5-aryl-3-ketotriazoles and methods of making and using the same

Abstract

The application discloses a kind of 5-aryl-3-ketotriazole derivatives and preparation method and application thereof, the structural formula of the 5-aryl-3-ketotriazole derivatives is as shown in general formula I: the compound can be used as vasopressin V1a / V2 receptor antagonist lead compound, and it is expected to be used for preparing the drug for preventing or treating the disease related to arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, sympathetic nerve or renin-angiotensin-aldosterone system.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of 5-aryl-3-one triazole derivatives, their preparation methods, and applications. 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 various biological functions, all mediated by its specific receptors. Three different vasopressin receptors have been isolated: V1a, V1b, 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, with a high incidence rate. The main reason for most heart failure hospitalizations is the 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 subsequent 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 signs of fluid retention should be treated with diuretics. Currently available 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 congestion symptoms in heart failure while inhibiting myocardial remodeling, 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, there is still a need to design and synthesize novel V1a / V2 receptor antagonists to provide entirely new treatment options for patients with heart failure. Summary of the Invention

[0005] One object of this invention is to provide compounds of general formula I or pharmaceutically acceptable salts, hydrates and / or solvates thereof.

[0006]

[0007] in:

[0008] X is C or N;

[0009] Y is either C or N;

[0010] Z can be -CH2-, -CHR1-, -CO-, N, or O;

[0011] Q can be -CH2-, -CHR1-, -CO-, N, or O;

[0012] R1 is an H, C1-C3 alkane or a haloal short-chain alkane;

[0013] R2 and R3 are hydrogen, halogen, -CN, -OCH3, -OCF3, C1-C3 alkanes or haloalkanes;

[0014] m = 0 or 1.

[0015] Furthermore, R2 can be hydrogen, -F, -Cl, -CN, -OCH3, -OCF3, -CH3, -CF2H, or -CF3;

[0016] R3 can be hydrogen, -F, -Cl, -CN, -OCH3, -OCF3, -CH3, -CF2H, or -CF3.

[0017] Furthermore, in the ring system One of the following:

[0018]

[0019] R1 is an H, C1-C3 alkane, or a short-chain haloalkane.

[0020] Furthermore, the six-membered or seven-membered rings composed of X, Y, Z, and Q, and the structures formed with R2 and R3, are selected from any one of the following groups:

[0021]

[0022] R2 and R3 are hydrogen, halogens, -CN, -OCH3, -OCF3, C1-C3 alkanes, or haloalkanes.

[0023] A second objective of this invention is to provide compounds as shown below, or pharmaceutically acceptable salts, hydrates, and / or solvates thereof.

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032] A third objective of this invention is to provide a pharmaceutical composition comprising an effective amount of an active ingredient and pharmaceutically acceptable excipients; the active ingredient comprising the aforementioned compound, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof. In the pharmaceutical composition, the excipients comprise pharmaceutically acceptable carriers, diluents, and / or excipients.

[0033] A fourth object of the present invention is to provide the use of the above-mentioned compound, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, or the above-mentioned pharmaceutical composition, in the preparation of a medicament antagonizing the arginine vasopressin receptor. The arginine vasopressin receptor is subtype 1a and / or 2.

[0034] A fifth objective of this invention is to provide the use of the above-mentioned compounds, stereoisomers, or pharmaceutically acceptable salts or pharmaceutically acceptable pharmaceutical compositions thereof in the preparation of a medicament for treating 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. Preferably, it is heart failure. Detailed Implementation

[0035] The preferred embodiments of the present invention will now be described in detail with reference to specific examples. It should be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from its spirit and essence.

[0036] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0037] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0038] The key intermediates involved in the following embodiments are synthesized as follows:

[0039] 1. Synthesis of (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0040]

[0041] Step 1. Ethyl glycine (2-(4-chlorobenzoyl)hydrazine-1-carbonyl)

[0042]

[0043] A solution of ethyl 2-isocyanate acetate (7.6 g, 0.059 mol) in tetrahydrofuran (THF, 100 mL) was added to a solution of 4-chlorophenylhydrazine amide (10 g, 0.059 mol) in tetrahydrofuran (THF, 100 mL). The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was cooled and filtered. The filter cake was collected and used directly for the next step.

[0044] LCMS: 300.1 (M+H) +

[0045] Step 2. 2-(3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)acetic acid

[0046]

[0047] Sodium hydroxide (10 g, 0.25 mol) was added to a solution of compounds 1-2 (15 g, 0.05 mol) in water (100 mL). The reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled and the pH was adjusted to 1 with 2N HCl. The solution was filtered. The filter cake was collected and used directly for the next step.

[0048] LCMS: 254.0 (M+H) +

[0049] Step 3. 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0050]

[0051] Trifluoroacetic anhydride (TFAA, 41.38 g, 0.197 mol) was added to a solution of compounds 1-3 (10 g, 0.039 mol) in pyridine (300 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated. Water (500 mL) was added to the residue, and the mixture was extracted three times with ethyl acetate (EA, 500 mL). The organic layers were combined, concentrated, and purified by silica gel column chromatography to give compound 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (4.4 g, 37% yield) as a white solid.

[0052] LCMS: 306.0 (M+H) +

[0053] Step 4. (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0054]

[0055] To a solution of compounds 1-4 (2 g, 0.0065 mol) in N,N-dimethylacetamide (DMA, 20 mL), [(1S,2S)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylhydrazide ruthenium chloride (1+), 1-methyl-4-isopropylbenzene (0.14 g, 0.00065 mol), formic acid (1.5 g, 0.0325 mol), and triethylamine (TEA, 0.53 g, 0.0052 mol) were added. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography to give compound (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.5 g, 70% yield) as a yellow solid.

[0056] LCMS: 308.0 (M+H) +

[0057] 2. Synthesis of 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0058]

[0059] Step 1. 4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0060]

[0061] 2,4-Dihydro-1,2,4-triazol-3-one (76.0 g, 0.893 mol), 2-(trifluoromethyl)ethylene oxide (100.1 g, 0.893 mol), and K₂CO₃ (370.4 g, 2.68 mol) were stirred in DMF (600 mL) and reacted at 80 °C for 4 h. After cooling, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (180.0 g, crude product) as a yellow oil.

[0062] MS(ESI)m / z 198[M+H] + .

[0063] Step 2. Tert-butyl 4-(2-((tert-butoxycarbonyl)oxy)-3,3,3-trifluoropropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylic acid ester

[0064]

[0065] Boc₂O (438.4 g, 2.02 mol) was added dropwise to a solution of 4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (180.0 g, 0.913 mol), DMAP (11.1 g, 0.091 mol), and TEA (277.2 g, 2.73 mol) in DCM (1000 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with water (1 L) and extracted with DCM (500 mL × 3 times). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 5:1) to give tert-butyl 4-(2-((tert-butoxycarbonyl)oxy)-3,3,3-trifluoropropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylic acid ester (108 g, 26%) as a yellow oil.

[0066] MS(ESI)m / z 398[M+H] +

[0067] Step 3. 4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0068]

[0069] 103.0 g (0.259 mol) of tert-butyl 4-(2-{[(tert-butoxy)carbonyl]oxy}-3,3,3-trifluoropropyl)-5-oxo-1,2,4-triazol-1-carboxylic acid ester was dissolved in DCM / TFA (1000 mL / 500 mL) and stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was added to water (300 mL) and the pH was adjusted to 8 with aqueous NaOH solution. This mixture was used directly for the next step without further purification.

[0070] MS(ESI)m / z 198[M+H] +

[0071] Step 4. 5-Bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0072]

[0073] Br2 (64.8 g, 0.405 mol) was added dropwise to a solution of NaOH (22.7 g, 0.568 mol) in water (800 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was extracted with EtOAc (500 mL × 3 times). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 1:1) to give 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (34.5 g, 27%) as a white solid.

[0074] MS(ESI)m / z 276[M+H] +

[0075] Step 5. Tert-butyl 3-bromo-4-(2-((tert-butoxycarbonyl)oxy)-3,3,3-trifluoropropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylic acid ester

[0076]

[0077] To a solution of 5-bromo-4-(3,3,3-trifluoro-2-hydroxypropyl)-2H-1,2,4-triazol-3-one (20.0 g, 72 mmol), DMAP (0.89 g, 7 mmol), and TEA (22 g, 0.217 mol) in DCM (300 mL), Boc₂O (34.8 g, 0.159 mol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with water (500 mL) and extracted with DCM (500 mL × 3 times). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 10:1) to give tert-butyl 3-bromo-4-(2-((tert-butoxycarbonyl)oxy)-3,3,3-trifluoropropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylic acid ester (27.5 g, 71%) as a yellow oil.

[0078] MS(ESI)m / z 476[M+H] +

[0079] Step 6. Tert-butyl 4-(2-((tert-butoxycarbonyl)oxy)-3,3,3-trifluoropropyl)-3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylic acid ester

[0080]

[0081] 20.0 g (42 mmol) of tert-butyl-3-bromo-4-(2-{[(tert-butoxy)carbonyl]oxy}-3,3,3-trifluoropropyl)-5-oxo-1,2,4-triazol-1-carboxylic acid ester, 7.88 g (50 mmol) of (4-chlorophenyl)borate pinacol ester, 3.05 g (4 mmol) of Pd(dppf)Cl2, and 17.4 g (0.126 mol) of K2CO3 were stirred in dioxane / H2O (200 mL / 50 mL) under nitrogen protection and reacted at 100 °C for 2 h. After cooling, the reaction was quenched with water (200 mL) and extracted with EtOAc (200 mL × 3 times). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 1:1) to give tert-butyl 4-(2-((tert-butoxycarbonyl)oxy)-3,3,3-trifluoropropyl)-3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylic acid ester (20 g, 84%) as a yellow oil.

[0082] MS(ESI)m / z 508[M+H] +

[0083] Step 7. 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0084]

[0085] 20.0 g (39 mmol) of tert-butyl 4-(2-{[(tert-butoxy)carbonyl]oxy}-3,3,3-trifluoropropyl)-3-(4-chlorophenyl)-5-oxo-1,2,4-triazol-1-carboxylic acid ester was dissolved in DCM / TFA (200 mL / 40 mL) and stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The reaction was quenched with 100 mL of NaHCO3 aqueous solution and extracted with EtOAc (100 mL × 3 times). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 1:1) to give 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.0 g, 74%) as a yellow solid.

[0086] MS(ESI)m / z 308[M+H] +

[0087] Example 1

[0088] 2-((4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0089]

[0090] Step 1. 2-(2-Aminophenoxy)acetonitrile

[0091] A mixture of 2-aminophenol (5 g, 45.8 mmol), 2-chloroacetonitrile (4.15 g, 54.9 mmol), and K₂CO₃ (9.48 g, 68.7 mmol) in acetone (30 mL) was stirred at 60 °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 PE / EA = 3:1 silica gel column to give 2-(2-aminophenoxy)acetonitrile (5.5 g, 69%) as a brown solid.

