CN114835688B

CN114835688B - Substituted 4-aryl imidazole-2-ketone derivative, preparation method and medical application thereof

Info

Publication number: CN114835688B
Application number: CN202210105143.3A
Authority: CN
Inventors: 吴俊军; 周世强; 肖瑛; 段振芳; 吕洋; 周鹏; 洪泽新; 陆银锁
Original assignee: Shenzhen Salubris Pharmaceuticals Co Ltd
Current assignee: Shenzhen Salubris Pharmaceuticals Co Ltd
Priority date: 2021-02-02
Filing date: 2022-01-28
Publication date: 2024-08-06
Anticipated expiration: 2042-01-28
Also published as: CN114835688A

Abstract

The invention belongs to the technical field of chemical medicaments, and provides a series of substituted 4-aryl imidazole-2-ketone derivatives, a preparation method and medical application thereof, wherein the derivatives are preferably used as vasopressin V1a/V2 receptor antagonists.

Description

Substituted 4-aryl imidazole-2-ketone derivative, preparation method and medical application thereof

Technical Field

Background

AVP (arginine vasopressin) is synthesized mainly by neurons from the supraoptic and paravisual nuclei of the hypothalamus, projected through the hypothalamic-pituitary axis and stored in the posterior pituitary, and its physiological secretion regulating factors include plasma crystal osmotic pressure, peripheral circulating blood volume and arterial blood pressure. Normally, the water reabsorption of the kidneys is stimulated to maintain the integrated water balance, and is the most important hormone for regulating the water balance of the human body. The physiological range of human plasma AVP is 0.3-80ng/ml, and half-life is 5-20min. Most AVPs are first metabolized in the liver, kidneys by disulfide bond reduction, peptide chain cleavage, with only a small amount of finished AVPs being cleared directly by the kidneys. Arginine Vasopressin (AVP) antagonists are useful for reducing accumulation of kidney water, increasing sodium concentration in the body, and improving hyponatremia without concomitant sodium excretion during urination.

At present, only the V1/V2 receptor antagonist of the type 1 is marketed globally, and the colpitan is marketed only in the United states and can only be used intravenously, and is mainly used for treating hyponatremia with normal blood volume (usually accompanied by patients suffering from abnormal secretion syndrome of antidiuretic hormone, hypothyroidism, adrenal hypofunction or pulmonary diseases) hospitalized patients, and has serious drug interaction and adverse injection reaction and can only be used for 4 days. There is thus still a need to design and synthesize V1a/V2 receptor antagonists that address the shortcomings and drawbacks of the prior art in therapeutic regimens.

Disclosure of Invention

In view of the problems of the prior art, the present invention provides a series of substituted 4-arylimidazol-2-one derivatives, a process for their preparation and their use in medicine. In particular, the invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein all variables are as defined herein.

The invention is realized by the following technical scheme, the compound of the formula (I) or pharmaceutically acceptable salt thereof,

Wherein R ^1A、R^1B and R ₂ are independently selected from hydrogen, cyano, halogen, alkyl or haloalkyl, alkoxy or haloalkoxy, X, Y and Z are independently selected from CH, N.

As a preferred embodiment of the present invention, a compound selected from the group consisting of the compounds of formulae (Ia), (Ib), (Ic) or a pharmaceutically acceptable salt thereof:

As a preferred embodiment of the present invention, the alkyl group is selected from the group consisting of C _1-4 alkyl groups, and the C _1-4 alkyl group is further selected from the group consisting of methane, ethane, propane, isopropyl, n-butane, isobutane, sec-butane, tert-butane; the alkoxy is selected from the group consisting of C _1-4 alkoxy, and the C _1-4 alkoxy is further selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

As a preferred embodiment of the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine.

As a preferred embodiment of the present invention, R ^1A、R^1B and R ₂ are independently selected from hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

As a preferred embodiment of the present invention, the following compounds are selected:

As a preferred technical scheme of the invention, the pharmaceutically acceptable salt refers to the preparation of a compound and a pharmaceutically acceptable acid or base.

As a preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof has one or more hydrogen atoms replaced with deuterium isotopes.

Specifically, it is preferable to select a compound selected from the group consisting of,

The invention further provides application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines, in particular, application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for treating and/or preventing vasopressin V1a/V2 antagonism related diseases is preferred.

Further, the diseases include hyponatremia and the like.

The invention further provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

The present invention further provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim, comprising:

(1) Allowing a compound of formula (II):

And (3) with Coupling in the presence of a copper catalyst and an amine base to obtain a target compound;

Or (2) obtaining the compound V through the following reaction route, and further forming a triazole ring to obtain the target compound, wherein the synthetic route is as follows:

Wherein R ^1A、R^1B and R ₂ are independently selected from hydrogen, cyano, halogen, alkyl, alkoxy, or haloalkoxy.

Further, the present invention provides novel intermediate compounds for use in the synthesis of target compounds, said intermediate compounds being selected from the group consisting of compounds represented by formulas (II), (III), (IV), (V):

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the invention wherein the parent compound is modified by salt formation with an acid or by salt formation with a base.

Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

Certain compounds of the invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.

The atoms of the compound molecule are isotopes, and the effects of prolonging half-life, reducing clearance rate, enhancing metabolic stability, improving in vivo activity and the like can be achieved through isotope derivatization. And, an embodiment is included in which at least one atom is substituted with an atom having the same atomic number (proton number) and different mass numbers (proton and neutron sum). Examples of isotopes included in the compounds of the invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, each of which includes ²H、³H、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl., particularly, radioisotopes such as 3H or 14C that emit radiation as they decay may be used for the topographic examination of pharmaceutical formulations or compounds in vivo. Stable isotopes neither decay or change with their amounts nor are radioactive, and therefore they can be safely used. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes may be converted according to general methods by substituting reagents used in the synthesis with reagents comprising the corresponding isotopes.

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as deuterium (² H), iodine-125 (¹²⁵ I) or C-14 (¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. Further, one or more hydrogen atoms of the compound are substituted by isotope deuterium (² H), and the compound has the effects of prolonging half-life, reducing clearance rate, enhancing metabolic stability, improving in vivo activity and the like after deuteration. The method of preparing the isotopic derivatives generally comprises: phase transfer catalysis method. For example, a preferred deuteration method employs a phase transfer catalyst (e.g., tetraalkylammonium salt, NBu ₄HSO₄). The exchange of methylene protons of diphenylmethane compounds using a phase transfer catalyst results in the introduction of higher deuterium than reduction with deuterated silanes (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with lewis acids such as aluminum trichloride using sodium deuterated borate.

The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active agents of the present invention, which does not interfere with the biological activity of the active agents and which does not have toxic or side effects to the host or patient, representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference may be made to remington: THE SCIENCE ANDPRACTICE ofPharmacy,21stEd, lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term "excipient" generally refers to the carrier, diluent, and/or medium required to make an effective pharmaceutical composition.

For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energybarrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (protontautomer) (also known as proton transfer tautomer (prototropictautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valence tautomer) include interconversions by recombination of some of the bond-forming electrons. Keto-enol tautomerism. Another example of tautomerism is phenol-ketone tautomerism. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

Optically active (R) -and (S) -isomers, as well as D and L isomers, can be prepared by chiral syntheses or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods well known in the art, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The beneficial effects of the invention compared with the prior art include:

The compounds of the present invention are less inhibited by multiple subtypes of CYP enzymes, and liver enzymes are expected to have less interference with drug metabolism of the compounds of the present invention relative to prior art compounds.

Detailed Description

The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.

The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 ^-6 (ppm). NMR was performed using a BrukerAVANCE-III magnetonucleator with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃) and an internal standard of Tetramethylsilane (TMS).

The MS was determined by ISQ EC mass spectrometry (manufacturer: thermo, model: ISQ EC).

High Performance Liquid Chromatography (HPLC) analysis used a Thermo U3000 HPLC DAD high performance liquid chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash rf+ LUMEN (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses a smoke table silver dragon HSGF ₂₅₄ or GF ₂₅₄ silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.17-0.23 mm, and the specification of the thin layer chromatography separation and purification product is 0.4-0.5 mm.

Silica gel column chromatography generally uses 100-200 mesh silica gel of Shangbang silica gel as a carrier.

THF tetrahydrofuran, meCN acetonitrile, et ₃ N triethylamine, acOH acetic acid, TFA trifluoroacetic acid, TEA triethylamine, DMF N, N-dimethylformamide, DMA dimethylacetamide, meOH methanol, etOH ethanol, sodium EtONa ethoxide, KOH potassium hydroxide, NCS N-chlorosuccinimide, pyridine, DIPEAN, N-diisopropylethylamine, toluene toluene, r.t. room temperature, ruCl (p-cymene) [ (S, S) -Ts-DPEN ] (CAS No. 192139-90-5).

The method comprises the following steps:

Step A:

4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (400 mg, 0.93 mmol) was dissolved in pyridine (4 ml), phenylboronic acid (2.33 mmol) and copper acetate (424 mg, 2.33 mmol) were added and reacted for 56 hours at 40 ℃.

LC-MS detection shows that the reaction is complete, concentrated to remove the organic solvent, diluted with water (5 ml) and ethyl acetate (5 ml), extracted with ethyl acetate (10 ml. Times.6), combined with the organic phases, washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness, the residue purified by column chromatography on silica gel (eluent: ethyl acetate, then dichloromethane/methanol=10/1), the crude product purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give two isomers, respectively, after lyophilization, the two products were obtained as white solids.

The second method is as follows:

step A:

(S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (220 mg, 0.58 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 ml) and toluene (3 ml), and N, N-diisopropylethylamine (0.2 ml, 1.16 mmol) was added in sequence under ice-water bath conditions to react for 1 hour (S) -1-chloro-1-oxopropan-2-ylacetate (0.08 ml, 0.64 mmol). Phenylhydrazine hydrochloride (0.64 mmol) and N, N-diisopropylethylamine (0.3 ml, 1.74 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. The reaction was carried out at room temperature for 1 hour and at 70℃for 18 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 140 mg of the product as a brown solid.

And (B) step (B):

The product from the previous step (0.24 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml) and sodium hydroxide (19 mg, 0.48 mmol) was added. Stirring was carried out at room temperature for 2 hours at celsius.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give 104 mg of the product of hydrolysis of acetyl groups.

And a third method:

step A:

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetylimine (238 mg, 0.58 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 ml) and toluene (3 ml), and N, N-diisopropylethylamine (0.2 ml, 1.16 mmol) was added in sequence under ice-water bath conditions to react for 1 hour (S) -1-chloro-1-oxypropane-2-yl acetate (0.08 ml, 0.64 mmol). Phenylhydrazine hydrochloride (0.64 mmol) and N, N-diisopropylethylamine (0.3 ml, 1.74 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. The reaction was carried out at room temperature for 1 hour and at 70℃for 18 hours.

And (B) step (B):

EXAMPLE 1 Synthesis of 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthesis route one is as follows:

step A: synthesis of 2-amino-1- (4-chlorophenyl) ethan-1-one hydrochloride

2-Bromo-1- (4-chlorophenyl) ethan-1-one (20.00 g, 85.84 mmol) and sodium diformylamide (19.78 g, 206.02 mmol) were added to the reaction flask, acetonitrile (400.0 ml) was added and stirred at 80℃for 2 hours.

TLC detection showed complete reaction, and after the reaction solution cooled to room temperature, filtration, concentration of the filtrate under reduced pressure, evaporation to dryness, addition of acetonitrile (90.0 ml), hydrochloric acid (90.0 ml, 6.00 mol/l) and stirring at 80 degrees celsius for 2 hours. LC-MS and TLC detection showed complete reaction, after the reaction solution had cooled to room temperature, concentrated under reduced pressure and evaporated to dryness, the solid was rinsed with methyl tert-butyl ether (30 ml. Times.4) and dried under vacuum to give 18.60 g of 2-amino-1- (4-chlorophenyl) ethan-1-one hydrochloride as a pale yellow solid (yield: 100.0%). LC-MS: rt=0.42 min, [ m+h ] ⁺ = 170.13.

And (B) step (B): synthesis of ethyl (2- (4-chlorophenyl) -2-oxoethyl) carbamoylglycinate

2-Amino-1- (4-chlorophenyl) ethyl-1-one hydrochloride (18.60 g, 90.29 mmol) was added to the reaction flask, tetrahydrofuran (200.0 ml) and triethylamine (29.0 ml, 212.18 mmol) were added, replaced three times with nitrogen, and ethyl 2-isocyanate (12.0 ml, 108.35 mmol) was slowly added dropwise under nitrogen and stirred at room temperature for 1 hour. LC-MS detection shows that the reaction is complete, and the reaction solution is directly used for the next step without treatment. LC-MS: rt=1.79 min, [ m+h ] ⁺ = 299.19.

Step C: synthesis of ethyl 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate

Trifluoroacetic acid (101.0 ml, 1.35 mol) was added to the reaction mixture in the previous step, and the mixture was stirred at 60℃for 3 hours. LC-MS detection showed complete reaction, after the reaction solution cooled to room temperature, water (400.0 ml) was added, ethyl acetate (200 ml. Times.3) was extracted, and the organic phases were combined, washed successively with saturated sodium bicarbonate (100X 4 ml), saturated sodium chloride (20.0 ml), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 24.40 g of ethyl 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate as a yellow solid (two-step yield: 96.3%). LC-MS: rt=1.84 min, [ m+h ] ⁺ =281.14.

Step D: synthesis of 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid

Ethyl 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate (24.40 g, 86.83 mmol) was added to the reaction flask, tetrahydrofuran (150.0 ml), methanol (50.0 ml) and water (50.0 ml) were added, followed by potassium hydroxide (19.45 g, 347.32 mmol). Stirred at 60 degrees celsius for 2 hours. LC-MS detection showed complete reaction. After the reaction solution was cooled to room temperature, the organic solvent was removed by concentration under reduced pressure, the aqueous phase was extracted once with methylene chloride (20.0 ml. Times.1), the organic phase and the aqueous phase were separated, the aqueous phase solution was adjusted to pH=3-4 with hydrochloric acid (6 mol/l), solids were precipitated, and the filter cake was washed with water (10 ml. Times.3) and dried under vacuum to give 16.54 g of 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid as a yellow solid (yield: 75.3%). LC-MS: rt=1.68 min, [ m+h ] ⁺ = 253.11.

