according to the present invention was evaluated in vitro.

[0183] (1) Experimental materials

[0184] Comparison drugs: Miconazole (MIC), Efinaconzole (EFC), Fluconazole (FLC), Oteseconazole (OTC).

[0185] Test sample: the effluconazole derivative involved in this invention

[0186] The tested strains were: Candida albicans ATCC 10231 (C. alb.), Cryptococcus neoformans ATCC 32609 (C. neo.), Microsporum gypseum (M. gyp.), Malassezia ATCC 43344 (M. fur.), Trichophyton mentagrophytes ATCC 18748 (T. men.), Trichophyton interdigitale ATCC 9533 (T. int.), and Trichophyton rubrum ATCC 28188 (T. rub.).

[0187] (2) Measurement principle

[0188] The determination of the minimum inhibitory concentration (MIC) in vitro is based on the inhibitory effect of antimicrobial drugs on microbial growth in vitro. Microorganisms are cultured in different concentrations of antimicrobial drugs, and their growth is observed to determine the lowest inhibitory concentration of the drug.

[0189] (3) Experimental procedure

[0190] Before the experiment, dissolve the target compound in 0.5 mL DMSO, 0.5 mL Tween 80, and 4.0 mL distilled water, store in sterile sample vials, seal with sealing film, and keep at 4°C. Add cocci to sterile physiological saline, shake well, count cells using the hemocytometer method, and serially dilute with RPMI-1640 medium, keeping at 4°C. Add filamentous fungi to distilled water, shake and filter, then dilute with sterile physiological saline to achieve an absorbance of 0.3-0.5 at 540 nm. Serially dilute with RPMI-1640 medium and keep at 4°C.

[0191] YEPD culture medium preparation: Prepare according to the ratio of 1.2g yeast extract, 2.4g tryptone, 2.4g glucose, and 150mL distilled water. After preparation, put it into an autoclave for sterilization and use.

[0192] Preparation of RPMI-1640 liquid culture medium: Dissolve RPMI-1640 culture medium powder in 500ml of sterile distilled water, add 200mL of morpholine propanesulfonic acid solution and 100mL of sodium bicarbonate solution, adjust the pH to 7 with 1M mol sodium hydroxide solution, make up to volume in a 1000mL volumetric flask, filter, and store in a refrigerator at 4℃.

[0193] Preparation of Malassezia spore culture medium: Dissolve 60g of Malassezia spore liquid culture medium base in 100ml of sterile distilled water, add 2.5g of glyceryl monooleate and 10g of Tween 40, and sterilize in an autoclave before use.

[0194] Sabouraud dextrose solid medium preparation: Prepare according to the ratio of 5g sodium chloride, 10g peptone, 40g glucose and 1000mL distilled water. After preparation, put it into an autoclave for sterilization and use.

[0195] (4) Determination of minimum inhibitory concentration (MIC) in vitro

[0196] The microdilution method was used in 96-well plates. 100 μL of RPMI-1640 medium was added to the growth control and experimental wells, and 200 μL of medium was added to the blank control wells. For the first well, 180 μL of medium and 20 μL of the drug solution were added, mixed thoroughly, and then 100 μL was added sequentially to the next 10 wells. No drug solution was added to the last two wells. Except for the blank control wells, 100 μL of diluted bacterial suspension was added to each well. The treated 96-well plates were placed in an incubator and maintained at 35°C. MIC values ​​were measured after 24 hours of culture for *Candida albicans*, *Cryptococcus neoformans*, *Microsporum gypseum*, and *Trichophyton rubrum*; after 48 hours of culture for *Trichophyton interdigitale*; after 72 hours of culture for *Malassezia*; and after 4 days of culture for *Trichophyton mentagrophytes*. Each experiment was performed three times independently, with an experimental error not exceeding 10%.

[0197] Table 1. Results of in vitro antifungal activity (MIC) determination of some target compounds.

[0198]

[0199]

[0200]

[0201] (5) Determination of minimum bactericidal concentration (MFC) in vitro

[0202] Using the microdilution method in a 96-well plate, 100 μL of RPMI-1640 medium was added to the growth control wells and experimental wells, and 200 μL of medium was added to the blank control wells. 180 μL was added to well 1, 100 μL to wells 2-11, and 200 μL to well 12. Then, 20 μL of the drug stock solution was added to well 1, mixed well, and 100 μL was transferred to well 2. Another 100 μL was added to well 2 and transferred to well 3, and so on, up to well 10. The medium was then discarded. Finally, 1×10⁻⁶ ppm of the drug stock solution was added to wells 1-11. 3 ~5×10 3 A bacterial suspension of cuf / mL was incubated in 96-well plates at 35°C for 48 hours. 100 mL of the corresponding fungal-free medium from each well was transferred to a PDA plate and incubated at 35°C for 24 hours. MFCs correspond to a concentration of less than 5 colonies on the SDA plate. All experiments were performed at least three times independently, with an experimental error not exceeding 10%.

