4-(trifluoro-2-hydroxypropyl)-1,2,4-triazolone derivatives and their medical use

Abstract

The application discloses a kind of 4-(trifluoro-2-hydroxypropyl)-1,2,4-triazolone derivatives and medical purposes thereof.A series of compounds provided by the application can be used as vasopressin V1a / V2 receptor antagonists as lead compounds, and are expected to be used for preparing drugs for treating heart failure and combinations thereof.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of 4-(trifluoro-2-hydroxypropyl)-1,2,4-triazolone derivatives and their pharmaceutical uses. Background Technology

[0002] Arginine vasopressin (AVP) is a neuroendocrine hormone synthesized by the hypothalamus, possessing antidiuretic and vasoconstrictive effects. Recent studies have shown that AVP also has multiple biological functions, classifying it as a multifunctional peptide, all mediated by its specific receptors. Three different vasopressin receptors have been isolated: V1a, V1b (also known as V3), and V2. V1a receptors are found in blood vessels, kidneys, and the heart. Activation of V1a receptors mediates vasoconstriction, promotes water reabsorption by regulating renal blood flow, and promotes myocardial hypertrophy. V1a receptors are G protein-coupled receptors that stimulate intracellular calcium mobilization through phosphatidylinositol hydrolysis. V2 receptors are mainly found in the renal collecting ducts. Activation of V2 receptors, through G protein-coupled receptor signaling, activates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels and aquaporin-2 (AQP2) transport, thereby increasing water permeability, reducing free water secretion, and concentrating urine. Therefore, excessive activation of Vla and V2 receptors by AVP signaling may promote the pathophysiology of heart failure in a variety of ways, including enhancing vasoconstriction / afterload, leading to myocardial hypertrophy, and exacerbating fluid retention and hyponatremia.

[0003] Heart failure is the final stage of most cardiovascular diseases and has a high incidence rate. The main reason for most heart failure hospitalizations is due to symptoms and signs of congestion and fluid retention. Once a patient is hospitalized due to worsening heart failure, the mortality and readmission rates are very high within the following 60-90 days. Although symptoms improve after standard treatment, many patients are discharged with residual congestion (incomplete congestion). Diuretics are the cornerstone of heart failure treatment; all heart failure patients with evidence of fluid retention should be treated with diuretics. Currently available loop diuretics have certain limitations, such as activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, electrolyte disturbances (especially hypokalemia, hypomagnesemia, and alkalosis), distal nephron hypertrophy, and renal nausea, which can lead to cardiorenal syndrome in severe cases. V1a / V2 receptor antagonists, on the other hand, have no effect on renal function. Simultaneous antagonism of vasopressin receptors V1a and V2 can improve symptoms of heart failure congestion while inhibiting myocardial remodeling, thus providing long-term benefits to heart failure patients.

[0004] Currently, only one V1a / V2 receptor antagonist, conivatan, is available globally. It can only be administered intravenously and is primarily used to treat hospitalized patients with hyponatremia and normal blood volume. It has serious drug interactions and is not suitable for patients with heart failure. Therefore, designing and synthesizing new V1a / V2 receptor antagonists to provide a novel treatment option for patients with heart failure is of great significance. Summary of the Invention

[0005] One object of this invention is to provide a class of 4-(trifluoro-2-hydroxypropyl)-1,2,4-triazolone derivatives, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, with the following structural formula:

[0006]

[0007] Among them, X, Y, Z, and Q are each independently selected from C, N, or O, and at least one of them is N;

[0008] R1 and R2 are each independently selected from H, halogens, C1-C4 alkyl or 3-6 membered cycloalkyl, or R1 and R2 are combined with the carbon atoms they are attached to to form a 3-6 membered ring;

[0009] R3 is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted 4-6 membered heterocyclic groups; n = 0 or 1;

[0010] R4 is selected from substituted or unsubstituted phenyl groups, or substituted or unsubstituted 4-6-membered heteroaryl groups;

[0011] R5 is selected from substituted or unsubstituted phenyl groups, or substituted or unsubstituted 4-6 heteroaryl groups.

[0012] Furthermore, the structure formed by the 5-membered ring of X, Y, Z, and Q, together with R3 and R4, is selected from one of the following:

[0013] .

[0014] Further, in R3, the substituted C1-C4 alkyl group is substituted with 1-2 substituents independently selected from F, hydroxyl, trifluoromethyl, acetaldehyde, cyano, dimethylamino, cyclopropyl, 4-6 membered oxetyl, methyloxetyl, and amide; the substituted C1-C4 alkoxy group is substituted with 1-2 substituents independently selected from F, hydroxyl, trifluoromethyl, acetaldehyde, cyano, dimethylamino, cyclopropyl, 4-6 membered oxetyl, methyloxetyl, and amide; and the substituted 4-6 membered heterocyclic group is substituted with 1-2 substituents independently selected from F, hydroxyl, trifluoromethyl, acetaldehyde, cyano, dimethylamino, cyclopropyl, 4-6 membered oxetyl, methyloxetyl, and amide.

[0015] In R4, the phenyl group is substituted with 1-2 substituents independently selected from H, halogen, hydroxyl, methoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, methanesulfonyl, sulfanil, hydroxyethyl, and pyridone; the substituted 4-6 heteroaryl group is substituted with 1-2 substituents independently selected from H, halogen, methoxy, difluoromethyl, difluoromethoxy, methanesulfonyl, sulfanil, hydroxyethyl, and pyridone.

[0016] In R5, the phenyl group is substituted with 1-3 substituents independently selected from H, halogen, methyl, mercapto, difluoromethyl, difluoroethyl, cyano, methylthio, cyclopropyl, and -CONH-R6, where R6 is methyl, tert-butyl, or thiazolyl; the substituted 4-6 heteroaryl group is substituted with 1-3 substituents independently selected from H, halogen, methyl, mercapto, difluoromethyl, difluoroethyl, cyano, methylthio, cyclopropyl, and -CONH-R6, where R6 represents methyl, tert-butyl, or thiazolyl.

[0017] Furthermore, R4 is selected from the following groups:

[0018] ,

[0019] R7 and R8 are each independently selected from H, halogen, hydroxyl, methoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, methanesulfonyl, sulfonamide, or hydroxyethyl.

[0020] Furthermore, R1 and R2 are each independently selected from H, F, or methyl, or R1 and R2 are combined with the carbon atom to which they are attached to form a cyclopropyl group.

[0021] In some embodiments of the present invention, X, Y, Z, and Q contain three N atoms. Preferably, R5 represents p-chlorophenyl, more preferably, R3 represents a C1-C4 alkyl group, wherein the C1-C4 alkyl group may be substituted by one or two substituents independently selected from hydroxyl and trifluoromethyl, and R4 represents a phenyl group, wherein the phenyl group may be substituted by one or three substituents independently selected from fluorine, chlorine, hydroxyl, and trifluoromethyl. The general structural formula is as follows:

[0022] .

[0023] In some embodiments of the present invention, X, Y, Z, and Q contain three N atoms. Preferably, R5 represents p-chlorophenyl, more preferably, R3 represents a C1-C4 alkyl group, wherein the C1-C4 alkyl group may be substituted by one or two substituents independently selected from hydroxyl and trifluoromethyl, and R4 represents a phenyl group, wherein the phenyl group may be substituted by one or three substituents independently selected from fluorine, chlorine, hydroxyl, and trifluoromethyl. The general structural formula is as follows:

[0024] .

[0025] In some embodiments of the present invention, X, Y, Z, and Q contain three N atoms. Preferably, R1 and R2 represent H, R4 represents m-chlorophenyl, and R5 represents p-chlorophenyl. More preferably, R3 represents a C1-C4 alkyl group, wherein the C1-C4 alkyl group may be substituted by one or two substituents independently selected from hydroxyl and trifluoromethyl groups, with the following general structural formula:

[0026] .

[0027] In this invention, the salt is in the form of any one of inorganic acid salts, inorganic base salts, organic acid salts, or organic base salts; wherein, the inorganic acid salt is any one of hydrochloride, hydrobromide, sulfate, phosphate, or nitrate; the organic acid salt is any one of acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or ascorbate; and the organic base salt is any one of arginine, benzyl benzoate, choline, diethylamine, diolamine, glycine, lysine, meglumine, ethanolamine, or aminobutanetriol.

[0028] The 4-(trifluoro-2-hydroxypropyl)-1,2,4-triazolone derivatives or their pharmaceutically acceptable salts, hydrates and / or solvates are selected from the following compounds:

[0029]

[0030]

[0031]

[0032] .

[0033] A second objective of this invention is to provide a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salts, hydrates and / or solvates, and pharmaceutically acceptable excipients.

[0034] A third objective of this invention is to provide the use of the above-mentioned compounds or their pharmaceutically acceptable salts, hydrates and / or solvates, or pharmaceutical compositions, in the preparation of a medicament for treating heart failure.

[0035] A fourth objective of this invention is to provide the use of the above-mentioned compounds or their pharmaceutically acceptable salts, hydrates and / or solvates, or pharmaceutical compositions, in the preparation of a medicament for the prevention or treatment of diseases associated with arginine vasopressin V1a receptors, arginine vasopressin V1b receptors, arginine vasopressin V2 receptors, the sympathetic nervous system, or the renin-angiotensin-aldosterone system.

[0036] The diseases associated with the arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system include: anxiety disorders, autism, Down syndrome, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, mood disorders, and other mental illnesses; hypertension, edema, ascites, heart failure, renal insufficiency, renal failure, polycystic kidney disease, angiotensin insufficiency syndrome, cirrhosis, hyponatremia, hypokalemia, diabetes, ischemia, motion sickness, water metabolism disorders, and ischemic diseases.

[0037] The series of compounds provided by this invention can be used as lead compounds for vasopressin V1a / V2 receptor antagonists and are expected to be used in the preparation of drugs and combinations thereof for the treatment of heart failure. Detailed Implementation

[0038] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0039] In this invention, the structure of the compounds was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (8) is given in units of 10⁻⁶ (ppm). NMR measurements were performed using a BruKer AM-400 / 500 MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d) and deuterated chloroform (CDCl) as solvents and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC). High-performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD HPLC system. A Combi Flash Rf+LUMEN (TELEDYNEISCO) rapid preparation system was used. Compound purity was determined using a Shimadzu HPLC system (Inertsil ODS-SP C18 column, 4.6 × 250 mm, 5 μm). Reagents and compounds were weighed using a Sartorius electronic balance (accuracy: 0.01 and 0.0001).

[0040] Thin-layer chromatography (TLC) silica gel plates (HSGF254) were purchased from Yantai Jiangyou Silica Gel Development Co., Ltd., and color development was performed using a ZF-20D darkroom UV analyzer at a wavelength of 254 nm; column chromatography used 200-300 mesh silica gel produced by Shanghai Titan Co., Ltd.

[0041] Abbreviations: THF (tetrahydrofuran), MeCN (acetonitrile), Et3N (triethylamine), AcOHZ (acid), TFA (trifluoroacetic acid), TEA (triethylamine), DMF (N,N-dimethylformamide), DMA (dimethylacetamide), MeOH (methanol), EtOH (ethanol), EtONa (sodium ethoxide), PE (petroleum ether), EA (ethyl acetate), KOH (potassium hydroxide), DCM (dichloromethane), Cu(OAc)2 (copper acetate), NCS (N-chlorosuccinimide), Pyridine, DIPEAN (N-diisopropylethylamine), Toluene, t-BuOK (potassium tert-butoxide), Boc (tert-butoxycarbonyl), MS (mass spectrometry), ESI (electro-electro-ionization), HPLC (high performance liquid chromatography), -OMs (p-toluenesulfonyl), NaNO2 (sodium nitrate), MTBE (methyl tert-butyl ether), NaBD4 (sodium deuterated borohydride), NH4Cl (ammonium chloride), Na2SO4 (sodium sulfate), NaHCO3 (sodium bicarbonate), Tf2O Trifluoromethanesulfonic anhydride, TsCl p-methylbenzenesulfonyl chloride, DIEA N,N-diisopropylethylamine, LiOH lithium hydroxide, TBSCl tert-butyldimethylchlorosilane, HUTA 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, dppp 1,3-bis(diphenylphosphine)propane, TBAF tetra-n-butylammonium fluoride, CuI cuprous iodide, Cs2CO3 cesium carbonate, Pd(dppf)Cl2 dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, Ph2O diphenyl ether, DMAP 4-dimethylaminopyridine, PPTS pyridine p-toluenesulfonate, NMR nuclear magnetic resonance spectroscopy, rt room temperature, R t Retention time, CHO cells (Chinese hamster ovarian epithelial cells), Hygromycin B, NADPH (reduced coenzyme II), HTD 96B (96-channel high-flux balanced dialysis system).

[0042] Example 1

[0043] 5-(4-Chlorophenyl)-2-((1-(3-chlorophenyl)-5-((1S)-1-hydroxyethyl)-1H-1,2,4-triazol-3-yl)difluoromethyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0044]

[0045]

[0046] Step 1. 2-[3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-1,2,4-triazol-1-yl]-2,2-difluoroacetic acid

[0047] 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (2 g, 6.5 mmol), methyl 2-bromo-2,2-difluoroacetate (1.2 g, 6.5 mmol), and t-BuOK (2.2 g, 19.5 mmol) were added to THF (40 mL) and heated to 50 °C. o The mixture was stirred at C for 12 h, cooled, quenched with water (150 mL), and the pH was adjusted to 3 with 2 M HCl. It was then extracted with EA (80 mL x 3). The combined organic layers were concentrated under vacuum to obtain 2-[3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-1,2,4-triazol-1-yl]-2,2-difluoroacetic acid (800 mg, 26% yield) as a yellow oil.

[0048] MS(ESI)m / z 402.1 [M+H] +

[0049] Step 2. Methyl 2-[3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-1,2,4-triazol-1-yl]-2,2-difluoroacetate

[0050] Add K₂CO₃ (552 mg, 4.00 mmol) and CH₃I (213 mg, 3.00 mmol) to a DMF (10 mL) solution of (S)-2-((3-(3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-1,1,1-trifluoropropane-2-yl)oxy)-2,2-difluoroacetic acid (800 mg, 2.00 mmol) . Heat the reaction mixture at 25 °C. o The mixture was stirred at C for 12 h. The reaction mixture was cooled, water (50 mL) was added, and the mixture was extracted with EA (50 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give methyl 2-[3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-1,2,4-triazol-1-yl]-2,2-difluoroacetate (380 mg, 41% yield) as a white solid.

[0051] MS(ESI) m / z 416.2 [M+H] +

[0052] Step 3. 2-[3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-1,2,4-triazol-1-yl]-2,2-difluoroacetylhydrazine: 2-[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-1,2,4-triazol-1-yl]-2,2-difluoroacetate methyl ester (25 mg, 0.6 mmol) and hydrazine hydrate (60 mg, 1.2 mmol) were added to an EtOH solution (15 mL) and heated at 80 °C. o The mixture was stirred at C for 5 h. The reaction mixture was cooled and extracted with EA (100 mL x 3). The combined organic layers were washed with water and brine and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound as a yellow solid (250 mg, 90% yield).

[0053] MS(ESI) m / z 416.2 [M+H] +

[0054] Step 4. 2-({5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}difluoromethyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-3H,2H,4H-1,2,4-triazol-3-one) was added to a solution of 2-[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl (100 mg, 0.24 mmol) and (2S)-2-hydroxypropanediamine (23 mg, 0.26 mmol) in DMF (5 mL) with EtONa (33 mg, 0.48 mmol). The reaction mixture was heated to 120 °C. o Stirred at C for 5 h. Cool the reaction mixture, pour it into water (30 mL), and extract with EA (30 mL). Wash the organic layer with brine, dry with Na2SO4, concentrate by vacuum filtration, and purify by silica gel column chromatography (DCM:MeOH=15:1) to give the title compound as a white solid (90 mg, 71% yield).

[0055] MS(ESI) m / z 469.2 [M+H] +

[0056] Step 5. 5-(4-chlorophenyl)-2-{[1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1,2,4-triazol-3-yl]difluoromethyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-3H,2H,4H-1,2,4-triazol-3-one

[0057] A solution of (3-chlorophenyl)borondiol, 5-(4-chlorophenyl)-4-((S)-2-(difluoro(5-((S)-1-hydroxyethyl)-1H-1,2,4-triazol-3-yl)methoxy)-3,3,3-trifluoropropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (130 mg, 0.2 mmol), 3-chlorophenylboronic acid (86 mg, 0.6 mmol), and Cu(OAc)₂ (100 mg, 0.6 mmol) were added to a Py (10 mL) solution. The reaction mixture was heated to 60 °C. o Stir at C for 2 hours, then at 25°C. o The mixture was stirred at C for 12 h. The reaction mixture was quenched with HCl 0.5 N (150 mL) and extracted with EA (80 mL * 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) and Prep-HPLC to give a white solid 5-(4-chlorophenyl)-2-{[1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1,2,4-triazol-3-yl]difluoromethyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-3H,2H,4H-1,2,4-triazol-3-one (14.4 mg, 8.5% yield).

[0058] MS (ESI) m / z 579.0 [M+H] +

[0059] 1 H NMR (500 MHz, Chloroform-d) δ 7.82 – 7.70 (m, 2H), 7.58 (t, J =2.1 Hz, 1H), 7.53 (ddd, J = 7.5, 2.2, 1.1 Hz, 1H), 7.48 – 7.38 (m, 2H), 7.34(t, J = 7.8 Hz, 1H), 7.18 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 4.93 – 4.65 (m,3H), 4.40 (m, 1H), 4.23 (dq, J = 8.3, 3.6 Hz, 1H), 4.15 (m, 1H), 1.56 (d, J =6.4 Hz, 3H). .

[0060] Example 2

[0061] 5-(4-chlorophenyl)-2-(2-(1-(3-chlorophenyl)-5-((1S)-1-hydroxyethyl)-1H-1,2,4-triazol-3-yl)propyl-2-yl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0062]

[0063]

[0064] Starting with methyl 2-bromoisobutyrate and (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 5-(4-chlorophenyl)-2-(2-(1-(3-chlorophenyl)-5-((1S)-1-hydroxyethyl)-1H-1,2,4-triazol-3-yl)propyl-2-yl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (11.6 mg, 4.7%) was synthesized according to the method of Example 1.

[0065] MS (ESI) m / z 571.1 [M+H] + .

[0066] 1 H NMR (500 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 2H), 7.55 (t, J =2.1 Hz, 1H), 7.52 – 7.46 (m, 2H), 7.32 – 7.26 (m, 1H), 7.23 – 7.13 (m, 2H),5.23 (m, 1H), 4.69 (qd, J = 6.5, 5.2 Hz, 1H), 3.63 (dq, J = 8.3, 3.6 Hz, 1H),3.49 (m, 1H), 3.28 – 3.20 (m, 1H), 2.80 (d, J = 5.2 Hz, 1H), 2.09 (s, 5H), 1.47 (s, 1H).

[0067] Example 3

[0068] 5-(4-chlorophenyl)-2-(1-(1-(3-chlorophenyl)-5-((1S)-1-hydroxyethyl)-1H-1,2,4-triazol-3-yl)cyclopropyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0069]

[0070]

[0071] Starting with methyl 1-bromocyclopropane carboxylate and (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 5-(4-chlorophenyl)-2-(1-(1-(3-chlorophenyl)-5-((1S)-1-hydroxyethyl)-1H-1,2,4-triazol-3-yl)cyclopropyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (4.9 mg, 4.1%) was synthesized according to the method of Example 1.

[0072] MS (ESI) m / z 569.1 [M+H] + .

[0073] 1 H NMR (500 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 2H), 7.55 (t, J =2.0 Hz, 1H), 7.52 – 7.46 (m, 2H), 7.32 – 7.26 (m, 1H), 7.20 (dd, J = 8.0, 7.3Hz, 1H), 7.16 (m, 1H), 5.33 (m, 1H), 4.69 (qd, J = 6.5, 5.2 Hz, 1H), 3.53(dq, J = 8.2, 3.6 Hz, 1H), 3.29 (m, 1H), 2.84 (m, 1H), 2.80 (d, J = 5.2 Hz,1H), 1.47 (s, 2H), 1.07 – 0.98 (m, 2H), 0.91 – 0.82 (m, 2H).

[0074] Example 4

[0075] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0076]

[0077]

[0078] Step 1. Methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-carboxylic acid ester

[0079] Methyl 5-bromo-1H-1,2,4-triazole-3-carboxylic acid (3 g, 14.6 mmol) was added to a solution in DMF (50 mL), and NaH (701 mg, 17.5 mmol, 60% mineral oil) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, and SEMCl (2.92 g, 17.5 mmol) was added. The reaction mixture was stirred overnight at room temperature under N2. The reaction mixture was quenched with water (150 mL) and extracted with EA (80 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carboxylic acid (2.6 g, 51% yield) as a colorless oil.

[0080] MS (ESI) m / z 358.1 [M+Na] + .

[0081] Step 2. Methyl 5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carboxylic acid ester

[0082] Pd(dppf)Cl2 (560 mg, 0.77 mmol) was added to a solution of methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-carboxylic acid (2.6 g, 7.7 mmol), (3-chlorophenyl)boronic acid (1.81 g, 11.6 mmol), and K2CO3 (2.13 g, 15.4 mmol) in dioxane / H2O (30 mL / 3 mL). The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled, water (50 mL) was added, and the mixture was extracted with EA (50 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica scintillation column (PE / EA = 3:1) to give methyl 5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carboxylic acid (1.2 g, 42%), as a white solid.

[0083] MS (ESI) m / z 368.2 [M+H] + .

[0084] Step 3. (5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methanol

[0085] NaBH4 (310 mg, 8.1 mmol) was added to a solution of methyl 5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-carboxylic acid (1 g, 2.7 mmol) in THF / MeOH (10 mL / 10 mL). The reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL x 3). The combined organic layers were concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to give (5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methanol (900 mg, 96% yield) as a colorless oil.

[0086] MS (ESI) m / z 340.2 [M+H] + .

[0087] Step 4. Methyl (5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methanesulfonate

[0088] MsCl (53 mg, 0.46 mmol) was added to a solution of (5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methanol (120 mg, 0.35 mmol) and TEA (72 mg, 0.71 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (30 mL) and extracted with EA (30 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give methyl (5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methanesulfonate (crude, 150 mg), which was used for the next step without further purification.

[0089] Step 5. (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0090] A solution of (5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methanesulfonate (crude, 150 mg), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (108 mg, 0.35 mmol) and K2CO3 (98 mg, 0.71 mmol) in DMF (5 mL) was prepared at 50 °C. ° The mixture was stirred at C for 5 hours. LCMS showed that the reaction was complete. The resulting mixture was cooled, poured into water (20 mL), and extracted with EA (30 mL). The organic layer was dried in anhydrous Na2SO4, filtered, and concentrated under vacuum to give (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (crude, 150 mg), which required no further purification.

[0091] MS (ESI) m / z 629.2 [M+H] + .

[0092] Step 6. (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0093] TFA (3 mL) was added to a solution of (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (crude, 150 mg) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The resulting mixture was concentrated. The residue was dissolved in DMF (3 mL) and K2CO3 (200 mg) was added. The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered. The filtrate was purified by Prep-HPLC (NH4HCO3) to give (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (45.8 mg, 26% yield in three steps), as a white solid.

[0094] MS (ESI) m / z 499.0 [M+H] + .

[0095] 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.98-7.90 (m, 2H), 7.76 (d, J =8.8 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 6.4 Hz, 1H), 5.25-5.00 (m, 2H), 4.38-4.25 (m, 1H), 4.00 (dd, J = 14.4, 6.4 Hz, 1H), 3.85 (dd, J = 14.4, 9.6 Hz, 1H).

[0096] Example 5

[0097] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0098]

[0099]

[0100] Step 1. Methyl 5-bromo-1-ethyl-1H-1,2,4-triazole-3-carboxylic acid

[0101] NaH (470 mg, 11.6 mmol, 60% mineral oil) was added to a solution of methyl 5-bromo-1H-1,2,4-triazol-3-carboxylic acid (2 g, 9.7 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, iodoethane (1.66 g, 10.7 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature under an N2 balloon. The resulting mixture was poured into water (100 mL) and extracted with EA (100 mL). The separated organic layer was washed with water (100 mL) and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by C18 column chromatography to give the title compound (400 mg, 17% yield) as a colorless oil.

[0102] MS (ESI) m / z 234.0 [M+H] + .

[0103] Step 2. Methyl 5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazole-3-carboxylic acid ester

[0104] Pd(dppf)Cl2 (125 mg, 0.17 mmol) was added to a solution of methyl 5-bromo-1-ethyl-1H-1,2,4-triazole-3-carboxylic acid (400 mg, 1.7 mmol), (3-chlorophenyl)boronic acid (347 mg, 2.22 mmol), and K2CO3 (472 mg, 3.4 mmol) in DMF (10 mL). The reaction mixture was stirred at 100 °C for 5 hours under N2. The reaction mixture was cooled, water (50 mL) was added, and the mixture was extracted with EA (50 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to give methyl 5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazole-3-carboxylic acid (260 mg, 52% yield) as a yellow oil.

[0105] MS (ESI) m / z 265.8 [M+H] + .

[0106] Step 3. (5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methanol

[0107] NaBH4 (111 mg, 2.94 mmol) was added to a solution of methyl 5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-carboxylic acid (260 mg, 0.98 mmol) in THF / MeOH (5 mL / 5 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water (50 mL) and extracted with EA (30 mL x 3). The combined organic layers were concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give (5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methanol (230 mg, 96% yield) as a white solid.

[0108] MS (ESI) m / z 237.8 [M+H] + .

[0109] Step 4. Methyl (5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methyl sulfonate

[0110] MsCl (75 mg, 0.66 mmol) was added to a solution of (5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methanol (120 mg, 0.50 mmol) and TEA (102 mg, 1.0 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (30 mL) and extracted with EA (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give methyl (5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methanesulfonate (crude, 150 mg), which was used for the next step without further purification.

[0111] Step 5. (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0112] A solution of (5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methyl methanesulfonate (crude, 150 mg), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (155 mg, 0.5 mmol) and K₂CO₃ (140 mg, 1.0 mmol) in DMF (5 mL) was prepared at 50 °C. ℃ The mixture was stirred for 16 hours. LCMS showed that the reaction was complete. The resulting mixture was cooled and filtered. The filtrate was concentrated. The residue was purified by Prep-HPLC (NH4HCO3) to (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (34.8 mg, 13% yield in two steps), as a white solid.

[0113] MS (ESI) m / z 527.0 [M+H] + .

[0114] 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.72 (m, 3H), 7.66-7.56 (m, 5H), 6.90 (d, J= 6.4 Hz, 1H), 5.04 (s, 2H), 4.31-4.19 (m, 3H), 4.00 (dd, J= 14.8, 3.2Hz, 1H), 3.85 (dd, J = 14.4, 9.6 Hz, 1H), 1.38-1.34 (m, 3H).

[0115] Example 6

[0116] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0117]

[0118]

[0119] Starting with methyl 5-bromo-4H-[1,2,4]thiazole-3-carboxylic acid and trifluoroethyl methanesulfonate, the product (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (103 mg, 42% yield) was synthesized as a white solid according to the synthetic method of Example 4.

[0120] MS (ESI) m / z 581 [M+H] + .

[0121] 1 H NMR (400 MHz, DMSO-d6) δ 7.77-7.73 (m, 3H), 7.69-7.58 (m, 5H), 6.89(d, J = 6.4 Hz, 1H), 5.28 (q, J = 8.8 Hz, 2H), 5.10 (s, 2H), 4.30 (s, 1H), 4.00 (dd, J = 3.6, 14.8 Hz, 1H), 3.85 (dd, J = 9.6, 14.4 Hz, 1H).