Step E: synthesis of 5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-oxo-propyl) -1, 3-dihydro-2H-imidazol-2-one

2- (5- (4-Chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid (16.54 g, 65.38 mmol) was added to the reaction flask, pyridine (250.0 ml) was added, nitrogen was replaced three times, and the nitrogen blanket was reduced to zero degrees Celsius. Trifluoroacetic anhydride (46.0 ml, 326.88 mmol) was slowly added and stirred at room temperature for 1 hour. Pyridine was removed by concentrating under reduced pressure, diluted hydrochloric acid (400.0 ml, 0.50 mol/l) was added, and stirred at 70℃for 1 hour.

LC-MS detection showed complete reaction, extraction with dichloromethane (200 ml. Times.3), washing of the combined organic phases with saturated brine (50 ml), drying over anhydrous magnesium sulfate, filtration, concentration under reduced pressure and evaporation of the crude compound to dryness, purification by column chromatography over silica gel (eluent: n-hexane/ethyl acetate=1/1) afforded 4.36 g of the product 5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-oxo-propyl) -1, 3-dihydro-2H-imidazol-2-one as a pale yellow solid (yield: 21.9%). LC-MS: rt=1.89 min, [ M-1] ^- = 303.14.

Step F: synthesis of (S) -5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

5- (4-Chlorophenyl) -1- (3, 3-trifluoro-2-oxo-propyl) -1, 3-dihydro-2H-imidazol-2-one (4.34 g, 14.23 mmol) was added to a reaction flask, DMA (50.0 ml) was added, replaced three times with nitrogen, formic acid (2.68 ml, 71.15 mmol), triethylamine (1.18 ml, 8.54 mmol) and (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (181.00 mg, 0.03 mmol) were added under nitrogen and stirred at room temperature for 16 hours.

LC-MS detection showed the reaction was complete, water (100 ml) was added to the reaction solution, ethyl acetate (150 ml. Times.3) was extracted, and the organic phases were combined, and washed successively with water (100 ml), saturated brine (50 ml. Times.6). Dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 4.46 g of (S) -5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (crude) as a brown solid product. LC-MS: rt=1.86 min, [ m+h ] ⁺ = 307.11.

Step G: synthesis of (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetic acid ethyl ester

(S) -5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (4.46 g, 14.53 mmol) was added to a reaction flask, acetonitrile (80.0 ml), potassium carbonate (4.00 g, 29.06 mmol), ethyl 2-bromoacetate (1.93 ml, 17.44 mmol) was added and stirred at 60℃for 4 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, the reaction solution is filtered, the filter cake is washed three times by acetonitrile, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The crude product was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 4.75 g of (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethyl acetate as a brown oily product (yield: 83.2%). LC-MS: rt=1.97 min, [ m+h ] ⁺ = 393.15.

Step H: synthesis of (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acethydrazide

Ethyl (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetate (4.72 g, 12.01 mmol) was added to the reaction flask, ethanol (50.0 ml), hydrazine hydrate (3.75 ml, 60.05 mmol, 80% purity) was added and stirred at 80 degrees celsius for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure and evaporated to dryness to obtain 4.52 mg of brown focal product (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acethydrazide (yield: 99.3%). LC-MS: rt=1.77 min, [ m+h ] ⁺ = 379.17.

Step I: synthesis of 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetylhydrazine (4.52 g, 11.93 mmol), (S) -2-hydroxypropionamide hydrochloride (1.78 mg, 14.32 mmol) and sodium ethoxide (1.95 g, 28.63 mmol) were added to a reaction flask, DMF (50.0 ml) was added, and stirred at 120℃for 2 hours.

LC-MS detection showed complete reaction, after the reaction solution had cooled to room temperature, water (100 ml) was added, ethyl acetate (60 ml. Times.6) was extracted, and the organic phases were combined, washed successively with water (20 ml. Times.2), saturated brine (20 ml. Times.4), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 5.00 g of the product 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a brown oil (yield: 97.1%). LC-MS: rt=1.80 min, [ m+h ] ⁺ = 432.22.

Step J:4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (400 mg, 0.93 mmol) was dissolved in pyridine (4 ml), 3-chlorobenzoic acid (363 mg, 2.33 mmol), copper acetate (424 mg, 2.33 mmol) was added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml×6), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, and purification of the residue by column chromatography on silica gel (eluent: ethyl acetate, then replaced with dichloromethane/methanol=10/1), the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase a: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to afford, after lyophilization, 63.24 mg of the white solid product 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield :12.6％),LC-MS：RT＝2.02min,[M+H]⁺＝542.16,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.80-7.76(m,1H),7.67-7.57(m,3H),7.53(dd,J＝8.8,18.4Hz,4H),6.83(s,1H),6.74(d,J＝6.4Hz,1H),5.78(d,J＝6.4Hz,1H),4.90(s,2H),4.85-4.75(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.4,3.2Hz,1H),3.77(dd,J＝14.4,9.2Hz,1H),1.47(d,J＝6.4Hz,3H); after lyophilization afforded 17.41 mg of the white solid product 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -3, 3-trifluoro-1H-chlorophenyl) -3- ((S) -3, 3-triazol-5-yl) methyl -2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.5%), LC-MS: rt=2.02 min, [ m+h ] ⁺ = 542.16.

The specific synthetic route II is as follows:

Step A: synthesis of (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetonitrile

(S) -5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (3.00 g, 9.80 mmol) was added to a reaction flask, acetonitrile (50.0 ml), potassium carbonate (2.50 g, 19.60 mmol), potassium iodide (11 mg), 2-chloroacetonitrile (1.10 g, 14.7 mmol) was added and stirred at 60℃for 5 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, the reaction solution is filtered, the filter cake is washed three times by acetonitrile, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The crude product was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 2.20 g of (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetonitrile as a brown solid product (yield: 65.1%). LC-MS: rt=1.93 min, [ m+h ] ⁺ = 346.09.

And (B) step (B): synthesis of (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine

(S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetonitrile (200 mg, 0.58 mmol) was added to the reaction flask, methanol (5.0 ml) was added, sodium methoxide methanol solution (5 mol/l, 10 μl, 0.029 mmol) was stirred at 50℃for 1 hour.

After the reaction was completed, the reaction mixture was concentrated under reduced pressure and evaporated to dryness to give 220 mg of (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine as a brown solid product (yield: 100%).

Step C: synthesis of ethyl (S) -1- (1- (3-chlorophenyl) -3- ((4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (220 mg, 0.58 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 ml) and toluene (3 ml), and N, N-diisopropylethylamine (0.2 ml, 1.16 mmol) and (S) -1-chloro-1-oxypropane-2-yl acetate (0.08 ml, 0.64 mmol) were sequentially added under ice-water bath conditions. Stirring was carried out at room temperature for 1 hour. (3-chlorophenyl) hydrazine hydrochloride (114 mg, 0.64 mmol) and N, N-diisopropylethylamine (0.3 ml, 1.74 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the reaction. Stirring at room temperature for 1 hour, and then heating to 70 ℃ and stirring for 18 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 140 mg of a brown solid product as ethyl (S) -1- (1- (3-chlorophenyl) -3- ((4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 41.3%). LC-MS: rt=2.09 min, [ m+h ] ⁺ = 584.19.

Step D: synthesis of 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

Ethyl (S) -1- (1- (3-chlorophenyl) -3- ((4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (140.0 mg, 0.24 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml) and sodium hydroxide (19 mg, 0.48 mmol) was added. Stirring was carried out at room temperature for 2 hours at celsius.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. Purification of the residue by column chromatography on silica gel (eluent: ethyl acetate) afforded 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield ：80.09％).LC-MS：RT＝2.02min,[M+H]⁺＝542.13.¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.80-7.76(m,1H),7.66-7.57(m,3H),7.53(dd,J＝8.8,18.0Hz,4H),6.83(s,1H),6.74(d,J＝6.4Hz,1H),5.77(d,J＝6.4Hz,1H),4.90(s,2H),4.85-4.75(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.77(dd,J＝14.4,9.2Hz,1H),1.47(d,J＝6.4Hz,3H).

EXAMPLE 2 Synthesis of 1- ((1- (3-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 1- ((1- (3-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 1- ((1- (3-chloro-4-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (300 mg, 0.69 mmol) was dissolved in pyridine (4 ml), 3-chloro-4-fluorophenylboronic acid (302 mg, 1.74 mmol) and copper acetate (316 mg, 1.74 mmol) were added and stirred at 50℃for 24 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml×5), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, and purification of the residue by column chromatography on silica gel (eluent: ethyl acetate, then replaced with dichloromethane/methanol=10/1) and purified by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase a: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 49.15 mg of white solid after lyophilization 1- ((1- (3-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield :12.6％),LC-MS：RT＝2.02min,[M+H]⁺＝560.20,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.95(dd,J＝6.4,2.4Hz,1H),7.71-7.60(m,2H),7.63(dd,J＝16.8,8.8Hz,4H),6.83(s,1H),6.75(d,J＝6.0Hz,1H),5.77(d,J＝6.0Hz,1H),4.89(s,2H),4.83-4.77(m,1H),4.30-4.20(m,1H),3.91(dd,J＝14.8,3.6Hz,1H),3.77(dd,J＝14.4,9.2Hz,1H),1.46(d,J＝6.8Hz,3H); after lyophilization to give 6.89 mg of white solid product 1- ((1- (3-chloro-4-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2H-imidazol-2-one) - ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 1.8%), LC-MS: rt=2.02 min, [ m+h ] ⁺ = 560.20.

EXAMPLE 3 Synthesis of 1- ((1- (5-chloro-2-methoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 1- ((1- (5-chloro-2-methoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (200.00 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), and (5-chloro-2-methoxyphenylboronic acid (173.00 mg, 0.93 mmol) and copper acetate (168.00 mg, 0.93 mmol) were added and stirred at 50℃for 24 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combining organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to remove organic solvent. The residue was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) and lyophilized to give 11.24 mg (yield: 4.27%) of a white solid. LC-MS: rt=2.00 min, [ m+h ] ⁺ = 572.21.

EXAMPLE 4 Synthesis of 4- (4-chlorophenyl) -1- (((5- ((S) -1-hydroxyethyl) -1- (2-methoxyphenyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- (((5- ((S) -1-hydroxyethyl) -1- (2-methoxyphenyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (200.00 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), 2-methoxyphenylboronic acid (140.00 mg, 0.93 mmol) and copper acetate (168.00 mg, 0.93 mmol) were added and stirred at 50℃for 24 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combining organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to remove organic solvent. The residue was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 25.07 mg of white solid 4- (4-chlorophenyl) -1- (((5- ((S) -1-hydroxyethyl) -1- (2-methoxyphenyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield) ：10.1％),LC-MS：RT＝1.93min,[M+H]⁺＝538.27,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.57-7.41(m,6H),7.37(dd,J＝7.6,1.6Hz,1H),7.24(d,J＝7.6Hz,1H),7.09(td,J＝7.6,0.8Hz,1H),6.82(s,1H),6.77(d,J＝4.4Hz),5.41(d,J＝5.6Hz,1H),4.87(s,2H),4.55-4.47(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.8,3.6Hz,1H),3.83-3.73(m,4H),1.36(d,J＝6.4Hz,3H).

EXAMPLE 5 Synthesis of 1- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 1- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 1- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (300 mg, 0.69 mmol) was dissolved in pyridine (4 ml), 3-chloro-5-fluorophenylboronic acid (302 mg, 1.74 mmol) and copper acetate (316 mg, 1.74 mmol) were added and stirred at 50℃for 24 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml×5), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, and purification of the residue by column chromatography on silica gel (eluent: ethyl acetate, then dichloromethane/methanol=10/1), the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase a: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give after lyophilization 41.36 mg of the white solid product 1- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield :10.6％),LC-MS：RT＝2.04min,[M+H]⁺＝560.24,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.70-7.62(m,3H),7.53(dd,J＝8.8,17.2Hz,4H),6.80-6.70(m,1H),4.89(s,2H),4.88-4.83(m,1H),4.30-4.20(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.77(dd,J＝14.4,9.2Hz,1H),1.49(d,J＝6.4Hz,3H); after lyophilization to give 14.96 mg of the pale yellow solid product 1- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.8%), LC-MS: rt=2.04 min, [ m+h ] ⁺ = 560.24.

EXAMPLE 6 Synthesis of 4- (4-chlorophenyl) -1- ((1- (3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4- (4-chlorophenyl) -1- ((1- (3-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (300 mg, 0.69 mmol) was dissolved in pyridine (4 ml), 3-fluorophenylboronic acid (243 mg, 1.74 mmol) and copper acetate (316 mg, 1.74 mmol) were added and stirred at 50℃for 24 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.5), combining the organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, purification of the residue by column chromatography over silica gel (eluent: ethyl acetate, then dichloromethane/methanol=10/1), purification of the crude product by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia), lyophilization to give 30.87 mg of pale yellow solid product 4- (4-chlorophenyl) -1- ((1- (3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (:8.4％),LC-MS：RT＝1.93min,[M+H]⁺＝526.21,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.64-7.48(m,7H),7.38(td,J＝8.0,1.6Hz,1H),6.84(s,1H),6.75(s,1H),5.79(d,J＝5.6Hz,1H),4.89(s,2H),4.83-4.78(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.8,4.0Hz,1H),3.77(dd,J＝14.8,9.2Hz,1H),1.47(d,J＝6.4Hz,3H); mg of pale yellow solid product (5725.05% saturated aqueous ammonia), and lyophilization to give 30.87 mg of pale yellow solid product 4- (4-chlorophenyl) -1- ((3-fluorophenyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3-trifluoro-2-hydroxypropyl) -1, 3-2-hydroxy-imidazol-2-one (:8.4％),LC-MS：RT＝1.93min,[M+H]⁺＝526.21,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.64-7.48(m,7H),7.38(td,J＝8.0,1.6Hz,1H),6.84(s,1H),6.75(s,1H),5.79(d,J＝5.6Hz,1H),4.89(s,2H),4.83-4.78(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.8,4.0Hz,1H),3.77(dd,J＝14.8,9.2Hz,1H),1.47(d,J＝6.4Hz,3H); mg of pale yellow solid product after lyophilization 3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 7.2%), LC-MS: rt=1.93 min, [ m+h ] ⁺ = 526.21.