[0203] Table 2 shows the results of in vitro fungicidal (MFC) activity assays for some target compounds.

[0204]

[0205]

[0206] In vivo experiments:

[0207] Nude mice were inoculated with a diluted pure culture of Candida albicans on their skin surface for three consecutive days, once a day. Erythema or scaly lesions appeared on the inoculation sites of the nude mice. A case-comparative treatment experiment was conducted using a topical ointment containing B12 of this invention and a 2% clotrimazole ointment, applied three times a day (morning, noon, and evening). The topical ointment of this invention achieved a cure rate of 99%, with an average cure time of 7 days. The 2% clotrimazole ointment achieved a cure rate of 90%, with an average cure time of 10 days.

[0208] Group Dosage Medication time symptom cure rate control group 2% Clotrimazole Ointment Morning, noon, and evening / 3 times Itching from athlete's foot 90％ experimental group Compound B12 coating Morning, noon, and evening / 3 times Itching from athlete's foot 99％

[0209] In vivo experiments on mice showed that treating tinea pedis with 2% clotrimazole ointment and 2% ointment containing B12 of this invention resulted in an average cure time of 7 days. Statistical results showed that the 2% clotrimazole ointment achieved a cure rate of 90% with an average cure time of 10 days; the ointment containing B12 of this invention achieved a cure rate of 99% with an average cure time of 7 days. This indicates that the ointment of this invention has a better curative effect.

[0210] in conclusion:

[0211] This invention uses the clinically used azole antifungal drug iefluconazole as a lead structure. Based on its structure-activity relationship and molecular docking studies with the target enzyme CYP51, and applying the principle of bioisosteric drug design, the 4-methylenepiperidine in its structure is modified by introducing amides, esters, or selenoesters into the methylene group, or by reducing the methylene group to a methyl group before introducing amides, esters, or selenoesters. This increases the number of hydrogen bond acceptors and donors in the target molecule, thereby increasing the interaction between the target molecule and the amino acid residues of the target enzyme. Simultaneously, by increasing molecular polarity to improve its water solubility, a series of iefluconazole derivatives as shown in Formula I were designed. Using the synthetic methods provided in this invention (synthetic routes 1 to 6), and commercially available or readily available raw materials, the target compounds of this invention were successfully prepared. The in vitro antifungal activity of the designed target compounds was tested using a two-fold dilution method. The results showed that the preliminary in vitro antifungal activity of several target compounds was significantly better than that of the lead compound iefluconazole and other widely used azole antifungal drugs in clinical practice (such as clotrimazole, miconazole, fluconazole, and octaconazole). Furthermore, these compounds exhibited better water solubility, a broad antibacterial spectrum, high activity, and favorable pharmacokinetic properties, demonstrating potential for further development. Further research and development of the preferred compounds of this invention aims to obtain antifungal drugs suitable for clinical application, and to overcome the shortcomings of iefluconazole, such as poor water solubility, unsatisfactory pharmacokinetic properties, limitation to topical use, single dosage form, and narrow antibacterial spectrum.