[0092] MS(ESI) m / z 149.0 [M+H] +

[0093] Step 2. Methyl (E)-2-chloro-2-((2-(cyanomethoxy)phenyl)azo)acetate

[0094] A solution of NaNO2 (930 mg, 13.5 mmol) in H2O (20 mL) was added dropwise to a mixture of 2-(2-aminophenoxy)acetonitrile (2 g, 13.5 mmol) in 0.5 N HCl (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Then, NaOAc (2.21 g, 27 mmol) was added, followed by a solution of methyl 2-chloro-3-oxobutyrate (2.03 g, 13.5 mmol) in MeOH (20 mL) at 0 °C. 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. Purification was performed by column chromatography at PE / EA = 5:1 to give methyl (E)-2-chloro-2-((2-(cyanomethoxy)phenyl)azo)acetate (3 g, 70%) as a brown solid.

[0095] MS(ESI) m / z 268.0 [M+H] +

[0096] Step 3. 4H-Benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylic acid methyl ester

[0097] A mixture of methyl 2-chloro-2-[(E)-2-[2-(cyanomethoxy)phenyl]azo-1-yl]acetate (1 g, 3.7 mmol), TEA (1.49 g, 14.8 mmol), and toluene (20 mL) was stirred at 100 °C for 5 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 by column chromatography with PE / EA = 2:1 to give methyl 4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylic acid (330 mg, 34%) as a yellow solid.

[0098] MS(ESI) m / z 232.0 [M+H] +

[0099] Step 4. (4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methanol

[0100] In a 12 mL THF / MeOH mixture, 162 mg (4.28 mmol) of NaBH4 and 330 mg (1.42 mmol) of 4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-carboxylic acid methyl ester 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 was performed by column chromatography at PE / EA = 1:1 to give (4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methanol (200 mg, 62%) as a yellow oil.

[0101] MS(ESI) m / z 204.0 [M+H] +

[0102] Step 5. (4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl methanesulfonate

[0103] At 0 °C, MsCl (112 mg, 0.98 mmol) was added to a solution of (4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methanol (100 mg, 0.49 mmol) and DIEA (190 mg, 1.47 mmol) in DCM (10 mL). 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 (4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl methanesulfonate (150 mg, 46%) as a yellow oil.

[0104] MS(ESI) m / z 282.0 [M+H] +

[0105] Step 6. 2-((4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0106] 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.32 mmol), (4H-benzo[b][1,2,4]triazol[1,5-d][1,4]oxazin-2-yl)methyl methanesulfonate (109 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. The reactants (NH4HCO3) were purified by HPLC to give 2-((4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (87.6 mg, 51%), as a grayish-white solid.

[0107] MS(ESI) m / z 493.0 [M+H] +

[0108] 1 H NMR (400MHz, DMSO-d6) δ7.75 (d, J=8.8Hz, 2H), 7.67-7.60 (m, 3H), 7.29-7.25 (m, 1H), 7.19-7.15 (m, 2H), 6.91 (d, J=6. 0Hz, 1H), 5.55 (s, 2H), 5.14 (s, 2H), 4.31 (brs, 1H), 4.01 (dd, J=3.2Hz, 14.8Hz, 1H), 3.85 (dd, J=14.4Hz, 14.8Hz, 1H).

[0109] Example 2

[0110] 2-((4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0111]

[0112] Starting with 2-amino-4-fluorophenol, 5-(4-chlorophenyl)-2-((8-fluoro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one was synthesized as a grayish-white solid (61.1 mg, 46%) according to the synthesis method of Example 1.

[0113] MS(ESI)m / z 511[M+H] +

[0114] 1 H NMR(500MHz,Chloroform-d)δ7.66–7.60(m,2H),7.52–7.46(m,2H),7.11–7.02(m,2H),6.86(dd,J=8.3,4.6Hz,1H), 5.20(s,2H),5.03(qdt,J=12.2,8.2,7.3Hz,1H),4.59(s,2H),3.63(dq,J=8.3,3.6Hz,1H),3.19(m,1H),2.94(m,1H).

[0115] Example 3

[0116] 2-((8-chloro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0117]

[0118] Starting with 2-amino-4-chlorophenol, 2-((8-chloro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one was synthesized as a white solid (30.2 mg, purity 98%, yield 14%) according to the synthesis method in Example 1.

[0119] MS(ESI) m / z 527.0 [M+H] +

[0120] 1H NMR (400MHz, DMSO-d6) δ7.75 (d, J=8.6Hz, 2H), 7.67-7.56 (m, 3H), 7.32 (dd, J=8.7, 2.5Hz, 1H), 7.21 (d, J=8.7Hz, 1H), 6.91 (s, 1H), 5.58 (s, 2H), 5.14 (s, 2H), 4.40-4.24 (m, 1H), 4.01 (dd, J=14.6, 3.5Hz, 1H), 3.86 (dd, J=14.6, 9.5Hz, 1H).

[0121] Example 4

[0122] 5-(4-Chlorophenyl)-2-((8-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0123]

[0124]

[0125] Starting with 2-amino-4-methylphenol, 5-(4-chlorophenyl)-2-((8-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-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 (12.6 mg, 12.6% yield) according to the synthesis method of Example 1.

[0126] MS(ESI) m / z 507.2 [M+H] +

[0127] 1 H NMR (400MHz, DMSO-d6) δ7.79-7.70 (m, 2H), 7.65-7.56 (m, 2H), 7.49 (s, 1H), 7.11-7.01 (m, 2H), 6.91 (d, J=6.4Hz, 1H ), 5.50 (s, 2H), 5.13 (s, 2H), 4.30 (s, 1H), 4.01 (dd, J=14.5, 3.3Hz, 1H), 3.85 (dd, J=14.6, 9.5Hz, 1H), 2.32 (s, 3H).

[0128] Example 5

[0129] 5-(4-Chlorophenyl)-2-((7-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0130]

[0131] Starting with 2-amino-5-methylphenol, 5-(4-chlorophenyl)-2-((7-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-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 (57.7 mg, purity 98%, yield 25%) according to the synthesis method in Example 1.

[0132] MS(ESI) m / z 507.0 [M+H] +

[0133] 1 H NMR (400MHz, DMSO-d6) δ7.75(d,J=8.5Hz,2H),7.61(d,J=8.5Hz,2H),7.53(d,J=8.0Hz,1H),7.01(s,1H),6.98(d,J=8.3Hz,1H),6.92( d,J=6.1Hz,1H),5.51(s,2H),5.12(s,2H),4.38-4.23(m,1H),4.00(dd,J=14.5,3.1Hz,1H),3.85(dd,J=14.5,9.6Hz,1H),2.30(s,3H).

[0134] Example 6

[0135] (S)-5-(4-chlorophenyl)-2-((8-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0136]

[0137] Starting with 2-amino-4-methylphenol, the product was synthesized according to the method described in Example 1 to obtain (S)-5-(4-chlorophenyl)-2-(8-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (37.4 mg, yield 12.5%), which was a white solid.

[0138] MS(ESI) m / z 507.1 [M+H] +

[0139] 1 H NMR (400MHz, DMSO-d6) δ7.83-7.68(m,2H),7.66-7.59(m,2H),7.49(s,1H),7.11-7.01(m,2H),6.91(d,J=6.4Hz,1H),5. 50(s,2H),5.13(s,2H),4.33(t,J=15.8Hz,1H),4.01(dd,J=14.6,3.4Hz,1H),3.85(dd,J=14.6,9.6Hz,1H),2.32(s,3H).

[0140] Example 7

[0141] 5-(4-Chlorophenyl)-2-[(8-ethyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0142]

[0143]

[0144] Starting with 2-amino-4-ethylphenol, 5-(4-chlorophenyl)-2-[(8-ethyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (52 mg, yield 17.3%) was synthesized according to the synthesis method of Example 1, and was obtained as a white solid.

[0145] MS(ESI) m / z 521.1 [M+H] +

[0146] 1H NMR(500MHz,Chloroform-d)δ7.64–7.56(m,6H),7.49–7.43(m,2H),7.34(dt,J=2.3,0.9Hz,2H),7.25–7.19(m,2H),6.86(d,J=8.2Hz,2H),5. 28(s,3H),5.13(m,2H),4.39(s,3H),3.61(dq,J=8.3,3.5Hz,2H),3.29 (m,2H),2.95–2.85(m,3H),2.89–2.82(m,3H),1.38(d,J=14.4Hz,3H).

[0147] Example 8

[0148] 5-(4-Chlorophenyl)-2-[(8-ethyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0149]

[0150] Starting with 2-amino-4-(prop-2-yl)phenol, 5-(4-chlorophenyl)-2-[(8-ethyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (36.9 mg, yield 13.1%) was synthesized according to the synthesis method in Example 1, and was obtained as a white solid.

[0151] MS(ESI) m / z 535.1 [M+H] +

[0152] 1 H NMR(500MHz,Chloroform-d)δ7.62(dd,J=8.3,1.5Hz,1H),7.53(dd,J=8.3,1.5Hz,1H),7.45(m,2H),7.33–7.29(m,1H),7.00(m,1H),6.72(d,J=7 .0Hz,1H),5.38(s,2H),5.33(m,1H),4.63(s,1H),3.43(dq,J=8.3,3.6Hz ,1H),3.33–3.17(m,2H),2.68–2.60(m,1H),1.38(dd,J=6.6,5.0Hz,6H).

[0153] Example 9

[0154] (S)-5-(4-chlorophenyl)-2-((8-difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0155]

[0156] Step 1. 2-(2-amino-4-bromophenoxy)acetonitrile

[0157] Potassium carbonate (1.33 g, 0.01 mol) was added to a solution of 2-amino-4-bromophenol (1.2 g, 0.006 mol) and 2-chloroacetonitrile (0.58 g, 0.007 mol) in acetonitrile (20 mL). The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 3). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography to give 2-(2-amino-4-bromophenoxy)acetonitrile (1.0 g, yield 21%), a yellow solid.

[0158] MS(ESI) m / z 227.0 [M+H] + .

[0159] Step 2. Methyl (E)-2-((5-bromo-2-(cyanomethoxy)phenyl)azo)-2-chloroacetate

[0160] At 0°C, a solution of 2-(2-amino-4-bromophenoxy)acetonitrile (850 mg, 3.7 mmol) in 0.5 N HCl (25 mL) was added dropwise to a solution of NaNO2 (232 mg, 3.4 mol) in H2O (10 mL). The reaction mixture was stirred at 0°C for 10 min, and then NaOAc (614 mg, 7.5 mmol) was added. A solution of methyl 2-chloro-3-oxobutyrate (563 mg, 3.8 mmol) in MeOH (10 mL) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 12 h. H2O (50 mL) was added to the reaction mixture, and the mixture was extracted twice with EA (50 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (PE / EA = 3:1) to give methyl 2-[(E)-2-[5-bromo-2-(cyanomethoxy)phenyl]azo-1-yl]-2-chloroacetate (1.0 g, yield 69%), as a yellow solid.