EXAMPLE 7 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (200.00 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), 2-chlorophenyl boric acid (144.00 mg, 0.93 mmol) and copper acetate (168.00 mg, 0.93 mmol) were added and stirred at 50℃for 36 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combining organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to remove organic solvent. The residue was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 7.13 mg (yield) of a white solid after lyophilization ：2.86％).LC-MS：RT＝1.97min,[M+H]⁺＝542.21.¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.78(s,1H),7.67-7.57(m,3H),7.53(dd,J＝8.8,18.4Hz,4H),6.83(s,1H),6.74(d,J＝6.4Hz,1H),5.80-5.75(m,1H),4.90(s,2H),4.85-4.75(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.4,3.2Hz,1H),3.77(dd,J＝14.4,9.2Hz,1H),1.47(d,J＝6.4Hz,3H).

EXAMPLE 8 Synthesis of 4- (4-chlorophenyl) -1- ((1- (5-fluoro-2-methoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (5-fluoro-2-methoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (200 mg, 0.46 mmol) was dissolved in pyridine (3 ml), 5-fluoro-2-methoxyphenylboronic acid (197 mg, 1.16 mmol) and copper acetate (211 mg, 1.16 mmol) were added and stirred at 40℃for 48 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.5), combining the organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, purification of the residue by column chromatography over silica gel (eluent: ethyl acetate, then dichloromethane/methanol=10/1), purification of the crude product obtained by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia), lyophilization to give 21.64 mg of white solid 4- (4-chlorophenyl) -1- ((1- (5-fluoro-2-methoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield :8.4％),LC-MS：RT＝1.95min,[M+H]⁺＝556.17,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.53(dd,J＝8.8,17.2Hz,4H),7.42(td,J＝2.4,8.8Hz,1H),7.36(dd,J＝3.2,8.8Hz,1H),7.26(dd,J＝4.8,9.2Hz,1H),6.81(s,1H),6.76(s,1H),5.44(d,J＝5.6Hz,1H),4.87(s,2H),4.60-4.50(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.70-3.70(m,4H),1.37(d,J＝6.8Hz,3H).

EXAMPLE 9 Synthesis of 4- (4-chlorophenyl) -1- (((1- (3, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- (((1- (3, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4- (4-chlorophenyl) -1- (((1- (3, 5-difluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (150.0 mg, 0.35 mmol) was dissolved in pyridine (4.0 ml), and (3, 5-difluorophenyl) boric acid (139.00 mg, 0.88 mmol) and copper acetate (159.30 mg, 0.88 mmol) were added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), washing of the combined organic phases with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, purification of the crude product by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia), lyophilization to give 3.13 mg of white solid 4- (4-chlorophenyl) -1- (((1- (3, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield ：4.0％),LC-MS：RT＝2.02min,[M+H]⁺＝545.17,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.58-7.45(m,7H),6.83(s,1H),6.74(d,J＝6.4Hz,1H),5.86(d,J＝6.0Hz,1H),4.90-4.79(m,3H),4.35-4.22(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.78(dd,J＝14.4,9.2Hz,1H),1.49(d,J＝6.4Hz,3H);) after lyophilization to give 2.20 mg of white solid 4- (4-chlorophenyl) -1- (((1, 5-difluorophenyl) -1- ((S) -3, 3-hydroxyethyl) -1-3-hydroxy-3-hydroxy-methyl) -3- ((S) -3, 3-trifluoro-2-hydroxy-imidazol-2-one (yield ：4.0％),LC-MS：RT＝2.02min,[M+H]⁺＝545.17,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.58-7.45(m,7H),6.83(s,1H),6.74(d,J＝6.4Hz,1H),5.86(d,J＝6.0Hz,1H),4.90-4.79(m,3H),4.35-4.22(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.78(dd,J＝14.4,9.2Hz,1H),1.49(d,J＝6.4Hz,3H);). LC-MS: rt=2.02 min, [ m+h ] ⁺ = 545.17.

EXAMPLE 10 Synthesis of 3- (3- ((4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1- (yl) methyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-1-yl) benzonitrile

The specific synthetic route is as follows:

step A: synthesis of 3- (3- ((4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1- (yl) methyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-1-yl) benzonitrile and 3- (5- ((4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-1-yl) benzonitrile

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (150.00 mg, 0.35 mmol) was dissolved in pyridine (4.0 ml), (3-cyanophenyl) boronic acid (129.40 mg, 0.88 mmol) and copper acetate (159.30 mg, 0.88 mmol) were added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, and purification of the crude product by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give after lyophilization 5.16 mg of white solid 3- (3- ((4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1- (yl) methyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-1-yl) benzonitrile ,LC-MS：RT＝1.98min,[M+H]⁺＝533.23,¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.17(s,1H),8.02-7.96(m,2H),7.78(t,J＝8.0Hz,1H),7.53(dd,J＝8.8,17.6Hz,4H),6.83(s,1H),6.74(d,J＝6.4Hz,1H),5.80(d,J＝6.4Hz,1H),4.91(s,2H),4.85(t,J＝6.4Hz),4.32-4.20(m,1H),3.91(dd,J＝14.4,3.2Hz,1H),3.77(dd,J＝14.4,9.2Hz,1H),1.48(d,J＝6.8Hz,3H); mg of white solid 4-3- (5- ((4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -3S) -1-hydroxyethyl) -1H-1,2, 4-triazol-1-yl) benzonitrile (yield: 4.5, 4-chlorophenyl) -2-trifluoro-2-hydroxypropyl) was obtained after lyophilization to give 3.22 mg of white solid 4-3- (4-chlorophenyl) -2-trifluoro-2-hydroxypropyl, LC-MS: rt=1.98 min, [ m+h ] ⁺ = 533.23.

EXAMPLE 11 Synthesis of 4- (4-chlorophenyl) -1- ((1- (4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4- (4-chlorophenyl) -1- ((1- (4-chlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (150.00 mg, 0.35 mmol) was dissolved in pyridine (4.0 ml), (4-chlorophenyl) boric acid (137.30 mg, 0.88 mmol) and copper acetate (159.30 mg, 0.88 mmol) were added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, and purification of the crude product by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase A acetonitrile, mobile phase B water+0.05% saturated aqueous ammonia) to give after lyophilization 6.16 mg of white solid 4- (4-chlorophenyl) -1- ((1- (4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield ：8.1％),LC-MS：RT＝2.00min,[M+H]⁺＝542.27,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.65(dd,J＝8.8,16.8Hz,4H),7.52(dd,J＝8.8,17.6Hz,4H),6.83(s,1H),6.75(d,J＝6.4Hz,1H),5.76(d,J＝6.0Hz,1H),4.89(s,2H),4.78(t,J＝0.8Hz,1H),4.32-4.20(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.77(dd,J＝14.4,9.2Hz,1H),1.48(d,J＝6.4Hz,3H);% freeze-dried to give 4.13 mg of white solid 4- (4-chlorophenyl) -1- ((1- (4-chlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 5.4%), LC-MS: rt=2.00 min, [ m+h ] ⁺ = 542.27.

EXAMPLE 12 Synthesis of 1- ((1- (2-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 1- ((1- (2-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (150.00 mg, 0.35 mmol) was dissolved in pyridine (4.0 ml), and (2-chloro-5-fluorophenyl) boric acid (153.10 mg, 0.88 mmol) and copper acetate (159.30 mg, 0.88 mmol) were added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, evaporation to dryness under reduced pressure to remove the organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), washing of the combined organic phases with saturated brine (5 ml), drying over anhydrous sodium sulphate, filtration, evaporation to dryness under reduced pressure, purification of the crude product by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia), lyophilization to give 2.02 mg of white solid 1- ((1- (2-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 1.0%). LC-MS: rt=2.02 min, [ m+h ] ⁺ = 560.13.

EXAMPLE 13 Synthesis of 4- (4-chlorophenyl) -1- (((1- (2, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- (((1- (2, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (150.00 mg, 0.35 mmol) was dissolved in pyridine (4.0 ml), and (2, 5-dichlorophenyl) boric acid (167.20 mg, 0.88 mmol) and copper acetate (159.30 mg, 0.88 mmol) were added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, reduced pressure concentration to remove organic solvent, adding water (5 ml) and ethyl acetate (5 ml) dilution, ethyl acetate (10 ml×6) extraction, combining organic phases, saturated saline (5 ml) washing, anhydrous sodium sulfate drying, filtration, reduced pressure concentration to dryness, purification of crude product by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated ammonia water), freeze drying to obtain 4.56 mg white solid 4- (4-chlorophenyl) -1- (((1- (2, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield) ：2.3％).LC-MS：RT＝2.02min,[M+H]⁺＝576.33.¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.84(d,J＝2.0Hz,1H),7.75(d,J＝2.0Hz,1H),7.70(dd,J＝8.8,2.4Hz,1H),7.52(dd,J＝14.4,8.8Hz,4H),6.77(s,1H),6.73(d,J＝6.4Hz,1H),5.55(d,J＝6.0Hz,1H),4.89(s,2H),4.75-4.60(m,1H),4.34-4.20(m,1H),3.91(dd,J＝14.8,3.6Hz,1H),3.78(dd,J＝14.4,9.2Hz,1H),1.41(d,J＝6.4Hz,3H).

EXAMPLE 14 Synthesis of 4- (4-chlorophenyl) -1- (((1- (2, 3-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- (((1- (2, 3-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (150.00 mg, 0.35 mmol) was dissolved in pyridine (4 ml), and (2, 3-dichlorophenyl) boric acid (167.20 mg, 0.88 mmol) and copper acetate (159.30 mg, 0.88 mmol) were added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, reduced pressure concentration to remove organic solvent, adding water (5 ml) and ethyl acetate (5 ml) dilution, ethyl acetate (10 ml×6) extraction, combining organic phases, saturated saline (5 ml) washing, anhydrous sodium sulfate drying, filtration, reduced pressure concentration to dryness, purification of crude product by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated ammonia water), freeze drying to obtain 6.13 mg white solid 4- (4-chlorophenyl) -1- (((1- (2, 3-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield) ：3.0％).LC-MS：RT＝2.02min,[M+H]⁺＝576.33.¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.88(dd,J＝8.0,1.6Hz,1H),7.66-7.62(m,1H),7.58-7.46(m,5H),6.79(s,1H),6.73(d,J＝6.4Hz,1H),5.54(d,J＝6.0Hz,1H),4.90(s,2H),4.70-4.60(m,1H),4.32-4.20(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.78(dd,J＝14.4,9.2Hz,1H),1.40(d,J＝6.8Hz,3H).

EXAMPLE 15 Synthesis of 4- (4-chlorophenyl) -1- (((1- (2, 3-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- (((1- (2, 3-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (150.00 mg, 0.35 mmol) was dissolved in pyridine (4.0 ml), and (2, 3-difluorophenyl) boric acid (139.10 mg, 0.88 mmol) and copper acetate (159.30 mg, 0.88 mmol) were added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, reduced pressure concentration to remove organic solvent, adding water (5 ml) and ethyl acetate (5 ml) dilution, ethyl acetate (10 ml×6) extraction, combining organic phases, saturated saline (5 ml) washing, anhydrous sodium sulfate drying, filtration, reduced pressure concentration to dryness, purification of crude product by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated ammonia water), freeze drying to obtain 0.78 mg white solid 4- (4-chlorophenyl) -1- (((1- (2, 3-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield) ：0.5％).LC-MS：RT＝1.98min,[M+H]⁺＝544.27.¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.72-7.63(m,1H),7.58-7.46(m,5H),7.44-7.36(m,1H),6.82(s,1H),6.73(d,J＝6.4Hz,1H),5.60(d,J＝6.0Hz,1H),4.91(s,2H),4.80-4.72(m,1H),4.32-4.20(m,1H),3.91(dd,J＝14.8,3.6Hz,1H),3.78(dd,J＝14.4,9.2Hz,1H),1.43(d,J＝6.4Hz,3H).

EXAMPLE 16 Synthesis of 1- ((1- (2-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 1- ((1- (2-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (150.00 mg, 0.35 mmol) was dissolved in pyridine (4.0 ml), and (2-chloro-4-fluorophenyl) boric acid (153.10 mg, 0.88 mmol) and copper acetate (159.30 mg, 0.88 mmol) were added and stirred at 40℃for 56 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), washing of the combined organic phases with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, purification of the crude product by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia), freeze-drying to give 1.72 mg of white solid 1- ((1- (2-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield) ：0.9％).LC-MS：RT＝2.02min,[M+H]⁺＝560.13.¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.76(dd,J＝8.4,2.8Hz,1H),7.71(dd,J＝9.2,5.6Hz,1H),7.52(dd,J＝14.4,8.8Hz,4H),7.44(dt,J＝8.4,3.2Hz,1H),6.78(s,1H),6.73(d,J＝6.0Hz,1H),5.53(d,J＝6.4Hz,1H),4.89(s,2H),4.70-4.55(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.78(dd,J＝14.8,9.6Hz,1H),1.39(d,J＝6.4Hz,3H).

EXAMPLE 17 Synthesis of 1- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of 2-bromo-1- (4-chlorophenyl) propan-1-one:

1- (4-chlorophenyl) -2-methylpropan-1-one (30.00 g, 164.80 mmol) was added to the reaction flask, acetic acid (100 ml) was added, and an acetic acid solution containing bromine (9.0 ml) was slowly added under ice bath and stirred at room temperature for 2 hours.

