Triazoles compounds

Abstract

The present application mainly relates to triazole compounds, belongs to the technical field of medicine, and particularly relates to synthesis of advanced glycation end product receptor inhibitors and application thereof in anti-breast cancer. The present application performs skeleton transition on the structure of azirige, replaces diazole in the original structure with 1,2,4-triazole, and then performs structure derivation. The in-vitro pharmacological activity experiment results show that some derivatives have good growth inhibition effect on human triple-negative breast cancer cell line SUM149, the IC 50 value is in the order of muM to nM, the best active compound is 0.220+ / -0.034 muM; the cytotoxic activity of the rest of the compounds is lower, and the inhibition rate at the maximum test concentration (10 muM) is less than 50%.

Description

[0001] This application is a divisional application of the invention entitled "Aziregane Triazole Derivatives and Their Use in Anti-Breast Cancer Treatment", filed on June 28, 2021, with application number 202110716283.X. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology and mainly relates to triazole compounds. Background Technology

[0003] The receptor for advanced glycation end products (RAGE) is an immunoglobulin on the cell membrane and belongs to the pattern recognition receptor family. RAGE is widely present in various cell types, and is commonly expressed in tissues such as monocytes / macrophages, vascular endothelial cells, tumor cells, renal mesangial cells, nerve cells, and smooth muscle cells. Numerous studies have demonstrated a close relationship between RAGE and the occurrence, development, and metastasis of breast cancer. With the growth, metastasis, and recurrence of breast cancer, the marker signal of RAGE increases significantly. Clinical trials (NCT02103387) on the relationship between RAGE-related receptors and breast cancer showed a strong correlation. Therefore, blocking RAGE is of great significance for the prevention and treatment of breast cancer and has become an emerging target for the development of various drugs, including anti-breast cancer drugs.

[0004] Azeliragon (formerly known as PF-04494700 or TTP488, CAS No.: 603148-36-3), with the following structural formula, is a RAGE inhibitor currently undergoing clinical trials.

[0005]

[0006] Azirig's research and development company has applied for patents to protect its patents, including patent WO200307592, which applies for the following compound patent:

[0007]

[0008] In the formula, R1 is -hydrogen, -aryl, -heterocyclic, -alkenyl, cycloalkyl, -alkyl, -alkylene-aryl, -alkylene-cycloalkyl, or -G1-G2-G3-R5.

[0009] Wherein, G1 and G3 are independently selected from the group consisting of: heterocyclic, aryl, alkyl, cycloalkyl, heteroaryl, and direct bond;

[0010] G is an alkylene group, -O-, -C(O), -CO2-, or a direct bond; and

[0011] R3 is hydrogen or alkyl;

[0012] R5 is hydrogen, aryl, or alkyl; and

[0013] R102 and R104 are independently selected from the following groups:

[0014] a) -aryl; b) -heteroaryl; c) -alkylene-aryl;

[0015] d)-Y4-NR 23 R 24 ;e)-Y4-NH-C(=NR 25 )NR 23 R 24 .

[0016] Patent WO2011041198 filed a patent for the following compound:

[0017]

[0018] In the formula, R1 and R2 are independently selected from the following groups: -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3;

[0019] Q1 is selected from: -CH2OCH2CH3 or -CH2CH2CH2CH3.

[0020] Hudson et al. discovered that compounds such as aziregane possess anti-breast cancer activity and applied for a related patent (WO2019094613A1). Our research group, through previous experiments and computer-aided drug design, discovered that a skeletal transition can be performed on the aziregane structure, replacing the diazole in the original structure with 1,2,4-triazole, followed by structural derivatization, as shown below. Molecular docking and other software calculations indicate that the skeletal transition exhibits a stronger affinity for RAGE. Therefore, it may still possess good anti-breast cancer activity.

[0021] Summary of the Invention

[0022] The purpose of this invention is to synthesize azirregular triazole derivatives, which are receptor inhibitors of advanced glycation end products (AGEs), to explore potential drugs or lead compounds for the treatment of breast cancer, and to provide triazole compounds.

[0023] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0024] First, following the synthetic method below, the diazole in the center of the azireg structure was replaced with 1,2,4-triazole to obtain the skeletal transition product KC-6.

[0025]

[0026] Following the synthetic route below, a series of derivatives were obtained, and finally the anti-breast cancer activity of the obtained compounds was tested.

[0027]

[0028]

[0029] Detailed Implementation

[0030] The present invention will be further described below with reference to embodiments.

[0031] Example 1

[0032]

[0033] 4-(3-(diethylamino)propoxy)benzaldehyde (3)

[0034] 4-Hydroxybenzaldehyde (2.4 g, 20 mmol) and potassium carbonate (8.3 g, 60 mmol) were added to a solution of 3-chloro-N,N-diethylpropane-1-amine (3.0 g, 20 mmol) in acetone (50 mL). The mixture was heated under reflux for 8 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the solvent in the filtrate was evaporated to dryness. The residue was dissolved in 100 mL of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to give a colorless oily liquid (4.6 g, 97.9% yield).