[0161] MS(ESI) m / z 346.1 [M+H] +

[0162] Step 3. Methyl 8-bromo-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate was added to a solution of methyl 2-[(E)-2-[5-bromo-2-(cyanomethoxy)phenyl]azo-1-yl]-2-chloroacetate (900 mg, 2.6 mmol) in toluene (30 mL). Triethylamine (1.05 g, 10.3 mmol) was added. The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was cooled and concentrated. The concentrate was purified by silica gel column chromatography to give methyl 8-bromo-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate (600 mg, yield 67%) as a yellow solid.

[0163] MS(ESI) m / z 310.1 [M+H] +

[0164] Step 4. Methyl 8-vinyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate

[0165] To a solution of methyl 8-bromo-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate (500 mg, 1.6 mmol), XPhosPdG2 (130 mg, 0.16 mmol), and tripotassium phosphate (850 mg, 4.0 mmol) in dioxane / water (20 mL / 4 mL), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxoborane (990 mg, 6.4 mmol) was added. The mixture was stirred at 80 °C under N2 for 12 h. The reaction system was cooled, quenched with water (50 mL), and extracted with DCM (50 mL * 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give methyl 8-vinyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylic acid (350 mg, yield 76%) as a yellow solid.

[0166] MS(ESI) m / z 258.1 [M+H] +

[0167] Step 5. Methyl 8-formyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate

[0168] At 0 °C, K₂O₄⁻ 2H₂O (44 mg, 0.12 mmol) was added to a THF / H₂O (10 mL / 2.5 mL) solution of methyl 8-vinyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate (310 mg, 1.2 mmol). The reaction mixture was stirred at 0 °C for 10 min. NaIO₄ (773 mg, 3.6 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was cooled, washed with H₂O (50 mL * 3), and extracted with EA (50 mL * 3). The organic phases were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 3:1) to give methyl 8-formyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylic acid (90 mg, yield 27%), as a white solid.

[0169] MS(ESI) m / z 260.1 [M+H] +

[0170] Step 6. 8-(difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylic acid methyl ester

[0171] A solution of methyl 8-formyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate (50 mg, 0.20 mmol) in BAST (2.0 mL) was stirred at 25 °C for 12 h. The reaction system was cooled, washed with water (50 mL x 3), and then extracted with EA (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (PE:EA = 1:1) to give methyl 8-(difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate (40 mg, yield 65%) as a yellow oil.

[0172] MS(ESI) m / z 282.1 [M+H] +

[0173] Step 7. (8-(difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methanol

[0174] Methyl 8-(difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-carboxylic acid (40 mg, 0.14 mmol) was added to a MeOH / THF (1:1, 6.0 mL) solution with NaBH4 (27 mg, 0.7 mmol), and stirred at 25 °C for 12 h. The reaction system was cooled, washed with H2O (50 mL * 3), and then extracted with EA (50 mL * 3). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. (8-(difluoromethyl)-4H-benzo[b][1,24]azolo[1,5-d][1,4]oxazin-2-yl)methanol (35 mg, yield 87%) was given as a white solid.

[0175] MS(ESI) m / z 254.1 [M+H] +

[0176] Step 8. (8-(difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl methanesulfonate

[0177] Methanesulfonyl chloride (36 mg, 0.3 mmol) was added to a DCM solution of (8-(difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methanol (35 mg, 0.14 mmol) and TEA (17 mg, 0.5 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was cooled, washed with water (50 mL x 3), and extracted with EA (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. Methyl (8-(difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methylmethanesulfonate (35 mg, yield 46%) was obtained as a yellow oil.

[0178] MS(ESI) m / z 332.1 [M+H] +

[0179] Step 9. (S)-5-(4-chlorophenyl)-2-((8-(difluoromethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d]

[14] oxo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0180] To a solution of (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (30 mg, 0.1 mmol) and potassium carbonate (34 mg, 0.24 mmol) in DMF (3 mL), add (8-(difluoromethyl)-4H-benzo[b][1,2,4]triazol[1,5-d][1,4]oxazin-2-yl)methylmethanesulfonate (32 mg, 0.1 mmol) and stir at 50 °C for 10 hours. Cool the reaction mixture, wash with water (50 mL x 3), and extract with EA (50 mL x 3). Combine the organic phases, wash with brine, dry to anhydrous Na₂SO₄, filter, and concentrate. The concentrate was purified by Prep-HPLC to give (S)-5-(4-chlorophenyl)-2-(8-(difluoromethyl)-4H-benzo[b][1,2,4]triazol[1,5-d][1,4]oxo-2-yl)methyl)-4-(3,3,3-trifluoro-2-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5.3 mg, yield 4.7%), as a white solid.

[0181] MS(ESI) m / z 543.0 [M+H] +

[0182] 1 H NMR (400MHz, DMSO-d6) δ7.83(s,1H),7.75(d,J=8.6Hz,2H),7.61(d,J=8.6Hz,2H),7.48(d,J=8.4Hz,1H),7.30(d,J=8.4Hz,1H ),7.23-6.86(m,2H),5.63(s,2H),5.14(s,2H),4.34-4.26(m,1H),4.01(dd,J=14.6,3.6Hz,1H),3.86(dd,J=4.6,9.4Hz,1H).

[0183] Example 10

[0184] (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-((8-trifluoromethyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0185]

[0186] Starting with 2-amino-4-trifluoromethylphenol, the product was synthesized according to the method in Example 1 to obtain (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-((8-(trifluoromethyl)-4H-benzo[b][1,24]triazolo[1,5-d][1,4]oxazin-2-2yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (38 mg, yield 10%), a white solid.

[0187] MS(ESI) m / z 561.1 [M+H] +

[0188] 1 H NMR (400MHz, DMSO-d6) δ7.85(d,J=2.0Hz,1H),7.77-7.70(m,2H),7.68-7.59(m,3H),7.37(d,J=8.6Hz,1H),6.92(s,1H ), 5.66 (d, J = 18.8Hz, 2H), 5.16 (s, 2H), 4.35-4.25 (m, 1H), 4.01 (dd, J = 14.6, 3.6Hz, 1H), 3.86 (dd, J = 14.6, 9.4Hz, 1H).

[0189] Example 11

[0190] 5-(4-Chlorophenyl)-2-[(8-methoxy-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0191]

[0192] Starting with 2-amino-4-methoxyphenol, 5-(4-chlorophenyl)-2-[(8-methoxy-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (46 mg, yield 11%) was synthesized according to the method in Example 1, and was a white solid.

[0193] MS(ESI) m / z 523.1 [M+H] +

[0194] 1H NMR(500MHz,Chloroform-d)δ7.65–7.59(m,2H),7.56–7.47(m,2H),7.51–7.45(m,2H),7.01(d,J=2.2Hz,2H),6.96(d,J=8.5Hz,2H),6.76 (dd,J=8.4,2.2Hz,2H),5.30(s,3H),5.13(m,2H),4.19(s,3H),3.88(s,4H),3.66(dq,J=8.2,3.5Hz,2H),3.29(m,2H),3.00–2.92(m,2H).

[0195] Example 12

[0196] 5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({8-[(trifluoromethyl)oxy]-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl}methyl)-2H,3H,4H-1,2,4-triazol-3-one

[0197]

[0198] Starting with 2-amino-4-[(trifluoromethyl)oxy]phenol, 5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({8-[(trifluoromethyl)oxy]-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl}methyl)-2H,3H,4H-1,2,4-triazol-3-one (33 mg, yield 13.8%) was synthesized according to the method in Example 1, and was obtained as a white solid.

[0199] MS(ESI) m / z 577.1 [M+H] +

[0200] 1 H NMR(500MHz,Chloroform-d)δ7.67(m,2H),7.45(dt,J=8.0,0.6Hz,2H),7.15(s,0H),6.85–6.75(m, 2H), 5.23 (m, 1H), 5.18 (s, 1H), 4.56 (s, 1H), 3.73 (dq, J = 8.2, 3.6Hz, 1H), 3.15 (m, 1H), 2.92 (m, 1H).

[0201] Example 13

[0202] 2-[(7-chloro-8-methoxy-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0203]

[0204] Starting with 2-amino-5-chloro-4-methoxyphenol, 2-[(7-chloro-8-methoxy-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (22.7 mg, yield 8.2%) was synthesized according to the method in Example 1, and was obtained as a white solid.

[0205] MS(ESI) m / z 557.1 [M+H] +

[0206] 1 H NMR(500MHz,Chloroform-d)δ7.72–7.66(m,2H),7.62–7.56(m,2H),7.11(s,1H),5.26(s,1H),5.13(qdt, J=12.2,8.2,7.3Hz,1H),4.39(s,1H),3.77(s,2H),3.53(dq,J=8.2,3.6Hz,1H),3.39m,1H),2.54(m,1H).

[0207] Example 14

[0208] 5-(4-Chlorophenyl)-2-[(8-fluoro-7-methoxy-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0209]

[0210] Starting with 2-amino-4-fluoro-5-methoxyphenol, 5-(4-chlorophenyl)-2-[(8-fluoro-7-methoxy-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (18.2 mg, yield 9.1%) was synthesized according to the method in Example 1, and was obtained as a white solid.

[0211] MS(ESI) m / z 541.1 [M+H] +

[0212] 1 H NMR(500MHz,Chloroform-d)δ7.69(ddt,J=8.3,1.5,0.6Hz,1H),7.53(ddt,J=8.2 ,1.4,0.7Hz,1H),7.29(dt,J=8.2,0.7Hz,1H),6.68(d,J=4.3Hz,1H),5.38(s,1H) ,5.23(qdt,J=12.2,8.2,7.3Hz,1H),4.44(s,1H),3.83(s,2H),3.73(dq,J=8.2,3 .6Hz, 1H), 3.29 (ddq, J=10.6, 7.1, 2.3Hz, 1H), 2.99 (ddq, J=10.6, 7.3, 2.2Hz, 1H).

[0213] Example 15

[0214] 5-(4-Chlorophenyl)-2-[(7,8-dimethyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0215]

[0216] Starting with 2-amino-4,5-dimethylphenol, 5-(4-chlorophenyl)-2-[(7,8-dimethyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (15 mg, yield 11.5%) was synthesized according to the method in Example 1, and was obtained as a white solid.

[0217] MS(ESI) m / z 521.1 [M+H] +

[0218] 1 H NMR(500MHz,Chloroform-d)δ7.83(m,1H),7.75(m,1H),7.51(dt,J=8.2,0.7Hz,2H),7.26(d,J=0.6Hz,1H),6.93(q,J=0.5H z,1H),5.28(s,1H),5.11(m,1H),4.47(s,1H),3.71(dq,J=8.2,3.5Hz,1H),3.16(m,1H),2.88(m,1H),2.53(d,J=0.5Hz,2H).

[0219] Example 16

[0220] (S)-5-(4-chlorophenyl)-2-((7-fluoro-8-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0221]

[0222] Starting with 5-fluoro-4-methyl-2-nitrophenol, the product was synthesized according to the method in Example 1 to obtain (S)-5-(4-chlorophenyl)-2-((7-fluoro-8-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (52 mg, yield 41%), a white solid.