TLC detection showed complete reaction. The reaction solution was quenched by pouring it into ice water, extracted with ethyl acetate (200 ml. Times.3), the organic phases were combined, washed with saturated brine (50X 2 ml), dried over anhydrous sodium sulfate, and concentrated to give 32.00 g of pale yellow 2-bromo-1- (4-chlorophenyl) propan-1-one (yield: 78.8%).

And (B) step (B): synthesis of 2-amino-1- (4-chlorophenyl) propan-1-one hydrochloride

2-Bromo-1- (4-chlorophenyl) propan-1-one (32.00 g, 130.10 mmol) and sodium diformylamide (29.95 g, 312.00 mmol) were added to the reaction flask, acetonitrile (500.0 ml) was added and stirred at 80℃for 2 hours.

TLC detection showed complete reaction. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness, to which acetonitrile (90.0 ml) and hydrochloric acid (90.0 ml, 6.0 mol/l) were added, and stirred at 80℃for 2 hours. LC-MS and TLC detection showed complete reaction, after the reaction solution had cooled to room temperature, concentrated under reduced pressure and evaporated to dryness, the solid was rinsed with methyl tert-butyl ether (30 ml. Times.4) and dried under vacuum to give 22.30 g of 2-amino-1- (4-chlorophenyl) propan-1-one hydrochloride as a pale yellow solid (yield: 93.6%). LC-MS: rt=0.42 min, [ m+h ] ⁺ = 184.13.

Step C: synthesis of ethyl (2- (4-chlorophenyl) -2-oxopropyl) carbamoylglycinate

2-Amino-1- (4-chlorophenyl) propan-1-one hydrochloride (22.30 g, 121.20 mmol) was added to the reaction flask, tetrahydrofuran (200.0 ml) and triethylamine (39.0 ml, 284.82 mmol) were added, replaced with nitrogen three times, and ethyl 2-isocyanate (16.0 ml, 145.20 mmol) was slowly added dropwise under nitrogen and stirred at room temperature for 1 hour. LC-MS detection showed that after the reaction was complete, the reaction solution was used directly for the next step without treatment. LC-MS: rt=1.79 min, [ m+h ] ⁺ = 313.17.

Step D: synthesis of ethyl 2- (5- (4-chlorophenyl) -4-methyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate

Trifluoroacetic acid (136.0 ml, 1.82 mol) was added to the reaction mixture from the previous step, and the mixture was stirred at 60℃for 3 hours. LC-MS detection showed complete reaction, after the reaction solution was cooled to room temperature, water (400 ml) was added, ethyl acetate (200 ml. Times.3) was extracted, and the organic phases were combined, washed successively with saturated sodium hydrogencarbonate (100X 4 ml), saturated sodium chloride (20 ml), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 27.1 g of ethyl 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate as a brown solid (two-step yield: 76.1%). LC-MS: rt=1.84 min, [ m+h ] ⁺ = 295.14.

Step E: synthesis of 2- (5- (4-chlorophenyl) -4-methyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid

Ethyl 2- (5- (4-chlorophenyl) -4-methyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate (27.10 g, 91.83 mmol) was added to the reaction flask, tetrahydrofuran (150.0 ml), methanol (50.0 ml) and water (50.0 ml) were added, followed by potassium hydroxide (20.57 g, 367.32 mmol). Stirred at 60 degrees celsius for 2 hours. LC-MS detection showed complete reaction. After the reaction solution was cooled to room temperature, the organic solvent was removed by concentration under reduced pressure, the resulting aqueous phase was extracted with methylene chloride (20 ml), the aqueous phase was cooled to zero degrees centigrade, the pH was adjusted to ph=3-4 with hydrochloric acid (6 mol/l), solids were precipitated, filtration was performed, and the cake was washed with water (10 ml×3), and dried under vacuum to give 15.66 g of 2- (5- (4-chlorophenyl) -4-methyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid (yield: 64.1%) as a yellow solid. LC-MS: rt=1.68 min, [ m+h ] ⁺ = 267.11.

Step F: synthesis of 5- (4-chlorophenyl) -4-methyl-1- (3, 3-trifluoro-2-oxopropyl) -1, 3-dihydro-2H-imidazol-2-one

2- (5- (4-Chlorophenyl) -4-methyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid (16.54 g, 58.87 mmol) was added to a reaction flask, pyridine (250.0 ml) was added, nitrogen was replaced three times, and the temperature was reduced to zero℃under nitrogen. Trifluoroacetic anhydride (41.0 ml, 294.35 mmol) was then added slowly and stirred at room temperature for 1 hour. Pyridine was removed by concentrating under reduced pressure, diluted hydrochloric acid (400.0 ml, 0.5 mol/l) was added, and stirred at 70℃for 1 hour.

LC-MS detection showed complete reaction. Dichloromethane (200 ml x 3), combined organic phases, washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness, the crude compound was purified by column chromatography over silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 7.32 g of the product 5- (4-chlorophenyl) -4-methyl-1- (3, 3-trifluoro-2-oxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a yellow solid (yield: 39.1%). LC-MS: rt=1.89 min, [ M-1] ^- =317.14.

Step G: synthesis of (S) -5- (4-chlorophenyl) -4-methyl-1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

5- (4-Chlorophenyl) -4-methyl-1- (3, 3-trifluoro-2-oxo-propyl) -1, 3-dihydro-2H-imidazol-2-one (7.32 g, 23.01 mmol) was added to a reaction flask, DMA (60.0 ml) was added, nitrogen was replaced three times, formic acid (4.3 ml, 115.05 mmol), triethylamine (1.9 ml, 13.80 mmol) and ruthenium (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) chloride (318.0 mg, 0.05 mmol) were added under nitrogen protection, and stirred at room temperature for 16 hours.

LC-MS detection showed the reaction was complete, water (100 ml) was added to the reaction solution, ethyl acetate (150 ml. Times.3) was extracted, and the organic phases were combined, and washed successively with water (100 ml), saturated brine (50 ml. Times.6). Dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 8.63 g of (S) -5- (4-chlorophenyl) -4-methyl-1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (crude) as a brown solid product. LC-MS: rt=1.86 min, [ m+h ] ⁺ = 321.11.

Step H: synthesis of (S) -2- (4- (4-chlorophenyl) -5-methyl-2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole) -acetic acid ethyl ester

To a reaction flask was added (S) -5- (4-chlorophenyl) -4-methyl-1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (4.00 g, 12.50 mmol), acetonitrile (80.0 ml), potassium carbonate 3.44 g, 25.06 mmol), ethyl 2-bromoacetate (1.7 ml, 15.00 mmol) and stirred at 60 degrees celsius for 4 hours.

LC-MS shows that the reaction is complete, the reaction solution is cooled to room temperature, filtered, the filter cake is washed three times with acetonitrile, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The crude product was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 3.6 g of (S) -2- (4- (4-chlorophenyl) -5-methyl-2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole) -acetic acid ethyl ester as a brown oily product (yield: 70.5%). LC-MS: rt=1.97 min, [ m+h ] ⁺ = 407.15.

Step I: synthesis of (S) -2- (4- (4-chlorophenyl) -5-methyl-2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acethydrazide

Ethyl (S) -2- (4- (4-chlorophenyl) -5-methyl-2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole) acetate (3.60 g, 8.86 mmol) was added to the reaction flask, ethanol (45.0 ml) was added, hydrazine hydrate (2.8 ml, 44.33 mmol, 80% purity) was stirred at 80 degrees celsius for 2 hours.

LC-MS showed complete reaction, after the reaction solution was cooled to room temperature, concentrated under reduced pressure and evaporated to dryness to give 2.90 g of (S) -2- (4- (4-chlorophenyl) -5-methyl-2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetylhydrazine as a brown oily product (yield: 82.8%). LC-MS: rt=1.77 min, [ m+h ] ⁺ = 393.17.

Step J: synthesis of 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -2- (4- (4-chlorophenyl) -5-methyl-2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acethydrazide (2.90 g, 7.39 mmol), (S) -2-hydroxy-prochloraz hydrochloride (1.10 mg, 8.87 mmol) and sodium ethoxide (1.20 g, 17.74 mmol) were added to a reaction flask, DMF (400.0 ml) was added and stirred at 120℃for 2 hours.

LC-MS showed complete reaction, after the reaction solution was cooled to room temperature, water (100 ml) was added, ethyl acetate (60 ml. Times.6) was extracted, and the organic phases were combined, washed successively with water (20 ml. Times.2), saturated brine (20 ml. Times.4), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 2.0 g of the product 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a brown oil (yield: 60.6%). LC-MS: rt=1.80 min, [ m+h ] ⁺ = 446.22.

Step K: synthesis of 1- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 1- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -4- (4-chlorophenyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (200.00 mg, 0.45 mmol) was dissolved in pyridine (4.0 ml), and (3-chloro-5-fluorophenyl) boric acid (156.60 mg, 0.90 mmol) and copper acetate (163.20 mg, 0.90 mmol) were added and stirred at 40℃for 56 hours.

LC-MS showed complete reaction, concentrated under reduced pressure to remove organic solvent, diluted with water (5 ml) and ethyl acetate (5 ml), extracted with ethyl acetate (10 ml. Times.6), combined organic phases, washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 3.95 mg of white solid 1- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -4- (4-chlorophenyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one after freeze drying, LC-MS: rt=2.07 min, [ m+h ] ⁺ = 574.27; after lyophilization 1.93 mg of 1- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -4- (4-chlorophenyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.0%) was obtained as a white solid, LC-MS: rt=2.07 min, [ m+h ] ⁺ = 574.27.

EXAMPLE 18 Synthesis of 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (200.00 mg, 0.45 mmol) was dissolved in pyridine (4.0 ml), (3-chlorophenyl) boric acid (140.40 mg, 0.90 mmol) and copper acetate (163.20 mg, 0.90 mmol) were added and stirred at 40℃for 56 hours.

LC-MS showed complete reaction, concentrated under reduced pressure to remove organic solvent, diluted with water (5 ml) and ethyl acetate (5 ml), extracted with ethyl acetate (10 ml×6), combined organic phases, washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the crude product was purified by preparative HPLC (column: agilent5Prep-C18100mm×30mm 5 μm, mobile phase A acetonitrile, mobile phase B water+0.05% saturated aqueous ammonia) to give after lyophilization 3.95 mg of a white solid 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield ：6.1％),¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.76(s,1H),7.64-7.56(m,3H),7.49(dd,J＝8.4,34.4Hz,4H),6.70-6.60(m,1H),5.65-5.55(m,1H),4.96(s,2H),4.85-4.75(m,1H),4.22-4.12(m,1H),3.80(dd,J＝14.4,4.0Hz,1H),3.62(dd,J＝14.4,8.8Hz,1H),2.11(s,3H),1.47(d,J＝6.4Hz,3H),LC-MS：RT＝2.02min,[M+H]⁺＝556.33; after lyophilization to give 1.93 mg of a white solid 4- (4-chlorophenyl) -1- ((1- (3-chlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -5-methyl-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one Yield: 3.0%). LC-MS: rt=2.02 min, [ m+h ] ⁺ = 556.33.

EXAMPLE 19 Synthesis of 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl 2- (4-chloro-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate

Ethyl 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate (11.0 g, 39.3 mmol) was dissolved in N, N-dimethylformamide (100.0 ml), acetic acid (20.0 ml) was added, and N-chlorosuccinimide (6.27 g, 47.1 mmol). Stir at 20 degrees celsius for 2 hours. The reaction mixture was added dropwise to saturated brine (200 ml), extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined, washed with saturated brine (30 ml×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 11.0 g of ethyl 2- (4-chloro-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate as a yellow solid product (yield: 88.8%). LC-MS: rt=1.89 min, [ m+h ] ⁺ = 315.23.

And (B) step (B): synthesis of 2- (4-chloro-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid

Ethyl 2- (4-chloro-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate (11.0 g, 34.9 mol) was added to the reaction flask, tetrahydrofuran (60.0 ml), methanol (30.0 ml) and water (30.0 ml) were added, followed by potassium hydroxide (7.79 g, 139 mmol). Stirred at 60 degrees celsius for 2 hours.

LC-MS detection showed complete reaction, after the reaction solution cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, the aqueous phase was extracted with dichloromethane (20.0 ml), the aqueous phase was reduced to zero degrees Celsius, hydrochloric acid (6 moles per liter) was adjusted to pH=3-4, solid precipitated, filtered, and the filter cake was washed with water (10 ml. Times.3), dried under vacuum to give 9.98 g of 2- (4-chloro-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid as a yellow solid (yield: 99.3%). LC-MS: rt=1.71 min, [ m+h ] ⁺ = 287.11.

Step C: synthesis of 4-chloro-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-oxopropyl) -1, 3-dihydro-2H-imidazol-2-one

2- (4-Chloro-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid (9.98 g, 34.6 mmol) was added to the reaction flask, pyridine (100.0 ml) was added, nitrogen was replaced three times, and the nitrogen blanket was reduced to zero degrees Celsius. Trifluoroacetic anhydride (36.0 g, 175 mmol) was slowly added and stirred at room temperature for 1 hour. Pyridine was removed by concentrating under reduced pressure, diluted hydrochloric acid (100.0 ml, 0.50 mol/l) was added, and stirred at 70℃for 1 hour.

LC-MS detection showed complete reaction. Dichloromethane (200 ml x 3) was extracted, the organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness, and the crude compound was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 5.10 g of 4-chloro-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-oxopropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 43.5%) as a pale yellow solid product. LC-MS: rt=1.93 min, [ M-H ] ^- = 339.14.

Step D: synthesis of (S) -4-chloro-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-oxo-propyl) -1, 3-dihydro-2H-imidazol-2-one (5.10 g, 15.0 mmol) was added to a reaction flask, N-dimethylacetamide (50.0 ml) was added, nitrogen was replaced three times, formic acid (2.7 ml, 73.5 mmol), triethylamine (1.20 ml, 8.80 mmol) and ruthenium (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) chloride (187 mg, 0.3 mmol) were added under nitrogen protection, and stirred at room temperature for 16 hours under nitrogen.