[0122] Example 7

[0123] (S)-2-((1-acetyl-5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0124]

[0125]

[0126] Starting with methyl 5-bromo-4H-[1,2,4]thiazol-3-carboxylic acid and acetyl bromide, the product (S)-2-((1-acetyl-5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (24.9 mg, 14% yield) was synthesized as a white solid according to the synthetic method of Example 4.

[0127] MS(ESI) M / Z m / z 541.1 [M+H] + .

[0128] 1 H NMR (500 MHz, Chloroform-d) δ 7.75 (dt, J = 7.3, 2.0 Hz, 1H), 7.62– 7.49 (m, 6H), 7.45 (t, J = 7.5 Hz, 1H), 6.46 (d, J = 12.4 Hz, 1H), 5.76 (d,J = 12.4 Hz, 1H), 5.03 (dddd, J = 15.9, 9.0, 5.0, 1.9 Hz, 1H), 4.18 (dd, J =12.4, 7.1 Hz, 1H), 3.61 (dd, J = 12.4, 7.1 Hz, 1H), 2.60 (s, 3H), 2.57 (d, J= 5.1 Hz, 1H).

[0129] Example 8

[0130] (S)-2-(5-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetonitrile

[0131]

[0132]

[0133] Starting with methyl 5-bromo-4H-[1,2,4]thiazol-3-carboxylic acid and bromoacetonitrile, the product (S)-2-(5-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetonitrile (15.5 mg, 7% yield) was synthesized as a white solid according to the synthetic method of Example 4.

[0134] MS(ESI) M / Z m / z 538.0 [M+H] +

[0135] 1 H NMR (500 MHz, Chloroform-d) δ 7.77 (dt, J = 7.3, 2.0 Hz, 1H), 7.66– 7.58 (m, 3H), 7.57 – 7.49 (m, 3H), 7.43 (t, J = 7.5 Hz, 1H), 6.08 (d, J =12.5 Hz, 1H), 5.60 (d, J = 12.3 Hz, 1H), 5.47 (d, J = 12.5 Hz, 1H), 5.38 (d,J = 12.4 Hz, 1H), 5.03 (dddd, J = 16.1, 9.1, 5.0, 2.0 Hz, 1H), 4.06 (dd, J =12.3, 6.9 Hz, 1H), 3.62 (dd, J = 12.4, 7.0 Hz, 1H), 2.57 (d, J = 5.1 Hz, 1H).

[0136] Example 9

[0137] 2-(5-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)propionitrile

[0138]

[0139]

[0140] Starting with methyl 5-bromo-4H-[1,2,4]thiazol-3-carboxylic acid and 2-bromopropionitrile, the product 2-(5-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)propionitrile (5.3 mg, 4% yield) was synthesized as a white solid according to the synthetic method of Example 4.

[0141] MS(ESI) M / Z m / z 552.0 [M+H] +

[0142] 1 H NMR (500 MHz, Chloroform-d) δ 7.79 (dt, J = 7.3, 2.0 Hz, 1H), 7.61(t, J = 2.0 Hz, 1H), 7.58 – 7.50 (m, 5H), 7.45 (t, J = 7.4 Hz, 1H), 6.31 (d,J = 12.5 Hz, 1H), 5.63 (d, J = 12.3 Hz, 1H), 5.25 (q, J = 6.9 Hz, 1H), 5.03 (dddd, J = 16.0, 9.1, 5.0, 2.0 Hz, 1H), 3.88 (dd, J = 12.4, 6.9 Hz, 1H), 3.73(dd, J = 12.4, 6.9 Hz, 1H), 2.57 (d, J = 5.1 Hz, 1H), 1.77 (d, J = 6.9 Hz, 3H).

[0143] Example 10

[0144] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0145]

[0146]

[0147] Starting with methyl 5-bromo-4H-[1,2,4]thiazol-3-carboxylic acid and 2-fluoro-1-iodoethane, the mixture was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (29.1 mg, 18% yield) as a white solid.

[0148] MS (ESI) m / z 545 [M+H] + .

[0149] 1 H NMR (400 MHz, DMSO-d6) δ 7.79-7.70 (m, 3H), 7.68-7.56 (m, 5H), 6.89(d, J = 6.4 Hz, 1H), 5.07 (s, 2H), 4.87 (t, J = 4.6 Hz, 1H), 4.75 (t, J = 4.6Hz, 1H), 4.56 (t, J = 4.6 Hz, 1H), 4.49 (t, J = 4.6 Hz, 1H), 4.35-4.25 (m,1H), 4.00 (dd, J = 14.7, 3.6 Hz, 1H), 3.85(dd, J = 14.6,9.5 Hz, 1H).

[0150] Example 11

[0151] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0152]

[0153]

[0154] Starting with methyl 5-bromo-4H-[1,2,4]thiazol-3-carboxylic acid and 2-(2-bromoethoxy)oxacyclohexane, a yellow oil (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (40 mg, 13%) was synthesized according to the method described in Example 4.

[0155] MS (ESI) m / z 627 [M+H] + .

[0156] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0157]

[0158] A solution of (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (40.0 mg, 0.063 mmol) and TsOH (1.1 mg, 0.006 mmol) in MeOH (2 mL) was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5.3 mg, 1.4%) as a white solid.

[0159] MS (ESI) m / z 543 [M+H] + .

[0160] 1H NMR (400 MHz, DMSO-d6) δ 7.86 (t, J = 1.6 Hz, 1H), 7.76-7.74 (m,3H), 7.63-7.61 (m, 3H), 7.58 (dd, J = 16.0, 8.0 Hz, 1H), 6.90 (s, 1H), 5.11(t, J =5.2 Hz, 1H), 5.01 (s, 2H), 4.30 (s, 1H), 4.21(t, J = 4.8 Hz, 2H), 4.00(dd, J =14.4 Hz, 3.2 Hz, 1H), 3.87-3.79(m, 3H).

[0161] Examples 12 and 13

[0162] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0163] (R)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0164]

[0165]

[0166] Step 1. Ethyl 1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazole-3-carboxylic acid

[0167] At 0°C, HCl (5.64 g, 154 mmol) and a solution of NaNO2 (3.55 g) in H2O (50 mL) were added to a solution of 1-methylpyrazole-3-amine (5 g, 51.5 mmol). The reaction mixture was then heated in a 0°C incubator. ℃Stir for 5 min. Then add ethyl 2-isocyanate (5.83 g, 51.5 mmol) in 10 mL MeOH solution and NaOAc (27.45 g, 334.7 mmol) in 50 mL H2O solution. Stir the reaction mixture overnight at room temperature. Add H2O to the reaction mixture and extract twice with EA. Wash the combined organic layers with brine, dry with Na2SO4, filter and concentrate. Purify by silica gel column chromatography to give ethyl 1-(1-methyl-1H-pyrazol-3-yl)-1H-1,2,4-triazol-3-carboxylic acid (4 g, 28%) as a yellow oil.

[0168] MS (ESI) m / z 222.0 [M+H] + .

[0169] Step 2. Ethyl 5-bromo-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazole-3-carboxylic acid

[0170] Ethyl 1-(1-methylpyrazol-3-yl)-1,2,4-triazole-3-carboxylate (687 mg, 3.1 mmol), NBS (718 mg, 4.03 mmol), and AIBN (51 mg, 0.31 mmol) in CCl4 (20 mL) were stirred overnight at 90 °C under N2. The reaction mixture was cooled, H2O was added, and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography (PE / EA = 3:1) yielded ethyl 5-bromo-1-(1-methyl-1H-pyrazol-3-yl)-1H-1,2,4-triazole-3-carboxylate (107 mg, 10%) as a yellow oil.

[0171] MS (ESI) m / z 300.0 [M+H] + .

[0172] Step 3. Ethyl 5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazole-3-carboxylic acid

[0173] A mixture of ethyl 5-bromo-1-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-carboxylate (107 mg, 0.35 mmol), (3-chlorophenyl)borondiol (61 mg, 0.39 mmol), Pd(dppf)Cl2 (26 mg, 0.035 mmol), and K2CO3 (98 mg, 0.71 mmol) in DMF (10 mL) was stirred at 100 °C for 3 h under N2. The reaction mixture was cooled, H2O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purified by silica gel column chromatography with PE / EA = 2:1, ethyl 5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazol-3-yl)-1H-1,2,4-triazol-3-carboxylate (80 mg, 60%) was obtained as a yellow oil.

[0174] MS (ESI) m / z 332.0 [M+H] + .

[0175] Step 4. (5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazol-3-yl)methanol

[0176] In a THF / MeOH mixture of 5:1 (12 mL), NaBH4 (27 mg, 0.72 mmol) and ethyl 5-(3-chlorophenyl)-1,2,4-triazol-3-carboxylic acid (80 mg, 0.24 mmol) were added. The reaction mixture was stirred overnight at room temperature. H2O was added to the reaction mixture, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography (PE / EA = 1:1) yielded (5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazol-3-yl)methanol (70 mg, 90%) as a yellow oil.

[0177] MS (ESI) m / z 290.0 [M+H] + .

[0178] Step 5. Methyl (5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazol-3-yl)methanesulfonate

[0179] At 0 °C, MsCl (55 mg, 0.48 mmol) was added to a solution of [5-(3-chlorophenyl)-1-(1-methylpyrazole-3-yl)-1,2,4-triazol-3-yl]methanol (70 mg, 0.24 mmol) and DIEA (93 mg, 0.72 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then added to H2O and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give methyl (5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazol-3-yl)methyl methanesulfonate (85 mg, 76%) as a yellow oil.

[0180] MS (ESI) m / z 368.0 [M+H] + .

[0181] Step 6. 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0182] A mixture of [5-(3-chlorophenyl)-1-(1-methylpyrazol-3-yl)-1,2,4-triazol-3-yl]methylmethanesulfonate (143 mg, 0.39 mmol), 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (100 mg, 0.32 mmol), and K₂CO₃ (89 mg, 0.65 mmol) in DMF (10 mL) was stirred overnight at 50 °C. The reaction mixture was cooled, H₂O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product (100 mg) was obtained by silica gel column purification (PE / EA = 1:1), followed by chiral HPLC purification (IE Hex-EtOH-75-25-20 min) to yield (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (35.7 mg, 19%, Rt = 10.943 min, Hex-EtOH-75-25-20 min) and (R)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-3-yl)-1H-1, 2,4-Triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20.2 mg, 10%, Rt = 13.722 min, Hex-EtOH-75-25-20 min) is a white solid.

[0183] MS (ESI) m / z 579.1 [M+H] + .

[0184] 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 2.4 Hz, 1H), 7.78-7.75 (m,2H), 7.63-7.61 (m, 2H), 7.57-7.53 (m, 2H), 7.45-7.44 (m, 2H), 6.90 (d, J =6.4 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 5.13 (s, 2H), 4.31(m, 1H), 4.01(dd, J= 3.6 Hz, 14.8 Hz, 1H), 3.90-3.78(m, 4H).

[0185] Example 14

[0186] 5-(4-Chlorophenyl)-2-((5-(3-Chlorophenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0187]

[0188]

[0189] Starting with 1-methyl-1H-pyrazole-4-amine, 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1-methyl-1H-pyrazole-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (21.4 mg, 19%) was synthesized according to the synthesis method of Example 12.

[0190] MS (ESI) m / z 579.1 [M+H] + .

[0191] 1 H NMR (500 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 3H), 7.49 (d, J =8.3 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.25 (d, J = 15.8 Hz, 0H), 5.03 (qdt, J =12.2, 8.2, 7.3 Hz, 1H), 4.59 (s, 1H), 4.03 (s, 2H), 3.67 – 3.54 (m, 2H), 3.24(ddq, J = 10.6, 7.3, 2.2 Hz, 1H).

[0192] Example 15

[0193] 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0194]

[0195]

[0196] Starting with 5-methyl-1,3,4-oxadiazol-2-amine, 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (25.1 mg, 17.8%) was synthesized according to the synthetic method of Example 12.

[0197] MS (ESI) m / z 581.1 [M+H] +

[0198] 1 H NMR (500 MHz, Chloroform-d) δ 7.87 (d, J = 8.0 Hz, 1H), 7.66 –7.60 (m, 3H), 7.52 – 7.46 (m, 2H), 7.35 (d, J = 7.9 Hz, 1H), 7.25 (d, J =15.8 Hz, 0H), 5.03 (m, 1H), 4.59 (s, 1H), 3.93 (dq, J = 8.2, 3.6 Hz, 1H), 3.68 (m, 1H), 3.44 (m, 1H), 2.76 (s, 2H).

[0199] Example 16

[0200] 5-(4-Chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1-methyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0201]

[0202]

[0203] Starting with 1-methyl-1H-imidazol-4-yl, 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1-methyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (17.5 mg, 11%) was synthesized according to the synthesis method of Example 12.

[0204] MS (ESI) m / z 579.1 [M+H] +

[0205] 1 H NMR (500 MHz, Chloroform-d) δ 7.87 (ddd, J = 8.0, 2.2, 1.2 Hz,1H), 7.66 – 7.57 (m, 3H), 7.52 – 7.46 (m, 2H), 7.35 (ddd, J = 7.9, 2.1, 1.2Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 5.13 (m, 1H), 4.69 (s, 1H), 3.93 (dq, J =8.2, 3.6 Hz, 1H), 3.78 (m, 1H), 3.52 (d, J = 0.7 Hz, 2H), 3.44 (m, 1H).

[0206] Example 17

[0207] 5-(4-Chlorophenyl)-2-((5-(3-Chlorophenyl)-1-(1H-pyrazol-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0208]

[0209]

[0210] Starting with 1H-pyrazole-4-yl, 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(1H-pyrazole-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (13.9 mg, 7.4%) was synthesized according to the synthesis method of Example 12.

[0211] MS (ESI) m / z 565.1 [M+H] +

[0212] 1H NMR (500 MHz, Chloroform-d) δ 12.72 – 12.68 (s, 1H), 7.87 (d, J =8.0 Hz, 1H), 7.66 – 7.60 (m, 2H), 7.52 – 7.46 (m, 3H), 7.35 (d, J = 7.9 Hz,1H), 5.03 (qdt, J = 12.2, 8.2, 7.3 Hz, 1H), 4.59 (s, 1H), 4.13 (dq, J = 8.2,3.5 Hz, 1H), 3.94 – 3.86 (m, 1H), 3.52 (m, 1H).

[0213] Example 18

[0214] 5-(4-Chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0215]

[0216]

[0217] Step 1. 2,2-Difluoropropyltrifluoromethanesulfonate

[0218]

[0219] At -20 °C, Tf₂O (17.6 g, 62.4 mmol) was added to a DCM (70 mL) solution of 2,2-difluoropropane-1-ol (5 g, 52.0 mmol) and TEA (6.84 g, 67.6 mmol). The reaction mixture was stirred at 0 °C for 16 hours. The resulting mixture was poured into water (200 mL) and extracted with DCM (300 mL). The separated organic layer was washed with aqueous solution. NaHCO₃ (100 mL), dried on Na₂SO₄, filtered, and concentrated to give the crude product (10 g, 76% yield), which could be used for the next step without further purification.

[0220] Starting with methyl 5-bromo-4H-[1,2,4]thiazol-3-carboxylic acid and 2,2-difluoropropyltrifluoromethanesulfonate, the mixture was synthesized according to the method described in Example 4 to obtain 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (12.3 mg, 6% yield in two steps), as a white solid.

[0221] MS (ESI) m / z 577.0 [M+H] + .

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 7.76-7.70 (m, 3H), 7.66-7.55 (m, 5H), 6.89(d, J= 6.4 Hz, 1H), 5.08 (s, 2H), 4.78 (t, J = 13.2 Hz, 2H), 4.35-4.23 (m,1H), 4.00 (dd, J = 14.8, 3.6 Hz, 1H), 3.85 (dd, J = 14.8, 9.6 Hz, 1H), 1.64(t, J = 19.2 Hz, 3H).

[0223] Example 19

[0224] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-((3-methyloxetane-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0225]

[0226]

[0227] Starting with methyl 5-bromo-4H-[1,2,4]thiazol-3-carboxylic acid and 3-(bromomethyl)-3-methyloxetane, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-((3-methyloxetane-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (3.3 mg, 3% yield), which was a white solid.

[0228] MS (ESI) m / z 583.1 [M+H] + .

[0229] 1 H NMR (400 MHz, DMSO-d6) δ 7.76-7.70 (m, 3H), 7.66-7.55 (m, 5H), 6.90(d, J = 5.2 Hz, 1H), 5.09-4.99 (m, 2H), 4.55-4.44 (m, 4H), 4.35-4.23 (m, 1H), 4.13 (d, J = 6.0 Hz, 2H), 4.00 (dd, J = 14.4, 3.2 Hz, 1H), 3.85 (dd, J =14.4, 9.6 Hz, 1H), 0.95 (s, 3H).

[0230] Example 20

[0231] (S)-1-(2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)phenyl)pyridin-2(1H)-one

[0232]

[0233]

[0234] Step 1. 2-Aminobenzoic acid

[0235] A solution of methyl 2-aminobenzoate (10 g, 66 mmol) in 100 mL of 3N NaOH / H₂O was stirred at 25 °C for 12 hours. The reaction mixture was acidified to adjust the pH to 3 and filtered. The filter cake was washed with 20 mL of water and dried to obtain the crude product for the next step, without further purification.

[0236] MS (ESI) m / z 138 [M+H] + .

[0237] Step 2. Pyridin-2-ylmethyl carbonate

[0238] Chloro(methoxy) ketone (49.6 g, 526 mmol) was added to a mixture of 2-hydroxypyridine (20.0 g, 210 mmol) and potassium carbonate (73 g, 526 mmol) in acetone (400 mL). The reaction mixture was heated at 40 °C for 12 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography to give a titrant (20 g, 59% yield) as a yellow oil.

[0239] MS (ESI) m / z 154 [M+H] + .

[0240] Step 3. Methyl 2-(2-oxopyridin-1(2H)-yl)benzoate

[0241] A solution of 2-aminobenzoic acid (9.35 g, 68.2 mmol) in acetone (90 mL) was added slowly via a syringe pump to a solution of pyridin-2-ylmethyl carbonate (9.5 g, 62 mmol) and isoamyl nitrite (8.72 g, 74.4 mmol) in DCM (250 mL) for 4 hours after reflux. The solution was further refluxed for 5 hours. The brown solution was cooled, washed first with 10% hydrochloric acid (200 mL x 2), then with water (200 mL x 2), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was eluented with a mixture of hexane and ethyl acetate (v / v = 3 / 2) on neutral alumina to give the desired product (3 g, 20% yield) as a brown solid.

[0242] MS (ESI) m / z 230 [M+H] + .

[0243] Step 4. 2-(2-oxopyridin-1(2H)-yl)benzoylhydrazine

[0244] A solution of methyl 2-(2-oxopyridin-1(2H)-yl)benzoate (1.5 g, 6.5 mmol) and hydrazine hydrate (1.63 g, 32.5 mmol) in EtOH (20 mL) was stirred at 80 °C for 12 h. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by catalytic cracking to give 2-(2-oxopyridin-1(2H)-yl)benzoylhydrazine (600 mg, 38% yield) as a yellow oil.

[0245] MS (ESI) m / z 230 [M+H] + .

[0246] Step 5. Ethyl 5-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,3,4-oxadiazole-2-carboxylate

[0247] 2-(2-oxopyridin-1(2H)-yl)benzoylhydrazide (600 mg, 2.62 mmol) and triethylamine (529.7 mg, 5.23 mmol) were added to 15 mL of DCM at 0 °C. 2-chloro-2-oxoethyl acetate (536.1 mg, 3.93 mmol) was added to the DCM solution. The reaction mixture was stirred at room temperature for 6 hours. Then, triethylamine (264.9 mg, 2.62 mmol) and TsCl (499.0 mg, 2.62 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for at least 18 hours. 200 mL of DCM was added to the reaction mixture. The separated organic layer was washed with 100 mL of saturated NaCl solution and concentrated. The residue was purified by silica gel column chromatography to give the target product (250 mg, 29% yield) as a yellow solid.

[0248] MS (ESI) m / z 312 [M+H] + .

[0249] Step 6. 1-(2-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)phenyl)pyridin-2(1H)-one

[0250] Ethyl 5-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,3,4-oxadiazol-2-carboxylic acid (250.0 mg, 1.08 mmol) was added to a THF / MeOH solution (5 mL / 1 mL) with NaBH4 (91 mg, 2.41 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give 1-(2-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)phenyl)pyridin-2(1H)-one (90 mg, 31% yield) as a yellow oil.

[0251] MS (ESI) m / z 270 [M+H] + .

[0252] Step 7. (5-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,3,4-oxadiazol-2-yl)methylmethanesulfonate

[0253] MsCl (72.0 mg, 0.63 mmol) was added to a solution of 1-(2-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)phenyl)pyridin-2(1H)-one (85.0 mg, 0.32 mmol) and DIEA (122.4 mg, 0.95 mmol) in DCM (4 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under vacuum to give a crude product that could be used directly in the next step without purification.

[0254] MS (ESI) m / z 348 [M+H] + .

[0255] Step 8. (S)-1-(2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)phenyl)pyridin-2(1H)-one

[0256] (S)-5-[4-(difluoromethyl)phenyl]-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (106.3 mg, 0.35 mmol), (5-(2-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,3,4-oxadiazol-2-yl)methylmethanesulfonate (120 mg, 0.35 mmol) and K2CO3 (95.5 mg, 0.69 mmol) were added to a solution of DMF (3 mL) and stirred overnight at 50 °C. The reaction mixture was cooled, quenched with water (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC. We obtain (S)-1-(2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)phenyl)pyridin-2(1H)-one

[0257] (15.5 mg, 8% yield) is a yellow solid.

[0258] MS (ESI) m / z 559 [M+H] + .

[0259] 1H NMR(400 MHz, DMSO-d6) δ 8.13-8.04 (m, 1H), 7.83-7.75 (m, 3H), 7.74-7.69 (m, 1H), 7.64 (dd, J = 8.6, 1.7 Hz, 2H), 7.63-7.56 (m, 1H), 7.53 (dt, J= 7.9, 1.5 Hz, 1H), 7.50-7.40 (m, 1H), 6.94 (dd, J = 10.7, 6.3 Hz, 1H), 6.39-6.12 (m, 2H), 5.30 (t, J = 2.7 Hz, 2H), 4.39-4.19 (m, 1H), 4.08-3.94(m, 1H), 3.94-3.79(m, 1H).

[0260] Example 21

[0261] (S)-1-(2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-3-yl)phenyl)pyridin-2(1H)-one

[0262]

[0263]

[0264] Step 1. 2-(2-oxopyridin-1(2H)-yl)benzoic acid

[0265] To a solution of methyl 2-(2-oxopyridin-1-yl)benzoate (1 g, 4.36 mmol) in THF / H₂O (12 mL / 3 mL), LiOH·H₂O (732.2 mg, 17.45 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by C18 chromatography to give 2-(2-oxopyridin-1(2H)-yl)benzoic acid (600 mg, 61% yield) as a white solid.

[0266] MS (ESI) m / z 216 [M+H] + .

[0267] Step 2. 2-(2-oxopyridin-1(2H)-yl)benzamide

[0268] DIEA (360.3 mg, 2.79 mmol) was added to a solution of 2-(2-oxopyridin-1(2H)-yl)benzoic acid (200 mg, 0.93 mmol), HATU (459.4 mg, 1.21 mmol), and NH4Cl (99.4 mg, 1.86 mmol) in DMF (5 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give 2-(2-oxopyridin-1(2H)-yl)benzamide (180 mg, 86% yield) as a yellow solid.

[0269] MS (ESI) m / z 215 [M+H] + .

[0270] Step 3. 2-(2-oxopyridin-1(2H)-yl)benzonitrile

[0271] TFAA (706.0 mg, 3.36 mmol) was added to a solution of 2-(2-oxopyridin-1(2H)-yl)benzamide (180 mg, 0.84 mmol) and TEA (170.1 mg, 1.68 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water (2 x 10 mL) and extracted with EA (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by catalytic cracking to give 2-(2-oxopyridin-1(2H)-yl)benzonitrile (150 mg, 86% yield) as a yellow oil.

[0272] MS (ESI) m / z 197 [M+H] + .

[0273] Step 4. (Z)-N'-hydroxy-2-(2-oxopyridin-1(2H)-yl)benzo[a]amine

[0274] A solution of methyl 2-(2-oxopyridin-1-yl)benzonitrile (150 mg, 0.76 mmol) in NH₂OH was prepared. HCl (159.4 mg, 2.29 mmol) and TEA (231.6 mg, 2.29 mmol) in EtOH (3 mL) were stirred at 80 °C for 12 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by catalytic cracking to give (Z)-N'-hydroxy-2-(2-oxopyridin-1(2H)-yl)benzo[a]amidine (170 mg, 93% yield) as a yellow solid.

[0275] MS (ESI) m / z 230 [M+H] + .

[0276] Step 5. 1-(2-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)pyridin-2(1H)-one

[0277] (Z)-N'-hydroxy-2-(2-oxopyridin-1(2H)-yl)benzo[a]amidine (120.0 mg, 0.52 mmol), ethyl 2-hydroxyacetate (81.8 mg, 0.79 mmol), and K2CO3 (86.8 mg, 0.63 mmol) were added to a toluene / DMF (9:1, 8 mL) solution and stirred under nitrogen for 12 h. The reaction mixture was cooled, quenched with water (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography to 1-(2-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)pyridin-2(1H)-one (50 mg, 34% yield), as a yellow oil.

[0278] MS (ESI) m / z 270 [M+H] + .

[0279] Step 6. (3-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,2,4-oxadiazol-5-yl)methylmethanesulfonate

[0280] MsCl (42.3 mg, 0.37 mmol) was added to a solution of 1-(2-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)pyridin-2(1H)-one (50.0 mg, 0.19 mmol) and DIEA (72.0 mg, 0.56 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under vacuum to give a crude product that could be used directly in the next step without further purification.

[0281] MS (ESI) m / z 348 [M+H] + .

[0282] Step 7. (S)-1-(2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-3-yl)phenyl)pyridin-2(1H)-one

[0283] A solution of 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (44.3 mg, 0.14 mmol), (3-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,2,4-oxadiazol-5-yl)methylmethanesulfonate (50.0 mg, 0.14 mmol), and K₂CO₃ (39.8 mg, 0.29 mmol) in DMF (2 mL) was stirred overnight at 50 °C. The reaction mixture was cooled, quenched with water (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give (S)-1-(2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-3-yl)phenyl)pyridine-2(1H)-one (20.6 mg, 24%) as a yellow solid.

[0284] MS (ESI) m / z 559 [M+H] + .

[0285] 1H NMR (400 MHz, DMSO-d6) δ 8.19-8.08 (m, 1H), 7.81-7.73 (m, 3H), 7.72-7.61 (m, 3H), 7.58-7.53 (m, 1H), 7.49 (dd, J = 7.8, 1.3 Hz, 1H), 7.48-7.41 (m, 1H), 6.93 (dd, J = 6.4, 4.2 Hz, 1H), 6.38-6.31 (m, 1H), 6.26 (tt, J= 6.7, 1.4 Hz, 1H), 5.46 (s, 2H), 4.40-4.14 (m, 1H), 4.01 (dd, J = 14.8, 3.5Hz, 1H), 3.95-3.80 (m, 1H).