[0223] MS(ESI) m / z 525.1 [M+H] +

[0224] 1 H NMR (400MHz, DMSO-d6) δ7.80-7.69(m,2H),7.64-7.56(m,3H),7.08(t,J=11.3Hz,1H),6.93(s,1H),5.55(s,2H),5 .12(s,2H),4.36-4.25(m,1H),4.01(dd,J=14.6,3.4Hz,1H),3.85(dd,J=14.6,9.5Hz,1H),2.24(d,J=1.7Hz,3H).

[0225] Example 18

[0226] (S)-2-((9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinolin-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0227]

[0228]

[0229] Step 1. Methyl (E)-5-chloro-2-(2-ethoxyvinyl)benzoate

[0230] A mixture of methyl 2-bromo-5-chlorobenzoate (4.0 g, 0.016 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxoborane (1.12 g, 0.016 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (38.11 mg, 0.052 mmol), and K₂CO₃ (4.42 g, 0.032 mmol) was stirred at 80 °C under N₂ for 16 h. The reaction mixture was cooled, quenched with water (50 mL), and extracted with EA (50 mL x 2). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give methyl (E)-5-chloro-2-(2-ethoxyvinyl)benzoate (3.1 g, 64.38% yield) as a pale yellow oil. MS(ESI)m / z 241[M+H] +

[0231] Step 2. Methyl 5-chloro-2-(2-oxoethyl)benzoate

[0232] HCOOH (3 mL) was added to a DCM (30 mL) solution of (E)-5-chloro-2-(2-ethoxyvinyl)benzoate (2.3 g, 9.58 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give methyl 5-chloro-2-(2-oxoethyl)benzoate (1.0 g, 50% yield) as a yellow oil.

[0233] MS(ESI) m / z 213.0 [M+H] +

[0234] Step 3. (7-Chloro-1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)tert-butyl carbamate

[0235] AcOH (1 mL) was added to a solution of methyl-5-chloro-2-(2-oxoethyl) (1.0 g, 4.70 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Then, NaCNBH3 (592.6 mg, 9.40 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (50 mL x 2). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give tert-butyl (7-chloro-1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)carbamate (150 mg, 10% yield) as a white solid.

[0236] MS(ESI) m / z 297.1 [M+H] +

[0237] Step 4. 2-Amino-7-chloro-3,4-dihydroisoquinoline-1(2H)-one

[0238] A solution of (7-chloro-1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)carbamate tert-butyl ester (150 mg, 0.50 mmol)) in HCl / EtOH (10 mL, 2 M) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under vacuum to give crude 2-amino-7-chloro-3,4-dihydroisoquinoline-1(2H)-one (85 mg, 76.95% yield) as a white solid, which was used directly for the next step. MS (ESI) m / z 197.1 [M+H] +

[0239] Step 5. Ethyl 9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-A]isoquinoline-2-carboxylate

[0240] A solution of 2-amino-7-chloro-3,4-dihydroisoquinoline-1(2H)-one (85 mg, 0.43 mmol) and ethyl 2-amino-2-thioethyl (115.14 mg, 0.86 mmol) in AcOH / Tol (1.0 mL / 10 mL) was stirred with a molecular sieve at 110 °C for 12 h. The reaction mixture was cooled to room temperature, filtered, and concentrated. The residue was diluted with EA (50 mL), washed with saturated NaHCO3 (30 mL) and brine (30 mL), and the washes were combined. The residue was purified by silica gel column chromatography (EA / PE = 1 / 5) to give ethyl 9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-carboxylate (70 mg, 49.5% yield) as a pale yellow solid.

[0241] MS(ESI) m / z 278.1 [M+H] +

[0242] Step 6. (9-Chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-yl)methanol

[0243] 9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-carboxylic acid ester (70 mg, 0.25 mmol) and NaBH4 (48 mg, 1.26 mmol) were added to a THF / MeOH solution (10 mL) at 0 °C. 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 * 3). The combined organic layers were concentrated under vacuum to give crude product (9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-yl)methanol (40 mg, 67.7% yield) as a pale yellow oil, which could be used directly in the next step without purification.

[0244] MS(ESI) m / z 236.1 [M+H] +

[0245] Step 7. (9-Chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-yl)methyl methanesulfonate

[0246] TEA (34.28 mg, 0.33 mmol) and methanesulfonyl chloride (25.14 mg, 0.22 mmol) were added to a DCM (8 mL) solution of (9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-yl)methanol (40 mg, 0.16 mmol) at 0 °C. 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 2). The combined organic layers were concentrated under vacuum, and the crude (9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-yl)methylmethanesulfonate was used directly for the next step without purification.

[0247] MS(ESI) m / z 314.2 [M+H] +

[0248] Step 8. (S)-2-((9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0249] A solution of (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (35 mg, 0.11 mmol), (9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-yl)methyl methanesulfonate (42.85 mg, 0.13 mmol), and K₂CO₃ (31.46 mg, 0.22 mmol) in DMF (5 mL) was stirred at 50 °C for 16 hours. 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 (S)-2-((9-chloro-5,6-dihydro-[1,2,4]triazolo[5,1-a]isoquinoline-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (15.6 mg, 21.53% yield) as a white solid.

[0250] MS(ESI) m / z 525.1 [M+H] +

[0251] 1 H NMR (400MHz, DMSO) - d6)7.76–7.49(m,7H),6.91(s,1H),5.47(dd,J=5.0,3.1Hz,1H),4.42(s,2H),4. 01(t,J=14.6,3.5Hz,2H), 3.5(dd,J=5.1,3.0Hz,2H), 3.2(t,J=14.6,3.5Hz,2H).

[0252] Example 19

[0253] (S)-9-chloro-2-((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]triazolo[1,5-c]quinazolin-5(6H)-one

[0254]

[0255]

[0256] Step 1. Methyl (4-chloro-2-cyanophenyl)carbamate

[0257] Methyl chloroformate (1.34 mg, 14.4 mmol) was added to a solution of 2-butanone (50 mL) containing 2-amino-5-chlorobenzonitrile (2 g, 13.1 mmol) and NaHCO3 (1.3 g, 15.7 mmol). The reaction mixture was stirred at 80 °C for 12 h. Then, 2,2-difluoroethyltrifluoromethanesulfonate (2.5 g, 11.6 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was 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 silica gel column chromatography to give methyl (4-chloro-2-cyanophenyl)carbamate (0.7 g, 22% yield) as a white solid.

[0258] MS(ESI)m / z 211[M+H] +

[0259] Step 2. 9-Chloro-2-hydroxymethyl-[1,2,4]triazolo[1,5-C]quinazolin-5(6H)-one

[0260] Methyl (4-chloro-2-cyanophenyl)carbamate (200.0 mg, 0.95 mmol) and 2-hydroxyacetylhydrazine (102.7 mg, 1.14 mmol) were added to a 5 mL NMP solution and stirred at 200 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled and purified by silica gel column chromatography to give 9-chloro-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (200 mg, 80% yield) as a yellow solid.

[0261] MS(ESI)m / z 251[M+H] +

[0262] Step 3. To a solution of 9-chloro-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methylmethanesulfonate, DMAP (3.9 mg, 0.032 mmol) and DIEA (123.8 mg, 0.96 mmol) in DCM (1 mL) of MSCl (72.8 mg, 0.64 mmol) were added. The reaction mixture was stirred under nitrogen at room temperature for 2 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, and the crude product (9-chloro-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methanesulfonate was used directly in the next step without purification.

[0263] MS(ESI)m / z 329[M+H] +

[0264] Step 4. (S)-9-chloro-2-(3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one

[0265] A solution of (9-chloro-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methanesulfonate (70 mg, 0.21 mmol), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (65.5 mg, 0.21 mmol), and K₂CO₃ (58.9 mg, 0.43 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 phases were concentrated under vacuum. The residue was purified by high-performance liquid chromatography (HPLC) to give (S)-9-chloro-2-((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]triazolo[1,5-c]quinazolin-5(6H)-one (6.4 mg, 5% yield) as a white solid. MS (ESI) m / z 540 [M+H] +

[0266] 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.06(d,J=2.4Hz,1H),7.81-7.74(m,2H),7.71(dd,J=8.8,2.4Hz,1H),7.62(d,J=8.6H z,2H),6.96(d,J=6.4Hz,1H),5.25(s,2H),4.33(d,J=6.9Hz,1H),4.03(dd,J=14.6,3.2Hz,1H),3.87(dd,J=14.7,9.5Hz,1H).

[0267] Example 20

[0268] (S)-2-((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]triazolo[1,5-a]quinoxaline-4(5H)-one

[0269]

[0270] Step 1. Ethyl (Z)-2-chloro-2-(2-(2-nitrophenyl)hydrazine)ethyl acetate

[0271] A solution of NaNO2 (2.5 g, 36.2 mmol) in H2O (40 mL) was added dropwise to a mixture of 2-nitroaniline (5 g, 36.2 mmol) in 0.5 N HCl (100 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Then, NaOAc (5.94 g, 72.4 mmol) was added, followed by a solution of methyl 2-chloro-3-oxobutyrate (5.44 g, 36.2 mmol) in MeOH (40 mL) at 0 °C. 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. Purification was achieved by column chromatography at PE / EA = 5:1 to give ethyl (Z)-2-chloro-2-(2-(2-nitrophenyl)hydrazine)acetate (7 g, 71.2%) as a yellow solid.

[0272] MS(ESI) m / z 272.0 [M+H] +

[0273] Step 2. Ethyl 2-imino-2-(2-(2-nitrophenyl)hydrazino)ethyl acetate

[0274] Ethyl (Z)-2-chloro-2-(2-(2-nitrophenyl)hydrazinyl)acetate (7 g, 25.7 mmol) was dissolved in THF (40 mL), and then the solution was added to 7 M ammonia water (100 mL). The mixture was stirred for 1 h, and a precipitate was formed. The precipitate was filtered and dried to obtain ethyl 2-imino-2-(2-(2-nitrophenyl)hydrazinyl)acetate (6 g, 92%), which was a yellow solid.

[0275] Step 3. (Z)-2-(2-ethoxy-2-oxoacetamido)-2-(2-(2-nitrophenyl)hydrazine)ethyl acetate

[0276] Ethyl 2-imino-2-(2-(2-nitrophenyl)hydrazino)acetate (3 g, 11.9 mmol) and triethylamine (2.4 g, 23.8 mmol) were added to a solution in DCM (20 mL). Ethyl 2-chloro-2-oxoacetate (2.4 g, 17.85 mmol) was added to a solution in DCM (15 mL). The reaction mixture was stirred at room temperature for 6 hours at 0 °C. Rotary evaporation under reduced pressure yielded 7.6 g of a yellow oil (Z)-2-(2-ethoxy-2-oxoacetamido)-2-(2-(2-nitrophenyl)hydrazino)acetate, which was directly added to the next reaction without purification. MS (ESI) m / z 353.1 [M+H] +

[0277] Step 4. Diethyl 1-(2-nitrophenyl)-1H-1,2,4-triazole-3,5-dicarboxylic acid ester

[0278] The yellow oily substance obtained in the previous step was dissolved in toluene (40 mL), and then triethylamine (2.4 g, 23.8 mmol) and TsCl (2.27 g, 11.9 mmol) were added to the reaction mixture. The reaction mixture was heated to reflux and stirred for at least 8 hours. 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 PE / EA = 2:1 column chromatography to give diethyl 1-(2-nitrophenyl)-1H-1,2,4-triazol-3,5-dicarboxylic acid (1.43 g, 36%) as a yellow solid.