LC-MS detection showed the reaction was complete, water (100 ml) was added to the reaction solution, ethyl acetate (150 ml. Times.3) was extracted, and the organic phases were combined, and washed successively with water (100 ml), saturated brine (50 ml. Times.6). Dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 4.80 g of (S) -4-chloro-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (crude product) as a brown solid. LC-MS: rt=1.90 min, [ m+h ] ⁺ = 341.11.

Step E: synthesis of (S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole) acetic acid ethyl ester

To a reaction flask was added (S) -4-chloro-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (4.80 g, 14.0 mmol), acetonitrile (50.0 ml), potassium carbonate (3.80 g, 28.0 mmol), ethyl 2-bromoacetate (2.60 g, 16.8 mmol) and stirred at 60 degrees celsius for 2 hours.

LC-MS detection shows that the reaction is complete, the reaction solution is cooled to room temperature, filtered, the filter cake is washed three times with acetonitrile, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The crude product was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 4.75 g of (S) -ethyl 2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole) acetate as a brown oily product (yield: 79.3%). LC-MS: rt=2.01 min, [ m+h ] ⁺ = 427.32.

Step F: synthesis of (S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acethydrazide

Ethyl (S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole) acetate (4.75 g, 11.1 mmol) was added to the reaction flask, ethanol (50.0 ml), hydrazine hydrate (3.75 ml, 60.05 mmol, 80% purity) was added and stirred at 80 degrees celsius for 2 hours.

LC-MS detection showed complete reaction, after the reaction solution was cooled to room temperature, concentrated under reduced pressure and evaporated to dryness, 4.50 g of (S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acethydrazide was obtained as a brown oily product (yield: 96.4%). LC-MS: rt=1.79 min, [ m+h ] ⁺ = 413.22.

Step G: synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyphenyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acethydrazide (4.50 g, 10.70 mmol), (S) -2-hydroxy-prochloraz hydrochloride (1.6 g, 12.80 mmol) and sodium ethoxide (1.70 g, 25.7 mmol) were added to a reaction flask, DMF (50.0 ml) was added and stirred at 120℃for 2 hours.

LC-MS detection showed complete reaction, after the reaction solution was cooled to room temperature, water (100 ml) was added, ethyl acetate (60 ml. Times.6) was extracted, and the organic phases were combined, washed successively with water (20 ml. Times.2), saturated brine (20 ml. Times.4), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 3.95 g of the product 4-chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyphenyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a brown oil (yield: 73.4%). LC-MS: rt=1.85 min, [ m+h ] ⁺ = 466.22.

Step H: synthesis of 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyphenyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (250.0 mg, 0.53 mmol) was dissolved in pyridine (4.0 ml), and (3-chloro-5-fluorophenyl) boric acid (186.00 mg, 1.07 mmol) and copper acetate (195.00 mg, 1.07 mmol) were added and stirred at 50 degrees celsius for 18 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and evaporation to dryness. The residue was purified by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase A acetonitrile, mobile phase B water+0.05% saturated aqueous ammonia) separated and purified to give 53.30 mg of white solid 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield ：16.9％).LC-MS：RT＝2.09min,[M+H]⁺＝594.12,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.67-7.62(m,2H),7.62-7.51(m,5H),6.71(s,1H),5.87(d,J＝5.6Hz,1H),5.00(d,J＝2.0Hz,1H),4.92-4.82(m,2H),4.22-4.10(m,1H),3.90(dd,J＝14.4,4.0Hz,1H),3.77(dd,J＝14.4,8.8Hz,1H),1.47(d,J＝6.4Hz,3H); after lyophilization yields 14.9 mg of white solid 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield ：16.9％).LC-MS：RT＝2.09min,[M+H]⁺＝594.12,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.67-7.62(m,2H),7.62-7.51(m,5H),6.71(s,1H),5.87(d,J＝5.6Hz,1H),5.00(d,J＝2.0Hz,1H),4.92-4.82(m,2H),4.22-4.10(m,1H),3.90(dd,J＝14.4,4.0Hz,1H),3.77(dd,J＝14.4,8.8Hz,1H),1.47(d,J＝6.4Hz,3H); after lyophilization to give 14.9 mg of white solid 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl ] -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2H-imidazol-2-one (yield 35.73. 37.37.09% by LC=3.09.7.m.

EXAMPLE 20 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyphenyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (250.0 mg, 0.53 mmol) was dissolved in pyridine (4.0 ml), (3-chlorophenyl) boric acid (156.00 mg, 1.07 mmol) and copper acetate (195 mg, 1.07 mmol) were added and stirred at 50 degrees celsius for 18 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combining the organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration of the organic phase under reduced pressure. The resulting residue was purified by preparative HPLC (column: agilent 5Prep-C18100mm x 30mm 5 μm, mobile phase a: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to afford, after lyophilization, 15.53 mg of white solid 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield ：5.08％).LC-MS：RT＝2.07min,[M+H]⁺＝576.11,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.67-7.62(m,2H),7.62-7.51(m,5H),6.71(s,1H),5.87(d,J＝5.6Hz,1H),5.00(d,J＝2.0Hz,1H),4.92-4.82(m,2H),4.22-4.10(m,1H),3.90(dd,J＝14.4,4.0Hz,1H),3.77(dd,J＝14.4,8.8Hz,1H),1.47(d,J＝6.4Hz,3H);) was lyophilized to afford 5.13 mg of white solid 4-chloro-3- ((1- (3-chloro-5-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield ：5.08％).LC-MS：RT＝2.07min,[M+H]⁺＝576.11,¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.67-7.62(m,2H),7.62-7.51(m,5H),6.71(s,1H),5.87(d,J＝5.6Hz,1H),5.00(d,J＝2.0Hz,1H),4.92-4.82(m,2H),4.22-4.10(m,1H),3.90(dd,J＝14.4,4.0Hz,1H),3.77(dd,J＝14.4,8.8Hz,1H),1.47(d,J＝6.4Hz,3H); after lyophilization to afford 5.13 mg of white solid [ 1- (3-chloro-5-fluorophenyl) -1- ((S) -3, 3-triazol-5-yl) methyl) -1H-3-dihydro-imidazol-2-one (yield: 86 m=52.07:86M =2.07.h =2.percent.

EXAMPLE 21 Synthesis of 4- (4-chlorophenyl) -1- ((1- (3-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A:4- (4-chlorophenyl) -1- ((1- (3-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4- (4-chlorophenyl) -1- ((1- (3-methylphenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (230 mg, 0.54 mmol) was dissolved in pyridine (4 ml), 3-methylphenylboronic acid (181 mg, 1.33 mmol) and copper acetate (243 mg, 1.33 mmol) were added and stirred at 40℃for 24 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml×6), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, and purification of the residue by column chromatography on silica gel (eluent: ethyl acetate, then replaced with dichloromethane/methanol=10/1), the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase a: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give after lyophilization 15.28 mg of the white solid product 4- (4-chlorophenyl) -1- ((1- (3-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield :5.5％)¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.53(dd,J＝19.2,6.8Hz,4H),7.46-7.38(m,3H),7.35-7.30(m,1H),6.82(s,1H),6.74(d,J＝6.0Hz,1H),5.69(d,J＝6.4Hz,1H),4.89(s,2H),4.79-4.74(m,1H),4.35-4.20(m,1H),3.91(dd,J＝14.4,3.6Hz,1H),3.77(dd,J＝14.4,9.2Hz,1H),2.38(s,3H),1.45(d,J＝6.4Hz,3H). and 7.25 mg of the white solid product 4- (4-chlorophenyl) -1- ((1- (3-methylphenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -3- ((S) -3, 3-trifluoro-17-chloro-propan-1- (4-chlorophenyl) methyl) 2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 2.8%). LC-MS: rt=1.98 min, [ m+h ] ⁺ = 522.19.

EXAMPLE 22 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-trifluoromethoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A:4- (4-chlorophenyl) -1- ((1- (2-trifluoromethoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (200 mg, 0.46 mmol) was dissolved in pyridine (4 ml), 2-trifluoromethoxybenzeneboronic acid (239 mg, 1.16 mmol) and copper acetate (316 mg, 1.74 mmol) were added and stirred at 50℃for 56 hours.

LC-MS detection showed complete reaction, reduced pressure concentration to remove organic solvent, adding water (5 ml) and ethyl acetate (5 ml) dilution, ethyl acetate (10 ml×5) extraction, combining organic phases, saturated saline (5 ml) washing, anhydrous sodium sulfate drying, filtration, reduced pressure concentration to dryness, purification of the residue by silica gel column chromatography (eluent: ethyl acetate, then dichloromethane/methanol=10/1) to obtain crude product, purification by preparative HPLC (column: agilent 5Prep-C18100mm×30mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated ammonia water), freeze drying to obtain 4.5 mg white solid 4- (4-chlorophenyl) -1- ((1- (2-trifluoromethoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (MS-6%) yield: rt=2.00 min, [ m+h ] ⁺ = 592.1

EXAMPLE 23 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A:4- (4-chlorophenyl) -1- ((1- (2-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (230 mg, 0.54 mmol) was dissolved in pyridine (4 ml), 2-methylphenylboronic acid (181 mg, 1.33 mmol) and copper acetate (243 mg, 1.33 mmol) were added and stirred at 40℃for 24 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combining the organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, purification of the residue by column chromatography over silica gel (eluent: ethyl acetate, then dichloromethane/methanol=10/1), purification of the crude product obtained by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia), freeze drying to give 30.5 mg of white solid product 4- (4-chlorophenyl) -1- ((1- (2-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 10.8%). LC-MS: rt=1.98 min, [ m+h ] ⁺ = 522.24.

EXAMPLE 24 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (200.0 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), and (3-fluorophenyl) boric acid (129.00 mg, 0.92 mmol) and copper acetate (168 mg, 0.92 mmol) were added and reacted to 50 degrees celsius for 18 hours at room temperature.

LC-MS detection showed complete reaction, concentration, addition of water (10 ml) and ethyl acetate (10 ml), ethyl acetate (10 ml. Times.6), washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration. The resulting residue was purified by preparative HPLC (mobile phase A: acetonitrile, mobile phase B: water+0.05% ammonia) and lyophilized to give 23.93 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 9.27%). LC-MS: rt=2.02 min, [ m+h ] ⁺ = 560.15 and 8.74 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.39%). LC-MS: rt=2.02 min, [ m+h ] ⁺ = 560.15.

EXAMPLE 25 Synthesis of 4-chloro-3- ((1- (3-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-3- ((1- (3-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4-chloro-3- ((1- (3-chloro-4-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (200.0 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), and (3-chloro-4-fluorophenyl) boric acid (161.00 mg, 0.92 mmol) and copper acetate (168 mg, 0.92 mmol) were added and heated to 50 degrees celsius for reaction for 18 hours at room temperature.

LC-MS detection showed complete reaction, concentration, addition of water (10 ml) and ethyl acetate (10 ml), ethyl acetate (10 ml. Times.6), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration. The resulting residue was purified by preparative HPLC (mobile phase A: acetonitrile, mobile phase B: water+0.05% ammonia) and lyophilized to give 9.39 mg of white solid 4-chloro-3- ((1- (3-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.44%). LC-MS: rt=2.07 min, [ m+h ] ⁺ = 594.07 and 5.6 mg of white solid 4-chloro-3- ((1- (3-chloro-4-fluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -5- (4-chloro) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 2.05%). LC-MS: rt=2.07 min, [ m+h ] ⁺ = 594.07.

EXAMPLE 26 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-difluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (200.0 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), and (3, 5-difluorophenyl) boric acid (155.00 mg, 0.92 mmol) and copper acetate (168 mg, 0.92 mmol) were added and reacted to 50 degrees celsius for 18 hours at room temperature.

LC-MS detection showed complete reaction, concentration, addition of water (10 ml) and ethyl acetate (10 ml), ethyl acetate (10 ml. Times.6), combined organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration. The resulting residue was purified by preparative HPLC (mobile phase A: acetonitrile, mobile phase B: water+0.05% ammonia) and lyophilized to give 16.72 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 6.28%). LC-MS: rt=2.05 min, [ m+h ] ⁺ = 578.13 and 5.57 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-difluorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 2.09%). LC-MS: rt=2.05 min, [ m+h ] ⁺ = 578.13.

EXAMPLE 27 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4-chloro-5- (4-chloro) -3- ((1- (3, 5-dichlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (200.0 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), and (3, 5-dichlorophenyl) boric acid (177.00 mg, 0.92 mmol) and copper acetate (168 mg, 0.92 mmol) were added and reacted at 50 degrees celsius for 18 hours at room temperature.

LC-MS detection showed complete reaction, concentration, addition of water (10 ml) and ethyl acetate (10 ml), ethyl acetate (10 ml. Times.6), washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration. The resulting residue was purified by preparative HPLC (mobile phase A: acetonitrile, mobile phase B: water+0.05% ammonia) and lyophilized to give 24.24 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 8.62%). LC-MS: rt=2.14 min, [ m+h ] ⁺ = 610.05 and 5.77 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 5-dichlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 2.05%). LC-MS: rt=2.14 min, [ m+h ] ⁺ = 610.05.

EXAMPLE 28 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (200.0 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), and (2-chlorophenyl) boric acid (144.00 mg, 0.92 mmol) and copper acetate (168 mg, 0.92 mmol) were added and reacted to 50 degrees celsius for 18 hours at room temperature.

LC-MS detection showed complete reaction, concentration, addition of water (10 ml) and ethyl acetate (10 ml), ethyl acetate (10 ml. Times.6), washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration. The resulting residue was purified by preparative HPLC (mobile phase a: acetonitrile, mobile phase B: water+0.05% aqueous ammonia) and lyophilized to give 5.22 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 1.97%), LC-MS: rt=2.02 min, [ m+h ] ⁺ = 576.08.