[0035]

[0036] 4-(4-Chlorophenoxy)phenylhydrazine (5)

[0037] 4-(4-Chlorophenoxy)aniline (2.2 g, 10 mmol) was added to a round-bottom flask containing 25 mL of 6N hydrochloric acid and stirred vigorously at 0 °C for 20 minutes. Sodium nitrite (760 mg, 11 mmol) was dissolved in water (6 mL) and added dropwise. After addition, the reaction mixture was stirred at 0 °C for 1.5 hours, and then stannous chloride solution (4.7 g, 25 mmol, dissolved in 25 mL of 12N concentrated hydrochloric acid) was added dropwise. After addition, the mixture was stirred at room temperature for another 2.5 hours, and then the pH was adjusted to >7 with ice-cold sodium hydroxide aqueous solution. 200 mL of ethyl acetate was added, and the precipitate formed was filtered off. The organic layer was washed with water, separated, dried, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid silica gel column chromatography, eluting with petroleum ether:ethyl acetate (4:1). The target compound was obtained as a brown solid (1.5 g, yield 64%).

[0038]

[0039] 3-(4-(2-(4-(4-chlorophenoxy)phenylhydrazine)methyl)phenoxy)-N,N-diethylpropane-1-amine (6)

[0040] 4-(4-chlorophenoxy)phenylhydrazine (2.3 g, 10 mmol) was dissolved in 20 mL of anhydrous ethanol, and then added dropwise to a solution containing 20 mL of anhydrous ethanol of 4-(3-(diethylamino)propoxy)benzaldehyde (2.3 g, 10 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours, and the solvent was removed under vacuum to obtain the crude product, which could be used in the next step without further purification.

[0041]

[0042] 3-(4-(5-butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-6)

[0043] Iodine I₂ (5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added to an acetonitrile (10 mL) solution containing 3-(4-((2-(4-(4-chlorophenoxy)phenyl)hydrazino)methyl)phenoxy)-N,N-diethylpropane-1-amine (90 mg, 0.2 mmol) and n-pentylamine (94 μL, 0.8 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried, concentrated, and purified by rapid silica gel column chromatography, eluting with petroleum ether:ethyl acetate (6:1) to give the purified product as a pale yellow oil (67 mg, 63% yield).

[0044] 1 H NMR (400MHz, Chloroform-d) δ8.07 (d, J=7.0Hz, 2H), 7.44 (d, J=7.0Hz, 2H), 7.36 (d, J=6.6Hz, 2H), 7.12 (d, J=7.3Hz, 2H), 7.02 (d, J=6.9Hz, 2H), 6.9 3(d, J=7.0Hz, 2H), 4.23-4.00 (m, 2H), 3.18-2.89 (m, 6H), 2.80 (t, J=8.0Hz , 2H), 2.27 (s, 2H), 1.80-1.72 (m, 2H), 1.26 (s, 8H), 0.90 (t, J=6.9Hz, 3H). 13C NMR (151MHz, Chloroform-d) δ161.09, 159.09, 157.58, 157.14, 154.96, 132.77, 130.05, 129.29, 128.00, 127.02, 12 4.28, 120.73, 119.07, 114.35, 64.86, 49.31, 46.71, 30.16, 26.24, 24.04, 22.40, 13.70, 8.74. HR-ESIMS (m / z): [M+H] + Calculated for C 31 H 38 ClN4O2533.2683, found 533.2682.

[0045]

[0046] 1-(4-bromobenzyl)-2-(4-(4-chlorophenoxy)phenyl)hydrazine(8)

[0047] (4-(4-chlorophenoxy)phenyl)hydrazine (2.3 g, 10 mmol) was dissolved in 20 mL of anhydrous ethanol, and then added dropwise to a 20 mL solution of 4-bromobenzaldehyde (1.85 g, 10 mmol) in anhydrous ethanol. The mixture was stirred for 2 hours, and the solvent was removed under vacuum to obtain the crude product, which could be used in the next step without further purification.

[0048]

[0049] 3-(4-Bromophenyl)-5-butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-1,2,4-triazole (KC-11)

[0050] Iodine I₂ (5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added to an acetonitrile (10 mL) solution containing 1-(4-bromobenzyl)-2-(4-(4-chlorophenoxy)phenyl)hydrazine (80 mg, 0.2 mmol) and n-pentanylamine (94 μL, 0.8 mmol). The crude product was obtained according to the KC-6 synthesis method, purified by rapid silica gel column chromatography, and eluted with petroleum ether:ethyl acetate (6:1) to give the purified product as a brown oil (70 mg, 73% yield).

[0051] 1H NMR (400MHz, Chloroform-d) δ8.01 (d, J=8.4Hz, 2H), 7.56 (d, J=8.4Hz, 2H), 7.43 (d, J=8.8Hz, 2H), 7.35 (d, J=8.8Hz, 2 H), 7.12 (d, J=8.8Hz, 2H), 7.02 (d, J=8.8Hz, 2H), 2.84-2.75 (m, 2H), 1.77 (m, 2H), 1.38 (m, 2H), 0.90 (t, J=7.4Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ160.68, 157.81, 157.49, 154.98, 132.71, 131.82, 130.16, 129.99, 129. 45, 128.10, 127.08, 123.53, 120.87, 119.13, 77.43, 77.31, 77.11, 76.79, 30.18, 26.33, 22.47, 13.78.