[0279] MS(ESI) m / z 334.1 [M+H] +

[0280] Step 5. Ethyl 4-oxo-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylate

[0281] Diethyl 1-(2-nitrophenyl)-1H-1,2,4-triazol-3,5-dicarboxylate (1.2 g, 3.6 mmol) was dissolved in acetic acid (20 mL), and iron powder (0.6 g, 10.8 mmol) was added. The mixture was heated at 90 °C for 1 h, the reaction mixture was cooled, filtered, and concentrated. Purification was performed by PE / EA = 2:1 column chromatography to give ethyl 4-oxo-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylate (789 mg, 85%) as a white solid.

[0282] MS(ESI) m / z 259.1 [M+H] +

[0283] Step 6. 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]quinoxaline-4(5H)-one

[0284] Ethyl 4-oxo-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid (500 mg, 1.94 mmol) was added to a THF / MeOH solution (5 mL / 1 mL) with NaBH4 (183 mg, 4.85 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 FCC (PE / EA = 1:1) to give 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]quinoxaline-4(5H)-one (138 mg, 33% yield) as a yellow oil.

[0285] MS(ESI) m / z 217.1 [M+H] +

[0286] Step 7. (4-oxo-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-2-yl)methyl methanesulfonate

[0287] MsCl (137.5 mg, 1.2 mmol) was added to a solution of 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]quinoxaline-4(5H)-one (130 mg, 0.6 mmol) and DIEA (232.7 mg, 1.8 mmol) in DCM (10 mL). The reaction mixture was stirred under nitrogen at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were concentrated under vacuum to give crude (4-oxo-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-2-yl)methanesulfonate, which could be used directly in the next step without purification.

[0288] MS(ESI) m / z 295.1 [M+H] +

[0289] Step 8. (S)-2-((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]triazolo[1,5-a]quinoxaline-4(5H)-one

[0290] A solution of (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (150 mg, 0.51 mmol), (5-(2-(2-(2-oxopyridin-1(2H)-yl)phenyl)-1,3,4-oxadiazol-2-yl)methylmethanesulfonate (175 mg, 0.51 mmol) and K2CO3 (141 mg, 1.02 mmol) in DMF (10 mL) was stirred at 50 °C. The reaction mixture was left overnight. It 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 HPLC to give (S)-2-((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]triazolo[1,5-a]quinoxaline-4(5H)-one (37.3 mg, 14.5% yield) as a gray solid.

[0291] MS(ESI) m / z 506.1 [M+H] +

[0292] 1 H NMR(500MHz,Chloroform-d)δ11.30(s,1H),7.66–7.56(m,3H),7.53–7.46(m,3H),7.44–7.38(m,1H),7.04(td,J=7.3 ,1.4Hz,1H),5.03(qdt,J=12.2,8.2,7.3Hz,1H),4.59(s,2H),3.63(dq,J=8.3,3.6Hz,1H),3.19(m,1H),2.94(m,1H).

[0293] Example 21

[0294] (S)-5-(4-chlorophenyl)-2-((5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0295]

[0296]

[0297] Step 1. 1-Bromo-2-(2-Bromoethoxy)benzene

[0298] In a solution of 2-bromophenol (2.0 g, 0.01 mol), Cs₂CO₃ (9.4 g, 0.03 mol) was added to a solution of 1,2-dibromoethane (8.7 g, 0.05 mol) in acetonitrile (100 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 10 h. The reaction mixture was cooled, quenched with water (100 mL), and extracted with EA (100 mL x 3). The combined organic layers were concentrated under vacuum to give crude 1-bromo-2-(2-bromoethoxy)benzene (1.1 g, 30% yield) as a yellow oil.

[0299] MS(ESI)m / z 279[M+H] +

[0300] Step 2. Ethyl 1-(2-(2-bromophenoxy)ethyl)-1H-1,2,4-triazole-3-carboxylic acid ester

[0301] K₂CO₃ (1.5 g, 10.8 mmol) was added to a solution of 1-bromo-2-(2-bromoethoxy)benzene (1.0 g, 3.6 mmol) and ethyl 1H-1,2,4-triazol-3-carboxylate (1.02 g, 7.2 mmol). The reaction mixture was stirred at 80 °C for 10 h. The reaction mixture was cooled, washed with H₂O (50 mL x 3), and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give ethyl 1-(2-(2-bromophenoxy)ethyl)-1H-1,2,4-triazol-3-carboxylate (0.3 g, 22% yield), a white solid.

[0302] MS(ESI) m / z 340.1 [M+H] +

[0303] Step 3. Ethyl 5,6-dihydrobenzo[F][1,2,4]triazolo[1,5-D][1,4]oxazolo-2-carboxylate

[0304] A solution of methyl 1-[2-(2-bromophenoxy)ethyl]-1,2,4-triazol-3-carboxylate (260 mg, 0.8 mmol), palladium diacetate (34 mg, 0.16 mmol), and PCy3 was prepared. HBF4 (880 mg, 2.4 mmol) and KOAc (470 mg, 4.8 mmol) were added to DMF (2 mL). The reaction mixture was stirred at 130 °C under N2 for 12 h. The reaction mixture was cooled, quenched with H2O, and extracted with EA (50 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a yellow oil, ethyl 5,6-dihydrobenzo[F][1,2,4]triazol[1,5-D][1,4]oxazolomide-2-carboxylate (200 mg, 92% yield).

[0305] MS(ESI) m / z 260.1 [M+H] +

[0306] Step 4. (5,6-Dihydrobenzo[F][1,2,4]triazolo[1,5-D][1,4]oxazolo-2-yl)methanol

[0307] A solution of ethyl 5,6-dihydrobenzo[F][1,2,4]triazolo[1,5-D][1,4]oxazolo-2-carboxylate (95 mg, 0.3235 mmol) in THF / MeOH (1:1, 5 mL) and sodium borohydride (36.72 mg, 0.9705 mmol) was stirred at 15 °C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL * 2). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to give a yellow oily crude product (5,6-dihydrobenzo[F][1,2,4]triazolo[1,5-D][1,4]oxazolo-2-yl)methanol (90 mg, 99% yield).

[0308] MS(ESI) m / z 218.1 [M+H] +

[0309] Step 5. (5,6-Dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methylmethanesulfonate

[0310] MsCl (63 mg, 0.55 mmol) was added to a DCM (5 mL) solution of (5,6-dihydrobenzo[F][1,2,4]triazolo[1,5-D][1,4]oxazolo-2-yl)methanol (80 mg, 0.37 mmol) and TEA (93 mg, 0.92 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with H2O and extracted with EA (80 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give a yellow oil (5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methylmethanesulfonate (120 mg, >100% yield).

[0311] MS(ESI) m / z 296.0 [M+H] +

[0312] Step 6. (S)-5-(4-chlorophenyl)-2-((5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0313] In a DMF (5 mL) solution of 9-oxa-3,5,6-triazatricyclo[8.4.0.0^{2,6}]tetradecane-1(14), 2,4,10,12-penten-4-ylmethylmethanesulfonate (120 mg, 0.4 mmol) and K₂CO₃ (117 mg, 0.85 mmol), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (104 mg, 0.34 mmol) was added at 25 °C. The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled, quenched with H₂O, and extracted with EA (80 mL * 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by Prep-HPLC to give (S)-5-(4-chlorophenyl)-2-((5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (8.7 mg, 4.8% yield), a white solid.

[0314] MS(ESI) m / z 507.1 [M+H] + .

[0315] 1H NMR (400MHz, DMSO-d6) δ8.31 (dd, J=8.0, 1.7Hz, 1H), 7.79-7.73 (m, 2H), 7.65-7.58 (m, 2H), 7.46-7.36 (m, 1H), 7.21-7.06 (m, 2H), 6.92 (s, 1H), 5.06 (d, J=16.1Hz, 2H), 4.61 (dd, J=5.1, 3.0Hz, 2H), 4.50 (dd, J=5.0, 3.1Hz, 2H), 4.31 (s, 1H), 4.01 (dd, J=14.6, 3.5Hz, 1H), 3.86 (f, J=14.7, 9.6Hz, 1H).

[0316] Example 22

[0317] (S)-5-(4-chlorophenyl)-2-((10-methyl-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0318]

[0319] Starting with 2-amino-4,5-dimethylphenol, the product was synthesized according to the method described in Example 21 to obtain (S)-5-(4-chlorophenyl)-2-(10-methyl-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d]14]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (35.7 mg, yield 21%), a white solid.

[0320] MS(ESI)m / z 521[M+H] +

[0321] 1 H NMR (400MHz, DMSO-d6)8.10(s,1H),7.76(d,J=2.4Hz,2H),7.23(dd,J=8.8,2.8Hz,2H),6.92(d,J=8.8Hz,1H),6.87-6 .82(m,2H),5.07(s,2H),4.9-4.52(m,4H),4.41(s,1H),4.02(dd,J=14.8,3.6Hz,1H),3.89-3.83(m,1H).2.49(s,3H).

[0322] Example 23

[0323] (S)-5-(4-chlorophenyl)-2-((10-fluoro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0324]

[0325] Starting with 2-bromo-4-fluorophenol, the product was synthesized according to the method described in Example 21 to obtain (S)-5-(4-chlorophenyl)-2-((10-fluoro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazono-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (23.4 mg, yield 28%), a white solid.

[0326] MS(ESI) m / z 525.1 [M+H] +

[0327] 1 H NMR (400MHz, DMSO-d6) δ7.96 (dd, J=9.9, 3.2Hz, 1H), 7.78-7.72 (m, 2H), 7.65-7.5 9(m,2H),7.30(ddd,J=9.0,7.5,3.3Hz,1H),7.15(dd,J=9.0,4.9Hz,1H),6.91(s,1 H),5.03(d,J=16.0Hz,2H),4.62(dd,J=5.1,3.0Hz,2H),4.51(dd,J=5.0,3.1Hz,2 H),4.35-4.25(m,1H),4.02(dd,J=14.6,3.6Hz,1H),3.86(dd,J=14.6,9.5Hz,1H).

[0328] Example 24

[0329] (S)-2-((10-chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0330]

[0331] Starting with 2-bromo-4-chlorophenol, (S)-2-((10-chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (35.7 mg, 21% yield) was synthesized as a white solid according to the synthesis method of Example 21.

[0332] MS(ESI)m / z 541[M+H] +

[0333] 1 H NMR (400MHz, DMSO-d6) δ8.24 (d, J=2.4Hz, 1H), 7.77-7.74 (m, 2H), 7.64-7.60 (m, 2H), 7.47 (dd, J=8.8, 2.8Hz, 1H), 7.15 (d, J=8.8Hz, 1H), 6.90 (s, 1H), 5.05 (s, 2H), 4.64-4.52 (m, 4H), 4.31 (s, 1H), 4.02 (dd, J=14.8, 3.6Hz, 1H), 3.89-3.83 (m, 1H).