Claims

1. An eloxonazole derivative, wherein the derivative is: 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-Triazol-1-yl)-2-butyl)piperidine-4-ylidene)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -Phenylacetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N- 4-Methoxyphenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -(4-Methylphenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -(4-Fluorophenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -(4-chlorophenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -(4-bromophenyl)acetamide; 4-(2-(1-((2R,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-Triazol-1-yl)-2-butyl)piperidin-4-ylidene)acetamido)methyl benzoate; 4-(2-(1-((2R,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-Triazol-1-yl)-2-butyl)piperidin-4-ylidene)acetamido)ethyl benzoate; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -(3-methoxyphenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -(3-Methylphenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -(3-Fluorophenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-Triazol-1-yl)-2-butyl)piperidine-4-methylene)- N -(3-chlorophenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- N -(3-bromophenyl)acetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene) -N -Hydroxyacetamide; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene) -N' -(2-hydroxybenzyl)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-methylene) -N' -(3-hydroxybenzyl)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-methylene) -N' -(4-hydroxybenzyl)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene) -N' -(2-Methylbenzyl)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene) -N' -(3-methylbenzyl)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene) -N' -(4-methylbenzyl)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene) -N' -(2-bromophenylmethylene)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene) -N' -(3-bromophenylmethylene)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene) -N' -(4-bromophenylmethylene)acetylhydrazine; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - methyl 1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylidene)acetate; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-Triazol-1-yl)-2-butyl)piperidin-4-ethylene)ethyl acetate; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-Triazol-1-yl)-2-butyl)piperidin-4-ylidene)phenyl acetate; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- O -(4-methoxyphenyl)acetic acid ester; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- O 4-(4-methylphenyl)acetic acid ester; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- O -(4-fluorophenyl)acetic acid ester; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- O -(4-chlorophenyl)acetic acid ester; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)- O 4-Bromophenyl)acetic acid ester; 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylide)-(Se-phenyl)selenoacetate; 2-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl)piperidin-4-ylide)-(Se-methyl)selenoacetate; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)piperidine-4-ylidene)-( Se -(4-trifluoromethoxy)phenyl)selenoacetate; 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)- N -(4-Fluorophenyl)acetamide 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)- N -(4-chlorophenyl)acetamide 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)- O 4-(methoxyphenyl)acetic acid ester 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)- O 4-Methylphenyl)acetic acid ester 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)- O 4-Fluorophenyl)acetate 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)- O 4-Chlorophenyl)acetate 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)- O 4-Bromophenyl)acetic acid ester 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)-( Se 1-phenyl)selenyl acetate 2-(1-((2 R ,3 R )-3-(2,4-difluorophenyl)-3-hydroxy-4-(1 H - 1,2,4-triazol-1-yl)-2-butyl)-4-piperidinyl)-( Se- Selenyl methyl acetate.

2. A drug with antifungal activity, characterized in that... It includes the effluconazole derivative as described in claim 1.

3. The method for preparing the eloxonazole derivative according to claim 1, characterized in that... The preparation method of this derivative includes the following steps: Synthesis method 1 of the target compound: by N Starting with Boc-4-piperidinone (2) and (2-amino-2-oxoethyl)phosphonate diethyl ester (3), the intermediate 2-(piperidin-4-yl)acetamide (4) was obtained by Wittig-Horner reaction and deprotection of Boc. (4) was then reacted with aniconazole intermediate (1) by alkylation to obtain the target compound A01. ； The structure of ivermectin intermediate (1) is as follows: The CA registration number is 127000-90-2; Method 2 for synthesizing the target compound: by N Starting with ethyl 2-diethoxyphosphonoethyl acetate (5) and 4-piperidinone (2), the product was obtained via Wittig-Horner reaction and ester hydrolysis. N -Boc-2-(piperidin-4-ylidene)acetic acid (7), (7) is reacted with various substituted anilines under HATU-DIPEA catalysis to obtain intermediate (8) or (9), (8) or (9) is then reacted with icofol intermediate (1) to obtain target compound A02-A14; ； Method 3 for synthesizing the target compound: Using ethyl 2-(piperidin-4-yl)ethyl acetate (10) and icorconazole intermediate (1) as raw materials, A28 is obtained by alkylation reaction. A28 is reacted with hydroxylamine hydrochloride or hydrazine hydrate to obtain target compound A15 or A16. Compound A16 is then reacted with various substituted benzaldehydes to form Schiff base to obtain target compounds A17-A25. ； Synthesis method 4 of the target compound: Using the previously prepared A28 as raw material, its free acid A26 is obtained by hydrolysis with lithium hydroxide. A26 undergoes esterification with various substituted phenols to obtain target compounds A29-A34. In the presence of isobutyl chloroformate, A26 undergoes Se-acylation with various alkyl diselenyl ethers or substituted phenyl diselenyl ethers under sodium borohydride catalysis to obtain target compounds A35-A37. ； Synthesis method 5 of the target compound: Starting with methyl 2-(piperidin-4-yl)acetate hydrochloride (12), BO5 was prepared by alkylation reaction with ivermectin intermediate (1). BO5 was hydrolyzed with lithium hydroxide to obtain its free acid BO4. BO4 was then subjected to amidation reaction with various substituted anilines under HATU catalysis to obtain... B02, B03, and B04 were esterified with various substituted phenols to obtain the target compounds B6-B10. ； Synthesis method 6 for the target compound: Using the previously prepared B04 as raw material, in the presence of isobutyl chloroformate, various alkyl diselenyl ethers or substituted phenyl diselenyl ethers undergo a Se-acylation reaction under sodium borohydride catalysis to obtain the target compounds B11-B13. 。 4. The use of the efconazole derivative of claim 1 in the preparation of a medicament for treating or preventing fungal infections.

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