[0052]

[0053] 5-Butyl-1-(4-(4-chlorophenoxy)phenyl)-3-(4′-methoxy-[1,1′-biphenyl]-4-yl)-1H-1,2,4-triazole (KC-12)

[0054] 3-(4-Bromophenyl)-5-butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of (4-methoxyphenyl)boric acid (91.2 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol). The solution was degassed with an argon stream for 3 minutes, and the reaction vessel was then sealed to form a sealed tube. The mixture was stirred at 90 °C for 12 hours to obtain a black mixture. The mixture was filtered, and the filtrate was diluted with water (20 mL) and extracted three times with dichloromethane (20 mL). The organic layers were combined, dried, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate (10:1) to give the target compound as a brown oil (119 mg, 57% yield).

[0055] 1H NMR (400MHz, Chloroform-d) δ8.19 (d, J=8.4Hz, 2H), 7.62 (m, 4H), 7.46 (d, J=8.8Hz, 2H), 7.35 (d, J=8.8Hz, 2H), 7.12 (d, J=8.8Hz, 2H), 7.00 (m, 4H), 3.86 (s, 3H), 2.91-2.75 (m, 2H), 1.83-1.74 (m, 2H), 1.44-1.35 (m, 2H), 0.91 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ161.28, 159.42, 157.72, 157.30, 155.05, 141.62, 133.26, 132.86, 130.14, 129.39, 129.2 0, 128.19, 127.14, 126.94, 126.84, 120.84, 119.17, 114.33, 55.46, 30.26, 26.35, 22.50, 13.80. HR-ESIMS (m / z): [M+H] + Calculated for C 31 H 29 ClN3O2510.1948, found510.1948.

[0056]

[0057] (4-Bromophenyl)hydrazine (10)

[0058] 4-Bromoaniline (1.7 g, 10 mmol) was added to a round-bottom flask containing 25 mL of 6N hydrochloric acid and stirred vigorously at 0 °C for 20 minutes. Sodium nitrite (760 mg, 11 mmol) was dissolved in water (6 mL) and added dropwise to the round-bottom flask. After the addition was complete, the reaction mixture was stirred at 0 °C for 1.5 hours, and then stannous chloride solution (4.7 g, 25 mmol, dissolved in 25 mL of 12M concentrated hydrochloric acid) was added dropwise. The mixture was stirred at room temperature for another 2.5 hours. After the reaction was complete, ice-cold sodium hydroxide aqueous solution was added dropwise to adjust the pH to >7. 200 mL of ethyl acetate was added, and the precipitate was filtered off. The organic layer of the filtrate was separated, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography, eluting with petroleum ether:ethyl acetate (4:1). The purified product was obtained as a yellow solid (1.1 g, yield 59%).

[0059]

[0060] 3-(4-((2-(4-bromophenyl)hydrazino)methyl)phenoxy)-N,N-diethylpropane-1-amine (11)

[0061] (4-Bromophenyl)hydrazine (1.87 g, 10 mmol) was dissolved in 20 mL of absolute ethanol and added dropwise to a 20 mL solution of 4-(3-(diethylamino)propoxy)benzaldehyde (2.3 g, 10 mmol) in anhydrous ethanol. The mixture was stirred for 2 hours, and the solvent was removed under vacuum to obtain the crude product, which could be used in the next step without further purification.

[0062]

[0063] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-23)

[0064] Iodine I₂ (5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added to an acetonitrile (10 mL) solution containing 3-(4-((2-(4-(bromophenyl)hydrazino)methyl)phenoxy)-N,N-diethylpropane-1-amine (81 mg, 0.2 mmol) and n-pentylamine (94 μL, 0.8 mmol). The mixture was stirred at room temperature for 3 hours, and then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, the organic layer was dried, concentrated, and purified by rapid silica gel column chromatography. The purified product was eluted with petroleum ether:ethyl acetate (8:1) to give a brown oily product (82 mg, 84% yield).

[0065] 1 H NMR (600MHz, Chloroform-d) δ8.03 (d, J=7.9Hz, 2H), 7.63 (d, J=7.7Hz, 2H), 7.35 (d, J=7.7Hz, 2H), 6.91 (d, J=7.9Hz, 2H), 4.09 (t, J=4.9Hz, 2H), 3. 19-3.11 (m, 2H), 3.07 (q, J=7.0Hz, 4H), 2.78 (t, J=7.7Hz, 2H), 2.37-2.24 (m, 2H), 1.73 (p, J=7.6Hz, 2H), 1.41-1.31 (m, 8H), 0.88 (t, J=7.2Hz, 3H). 13 C NMR (151MHz, Chloroform-d) δ160.66, 158.63, 156.38, 135.95, 131.99, 127.35, 125.98, 123.35, 122.01, 113.76, 64.36, 48.54, 46.15, 29.40, 25.70, 23.56, 21.72, 13.02, 8.37.

[0066]

[0067] 3-(4-(5-butyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-36)

[0068] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-ylphenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of (4-(trifluoromethyl)phenyl)boronic acid (114 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and a 2M potassium carbonate aqueous solution (276 mL). The solution was degassed with an argon stream for 3 minutes, then the reaction vessel was sealed and stirred at 90°C for 20 hours to obtain a black mixture. The mixture was filtered, and the filtrate was diluted with water (20 mL) and extracted three times with dichloromethane (20 mL). The organic layers were combined, dried, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to obtain the purified product, which was a colorless oil (82 mg, yield 38%).