[0286] Example 22

[0287] (S)-1-(2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)phenyl)pyridin-2(1H)-one

[0288]

[0289]

[0290] Step 1. Ethyl (E)-2-(hydroxyimino)-2-(2-(2-oxopyridin-1(2H)-yl)benzamido)ethyl acetate

[0291] DIEA (480.4 mg, 3.72 mmol) was added to a solution of 2-(2-oxopyridin-1(2H)-yl)benzoic acid (200 mg, 0.93 mmol), HATU (459.4 mg, 1.21 mmol), and ethyl((Z)-N'-hydroxycarbamoylamidinium)carboxylate (122.8 mg, 0.93 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give ethyl (E)-2-(hydroxyimino)-2-(2-(2-oxopyridin-1(2H)-yl)benzamido)acetate (200 mg, 48% yield) as a yellow solid.

[0292] MS (ESI) m / z 330 [M+H] + .

[0293] Step 2. Ethyl 5-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,2,4-oxadiazole-3-carboxylate

[0294] Ethyl (E)-2-(hydroxyimino)-2-(2-(2-oxopyridin-1(2H)-yl)benzamido)acetate (200 mg, 0.61 mmol) was added to a DMF solution (3 mL), and the mixture was stirred at 150 °C for 5 h. The reaction mixture was cooled, quenched with water (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography to give ethyl 5-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,2,4-oxadiazole-3-carboxylic acid (150 mg, 76% yield) as a white solid.

[0295] MS (ESI) m / z 312 [M+H] + .

[0296] Step 3. 1-(2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)phenyl)pyridin-2(1H)-one

[0297] To a solution of ethyl 5-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,2,4-oxadiazol-3-carboxylic acid (150.0 mg, 0.48 mmol) in MeOH / THF (1:5, 6 mL), NaBH4 (72.9 mg, 1.93 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give 1-(2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)phenyl)pyridin-2(1H)-one (50 mg, 37% yield) as a colorless oil.

[0298] MS (ESI) m / z 270 [M+H] + .

[0299] Step 4. (5-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,2,4-oxadiazol-3-yl)methylmethanesulfonate

[0300] MsCl (42.3 mg, 0.37 mmol) was added to a solution of 1-(2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)phenyl)pyridin-2(1H)-one (50.0 mg, 0.19 mmol) and DIEA (72 mg, 0.56 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 h. The mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under vacuum to give a crude product that could be used directly in the next step without purification.

[0301] MS (ESI) m / z 348 [M+H] + .

[0302] Step 5. (S)-1-(2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)phenyl)pyridin-2(1H)-one

[0303] (S)-(5-(2-(2-oxopyridin-1-yl)phenyl)-1,2,4-oxadiazol-3-yl)methylmethanesulfonate (55 mg, 0.16 mmol), 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (48.7 mg, 0.16 mmol), and K₂CO₃ (44 mg, 0.32 mmol) were added to a solution of DMF (2 mL), and the mixture was stirred overnight at 50 °C. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give (S)-1-(2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)phenyl)pyridine-2(1H)-one (20.1 mg, 22% yield), as a white solid.

[0304] MS (ESI) m / z 559 [M+H] + .

[0305] 1H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J = 7.8, 1.5 Hz, 1H), 7.87 (td,J = 7.7, 1.6 Hz, 1H), 7.80-7.70 (m, 3H), 7.68-7.60 (m, 3H), 7.56 (d, J = 7.8Hz, 1H), 7.47 (ddt, J = 8.9, 6.7, 2.0 Hz, 1H), 6.93 (dd, J = 7.9, 6.3 Hz, 1H), 6.38-6.25 (m, 2H), 5.17 (d, J = 3.0 Hz, 2H), 4.36-4.21 (m, 1H), 4.00 (dt, J = 14.7, 3.9 Hz, 1H), 3.87 (ddd, J = 14.7, 9.5, 3.5 Hz, 1H).

[0306] Example 23

[0307] (S)-N-(tert-butyl)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)benzamide

[0308]

[0309]

[0310] Step 1. Ethyl (Z)-2-(hydroxyimino)-2-(2-iodobenzoamide)acetate

[0311] HATU (3.18 g, 8.3 mmol) was added to a solution of 2-iodobenzoic acid (1.88 g, 7.6 mmol), ethyl ethyl [(Z)-N'-hydroxycarbamoylamidinium]formate (1 g, 7.6 mmol), and DIEA (1.96 g, 15.2 mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then added to H2O and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification was performed using a silica gel column with PE / EA ratio of 3:1 to give ethyl (Z)-2-(hydroxyimino)-2-(2-iodobenzoamido)acetate (2.24 g, 73%) as a white solid.

[0312] MS (ESI) m / z 362.9 [M+H]+ .

[0313] Step 2. Ethyl 5-(2-iodophenyl)-1,2,4-oxadiazole-3-carboxylate

[0314] A mixture of ethyl 5-(2-iodophenyl)-1,2,4-oxadiazole-3-carboxylate (2.2 g, 6.4 mmol) in DMF (20 mL) was stirred at 150 °C for 4 h. The reaction mixture was cooled, H₂O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purification by silica gel column chromatography (PE / EA = 5:1) yielded ethyl 5-(2-iodophenyl)-1,2,4-oxadiazole-3-carboxylate (1.65 g, 64%) as a yellow oil.

[0315] MS (ESI) m / z 344.9 [M+H] + .

[0316] Step 3. (5-(2-iodophenyl)-1,2,4-oxadiazol-3-yl)methanol

[0317] At 0 °C, NaBH4 (0.55 g, 14.4 mmol) was added to a solution of ethyl 5-(2-iodophenyl)-1,2,4-oxadiazol-3-carboxylate (1.65 g, 4.8 mmol) in THF / MeOH (20 mL / 4 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to H2O and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification was performed using a silica gel column with PE / EA ratio of 3:1 to give (5-(2-iodophenyl)-1,2,4-oxadiazol-3-yl)methanol (1.05 g, 64%) as a yellow oil.

[0318] MS (ESI) m / z 302.9 [M+H] + .

[0319] Step 4. 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-iodophenyl)-1,2,4-oxadiazole

[0320] At 0 °C, imidazole (0.71 g, 10.5 mmol) in TBSCl (0.68 g, 4.5 mmol) in DCM (20 mL) was added to a solution of [5-(2-iodophenyl)-1,2,4-oxadiazole-3-yl]methanol (1.05 g, 3.5 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to H2O and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification was performed using a silica gel column with PE / EA ratio of 5:1 to give 3-((tert-butyldimethylsilyl)oxy)methyl)-5-(2-iodophenyl)-1,2,4-oxadiazole (1.4 g, 85%) as a colorless oil.

[0321] MS (ESI) m / z 417.0 [M+H] + .

[0322] Step 5. Methyl 2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol-5-yl)benzoate

[0323] 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-iodophenyl)-1,2,4-oxadiazole

[0324] (1.3 g, 3.1 mmol), TEA (940 mg, 9.3 mmol), Pd(OAc)2 (70 mg, 0.3 mmol), and dppp (130 mg, 0.3 mmol) were added to DMF / MeOH = 1:1 (30 mL), and the mixture was stirred at 80 °C. o The mixture was stirred overnight at C under CO (1 atm). The reaction mixture was cooled, H2O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification was performed by silica gel column chromatography (PE / EA = 10:1) to give methyl 2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol-5-yl)benzoate (850 mg, 70%) as a yellow oil.

[0325] MS (ESI) m / z 349.1 [M+H] + .

[0326] Step 6. 2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)benzoic acid

[0327] Methyl 2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol-5-yl)benzoate (918 mg, 2.63 mmol) was added to a 20 mL solution of THF / H₂O (1:1 ratio) with LiOH·H₂O (221 mg, 5.28 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated. The residue was adjusted to pH 2 with 1N HCl and concentrated under high vacuum to give 2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)benzoic acid (840 mg, 94%) as a white solid.

[0328] MS (ESI) m / z 221.0 [M+H] + .

[0329] Step 7. N-tert-butyl-2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)benzamide

[0330] HATU (1.42 g, 3.74 mmol) was added to a mixture of 2-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]benzoic acid (750 mg, 3.4 mmol), 2-methylpropane-2-amine (298 mg, 4.08 mmol), and DIEA (878 mg, 6.81 mmol) in DMF (20 mL). The reaction mixture was stirred overnight at room temperature. H₂O was added to the reaction mixture, and it was extracted twice with EA. The reaction mixture was washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purification by silica gel column chromatography (PE / EA = 1:1) yielded N-(tert-butyl)-2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)benzamide (800 mg, 74%) as a yellow solid.

[0331] MS (ESI) m / z 276.1 [M+H] + .

[0332] Step 8. (5-(2-(tert-butylcarbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)methylmethanesulfonate

[0333] N-tert-butyl-2-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]benzamide (160 mg, 0.58 mmol) and DIEA (225 mg, 1.74 mmol) were added to a solution of DCM (15 mL). MsCl (132 mg, 1.16 mmol) was added to the DCM (15 mL) solution. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was added to H2O and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give methyl (5-(2-(tert-butylcarbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)methylmethanesulfonate (140 mg, 54%) as a yellow oil.

[0334] MS (ESI) m / z 354.1 [M+H] + .

[0335] Step 9. (S)-N-tert-butyl-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)benzamide

[0336] (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (100 mg, 0.32 mmol), (5-(2-(tert-butylcarbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)methylmethanesulfonate (137 mg, 0.39 mmol), and K₂CO₃ (89 mg, 0.65 mmol) were added to a 10 mL DMF solution. The mixture was stirred overnight at 50 °C. The reaction mixture was cooled, H₂O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purified by HPLC, (S)-N-(tert-butyl)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)benzamide (47.3 mg, 24%) was obtained as a yellow solid.

[0337] MS (ESI) m / z 565.1 [M+H] + .

[0338] 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.94 (dd, J = 0.8 Hz, 7.2Hz,1H), 7.78-7.50 (m, 2H), 7.69 (td, J = 1.6 Hz, 7.6 Hz, 1H), 7.63-7.60 (m, 3H), 7.20 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 5.23 (d, J = 1.6Hz, 2H), 4.31 (brs, 1H), 4.0 (dd, J = 3.2 Hz, 14.4 Hz, 1H), 3.86 (dd, J = 2.0Hz, 14.4 Hz, 1H), 1.30(s, 9H).

[0339] Example 24

[0340] (S)-N-(tert-butyl)-2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)benzamide

[0341]

[0342]

[0343] Step 1. Ethyl 5-(2-bromophenyl)-1,3,4-oxadiazole-2-carboxylic acid ester

[0344] Ethyl 2-chloro-2-oxoethyl acetate (3.82 g, 28.0 mmol) was added to a solution of 2-bromobenzoyl hydrazine (5 g, 23.3 mmol), triethylamine (4.72 g, 46.6 mmol), and DCM (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for at least 6 h. Then, triethylamine (2.36 g, 23.3 mmol) and TsCl (4.44 g, 23.3 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for at least 18 h. The reaction mixture was then added to 200 mL of DCM. The separated organic layer was washed with 100 mL of saturated NaCl solution and purified by silica gel column chromatography to give the title product (4 g, 55% yield) as a yellow solid.

[0345] MS(ESI) m / z 297 [M+H] +

[0346] Step 2. (5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)methanol

[0347] Add NaBH4 (1.65 g, 43.5 mmol) to a THF / MeOH (15 mL / 3 mL) solution of ethyl 5-(2-bromophenyl)-1,3,4-oxadiazole-2-carboxylate (4.3 g, 14.5 mmol) and CaCl2 (3.22 g, 29 mmol). Heat the reaction mixture at 25°C. ℃ The mixture was stirred for 4 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give a yellow oil (3 g, 77% yield).

[0348] MS(ESI) m / z 255 [M+H] +

[0349] Step 3. 2-(2-Bromophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3,4-oxadiazole

[0350] TBSCl (2.83 g, 18.8 mmol) was added to a DCM (60 mL) solution of ethyl 5-(2-bromophenyl)-1,3,4-oxadiazole-2-carboxylate (3.2 g, 12.5 mmol) and imidazole (1.7 g, 25.0 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give a yellow oil (3 g, 62% yield).

[0351] MS(ESI) m / z 369 [M+H] +

[0352] Step 4. Methyl 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)benzoate

[0353] 2-(2-bromophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3,4-oxadiazole (1.35 g, 3.7 mmol), TEA (1.12 g, 11.1 mmol), and Pd(dppf)Cl2 (0.17 g, 0.7 mmol) were added to MeOH (50 mL). The reaction mixture was then heated with saturated CO (5 MPa) at 100 °C. oThe mixture was stirred at C for 12 h. The reaction mixture was cooled, quenched with water (30 mL), and extracted with EA (30 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to give a colorless oil (0.65 g, 49% yield).

[0354] MS(ESI) m / z 349 [M+H] +

[0355] Step 5. Methyl 2-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)benzoate

[0356] Methyl 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)benzoate (270 mg, 0.77 mmol) was stirred in 1 M TBAF solution in THF (1.5 mL) at 50 °C for 4 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oil (100 mg, 52% yield).

[0357] MS(ESI) m / z 235 [M+H] +

[0358] Step 6. Methyl 2-[5-(((methanesulfonyl)oxy)methyl]-1,3,4-oxadiazol-2-yl)benzoate

[0359] MsCl (97.31 mg, 0.85 mmol) was added to a solution of methyl 2-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]benzoate (100 mg, 0.43 mmol) and DIEA (165.56 mg, 1.28 mmol) in DCM (5 mL). The reaction mixture was heated to 25 °C. ℃ The mixture was stirred under nitrogen for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under vacuum so that the crude compound could be used directly in the next step without purification.

[0360] MS (ESI) m / z 313 [M+H] +

[0361] Step 7. Methyl (S)-2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)benzoate

[0362] (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (118.2 mg, 0.38 mmol), methyl 2-[5-((((methanesulfonyl)oxy)methyl]-1,3,4-oxadiazol-2-yl)benzoate (120 mg, 0.38 mmol) and K₂CO₃ (106.2 mg, 0.77 mmol) were added to a solution of DMF (3 mL), and the mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled, quenched with water (10 mL), and extracted with DCM (10 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oil (90 mg, 40% yield).

[0363] MS(ESI) m / z 524 [M+H] +

[0364] Step 8. (S)-2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)benzoic acid

[0365] LiOH was added to a THF / H₂O (1.6 mL / 0.4 mL) solution of methyl (S)-2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,3,4-oxadiazol-2-yl)benzoate (90 mg, 0.17 mmol). . H2O (28.83 mg, 0.69 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by preparative HPLC to give a white solid product (10 mg, 11% yield).

[0366] MS(ESI) m / z 510 [M+H] +

[0367] 1H NMR (400 MHz, CD3OD) δ 7.81-7.78 (m, 3H), 7.56-7.49 (m, 5H), 4.72(s, 2H), 4.47-4.43 (m, 1H), 4.02(dd, J = 14.4 Hz, 3.2 Hz, 1H), 3.92 (dd, J =14.4 Hz, 10.0 Hz, 1H).

[0368] Example 25

[0369] (S)-N-(tert-butyl)-2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-3-yl)benzamide

[0370]

[0371]

[0372] Step 1. (Z)-2-bromo-N'-hydroxybenzomidine

[0373] 2-Bromobenzonitrile (5.0 g, 27 mmol) and TEA (8.3 g, 82 mmol) were added to an NH₂OH solution, followed by an EtOH solution of HCl (5.7 g, 82 mmol) in 50 mL. The mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled, quenched with water (200 mL), and extracted with EA (200 mL x 3). The combined organic layers were concentrated under vacuum to give 5.3 g of (Z)-2-bromo-N'-hydroxybenzoylamidinium as a yellow solid.

[0374] MS (ESI) m / z 215 [M+H] + .

[0375] Step 2. (3-(2-bromophenyl)-1,2,4-oxadiazol-5-yl)methanol

[0376] Under nitrogen atmosphere, 2-bromo-N'-hydroxybenzoic acid (4.3 g, 20 mmol), ethyl 2-hydroxyacetate (3.1 g, 30 mmol), and K₂CO₃ (3.3 g, 24 mmol) were added to a toluene / DMF (54 mL / 6 mL) solution. The reaction mixture was stirred at 130 °C for 12 h. The reaction mixture was cooled, quenched with water (200 mL), and extracted with EA (200 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give (3-(2-bromophenyl)-1,2,4-oxadiazol-5-yl)methanol (3.3 g, 58% yield) as a yellow solid.

[0377] MS (ESI) m / z 255 [M+H] + .

[0378] Step 3. 3-(2-Bromophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazole

[0379] [3-(2-bromophenyl)-1,2,4-oxadiazol-5-yl]methanol (2.3 g, 9 mmol), TBSCl (2.0 g, 13 mmol), and imidazole (1.5 g, 22 mmol) were added to a solution of DCM (20 mL), and stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give 3-(2-bromophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol (2 g, 54%) as a colorless oil.

[0380] MS (ESI) m / z 369 [M+H] + .

[0381] Step 4. Methyl 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol-3-yl)benzoate

[0382] 3-(2-bromophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazole (1340.0 mg, 3.62 mmol), TEA (1101.4 mg, 10.8 mmol), palladium diacetate (81.4 mg, 0.362 mmol), and DPPP (149.6 mg, 0.362 mmol) were stirred at 70 °C for 8 h under CO2 (balloon) in a solution of MeOH (20 mL) and DMF (20 mL). The reaction mixture was cooled, quenched with water (50 mL), and extracted with EA (50 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=10:1) to obtain methyl 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol-3-yl)benzoate (260 mg, 18%), which was a yellow oil.

[0383] MS (ESI) m / z 349 [M+H] + .

[0384] Step 5. 2-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

[0385] Methyl 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol-3-yl)benzoate (200.0 mg, 0.573 mmol) and LiOH·H₂O (48.1 mg, 1.14 mmol) were stirred overnight in a THF / H₂O (4 mL / 1 mL) solution. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The pH of the aqueous layer was adjusted to 3 with 2 M HCl (aqueous solution). The reaction mixture was extracted with EA (30 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by prep-HPLC to give 2-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (120 mg, 85%) as a white solid.

[0386] MS (ESI) m / z 221 [M+H] + .

[0387] Step 6. N-tert-butyl-2-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)benzamide

[0388] 2-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]benzoic acid (100.0 mg, 0.454 mmol), 2-methylpropyl-2-amine (49.8 mg, 0.681 mmol), DIEA (176.1 mg, 0.362 mmol), and HATU (259.0 mg, 0.681 mmol) were stirred in DMF (4 mL) for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by catalytic cracking (DCM / MeOH = 10:1) to give N-(tert-butyl)-2-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)benzamide (70 mg, 50%) as a yellow solid.

[0389] MS (ESI) m / z 276 [M+H] + .

[0390] Step 7. (3-(2-(tert-butylcarbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)methylmethanesulfonate

[0391] N-tert-butyl-2-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]benzamide (70.0 mg, 0.254 mmol) and TEA (77.2 mg, 0.762 mmol) were added to a 2 mL solution of DCM. A 2 mL solution of methanesulfonyl chloride (34.7 mg, 0.305 mmol) in DCM was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with 20 mL of water and extracted with 3 20 mL solutions of DCM. The combined organic layers were concentrated under vacuum to give (3-(2-(tert-butylcarbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)methylmethanesulfonate (100.0 mg, crude) as a yellow oil.

[0392] MS (ESI) m / z 354 [M+H] + .

[0393] Step 8. (S)-N-(tert-butyl)-2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-3-yl)benzamide

[0394] A solution of (3-(2-(tert-butylcarbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)methylmethanesulfonate (100.0 mg, 0.283 mmol), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (86.0 mg, 0.283 mmol), and K₂CO₃ (117.2 mg, 0.849 mmol) in DMF (3 mL) was stirred at 50 °C for 12 h. The reaction mixture was cooled, quenched with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give (S)-N-(tert-butyl)-2-(5-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-3-yl)benzamide (2.6 mg, 1.4%), as a white solid.

[0395] MS (ESI) m / z 565 [M+H] + .

[0396] 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.4 Hz, 3H), 7.64-7.62 (m, 2H), 7.61-7.51 (m, 2H), 7.45 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 6.94(d, J = 6.0 Hz, 1H), 5.48 (s, 2H), 4.30 (s, 1H), 4.00 (dd, J = 14.4 Hz, 3.2Hz, 1H), 3.86 (dd, J = 14.4 Hz, 3.2 Hz, 1H), 1.27 (s, 9H)

[0397] Example 26

[0398] (S)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazol-1-yl)-N-(thiazolyl-2-yl)benzamide

[0399]

[0400]

[0401] Step 1. Methyl 2-(3-(hydroxymethyl)-1H-pyrazole-1-yl)benzoate

[0402] 1H-pyrazole-3-methanol (5.0 g, 19 mmol), 1H-pyrazole-3-methanol (2.1 g, 21 mmol), 2-(2-pyridyl)benzimidazole (0.75 g, 4.0 mmol), Cs₂CO₃ (12.5 g, 38 mmol) and copper iodide (I) were added to a DMF (80 mL) solution and stirred at 80 °C under N₂ for 12 hours. The reaction mixture was cooled, quenched with water (20 mL), and extracted with EA (20 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography to give methyl 2-[3-(hydroxymethyl)pyrazole-1-yl]benzoate (450 mg, 9% yield) as a yellow solid.

[0403] MS (ESI) m / z 233 [M+H] + .

[0404] Step 2. Methyl 2-(3-(((methanesulfonyl)oxy)methyl)-1H-pyrazole-1-yl)benzoate

[0405] Methyl 2-[3-(hydroxymethyl)pyrazol-1-yl]benzoate (160 mg, 0.69 mmol), DIEA (267.14 mg, 2.07 mmol), and MsCl (157.02 mg, 1.38 mmol) were added to a solution of DCM (8 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was used directly in the next step without purification.

[0406] MS (ESI) m / z 311 [M+H] + .

[0407] Step 3. Methyl (S)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazole-1-yl)benzoate

[0408] (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (158.63 mg, 0.52 mmol), methyl 2-(3-((((methanesulfonyl)oxy)methyl)-1H-pyrazole-1-yl)benzoate (160 mg, 0.52 mmol), and K₂CO₃ (142.31 mg, 1.03 mmol) were added to a solution of DMF (2 mL), and the mixture was stirred overnight at 50 °C. The reaction mixture was cooled, quenched with water (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give methyl (S)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazole-1-yl)benzoate (200 mg, 71% yield), as a yellow solid.

[0409] MS (ESI) m / z 522 [M+H] + .

[0410] Step 4. (S)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazole-1-yl)benzoic acid

[0411] To a solution of (S)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazole-1-yl)benzoate (150 mg, 0.29 mmol) in THF / H2O (4 / 1 mL), LiOH·H2O (36.2 mg, 0.86 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under vacuum. The residue was purified by C18 to give the title product (90 mg, 59% yield) as a white solid.

[0412] MS (ESI) m / z 508 [M+H] + .

[0413] Step 5. (S)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazole-1-yl)-N-(thiazolyl-2-yl)benzamide

[0414] (S)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazol-1-yl)benzoic acid (45 mg, 0.09 mmol), 1,3-thiazolyl-2-amine (18 mg, 0.18 mmol), DIEA (57 mg, 0.44 mmol), and HATU (44 mg, 0.12 mmol) were added to a solution of DMF (1 mL), and the mixture was stirred for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give the title product (22.6 mg, 41% yield) as a white solid.

[0415] MS (ESI) m / z 590 [M+H] +

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.76 -7.69 (m, 2H), 7.69-7.57 (m, 5H), 7.53-7.47 (m, 1H), 7.45 (d, J = 3.5Hz, 1H), 7.22 (d, J = 3.6 Hz, 1H), 6.88 (d, J = 6.4 Hz, 1H), 6.38 (d, J = 2.5Hz, 1H), 4.81 (d, J = 3.2 Hz, 2H), 4.40 -4.17 (m, 1H), 3.93 (dd, J = 14.7,3.5 Hz, 1H), 3.78 (dd, J = 14.6, 9.5 Hz, 1H).

[0417] Example 27

[0418] (S)-N-(tert-butyl)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazole-1-yl)benzamide

[0419]

[0420]

[0421] Step 1. N-tert-butyl-2-(3-(hydroxymethyl)-1H-pyrazole-1-yl)benzamide

[0422] 2-Bromo-N-tert-butylbenzamide (200 mg, 0.78 mmol), 1H-pyrazole-3-methanol (84 mg, 0.86 mmol), CuI (15 mg, 0.078 mmol), Cs₂CO₃ (507 mg, 1.56 mmol), and 2-(2-pyridyl)benzimidazole (30 mg, 0.15 mmol) were added to DMF (10 mL), and the mixture was incubated at 100 °C under N₂. ℃ Stir for 8 hours. Cool the reaction mixture, add H2O, and extract twice with EA. Wash the combined organic layers with brine, dry with Na2SO4, filter, and concentrate. Purify by silica gel column chromatography with PE / EA = 2:1 to give the title product (41 mg, 16% yield) as a yellow solid.

[0423] MS (ESI) m / z 274 [M+H] + .

[0424] Step 2. Methyl (1-(2-(tert-butylcarbamoyl)phenyl)-1H-pyrazole-3-yl)methanesulfonate

[0425] At 0 °C, N-tert-butyl-2-[3-(hydroxymethyl)pyrazol-1-yl]benzamide (41 mg, 0.15 mmol), DIEA (58 mg, 0.45 mmol), and MsCl (34 mg, 0.3 mmol) were added to a DCM solution (10 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then added to H2O and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (70 mg, 92% yield) as a yellow oil, which could be used directly in the next step without purification.

[0426] MS (ESI) m / z 352 [M+H] + .

[0427] Step 3. (S)-N-(tert-butyl)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazole-1-yl)benzamide

[0428] 5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H-1,2,4-triazol-3-one (58 mg, 0.19 mmol), [5-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]methylmethanesulfonate (70 mg, 0.19 mmol), and K₂CO₃ (52 mg, 0.37 mmol) were added to DMF (10 mL), and the mixture was stirred overnight at 50 °C. The reaction mixture was cooled, H₂O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine and concentrated. Purified by HPLC to the title product (S)-N-(tert-butyl)-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-pyrazole-1-yl)benzamide (6.7 mg, 5% yield), it was a white solid.

[0429] MS (ESI) m / z 563 [M+H] + .

[0430] 1 H NMR(400 MHz, DMSO-d6) δ 7.93(d, J = 2.4 Hz, 1H), 7.76 (d, J = 8.4Hz, 3H), 6.62 (d, J = 8.4 Hz, 2H), 7.56-7.50(m, 2H), 7.44-7.42 (m, 2H), 6.91(d, J = 6.4 Hz, 1H), 6.39(d, J = 2.4 Hz, 1H), 4.99(s, 2H), 4.33-4.30 (m, 1H), 3.99(dd, J = 3.2 Hz, 14.4 Hz, 1H), 3.83 (dd, J = 9.6 Hz, 14.8 Hz, 1H), 1.28 (s, 9H).

[0431] Example 28

[0432] (S)-2-(4-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-imidazol-1-yl)-N-(thiazolyl-2-yl)benzamide

[0433]

[0434]

[0435] Step 1. (1-(2-nitrophenyl)-1H-imidazol-4-yl)methanol

[0436] 1H-imidazolium-4-methanol hydrochloride (5 g, 37.2 mmol), 1-fluoro-2-nitrobenzene (5.77 g, 40.9 mmol), and K₂CO₃ (10.28 g, 74.4 mmol) were added to a 70 mL solution of DMF. The reaction mixture was then heated to 70 °C. ℃ The mixture was stirred for 16 hours. LC-MS showed that the reaction was complete. The resulting mixture was cooled, poured into water (200 mL), and extracted with EA (300 mL). The separated organic layer was washed with water (200 mL) and brine (200 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the title compound (3.3 g, 90% purity, 36% yield) as a yellow solid.

[0437] MS (ESI) m / z 219.8 [M+H] + .