[0334] Example 25

[0335] (S)-5-(4-chlorophenyl)-2-((10-(difluoromethyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0336]

[0337] Starting from 3-bromo-4-hydroxybenzyl-1-carboxaldehyde, the product was synthesized according to the method described in Example 21 to obtain (S)-5-(4-chlorophenyl)-2-((10-(difluoromethyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (3.2 mg, yield 8.3%), a white solid.

[0338] MS(ESI) m / z 557.1 [M+H] +

[0339] 1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.76-7.74(m,2H),7.63-7.61(m,3H),7.26-7.12(m,2H),6.98-6 .90(m,1H),5.06(s,2H),4.66-4.56(m,4H),4.32-4.29(m,1H),4.04-3.99(m,1H),3.89-3.83(m,1H).

[0340] Example 26

[0341] (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-((10-(trifluoromethyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0342]

[0343] Starting with 2-bromo-4-(trifluoromethyl)phenol, the product was synthesized according to the method described in Example 21 to obtain (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-((10-(trifluoromethyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (29.7 mg, yield 30%), a white solid.

[0344] MS(ESI) m / z 575.1 [M+H] +

[0345] 1 H NMR (400MHz, DMSO-d6) δ8.60-8.59(m,1H),7.79-7.74(m,3H),7.64-7.60(m,2H),7.32(d,J=8.4Hz,1H),6.9 0(d,J=6.4Hz,1H),5.08(s,2H),4.68-4.61(m,4H),4.31-4.28(m,1H),4.04-4.00(m,1H),3.89-3.33(m,1H).

[0346] Example 27

[0347] 5-(4-Chlorophenyl)-2-((4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0348]

[0349]

[0350] Step 1. 1-(2-bromoethoxy)-2-nitrobenzene

[0351] 1,2-Dibromoethane (21.6 g, 115 mmol) was added to a solution of 2-nitrophenol (3.2 g, 23 mmol) and K₂CO₃ (6.35 g, 46 mmol) in acetonitrile (70 mL). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was then cooled, filtered, and washed twice with 100 mL of DCM. The combined organic layers were washed with 2 M NaOH and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with n-hexane and ethyl acetate, to give 1-(2-bromoethoxy)-2-nitrobenzene (4.0 g, 71% yield).

[0352] MS(ESI)m / z 246[M+H] +

[0353] Step 2. 3-(2-Nitrophenoxy)propionitrile

[0354] At 45 °C, 1-(2-bromoethoxy)-2-nitrobenzene (4.00 g, 16.3 mmol) was added to a solution of sodium cyanide (0.8 g, 16.3 mmol) in 60 mL of DMSO. The reaction mixture was stirred at 70 °C for 4 h. The reaction mixture was then cooled and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography with hexane and ethyl acetate elution to give 3-(2-nitrobenzenoxy)propionitrile (1.0 g, 32% yield).

[0355] MS(ESI)m / z 192[M+H] +

[0356] Step 3. 3-(2-Aminophenoxy)propionitrile

[0357] Pd / C (50 mg) was added to a solution of 1 g (5.2 mmol) of 3-(2-nitrophenoxy)propionitrile in 10 mL of ethyl acetate. The reaction mixture was stirred vigorously under H2 for 4 h. The reaction mixture was filtered through a Celite filter and washed with ethyl acetate. The organic layer was concentrated to give crude 3-(2-aminophenoxy)propionitrile for the next step, without further purification.

[0358] MS(ESI)m / z 163[M+H] +

[0359] Step 4. Methyl (Z)-2-chloro-2-(2-(2-(2-(2-cyanoethoxy)phenyl)hydrazine)acetate

[0360] To a solution of 3-(2-aminophenoxy)propionitrile (500 mg, 3.08 mmol) in acetic acid (2.5 mL), 2 M aqueous hydrogen chloride solution (4.5 mL) and sodium nitrite solution (319.1 mg, 4.62 mmol) were added, and the mixture was stirred vigorously at 0 °C. After stirring the reaction mixture for 30 minutes, methyl 2-chloro-3-oxobutyrate (464.2 mg, 3.08 mmol) was added dropwise using a syringe. The reaction mixture was heated to room temperature for more than 5.5 h. The organic layer was then extracted twice with 100 mL of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl (Z)-2-chloro-2-(2-(2-(2-cyanoethoxy)phenyl)hydrazinedimethyl)acetate, which was used directly for the next step without further purification.

[0361] MS(ESI)m / z 282[M+H] +

[0362] Step 5. Methyl 4,5-dihydrobenzo[B][1,2,4]triazolo[1,5-D][1,4]oxazolo-2-carboxylic acid

[0363] Methyl (2Z)-2-chloro-2-{2-[2-(2-cyanoethoxy)phenyl]hydrazine-1-ylene}acetate (250 mg, 0.89 mmol) was added to a solution of 1,4-dioxane (10 mL), followed by the addition of silver carbonate (367.1 mg, 1.33 mmol) under N2 protection. The reaction mixture was refluxed at 110 °C for 4 h. The reaction mixture was then cooled, filtered, and concentrated. The residue was purified by silica gel column chromatography to give methyl 4,5-dihydrobenzo[B][1,2,4]triazolo[1,5-D][1,4]oxazolo-2-carboxylic acid (100 mg, 44% yield) as a yellow solid. MS (ESI) m / z 246 [M+H] +

[0364] Step 6. (1,5-Dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazono-2-yl)methanol

[0365] To a solution of methyl 4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazapine-2-carboxylic acid (100 mg, 0.41 mmol) in THF / MeOH (5:1, 3 mL), NaBH4 (77.1 mg, 2.04 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with 10 mL of aqueous HCl solution and extracted three times with 10 mL of ethyl acetate. The combined organic layers were concentrated under vacuum to give (1,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazapine-2-yl)methanol, which was used directly in the next step.

[0366] MS(ESI)m / z 218[M+H] +

[0367] Step 7. Methyl (4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methanesulfonate

[0368] MsCl (78.7 mg, 0.69 mmol) was added to a solution of (1,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methanol (75.0 mg, 0.35 mmol) and DIEA (133.9 mg, 1.04 mmol) in DCM (5 mL). The reaction mixture was stirred under nitrogen at room temperature 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 methyl (4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methanesulfonate, which was used directly for the next step without purification.

[0369] MS(ESI)m / z 296[M+H] +

[0370] Step 8. 5-(4-chlorophenyl)-2-(4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0371] A DMF solution (2 mL) of 9-oxa-2,3,5-triazatricyclo[8.4.0.0^{2,6}]tetradecane-1(14), 3,5,10,12-penten-4-ylmethylmethanesulfonate (75 mg, 0.25 mmol), 5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H-1,2,4-triazol-3-one (78 mg, 0.25 mmol) and K₂CO₃ (70 mg, 0.51 mmol) was stirred at 50 °C for 16 h. The reaction mixture was cooled, quenched with water (10 mL), and extracted with EA (10 mL * 3). The combined organic phases were concentrated under vacuum. The residue was purified by preparative HPLC to give 5-(4-chlorophenyl)-2-(4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (12.2 mg, 9% yield) as a white solid. MS (ESI) m / z 507 [M+H] +

[0372] 1 H NMR (400MHz, DMSO-d6) δ8.01(dd,J=8.1,1.7Hz,1H),7.73(d,J=8.6Hz,2H),7.59(d,J=8.6Hz,2H),7.34-7.15(m,3H),6.89(d,J=6.3Hz,1H) ,5.05(s,2H),4.40(t,J=5.6Hz,2H),4.32-4.26(m,1H),3.99(dd,J=14.5,3.5Hz,1H),3.83(dd,J=14.6,9.6Hz,1H),3.36(t,J=5.7Hz,2H).

[0373] Example 28

[0374] (S)-5-(4-chlorophenyl)-2-((9-methyl-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0375]

[0376]

[0377] Starting with 4-methyl-2-nitrophenol, the product was synthesized according to the method described in Example 27 to obtain (S)-5-(4-chlorophenyl)-2-(9-methyl-4,5-dihydrobenzo[b]1,2,4]triazolo[15-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (11 mg, yield 6.37%), which was a white solid.

[0378] MS(ESI)m / z 521[M+H] +

[0379] 1 H NMR(400MHz, DMSO-d6)7.82(s,1H),7.75(dd,J=8.0,2.2Hz,2H),7.62(dd,J=8.0,2.2Hz,2H),7.13-7.07(m,2H),6.91(dd,J=8.0,2.2 Hz,1H),5.06(s,2H),4.40-4.37(m,2H),4.31(s,1H),4.02(dd,J=12,2.2Hz,1H),3.87-3.81(m,1H),3.37-3.32(m,2H),2.33(s,3H).

[0380] Example 29

[0381] (S)-5-(4-chlorophenyl)-2-((9-fluoro-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0382]

[0383] Starting with 4-chloro-2-nitrophenol, the product was synthesized according to the method described in Example 27 to obtain (S)-5-(4-chlorophenyl)-2-((9-fluoro-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (3.4 mg, yield 5%), a white solid.

[0384] MS(ESI)m / z 541[M+H] +

[0385] 1H NMR (400MHz, DMSO-d6) δ8.06(d,J=2.6Hz,1H),7.78-7.73(m,2H),7.64-7.60(m,2H),7.36(dd,J=8.7,2.6Hz,1H),7.23(d,J=8.7Hz,1H),6.9 2(s,1H),5.08(s,2H),4.43(t,J=5.5Hz,2H),4.30(s,1H),4.02(dd,J=14.6,3.6Hz,1H),3.86(dd,J=14.6,9.4Hz,1H),3.42(t,J=5.5Hz,2H).

[0386] Example 30

[0387] 5-(4-Chlorophenyl)-2-[(9-ethyl-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0388]

[0389] Starting with 4-ethyl-2-nitrophenol, 5-(4-chlorophenyl)-2-[(9-ethyl-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (4.8 mg, yield 5%) was synthesized according to the method of Example 27, and was obtained as a white solid.

[0390] MS(ESI) m / z 535.1 [M+H] +

[0391] 1H NMR(500MHz,Chloroform-d)δ7.68–7.62(m,2H),7.54–7.48(m,2H),7.43(dt,J =2.1,0.8Hz,1H),7.17–7.11(m,1H),6.95(d,J=8.3Hz,1H),5.13(m,1H),4.64(s ,1H),4.33(t,J=6.3Hz,2H),3.73(dq,J=8.2,3.6Hz,1H),3.29(m,1H),3.14–3.0 8(m,2H),3.02–2.94(m,1H),2.72(qt,J=7.2,0.9Hz,2H),1.34(t,J=7.2Hz,3H).

[0392] Example 31

[0393] 5-(4-Chlorophenyl)-2-{[9-(propyl-2-yl)-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0394]

[0395] Starting with 2-nitro-4-(prop-2-yl)phenol, 5-(4-chlorophenyl)-2-{[9-(prop-2-yl)-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (2.4 mg, yield 3.2%) was synthesized according to the synthesis method in Example 27, and was obtained as a white solid.

[0396] MS(ESI) m / z 549.1 [M+H] + .