[0069] 1 H NMR (400MHz, Chloroform-d) δ8.14 (d, J=8.4Hz, 2H), 8.08 (d, J=8.8Hz, 2H), 7.76 (d, J= 8.5Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 7.57 (d, J=8.5Hz, 2H), 6.92 (d, J=8.9Hz, 2H), 4.40 (q , J=7.1Hz, 2H), 4.13 (t, J=5.4Hz, 2H), 3.28-3.11 (m, 6H), 2.91-2.80 (m, 2H), 2.40 (dq, J =11.1, 5.4Hz, 2H), 1.79 (p, J = 7.7Hz, 2H), 1.43 (t, J = 6.9Hz, 8H), 0.90 (t, J = 7.4Hz, 3H). 13 CNMR (101MHz, Chloroform-d) δ160.62, 140.74, 137.17, 132.86, 128.50, 128.37, 128.30, 127.62, 126 .77, 126.09, 126.05, 115.87, 114.56, 77.43, 64.78, 49.19, 46.66, 30.24, 26.22, 22.47, 13.72, 8.50.

[0070]

[0071] 3-(4-(5-butyl-1-(4'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-37)

[0072] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (143 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol). The crude product was obtained according to the KC-36 synthesis method, purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to give the purified product as a brown oil (121 mg, 57% yield).

[0073] 1 H NMR (400MHz, Chloroform-d) δ8.05 (d, J=8.8Hz, 2H), 7.72 (d, J=8.8Hz, 2H), 7.58-7.51 (m, 4H), 7.45 (d, J=8.8Hz, 2H), 6.94 (d, J=8.8Hz, 2H), 4.11(t, J=5.6Hz, 2H), 3.51-3.08(m, 6H), 3.04-2.85(m, 2H), 2.30-2.2 0 (m, 2H), 1.82-1.70 (m, 2H), 1.39-1.31 (m, 8H), 0.88 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ159.87, 159.08, 156.88, 141.66, 137.97, 135.92, 134.55, 129.35, 128.56, 128.30 , 125.76, 121.84, 114.74, 64.76, 49.27, 46.79, 30.17, 25.67, 23.85, 22.40, 13.59, 8.49.HR-ESIMS(m / z):[M+H] + calculated for C 31 H 38 ClN4O 517.2734, found 517.2737.

[0074]

[0075] 3-(4-(5-Butyl-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-38)

[0076] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of (4-methoxyphenyl)boric acid (91 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol). The crude product was obtained according to the KC-36 synthesis method, purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to give the purified product as a yellow oil (107 mg, 51% yield).

[0077] 1 H NMR (400MHz, Chloroform-d) δ8.06 (d, J=8.8Hz, 2H), 7.72 (d, J=8.8Hz, 2H), 7.57 (d, J=8.8Hz, 2H), 7.51 (d, J=8.8Hz, 2H), 7.01 (d, J=8.8Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 4.13-4.07 (m, 2H), 3.86 (s, 3H), 3.33-3.13 (m, 6H), 3.02-2.90 (m, 2H), 2.34-2.15(m, 2H), 1.82-1.70(m, 2H), 1.42-1.30(m, 8H), 0.88(t, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ159.96, 159.86, 158.80, 156.81, 142.61, 134.97, 131.93, 128.59, 128.39, 127.90, 125.6 6, 121.76, 114.74, 114.59, 64.79, 55.51, 49.27, 46.75, 30.18, 25.59, 23.87, 22.41, 13.59, 8.50. HR-ESIMS (m / z): [M+H] + Calculated for C 32 H 41N4O2513.32230, found513.3227.

[0078]

[0079] 4'-(5-Butyl-3-(4-(3-(diethylamino)propoxy)phenyl)-1H-1,2,4-triazol-1-yl)-[1,1'-biphenyl]-4-nitrile (KC-40)

[0080] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzonitrile (137 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol). The crude product was obtained according to the KC-36 synthesis method, purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to give the purified product as a yellow oil (131 mg, 63% yield).

[0081] 1 H NMR (400MHz, Chloroform-d) δ8.02 (dd, J=11.2, 8.4Hz, 2H), 7.82-7.74 (m, 2H), 7.74 -7.66 (m, 2H), 7.61 (d, J=8.5Hz, 1H), 7.40-7.34 (m, 1H), 6.94 (dd, J=8.4, 6.1Hz, 2H) , 6.61 (s, 2H), 4.11 (t, J=4.9Hz, 2H), 3.25 (d, J=28.4Hz, 6H), 2.95 (dt, J=31.3, 7.8H z, 2H), 2.24 (s, 2H), 1.71 (s, 2H), 1.35 (t, J=6.8Hz, 9H), 0.87 (td, J=7.3, 5.2Hz, 3H). 13C NMR (101MHz, Chloroform-d) δ159.12, 156.92, 140.87, 136.69, 133.10, 132.97, 128.69, 128.63, 128.59, 127.98, 126.8 4, 125.92, 124.00, 114.80, 114.76, 64.73, 49.36, 46.88, 30.15, 30.10, 25.57, 23.86, 22.39, 22.36, 13.55, 8.48.HR-ESI MS(m / z):[M+H] + Calculated for C 32 H 38 N5O 508.3076, found 508.3077.