EXAMPLE 29 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one and 4-chloro-5- (4-chlorophenyl) -3- ((1- (4-chlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (200.0 mg, 0.46 mmol) was dissolved in pyridine (4.0 ml), and (4-chlorophenyl) boric acid (144.00 mg, 0.92 mmol) and copper acetate (168 mg, 0.92 mmol) were added and reacted to 50 degrees celsius for 18 hours at room temperature.

LC-MS detection showed complete reaction, concentration, addition of water (10 ml) and ethyl acetate (10 ml), ethyl acetate (10 ml. Times.6), washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration. The resulting residue was purified by preparative HPLC (mobile phase a: acetonitrile, mobile phase B: water+0.05% aqueous ammonia) and lyophilized to give 40.48 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 15.2%), [ m+h ] ⁺ =2.04 min and 6.38 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (4-chlorophenyl) -3- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-5-yl) methyl) -1- (((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 15.2%), [ m+h ] ⁺ = 576.09 and [ m+h ] ⁺ =35 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((S) -1,2, 4-triazol-5-yl) methyl).

EXAMPLE 30 Synthesis of 4- (4-chlorophenyl) -1- ((1- (3, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (3, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method one, starting material 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (250 mg, 0.58 mmol) was added and after lyophilization 9.0 mg of white solid product 4- (4-chlorophenyl) -1- ((1- (3, 5-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 2.7%) was obtained, LC-MS: rt=2.09 min, [ m+h ] += 576.10

EXAMPLE 31 Synthesis of 4- (4-chlorophenyl) -1- ((1- (pyridin-3-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (pyridin-3-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method one, starting material 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (250 mg, 0.58 mmol) was added to give 9.0 mg of white solid product 4- (4-chlorophenyl) -1- ((1- (pyridin-3-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 6.8%) after lyophilization, LC-MS: rt=1.77 min, [ m+h ] += 509.14

EXAMPLE 32 Synthesis of 4- (4-chlorophenyl) -1- ((1- (pyridin-4-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (pyridin-4-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method one, starting material 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (250 mg, 0.58 mmol) was added to give 9.0 mg of white solid product 4- (4-chlorophenyl) -1- ((1- (pyridin-4-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.0%) after lyophilization, LC-MS: rt=1.84 min, [ m+h ] += 509.12

EXAMPLE 33 Synthesis of 4- (4-chlorophenyl) -1- ((1- (4-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (4-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method one, starting material 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (250 mg, 0.58 mmol) was added and after lyophilization 18.0 mg of white solid product 4- (4-chlorophenyl) -1- ((1- (4-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 5.5%) was obtained, LC-MS: rt=2.04 min, [ m+h ] += 560.13

EXAMPLE 34 Synthesis of 4- (4-chlorophenyl) -1- ((1- (3, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (3, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method one, starting material 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (250 mg, 0.58 mmol) was added and after lyophilization 16.0 mg of white solid product 4- (4-chlorophenyl) -1- ((1- (3, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 2.7%) was obtained, LC-MS: rt=2.00 min, [ m+h ] += 576.10

EXAMPLE 35 Synthesis of 4- (4-chlorophenyl) -1- ((1- (3, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (3, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method one, starting material 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (250 mg, 0.58 mmol) was added and after lyophilization 13.0 mg of white solid product 4- (4-chlorophenyl) -1- ((1- (3, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.9%) was obtained, LC-MS: rt=2.04 min, [ m+h ] += 576.10

EXAMPLE 36 Synthesis of 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1- (3- (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1- (3- (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method one, starting material 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (400 mg, 0.93 mmol) was added and after lyophilization 63.24 mg of white solid product 4- (4-chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1- (3- (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 12.6%) was obtained, LC-MS: rt=2.04 min, [ m+h ] += 576.22; after lyophilization 17.41 mg of white solid 4- (4-chlorophenyl) -1- ((3- ((S) -1-hydroxyethyl) -1- (3- (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-5-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.5%), LC-MS: rt=2.07 min, [ m+h ] += 576.22.

EXAMPLE 37 Synthesis of 4- (4-chlorophenyl) -1- ((1- (3-chloropyridin-2-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (3-chloropyridin-2-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 9.0 mg of 4- (4-chlorophenyl) -1- ((1- (3-chloropyridin-2-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 3.0%) as a white solid after addition of starting (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (214.9 mg, 0%). LC-MS: rt=1.91 min, [ m+h ] += 543.13.

EXAMPLE 38 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2- (trifluoromethyl) phenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2- (trifluoromethyl) phenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (214.9 mg, 0.57 mmol) was added and the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 23.0 mg of 4- (4-chlorophenyl) -1- ((1- (2- (trifluoromethyl) phenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 7.0%). LC-MS: rt=1.98 min, [ m+h ] += 576.15.

EXAMPLE 39 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 30 mg of 4- (4-chlorophenyl) -1- ((1- (2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 19.70%). LC-MS: rt=1.95 min, [ m+h ] += 526.15.

EXAMPLE 40 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 6-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 6-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 32 mg of 4- (4-chlorophenyl) -1- ((1- (2, 6-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 19.16%). LC-MS: rt=1.98 min, [ m+h ] += 576.08.

EXAMPLE 41 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 15 mg of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 9.25%). LC-MS: rt=2.00 min, [ m+h ] += 560.10.

EXAMPLE 42 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 35 mg of white solid 4- (4-chlorophenyl) -1- ((1- (2, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 20.92%). LC-MS: rt=2.04 min, [ m+h ] += 578.08/576.10.

EXAMPLE 43 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-5-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-5-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 38 mg of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-5-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 23.44%). LC-MS: rt=2.00 min, [ m+h ] += 560.10.

EXAMPLE 44 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 36 mg of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-4-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 22.21%). LC-MS: rt=2.02 min, [ m+h ] += 560.10.

EXAMPLE 45 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 42 mg of 4- (4-chlorophenyl) -1- ((1- (2, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 26.67%). LC-MS: rt=1.97 min, [ m+h ] += 544.13.

EXAMPLE 46 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 6-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 6-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 18 mg of 4- (4-chlorophenyl) -1- ((1- (2, 6-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 11.43%). LC-MS: rt=1.97 min, [ m+h ] += 544.13.

EXAMPLE 47 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-6-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-6-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 32 mg of 4- (4-chlorophenyl) -1- ((1- (2-fluoro-6-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 19.74%). LC-MS: rt=1.98 min, [ m+h ] += 560.10.

EXAMPLE 48 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 27 mg of 4- (4-chlorophenyl) -1- ((1- (2-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 16.66%). LC-MS: rt=1.98 min, [ m+h ] += 560.15.

EXAMPLE 49 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4- (4-chlorophenyl) -1- ((1- (2, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method two, starting material (S) -2- (4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (110 mg, 0.29 mmol) was added and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate) or by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. Mu.m, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 28 mg of 4- (4-chlorophenyl) -1- ((1- (2, 5-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 17.78%). LC-MS: rt=1.97 min, [ m+h ] += 544.17.

EXAMPLE 50 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

Following procedure three, starting (S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetylimine (238 mg, 0.58 mmol) was added and the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100mm x 30mm 5 μm, mobile phase a: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 95 mg of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 4-dichlorophenyl) -5- ((S) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (two step total yield: 26.80%) as a white solid. LC-MS: rt=2.07 min, [ m+h ] += 612.17.

EXAMPLE 51 Synthesis of 4-chloro-3- ((1- (4-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of 4-chloro-3- ((1- (4-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method three, starting material (S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetylimine (238 mg, 0.58 mmol) was added and the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 124 mg of white solid 4-chloro-3- ((1- (4-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -5- (4-chlorophenyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (two step total yield: 36.04%). LC-MS: rt=2.07 min, [ m+h ] += 594.17.

EXAMPLE 52 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method three, starting material (S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetylimine (238 mg, 0.58 mmol) was added and the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 107 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3, 4-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- (S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (two step total yield: 31.94%). LC-MS: rt=2.07 min, [ m+h ] += 578.33.

EXAMPLE 53 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1- (2-methylpyridin-3-yl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1- (2-methylpyridin-3-yl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

According to method three, starting material (S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetylimine (238 mg, 0.58 mmol) was added and the crude product was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm. 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to give 84 mg of 4-chloro-5- (4-chlorophenyl) -3- ((5- ((S) -1-hydroxyethyl) -1- (2-methylpyridin-3-yl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (two step total yield: 26.09%). LC-MS: rt=1.98 min, [ m+h ] += 557.33.

EXAMPLE 54 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 3-difluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 3-difluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (2, 3-dichlorophenyl) hydrazine hydrochloride (124 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 113 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 3-dichlorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 32.7%). LC-MS: rt=2.16 min, [ m+h ] ⁺ = 652.10.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 3-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 3-dichlorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (113 mg, 0.17 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (27.7 mg, 0.69 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 102 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 3-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 98.4%). LC-MS: rt=2.07 min, [ m+h ] ⁺ = 610.05.

EXAMPLE 55 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-5-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (2-chloro-5-fluorophenyl) hydrazine hydrochloride (114 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 117 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-5-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 34.7%). LC-MS: rt=2.13 min, [ m+h ] ⁺ = 636.10.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-5-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (117 mg, 0.18 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (29.4 mg, 0.72 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 102 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 98.4%). LC-MS: rt=2.04 min, [ m+h ] ⁺ = 594.10.

EXAMPLE 56 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-4-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (2-chloro-4-fluorophenyl) hydrazine hydrochloride (114 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 103 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-4-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 30.6%). LC-MS: rt=2.12 min, [ m+h ] ⁺ = 636.08.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-4-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (103 mg, 0.16 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (25.9 mg, 0.65 mmol) was added to react for 2 hours.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 95 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-4-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 98.4%). LC-MS: rt=2.06 min, [ m+h ] ⁺ = 594.09.

EXAMPLE 57 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-6-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-6-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (2-chloro-6-fluorophenyl) hydrazine hydrochloride (114 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 120 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-6-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 35.6%). LC-MS: rt=2.11 min, [ m+h ] ⁺ = 636.12.

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-6-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (120 mg, 0.19 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (25.9 mg, 0.65 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 109 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-6-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 96.6%). LC-MS: rt=2.04 min, [ m+h ] ⁺ = 594.10.

EXAMPLE 58 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (3-chloro-4-fluorophenyl) hydrazine hydrochloride (94 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 75 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 23.5%). LC-MS: rt=2.09 min, [ m+h ] ⁺ = 602.17.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (75 mg, 0.12 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (20 mg, 0.5 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 65 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 96.7%). LC-MS: rt=2.00 min, [ m+h ] ⁺ = 560.12.

EXAMPLE 59 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloropyridin-2-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloropyridin-2-yl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (3-chloropyridin-2-yl)) hydrazine hydrochloride (104 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was then added and reacted at room temperature for 1 hour, and at 70 degrees celsius for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 100 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloropyridin-2-yl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 30.5%). LC-MS: rt=2.05 min, [ m+h ] ⁺ = 619.04.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloropyridin-2-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloropyridin-2-yl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (100 mg, 0.16 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (26 mg, 0.65 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 70 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloropyridin-2-yl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 75.8%). LC-MS: rt=1.98 min, [ m+h ] ⁺ = 577.17.

EXAMPLE 60 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloro-6-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloro-6-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (3-chloro-6-fluorophenyl) hydrazine hydrochloride (114 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 100 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloro-6-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 29.7%). LC-MS: rt=2.13 min, [ m+h ] ⁺ = 636.11.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloro-6-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloro-6-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (100 mg, 0.16 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (25.6 mg, 0.64 mmol) was added to react for 2 hours.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 81 mg of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloro-6-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 85.2%). LC-MS: rt=2.07 min, [ m+h ] ⁺ = 594.07.

EXAMPLE 61 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloro-2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloro-2-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (3-chloro-2-fluorophenyl) hydrazine hydrochloride (114 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 106 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloro-2-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 31.4%). LC-MS: rt=2.14 min, [ m+h ] ⁺ = 636.14.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloro-2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-chloro-2-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (106 mg, 0.17 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (26.7 mg, 0.67 mmol) was added to react for 2 hours.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 79 mg of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-chloro-2-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 79.4%). LC-MS: rt=2.07 min, [ m+h ] ⁺ = 594.07.

EXAMPLE 62 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 6-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 6-dichlorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (2, 6-dichlorophenyl) hydrazine hydrochloride (124 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 128 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 6-dichlorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 37.1%). LC-MS: rt=2.14 min, [ m+h ] ⁺ = 652.11.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 6-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 6-dichlorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (128 mg, 0.20 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (32 mg, 0.80 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 102 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 6-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 83.6%). LC-MS: rt=2.05 min, [ m+h ] ⁺ = 610.03.

EXAMPLE 63 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-trifluoromethylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-trifluoromethylphenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (2-trifluoromethylphenyl) hydrazine hydrochloride (123 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 82 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-trifluoromethylphenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 23.7%). LC-MS: rt=2.13 min, [ m+h ] ⁺ = 652.17.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-trifluoromethylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-trifluoromethylphenyl) -1H-1,2, 4-triazol-5-yl) ethyl acetate (82 mg, 0.13 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (20 mg, 0.50 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 70 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-trifluoromethylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 88.3%). LC-MS: rt=2.07 min, [ m+h ] ⁺ =610.15.

EXAMPLE 64 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-trifluoromethylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-trifluoromethylphenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (3-trifluoromethylphenyl) hydrazine hydrochloride (123 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 87 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-trifluoromethylphenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 25.2%). LC-MS: rt=2.14 min, [ m+h ] ⁺ = 652.12.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-trifluoromethylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-trifluoromethylphenyl) -1H-1,2, 4-triazol-5-yl) ethyl acetate (87 mg, 0.13 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (20 mg, 0.50 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 81 mg of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-trifluoromethylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 88.3%). LC-MS: rt=2.09 min, [ m+h ] ⁺ =610.14.