[0438] Step 2. 4-Chloromethyl-1-(2-nitrophenyl)-1H-imidazolium

[0439] At 25 °C, methanesulfonyl chloride (385 mg, 3.4 mmol) was added to a DCM solution of [1-(2-nitrophenyl)imidazol-4-yl]methanol (570 mg, 2.6 mmol) and triethylamine (526 mg, 5.2 mmol) in 10 mL. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 3:1) to give the title compound (260 mg, 78% purity, 33% yield) as a yellow solid.

[0440] MS (ESI) m / z 238.1 [M+H] + .

[0441] Step 3. (S)-5-(4-chlorophenyl)-2-((1-(2-nitrophenyl)-1H-imidazol-4-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0442] (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (250 mg, 0.81 mmol), 4-(chloromethyl)-1-(2-nitrophenyl)imidazole (251 mg, 1.06 mmol), and K₂CO₃ (225 mg, 1.63 mmol) were added to DMF (5 mL), and the mixture was stirred at 50 °C for 5 hours. LC-MS showed that the reaction was complete. The resulting mixture was cooled, water (50 mL) was added, and the mixture was extracted with EA (50 mL). The separated organic layer was washed with water (50 mL) and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give the title compound (390 mg, 90% purity, 85% yield) as a yellow oil.

[0443] MS (ESI) m / z 509.1 [M+H] + .

[0444] Step 4. 2-((1-(2-aminophenyl)-1H-imidazol-4-yl)methyl)-(S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0445] (S)-5-(4-chlorophenyl)-2-((1-(2-nitrophenyl)-1H-imidazol-4-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (390 mg, 0.77 mmol), Fe (428 mg, 7.67 mmol), and ammonium chloride (410 mg, 7.67 mmol) were added to a solution of EtOH / H2O = 1:1 (10 mL), and the mixture was stirred for 3 hours. LCMS showed that the reaction was complete. The resulting mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give the title compound (200 mg, 90% purity, 49% yield) as a yellow oil.

[0446] MS (ESI) m / z 478.8 [M+H] + .

[0447] Step 5.

[0448] (S)-2-(4-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-imidazol-1-yl)-N-(thiazolyl-2-yl)benzamide

[0449] 2-((1-(2-aminophenyl)-1H-imidazol-4-yl)methyl)-(S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.21 mmol), HATU (119 mg, 0.31 mmol), 1,3-thiazol-2-carboxylic acid (40 mg, 0.31 mmol), and DIEA (81 mg, 0.63 mmol) were added to a 2 mL solution of DMF. The reaction mixture was heated to 25 °C. ℃ The mixture was stirred for 2 hours. LCMS showed that the reaction was complete. The resulting mixture was filtered. The filtrate was purified by Prep-HPLC (NH4HCO3) to give the target compound (S)-N-(2-(4-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-imidazol-1-yl)phenyl)thiazole-2-carboxamide (48.9 mg, purity 99%, yield 39%), as a white solid.

[0450] MS (ESI) m / z 590.0 [M+H] + .

[0451] 1 H NMR (400 MHz, DMSO-d6) δ 10.29(s, 1H), 8.06(d, J = 3.2 Hz, 1H), 7.98(d, J = 3.2 Hz, 1H), 7.84(d, J = 1.2 Hz, 1H), 7.75-7.68(m, 3H), 7.62-7.59(m, 2H), 7.52-7.41(m, 3H), 7.33(s, 1H), 6.90(d, J = 5.6 Hz, 1H), 4.86(s, 2H),4.36-4.24(m, 1H), 3.93(dd, J = 14.4, 3.2 Hz, 1H), 3.85(dd, J = 14.4, 9.6 Hz, 1H).

[0452] Example 29

[0453] (S)-N-(tert-butyl)-2-(2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)oxazol-5-yl)benzamide

[0454]

[0455]

[0456] Step 1. 2-(((tert-butyldimethylsilyl)oxy)methyl)oxazole

[0457] TBSCl (988.6 mg, 6.6 mmol) was added to a solution of oxazole-2-methanol (500.0 mg, 5.05 mmol) and imidazole (687.0 mg, 10.1 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)oxazole (650 mg, 57% yield) as a yellow oil.

[0458] MS (ESI) m / z 214 [M+H] + .

[0459] Step 2. 5-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)oxazole

[0460] n-BuLi (1.6 mL, 3.64 mmol) was added dropwise over 15 minutes to a THF (20 mL) solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)oxazole (650 mg, 3.06 mmol) at -78 °C. The reaction mixture was stirred at -78 °C under N2 for 30 minutes. Then, Br2 (728 mg, 4.55 mmol) was added dropwise over 15 minutes to a THF (2 mL) solution. The resulting solution was slowly heated to room temperature and stirred for 2 hours. The resulting mixture was diluted with NH4Cl / H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)oxazole (275 mg, 31% yield), as a yellow oil.

[0461] MS (ESI) m / z 292 [M+H] + .

[0462] Step 3. Methyl 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-5-yl)benzoate

[0463] 5-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)oxazole (275.0 mg, 0.94 mmol), (2-(methoxycarbonyl)phenyl)boronic acid (254.0 mg, 1.41 mmol), Na₂CO₃ (199.4 mg, 1.88 mmol), and Pd(dppf)Cl₂ (137.7 mg, 0.19 mmol) were added to a dioxane / H₂O (10 mL / 2 mL) solution and stirred under nitrogen for 12 h. The reaction mixture was cooled, quenched with water (10 mL), and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1:1) to give methyl 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-5-yl)benzoate (170 mg, yield 18%) as a yellow oil.

[0464] MS (ESI) m / z 348 [M+H] + .

[0465] Step 4. 2-(2-(hydroxymethyl)oxazol-5-yl)benzoic acid

[0466] Methyl 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-5-yl)benzoate (150 mg, 0.43 mmol) was added to a solution of THF / H₂O (2 mL / 0.5 mL), followed by the addition of LiOH·H₂O (36 mg, 0.86 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum to obtain the crude product for the next step without further purification.

[0467] MS (ESI) m / z 220 [M+H] + .

[0468] Step 5. N-tert-butyl-2-(2-(hydroxymethyl)oxazol-5-yl)benzamide

[0469] 2-(2-(hydroxymethyl)oxazol-5-yl)benzoic acid (200 mg, 0.91 mmol), HATU (451.0 mg, 1.19 mmol), DIEA (353.8 mg, 2.73 mmol), and 2-methylpropane-2-amine (133.5 mg, 1.82 mmol) were added to a DMF (3 mL) solution. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give N-(tert-butyl)-2-(2-(hydroxymethyl)oxazol-5-yl)benzamide (100 mg, 57% yield) as a yellow solid.

[0470] MS (ESI) m / z 275 [M+H] + .

[0471] Step 6. (5-(2-(tert-butylcarbamoyl)phenyl)oxazol-2-yl)methylmethanesulfonate

[0472] In 0 ℃ Next, N-(tert-butyl)-2-(2-(hydroxymethyl)oxazol-5-yl)benzamide (100.0 mg, 0.36 mmol), DIEA (141.3 mg, 1.09 mmol), and MsCl (83.1 mg, 0.73 mmol) were added to a DCM (5 mL) solution. The reaction mixture was stirred at room temperature under nitrogen for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under vacuum to obtain a crude product that could be used directly in the next step without purification.

[0473] MS (ESI) m / z 353 [M+H] + .

[0474] Step 7. (S)-N-(tert-butyl)-2-(2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)oxazol-5-yl)benzamide

[0475] (5-(2-(tert-butylcarbamoyl)phenyl)oxazol-2-yl)methylmethanesulfonate (90.0 mg, 0.26 mmol), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (78.6 mg, 0.26 mmol), and K₂CO₃ (70.6 mg, 0.51 mmol) were added to a DMF (2 mL) solution and stirred overnight at 50 °C. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give (S)-N-(tert-butyl)-2-(2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)oxazol-5-yl)benzamide (4.8 mg, 3% yield), as a white solid.

[0476] MS (ESI) m / z 564 [M+H] + .

[0477] 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.81-7.72 (m, 2H), 7.66-7.58(m, 3H), 7.50 (td, J = 7.6, 1.4 Hz, 1H), 7.42 (td, J = 7.4, 1.3 Hz, 1H), 7.34(d, J = 7.4 Hz, 2H), 6.91 (d, J = 6.3 Hz, 1H), 5.20 (d, J = 1.2 Hz, 2H), 4.41-4.21 (m, 1H), 4.00 (dd, J = 14.6, 3.5 Hz, 1H), 3.85 (dd, J = 14.6, 9.5 Hz (1H), 1.34 (s, 9H).

[0478] Example 30

[0479] (S)-5-chloro-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)-N-methylbenzamide

[0480]

[0481]

[0482] Step 1. Ethyl(Z)-2-(4-chloro-2-iodobenzoylamino)-2-(hydroxyimino)acetic acid ester

[0483] 4-Chloro-2-iodobenzoic acid (3.0 g, 10 mmol), ethyl [(Z)-N'-hydroxycarbonylimino]carbamate (1.4 g, 10 mmol), HATU (6.1 g, 16 mmol), and DIEA (4.1 g, 31 mmol) were dissolved in DMF (30 mL) and stirred at 25°C for 12 hours. After the reaction was complete, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (EA, 100 mL × 3). The combined organic phases were concentrated under vacuum, and the residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 3:1) to give ethyl (Z)-2-(4-chloro-2-iodobenzoylamino)-2-(hydroxyimino)acetic acid ester (2.4 g, 51% yield) as a white solid.

[0484] MS(ESI)m / z 397 [M+H] +

[0485] Step 2. Ethyl 5-(4-chloro-2-iodophenyl)-1,2,4-oxadiazole-3-carboxylic acid ester

[0486] The product (1.0 g, 2 mmol) was dissolved in DMF (20 mL) and heated at 150°C for 4 hours. After cooling, the reaction was quenched with water (50 mL), the solid was collected by filtration, and dried under vacuum to give ethyl 5-(4-chloro-2-iodophenyl)-1,2,4-oxadiazole-3-carboxylic acid ester (700 mg, 68% yield), a white solid.

[0487] MS(ESI)m / z 379 [M+H] +

[0488] Step 3. (5-(4-chloro-2-iodophenyl)-1,2,4-oxadiazol-3-yl)methanol

[0489] To a THF / MeOH (10 mL / 10 mL) solution containing the above product (700 mg, 1.84 mmol), NaBH4 (349.5 mg, 9.24 mmol) was added fractionally at 0°C. After stirring at room temperature for 2 hours, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (EA, 30 mL × 3). The combined organic phases were concentrated under vacuum, and the residue was purified by rapid column chromatography (FCC, petroleum ether / ethyl acetate = 3:1) to give (5-(4-chloro-2-iodophenyl)-1,2,4-oxadiazol-3-yl)methanol (400 mg, 51% yield) as a white solid.

[0490] MS(ESI)m / z 337 [M+H] + .

[0491] Step 4. 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-chloro-2-iodophenyl)-1,2,4-oxadiazole

[0492] The above product (400 mg, 1.18 mmol), TBSCl (268.7 mg, 1.78 mmol), and imidazole (202.3 mg, 2.97 mmol) were dissolved in DCM (10 mL) and stirred at room temperature for 12 hours. The reaction was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic phases were concentrated under vacuum, and the residue was purified by rapid column chromatography (FCC, petroleum ether / ethyl acetate = 10:1) to give 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-chloro-2-iodophenyl)-1,2,4-oxadiazole (480 mg, 44% yield), a colorless oil.

[0493] MS(ESI)m / z 451 [M+H] +

[0494] Step 5. Methyl 2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol-5-yl)-5-chlorobenzoate

[0495] The above products (480 mg, 1.06 mmol), TEA (323.2 mg, 3.19 mmol), Pd(OAc)2 (23.9 mg, 0.106 mmol), and DPPP (43.9 mg, 0.106 mmol) were dissolved in DMF / MeOH (7 mL / 7 mL) and heated at 80°C for 16 hours under CO balloon pressure. After cooling, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (EA, 30 mL × 3). The combined organic phases were concentrated under vacuum, and the residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 10:1) to give methyl 2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,4-oxadiazol-5-yl)-5-chlorobenzoate (150 mg, 33% yield), a yellow oil.

[0496] MS(ESI)m / z 383 [M+H] +

[0497] Step 6. 5-Chloro-2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)benzoic acid

[0498] The above product (150 mg, 0.391 mmol) and LiOH·H2O (32.8 mg, 0.783 mmol) were dissolved in THF / H2O (4 mL / 1 mL) and stirred at room temperature for 12 hours. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (EA, 30 mL × 3). The aqueous phase was adjusted to pH 2-3 with 2 M HCl and then extracted with ethyl acetate (EA, 30 mL × 3). The combined organic phases were concentrated under vacuum to give 5-chloro-2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)benzoic acid (110 mg, 88% yield), a yellow oil.

[0499] MS(ESI)m / z 255 [M+H] +

[0500] Step 7. 5-Chloro-2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)-N-methylbenzamide

[0501] The above product (90 mg, 0.353 mmol), methylamine (16.5 mg, 0.530 mmol), HATU (201.6 mg, 0.530 mmol), and DIEA (137.1 mg, 1.06 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 1 hour. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (EA, 30 mL × 3). The combined organic phases were concentrated under vacuum, and the residue was purified by rapid column chromatography (FCC, petroleum ether / ethyl acetate = 0:1) to give a yellow oily 5-chloro-2-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)-N-methylbenzamide (34 mg, 32% yield).

[0502] MS(ESI)m / z 268 [M+H] +

[0503] Step 8. (5-(4-chloro-2-(methylcarbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)methylmethanesulfonate

[0504] The above product (34 mg, 0.127 mmol) and TEA (38.5 mg, 0.381 mmol) were dissolved in DCM (2 mL), and methanesulfonyl chloride (17.4 mg, 0.152 mmol) was added dropwise at 0°C. After stirring at room temperature for 12 hours, the reaction was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic phases were concentrated under vacuum to give a yellow oil (5-(4-chloro-2-(methylcarbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)methylmethanesulfonate (50 mg, 91% yield).

[0505] MS(ESI)m / z 346 [M+H] +

[0506] Step 9. (S)-5-chloro-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)-N-methylbenzamide

[0507] The above product (50 mg, 0.237 mmol), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (87.6 mg, 0.284 mmol), and K2CO3 (98.3 mg, 0.711 mmol) were dissolved in DMF (2 mL) and stirred at 50°C for 12 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (EA, 20 mL × 3). The combined organic phases were concentrated under vacuum, and the residue was purified by high performance liquid chromatography (HPLC) to give a white solid (S)-5-chloro-2-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1,2,4-oxadiazol-5-yl)-N-methylbenzamide (2.9 mg, 1.7% yield).

[0508] MS(ESI)m / z 557 [M+H] +

[0509] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (dd, J = 8.8, 4.4 Hz, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.78-7.73 (m, 3H), 7.70 (d, J = 2.0 Hz, 1H), 7.64-7.61 (m,2H), 6.93 (d, J = 6.0, 1H), 5.25 (s, 2H), 4.31 (s, 1H), 4.03 (dd, J =14.4 Hz, 3.2 Hz, 1H), 3.85 (dd, J =14.8 Hz, 9.6 Hz, 1H), 2.68 (d, J = 4.8 Hz, 3H).

[0510] Example 31

[0511] 5-(4-Chlorophenyl)-2-((5-(3-Chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0512]

[0513]

[0514] Step 1. Ethyl (Z)-2-(3-chlorobenzamido)-2-(hydroxyimino)acetate

[0515] 3-Chlorobenzoic acid (500 mg, 3.19 mmol), ethyl[(Z)-N'-hydroxycarbamoylurea]formate (464 mg, 3.51 mmol), and NMI (1256 mg, 15.3 mmol) were added to acetonitrile (20 mL), and the mixture was stirred at room temperature for 5 minutes. Then, TCFH (1256 mg, 4.47 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was added to H₂O and extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The reaction mixture was purified by silica gel column chromatography with PE / EA = 2:1 to give (Z)-2-(3-chlorobenzoamide)-2-(hydroxyimino)ethyl acetate (800 mg, 83%) as a white solid.

[0516] MS (ESI) m / z 271.0 [M+H] + .

[0517] Step 2. Ethyl 5-(3-chlorophenyl)-1,2,4-oxadiazole-3-carboxylate

[0518] Ethyl (2Z)-2-[(3-chlorophenyl)formamido]-2-(N-hydroxyimino)acetate (800 mg, 2.95 mmol) was added to DMF (10 mL), and the mixture was stirred at 150 °C for 4 h. The reaction mixture was cooled, H2O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification was performed using a silica gel column with PE / EA ratio of 5:1 to give ethyl 5-(3-chlorophenyl)-1,2,4-oxadiazole-3-carboxylate (600 mg, 72%) as a yellow solid.

[0519] MS (ESI) m / z 253.0 [M+H] + .

[0520] Step 3. (5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl)methanol

[0521] To a THF / MeOH solution of 5:1 (12 mL), add NaBH4 (270 mg, 7.12 mmol) and ethyl 5-(3-chlorophenyl)-1,2,4-oxadiazol-3-carboxylate (600 mg, 2.37 mmol). Stir the reaction mixture overnight at room temperature. Add H2O to the reaction mixture and extract twice with EA. Wash the combined organic layers with brine, dry with Na2SO4, filter, and concentrate. Purify using a PE / EA 2:1 silica gel column to give (5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl)methanol (230 mg, 41%) as a white solid.

[0522] MS (ESI) m / z 211.0 [M+H] + .

[0523] Step 4. Methyl (5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl sulfonate

[0524] In 0 ℃ MsCl (108 mg, 0.94 mmol) was added to a DCM solution of [5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methanol (100 mg, 0.47 mmol) and DIEA (183 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then added to H2O and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give methyl (5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl methanesulfonate (150 mg, 98%) as a yellow oil.

[0525] MS (ESI) m / z 289.0 [M+H] + .

[0526] Step 5. 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0527] 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (100 mg, 0.32 mmol), methyl 5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl)methanesulfonate (128 mg, 0.39 mmol), and K₂CO₃ (89 mg, 0.65 mmol) were added to DMF (10 mL), and the mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled, H₂O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purified by HPLC (NH4HCO3), 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (78.7 mg, 42%) was obtained as a white solid.

[0528] MS (ESI) m / z 500.0 [M+H] + .

[0529] 1 H NMR (400 MHz, DMSO-d6) δ 8.10-8.05 (m, 2H), 7.82-7.75 (m, 3H), 7.69-7.62 (m, 3H), 6.92 (d, J = 6.4 Hz, 1H), 5.28 (s, 2H), 4.30 (brs, 1H), 4.02 (dd, J = 3.2 Hz, 14.8 Hz, 1H), 3.86 (dd, J = 11.2 Hz, 14.8 Hz, 1H).

[0530] Example 32

[0531] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-cyclopropylphenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0532]

[0533]

[0534] Step 1. 5-(4-Cyclopropylphenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0535] 5-Bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (300 mg, 1.08 mmol), (4-cyclopropylphenyl)borondiol (211 mg, 1.30 mmol), Pd(dppf)Cl2 (79 mg, 0.10 mmol), and K2CO3 (299 mg, 2.17 mmol) were added to a 1,4-dioxane / H2O = 5 / 1 (15 mL / 3 mL) solution and stirred under N2 for 2 h. The reaction mixture was cooled, H2O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification with a silica gel column of PE / EA = 3:1 yielded 5-(4-cyclopropylphenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (85 mg, 22%), as a yellow oil.

[0536] MS (ESI) m / z 314.1 [M+H] + .

[0537] Step 2. 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-cyclopropylphenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0538] 5-(4-cyclopropylphenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (87 mg, 0.27 mmol), [5-acetyl-1-(3-chlorophenyl)-1,2,4-triazol-3-yl]methylmethanesulfonate (91 mg, 0.27 mmol), and K₂CO₃ (76 mg, 0.55 mmol) were added to DMF (10 mL), and the mixture was stirred overnight at 50 °C. The reaction mixture was cooled, H₂O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purified by HPLC (NH4HCO3), 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-cyclopropylphenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (27.3 mg, 17%) was obtained as a grayish-white solid.

[0539] MS (ESI) m / z 547.1 [M+H] + .

[0540] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (t, J = 1.6 Hz, 1H), 7.61-7.58 (m,3H), 7.54-7.49 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 6.0 Hz, 1H),5.15 (s, 2H), 4.30 (s, 1H), 4.00 (dd, J = 3.6 Hz, 14.8 Hz, 1H), 3.86(dd, J =9.2 Hz, 18.0 Hz, 1H), 2.61 (s, 3H), 2.02-1.95(m, 1H), 1.04-0.99(m, 2H), 0.76-0.72(m, 2H).

[0541] Example 33

[0542] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-(difluoromethyl)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0543]

[0544]

[0545] Step 1. 5-(4-(difluoromethyl)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0546] 5-Bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (300.0 mg, 1.08 mmol), [4-(difluoromethyl)phenyl]borondiol (205.5 mg, 1.19 mmol), K₂CO₃ (450.6 mg, 3.26 mmol), and Pd(dppf)Cl₂ (78.8 mg, 0.108 mmol) were added to a dioxane / H₂O (10 mL / 2.5 mL) solution and stirred under nitrogen for 12 h. The reaction mixture was cooled, quenched with water (50 mL), and extracted with EA (50 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1:1) to give 5-(4-(difluoromethyl)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 12% yield), which was a yellow oil.

[0547] MS (ESI) m / z 324 [M+H] + .

[0548] Step 2. (5-Acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate

[0549] 1-[2-(3-chlorophenyl)-5-(hydroxymethyl)-1,2,4-triazol-3-yl]acetone (2 g, 0.008 mol) and TEA (2.40 g, 0.023 mol) were added to a DCM (40 mL) solution, and methanesulfonyl chloride (1.08 g, 9 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were concentrated under vacuum to give (5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate (1.78 g, 63% yield) as a yellow solid.

[0550] MS (ESI) m / z 330 [M+H] + .

[0551] Step 3. 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-(difluoromethyl)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0552] 5-[4-(difluoromethyl)phenyl]-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (60.0 mg, 0.185 mmol), [5-acetyl-1-(3-chlorophenyl)-1,2,4-triazol-3-yl]methylmethanesulfonate (73.4 mg, 0.222 mmol), and K₂CO₃ (76.9 mg, 0.556 mmol) were added to a DMF (2 mL) solution and stirred at 50 °C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-(difluoromethyl)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6.7 mg, 6%) as a white solid.

[0553] MS (ESI) m / z 557 [M+H] +

[0554] 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.4 Hz, 2H), 7.74-7.71 (m,3H), 7.61-7.50 (m, 3H), 7.12 (t, J = 55.6 Hz, 1H), 6.88 (d, J = 6.4 Hz, 1H), 5.18 (s, 2H), 4.34-4.10 (m, 1H), 4.04 (dd, J = 14.8, 4.0 Hz, 1H), 3.92-3.86 (m, 1H), 2.61 (s, 3H).

[0555] Example 34

[0556] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-(1,1-difluoroethyl)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0557]

[0558]

[0559] Starting from 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and (4-(1,1-difluoroethyl)phenyl)boronic acid, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-(1,1-difluoroethyl)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one) was synthesized according to the method described in Example 32, as a white solid.

[0560] MS (ESI) m / z 571 [M+H] +

[0561] 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.1 Hz, 2H), 7.77-7.68 (m,3H), 7.60 (dt, J = 7.6, 1.9 Hz, 1H), 7.57-7.49 (m, 2H), 6.90 (d, J = 6.3 Hz,1H), 5.18 (s, 2H), 4.41-4.23 (m, 1H), 4.04 (dd, J = 14.7, 3.6 Hz, 1H), 3.89(dd, J = 14.7, 9.4 Hz, 1H), 2.62 (s, 3H), 2.00(t, J=19.0Hz, 3H).

[0562] Example 35

[0563] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-(methylthio)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0564]

[0565]

[0566] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and [4-(methylthio)phenyl]borondiol, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-(methylthio)phenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one) was synthesized as a white solid according to the synthetic method of Example 32.

[0567] MS (ESI) m / z 553.0 [M+H] + .

[0568] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (t, J = 1.6 Hz, 1H), 7.60 (d, J = 8.8Hz, 2H), 7.62-7.58 (m, 1H), 7.57-7.49 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 6.88(d, J = 6.0 Hz, 1H), 5.16 (s, 2H), 4.36- 4.25 (m, 1H), 4.01 (dd, J = 14.4,3.2 Hz, 1H), 3.86 (dd, J = 14.8, 9.6 Hz, 1H), 2.62 (s, 3H), 2.52 (s, 3H).

[0569] Example 36

[0570] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-mercaptophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0571]

[0572]

[0573] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and [5-acetyl-1-(3-chlorophenyl)-1,2,4-triazol-3-yl]methylmethanesulfonate, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-mercaptophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.2 mg, 3%) was synthesized according to the method described in Example 32, yielding a white solid.

[0574] MS (ESI) m / z 539.0 [M+H] + .

[0575] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (t, J = 2.4 Hz, 1H), 7.20 (dt, J =1.2 Hz, 6.8 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.51 (dt, J = 1.6 Hz, 6.8 Hz,1H), 7.39-7.37 (m, 2H), 7.33-7.27 (m, 3H), 6.79 (s, 1H), 5.18 (s, 2H), 4.33-4.28 (m, 1H), 3.86-3.75 (m, 2H), 2.62 (s, 3H).

[0576] Example 37

[0577] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(3,4,5-trifluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0578]

[0579]

[0580] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and (3,4,5-trifluorophenyl)boronic acid, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(3,4,5-trifluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one) was synthesized as a white solid according to the synthetic method of Example 32.

[0581] MS (ESI) m / z 561 [M+H] + .

[0582] 1 H NMR (400 MHz, DMSO-d6) δ 7.79-7.68 (m, 3H), 7.60 (dt, J = 7.7, 1.8Hz, 1H), 7.58-7.48 (m, 2H), 6.94 (d, J = 6.3 Hz, 1H), 5.17 (s, 2H), 4.36-4.18(m, 1H), 4.03 (dd, J = 14.8, 3.6 Hz, 1H), 3.90 (dd, J = 14.8, 9.3 Hz, 1H), 2.61 (s, 3H).

[0583] Example 38

[0584] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(2,4,6-trifluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0585]

[0586]

[0587] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and 2,4,6-trifluorophenylboronic acid, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(2,4,6-trifluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (11.6 mg, 6.2% yield) was synthesized as a white solid according to the synthesis method in Example 32.

[0588] MS (ESI) m / z 561.1 [M+H] +

[0589] 1 H NMR (500 MHz, Chloroform-d) δ 7.45 (t, J = 2.1 Hz, 1H), 7.36 (ddd,J = 8.0, 2.1, 1.0 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.15 (dd, J = 8.1, 7.5 Hz,1H), 6.82 (ddd, J = 12.3, 11.5, 0.9 Hz, 2H), 5.03 (m, 1H), 4.49 (s, 1H), 3.67– 3.54 (m, 2H), 3.34 (m, 1H), 2.61 (s, 2H).

[0590] Example 39

[0591] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(2,3,4-trifluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0592]

[0593]

[0594] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and 2,3,4-trifluorophenylboronic acid, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(2,3,4-trifluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one) was synthesized as a white solid according to the synthetic method of Example 32.

[0595] MS (ESI) m / z 561.1 [M+H] +

[0596] 1H NMR (500 MHz, Chloroform-d) δ 7.47 (t, J = 2.1 Hz, 1H), 7.34 –7.22 (m, 2H), 7.15 (ddd, J = 10.1, 9.1, 4.8 Hz, 1H), 7.06 (ddd, J = 8.0, 2.1,1.1 Hz, 1H), 5.13 (m, 1H), 4.47 (s, 1H), 3.93 (dq, J = 8.2, 3.6 Hz, 1H), 3.58(m, 1H), 3.34 (m, 1H), 2.75 (s, 2H).