[0082]

[0083] 3-(4-(5-butyl-1-(4'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-43)

[0084] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborane (131 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol) were added sequentially. The crude product was obtained according to the KC-36 synthesis method, purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to give the purified product as a yellow oil (92 mg, 45% yield).

[0085] 1H NMR (400MHz, Chloroform-d) δ8.05 (d, J=8.4Hz, 2H), 7.75 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 4H), 7.29 (d, J=8.4Hz, 2H), 6.95 (d, J=8.4Hz, 2H) , 4.11(brs, 2H), 3.36-3012(m, 6H), 3.05-2.94(m, 2H), 2.41(s, 3H), 2. 25(s, 2H), 1.82-1.68(m, 2H), 1.48-1.30(m, 8H), 0.87(t, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ160.07, 158.26, 156.71, 143.15, 138.38, 136.52, 135.01, 129.90, 128.68, 128.25, 127.1 3, 125.64, 121.09, 114.82, 64.77, 49.28, 46.86, 30.11, 25.41, 23.83, 22.37, 21.24, 13.54, 8.49. HR-ESIMS (m / z): [M+H] + Calculated for C 32 H 41 N4O 497.3280, found 497.3275.

[0086]

[0087] Ethyl 4'-(5-butyl-3-(4-(3-(diethylamino)propoxy)phenyl)-1H-1,2,4-triazol-1-yl)-[1,1'-biphenyl]-4-carboxylate (KC-44)

[0088] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of (4-(ethoxycarbonyl)phenyl)boronic acid (116 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol). The crude product was obtained according to the KC-36 synthesis method, purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to give the purified product as a brown oil (116 mg, 51% yield).

[0089] 1H NMR (400MHz, Chloroform-d) δ8.14 (d, J=8.8Hz, 2H), 8.03 (d, J=8.8Hz, 2H), 7.80 (d, J=8 .8Hz, 2H), 7.68 (d, J=8.8Hz, 2H), 7.58 (d, J=8.8Hz, 2H), 6.95 (d, J=8.8Hz, 2H), 4.44-4. 36 (m, 2H), 4.10 (t, J=5.4Hz, 2H), 3.43-3.14 (m, 6H), 3.07-2.95 (m, 2H), 2.28-2.18 (m, 2 H), 1.82-1.70 (m, 2H), 1.41 (t, J=7.1Hz, 3H), 1.38-1.28 (m, 8H), 0.87 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ166.39, 160.20, 158.18, 156.72, 143.59, 135.90, 130.41, 130.30, 128.74, 128.71, 127.24, 125.7 8, 117.36, 114.86, 114.48, 64.74, 61.31, 49.31, 46.94, 30.08, 25.39, 23.81, 22.36, 14.41, 13.51, 8.48. HR-ESIMS (m / z): [M+H] + Calculated for C 34 H 43 N4O3555.3335, found 555.3333.

[0090]

[0091] 3-(4-(5-butyl-1-(2',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-46)

[0092] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of (2,4-dimethoxyphenyl)boric acid (109 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol). The crude product was obtained according to the KC-36 synthesis method, purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to give the purified product as a brown oil (104 mg, 47% yield).

[0093] 1 H NMR (400MHz, Chloroform-d) δ8.05 (d, J=8.8Hz, 2H), 7.69 (d, J=8.8Hz, 2H), 7.47 (d , J=8.8Hz, 2H), 7.27 (d, J=8.4Hz, 1H), 6.95 (d, J=8.8Hz, 3H), 6.64-6.56 (m, 2H), 4. 11(t, J=4.8Hz, 2H), 3.86(s, 3H), 3.82(s, 3H), 3.32-3.13(m, 6H), 3.08-2.93(m, 2H ), 2.34-2.09(m, 2H), 1.84-1.68(m, 2H), 1.44-1.28(m, 8H), 0.89(t, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ161.16, 160.12, 157.86, 157.58, 156.56, 140.67, 134.21, 131.38, 130.80, 128.72, 124.8 2, 121.62, 114.84, 105.06, 99.17, 64.78, 55.66, 55.58, 49.27, 46.83, 30.14, 25.33, 23.83, 22.39, 13.54, 8.49.HR-ESI MS(m / z):[M+H] + Calculated for C 33 H 43 N4O3543.3335, found 543.3339.

[0094]

[0095] 3-(4-(5-Butyl-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-48)

[0096] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of (4-(trifluoromethoxy)phenyl)boronic acid (124 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol). The crude product was obtained according to the KC-36 synthesis method, purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to give the purified product as a yellow oil (116 mg, 50% yield).

[0097] 1 H NMR (400MHz, Chloroform-d) δ 8.04 (d, J = 8.8Hz, 2H), 7.75 (d, J = 8.8Hz, 2H), 7.64 (d, J = 8.8Hz, 2H), 7.57 (d, J = 8.8Hz, 2H), 7.34 (d, J = 8.8Hz, 2H), 6.96 (d, J =8.8Hz, 2H), 4.12 (t, J = 5.4Hz, 2H), 3.40-3.10 (m, 6H), 3.08-2.89 (m, 2H), 2. 35-2.22(m, 2H), 1.85-1.68(m, 2H), 1.42-1.30(m, 8H), 0.88(t, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ159.75, 157.01, 135.87, 133.00, 128.46, 126.82, 123.68, 122.28 ,114.67,64.73,49.28,46.80,30.13,25.78,23.84,22.39,13.60,8.48.HR-ESIMS(m / z):[M+H] + Calculated for C 32 H 38 F3N4O2567.2947, found 567.2947.