EXAMPLE 65 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-methylphenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (2-methylphenyl) hydrazine hydrochloride (92 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 67 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-methylphenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 21.1%). LC-MS: rt=2.11 min, [ m+h ] ⁺ = 598.19.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-methylphenyl) -1H-1,2, 4-triazol-5-yl) ethyl acetate (67 mg, 0.11 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (17.9 mg, 0.45 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 51 mg of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one as a white solid (yield: 83.4%). LC-MS: rt=2.04 min, [ m+h ] ⁺ = 556.15.

EXAMPLE 66 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-methylphenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-ylacetate (73. Mu.l, 0.58 mmol) was added under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (3-methylphenyl) hydrazine hydrochloride (92 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 83 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-methylphenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 26.2%). LC-MS: rt=2.13 min, [ m+h ] ⁺ = 598.20.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (3-methylphenyl) -1H-1,2, 4-triazol-5-yl) ethyl acetate (83 mg, 0.14 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (22 mg, 0.56 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 76 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (3-methylphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 97.6%). LC-MS: rt=2.05 min, [ m+h ] ⁺ = 556.17.

EXAMPLE 67 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-3-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (2-chloro-3-fluorophenyl) hydrazine hydrochloride (114 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Glacial acetic acid (2 ml) was added and reacted at room temperature for 1 hour, and the temperature was raised to 70℃and reacted for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 112 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-3-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 33.2%). LC-MS: rt=2.13 min, [ m+h ] ⁺ = 636.12.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2-chloro-3-fluorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (112 mg, 0.18 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml) and sodium hydroxide (28.2 mg, 0.70 mmol) was added. The reaction was carried out at room temperature for 2 hours.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 100 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2-chloro-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 93.5%). LC-MS: rt=2.04 min, [ m+h ] ⁺ = 594.10.

EXAMPLE 68 Synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 4-dichlorophenyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-chloro-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (218.36 mg, 0.53 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 ml) and toluene (2 ml) at room temperature, and N, N-diisopropylethylamine (175. Mu.l, 1.06 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (73. Mu.l, 0.58 mmol) was added sequentially under ice-water bath conditions. Stirring was carried out at room temperature for 1 hour. (2, 4-dichlorophenyl) hydrazine hydrochloride (124 mg, 0.58 mmol) and N, N-diisopropylethylamine (262. Mu.l, 1.59 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the reaction system. Glacial acetic acid (2 ml) was then added and reacted at room temperature for 1 hour, and at 70 degrees celsius for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 123 mg of a brown solid product as ethyl (S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 4-dichlorophenyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 35.6%). LC-MS: rt=2.16 min, [ m+h ] ⁺ = 652.11.

And (B) step (B): synthesis of 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

(S) -1- (3- ((5-chloro-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1- (2, 4-dichlorophenyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (123 mg, 0.19 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml), and sodium hydroxide (30 mg, 0.75 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (40 ml), extracted with ethyl acetate (20 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 95 mg of white solid 4-chloro-5- (4-chlorophenyl) -3- ((1- (2, 4-dichlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 82.0%). LC-MS: rt=2.11 min, [ m+h ] ⁺ = 610.09.

Example 69 Synthesis of 5- (4-chlorophenyl) -3- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile

The specific synthesis route one is as follows:

step A: synthesis of 2-amino-1- (4-chlorophenyl) ethan-1-one hydrochloride

2-Bromo-1- (4-chlorophenyl) ethan-1-one (20.00 g, 85.84 mmol) and sodium diformylamide (19.78 g, 206.02 mmol) were added to the reaction flask at room temperature, acetonitrile (400.0 ml) was added and the temperature was raised to 80℃for 2 hours.

2-Amino-1- (4-chlorophenyl) ethyl-1-one hydrochloride (18.60 g, 90.29 mmol) was added to a reaction flask at room temperature, tetrahydrofuran (200.0 ml) and triethylamine (29.0 ml, 212.18 mmol) were added, nitrogen was replaced three times, and ethyl 2-isocyanate (12.0 ml, 108.35 mmol) was added dropwise under nitrogen protection for 1 hour. LC-MS detection shows that the reaction is complete, and the reaction solution is directly used for the next step without treatment. LC-MS: rt=1.79 min, [ m+h ] ⁺ = 299.19.

Trifluoroacetic acid (101.0 ml, 1.35 mol) was added to the reaction mixture at room temperature, and the mixture was heated to 60℃for 3 hours. LC-MS detection showed complete reaction, after the reaction solution cooled to room temperature, water (400.0 ml) was added, ethyl acetate (200 ml. Times.3) was extracted, and the organic phases were combined, washed successively with saturated sodium bicarbonate (100X 4 ml), saturated sodium chloride (20.0 ml), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 24.40 g of ethyl 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate as a yellow solid (two-step yield: 96.3%). LC-MS: rt=1.84 min, [ m+h ] ⁺ =281.14.

Step D: synthesis of ethyl 2- (4-bromo-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate

Ethyl 2- (5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate (15.00 g, 53.38 mmol) was added to the reaction flask at room temperature, acetonitrile (150.0 ml) was added, and N-bromosuccinimide (9.50 g, 53.38 mmol) was added under ice bath to react for 30 minutes at zero degrees celsius.

LC-MS detection showed complete reaction, extraction with water (200 ml), ethyl acetate (150 ml. Times.3) and combined organic phases, which were washed successively with water (100 ml), saturated brine (50 ml. Times.1). Dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 11.16 g of a brown solid product synthesized 2- (4-bromo-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid ethyl ester crude (yield: 58.40%). LC-MS: rt=1.92 min, [ m+h ] ⁺ = 359.25.

Step E: synthesis of 2- (4-bromo-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid

Ethyl 2- (4-bromo-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetate (11.10 g, 31.01 mmol) was added to the reaction flask at room temperature, tetrahydrofuran (75.0 ml), methanol (25.0 ml) and water (25.0 ml) were added, and potassium hydroxide (6.94 g, 124.02 mmol) was added. The temperature is raised to 60 ℃ and the reaction is carried out for 2 hours.

LC-MS detection showed complete reaction. After the reaction solution was cooled to room temperature, the organic solvent was removed by concentration, dichloromethane (30.0 ml. Times.1) was extracted, the aqueous solution was adjusted to pH=3-4 with hydrochloric acid (6 mol/l), a solid was precipitated, filtration was performed, and the cake was washed with water (10 ml. Times.3), and dried under vacuum to give 8.20 g of 2- (4-bromo-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid (yield: 80.1%) as a yellow solid. LC-MS: rt=1.77 min, [ m+h ] ⁺ = 330.98.

Step F: synthesis of 4-bromo-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-oxopropyl) -1, 3-dihydro-2H-imidazol-2-one

2- (4-Bromo-5- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl) acetic acid (8.10 g, 24.55 mmol) was added to the reaction flask at room temperature, pyridine (150.0 ml) was added, nitrogen replaced three times, and nitrogen blanket was reduced to zero degrees Celsius. Trifluoroacetic anhydride (17.07 ml, 122.75 mmol) was added and the reaction was carried out at room temperature for 1 hour. Concentrated, diluted hydrochloric acid (200.0 ml, 0.50 mol/l) was added, and the mixture was heated to 70℃to react for 1 hour.

LC-MS detection showed complete reaction, extraction with dichloromethane (100 ml. Times.3), washing of the combined organic phases with saturated brine (50 ml), drying over anhydrous magnesium sulfate, filtration, concentration under reduced pressure and evaporation of the crude compound by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) gave 1.59 g of 4-bromo-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-oxopropyl) -1, 3-dihydro-2H-imidazol-2-one (yield: 16.95%) as a pale yellow solid. LC-MS: rt=1.96 min, [ M-1] ^- = 380.98.

Step G: synthesis of (S) -4-bromo-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4-Bromo-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-oxo-propyl) -1, 3-dihydro-2H-imidazol-2-one (1.59 g, 4.16 mmol) was added to a reaction flask, DMA (20.0 ml) was added, nitrogen was replaced three times, formic acid (0.78 ml, 20.81 mmol) was added under nitrogen, triethylamine (0.32 ml, 2.50 mmol) and ruthenium (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine (p-isopropylbenzene) chloride (52.93 mg, 0.08 mmol) were reacted for 3 hours at room temperature.

LC-MS detection showed complete reaction, addition of water (100 ml), extraction with ethyl acetate (50 ml. Times.3), combining the organic phases, washing sequentially with water (100 ml), saturated brine (50 ml. Times.2). Dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness to give 1.38 g of (S) -4-bromo-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (crude) as a brown solid product. LC-MS: rt=1.94 min, [ M-1] ^- = 382.99.

Step H: synthesis of (S) -2- (5-bromo-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetonitrile

(S) -4-bromo-5- (4-chlorophenyl) -1- (3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (1.50 g, 4.95 mmol) was added to a reaction flask at room temperature, acetonitrile (20.0 ml), potassium carbonate (1.25 g, 9.80 mmol), 2-bromoacetonitrile (712.8 mg, 5.94 mmol) was added and the temperature was raised to 60℃for 2 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, the reaction solution is filtered, the filter cake is washed three times by acetonitrile, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The crude product was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 1.30 g of (S) -2- (5-bromo-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetonitrile as a brown solid product (yield: 78.7%). LC-MS: rt=1.98 min, [ m+h ] ⁺ = 423.99.

Step I: synthesis of (S) -2- (5-bromo-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine

(S) -2- (5-bromo-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) acetonitrile (341 mg, 0.75 mmol) was added to the reaction flask at room temperature, methanol (5.0 ml) was added, and sodium methoxide methanol solution (5 mol/liter, 10 μl, 0.75 mmol) was warmed to 50℃for 1 hour. After completion of the reaction, the mixture was concentrated to give 320 mg of crude (S) -2- (5-bromo-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine as a brown solid product (yield: 100%).

Step J: synthesis of ethyl (S) -1- (1- (3-chlorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-bromo-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (341 mg, 0.75 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 ml) and toluene (3 ml), and N, N-diisopropylethylamine (0.27 ml, 1.50 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (0.10 ml, 0.83 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (3-chlorophenyl) hydrazine hydrochloride (148.6 mg, 0.83 mmol) and N, N-diisopropylethylamine (0.4 ml, 2.25 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction. After 1 hour of reaction at room temperature, the temperature was raised to 70℃for 18 hours of reaction.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 172 mg of a brown solid product as ethyl (S) -1- (1- (3-chlorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 34.8%). LC-MS: rt=2.13 min, [ m+h ] ⁺ = 664.11.

Step K: synthesis of ethyl (S) -1- (1- (3-chlorophenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate

Ethyl (S) -1- (1- (3-chlorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (170 mg, 0.26 mmol) was added to the reaction flask, and cuprous cyanide (115.16 mg, 1.29 mmol) was added and a solution of N, N-dimethylformamide (10 μl) was warmed to 130 degrees celsius for 10 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (20 ml) is added for dilution, ethyl acetate (10 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (10 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. 109 mg of crude ethyl (S) -1- (1- (3-chlorophenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 68.95%) was obtained as a brown solid. LC-MS: rt=2.09 min, [ m+h ] ⁺ = 609.22.

Step L: synthesis of 5- (4-chlorophenyl) -3- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile

Ethyl (S) -1- (1- (3-chlorophenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (50 mg, 0.08 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml) and sodium hydroxide (16 mg, 0.40 mmol) was added. The reaction was carried out at room temperature for 2 hours.

LC-MS detection showed that the reaction was complete, diluted with water (20 ml), extracted with ethyl acetate (5 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 31 mg of 5- (4-chlorophenyl) -3- ((1- (3-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile as a white solid (yield: 66.7%). LC-MS: rt=2.04 min, [ m+h ] ⁺ = 567.14.

EXAMPLE 70 Synthesis of 5- (4-chlorophenyl) -3- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile

The specific synthetic route is as follows:

Step A: synthesis of ethyl (S) -1- (1- (3-chloro-5-fluorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-bromo-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (341 mg, 0.75 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 ml) and toluene (3 ml), and N, N-diisopropylethylamine (0.27 ml, 1.50 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (0.10 ml, 0.83 mmol) was added sequentially under ice-water bath conditions. The reaction was carried out at room temperature for 1 hour. (3-chloro-5-fluorophenyl) hydrazine hydrochloride (162.68 mg, 0.83 mmol) and N, N-diisopropylethylamine (0.4 ml, 2.25 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction system. Stirring for 1 hour at room temperature, and heating to 70 ℃ for reaction for 18 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 195 mg of a brown solid product as ethyl (S) -1- (1- (3-chloro-5-fluorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 38.17%). LC-MS: rt=2.14 min, [ m+h ] ⁺ = 682.09.

And (B) step (B): synthesis of ethyl (S) -1- (1- (3-chloro-5-fluorophenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate

Ethyl (S) -1- (1- (3-chloro-5-fluorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (177 mg, 0.26 mmol) was added to the reaction flask, and cuprous cyanide (115.16 mg, 1.29 mmol) and a solution of N, N-dimethylformamide (10 μl) was added and the reaction was warmed to 130 degrees celsius for 10 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (20 ml) is added for dilution, ethyl acetate (10 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (10 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. 117 mg of crude ethyl (S) -1- (1- (3-chloro-5-fluoro-phenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 71.78%) were obtained as a brown solid. LC-MS: rt=2.11 min, [ m+h ] ⁺ = 627.19.

Step C: synthesis of 5- (4-chlorophenyl) -3- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile

(S) -1- (1- (3-chloro-5-fluorophenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetic acid ethyl ester (54.5 mg, 0.08 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml) and sodium hydroxide (16 mg, 0.40 mmol) was added to react for 2 hours at room temperature.

LC-MS detection showed that the reaction was complete, diluted with water (20 ml), extracted with ethyl acetate (5 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 35 mg of 5- (4-chlorophenyl) -3- ((1- (3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile as a white solid (yield: 74.9%). LC-MS: rt=2.06 min, [ m+h ] ⁺ = 585.15.