[0597] Example 40

[0598] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(4-cyano-3,5-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0599]

[0600]

[0601] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and 4-cyano-3,5-difluorophenylboronic acid, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(4-cyano-3,5-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one) was synthesized as a white solid according to the synthetic method of Example 32.

[0602] MS (ESI) m / z 568.1 [M+H] +

[0603] 1H NMR (500 MHz, Chloroform-d) δ 7.75 (dt, J = 12.0, 0.6 Hz, 2H), 7.45 (t, J = 2.0 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.22–7.11 (m, 2H), 5.03 (m,1H), 4.44 (s, 1H), 4.21 (dq, J = 8.2, 3.5 Hz, 1H), 3.68 (m, 1H), 3.34 (m,1H), 2.78 (s, 2H).

[0604] Example 41

[0605] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0606]

[0607]

[0608] A mixture of 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (100 mg, 0.32 mmol), [5-acetyl-1-(3-chlorophenyl)-1,2,4-triazol-3-yl]methylmethanesulfonate (107 mg, 0.32 mmol), and K₂CO₃ (89 mg, 0.65 mmol) in DMF (10 mL) was stirred overnight at 50°C. The reaction mixture was cooled, H₂O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purified by HPLC (NH4HCO3), 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.5 mg, 5%) was given as a white solid.

[0609] MS(ESI) m / z 541.0 [M+H] + .

[0610] 1H NMR (400 MHz, DMSO-d6)δ 7.77-7.71 (m, 3H), 7.64-7.59 (m, 3H), 7.57-7.50 (m, 2H), 6.89 (d, J = 2.0 Hz, 1H), 5.17 (s, 2H), 4.30 (s, 1H), 4.01 (dd, J = 3.6 Hz, 14.8 Hz, 1H), 3.85 (dd, J = 9.6 Hz, 14.8 Hz, 1H), 2.62 (s, 3H).

[0611] Example 42

[0612] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(1-methyl-1H-indol-5-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0613]

[0614]

[0615] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and N-methylindole-5-boronic acid, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-5-(2,4,6-trifluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6.0 mg, 5% yield) was synthesized as a white solid according to the synthesis method in Example 32.

[0616] MS(ESI) m / z 560.1 [M+H] + .

[0617] 1H NMR (500 MHz, Chloroform-d) δ 8.60 (m, 1H), 7.85 (dt, J = 7.8, 0.6Hz, 1H), 7.78 (dd, J = 7.6, 1.5 Hz, 1H), 7.45 (t, J = 2.1 Hz, 1H), 7.29 –7.23 (m, 1H), 7.21 – 7.15 (m, 1H), 7.11 (dp, J = 5.1, 0.7 Hz, 1H), 6.36 –6.30 (m, 1H), 5.03 (m, 1H), 4.49 (s, 1H), 3.93 (dq, J = 8.2, 3.6 Hz, 1H),3.84 (d, J = 0.7 Hz, 2H), 3.68 (m, 1H), 3.34 (m, 1H), 2.71 (s, 2H).

[0618] Example 43

[0619] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(cyclohex-1-en-1-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0620]

[0621]

[0622] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and cyclohex-1-en-1-boronic acid, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(cyclohex-1-en-1-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one) was synthesized according to the method described in Example 32, yielding a white solid (59.8 mg, 28% yield).

[0623] MS (ESI) m / z 511 [M+H] + .

[0624] 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.68 (m, 1H), 7.60 (dt, J = 7.8, 1.8Hz, 1H), 7.59-7.47 (m, 2H), 6.78 (d, J = 6.5 Hz, 1H), 6.44-6.26 (m, 1H), 5.06(s, 2H), 4.48-4.20 (m, 1H), 4.01-3.76 (m, 2H), 2.61 (s, 3H), 2.35-2.25(m,1H), 2.16 (s, 3H), 1.72-1.49 (m, 4H).

[0625] Example 44

[0626] 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(3,6-dihydro-2H-thiaran-4-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0627]

[0628]

[0629] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and 2-(3,6-dihydro-2H-thiaran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane, 2-((5-acetyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(3,6-dihydro-2H-thiaran-4-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6.5 mg, 3%) white solid was synthesized according to the method described in Example 32.

[0630] MS (ESI) m / z 529.1 [M+H] + .

[0631] 1H NMR (400 MHz, DMSO-d6) δ7.71 (t, J = 1.6 Hz, 1H), 7.62-7.50 (m,3H), 6.83 (d, J = 6.4 Hz, 1H), 6.53-6.51 (m, 1H), 5.08 (s, 2H), 4.39-4.32(m,1H), 3.97-3.83 (m, 2H), 3.31-3.25 (m, 2H), 2.77(td, J = 2.0 Hz, 6.0 Hz, 2H), 2.61 (s, 3H), 2.51-2.49 (m, 2H).

[0632] Example 45

[0633] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0634]

[0635]

[0636] Step 1. Ethyl (Z)-2-amino-2-(2-(3-chlorobenzoyl)hydrazine)ethyl acetate

[0637] A solution of 3-chlorobenzoylhydrazine (5.0 g, 29 mmol), ethyl 2-ethoxy-2-iminohydrazine (4.3 g, 29 mmol), and TEA (3.6 g, 35 mmol) in EtOH (50 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered. The filtered cake was concentrated to give a white solid (Z)-2-amino-2-(2-(3-chlorobenzoyl)hydrazine)ethyl acetate (5.6 g, 68% yield).

[0638] MS(ESI) m / z 270 [M+H] +

[0639] Step 2. Ethyl 5-(3-chlorophenyl)-1H-1,2,4-triazole-3-carboxylic acid ester

[0640] A solution of (Z)-2-amino-2-(2-(3-chlorobenzoyl)hydrazine)ethyl acetate (5.6 g, 20 mmol) in Ph₂O (30 mL) was stirred at 260 °C for 12 h. The reaction mixture was cooled and filtered. The filter cake was dried under vacuum to give a white solid of ethyl 5-(3-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate (5.2 g, 89%).

[0641] MS(ESI) m / z 252 [M+H] +

[0642] Step 3. (5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methanol

[0643] Lithium aluminum hydride (28.6 mL, 28.6 mmol) was added dropwise to a THF (30 mL) solution of ethyl 5-(3-chlorophenyl)-1H-1,2,4-triazol-3-carboxylic acid (2.4 g, 9.53 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (2 mL) and washed with aqueous NaOH solution (2 mL) and water (6 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give (5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)methanol (1500 mg, 67%) as a white solid.

[0644] MS(ESI) m / z 210 [M+H] +

[0645] Step 4. Methyl (5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)acetate

[0646] [5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl]methanol (1.1 g, 5.24 mmol), Ac₂O (589.2 mg, 5.77 mmol), DIEA (1356.3 mg, 10.4 mmol), and DMAP (64.1 mg, 0.524 mmol) were added to a DCM solution (20 mL) and stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give methyl 5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)acetate (800 mg, 54%) as a yellow oil.

[0647] MS (ESI) m / z 252 [M+H] + .

[0648] Step 5. Methyl (5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)acetate

[0649] Methyl [5-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl]acetate (750 mg, 2.98 mmol), 3-(bromomethyl)oxetane (900 mg, 5.96 mmol), and K₂CO₃ (1235.6 mg, 8.94 mmol) were added to a DMF (15 mL) solution and stirred at 80 °C for 12 h. The reaction mixture was cooled, quenched with water (30 mL), and extracted with EA (30 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by preparative HPLC to give a yellow oil (methyl 5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)acetate (100.0 mg, 9%).

[0650] MS(ESI) m / z 322 [M+H] +

[0651] Step 6. (5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)methanol

[0652] Methyl [5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1,2,4-triazol-3-yl]acetate (90 mg, 0.279 mmol) and K₂CO₃ (115.9 mg, 0.839 mmol) were added to a solution of MeOH (2 mL) and stirred at 25 °C for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic phases were concentrated under vacuum to give a yellow oil (5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)methanol (100 mg, crude).

[0653] MS(ESI) m / z 280 [M+H] +

[0654] Step 7. (5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate

[0655] [5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1,2,4-triazol-3-yl]methanol (90 mg, 0.321 mmol) and TEA (97.6 mg, 0.965 mmol) were added to a DCM solution (5 mL), followed by dropwise addition of methanesulfonyl chloride (73.3 mg, 0.643 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were concentrated under vacuum to give (5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate (100 mg, 78%) as a yellow oil.

[0656] MS (ESI) m / z 358 [M+H] + .

[0657] Step 8. (S)-5-(4-chlorophenyl)-2-(5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0658] [5-(3-chlorophenyl)-1-(oxetane-3-ylmethyl)-1,2,4-triazol-3-yl]methylmethanesulfonate (90 mg, 0.251 mmol), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (77.3 mg, 0.251 mmol), and K₂CO₃ (34.7 mg, 0.251 mmol) were added to a DMF (2 mL) solution and stirred at 50 °C for 12 h. The reaction mixture was cooled, quenched with water (20 mL), and extracted with EA (20 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by high performance liquid chromatography to give (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(oxacyclobutane-3-ylmethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (22.1 mg, 15%), as a white solid.

[0659] MS (ESI) m / z 569 [M+H] +

[0660] 1H NMR (400 MHz, DMSO-d6) δ 7.79-7.72 (m, 3H), 7.67-7.56 (m, 5H), 6.91(d, J = 6.0 Hz, 1H), 5.02 (s, 2H), 4.59 (dd, J = 8.0 Hz, 6.4 Hz, 2H), 4.52(d, J = 7.6 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H), 4.30 (s, 1H), 4.03 (dd J =14.4Hz, 3.2 Hz, 1H), 3.85 (dd, J =14.8 Hz, 9.6 Hz, 1H), 3.46-3.36(m, 1H).

[0661] Example 46

[0662] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0663]

[0664]

[0665] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and 2,2-difluoroethyl p-toluenesulfonate, the product was synthesized according to the method in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (24.2 mg, yield 22%), a white solid.

[0666] MS (ESI) m / z 563 [M+H] + .

[0667] 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.71 (m, 3H), 7.69-7.55 (m, 5H), 6.89(d, J = 6.3 Hz, 1H), 6.42 (tt, J = 54.3, 3.5 Hz, 1H), 5.08 (s, 2H), 4.74 (td,J = 14.9, 3.5 Hz, 2H), 4.39-4.21 (m, 1H), 4.00 (dd, J = 14.6, 3.5 Hz, 1H), 3.85 (dd, J = 14.7, 9.5 Hz, 1H).

[0668] Example 47

[0669] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0670]

[0671]

[0672] Starting with 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one and (2-bromomethyl)dimethylamine, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (59.4 mg, yield 18%), a white solid.

[0673] MS (ESI) m / z 570.1 [M+H] + .

[0674] 1H NMR (500 MHz, Chloroform-d) δ 7.76 (dt, J = 7.5, 2.1 Hz, 1H), 7.60– 7.46 (m, 6H), 7.41 (t, J = 7.4 Hz, 1H), 6.32 (d, J = 12.5 Hz, 1H), 5.58 (d,J = 12.5 Hz, 1H), 5.03 (dddd, J = 16.0, 9.1, 5.0, 2.0 Hz, 1H), 4.81 (td, J =12.2, 2.5 Hz, 1H), 4.65 (td, J = 11.9, 4.2 Hz, 1H), 4.09 (dd, J = 12.4, 7.1Hz, 1H), 3.61 (dd, J = 12.5, 7.0 Hz, 1H), 3.14 (ddd, J = 12.5, 11.5, 2.5 Hz, 1H), 2.57 (d, J = 5.1 Hz, 1H), 2.27 (s, 6H), 2.28 – 2.19 (m, 1H).

[0675] Example 48

[0676] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0677]

[0678]

[0679] Starting with methyl 5-bromo-1H-1,2,4-triazol-3-carboxylic acid and (bromomethyl)cyclopropane, the mixture was synthesized according to the method in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (35.7 mg, 26% yield) as a white solid.

[0680] MS (ESI) m / z 553 [M+H] + .

[0681] 1H NMR (400 MHz, DMSO-d6) δ 7.78-7.71 (m, 3H), 7.69-7.55 (m, 5H), 6.89(d, J = 6.3 Hz, 1H), 5.05 (s, 2H), 4.45-4.20 (m, 1H), 4.10 (d, J = 7.0 Hz, 2H), 4.00 (dd, J = 14.6, 3.5 Hz, 1H), 3.84 (dd, J = 14.6, 9.4 Hz, 1H), 1.23-1.07 (m, 1H), 0.54-0.38 (m, 2H), 0.39-0.15 (m, 2H).

[0682] Example 49

[0683] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0684]

[0685]

[0686] Starting with methyl 5-bromo-1H-1,2,4-triazol-3-carboxylic acid and 1-iodo-2-methoxyethane, the mixture was synthesized according to the method in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (32.8 mg, 12%), a white solid.

[0687] MS (ESI) m / z 557 [M+H] + .

[0688] 1H NMR (400 MHz, DMSO-d6) δ 7.79 (t, J = 1.6 Hz, 1H), 7.76-7.73 (m,2H), 7.71-7.68 (m, 1H), 7.64-7.55 (m, 4H), 6.89 (d, J = 6.4 Hz, 1H), 5.05(s, 2H), 4.33-4.31 (m, 3H), 4.00 (dd, J =14.4 Hz, 3.2 Hz, 1H), 3.85 (dd, J =14.8 Hz, 9.6 Hz, 1H), 3.73 (t, J = 4.8 Hz, 2H), 3.15 (s, 3H).

[0689] Example 50

[0690] 5-(4-Chlorophenyl)-2-((5-(3-chlorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0691]

[0692]

[0693] Starting with methyl 5-bromo-2H-1,2,4-triazol-3-carboxylic acid and CH3I, the synthesis was carried out according to the method in Example 4 to obtain 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (56.8 mg, purity 99%), a white solid.

[0694] MS (ESI) m / z 513.0 [M+H] + .

[0695] 1H NMR(400 MHz, DMSO-d6) δ 7.81 (t, J = 1.6 Hz, 1H), 7.77-7.71(m, H), 7.65-7.56 (m, 4H), 6.90 (s, 1H), 5.03 (s, 2H), 4.35-4.25 (m, 1H), 4.00(dd, J= 14.8, 3.6 Hz, 1H), 3.94 (s, 3H), 3.85 (dd, J= 14.8, 9.6 Hz, 1H).

[0696] Example 51

[0697] 3-(5-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)propionitrile

[0698]

[0699]

[0700] Starting with methyl 5-bromo-2H-1,2,4-triazol-3-carboxylic acid and 3-bromopropionitrile, 3-(5-(3-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)propionitrile (15.46 mg, yield 14.9%) was synthesized according to the method in Example 4, yielding a white solid.

[0701] MS (ESI) m / z 552.1 [M+H] + .

[0702] 1H NMR (500 MHz, Chloroform-d) δ 7.84 (dt, J = 7.5, 2.0 Hz, 1H), 7.58– 7.49 (m, 3H), 7.53 – 7.40 (m, 3H), 6.29 (d, J = 12.3 Hz, 1H), 5.62 (d, J =12.3 Hz, 1H), 5.10 – 4.97 (m, 2H), 4.95 (ddd, J = 12.5, 9.7, 1.7 Hz, 1H), 4.03 (dd, J = 12.4, 6.9 Hz, 1H), 3.70 (dd, J = 12.3, 7.0 Hz, 1H), 2.91 – 2.77(m, 2H), 2.57 (d, J = 5.1 Hz, 1H).

[0703] Example 52

[0704] 5-(4-Chlorophenyl)-2-((5-(3-Chlorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0705]

[0706]

[0707] Step 1. 1,1,1-Trifluoro-3-hydrazino-2-propanol

[0708] NH₂NH₂H₂O (11.28 g, 223 mmol) was added dropwise to 2-(trifluoromethyl)ethylene oxide (5 g, 44.6 mmol). The reaction mixture was stirred at 25 °C for 16 h, and LC-MS showed that the reaction was complete. The resulting mixture was concentrated with xylene under vacuum pressure to give a yellow oil (3 g, 90% purity, 42% yield).

[0709] MS (ESI) m / z 144.6 [M+H] +

[0710] Step 2. 3-Chloro-N-(3,3,3-trifluoro-2-hydroxypropyl)benzoylhydrazine

[0711] EDCI (1.35 g, 7.04 mmol) was added to a DCM (10 mL) solution of 3-chlorobenzoic acid (1 g, 6.4 mmol) and pentafluorophenol (1.3 g, 7.04 mmol). The reaction mixture was stirred at 25 °C for 30 min. Then, DIEA (2.48 g, 19.2 mmol) and 1,1,1-trifluoro-3-hydrazinopropane-2-ol (1.84 g, 12.8 mmol) were added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h, and the reaction was complete as indicated by LCMS. The resulting mixture was poured into water (50 mL) and extracted with DCM (50 mL). The separated organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated to give a yellow oil (1 g, 50% purity, 14% yield).

[0712] MS(ESI) m / z 282.8 [M+H] +

[0713] Step 3. Ethyl 5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-1,2,4-triazole-3-carboxylic acid ester

[0714] A solution of 3-chloro-N-(3,3,3-trifluoro-2-hydroxypropyl)benzoylhydrazine (800 mg, 2.81 mmol) and ethyl thiocarbamate (748 mg, 5.62 mmol) was stirred at 90 °C for 16 h. LC-MS showed the reaction was complete. The resulting mixture was cooled and concentrated. The residue was poured into water (50 mL) and extracted with EA (50 mL). The separated organic layer was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to give the title compound (180 mg, 90% purity, 16% yield) as a yellow oil.

[0715] MS(ESI) m / z 363.8 [M+H] +

[0716] Step 4. Ethyl 5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-1,2,4-triazol-3-carboxylic acid ester

[0717] Ethyl 5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1,2,4-triazol-3-carboxylate (180 mg, 0.49 mmol), 3,4-dihydro-2H-pyran (125 mg, 1.48 mmol), and PPTS (25 mg, 0.10 mmol) were added to a 10 mL solution of DCM. The reaction mixture was heated to 25 °C. ℃ The mixture was stirred for 16 h, and LCMS showed that the reaction was complete. The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA=2 / 1) to give a yellow oil (140 mg, purity 90%, yield 57%).

[0718] MS(ESI) m / z 447.8 [M+H] +

[0719] Step 5. (5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-1,2,4-triazol-3-yl)methanol

[0720] Sodium borohydride (35 mg, 0.94 mmol) was added to a MeOH / THF (5 mL) solution of ethyl 5-(3-chlorophenyl)-1-[3,3,3-trifluoro-2-(oxehera-2-yloxy)propyl]-1,2,4-triazol-3-carboxylate (140 mg, 0.31 mmol). The reaction mixture was then heated to 25 °C. ℃ The mixture was stirred for 2 hours, and LCMS showed that the reaction was complete. The resulting mixture was poured into water (30 mL) and extracted with EA (30 mL). The separated organic layer was washed with brine, dried with Na2SO4, filtered and concentrated to give a yellow oily crude compound (80 mg, purity 90%, yield 57%).

[0721] MS (ESI) m / z 405.8 [M+H] +

[0722] Step 6. (5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate

[0723] To a solution of [5-(3-chlorophenyl)-1-[3,3,3-trifluoro-2-(oxecyclo-2-yloxy)propyl]-1,2,4-triazol-3-yl]methanol (80 mg, 0.20 mmol) and triethylamine (40 mg, 0.39 mmol) in DCM (5 mL), methanesulfonyl chloride (29 mg, 0.26 mmol) was added. The reaction mixture was heated to 25 °C. ℃ The mixture was stirred for 1 h, and LCMS showed that the reaction was complete. The resulting mixture was poured into water (20 mL) and extracted with DCM (20 mL). The separated organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated to give a yellow oily crude compound (90 mg, purity 90%, yield 85%).

[0724] MS(ESI) m / z 483.8 [M+H] +

[0725] Step 7. 5-(4-chlorophenyl)-2-(5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-(tetrahydro-2H-pyran-2-yl)oxy)-1D-1D-2,1,2-4-triazol-3-yl)-4-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0726] 5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H-1,2,4-triazol-3-one (57 mg, 0.19 mmol), [5-(3-chlorophenyl)-1-[3,3,3-trifluoro-2-(oxehera-2-yloxy)propyl]-1,2,4-triazol-3-yl]methylmethanesulfonate (90 mg, 0.19 mmol), and potassium carbonate (51 mg, 0.37 mmol) were added to a 5 mL DMF solution. o The mixture was stirred at C for 5 h. LCMS showed that the reaction was complete. The resulting mixture was poured into water (20 mL) and extracted with EA (20 mL). The separated organic layer was washed with water and brine, dried with Na2SO4, filtered, and concentrated to give a yellow oily crude compound (150 mg, purity 54%, yield 63%).

[0727] MS (ESI) m / z 695.4 [M+H] +

[0728] Step 8. 5-(4-chlorophenyl)-2-(5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-4-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0729] TsOH was added to a MeOH (3 mL) solution of 150 mg (0.22 mmol) of 3-chloro-N-(3,3,3-trifluoro-2-hydroxypropyl)benzoylhydrazine. . H2O (8 mg, 0.04 mmol). The reaction mixture was heated to 25 °C. ℃ The mixture was stirred for 2 hours, and LCMS showed that the reaction was complete. The resulting mixture was filtered. The filtrate was purified by Prep-HPLC (NH4HCO3) to give 5-(4-chlorophenyl)-2-(5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-4-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (23.2 mg, purity 99%, yield 17%), as a white solid.

[0730] MS(ESI) m / z 611.0 [M+H] +

[0731] 1 H NMR (400 MHz, DMSO-d6) δ 7.87-7.81 (m, 1H), 7.79-7.71 (m, 3H), 7.69-7.56 (m, 4H), 6.97 (dd, J = 6.5, 3.0 Hz, 1H), 6.89 (dd, J = 6.3, 3.3 Hz,1H), 5.07 (s, 2H), 4.57-4.42(m, 2H), 4.35-4.23 (m, 2H), 4.01 (dd, J = 14.6,3.5 Hz, 1H), 3.85 (dd, J = 14.6, 9.4 Hz, 1H).

[0732] Examples 53 and 54

[0733] 5-(4-chlorophenyl)-2-(5-(3-chlorophenyl)-1-(S)-3,3,3-trifluoro-2-hydroxypropyl)-1H-1,24-triazol-3-yl)-4-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0734] 5-(4-chlorophenyl)-2-(5-chlorophenyl)-1-(R)-3,3-trifluoro-2-hydroxypropyl)-1H-1,20004-triazol-3-yl)-4-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3D-1,2,4-triazol-3-one

[0735]

[0736] 5-(4-chlorophenyl)-2-(5-(3-chlorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20 mg, 0.03 mmol) was purified by SFC 150 (column: Daicel CHIRALCEL AS, 250 mm, 30 mm ID, 10 μm).

[0737] The flow phase is CO2 / MeOH [0.2%NH3 (7M MeOH solution)] = 85 / 15.

[0738] Flow rate: 80 g / min.

[0739] Wavelength: UV 214 nm.

[0740] Temperature: 35℃

[0741] Examples 53 (5.0 mg, yield 25%) and 54 (6.0 mg, yield 30%) were obtained.

[0742] Example 53

[0743] MS (ESI) m / z 611.1 [M+H] + .

[0744] 1H NMR (400 MHz, DMSO-d6) δ 7.87-7.81 (m, 1H), 7.79-7.71 (m, 3H), 7.69-7.56 (m, 4H), 6.97 (dd, J = 6.5, 3.0 Hz, 1H), 6.89 (dd, J = 6.3, 3.3 Hz,1H), 5.07 (s, 2H), 4.57-4.42 (m, 2H), 4.35-4.23 (m, 2H), 4.01 (dd, J = 14.6,3.5 Hz, 1H), 3.85 (dd, J = 14.6, 9.4 Hz, 1H).

[0745] Example 54

[0746] MS (ESI) m / z 611.1 [M+H] + .

[0747] 1 H NMR (400 MHz, DMSO-d6) δ 7.87-7.81 (m, 1H), 7.79-7.71 (m, 3H), 7.69-7.56 (m, 4H), 6.97 (dd, J = 6.5, 3.0 Hz, 1H), 6.89 (dd, J = 6.3, 3.3 Hz,1H), 5.07 (s, 2H), 4.57-4.42 (m, 2H), 4.35-4.23 (m, 2H), 4.01 (dd, J = 14.6,3.5 Hz, 1H), 3.85 (dd, J = 14.6, 9.4 Hz, 1H).

[0748] Example 55

[0749] 5-(4-Chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0750]

[0751] Starting with propylene oxide, the mixture was synthesized according to the method described in Example 52 to obtain 5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (14.1 mg, 9.7%), which was a white solid.

[0752] MS (ESI) m / z 557.1 [M+H] + .

[0753] 1 H NMR (500 MHz, Chloroform-d) δ 7.91 – 7.83 (m, 1H), 7.71 – 7.67 (m,1H), 7.57 (m, 2H), 7.51 (dd, J = 8.1, 1.5 Hz, 1H), 7.45 (dd, J = 8.2, 1.4 Hz,1H), 7.38 – 7.32 (m, 2H), 5.33 (m, 1H), 4.63 (dd, J = 15.2, 5.1 Hz, 1H), 4.56(s, 1H), 4.39 (dd, J = 15.2, 5.2 Hz, 1H), 3.89 (dq, J = 8.2, 3.5 Hz, 1H),3.70 (qq, J = 6.6, 5.2 Hz, 1H), 3.37 – 3.25 (m, 2H), 2.88 (m, 1H), 1.34 (s,1H).

[0754] Example 56

[0755] 5-(4-Chlorophenyl)-2-((5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0756]

[0757]

[0758] Step 1. 3-Chloro-N-(tetrahydro-2H-pyran-4-yl)benzoylhydrazine

[0759] EDCI (2.69 g, 14.04 mmol) was added to a DCM (30 mL) solution of 3-chlorobenzoic acid (2.0 g, 12.76 mmol) and pentafluorophenol (2.58 g, 14.04 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. Then, DIEA (4.96 g, 38.32 mmol) and oxecyclo-4-ylhydrazine hydrochloride (4.0 g, 25.56 mmol) were added to the reaction mixture. The reaction mixture was stirred at 25 °C for 12 h. The solution was concentrated under vacuum and purified by silica gel column chromatography (PE:EA = 2:1) to give 3-chloro-N-(oxecyclopentan-4-yl)benzoylhydrazine (2.0 g, 62% yield) as a yellow solid.

[0760] MS (ESI) m / z 255.2 [M+H] +

[0761] Step 2. Ethyl 5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazole-3-carboxylate

[0762] 3-chloro-N-(oxacyclohexane-4-yl)benzoylhydrazide (2 g, 8.0 mmol) and ethyl thiocarbamate (2.7 g, 16 mmol) were added to an ACOH / Tol (50 mL / 5 mL) solution and heated to 110 °C. o The mixture was stirred at C for 12 h. The reaction mixture was cooled, and saturated NH4Cl aqueous solution (100 mL) was added and extracted with EA (100 mL * 3). The combined organic layers were washed with brine (100 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give a yellow solid sample of the title compound (300 mg, 10% yield).