[0098]

[0099] 3-(4-(5-butyl-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-49)

[0100] 3-(4-(1-(4-bromophenyl)-5-butyl-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (200 mg, 0.41 mmol) was dissolved in dichloroethane (8 mL), followed by the addition of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborborane)-2-yl)-1H-pyrazole (125 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and 2M potassium carbonate aqueous solution (276 mg, 2.05 mmol). The crude product was obtained according to the KC-36 synthesis method, purified by rapid silica gel column chromatography, eluting with dichloromethane:methanol (10:1) to give the purified product as a brown oil (104 mg, 52% yield).

[0101] 1 H NMR (400MHz, Chloroform-d) δ8.06 (s, 1H), 8.03 (s, 1H), 7.74 (d, J=8.8Hz, 2H) , 7.64 (d, J=8.8Hz, 3H), 7.57 (d, J=8.8Hz, 2H), 7.34 (d, J=8.8Hz, 2H), 6.95 (d, J=8.8Hz, 2H), 4.12 (t, J=5.4Hz, 2H), 3.38-3.16 (m, 7H), 3.05-2.95 (m, 2H), 2. 32-2.20(m, 2H), 1.82-1.70(m, 2H), 1.42-1.30(m, 8H), 0.88(t, J=7.2Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ161.44, 160.07, 158.47, 156.80, 149.44, 141.77, 138.14, 135.71, 128.74, 128.52 , 125.81, 121.60, 114.83, 64.76, 49.35, 46.85, 30.14, 25.46, 23.87, 22.38, 13.54, 8.49.HR-ESIMS(m / z):[M+H] + Calculated for C 29 H 39 N6O 487.3185, found487.3184.

[0102]

[0103] 4-((2-(4-(4-chlorophenoxy)phenyl)hydrazyl)methyl)phenol(12)

[0104] (4-(4-chlorophenoxy)phenyl)hydrazine (2.3 g, 10 mmol) was dissolved in 20 mL of anhydrous ethanol, and then added dropwise to a 20 mL anhydrous ethanol solution containing 4-hydroxybenzaldehyde (1.2 g, 10 mmol). The mixture was stirred at room temperature for 6 hours, and the solvent was removed under vacuum to obtain the crude product, which could be used in the next step without further purification.

[0105]

[0106] 4-(5-Butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenol (KC-45)

[0107] Iodine (I₂) (5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added sequentially to an acetonitrile (10 mL) solution containing 4-((2-(4-(4-chlorophenoxy)phenyl)hydrazino)methyl)phenol (68 mg, 0.2 mmol) and n-pentanylamine (94 μL, 0.8 mmol). The mixture was stirred at room temperature for 3 hours, then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, separated, the organic layer was dried, and concentrated under reduced pressure to give a crude product. This crude product was purified by rapid silica gel column chromatography, eluting with petroleum ether:ethyl acetate (8:1) to give a purified product as a brown oil (72 mg, 86% yield).

[0108] 1 H NMR (400MHz, Chloroform-d) δ7.93 (ddd, J=8.7, 4.7, 2.3Hz, 2H), 7.78-7.70 (m, 0H), 7.45-7.38 (m, 2H), 7.37-7.30 (m, 2H), 7.13-7.05 (m, 2H), 7. 03-6.95 (m, 2H), 6.82 (ddd, J=8.8, 3.1, 1.7Hz, 2H), 2.83-2.74 (m, 2H), 1 .77-1.65 (m, 2H), 1.40-1.21 (m, 3H), 0.84 (qdd, J=7.4, 4.1, 1.3Hz, 4H). 13C NMR (101MHz, Chloroform-d) δ161.27, 157.86, 157.30, 154.94, 132.50, 130.16, 128.2 5, 127.23, 120.90, 119.13, 116.17, 30.23, 26.10, 22.42, 13.72.HR-ESIMS(m / z):[M+H] + Calculated for C 24 H 23 ClN3O2420.1479, found420.1484.

[0109]

[0110] 5-Butyl-1-(4-(4-chlorophenoxy)phenyl)-3-(4-(ethylene oxide-2-ylmethoxy)phenyl)-1H-1,2,4-triazole (KC-63)

[0111] Butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenol (100 mg, 0.23 mmol), 1-chloro-2,3-epoxypropane (53 μL, 0.69 mmol), cesium carbonate (300 mg, 0.92 mmol), and potassium iodide (114 mg, 0.69 mmol) were added sequentially to 10 mL of N,N-dimethylformamide. The reaction mixture was refluxed at 80 °C for 12 hours, and the reaction was quenched by adding a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the organic phases were separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography, eluting with petroleum ether:ethyl acetate (6:1) to give the purified product as a pale yellow oil (82 mg, 75% yield).