[0397] Example 32

[0398] 5-(4-Chlorophenyl)-2-[(9-methoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0399]

[0400]

[0401] Starting with 4-methoxy-2-nitrophenol, 5-(4-chlorophenyl)-2-[(9-methoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (7.3 mg, yield 6.2%) was synthesized according to the synthetic method of Example 27, and was obtained as a white solid.

[0402] MS(ESI) m / z 537.1 [M+H] +

[0403] 1 H NMR(500MHz,Chloroform-d)δ7.71–7.63(m,2H),7.56–7.48(m,2H),7.02(d,J=2.0Hz,1H),6.99–6.91(m,2H),5.16(m,1H),4 .63(s,1H),4.22–4.16(m,2H),3.91(s,2H),3.83(dq,J=8.3,3.6Hz,1H),3.31(m,1H),3.14–3.08(m,2H),3.02–2.94(m,1H).

[0404] Example 33

[0405] 5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({9-[(trifluoromethyl)oxy]-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl}methyl)-2H,3H,4H-1,2,4-triazol-3-one

[0406]

[0407] Starting with 2-nitro-4-[(trifluoromethyl)oxy]phenol, 5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({9-[(trifluoromethyl)oxy]-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl}methyl)-2H,3H,4H-1,2,4-triazol-3-one (5.1 mg, 7% yield) was synthesized as a white solid. MS (ESI) m / z 591.1 [M+H] +

[0408] 1H NMR(500MHz,Chloroform-d)δ7.69–7.63(m,2H),7.55–7.49(m,2H),7.02–6.93(m,3H),5.13(qdt,J=12.2,8.2,7.3Hz,1H),4.63(s,1 H), 4.17 (t, J = 6.3Hz, 2H), 3.73 (dq, J = 8.2, 3.6Hz, 1H), 3.27–3.19 (m, 1H), 3.12 (ddq, J = 10.5, 7.3, 2.2Hz, 1H), 2.76 (t, J = 6.3Hz, 2H).

[0409] Example 34

[0410] (S)-5-(4-chlorophenyl)-2-((9-fluoro-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0411]

[0412] Starting with 2-nitro-4-[(trifluoromethyl)oxy]phenol, the product was synthesized according to the method described in Example 27 to obtain (S)-5-(4-chlorophenyl)-2-((9-fluoro-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (7.3 mg, yield 5%), a white solid.

[0413] MS(ESI)m / z 525[M+H] +

[0414] 1 H NMR (400MHz, DMSO-d6) δ7.81-7.73(m,3H),7.64-7.59(m,2H),7.20(tdd,J=9.0,8.3,4.3Hz,2H),6.91(d,J=6.4Hz,1H),5.08(s,2H ), 4.41 (t, J = 5.6Hz, 2H), 4.31 (d, J = 7.0Hz, 1H), 4.02 (dd, J = 14.6, 3.4Hz, 1H), 3.86 (dd, J = 14.6, 9.4Hz, 1H), 3.40 (t, J = 5.6Hz, 2H).

[0415] Example 35

[0416] (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-(9-(difluoromethyl)-45-dihydrophenyl[b][12,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0417]

[0418] Starting from 4-(difluoromethyl)-2-nitrophenol, (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-(9-(difluoromethyl)-45-dihydrophenyl[b][12,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (4.3 mg, yield 15.7%) was synthesized according to the synthetic method of Example 27, and was obtained as a white solid.

[0419] MS(ESI) m / z 557.1 [M+H] +

[0420] 1 H NMR(500MHz,Chloroform-d)δ7.66–7.60(m,4H),7.54–7.46(m,6H),7.33–7.27(m,2H),6.91(d,J=6.9Hz,2H),6.44(t,J=0.7Hz,1H ),5.03(qdt,J=12.2,8.2,7.3Hz,2H),4.59(s,4H),4.30–4.24(m,4H),3.63(dq,J=8.3,3.6Hz,2H),3.19(m,2H),3.00–2.90(m,6H).

[0421] Example 36

[0422] (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-((9-trifluoromethyl-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0423]

[0424]

[0425] Starting from 4-(trifluoromethyl)-2-nitrophenol, the title compound (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2-((9-trifluoromethyl-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.8 mg, yield 1.8%) was synthesized according to the synthetic method of Example 27, and was a white solid.

[0426] MS(ESI) m / z 575.1 [M+H] +

[0427] 1 H NMR(400MHz,DMSO-d6)δ7.60-7.56(m,2H),7.52-7.41(m,4H),7.35(s,1H) ,6.91(d,J=8.4Hz,1H),5.14(s,2H),4.51-4.12(m,4H),4.03-3.93(m,3H).

[0428] Example 37

[0429] 2-[(8-chloro-9-methoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0430]

[0431]

[0432] Starting with 5-chloro-4-methoxy-2-nitrophenol, 2-[(8-chloro-9-methoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (2.1 mg, yield 2.3%) was synthesized according to the method described in Example 27, and was obtained as a white solid.

[0433] MS(ESI) m / z 571.1 [M+H] +

[0434] 1H NMR(500MHz,Chloroform-d)δ7.76–7.68(m,2H),7.59(dt,J=8.0,0.6Hz,2H),7.13(s,1H),5.13(m,1H),4. 64(s,1H),4.44(t,J=6.3Hz,2H),4.04(s,2H),3.69(dq,J=8.2,3.5Hz,1H),3.16(m,1H),3.07–2.98(m,3H).

[0435] Example 38

[0436] 5-(4-Chlorophenyl)-2-[(9-fluoro-8-methoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one

[0437]

[0438] Starting with 4-fluoro-5-methoxy-2-nitrophenol, 5-(4-chlorophenyl)-2-[(9-fluoro-8-methoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazolo-2-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2H,3H,4H-1,2,4-triazol-3-one (2.1 mg, yield 2%) was synthesized according to the method of Example 27, and was obtained as a white solid.

[0439] MS(ESI) m / z 555.1 [M+H] +

[0440] 1 H NMR(500MHz,Chloroform-d)δ7.72–7.66(m,1H),7.47–7.41(m,1H),6.58(d,J=4.3Hz,1H), 5.13(qdt,J=12.2,8.2,7.3Hz,1H),4.65(s,1H),4.13(t,J=6.3Hz,1H),3.83(s,2H),3.24(m 1H),3.17–3.09(m,2H),2.89–2.81(m,1H).

[0441] Example 39

[0442] 2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-4,5-dihydro-6H-benzo[f][1,2,4]triazol[1,5-a][1,4]diazepine-6-one

[0443]

[0444] Step 1. N-Benzyl-N-cyanomethyl-2-nitrobenzamide

[0445] A solution of 2-(benzylamino)acetonitrile (2 g, 10.8 mmol) in pure toluene (50 mL) was added to a solution of K₂CO₃ (3.73 g, 27 mmol) and 2-(benzylamino)acetonitrile (1.58 g, 10.8 mmol) in pure toluene (3 mL). The reaction mixture was refluxed for 5 h. The reaction mixture was cooled and filtered. The organic layer was washed with water (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-benzyl-N-cyanomethyl-2-nitrobenzamide (2.4 g, 71% yield) as a yellow solid.

[0446] MS(ESI)m / z 296[M+H] +

[0447] Step 2. 2-Amino-N-benzyl-N-(cyanomethyl)benzamide

[0448] Treated iron powder (3.35 g, 60 mmol) and N-benzyl-N-(cyanomethyl)-2-nitrobenzamide (2.2 g, 7.5 mmol) were added to a solution of ethanol (35 mL) and acetic acid (7 mL). The reaction mixture was refluxed for 2.5 h. The reaction mixture was cooled, filtered, and concentrated under reduced pressure. The residue was extracted with ethyl acetate (80 mL), and the organic solution was washed with 5% NaHCO3 aqueous solution (20 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and removed under reduced pressure. The residue was purified by silica gel column chromatography to give 2-amino-N-benzyl-N-(cyanomethyl)benzamide (0.9 g, 43% yield), a yellow oil.

[0449] MS(ESI)m / z 266[M+H] +

[0450] Step 3. Methyl (Z)-2-(2-(2-(benzyl(cyanomethyl)carbamoyl)phenyl)hydrazine)-2-chloroacetate

[0451] 2-Amino-N-benzyl-N-(cyanomethyl)benzamide (700 mg, 2.64 mmol) was added to a solution of 6M hydrochloric acid (4 mL) and methanol (4 mL). Sodium nitrite (254.9 mg, 3.69 mmol) was added while stirring under ice-cold conditions. After stirring for 30 minutes, the pH of the cold mixture was adjusted to 5 with sodium acetate, and a cooled methanol solution (4 mL) of methyl 2-chloro-3-oxobutyrate (397.24 mg, 2.64 mmol) was added dropwise. The reaction mixture was cooled and stirred for 4 h, then stirred at room temperature for 15 h. The solvent was partially removed under reduced pressure, and the residue was dissolved with EA (25 mL). The organic layer was washed with an aqueous solution of sodium bicarbonate (25 mL) and water (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give (Z)-2-(2-(2-(benzyl(cyanomethyl)carbamoyl)phenyl)hydrazinyl)-2-chloroacetic acid methyl ester (800 mg, 75% yield), a yellow oil.

[0452] MS(ESI)m / z 385[M+H] +

[0453] Step 4. Methyl 5-benzyl-6-oxo-5,6-dihydro-4D-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-2-carboxylic acid ester

[0454] Methyl (2Z)-2-(2-{2-[benzyl(cyanomethyl)carbamoyl]phenyl}hydrazido-1-ylidene)-2-chloroacetate (450 mg, 1.17 mmol) was treated with silver carbonate (645 mg, 2.34 mmol) and dissolved in a dry solution of dioxane (10 mL). The reaction mixture was stirred at room temperature in the dark for 120 h. Undissolved substances were filtered off. The solvent was evaporated. The residue was purified by silica gel column chromatography to give methyl 5-benzyl-6-oxo-5,6-dihydro-4D-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-2-carboxylic acid (180 mg, 44% yield), a yellow oil.

[0455] MS(ESI)m / z 349[M+H] +

[0456] Step 5. 5-Benzyl-2-hydroxymethyl-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-6-one

[0457] To a solution of methyl 5-benzyl-6-oxo-5,6-dihydro-4D-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-2-carboxylic acid (180.0 mg, 0.52 mmol) in THF / MeOH (2.5 mL / 0.5 mL), NaBH4 (98 mg, 2.58 mmol) was added. 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 phases were concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give 5-benzyl-2-hydroxymethyl-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-6-one (100 mg, 57% yield) as a yellow oil.

[0458] MS(ESI)m / z 321[M+H] +

[0459] Step 6. (5-Benzyl-6-oxo-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-2-yl)methylmethanesulfonate

[0460] MsCl (71 mg, 0.6 mmol) was added to a DCM (3 mL) solution of 5-benzyl-2-hydroxymethyl-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-6-one (100 mg, 0.3 mmol) and DIEA (112.1 mg, 0.9 mmol). The reaction mixture was stirred at 25 °C for 2 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 to give (5-benzyl-6-oxo-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-2-yl)methylmethanesulfonate, which was used directly for the next step without purification.