EXAMPLE 71 Synthesis of 5- (4-chlorophenyl) -3- ((1- (2-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile

The specific synthesis route one is as follows:

Step A: synthesis of ethyl (S) -1- (1- (2-chlorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate

(S) -2- (5-bromo-4- (4-chlorophenyl) -2-oxo-3- (3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) ethylimine (341 mg, 0.75 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 ml) and toluene (3 ml), and N, N-diisopropylethylamine (0.27 ml, 1.50 mmol), (S) -1-chloro-1-oxypropane-2-yl acetate (0.10 ml, 0.83 mmol) was added sequentially under ice-water bath conditions. The reaction was allowed to warm to room temperature for 1 hour. (2-chlorophenyl) hydrazine hydrochloride (148.6 mg, 0.83 mmol) and N, N-diisopropylethylamine (0.4 ml, 2.25 mmol) were dissolved in tetrahydrofuran (2 ml) and added to the above reaction. Stirring for 1 hour at room temperature, and heating to 70 ℃ for reaction for 18 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (50 ml) is added for dilution, ethyl acetate (30 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (20 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give 181 mg of a brown solid product as ethyl (S) -1- (1- (2-chlorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 36.5%). LC-MS: rt=2.11 min, [ m+h ] ⁺ = 662.04.

And (B) step (B): synthesis of ethyl (S) -1- (1- (2-chlorophenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate

Ethyl (S) -1- (1- (2-chlorophenyl) -3- ((5-bromo-4- (4-chlorophenyl) -2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (177 mg, 0.26 mmol) was added to the reaction flask, and cuprous cyanide (115.16 mg, 1.29 mmol) was added and a solution of N, N-dimethylformamide (10 μl) was warmed to 130 degrees celsius for 10 hours.

LC-MS detection shows that the reaction is complete, after the reaction solution is cooled to room temperature, water (20 ml) is added for dilution, ethyl acetate (10 ml. Times.3) is used for extraction, the organic phases are combined, saturated saline (10 ml. Times.3) is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the filtrate is concentrated under reduced pressure and evaporated to dryness. 124 mg of crude ethyl (S) -1- (1- (2-chlorophenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (yield: 71.78%) were obtained as a brown solid. LC-MS: rt=2.09 min, [ m+h ] ⁺ = 609.14.

Step C: synthesis of 5- (4-chlorophenyl) -3- ((1- (2-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile

Ethyl (S) -1- (1- (2-chlorophenyl) -3- ((4- (4-chlorophenyl) -5-cyano-2-oxo-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl) methyl) -1H-1,2, 4-triazol-5-yl) acetate (50.0 mg, 0.08 mmol) was dissolved in tetrahydrofuran/methanol/water (2:1:1, 4.0 ml) and sodium hydroxide (16 mg, 0.40 mmol) was added at room temperature. The reaction was carried out at room temperature for 2 hours.

LC-MS detection showed that the reaction was complete, diluted with water (20 ml), extracted with ethyl acetate (5 ml. Times.3), combined with the organic phase, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=0/100) to give 38 mg of 5- (4-chlorophenyl) -3- ((1- (2-chlorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -2-oxo-1- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazole-4-carbonitrile as a white solid (yield: 82.6%). LC-MS: rt=1.98 min, [ m+h ] ⁺ = 567.19.

EXAMPLE 72 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-deuterated methoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A:4- (4-chlorophenyl) -1- ((1- (2-deuterated methoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (230 mg, 0.54 mmol) was dissolved in pyridine (4 ml), 2-deutero-methoxyphenylboronic acid (206.15 mg, 1.33 mmol) was added, copper acetate (243 mg, 1.33 mmol) and the mixture was heated to 40℃for 24 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove the organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.6), combining the organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, purification of the crude residue by column chromatography over silica gel (eluent: n-hexane/ethyl acetate=0/100, then dichloromethane/methanol=10/1) afforded the crude product which was purified by preparative HPLC (column: agilent 5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) to afford 18.25 mg of the white solid product 4- (4-chlorophenyl) -1- ((1- (2-deuterated methoxyphenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (6.3% yield). LC-MS: rt=1.98 min, [ m+h ] ⁺ = 541.15

EXAMPLE 73 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-methoxy-3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

Step A:4- (4-chlorophenyl) -1- ((1- (2-methoxy-3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (200 mg, 0.46 mmol) was dissolved in pyridine (4 ml), 2-methoxy-3-chloro-5-fluorophenylboronic acid (236.7 mg, 1.16 mmol) and copper acetate (316 mg, 1.74 mmol) were added and the mixture was warmed to 50℃for 56 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate () 10ml×5, combining organic phases, washing with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, purification of the crude residue by column chromatography over silica gel (eluent: n-hexane/ethyl acetate=0/100, then dichloromethane/methanol=10/1) afforded the crude product, purification by preparative HPLC (column: agilent5Prep-C18100mm×30mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water+0.05% saturated aqueous ammonia) afforded 10.3 mg of white solid 4- (4-chlorophenyl) -1- ((1- (2-methoxy-3-chloro-5-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-imidazol-2H-2-one (MS: 3.8%) yield: rt=2.02 min, [ m+h ] ⁺ = 590.09.

EXAMPLE 74 Synthesis of 4- (4-chlorophenyl) -1- ((1- (2-methoxy-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

The specific synthetic route is as follows:

step A:4- (4-chlorophenyl) -1- ((1- (2-methoxy-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one

4- (4-Chlorophenyl) -1- ((5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3-yl) methyl) -3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1, 2, 4-triazol-2-one (200 mg, 0.46 mmol) was dissolved in pyridine (4 ml), 2-methoxy-3-fluorophenylboronic acid (197.2 mg, 1.16 mmol) and copper acetate (316 mg, 1.74 mmol) were added and the mixture was warmed to 50℃for 56 hours.

LC-MS detection showed complete reaction, concentration under reduced pressure to remove organic solvent, dilution with water (5 ml) and ethyl acetate (5 ml), extraction with ethyl acetate (10 ml. Times.5), washing of the combined organic phases with saturated brine (5 ml), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to dryness, purification of the crude residue by column chromatography over silica gel (eluent: n-hexane/ethyl acetate=0/100, then dichloromethane/methanol=10/1) afforded the crude product, purification by preparative HPLC (column: agilent5Prep-C18100 mm. Times.30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: aqueous+0.05% saturated) afforded 11.2 mg of white solid 4- (4-chlorophenyl) -1- ((1- (2-methoxy-3-fluorophenyl) -5- ((S) -1-hydroxyethyl) -1H-1,2, 4-triazol-3- ((S) -3, 3-trifluoro-2-hydroxypropyl) -1, 3-dihydro-2H-imidazol-2-one (LC-4.5%) yield: MS: rt=2.00 min, [ m+h ] ⁺ = 556.17.

Example 75 cell level assay for determining vasopressin receptor Activity in vitro

1. Vasopressin V1a receptor activity assay

1.1 Cell culture and reagent preparation

(1) Human V1a receptor stable cell line: flpIn-CHO-AVPR1Astable pool;

(2) Complete medium, ham's F-12K+10% FBS+1xPenicilin-Streptomycin (PS) +600 μg/ml Hygromycin B;

(3) Cell inoculation culture medium Ham's F-12K+10% FBS

(4) Test buffer 1X HBSS+20mM HEPES.

1.2 Determination of the Activity of test Compounds on the AVPR1A receptor

(1) FlpIn-CHO-AVPR1A stablepool cell line is cultivated in complete medium at 37 ℃ and 5% CO ₂ to 70% -90% fusion degree.

(2) After the TrypLE digestion treatment, the cells were resuspended in seeding medium, seeded in 384 well cell culture plates (Corning, 3764), 7,000 cells were seeded per well and incubated overnight at 37 ℃,5% co ₂.

(3) Freezing and thawing 20X ComponentA to room temperature, diluting to 2X working concentration of 5mM Probenecid with experimental buffer, and standing at room temperature for use.

(4) The cell culture plate was removed, allowed to stand at room temperature for 10min, the concentration of FBS was diluted to 0.03% using Apricot and assay buffer, and 20. Mu.l was finally left in 3764 culture plate, followed by addition of 20. Mu.l 2X ComponentA containing 5mM Probenecid to each assay well, 200g, centrifugation at RT for 3-5sec, and incubation at 37℃for 2hr.

(5) Preparing working solutions (6X) of positive control compounds and compounds to be tested, and standing at room temperature for standby.

(6) ARGIPRESSIN was diluted to 0.6nM (6X) with assay buffer, transferred to 50. Mu.l to 384 well plates (Corning, 3657) and left at room temperature for use.

(7) Taking out the cell culture plate, and standing for 10 minutes at room temperature; add 10. Mu.L of the corresponding compound working solution from step 5 to the corresponding experimental wells of 384 well cell culture plates and incubate at room temperature for 30 minutes.

(8) Mu.l of the compound working solution diluted in step 6 was added to each experimental well using FLIPR TETRA, and the data was collected.

(9) Compound IC50 was calculated using GraphPad nonlinear fit formula.

2. Assay of V2 receptor activity by test compounds

2.1 Cell culture and reagent preparation

(1) Cell lines: flpin-CHO-AVPR2

(2) Complete medium F12K+10% foetal calf serum+1 penicillin streptomycin+800. Mu.g/ml hygromycin

(3) Experimental buffer 1*HBSS+20mM HEPES+0.1%BSA+500. Mu.M IBMX

2.2 Determination of the Activity of test Compounds on V2 receptors

(1) Cells were digested, resuspended in assay buffer, seeded into 384 cell culture plates at a seeding density of 8000 per well and a seeding volume of 15 μl per well.

(2) The compounds were diluted with assay buffer.

(3) Mu.l of compound was added to each well and incubated at 37℃for 10 minutes.

(4) ARGIPRESSIN was diluted to 8 x argipress in (16 pM) with assay buffer.

(5) 2.5 Μl of diluted 8 x argipress was added and incubated for 30 min at 37 ℃.

(6) Freeze thawing Eu-CAMP TRACER and Mlight-anti-cAMP, and diluting with lysis buffer.

(7) Mu.l Eu-CAMP TRACER was added to the wells, followed by 10. Mu. lMlight-anti-cAMP to the wells.

(8) After the reaction plate was centrifuged at 200g at room temperature for 30s and left to stand at 25℃for 1 hour, data were collected by Envision.

(9) Compound IC ₅₀ was calculated using GraphPad nonlinear fit formula.

Table one: in vitro Activity test data for Compounds of the invention

Remarks: "-" means data to be measured

Conclusion: from the above table data, it can be seen that the compounds of the present invention have very high inhibitory activity against vasopressin receptors V1a and V2 and can act as dual antagonists, thereby having utility in the treatment or prevention of antagonism-related disease drugs.

Example 76 inhibition study on major CYP enzymes:

1. Sample preparation: the probe substrates were phenacetin, bupropion, amodiaquine, diclofenac, S-mefenadine, dextromethorphan, testosterone, and midazolam, and stock solutions (100×) of 75mM, 80mM, 10mM, 20mM, 40mM, and 10mM were prepared with methanol, respectively; the positive inhibitor is alpha-naphthacene, ticlopidine, montelukast, sulfabenzene pyrazole, (+) -N-3-benzylnirvanol, quinidine, ketoconazole, and 1mM, 10mM, 3mM, 1mM, 3mM stock solution (100X) prepared by DMSO or methanol; test compounds were formulated with DMSO as 100mM stock; human liver microsomes were diluted to 0.127mg/ml with 100mM potassium phosphate+33 mM MgCl ₂ buffer; the cofactor NADPH was formulated as a 10mM stock solution with 100mM potassium phosphate+33 mM MgCl ₂.

2. Experimental operation: 1. the total volume of the incubation system was 200. Mu.l and the medium was 100mM phosphate buffer. The system comprises human liver particles with a final concentration of 0.10mg/ml, a test compound or positive inhibitor with a final concentration of 30. Mu.M, NADPH with a final concentration of 1mM and a probe substrate with a corresponding concentration; 2. the incubation system was incubated in a 37 ℃ water bath with CYP2C19, CYP2D6 for 20 minutes, CYP3A4-M for 3 minutes and the other subenzymes for 10 minutes. 3. At the end of the reaction, 400. Mu.l of cold stop solution is added to stop the reaction, and the reaction is centrifuged at 4000rpm for 20 minutes to precipitate protein; 4. 200 μl of supernatant was diluted with 100 μl and shaken for 10min; 5. the treated samples were analyzed by LC/MS.

TABLE 2 CYP enzyme inhibition test data for the compounds of the invention

Conclusion: from the above table data, positive drug (BAY 1753011) showed stronger inhibition of multiple major subtypes of CYP enzyme at 30 μm data concentration; however, the compounds of example 1 and the like of the present invention showed weak inhibition of multiple subtypes of CYP enzymes, far superior to positive drugs, indicating less risk of drug interactions.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that,

Wherein R ^1A、R^1B and R ₂ are independently selected from hydrogen, cyano, halogen, alkyl or haloalkyl, alkoxy or haloalkoxy, X, Y and Z are independently selected from CH, N; the alkyl is selected from the group consisting of C _1-4 alkyl and the alkoxy is selected from the group consisting of C _1-4 alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from compounds of formula (Ia), (Ib), (Ic):

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the alkyl group of C _1-4 is selected from methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, tert-butyl; the alkoxy of C _1-4 is selected from methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the halogen is selected from fluorine, chlorine, bromine, iodine.

5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^1A、R^1B and R ₂ are independently selected from hydrogen, fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

。

7. The compound of claim 1,2 or 6, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt refers to the preparation of the compound with a pharmaceutically acceptable acid or base.

8. The compound according to claim 1,2 or 6, or a pharmaceutically acceptable salt thereof, wherein: more than one hydrogen atom of the compound or a pharmaceutically acceptable salt thereof is substituted with an isotope deuterium.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: selected from the following compounds or pharmaceutically acceptable salts thereof,

10. Use of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of a vasopressin V1a/V2 antagonism-related disorder, which vasopressin V1a/V2 antagonism-related disorder is hyponatremia.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is an orally or parenterally administered pharmaceutical composition.