[0763] MS (ESI) m / z 336.2 [M+H] +

[0764] Step 3. (5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)methanol

[0765] In 0 oAt C, NaBH4 (84 mg, 2.23 mmol) was added to a THF / MeOH (15 mL: 3 mL) solution of ethyl 5-(3-chlorophenyl)-1-(oxepyl-4-yl)-1,2,4-triazol-3-carboxylic acid (250 mg, 0.75 mmol). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give [5-(3-chlorophenyl)-1-(oxepyl-4-yl)-1,2,4-triazol-3-yl]methanol (140 mg, 57% yield) as a yellow oil.

[0766] MS (ESI) m / z 294.2 [M+H] +

[0767] Step 4. (5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate

[0768] In a DCM (5 mL) solution of [5-(3-chlorophenyl)-1-(oxacyclopentan-4-yl)-1,2,4-triazol-3-yl]methanol (140 mg, 0.48 mmol) and TEA (120 mg, 1.19 mmol), at 0 o Methanesulfonyl chloride (82 mg, 0.71 mmol) was added at C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under vacuum to obtain a crude product, which could be used directly for the next step without purification.

[0769] MS (ESI) m / z 372.0 [M+H] + .

[0770] Step 5. 5-(4-chlorophenyl)-2-(5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0771] In 25 oAt C, K₂CO₃ (117 mg, 0.85 mmol) was added to a DMF (5 mL) solution of 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (130 mg, 0.43 mmol) and [5-(3-chlorophenyl)-1-(oxetine-4-yl)-1,2,4-triazol-3-yl]methylmethanesulfonate (188 mg, 0.51 mmol). The reaction mixture was then heated in a 50 mL container. ℃ The mixture was stirred for 12 h. The reaction mixture was cooled, quenched with water (10 mL), and extracted with EA (10 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by high performance liquid chromatography to give 5-(4-chlorophenyl)-2-(5-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (45.0 mg, 17% yield) as a white solid.

[0772] MS(ESI) m / z 583.0 [M+H] +

[0773] 1 H NMR(400 MHz, DMSO-d6) δ 7.78-7.73 (m, 2H), 7.70-7.57 (m, 6H), 6.88(d, J = 6.4 Hz, 1H), 5.06 (s, 2H), 4.53-4.44(m, 1H), 4.29(s, 1H), 3.92(dtd, J= 24.1, 14.6, 6.5 Hz, 4H), 3.39(t, J = 11.1 Hz, 2H), 2.05 (dt, J = 12.1, 7.8Hz, 2H), 1.89(d, J = 11.8 Hz, 2H).

[0774] Example 57

[0775] (S)-5-(4-chlorophenyl)-2-((5-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0776]

[0777]

[0778] Step 1. Methyl 3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-carboxylic acid ester

[0779] Methyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-carboxylic acid (1 g, 3.0 mmol), (2-chlorophenyl)borondiol (0.52 g, 3.3 mmol), Pd(dppf)Cl2 (0.22 g, 0.3 mmol), and K2CO3 (0.83 g, 6.0 mmol) were added to DMF (20 mL), and the mixture was stirred at 100 °C under N2 for 3 h. The reaction mixture was cooled, H2O was added, and the mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purified by silica gel column chromatography with PE / EA = 5:1, methyl 3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-5-carboxylic acid (300 mg, 23%) was obtained as a yellow oil.

[0780] MS (ESI) m / z 368.1 [M+H] + .

[0781] Step 2. (3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methanol

[0782] To a solution of methyl 3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-carboxylic acid (300 mg, 0.81 mmol) in THF / MeOH = 5 / 1 (12 mL), NaBH4 (92 mg, 2.44 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to H2O and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purified by silica gel column chromatography with PE / EA = 2:1, (3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methanol (100 mg, 32%) was obtained as a yellow oil.

[0783] MS (ESI) m / z 340.1 [M+H] +

[0784] Step 3. (3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methylmethanesulfonate

[0785] MsCl (67 mg, 0.58 mmol) was added to a mixture of (3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methanol (100 mg, 0.29 mmol) and DIEA (113 mg, 0.88 mmol) in 10 mL of DCM at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then added to H2O and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give lithium (3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methylmethanesulfonate (150 mg, 97%) as a yellow oil.

[0786] MS (ESI) m / z 418.0 [M+H] + .

[0787] Step 4. (S)-5-(4-chlorophenyl)-2-((3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0788] A mixture of (3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methylmethanesulfonate (150 mg, 0.35 mmol), 5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H-1,2,4-triazol-3-one (92 mg, 0.29 mmol), and K₂CO₃ (82 mg, 0.59 mmol) in DMF (10 mL) was stirred overnight at 50 °C. The reaction mixture was added to H₂O and extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purification was performed using a silica gel column with PE / EA ratio of 3:1 to obtain (S)-5-(4-chlorophenyl)-2-((3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (210 mg, 89%), as a yellow oil.

[0789] MS (ESI) m / z 629.1 [M+H] + .

[0790] Step 5. (S)-5-(4-chlorophenyl)-2-((5-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0791] The mixture of (S)-5-(4-chlorophenyl)-2-((3-(2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.15 mmol) in TFA / DCM = 1 / 2 (9 mL) was stirred for 1 h. The reaction mixture was concentrated. The residue was diluted with EA, and the pH was adjusted to 9 with Na₂CO₃ solution. The mixture was extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purified by HPLC (NH4HCO3), (S)-5-(4-chlorophenyl)-2-((5-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (25.8 mg, 30%) was obtained as a white solid.

[0792] MS (ESI) m / z 499.0 [M+H] + .

[0793] 1 H NMR (400 MHz, DMSO-d6) δ 14.22 (brs, 1H), 7.79-7.74 (m, 3H), 7.64-7.59 (m, 3H), 7.52-7.44 (m, 2H), 6.91 (d, J = 6.4 Hz, 1H), 5.15 (s, 2H), 4.14(brs, 1H), 3.99 (dd, J = 3.6 Hz, 14.8 Hz, 1H), 3.85 (dd, J = 11.2 Hz, 14.4Hz, 1H).

[0794] Example 58

[0795] (S)-2-(5-(2-chlorophenyl)-3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetamide

[0796]

[0797]

[0798] Step 1. Ethyl (Z)-2-amino-2-(2-(2-chlorobenzoyl)hydrazide)ethyl acetate

[0799] Triethylamine (7.0 g, 0.08 mol) was added to a solution of 2-chlorobenzoylhydrazine (4 g, 0.02 mol) and ethyl 2-ethoxy-2-iminoacetate (3.4 g, 0.02 mol) in EtOH (30 mL), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered, washed with EtOH, and the filtrate was concentrated to give compound (Z)-2-amino-2-(2-(2-chlorobenzoyl)hydrazineide)ethyl acetate (4.5 g, yield 83.3%) as a white solid.

[0800] MS (ESI) m / z 270.1 [M+H] +

[0801] Step 2. Ethyl 5-(2-chlorophenyl)-1H-1,2,4-triazole-3-carboxylic acid ester

[0802] Ethyl (Z)-2-amino-2-(2-(2-chlorobenzoyl)hydrazide)acetate (4.0 g, 14.8 mmol) was stirred in 5.0 mL of Ph₂O at 260 °C for 1 h. After cooling, the reaction system was purified by silica gel column chromatography (PE / EA = 1:1) to give ethyl 5-(2-chlorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (3.5 g, yield 94%), a yellow solid.

[0803] MS (ESI) m / z 252.1 [M+H] + .

[0804] Step 3. Ethyl 5-(2-chlorophenyl)-1-cyanomethyl-1H-1,2,4-triazole-3-carboxylic acid ester

[0805] Ethyl 5-(2-chlorophenyl)-1H-1,2,4-triazol-3-carboxylate (3.0 g, 11.7 mmol) and 2-bromoacetonitrile (1.7 g, 14.4 mmol) were added to a solution of DMF (30 mL) with potassium carbonate (4.9 g, 36.0 mmol), and the mixture was stirred at 60 °C for 48 h. The reaction mixture was cooled, quenched with water (30 mL), and extracted with DCM (30 mL x 3). The organic phases were combined and concentrated under vacuum. The concentrate was purified by prep-HPLC to give ethyl 5-(2-chlorophenyl)-1-(cyanomethyl)-1,2,4-triazol-3-carboxylate (300 mg, yield 7.5%) as a yellow oil.

[0806] MS (ESI) m / z 291.1 [M+H] +

[0807] Step 4. Methyl 2-(5-(2-chlorophenyl)-3-hydroxymethyl-1H-1,2,4-triazol-1-yl)acetate

[0808] Methyl 5-(2-chlorophenyl)-1-(cyanomethyl)-1,2,4-triazol-3-carboxylic acid (300 mg, 0.11 mmol) was added to a THF / MeOH solution (1:1, 4 mL) with sodium borohydride (204 mg, 5.4 mmol), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was cooled, quenched with water (50 mL), and extracted with EA (50 mL x 3). The organic phases were combined and concentrated under vacuum to give methyl 2-(5-(2-chlorophenyl)-3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)acetate (130 mg, yield 45%) as a yellow oil.

[0809] MS (ESI) M / z 282.1 [M+H] + .

[0810] Step 5. Methyl 2-(5-(2-chlorophenyl)-3-(((methanesulfonyl)oxy)methyl)-1H-1,2,4-triazol-1-yl)acetate

[0811] Methyl 2-[5-(2-chlorophenyl)-3-(hydroxymethyl)-1,2,4-triazol-1-yl]acetate (130 mg, 0.46 mmol) and triethylamine (116 mg, 1.15 mmol) in DCM (10 mL) were added to a solution of methyl 2-[5-(2-chlorophenyl)-3-[(methanesulfonyloxy)methyl]-1,2,4-triazol-1-yl]acetate (80 mg, 0.69 mmol) and stirred at 25 °C for 1 h. H₂O was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give methyl 2-[5-(2-chlorophenyl)-3-[(methanesulfonyloxy)methyl]-1,2,4-triazol-1-yl]acetate (180 mg, 97% yield), as a yellow oil.

[0812] MS (ESI) m / z 360.0 [M+H] +

[0813] Step 6. Methyl (S)-2-(5-(2-chlorophenyl)-3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetate

[0814] Add 5-(4-chlorophenyl)-4-[(2S)-3,3-trifluoro-2-hydroxypropyl]-2H-1,2,4-triazol-1-yl]acetate (180 mg, 0.5 mmol) and potassium carbonate (207 mg, 1.5 mmol) to a DMF solution (5.0 mL) and add 5-(4-chlorophenyl)-4-[(2S)-3,3-trifluoro-2-hydroxypropyl]-1,2,4-triazol-3-one (154 mg, 0.5 mmol). Stir at 50 °C for 12 h. Cool the reaction mixture, quench with water (30 mL), and extract with EA (30 mL x 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography to give (S)-2-(5-(2-chlorophenyl)-3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetate (100 mg, yield 33%), a yellow solid.

[0815] MS (ESI) m / z 571.2 [M+H] + .

[0816] Step 7. (S)-2-(5-(2-chlorophenyl)-3-(3-(4-chlorophenyl)-5-oxo-4-(3,33-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetic acid

[0817] A solution of (S)-2-(5-(2-chlorophenyl)-3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetate (100 mg, 0.17 mmol) in MeOH (4 mL) was added, and the mixture was stirred at 25 °C for 12 h. The organic phases were combined and concentrated under vacuum. The pH was adjusted to 3 with 1N HCl, the mixture was washed with water (30 mL), and extracted with EA (30 mL x 3). The organic phases were combined and concentrated under vacuum to give (S)-2-(5-(2-chlorophenyl)-3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetic acid (80 mg, yield 74%), a yellow solid.

[0818] MS (ESI) m / z 557.1 [M+H] + .

[0819] Step 8. (S)-2-(5-2-chlorophenyl)-3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)4,5-dihydro-1H-1,2,4-triazol-1-yl)-1H-1,2,4-triazol-1-yl)acetamide

[0820] Add N-(3-dimethylaminopropyl)-N-ethylcarbodiaminocyanate (18 mg, 0.09 mmol) to a solution of (S)-2-(5-(2-chlorophenyl)-3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetic acid (40 mg, 0.07 mmol) and HOBT (12.6 mg, 0.09 mmol) in DMF (5.0 mL), and incubate at 25 °C. oThe mixture was stirred at C for 10 minutes. Then, ammonia (48 mg, 1.4 mmol) was added, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL * 3). The organic phases were combined and concentrated under vacuum. The concentrate was purified by Prep-HPLC to give (S)-2-(5-(2-chlorophenyl)-3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1H-1,2,4-triazol-1-yl)acetamide (11.8 mg, yield 28%), a white solid.

[0821] MS (ESI) m / z 556.1 [M+H] + .

[0822] 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.6 Hz, 2H), 7.67-7.47 (m,7H), 7.23 (s, 1H), 6.89(s, 1H), 5.06 (s, 2H), 4.64 (s, 2H), 4.30 (d, J = 6.4Hz, 1H), 4.00 (dd, J = 14.6, 3.4 Hz, 1H), 3.85 (dd, J = 14.8, 9.6 Hz, 1H).

[0823] Example 59

[0824] 5-(4-Chlorophenyl)-2-((5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0825]

[0826]

[0827] Starting with methyl 5-bromo-1H-1,2,4-triazole-3-carboxylic acid and 2,2,2-trifluoroethyltrifluoromethanesulfonate, the mixture was synthesized according to the method described in Example 4 to obtain 5-(4-chlorophenyl)-2-((5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazole-3-one (8.0 mg, 12.74% yield), a white solid.

[0828] MS (ESI) m / z 546.8 [M+H] + .

[0829] 1H NMR (400 MHz, DMSO-d6)7.76-7.67(m, 4H), 7.63-7.54 (m, 5H), 6.88(s,1H), 5.25(q, J = 8.8 Hz, 2H), 5.09(s, 2H), 4.3(s, 1H), 4.02-3.97(dd, J = 18,3.5 Hz, 1H), 3.87-3.8(m, 1H),

[0830] Example 60

[0831] 5-(4-chlorophenyl)-2-((5-(2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0832]

[0833]

[0834] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and (2-methoxyphenyl)borondiol, 5-(4-chlorophenyl)-2-((5-(2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one) was synthesized as a white solid according to the method described in Example 4.

[0835] MS (ESI) m / z 576.9 [M+H] +

[0836] 1H NMR (400 MHz, DMSO)δ 7.5(dd, J = 7.0, 2.2 Hz, 2H), 7.63-7.56 (m,3H), 7.37(dd, J = 8.0, 2.2 Hz, 1H), 7.21(dd, J = 7.0, 2.3 Hz, 1H), 7.12-7.08(m, 1H), 6.89(dd, J = 8.0, 2.3 Hz, 1H), 5.08(s, 2H), 4.99 (q, J = 8.8 Hz,2H), 4.29(s, 1H), 4.00(dd, J = 14.6, 3.5 Hz, 1H), 3.83(f, J=8, 3.5 Hz, 1H), 3.82(s, 3H)

[0837] Example 61

[0838] (S)-5-(4-chlorophenyl)-2-((5-(2-(difluoromethyl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0839]

[0840]

[0841] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and (2-(difluoromethyl)phenyl)boronic acid, the mixture was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(2-(difluoromethyl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (26.4 mg, 17.9% yield), a white solid.

[0842] MS (ESI) m / z 597.1 [M+H] +

[0843] 1H NMR (500 MHz, Chloroform-d) δ 7.70 – 7.61 (m, 3H), 7.64 – 7.56 (m,2H), 7.53 – 7.40 (m, 3H), 5.33 (m, 1H), 5.11 (q, J = 11.9 Hz, 1H), 4.74 (s,1H), 3.63 (dq, J = 8.3, 3.6 Hz, 1H), 3.29 (m, 1H), 2.68 (m, 1H).

[0844] Example 62

[0845] (S)-5-(4-chlorophenyl)-2-((5-(2-(difluoromethoxy)phenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0846]

[0847]

[0848] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and o-difluoromethoxyphenylboronic acid, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(2-(difluoromethoxy)phenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (31.8 mg, 15.6% yield), a white solid.

[0849] MS (ESI) m / z 613.1 [M+H] +

[0850] 1H NMR (500 MHz, Chloroform-d) δ 7.96 (dd, J = 7.9, 1.2 Hz, 1H), 7.66– 7.60 (m, 2H), 7.52 – 7.46 (m, 2H), 7.32 – 7.25 (m, 1H), 7.11 (td, J = 7.7,1.2 Hz, 1H), 6.99 (dd, J = 8.1, 1.2 Hz, 1H), 5.16 – 4.95 (m, 2H), 4.59 (s,1H), 3.63 (dq, J = 8.3, 3.6 Hz, 1H), 3.19 (m, 1H), 2.94 (m, 1H).

[0851] Example 63

[0852] 5-(4-Chlorophenyl)-2-((5-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0853]

[0854]

[0855] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and 2-chlorophenylboronic acid, 5-(4-chlorophenyl)-2-((5-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (43 mg, 37% yield) was synthesized as a white solid according to the synthesis method of Example 4.

[0856] MS (ESI) m / z 581.1 [M+H] +

[0857] 1H NMR (500 MHz, Chloroform-d) δ 7.89 – 7.81 (m, 1H), 7.66 – 7.55 (m,2H), 7.52 – 7.42 (m, 3H), 5.22 (q, J = 11.9 Hz, 1H), 5.03 (m, 1H), 4.64 (s,1H), 4.43 (dq, J = 8.2, 3.5 Hz, 1H), 3.66 – 3.58 (m, 1H), 3.44 (m, 1H).

[0858] Example 64

[0859] 5-(4-chlorophenyl)-2-((5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0860]

[0861]

[0862] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and (2-fluorophenyl)borondiol, 5-(4-chlorophenyl)-2-((5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one) was synthesized as a white solid according to the synthesis method in Example 4.

[0863] MS (ESI) m / z 565.0 [M+H] +

[0864] 1H NMR(400 MHz, DMSO-d6) δ 7.77-7.72(m, 2H), 7.68(ddd, J = 7.4, 5.5,2.7Hz, 1H), 7.64-7.57 (m, 3H), 7.48-7.37(m, 2H), 6.89(d, J = 6.3 Hz, 1H), 5.18-5.03 (m, 4H), 4.30 (d, J = 7.0 Hz, 1H), 4.00 (dd, J = 14.6, 3.4 Hz, 1H), 3.84 (dd, J = 14.6, 9.5 Hz, 1H).

[0865] Example 65

[0866] 5-(4-Chlorophenyl)-2-((5-(m-tolyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0867]

[0868]

[0869] The product was synthesized from methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and (3-methylphenyl)borondiol according to the synthetic method of Example 4, yielding 5-(4-chlorophenyl)-2-((5-(m-tolyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (13.5 mg, 5.3% yield), as a white solid.

[0870] MS (ESI) m / z 561.0 [M+H] +

[0871] 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 8.6 Hz, 2H), 7.66-7.58 (m,2H), 7.44 (dt, J = 16.3, 8.6 Hz, 4H), 6.89 (d, J = 6.3 Hz, 1H), 5.24 (q, J =8.8 Hz, 2H), 5.10 (d, J = 16.5 Hz, 2H), 4.29 (s, 1H), 4.00 (dd, J = 14.6, 3.5Hz, 1H), 3.85 (dd, J = 14.6, 9.5 Hz, 1H), 2.38 (s, 3H).

[0872] Example 66

[0873] 5-(4-chlorophenyl)-2-((5-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0874]

[0875]

[0876] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane, 5-(4-chlorophenyl)-2-((5-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (4.8 mg, 10% yield) was synthesized according to the method of Example 4.

[0877] MS(ESI) m / z 565.1 [M+H] + .

[0878] 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 8.6 Hz, 2H), 7.66-7.52 (m,5H), 7.49-7.40 (m, 1H), 6.90 (d, J = 5.2 Hz, 1H), 5.30 (dd, J = 17.6, 8.8 Hz,2H), 5.10 (s, 2H), 4.40-4.20 (m, 1H), 4.00(dd, J = 14.6, 3.5 Hz, 1H), 3.85(dd, J = 14.7, 9.4 Hz, 1H).

[0879] Examples 67, 68, and 69

[0880] 5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0881]

[0882]

[0883] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and (5-fluoro-2-methoxyphenyl)borondiol, 5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (38 mg, yield 16%) was synthesized as a white solid according to the synthesis method of Example 4.

[0884] MS(ESI) m / z 595.0 [M+H] +

[0885] 1H NMR (400 MHz, DMSO-d6)δ7.75(d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7Hz, 2H), 7.48-7.41(m, 1H), 7.28 (dd, J = 8.5, 3.2 Hz, 1H), 7.24 (dd, J = 9.3,4.3 Hz, 1H), 6.90(d, J = 6.0 Hz, 1H), 5.08 (s, 2H), 5.03 (dd, J = 17.6, 8.8Hz, 2H), 4.36-4.24(m, 1H), 4.00 (f, J = 14.6, 3.4 Hz, 1H), 3.85 (f, J = 14.6,9.5 Hz, 1H), 3.80(s, 3H)

[0886] Purified by SFC 150 (column: Daicel CHIRALCEL IA-H, 250 mm 30 mm ID, 10 μm; mobile phase: CO2 / MeOH [0.2% NH3 (7 M MeOH solution)] = 90 / 10; flow rate: 80 g / min; wavelength: UV 214 nm; temperature: 35°C) yielded (S)-5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (12.9 μm) (mg, yield 32%) and (R)-5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (13.8 mg, yield 34.5%).

[0887] Example 68: (S)-5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0888] MS (ESI) m / z 595.1 [M+H] + .

[0889] 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7Hz, 2H), 7.48-7.41 (m, 1H), 7.28 (dd, J = 8.5, 3.2 Hz, 1H), 7.24 (dd, J =9.3, 4.3 Hz, 1H), 6.90 (d, J = 6.0 Hz, 1H), 5.08 (s, 2H), 5.03 (dd, J = 17.6,8.8 Hz, 2H), 4.36-4.24 (m, 1H), 4.00 (dd, J = 14.6, 3.4 Hz, 1H), 3.85 (dd, J= 14.6, 9.5 Hz, 1H), 3.80 (s, 3H).

[0890] Example 69: (R)-5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0891] MS (ESI) m / z 595.1 [M+H] + .

[0892] 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7Hz, 2H), 7.48-7.41 (m, 1H), 7.28 (dd, J = 8.5, 3.2 Hz, 1H), 7.24 (dd, J =9.3, 4.3 Hz, 1H), 6.90 (d, J = 6.0 Hz, 1H), 5.08 (s, 2H), 5.03 (dd, J = 17.6,8.8 Hz, 2H), 4.36-4.24 (m, 1H), 4.00 (dd, J = 14.6, 3.4 Hz, 1H), 3.85 (dd, J= 14.6, 9.5 Hz, 1H), 3.80 (s, 3H).

[0893] Example 70

[0894] (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0895]

[0896]

[0897] Starting with methyl 5-bromo-1H-1,2,4-triazol-3-carboxylic acid and 2,2-difluoropropyltrifluoromethanesulfonate, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(3-chlorophenyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (28.4 mg, 21% yield), which was a white solid.

[0898] MS (ESI) m / z 577.0 [M+H] +

[0899] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (dt, J = 7.0, 2.2 Hz, 3H), 7.68-7.55(m, 5H), 6.90 (s, 1H), 5.08 (s, 2H), 4.78 (t, J = 13.3 Hz, 2H), 4.36-4.21 (m,1H), 4.00 (dd, J = 14.6, 3.5 Hz, 1H), 3.84 (dd, J = 14.6, 9.4 Hz, 1H), 1.64(t, J = 19.3 Hz, 3H).

[0900] Example 71

[0901] (S)-2-((5-(3-chloro-4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0902]

[0903]

[0904] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-carboxylic acid and (3-chloro-4-fluorophenyl)borondiol, the product was synthesized according to the method described in Example 4 to obtain (S)-2-((5-(3-chloro-4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.2 mg, 8% yield), a white solid.

[0905] MS (ESI) m / z 599 [M+H] +

[0906] 1 H NMR (400 MHz, DMSO-d6)δ 7.95(dd, J = 7.0, 2.2 Hz, 1H), 7.77-7.69(m, 3H), 7.66-7.59 (m, 3H), 6.90 (s, 1H), 5.29 (q, J = 8.8 Hz, 2H), 5.19-5.01(m, 2H), 4.29 (s, 1H), 4.00 (dd, J = 14.6, 3.5 Hz, 1H), 3.85(dd, J = 14.6,9.5 Hz, 1H)

[0907] Example 72

[0908] (S)-2-((5-(2-chloro-4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0909]

[0910]

[0911] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-carboxylic acid and (2-chloro-4-fluorophenyl)borondiol, the product was synthesized according to the method described in Example 4 to obtain (S)-2-((5-(2-chloro-4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.2 mg, 8% yield), a white solid.

[0912] MS (ESI) m / z 599 [M+H] +

[0913] 1 H NMR (500 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 2H), 7.59 – 7.48 (m,4H), 7.02 (ddd, J = 10.1, 8.4, 2.2 Hz, 1H), 5.31 (q, J = 11.9 Hz, 1H), 5.13(m, 1H), 4.69 (s, 1H), 3.93 (dq, J = 8.2, 3.6 Hz, 1H), 3.39 (m, 1H), 3.14 (m,1H).

[0914] Example 73

[0915] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0916]

[0917]

[0918] Starting with methyl 5-bromo-1-(2,2-difluoropropyl)-1,2,4-triazol-3-carboxylic acid ester and 2-pyridineboronic acid, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (28.4 mg, 21% yield), which was a white solid.

[0919] MS (ESI) m / z 544.1 [M+H] +

[0920] 1 H NMR (500 MHz, Chloroform-d) δ 8.80 (dd, J = 4.0, 1.7 Hz, 1H), 8.29 (dd, J = 7.7, 1.4 Hz, 1H), 7.82 – 7.76 (m, 1H), 7.66 – 7.60 (m, 2H), 7.52 –7.46 (m, 2H), 7.34 – 7.28 (m, 1H), 5.03 (qdt, J = 12.2, 8.2, 7.3 Hz, 1H), 4.59 (s, 1H), 4.03 (t, J = 11.9 Hz, 2H), 3.63 (dq, J = 8.3, 3.6 Hz, 1H), 3.19(m, 1H), 2.94 (m, 1H), 1.82 (s, 1H), 1.78 (s, 1H).

[0921] Example 74

[0922] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0923]

[0924]

[0925] Starting with (5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methanol and pyridin-3-yldiborondiol, the mixture was synthesized according to the method in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (28.7 mg, yield 29%), a white solid.

[0926] MS (ESI) m / z 544.1 [M+H] +

[0927] 1H NMR (400 MHz, DMSO-d6) δ 8.82-8.81 (m, 1H), 8.75-8.73(m, 1H), 8.14-8.11(m, 1H), 7.76-7.73 (m, 2H), 7.64-7.57 (m, 3H), 6.91-6.90 (m, 1H), 5.10(s, 2H), 4.82 (t, J = 13.6 Hz, 2H), 4.30 (s, 1H), 4.02-3.98 (m, 1H), 3.88-3.82 (m, 1H), 1.64 (t, J =19.2 Hz, 3H).

[0928] Example 75

[0929] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0930]

[0931]

[0932] Starting with methyl 5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-carboxylic acid and pyridine-4-boronic acid, the mixture was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.32 mg, yield 2.4%), a white solid.

[0933] MS (ESI) m / z 544.1 [M+H] +

[0934] 1H NMR (400 MHz, DMSO-d6) δ 8.77-7.75 (m, 2H), 7.75-7.71 (m, 4H), 7.63-7.61 (m, 2H), 6.91-6.89 (m, 1H), 5.10 (s, 2H), 4.87 (t, J = 13.6 Hz,2H), 4.31-4.29 (m, 1H), 4.02-3.98 (m, 1H), 3.87-3.81 (m, 1H), 1.65 (t, J =19.2 Hz, 3H).