[0112] 1 H NMR (400MHz, Chloroform-d) δ8.00 (s, 1H), 7.48 (s, 2H), 7.44 (d, J=8.3Hz, 1H), 7.39-7.32 (m, 1H), 7.13 (dd, J=8.4 , 4.3Hz, 1H), 7.05-6.99 (m, 1H), 6.97 (s, 1H), 4.06 (s, 2H), 2.99 (s, 1H), 1.38-1.26 (m, 1H), 0.85 (q, J=6.6Hz, 2H). 13C NMR (101MHz, Chloroform-d) δ161.05, 159.28, 156.54, 156.31, 154.24, 132.20, 130.33, 130.0 7, 128.77, 127.23, 121.36, 118.99, 118.76, 115.20, 29.94, 29.84, 24.89, 22.30, 13.43, 13.39.

[0113]

[0114] 5-Butyl-1-(4-(4-chlorophenoxy)phenyl)-3-(4-(2-ethoxyethoxy)phenyl)-1H-1,2,4-triazole (KC-64)

[0115] Butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenol (100 mg, 0.23 mmol), 2-chloroethyl ether (76 μL, 0.69 mmol), cesium carbonate (300 mg, 0.92 mmol), and potassium iodide (114 mg, 0.69 mmol) were added sequentially to 10 mL of N,N-dimethylformamide. The target compound was obtained according to the KC-63 synthetic method, purified by rapid silica gel column chromatography, and eluted with petroleum ether:ethyl acetate (6:1) to give the purified product as a pale yellow oil (92 mg, 81% yield).

[0116] 1 H NMR (400MHz, Chloroform-d) δ8.03 (d, J=8.9Hz, 2H), 7.41 (d, J=8.8Hz, 2H), 7.32 (d, J=8.8Hz, 2H), 7.09 (d, J=8.8Hz, 2H), 7.03-6.93 (m, 4H), 4.17-4.11 ( m, 2H), 3.81-3.75 (m, 2H), 3.59 (q, J=7.0Hz, 2H), 2.99-2.62 (m, 2H), 1.78-1 .68(m, 2H), 1.40-1.28(m, 2H), 1.23(t, J=7.2Hz, 3H), 0.87(t, J=7.2Hz, 3H). 13C NMR (101MHz, Chloroform-d) δ160.79, 160.08, 157.80, 157.05, 154.98, 132.61, 130.14, 129.42, 128.02, 127.12, 123.14, 120.86, 119.13, 114.79, 68.99, 67.57, 66.98, 30.22, 26.10, 22.45, 15.25, 13.73.HR-ESIMS(m / z):[M+H] + Calculated for C 28 H 31 ClN3O3492.2054, found 492.2052.

[0117]

[0118] 1-(2-(4-(5-butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenoxy)ethyl)piperidine (KC-65)

[0119] Butyl-1-(4-(4-chlorophenoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenol (100 mg, 0.23 mmol), 1-(2-chloroethyl)piperidine hydrochloride (127 mg, 0.69 mmol), cesium carbonate (300 mg, 0.92 mmol), and potassium iodide (114 mg, 0.69 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The target compound was obtained according to the KC-63 synthetic method, purified by rapid silica gel column chromatography, and eluted with dichloromethane:methanol (30:1) to give the purified product as a pale yellow oil (97 mg, 80% yield).

[0120] 1 H NMR (400MHz, Chloroform-d) δ8.02 (d, J=8.0Hz, 2H), 7.42 (d, J=8.8Hz, 2H), 7.35 (d , J=8.8Hz, 2H), 7.12 (d, J=8.8Hz, 2H), 7.01 (d, J=8.8Hz, 2H), 6.95 (d, J=8.0Hz, 2H) , 4.39 (s, 2H), 3.82-3.60 (m, 2H), 3.49 (s, 2H), 3.03-2.91 (m, 2H), 2.91-2.76 (m, 2H ), 2.02-1.80(m, 4H), 1.78-1.64(m, 2H), 1.50-1.20(m, 4H), 0.85(t, J=7.2Hz, 3H). 13C NMR (101MHz, Chloroform-d) δ159.20, 158.89, 157.73, 156.76, 154.43, 130.95, 130.28, 129.90, 128.77, 127.19, 121 .28, 121.24, 119.02, 114.96, 62.64, 56.07, 54.20, 30.01, 25.21, 22.91, 22.32, 21.75, 13.48.HR-ESIMS(m / z):[M+H] + Calculated for C 31 H 36 ClN4O2531.2527, found 531.2528.

[0121]

[0122] 4-(5-butyl-1-(4-phenoxyphenyl)-1H-1,2,4-triazol-3-yl)phenol(KC-74):

[0123] Iodine I₂ (5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added to an acetonitrile (10 mL) solution containing 4-((2-(4-phenoxyphenyl)hydrazino)methyl)phenol (61 mg, 0.2 mmol) and n-pentylamine (94 μL, 0.8 mmol). The mixture was stirred at room temperature for 3 hours, and then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, the organic layer was dried, concentrated, and purified by rapid silica gel column chromatography, eluting with petroleum ether:ethyl acetate (8:1) to give the purified product as a brown oil (58 mg, 75%).