[0461] MS(ESI)m / z 399[M+H] +

[0462] Step 7. 5-Benzyl-2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-4,5-dihydro-6H-benzo[f][1,2,4]triazol[1,5-a][1,4]diazaphen-6-one

[0463] A solution of (5-benzyl-6-oxo-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[1,5-a][1,4]diazaphen-2-yl)methylmethanesulfonate (10 mg, 0.03 mmol), 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-onemethane (7.72 mg, 0.025 mmol), and K₂CO₃ (6.94 mg, 0.05 mmol) in DMF (1 mL) was stirred at 50 °C for 16 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 silica gel column chromatography to give 5-benzyl-2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-4,5-dihydro-6H-benzo[f][1,2,4]triazol[1,5-a][1,4]diazazo-6-one (125 mg, 78% yield) as a white solid.

[0464] MS(ESI)m / z 610[M+H] +

[0465] Step 8. 2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,24-triazol-1-yl)methyl)-4,5-dihydro-6H-benzo[f][1,2,4]triazol[1,5-a][1,4]diazaphen-6-one

[0466] A solution of 5-benzyl-2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-4,5-dihydro-6H-benzo[f][1,2,4]triazol[1,5-a][1,4]diazepine-6-one (60 mg, 0.1 mmol) in TFA (2 mL) and TfOH (0.5 mL) was stirred at 90 °C 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 preparative HPLC to give 2-((3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,24-triazol-1-yl)methyl)-4,5-dihydro-6H-benzo[f][1,2,4]triazol[1,5-a][1,4]diazazo-6-one (20.4 mg, 38% yield) as a white solid.

[0467] MS(ESI)m / z 520[M+H] +

[0468] 1 H NMR(400MHz, DMSO-d6)δ8.79(t,J=5.6Hz,1H),7.96(d,J=7.6Hz,1H),7.82-7.71(m,4H),7.66-7.53(m,3H),6.91 (d, J=6.2Hz, 1H), 5.12 (s, 2H), 4.33 (d, J=5.7Hz, 3H), 4.01 (dd, J=14.6, 3.4Hz, 1H), 3.85 (dd, J=14.6, 9.5Hz, 1H).

[0469] Example 40

[0470] (S)-2-((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]triazolo[1,5-c]quinazolin-5(6H)-one

[0471]

[0472] Step 1. Methyl (2-cyanophenyl)carbamate

[0473] Methyl chloroformate (2.64 g, 27.9 mmol) was added to a solution of 2-butanone (50 mL) containing 2-aminobenzonitrile (3 g, 25.4 mmol) and NaHCO3 (2.6 g, 30.5 mmol). The reaction mixture was stirred at 80 °C for 12 h. Then, 2,2-difluoroethyltrifluoromethanesulfonate (4.84 g, 22.5 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was 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 silica gel column chromatography to give methyl (4-chloro-2-cyanophenyl)carbamate (0.85 g, 19% yield) as a white solid.

[0474] MS(ESI)m / z 177[M+H] +

[0475] Step 2. 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one

[0476] Methyl (2-cyanophenyl)carbamate (800.0 mg, 4.5 mmol) and 2-hydroxyacetylhydrazine (486.5 mg, 5.4 mmol) were added to a 5 mL NMP solution and stirred at 200 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled and purified to give 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (759 mg, 78% yield) as a yellow solid.

[0477] MS(ESI)m / z 217[M+H] + .

[0478] Step 3. (5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methanesulfonate

[0479] To a solution of 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (600 mg, 2.78 mmol), add MSCl (637 mg, 5.56 mmol) of DCM (1 mL) containing DMAP (31.2 mg, 0.278 mmol) and DIEA (1078 mg, 8.34 mmol). Stir the reaction mixture under nitrogen at room temperature for 2 h. Quench the reaction mixture with water (10 mL) and extract with DCM (10 mL x 3). Concentrate the combined organic phases under vacuum to give crude (5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl methanesulfonate, which can be used directly in the next step without purification.

[0480] MS(ESI)m / z 295[M+H] + .

[0481] Step 4. (S)-2-((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]triazolo[1,5-c]quinazolin-5(6H)-one

[0482] A solution of (5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)methyl methanesulfonate (200 mg, 0.68 mmol), (S)-5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (212.1 mg, 0.68 mmol), and K₂CO₃ (188 mg, 1.36 mmol) in DMF (5 mL) was stirred overnight at 50 °C. 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)-2-((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]triazolo[1,5-c]quinazolin-5(6H)-one (10.3 mg, 3% yield) as a white solid.

[0483] MS(ESI)m / z 506[M+H] + .

[0484] 1 H NMR(500MHz,Chloroform-d)δ10.10(s,1H),7.69–7.60(m,3H),7.58–7.46(m,3H),7.38–7.32(m,1 H), 7.26 (s, 1H), 5.03 (m, 1H), 4.59 (s, 2H), 3.63 (dq, J = 8.3, 3.6Hz, 1H), 3.19 (m, 1H), 2.94 (m, 1H).

[0485] Test case

[0486] 1. Assay method for vasopressin V1a receptor activity

[0487] 1.1 Cell Information

[0488] 1) A stable receptor CHO cell line expressing V1a was used. After stimulation with different concentrations of test compounds, the inhibitory effect of the compounds on the V1a receptor was determined by the IP-One-Gq kit.

[0489] 2) The CHO cell line stably expressing V1a was cultured in F12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at 37°C and 5% carbon dioxide.

[0490] 3) To maintain the physiological activity of the cells, the degree of cell fusion in the experiment was controlled at around 80%.

[0491] 1.2 Determination of the inhibitory activity of the compound on V1a receptors

[0492] 1) Prepare 1×Stimulation Buffer according to the kit instructions;

[0493] 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.

[0494] 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;

[0495] 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.

[0496] 5) Add 3.5 μL of agonist solution, centrifuge, and incubate at 37°C for 1 hour;

[0497] 6) Dilute d2-IP1 and Anti-IP1-Cryptate to working concentrations using Lysis & Detection Buffer;

[0498] 7) After incubation, add 3 μL of d2-IP1 to all wells;

[0499] 8) Add 3 μL of Lanti-IP1-Cryptate to all experimental wells, centrifuge, and incubate at room temperature for 1 hour;

[0500] 9) After incubation, use an ELISA reader to detect the readings at 665nm and 620nm under excitation at a wavelength of 330nm;

[0501] 10) Calculate the compound IC using the GraphPad nonlinear fitting formula. 50 .

[0502] 2. Assay method for vasopressin V2 receptor activity

[0503] 2.1 Cell Information

[0504] 1) A stable receptor CHO cell line expressing V2 was used. After stimulation with different concentrations of the test compound, the inhibitory effect of the compound on the V2 receptor was determined by the LANCE@UItracAMPKi kit.

[0505] 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.

[0506] 3) To maintain the physiological activity of the cells, the degree of cell fusion in the experiment was controlled at around 80%.

[0507] 2.2 Determination of the inhibitory activity of the compound on V2 receptor

[0508] 1) Prepare 1x Stimulation Buffer according to the kit instructions;

[0509] 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 well and set aside.

[0510] 3) Culture stable transgenic cells to 80% confluence; trypsin digestion to collect cells, count them, and seed 5 μL / well into 384-WE1 plates in activation mode;

[0511] 4) Add 1 μL of the diluted 10x compound to the corresponding experimental well and incubate at 37°C for 10 minutes;

[0512] 5) Prepare 0.025 nM Argipressin buffer with 1x Stimulation Buffer, then add 4 μL / well to the corresponding experimental wells and incubate for 30 minutes;

[0513] 6) Dilute Eu-cAM to the working concentration with detection buffer, and add 5 μL / well to the corresponding experimental well;

[0514] 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;

[0515] 8) After incubation, use an ELISA reader to detect the readings at 665nm and 620nm under excitation at a wavelength of 330nm;

[0516] 9) Calculate the compound IC using the GraphPad nonlinear fitting formula. 50 .

[0517] Table 1: In vitro activity test data of the compounds of this invention

[0518]

[0519]

[0520] Conclusion: As shown in the table above, the compounds of this invention have very high inhibitory activity against angiotensin receptors V1a and V2, and can act as dual antagonists. The compounds are used to prevent or treat diseases related to arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, sympathetic nervous system or renin-angiotensin-aldosterone system.

[0521] The above-mentioned compounds or their salts may be used in the manufacture of pharmaceuticals for the treatment, prevention and / or diagnosis of diseases selected from the following: 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, vasopressin secretion disorder, cirrhosis, hyponatremia, hypokalemia, diabetes, ischemia, motion sickness, water metabolism disorders and ischemic diseases.

[0522] The heart failure described herein is caused by one or more of the following conditions: myocardial infarction, coronary artery disease, coronary microcirculation abnormalities, cardiotoxic injury, immune and inflammatory mediated myocardial damage, cardiac overload, and arrhythmia. The conditions leading to cardiac overload include hypertension, valvular and cardiac structural abnormalities, pericardial and endocardial diseases, high cardiac output, volume overload, and pulmonary diseases.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof. in: X is C or N; Y is either C or N; Z can be -CH2-, -CHR1-, -CO-, N, or O; Q can be -CH2-, -CHR1-, -CO-, N, or O; R1 is an H, C1-C3 alkane or a haloal short-chain alkane; R2 and R3 are hydrogen, halogen, -CN, -OCH3, -OCF3, C1-C3 alkanes or haloalkanes; m = 0 or 1.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, and / or solvate, characterized in that, R2 can be hydrogen, -F, -Cl, -CN, -OCH3, -OCF3, -CH3, -CF2H, or -CF3; R3 can be hydrogen, -F, -Cl, -CN, -OCH3, -OCF3, -CH3, -CF2H, or -CF3.

3. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, and / or solvate, characterized in that, In the ring system One of the following: R1 is an H, C1-C3 alkane, or a short-chain haloalkane.

4. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, and / or solvate, characterized in that, A six-membered or seven-membered ring composed of X, Y, Z, and Q, and a structure composed of R2 and R3, selected from any one of the following groups: R2 and R3 are hydrogen, halogens, -CN, -OCH3, -OCF3, C1-C3 alkanes, or haloalkanes.

5. The following compounds, or their pharmaceutically acceptable salts, hydrates, and / or solvates, 6. A pharmaceutical composition, characterized in that, It includes an effective amount of active ingredient and pharmaceutically acceptable excipients; the active ingredient includes the compound of any one of claims 1-5, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof.

7. Use of the compound of any one of claims 1-5, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, or the pharmaceutical composition of claim 6 in the preparation of a medicament antagonizing the arginine vasopressin receptor.

8. The use according to claim 7, characterized in that, The arginine vasopressin receptor is subtype 1a and / or 2.

9. Use of the compound, stereoisomer or pharmaceutically acceptable salt thereof of any one of claims 1-5, or the pharmaceutical composition of claim 6, in the preparation of a medicament for treating diseases associated with arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, sympathetic nervous system or renin-angiotensin-aldosterone system.

10. The use according to claim 9, characterized in that, The disease in question is heart failure.

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