[0935] Example 76

[0936] 5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(3-(1-hydroxyethyl)phenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0937]

[0938]

[0939] Step 1. Methyl 1-(2,2-difluoropropyl)-5-(3-(1-hydroxyethyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid ester

[0940] Methyl 5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-carboxylic acid (300 mg, 1.05 mmol), (3-(1-hydroxyethyl)phenyl) (214.5 mg, 1.374 mmol), Pd(PPh3)4 (122.04 mg, 0.10 mmol) and NaHCO3 (117.5 mg, 2.11 mmol) were added to a dioxane / water solution (16 mL / 4 mL). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled, quenched with water (20 mL), and extracted with EA (50 mL*2). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=1:1) to give methyl 1-(2,2-difluoropropyl)-5-(3-(1-hydroxyethyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid (180 mg, yield 31.4%), as a yellow solid.

[0941] MS (ESI) m / z 326.0 [M+H] +

[0942] Step 2. Methyl 1-(2,2-difluoropropyl)-5-(3-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid ester

[0943] In 0 o At C, 3,4-dihydro-2H-pyran (77.58 mg, 0.92 mmol) and PPTS (23.17 mg, 0.09 mmol) were added to a solution of methyl 1-(2,2-difluoropropyl)-5-(3-(1-hydroxyethyl)phenyl)-1H-1,2,4-triazol-3-carboxylic acid ester (150 mg, 0.46 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 16 h. Ice water (20 mL) was added to the mixture, and the mixture was extracted with EA (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the organic phase was concentrated under vacuum. The concentrate was purified by silica gel column chromatography (PE / EA=3 / 1) to give methyl 1-(2,2-difluoropropyl)-5-(3-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid (60 mg, yield 27.02%), as a yellow oil.

[0944] MS (ESI) m / z 410.1 [M+H] +

[0945] Step 3. (1-(2,2-difluoropropyl)-5-(3-(1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanol

[0946] At 0 °C, NaBH4 (27.71 mg, 0.73 mmol) was added to a THF / MeOH (1:1, 10 mL) solution of methyl 1-(2,2-difluoropropyl)-5-(3-(1-hydroxyethyl)phenyl)-1H-1,2,4-triazol-3-carboxylic acid (60 mg, 0.14 mmol). The reaction was stirred at 25 °C for 12 h. The mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated under vacuum. The concentrate was purified by silica gel column chromatography (PE / EA = 1:1) to give (1-(2,2-difluoropropyl)-5-(3-(1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanol (50 mg, 71.6% yield) as a yellow oil.

[0947] MS (ESI) m / z 382.2 [M+H] +

[0948] Step 4. Methyl (1-(2,2-difluoropropyl)-5-(3-(1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanesulfonate

[0949] At 0 °C, TEA (26.48 mg, 0.26 mmol) and methanesulfonyl chloride (19.42 mg, 0.17 mmol) were added to a solution of (1-(2,2-difluoropropyl)-5-(3-(1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanol (50 mg, 0.13 mmol) in 10 mL of DCM. The reaction mixture was stirred at 25 °C for 1.5 h. The mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were concentrated under vacuum, and the crude product was used directly for the next step without purification.

[0950] MS (ESI) m / z 460.1 [M+H] +

[0951] Step 5. 5-(4-chlorophenyl)-2-(1-(2,2-difluoropropyl)-5-(3-(1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-1H-1,4-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0952] 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (28 mg, 0.09 mmol), methyl (1-(2,2-difluoropropyl)-5-(3-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-1H-1,2,4-triazol-3-yl)methylformate (50.18 mg, 0.1 mmol) and K2CO3 (25.1 mg, 0.18 mmol) were added to a DMF (5 mL) solution and heated to 50 °C. oThe mixture was stirred at C for 16 h. The reaction system was cooled, quenched with water (10 mL), and extracted with EA (10 mL * 3). The combined organic layers were concentrated under vacuum. The residue was purified by HPLC to give 5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(3-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-1H-1,24-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (40 mg, yield 49.08%), as a yellow oil.

[0953] MS (ESI) m / z 671.1 [M+H] +

[0954] Step 6. 5-(4-chlorophenyl)-2-(1-(2,2-diphenylpropyl)-5-(1-hydroxyethyl)phenyl)-1H-1,24-triazol-3-yl)-4-(S)-3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0955] PPTS (1.12 mg, 0.004 mmol) was added to an EtOH solution of 5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(3-(1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (30 mg, 0.04 mmol) in 8 mL at room temperature. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was then concentrated under vacuum. The concentrate was purified by HPLC to give 5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(3-(1-hydroxyethyl)phenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (9.2 mg, yield 35.2%), as a white solid.

[0956] MS (ESI) m / z 587.1 [M+H] +

[0957] 1H NMR (400 MHz, DMSO-d6) 7.72 (dd, J = 8.0, 2.2 Hz, 2H), 7.63-7.60(m, 3H), 7.53 -7.48 (m, 3H), 6.89 (dd, J = 8.0, 2.2 Hz, 1H), 5.28 (dd, J =12, 2.2Hz, 1H), 4.80 (s, 2H), 4.79-4.70 (m, 3H), 4.30 (s, 1H), 4.01 (f, J =12, 2.2 Hz, 1H), 3.87-3.81 (m, 1H), 1.64 (t, J = 8.0, 2.0 Hz, 3H), 1.33 (f, J= 14.6, 3.5 Hz, 3H).

[0958] Example 77

[0959] 5-(4-Chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(4-(1-hydroxyethyl)phenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0960]

[0961]

[0962] Starting with (5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methanol and 4-acetylphenylboronic acid ester, the product was synthesized according to the method in Example 4 to obtain (S)-2-(5-(4-acetylphenyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (240 mg, yield 86%), which was a yellow oil.

[0963] MS (ESI) m / z 585.1 [M+H] +

[0964] 5-(4-chlorophenyl)-2-(1-(2,2-diphenylpropyl)-5-(4-(1-hydroxyethyl)phenyl)-1H-1,24-triazol-3-yl)-4-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0965]

[0966] To a THF (3 mL) solution of (S)-2-((5-(4-acetylphenyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (70 mg, 0.120 mmol), NaBH4 (9.0 mg, 0.240 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (15 mL). The organic layer was washed with brine, the combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The concentrate was purified by Prep-HPLC (NH4HCO3) to give the title compound (31.9 mg, 45% yield) as a white solid.

[0967] MS (ESI) m / z 587.2 [M+H] +

[0968] 1 H NMR (400 MHz, DMSO-d6) δ 7.77-7.70 (m, 2H), 7.66-7.57 (m, 4H), 7.50 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 6.3 Hz, 1H), 5.30 (d, J = 4.3 Hz, 1H), 5.05(d, J = 16.3 Hz, 2H), 4.78 (dt, J = 24.0, 9.8 Hz, 3H), 4.30 (d, J = 6.5 Hz, 1H), 4.00 (dd, J = 14.6, 3.3 Hz, 1H), 3.84 (dd, J = 14.6, 9.5 Hz, 1H), 1.64(t, J = 19.3 Hz, 3H), 1.35 (d, J = 6.5 Hz, 3H).

[0969] Example 78

[0970] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0971]

[0972]

[0973] Starting with methyl 5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-carboxylic acid and (3-methoxyphenyl)boronic acid, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20.0 mg, 30.40% yield), a white solid.

[0974] MS (ESI) m / z 573.2 [M+H] +

[0975] 1 H NMR (400 MHz, DMSO) δ 7.74(dd, J = 8.0, 2.2 Hz, 2H), 7.61(dd, J =8.0, 2.0Hz, 2H), 7.46(t, J = 8.0, 2.2Hz, 1H), 7.25–7.18 (m, 2H), 7.12 (t, J =8.0, 2.0 Hz, 1H), 6.90 (s, 1H), 5.07 (s, 2H), 4.74 (t, J = 12, 2.2 Hz, 2H), 4.28 (s, 1H), 4.01 (dd, J = 12, 2.2 Hz, 1H), 3.86 (dd, J = 14.6, 3.5 Hz, 1H), 3.80 (s, 3H), 1.64 (t, J = 8.0, 2.0 Hz, 3H).

[0976] Example 79

[0977] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0978]

[0979]

[0980] Starting with methyl 5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-carboxylic acid (200 mg, 0.704 mmol) and (2-methoxyphenyl)boronic acid, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (49.9 mg, yield 31%), a white solid.

[0981] MS (ESI) m / z 573.1 [M+H] +

[0982] 1 H NMR (400 MHz, DMSO-d6) δ 7.76-7.73 (m, 2H), 7.64-7.61 (m, 2H), 7.57-7.53 (m, 1H), 7.37-7.34 (m, 1H), 7.21-7.19 (m, 1H), 7.10-7.06 (m, 1H),6.91-6.90 (m, 1H), 5.06 (s, 2H), 4.51 (t, J = 13.2 Hz, 2H), 4.31-4.29 (m,1H), 4.02-3.97 (m, 1H), 3.87-3.83 (m, 1H), 3.81 (s, 3H), 1.54 (t, J = 19.2Hz, 3H).

[0983] Example 80

[0984] (S)-3-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-5-yl)benzenesulfonamide

[0985]

[0986]

[0987] Step 1. (5-Bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methanol

[0988] At 0 °C, NaBH4 (2.01 g, 0.053 mol) was added to a THF / MeOH (15 mL / 15 mL) solution of methyl 5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-carboxylic acid (1.5 g, 0.0053 mol). The reaction mixture was stirred at 25 °C for 12 h. The mixture was quenched with water (30 mL) and extracted with EA (50 mL x 3). The organic phases were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give (5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methanol (800 mg, yield 47.2%) as a yellow oil.

[0989] MS (ESI) m / z 256 [M+H] +

[0990] Step 2. (5-Bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate

[0991] At 0 °C, TEA (39.45 mg, 0.39 mmol) and methanesulfonyl chloride (28.93 mg, 0.25 mmol) were added to a solution of (5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methanol (50 mg, 0.19 mmol) in DCM (10 mL). The reaction mixture was stirred at 25 °C for 1.5 h. The mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The organic phases were combined and concentrated under vacuum. The crude product obtained did not require purification and was used directly in the next reaction.

[0992] MS (ESI) m / z 334 [M+H] +

[0993] Step 3. (S)-2-(5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0994] 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (35 mg, 0.11 mmol), methyl (5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate (49.43 mg, 0.14 mmol), and K₂CO₃ (22.99 mg, 0.22 mmol) were added to DMF (8 mL) solution and stirred at 50 °C for 16 h. The reaction system was cooled, quenched with water (20 mL), and extracted with EA (20 mL x 3). The reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give (S)-2-(5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (40 mg, yield 58.0%), as a yellow oil.

[0995] MS (ESI) m / z 546.1 [M+H] + .

[0996] Step 4. (S)-3-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-45-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-5-yl)benzenesulfonamide

[0997] (S)-2-((5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20 mg, 0.03 mmol), (3-(methanesulfonyl)phenyl)boronic acid (11.01 mg, 0.07 mmol), Cs₂CO₃ (23.92 mg, 0.07 mmol), and Pd(PPh₃)₄ (4.2 mg, 0.003 mmol) were added to a 1,4-dioxane / water solution (5:1, 10 mL) and stirred at N₂ and 80 °C for 5 h. The reaction mixture was cooled, filtered, and concentrated under vacuum. The concentrate was purified by HPLC to give (S)-3-(3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-5-yl)benzenesulfonamide (4.9 mg, yield 10.63%), as a white solid.

[0998] MS (ESI) m / z 622.1 [M+H] +

[0999] 1 H NMR (400 MHz, DMSO-d6) δ 8.1 (s, 1H), 7.98-7.93 (m, 2H), 7.77-7.73(m, 3H), 7.61(dd, J = 8.0, 2.2 Hz, 2H), 7.51 (s, 2H), δ 6.89 (dd, J = 8.0, 2.2Hz, 1H), 5.09 (dd, J = 12, 2.2 Hz, 2H), 4.82 (t, J = 8.0, 2.0 Hz, 2H), 4.29 (s, 1H), 4.01 (dd, J = 12, 2.2 Hz, 1H), 3.84-3.81 (m, 1H), 1.64 (t, J =8.0, 2.0 Hz, 3H).

[1000] Example 81

[1001] (S)-4-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-5-yl)benzenesulfonamide

[1002]

[1003]

[1004] Step 1. (S)-4-(3-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-45-dihydro-1H-1,2,4-triazol-1-yl)methyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-5-yl)benzenesulfonamide

[1005] (S)-2-((5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20 mg, 0.03 mmol), (3-aminosulfonylphenyl)boronic acid (11.01 mg, 0.07 mmol), Cs₂CO₃ (23.92 mg, 0.07 mmol), and Pd(PPh₃)₄ (4.2 mg, 0.003 mmol) were added to a 1,4-dioxane / water solution (5:1, 10 mL) and stirred at N₂ and 80 °C for 5 h. The reaction mixture was then concentrated under vacuum. The residue was purified by HPLC to give (S)-4-(3-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,,2,4-triazol-1-yl)methyl)-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-5-yl)benzenesulfonamide (4.3 mg, yield 9.26%), as a white solid.

[1006] MS (ESI) m / z 622.1 [M+H] +

[1007] 1H NMR(400 MHz, DMSO-d6) 7.91 (dd, J = 8.0, 2.2 Hz, 2H), 7.87 (dd, J =8.0, 2.2 Hz, 2H), 7.74 (dd, J = 12, 2.2 Hz, 2H), 7.62 (dd, J = 12, 2.2 Hz,2H), 7.13 (s, 2H), 5.09 (s, 2H), 4.82 (t, J = 8.0, 2.0 Hz, 2H), 4.79 (s, 1H),δ 4.01 (dd, J = 12, 2.2 Hz, 1H), 3.87-3.81(m, 1H), 1.64(t, J = 8.0, 2.0Hz, 3Hz).

[1008] Example 82

[1009] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(3-(methylsulfonyl)phenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1010]

[1011]

[1012] Starting with methyl 5-bromo-1H-1,2,4-triazole-3-carboxylic acid and 2,2-difluoropropyltrifluoromethanesulfonate, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(3-(methylsulfonyl)phenyl)-1H-1,4-triazole-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazole-3-one (55.1 mg, yield 45.03%), a white solid.

[1013] MS (ESI) m / z 621[M+H] + .

[1014] 1H NMR (400 MHz, DMSO-d6) δ 8.18(dd, J = 8.0, 2.2 Hz, 1H), 8.12-8.10(m, 2H), 7.84 (dd, J = 8.0, 2.2Hz, 1H), 7.74 (dd, J = 8.0, 2.2Hz, 2H), 7.62(dd, J = 12, 2.2 Hz, 2H), 6.89 (dd, J = 12, 2.2 Hz, 1H), 5.14 (s, 2H), 4.82(t, J = 8.0, 2.0 Hz, 2H), 4.30 (s, 1H), 4.01 (dd, J = 12, 2.2 Hz, 1H), 3.87-3.81(m, 1H), 3.30 (f, J = 14.6, 3.5 Hz, 3H), 1.65 (t, J = 8.0, 2.0 Hz, 3H).

[1015] Example 83

[1016] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(4-(methylsulfonyl)phenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1017]

[1018]

[1019] Starting with (5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methanol and (4-(methanesulfonyl)phenyl)boronic acid, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(4-(methanesulfonyl)phenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (27.1 mg, yield 11.7%), a white solid.

[1020] MS (ESI) m / z 621.1 [M+H] +

[1021] 1H NMR (400 MHz, DMSO-d6) δ 8.10-8.08 (m, 2H), 7.99-7.97 (m, 2H), 7.7-7.73(m, 2H), 7.64-7.60 (m, 2H), 6.90 (s, 1H), 5.11 (s, 2H), 4.85 (t, J = 13.2Hz, 2H), 4.30-4.28 (m, 1H), 4.02-3.98 (m, 1H), 3.88-3.82 (m, 1H), 3.32-3.30(m, 3H), 1.65 (t, J = 19.2 Hz, 3H).

[1022] Example 84

[1023] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoroethyl)-5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1024]

[1025]

[1026] Starting from [5-bromo-1-(2,2-difluoroethyl)-1,2,4-triazol-3-yl]methanol and 5-fluoro-2-methoxyphenylboronic acid ester, the product was synthesized according to the method of Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoroethyl)-5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (39.3 mg, yield 33%), a white solid.

[1027] MS (ESI) m / z 577.0 [M+H] +

[1028] 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.74 (m, 2H), 7.63-7.60 (m, 2H), 7.45-7.41 (m, 1H), 7.26-7.22 (m, 1H), 6.91 (s, 1H), 6.29 (t, J = 54.4 Hz,1H), 5.07 (s, 2H), 4.53-4.45 (m, 2H), 4.32-4.28 (m, 1H), 4.02-3.98 (m, 1H), 3.87-3.80 (m, 4H).

[1029] Example 85

[1030] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoroethyl)-5-(4-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1031]

[1032]

[1033] Starting from 5-bromo-1H-1,2,4-triazol-3-carboxylic acid methyl and 2,2-difluoroethyl trifluoromethanesulfonate, the product was synthesized according to the method in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoroethyl)-5-(4-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (62.6 mg, yield 33%), a white solid.

[1034] MS (ESI) m / z 577.1 [M+H] +

[1035] 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.74 (m, 2H), 7.73-7.63 (m, 2H), 7.42(t, J = 6.8 Hz, 1H), 7.15 (dd, J = 2.4, 2.4 Hz, 1H), 6.96-6.91 (m, 2H), 6.29(t, J = 3.6 Hz, 1H), 5.05 (s, 2H), 4.50-4.43 (m, 2H), 4.32-4.27 (m, 1H), 4.02-3.97 (m, 1H), 3.87-3.81 (m, 4H).

[1036] Example 86

[1037] (S)-5-(4-chlorophenyl)-4-(3,3-difluoro-2-hydroxypropyl)-2-((1-(2,2-difluoroethyl)-5-(4-fluoro-2-methylphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1038]

[1039]

[1040] Starting with methyl 5-bromo-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-carboxylic acid and 4-fluoro-2-methylphenylboronic acid ester, the mixture was synthesized according to the method in Example 4 to obtain (S)-5-(4-chlorophenyl)-4-(3,3-difluoro-2-hydroxypropyl)-2-((1-(2,2-difluoroethyl)-5-(4-fluoro-2-methylphenyl)-1H-1,2,4-triazol-3-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (39.3 mg, yield 33%) as a white solid.

[1041] MS (ESI) m / z 561.1 [M+H] + .

[1042] 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.72 (m, 2H), 7.64-7.60 (m, 2H), 7.46-7.42 (m, 1H), 7.30-7.27 (m, 1H), 7.22-7.17 (m, 1H), 6.91 (s, 1H), 6.32(t, J = 54.4 Hz, 1H), 5.09 (s, 2H), 4.50-4.42 (m, 2H), 4.31-4.28 (m, 1H), 4.02-3.98 (m, 1H), 3.88-3.82 (m, 1H), 2.13 (s, 3H).

[1043] Example 87

[1044] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoroethyl)-5-(4-fluoro-3-methylphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1045]

[1046]

[1047] Starting with methyl 5-bromo-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-carboxylic acid and 4-fluoro-3-methylphenylboronic acid ester, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoroethyl)-5-(4-fluoro-3-methylphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (34.3 mg, yield 24%), a white solid.

[1048] MS (ESI) m / z 561.1 [M+H] +

[1049] 1H NMR (400 MHz, DMSO-d6) δ 7.77-7.74 (m, 2H), 7.63-7.61 (m, 3H), 7.56-7.52 (m, 1H), 7.33 (t, J =8.8 Hz, 1H), 6.91 (d, J = 5.6 Hz, 1H), 6.42 (tJ = 54.4 Hz, 1H), 5.06 (s, 2H), 4.75-4.69 (m, 2H), 4.33-4.31 (m, 1H), 4.02-3.98 (m, 1H), 3.87-3.81 (m, 1H), 3.33 (s, 3H).

[1050] Example 88

[1051] (S)-5-(4-chlorophenyl)-2-((5-(4-fluoro-2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1052]

[1053]

[1054] Starting with methyl 5-bromo-1H-1,2,4-triazole-3-carboxylic acid and trifluoroethyl methanesulfonate, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(4-fluoro-2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazole-3-one (9.3 mg, yield 28%), a white solid.

[1055] MS (ESI) m / z 595 [M+H] + .

[1056] 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6Hz, 2H), 7.43 (dd, J = 8.5, 6.7 Hz, 1H), 7.15 (dd, J = 11.4, 2.3 Hz, 1H), 6.94 (td, J = 8.4, 2.4 Hz, 1H), 6.05 (s, 1H), 5.09-4.95 (m, 4H), 4.29 (d, J =6.3 Hz, 1H), 3.99 (dd, J = 14.6, 3.4 Hz, 1H), 3.89-3.79 (m, 4H).

[1057] Example 89

[1058] (S)-5-(4-chlorophenyl)-2-((5-(4-fluoro-2-methoxyphenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1059]

[1060]

[1061] Step 1. Methyl 5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazole-3-carboxylic acid ester

[1062] At 0 °C, NaH (640 mg, 0.026 mmol, 60% mineral oil) was added to a solution of methyl 5-bromo-1H-1,2,4-triazol-3-carboxylic acid (5.0 g, 0.02 mol) in DMF (60 mL). The reaction mixture was stirred at 0 °C for 30 minutes. Then, 1-fluoro-2-iodoethane (5.07 mg, 0.029 mmol) was added. The mixture was stirred overnight at room temperature under N2. The reaction mixture was quenched with water (200 mL) and extracted with EA (100 mL x 3). The organic phases were combined and concentrated under vacuum. The concentrate was subjected to C24-distillation. 18 Column purification yielded methyl 5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazole-3-carboxylic acid (0.8 g, yield 9.35%), a white solid.

[1063] MS (ESI) m / z 252.0 [M+H] +

[1064] Step 2. (5-Bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methanol

[1065] At 0 °C, methyl 5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-carboxylic acid (800 mg, 3.17 mmol) was added to a THF / MeOH solution (10 mL / 10 mL). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (50 mL x 3). The organic phases were combined and concentrated to give a crude compound as a white solid (500 mg, yield 49.22%), which was used directly in the next step without further purification.

[1066] MS (ESI) m / z 224[M+H] + .

[1067] Step 3. (5-Bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate

[1068] At 0 °C, TEA (451.6 mg, 4.46 mmol) and methanesulfonyl chloride (330.6 mg, 2.90 mmol) were added to a solution of (5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methanol (500 mg, 2.23 mmol) in DCM (20 mL). The reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The organic phases were combined, concentrated, and the title compound was obtained. This compound was used directly in the next step without further purification.

[1069] MS (ESI) m / z 302[M+H] + .

[1070] Step 4. (S)-2-((5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1071] 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (400 mg, 1.30 mmol), (5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methylmethanesulfonate (471.3 mg, 1.56 mmol), and K2CO3 (358.8 mg, 2.60 mmol) were added to a 20 mL solution of DMF and stirred at 50 °C for 16 h. The reaction system was cooled, quenched with water (20 mL), and extracted with EA (20 mL * 3). The organic layers were combined, concentrated, and the concentrate was purified by silica gel column chromatography (PE / EA = 1:1) to give (S)-2-(5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg, yield 38.18%), as a yellow oil.

[1072] MS (ESI) m / z 514.0 [M+H] +

[1073] Step 5. (S)-5-(4-chlorophenyl)-2-(5-(4-fluoro-2-hydroxyphenyl)-1-(2-fluoroethyl)-1H-1,2,tris-4-azol-3-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1074] (S)-2-((5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.097 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (33.07 mg, 0.19 mmol), Cs₂CO₃ (63.4 mg, 0.19 mmol), and Pd(PPh₃)₄ (8.48 mg, 0.0073 mmol) were reacted in 1,4-dioxane / water (5:1, 20 mL) under N₂ for 5 h. The reaction mixture was then cooled and concentrated. The residue was purified by HPLC to give (S)-5-(4-chlorophenyl)-2-(5-(4-fluoro-2-methoxyphenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-)methyl)-4-(3,3,3-trifluoro-2-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (25.2 mg, yield 22.71%), a white solid.

[1075] MS (ESI) m / z 559.0 [M+H] + .

[1076] 1 H NMR (400 MHz, DMSO-d6) 7.76 (dd, J = 8.0, 2.2 Hz, 2H), 7.74 (dd, J= 8.0, 2.2 Hz, 2H), 7.35 (dd, J = 12, 2.2 Hz, 1H), 7.13 (dd, J = 12, 2.2 Hz,1H), 6.95-6.90 (m, 2H), 5.04 (s, 2H), 4.73 (dd, J = 12, 2.2 Hz, 1H), 4.61(dd,J = 12, 2.2 Hz, 1H), 4.30-4.25 (m, 3H), 4.01 (dd, J = 12, 2.2 Hz, 1H), 3.84-3.81 (m, 1H), 3.32 (s, 3H).

[1077] Example 90

[1078] (S)-5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1079]

[1080]

[1081] Step 1. (S)-5-(4-chlorophenyl)-2-(5-fluoro-2-hydroxyphenyl)-1-(2-fluoroethyl)-1H-1,24-triazol-3-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1082] (S)-2-((5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.19 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (66.18 mg, 0.38 mmol), Cs₂CO₃ (126.7 mg, 0.38 mmol) and Pd(PPh₃)₄ (22.50 mg, 0.019 mmol) were added to 1,4-dioxane / water In a 5:1, 15 mL mixture, the reaction system was stirred at 100 °C under N2 for 5 h. The reaction system was cooled, filtered, and concentrated under vacuum. The concentrate was purified by HPLC to give (S)-5-(4-chlorophenyl)-2-(5-(5-fluoro-2-methoxyphenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (40.2 mg, yield 18.1%), as a white solid.

[1083] MS (ESI) m / z 559.0 [M+H] + .

[1084] 1H NMR (400 MHz, DMSO-d6) 7.75 (dd, J = 8.0, 2.2 Hz, 2H), 7.62 (dd, J= 8.0, 2.2 Hz, 2H), 7.39 (dd, J = 12, 2.2 Hz, 1H), 7.22 (dd, J = 12, 2.2 Hz,2H), 6.90 (dd, J = 12, 2.2 Hz, 1H), 5.04 (s, 2H), 4.73(dd, J = 12, 2.2 Hz,1H), 4.61 (dd, J = 12, 2.2 Hz, 1H), 4.30-4.25 (m, 3H), 3.86 (dd, J = 12, 2.2Hz, 1H), 3.84-3.81 (m, 1H), 3.78 (s, 3H).

[1085] Example 91

[1086] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(4-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1087]

[1088]

[1089] Starting with methyl 5-bromo-1-(2,2-difluoropropyl)-1,2,4-triazol-3-carboxylic acid and using (4-fluoro-2-hydroxyphenyl)borondiol as a key intermediate, the product was synthesized according to the method described in Example 85 to yield (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(4-fluoro-2-methoxyphenyl)-1H-1,24-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (12.9 mg, 22% yield), a white solid.

[1090] MS (ESI) m / z 591.1 [M+H] + .

[1091] 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.69 (m, 2H), 7.65-7.59 (m, 2H), 7.40(dd, J = 8.4, 6.8 Hz, 1H), 7.14 (dd, J = 11.4, 2.4 Hz, 1H), 1.55 (t, J = 19.2 Hz, 3H).

[1092] Example 92

[1093] (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1094]

[1095]

[1096] Step 1. (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(5-fluoro-2-methoxyphenyl)-1H-1,24-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1097] To (S)-2-((5-bromo-1-(2,2-difluoropropyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.09 mmol), (4-fluoro-2-hydroxyphenyl)borondiol (28 mg, 0.18 mmol) and cesium carbonate (56 μg, 0.18 mmol) dioxane / H2O (Pd(PPh3)4 (11 mg, 0.009 mmol) was added to a 5.0 mL / 1.0 mL solution. The reaction system was stirred at 100 °C under N2 for 6 h, cooled, and extracted with H2O (50 mL*3) followed by EA (50 mL*3). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by Prep-HPLC to give (S)-5-(4-chlorophenyl)-2-((1-(2,2-difluoropropyl)-5-(5-fluoro-2-methoxyphenyl)-1H-1,24-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (22.5 mg, 39% yield), as a white solid.

[1098] MS (ESI) m / z 591.1 [M+H] + .

[1099] 1 H NMR (400 MHz, DMSO-d6) δ 7.78-7.71 (m, 2H), 7.65-7.59 (m, 2H), 7.46-7.36 (m, 1H), 7.26-7.18 (m, 2H), 6.90 (d, J = 6.4 Hz, 1H), 5.07 (s, 2H), 4.54 (t, J = 13.4 Hz, 2H), 4.30 (d, J = 6.6 Hz, 1H), 4.02-3.89 (m, 1H), 3.90-3.74 (m, 4H), 1.55 (t, J = 19.2 Hz, 3H).

[1100] Example 93

[1101] (S)-2-((5-(2-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1102]

[1103]

[1104] Starting with (5-bromo-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)methanol and (2-chloro-4-fluorophenyl)boronic acid, the product was synthesized according to the method of Example 4 to obtain (S)-2-((5-(2-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.7 mg, yield 34%), a white solid.

[1105] MS (ESI) m / z 581.0 [M+H] +

[1106] 1 H NMR (400 MHz, DMSO-d6) δ 7.76-7.70 (m, 3H), 7.66-7.61 (m, 3H), 7.45-7.40 (m, 1H), 6.91 (s, 1H), 6.44-6.17 (m, 1H), 5.10 (s, 2H), 4.55-4.47(m, 2H), 4.31-4.28 (m, 1H), 4.02-3.98 (m, 1H), 3.88-3.82 (m, 1H).

[1107] Example 94

[1108] (S)-2-((5-(2-chloro-4-fluorophenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1109]

[1110]

[1111] Step 1. (S)-2-((5-(2-chloro-4-fluorophenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1112] (S)-2-((5-bromo-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.09 mmol), (2-chloro-4-fluorophenyl)boronic acid (33.9 mg, 0.19 mmol), Cs₂CO₃ (63.4 mg, 0.19 mmol) and Pd(PPh₃)₄ (11.24 mg, 0.0097 mmol) were added to 1,4-dioxane / water. The reaction system was stirred for 5 h at 100 °C under N2 in a (5:1, 15 mL) solution. The reaction system was then cooled and concentrated. The concentrate was purified by HPLC to give (S)-2-((5-(2-chloro-4-fluorophenyl)-1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (7.3 mg, yield 6.7%), as a white solid.

[1113] MS (ESI) m / z 563.0 [M+H] +

[1114] 1 H NMR (400 MHz, DMSO-d6) 7.76-7.70 (m, 3H), 7.63-7.60 (m, 3H), 7.41(dd, J = 8.0, 2.2 Hz, 1H), 6.93 (s, 1H), 5.09 (s, 2H), 4.73 (dd, J = 12, 2.2Hz, 1H), 4.62 (dd, J = 12, 2.2 Hz, 1H), 4.31-4.25 (m, 3H), 4.02-3.97 (m, 1H), 3.87-3.81 (m, 1H).

[1115] Example 95

[1116] 2-((5-(2-chloro-4-(1-hydroxyethyl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-((S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1117]

[1118]

[1119] Step 1. 1-(3-chloro-4-(4,4,5,5,5-methyl-1,3,2-dioxy)-2-yl)ethyl-1-methyl)ethyl-1-one

[1120] Pd(dppf)Cl2 (94.0 mg, 0.0128 mmol) was added to a solution of 1,4-dioxane (10 mL) containing 1-(4-bromo-3-chlorophenyl)ethyl-1-one (300 mg, 1.28 mmol), bis(pincorato)diborone (424.2 mg, 1.67 mmol), and KOAc (441.4 mg, 4.50 mmol). The mixture was stirred at 80 °C under N2 for 3 h. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the standard compound as a white solid (240 mg, 60% yield).

[1121] MS (ESI) M / z 281 [M+H] +

[1122] Step 2. (S)-2-((5-(4-acetyl-2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1123] Add Pd(PPh3)4 (12.6 mg, 0.0109 mmol) to a solution of (S)-2-((5-bromo-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.109 mmol), 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)ethyl-1-one (46.0 mg, 0.164 mmol) and Cs2CO3 (71.2 mg, 0.218 mmol) in 1,4-dioxane / H2O (5:1, 6 mL). The reaction mixture was stirred at 100°C under N2 for 4 h. The mixture was then cooled and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give the title compound (60 mg, 79% yield) as a yellow oil.

[1124] MS (ESI) M / z 623 [M+H] + .

[1125] Step 3. 2-(5-(2-chloro-4-(1-hydroxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)-5-(4-chlorophenyl)-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1126] To a solution of (S)-2-((5-(4-acetyl-2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.0963 mmol) in THF (5 mL), NaBH4 (18.2 mg, 0.482 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Water (10 mL) was added to the mixture, and it was extracted with EA (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC (NH4HCO3) to give the title compound 2-(5-(2-chloro-4-(1-hydroxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)-5-(4-chlorophenyl)-(S)-3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (8.9 mg, yield 14%), as a white solid.

[1127] MS (ESI) M / z 625 [M+H] + .

[1128] 1H NMR (400 MHz, DMSO-d6) δ 7.77-7.72 (m, 2H), 7.65-7.60 (m, 3H), 7.48 (dt, J = 8.0, 4.6 Hz, 2H), 6.90 (d, J = 6.3 Hz, 1H), 5.46 (d, J = 4.6Hz, 1H), 5.14-4.99 (m, 4H), 4.85-4.77 (m, 1H), 4.30 (d, J = 6.7 Hz, 1H), 4.00 (dd, J = 14.6, 3.4 Hz, 1H), 3.85 (dd, J = 14.6, 9.5 Hz, 1H), 1.36 (d, J = 6.5Hz, 3H).

[1129] Example 96

[1130] (S)-5-(4-chlorophenyl)-2-((5-(2-fluoro-5-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1131]

[1132]

[1133] Step 1. (S)-5-(4-chlorophenyl)-2-((5-(2-fluoro-5-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1134] Pd(PPh3)4 (6.3 mg, 0.00546 mmol) was added to a solution of (S)-2-((5-bromo-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (30 mg, 0.0546 mmol), (2-fluoro-5-methoxyphenyl)borondiol (18.6 mg, 0.109 mmol), and Cs2CO3 (35.6 mg, 0.109 mmol) in 1,4-dioxane / water (5:1, 5 mL). The reaction mixture was stirred at 100 °C under N2 for 6 h. The reaction system was cooled, filtered, and concentrated. The concentrate was purified by preparative-HPLC (NH4HCO3) to give the title compound (6.3 mg, yield 19%) as a white solid.

[1135] MS (ESI) m / z 595 [M+H] + .

[1136] 1H NMR (400 MHz, DMSO-d6) δ 7.77-7.73 (m, 2H), 7.65-7.60 (m, 2H), 7.37(t, J = 9.2 Hz, 1H), 7.23-7.17 (m, 1H), 7.12 (dd, J = 5.6, 3.2 Hz, 1H), 5.18-5.06 (m, 4H), 4.34-4.24 (m, 1H), 3.99 (dt, J = 8.9, 4.4 Hz, 1H), 3.89-3.75(m, 4H).

[1137] Example 97

[1138] (S)-5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1139]

[1140]

[1141] Starting with methyl 5-bromo-1H-1,2,4-triazol-3-carboxylic acid ester and 4-methylbenzenesulfonate oxane-4-yl ester, and using 5-fluoro-2-methoxyphenylboronic acid as a key intermediate, the mixture was synthesized according to the method of Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(5-fluoro-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (19.7 mg, yield 13%), a white solid.

[1142] MS (ESI) m / z 597.1 [M+H] + .

[1143] 1H NMR (500 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 2H), 7.52 – 7.46 (m,2H), 7.10 (dd, J = 12.1, 2.6 Hz, 1H), 6.97 (m, 1H), 6.88 (dd, J = 8.4, 4.7Hz, 1H), 5.03 (m, 1H), 4.59 (s, 1H), 4.03 (dq, J = 8.3, 3.6 Hz, 1H), 3.95 (s,2H), 3.89 (m, 2H), 3.80 (p, J = 4.3 Hz, 1H), 3.67 (ddd, J = 10.5, 6.2, 3.4Hz, 2H), 3.29 (m, 1H), 3.14 (m, 1H), 2.17 (m, 2H), 1.97 – 1.87 (m, 2H).

[1144] Example 98

[1145] (S)-5-(4-chlorophenyl)-2-((5-(4-fluoro-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1146]

[1147]

[1148] Using [5-bromo-1-(3,4,5,6-tetrahydro-2H-pyran-4-yl)-1,2,4-triazol-3-yl]methanol and 4-fluoro-2-methoxyphenylboronic acid as key intermediates, the synthesis was carried out according to the method of Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(4-fluoro-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (24 mg, yield 16%), as a white solid.

[1149] MS (ESI) m / z 597.1 [M+H] + .

[1150] 1H NMR (500 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 2H), 7.57 – 7.48 (m,3H), 6.88 (dd, J = 12.1, 2.1 Hz, 1H), 6.82 (m, 1H), 5.03 (m, 1H), 4.79 (s,1H), 3.96 (s, 3H), 4.00 – 3.70 (m, 5H), 3.63 (dq, J = 8.3, 3.6 Hz, 1H), 3.34(m, 1H), 3.07 – 2.99 (m, 1H), 2.47 (m, 1H), 2.22 – 2.12 (m, 1H), 2.03 – 1.91 (m, 2H).

[1151] Example 99

[1152] (S)-5-(4-chlorophenyl)-2-((5-(2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1153]

[1154]

[1155] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-carboxylic acid and (2-methoxyphenyl)boronic acid, the product was synthesized according to the method in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(2-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (13.1 mg, yield 14%), a white solid.

[1156] MS (ESI) m / z 577.1 [M+H] + .

[1157] 1H NMR(400 MHz, DMSO-d6) δ 7.77-7.73 (m, 2H), 7.64-7.56 (m, 3H), 7.39-7.37 (m, 1H), 7.23-7.21 (m, 1H), 7.21-7.08 (m, 1H), 6.91 (m, 1H), 5.08 (s,2H), 5.03-4.97 (m, 2H), 4.30-4.28 (m, 1H), 4.02-3.97 (m, 1H), 3.87-3.81 (m,4H).

[1158] Example 100

[1159] (S)-5-(4-chlorophenyl)-2-((5-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1160]

[1161]

[1162] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and (2-chlorophenyl)boronic acid, the mixture was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.6 mg, yield 12.1%), a white solid.

[1163] MS (ESI) m / z 581.10 [M+H] + .

[1164] 1 H NMR (400 MHz, DMSO-d6) δ 7.76-7.69 (m, 2H), 7.68-7.61 (m, 6H), 6.91(s, 1H), 5.12 (s, 2H), 5.08-5.04 (m, 2H), 4.28 (s, 1H), 3.87 (dd, J = 14.8,3.3 Hz, 1H), 3.85-3.81 (m, 1H).

[1165] Example 101

[1166] (S)-5-(4-chlorophenyl)-2-((5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1167]

[1168]

[1169] Starting with methyl 5-bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-carboxylic acid and 2-fluorophenylboronic acid, the product was synthesized according to the method described in Example 4 to obtain (S)-5-(4-chlorophenyl)-2-((5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (26.1 mg, 39% yield), which was a white solid.

[1170] MS (ESI) m / z 565.1 [M+H] +

[1171] 1 H NMR (400 MHz, DMSO-d6) δ 7.76-7.58 (m, 6H), 7.49-7.33 (m, 2H), 6.90(d, J = 6.4 Hz, 1H), 5.18-5.07 (m, 4H), 4.29 (s, 1H), 4.00 (dd, J = 14.8, 3.2Hz, 1H), 3.84 (dd, J = 14.6, 9.6 Hz, 1H).

[1172] Test Example 1

[1173] 1. Assay method for vasopressin V1a receptor activity

[1174] 1.1 Cell Information

[1175] 1) Using a stable V1a receptor CHO cell line, the inhibitory effect of different concentrations of test compounds on the V1a receptor was determined using the IP-One-Gq kit after stimulation.

[1176] 2) CHO cell lines stably expressing V1a were cultured in F12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at 37°C and 5% carbon dioxide.

[1177] 3) To maintain the physiological activity of the cells, the degree of cell fusion in the experiment was controlled at around 80%.

[1178] 1.2 Determination of the inhibitory activity of the compound against the -V1a receptor

[1179] 1) Prepare 1× Stimulation Buffer according to the kit instructions;

[1180] 2) Use DMSO to perform serial dilutions of the positive compound and the test compound to five concentrations, and then use 1×Stimulation Buffer to dilute the compound to 10×, shake to mix well and set aside.

[1181] 3) Culture stable transgenic cells to 80% confluence; trypsin digestion to collect cells, count them, and then seed 9.1 μL / well in 384-well plates in inhibition mode;

[1182] 4) Take 1.4 μL of the diluted 10× compound from step 2 and add it to the corresponding experimental wells. Add 1.4 μL of the 10× initial concentration positive compound to the PC well and 1.4 μL of 10× DMSO buffer (1%) to the VC well. After centrifugation, incubate at 37°C for 10 minutes.

[1183] 5) Add 3.5 μL of agonist solution, centrifuge, and incubate at 37°C for 1 hour;

[1184] 6) Dilute d2-IP1 and Anti-IP1-Cryptate to working concentrations using Lysis & Detection Buffer;

[1185] 7) After incubation, add 3 μL of d2-IP1 to all wells;

[1186] 8) Add 3 μL of Anti-IP1-Cryptate to all experimental wells, centrifuge, and incubate at room temperature for 1 hour;

[1187] 9) After incubation, use a microplate reader to detect the readings at 665 nm and 620 nm under excitation at a wavelength of 330 nm;

[1188] 10) Calculate the IC50 of the compound using a nonlinear fitting formula.

[1189] 2. Assay method for vasopressin V2 receptor activity

[1190] 2.1 Cell Information

[1191] 1) A stable receptor CHO cell line expressing V2 was used. After stimulation with different concentrations of the test compounds, the inhibitory effect of the compounds on the V2 receptor was determined using the L.ANCE@UItrac AMP Ki kit.

[1192] 2) The CHO cell line stably expressing V2 was cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / ml Hygromycin B at 37°C and 5% carbon dioxide.

[1193] 3) To maintain the physiological activity of the cells, the degree of cell fusion in the experiment was controlled at around 80%.

[1194] 2.2 Determination of the inhibitory activity of the compound on V2 receptor

[1195] 1) Prepare 1x Stimulation Buffer according to the kit instructions;

[1196] 2) Use DMSO to perform serial dilutions of the positive compound and the test compound to 6 concentrations, and then use 1x Stimulation Buffer to dilute the compound to 10x, shake to mix well and set aside.

[1197] 3) Culture stable transgenic cells to 80% confluence; trypsin digestion to collect cells, count them, and seed 5 μL / well in 384-well plates in activation mode;

[1198] 4) Add 1 μL of the diluted 10x compound to the corresponding experimental well and incubate at 37°C for 10 minutes;

[1199] 5) Prepare 0.025 nM Argipressin buffer with 1xStimulation Buffer, then add 4 μL / well to the corresponding experimental well and incubate for 30 minutes;

[1200] 6) Dilute Eu-cAM to the working concentration with detection buffer, and add 5 μL / well to the corresponding experimental well;

[1201] 7) Dilute the ULightn anti-cAMP antibody to the working concentration with detection buffer, and add 5 μL / well to the corresponding experimental well; centrifuge and incubate at room temperature for 1 hour;

[1202] 8) After incubation, use a microplate reader to detect the readings at 665 nm and 620 nm under excitation at a wavelength of 330 nm;

[1203] 9) Calculation of compound IC using nonlinear fitting formula 50 .

[1204] 10) Table 1: In vitro activity test data of the embodiments of the present invention

[1205]

[1206]

[1207] Conclusion: The compounds of this invention exhibit inhibitory activity against both angiotensin receptors V1a and V2 less than 10 μM.

[1208] Test Example 2: Inhibition Study of Major CYP Enzymes

[1209] 1. Test sample preparation:

[1210] 1) Preparation of test compounds: Weigh the required amount of powder into a separate sample vial and dilute to 10 mM with the corresponding volume of DMSO;

[1211] 2) Preparation of probe substrates: phenacetin, coumarin, bupropion, amodiaquine, diclofenac, toxotoxin sodium, dextromethorphan, chlorzoxazone, midazolam; the final concentrations were 40 µM, 2 µM, 40 µM, 1 µM, 6 µM, 50 µM, 2 µM, 40 µM, 1 µM, and 40 µM, respectively.

[1212] 3) Preparation of positive inhibitors: furazolidone, trans-cyclopropylamine, ketoconazole, quercetin, sulfamethoxazole, trans-cyclopropylamine, quinidine, quercetin, ketoconazole; prepared to final concentrations of 25 µM, 5 µM, 25 µM, 25 µM, 5 µM, 25 µM, 0.5 µM, 200 µM, 0.5 µM;

[1213] 4) Phosphate buffer (100 mM, pH 7.4)

[1214] 5)10 mM NADPH solution

[1215] 6) Human liver microsomes (HLM): final concentration 0.2 mg / mL.

[1216] 2. Experimental Procedure:

[1217] 1) Incubate in a 96-well plate. Dispense the following volumes into each well of the incubation plate: 169 μL of main solution and 1 μL of compound working solution or carrier (DMSO). Place the incubation plate in a water bath and incubate at 37°C. oPreheat at C for 5 minutes. Add 10 μL of substrate to the incubation plate, mix the incubation mixture on a rotary mixer for 15 seconds, then add 20 μL of 10 mM NADPH solution to start the reaction at a final concentration of 1 mM. This assay is performed in duplicate.

[1218] 2) The reaction was quenched by adding 1.5 volumes (300 μL) of cold acetonitrile containing 3% formic acid and 200 nM tolbutamide, 200 nM alprazolam, and 200 nM labetalol. The plate was centrifuged at 3,220 g for 40 minutes. 150 μL of the supernatant was transferred to a new plate. The supernatant could be diluted with 150 μL of pure water. The mixture was thoroughly mixed and the sample was analyzed by UPLC-MS / MS.

[1219] 3) Examine the automated peak integration region for all samples. Export the analyte peak area and internal standard peak area to an Excel spreadsheet. The inhibitory activity of each P450 enzyme in human liver microsomes is measured as the percentage reduction in marker metabolite formation activity compared to the non-inhibitory control (= 100% activity).

[1220] 4) Calculation method:

[1221] Area ratio = Analyte peak area / Peak area internal standard

[1222] Residual activity (%) = Area ratio of test compound / Area ratio of support * 100%

[1223] Inhibition % = 100 - Residual activity (%).

[1224] Table 2: Inhibition data of major CYP enzymes in the embodiments of the present invention (10 μM)

[1225]

[1226] Conclusion: The results showed that the tested compounds had no significant inhibitory effect on major CYP enzymes.

[1227] Test Example 3: Determination of Plasma Protein Binding Rate

[1228] 1. Compound information, instruments and equipment

[1229] 1) Experimental compounds

[1230] 2) Specially formulated methanol (containing 35 ng / mL ketoprofen, 7.5 ng / mL carbamazepine, 5 ng / mL diphenhydramine, and 10 ng / mL tolbutamide)

[1231] 3) Human plasma

[1232] 4) HTD 96B complete dialysis unit

[1233] 5)HTD 96A / B dialysis membrane

[1234] 6) Adhesive sealing film

[1235] 2. Operating Procedures

[1236] 1) Soak the dialysis membrane (water: 60 minutes, 20% ethanol: 20 minutes, dialysis buffer: 20 minutes)

[1237] 2) Dilute the test compound to 200 μM with DMSO.

[1238] 3) In 37 o Thaw the plasma in a water bath at C and centrifuge it at 3220 g for 10 minutes to remove clots.

[1239] 4) Transfer the supernatant to a new tube and sterilize at 37°C. o Preheat in a water bath for 10 minutes.

[1240] 5) Assemble the HTD dialysis unit according to the manufacturer's instructions.

[1241] 6) Add 3 μL of 200 μM test compound to 597 μL of plasma and vortex at 1000 rpm for 2 minutes.

[1242] 7) Transfer 50 μL of spiked plasma to a 96-well plate, then add 50 μL of dialysis buffer and 200 μL of specially prepared methanol as the T0 sample.

[1243] 8) Add two portions of 120 μL spiked plasma and 120 μL dialysis buffer to the chamber of the HTD dialysis device.

[1244] 9) Cover the dialysis unit with the vent cap, and place the dialysis unit and the remaining spiked plasma at 37°C. o Incubate at C (100 rpm, 5% CO2) for 6 hours.

[1245] 10) Transfer 50 μL of the post-dialysis sample from the dialysis buffer and plasma chamber to a separate 96-well plate, and then add 50 μL of blank plasma or dialysis buffer and 200 μL of specially prepared methanol as B and P samples.

[1246] 11) Transfer 50 μL of the remaining spiked plasma (as described in step 9) to a 96-well plate, and then add 50 μL of dialysis buffer and 200 μL of specially prepared methanol as the T6 sample.

[1247] 12) Centrifuge the sample plate at 3220 g for 40 minutes.

[1248] 13) Transfer 100 µL of supernatant to an analytical plate containing an appropriate volume of water for LC-MS / MS analysis.

[1249] 3. Data Analysis

[1250] Calculate the binding rate of the test compound.

[1251]

[1252]

[1253]

[1254]

[1255] Table 3: Data on plasma protein binding rate determination in embodiments of the present invention

[1256]

[1257] Conclusion: The plasma protein binding rates in all embodiments of the present invention are less than 99%.

[1258] Test Example 4: Cytotoxicity Test

[1259] 1. Cell Culture

[1260] 1) Prepare HepG2 cell culture medium consisting of Duchenne Modified Eagle Medium (DMEM) supplemented with: 10% FBS, 1× penicillin-streptomycin mixture, 1× non-essential amino acids (NEAA) and 1% Hepes.

[1261] 2) Rinse the cultured cells in the T-75 flask with 5 mL PBS, aspirate dry, add 3 mL trypsin / EDTA solution, and incubate at 37°C for about 2 minutes or until the cells detach and float. Inactivate trypsin / EDTA by adding cell culture medium containing FBS.

[1262] 3) Transfer the cell suspension to a conical tube and centrifuge at 150 xg for 5 minutes to pellet the cells. Carefully aspirate the supernatant and resuspend the HepG2 cells in cell culture medium at a density of 150,000 cells / mL. Add 20 μL of the cell suspension to each well of a 384-well plate.

[1263] 4) Incubate the petri dishes overnight at 37°C and 5% CO2, and then perform toxicity testing.

[1264] 2. Compound preparation and processing

[1265] 1) The test compound was started with a 30 mM stock solution and serially diluted 3 times for a total of 8 doses. The control compound was started with a 30 mM stock solution and serially diluted 3 times for a total of 8 doses.

[1266] 2) Remove the culture plate from the incubator and add 100 nL of positive control and test sample solution directly. Repeat each solution three times.

[1267] 3) Place the culture plate back into the incubator and incubate for 48 hours in a humidified environment at 37°C and 5% CO2.

[1268] 3. Testing Procedures

[1269] 1) After incubation, remove the plate from the incubator. Add the premixed Cell Titer-Glo reagent (20 µL per well) directly to the 384-well plate.

[1270] 2) Place the board on the board oscillator and oscillate for 5 minutes.

[1271] 3) Incubate the plate at room temperature for 10 minutes.

[1272] 4) After 10 minutes, record the light emission status on the board reader.

[1273] 4. Data Analysis

[1274] The percentage of the carrier control for the test compound was calculated using the following formula:

[1275] Vector control percentage = [(Compound reads - Blank reads) / (Vector reads - Blank reads)] * 100%

[1276] Table 5: Cytotoxicity data of the present invention against HepG2 cells in embodiments of the present invention

[1277]

[1278] Conclusion: The tested compounds all had IC50 values ​​greater than 30 μM against HepG2 cells and showed no cytotoxic effects.

Claims

1. A compound represented by formula I, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof. in, X, Y, Z, and Q are each independently selected from C, N, or O, and at least one of them is N; R1 and R2 are each independently selected from H, halogens, C1-C4 alkyl or 3-6 membered cycloalkyl, or R1 and R2 are combined with the carbon atoms they are attached to to form a 3-6 membered ring; R3 is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted 4-6 membered heterocyclic groups; n = 0 or 1; R4 is selected from substituted or unsubstituted phenyl groups, or substituted or unsubstituted 4-6-membered heteroaryl groups; R5 is selected from substituted or unsubstituted phenyl groups, or substituted or unsubstituted 4-6 heteroaryl groups.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, characterized in that, The 5-membered ring formed by X, Y, Z, and Q, together with R3 and R4, forms a structure selected from one of the following: 。 3. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, characterized in that, In R3, the substituted C1-C4 alkyl group is substituted with 1-2 substituents independently selected from F, hydroxyl, trifluoromethyl, acetaldehyde, cyano, dimethylamino, cyclopropyl, 4-6 membered oxetyl, methyloxetyl, and amide; the substituted C1-C4 alkoxy group is substituted with 1-2 substituents independently selected from F, hydroxyl, trifluoromethyl, acetaldehyde, cyano, dimethylamino, cyclopropyl, 4-6 membered oxetyl, methyloxetyl, and amide; and the substituted 4-6 membered heterocyclic group is substituted with 1-2 substituents independently selected from F, hydroxyl, trifluoromethyl, acetaldehyde, cyano, dimethylamino, cyclopropyl, 4-6 membered oxetyl, methyloxetyl, and amide. In R4, the phenyl group is substituted with 1-2 substituents independently selected from H, halogen, hydroxyl, methoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, methanesulfonyl, sulfanil, hydroxyethyl, and pyridone; the substituted 4-6 heteroaryl group is substituted with 1-2 substituents independently selected from H, halogen, methoxy, difluoromethyl, difluoromethoxy, methanesulfonyl, sulfanil, hydroxyethyl, and pyridone. In R5, the phenyl group is substituted with 1-3 substituents independently selected from H, halogen, methyl, mercapto, difluoromethyl, difluoroethyl, cyano, methylthio, cyclopropyl, and -CONH-R6, where R6 is methyl, tert-butyl, or thiazolyl; the substituted 4-6 heteroaryl group is substituted with 1-3 substituents independently selected from H, halogen, methyl, mercapto, difluoromethyl, difluoroethyl, cyano, methylthio, cyclopropyl, and -CONH-R6, where R6 represents methyl, tert-butyl, or thiazolyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, characterized in that, R4 is selected from the following groups: ， R7 and R8 are each independently selected from H, halogen, hydroxyl, methoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, methanesulfonyl, sulfonamide, or hydroxyethyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, characterized in that, R1 and R2 are each independently selected from H, F or methyl, or R1 and R2 are combined with the carbon atom they are attached to to form a cyclopropyl group.

6. The following compounds, or their pharmaceutically acceptable salts, hydrates, and / or solvates, 。 7. A pharmaceutical composition, characterized in that, It includes an effective amount of the active ingredient and pharmaceutically acceptable excipients; the active ingredient is the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

8. The use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating heart failure.

9. The use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament, characterized in that, The drug is used to prevent or treat diseases associated with arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system.

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