[0124] 1 H NMR (400MHz, Chloroform-d) δ7.96 (d, J=8.7Hz, 2H), 7.44-7.35 (m, 4H), 7.17 (t, J=7.4Hz, 1H), 7.10 (d, J=8.9Hz, 2H), 7.06 ( d, J=7.6Hz, 2H), 6.84 (d, J=8.7Hz, 2H), 2.86-2.72 (m, 2H), 1.72 (p, J=7.6Hz, 2H), 1.39-1.28 (m, 2H), 0.85 (t, J=7.3Hz, 3H). 13CNMR (101MHz, Chloroform-d) δ161.25, 158.18, 157.35, 157.24, 156.32, 132.31, 130.14, 128.22, 1 27.09, 124.31, 123.06, 119.67, 119.04, 115.68, 30.26, 26.18, 22.45, 13.76.HR-ESIMS(m / z):[M+H] + Calculated for C 24 H 24 N3O2386.1869, found 386.1868.

[0125]

[0126] 5-Butyl-1-(4-phenoxyphenyl)-3-(4-propoxyphenyl)-1H-1,2,4-triazole (KC-57)

[0127] 4-(5-Butyl-1-(4-phenoxyphenyl)-1H-1,2,4-triazol-3-yl)phenol (89 mg, 0.23 mmol), 1-iodopropane (200 μL, 2.1 mmol), and potassium carbonate (127 mg, 0.92 mmol) were added sequentially to 10 mL of acetonitrile. The reaction mixture was refluxed at 80 °C for 12 hours. After the reaction was complete, the product was cooled to room temperature, filtered, and the solvent in the filtrate was removed under reduced pressure. The residue was dissolved in 30 mL of ethyl acetate, washed with water, separated, and the organic layer was dried. The crude product was concentrated under reduced pressure and purified by rapid silica gel column chromatography, eluting with petroleum ether:ethyl acetate (4:1) to obtain a purified product, which was a pale yellow oil (76 mg, yield 77%).

[0128] 1 H NMR (400MHz, Chloroform-d) δ8.03 (d, J=8.8Hz, 2H), 7.46-7.31 (m, 4H), 7.18 (t, J=7.2Hz, 1H), 7.14-7.04 (m, 4H), 3.95 ( t, J=6.4Hz, 2H), 2.93-2.82 (m, 2H), 1.87-1.67 (m, 4H), 1.42-1.28 (m, 2H), 1.03 (t, J=7.2Hz, 3H), 0.87 (t, J=7.2Hz, 3H). 13C NMR (101MHz, Chloroform-d) δ160.78, 159.68, 158.67, 156.86, 156.11, 131.59, 130.19, 128.25, 127.07, 1 24.50, 121.52, 119.81, 118.99, 114.77, 69.65, 30.20, 25.69, 22.64, 22.41, 13.65.HR-ESIMS(m / z):[M+H] + Calculated for C 27 H 30 N3O2428.2338, found428.2343.

[0129]

[0130] 5-Butyl-3-(4-isopropoxyphenyl)-1-(4-phenoxyphenyl)-1H-1,2,4-triazole (KC-58)

[0131] 4-(5-Butyl-1-(4-phenoxyphenyl)-1H-1,2,4-triazol-3-yl)phenol (89 mg, 0.23 mmol), 2-iodopropane (200 μL, 2.0 mmol), and potassium carbonate (127 mg, 0.92 mmol) were added sequentially to 10 mL of acetonitrile. The target compound was obtained according to the KC-57 synthetic method, purified by rapid silica gel column chromatography, and eluted with petroleum ether:ethyl acetate (4:1) to give the purified product as a pale yellow oil (84 mg, 85% yield).

[0132] 1 H NMR (400MHz, Chloroform-d) δ8.03 (d, J=8.8Hz, 2H), 7.44-7.33 (m, 4H), 7.17 (t, J=7.4Hz, 1H), 7.13-7.04 (m, 4H), 6.9 4 (d, J=8.8Hz, 2H), 4.66-4.54 (m, 1H), 2.99-2.76 (m, 2H), 1.80-1.68 (m, 2H), 1.45-1.25 (m, 8H), 0.87 (t, J=7.2Hz, 3H). 13C NMR (101MHz, Chloroform-d) δ159.71, 159.56, 158.65, 156.84, 156.11, 131.61, 130.18, 128.29, 127. 06, 124.50, 121.46, 119.81, 118.98, 115.95, 70.00, 30.19, 25.70, 22.40, 22.08, 13.65, 10.60.HR-ESI MS(m / z):[M+H] + Calculated for C 27 H 30 N3O2428.2338, found 428.2338.

[0133]

[0134] 3-(4-(5-Butyl-1-(4-phenoxyphenyl)-1H-1,2,4-triazol-3-yl)phenoxy)-N,N-diethylpropane-1-amine (KC-59)

[0135] 4-(5-Butyl-1-(4-phenoxyphenyl)-1H-1,2,4-triazol-3-yl)phenol (89 mg, 0.23 mmol), 3-chloro-N,N-diethylpropane-1-amine (112 μL, 0.69 mmol), cesium carbonate (300 mg, 0.92 mmol), and sodium iodide (114 mg, 0.69 mmol) were sequentially added to 10 mL of N,N-dimethylformamide. The target compound was obtained according to the KC-63 synthetic method, purified by rapid silica gel column chromatography, and eluted with dichloromethane:methanol (30:1) to give the purified product as a pale yellow oil (92 mg, 80% yield).

[0136] 1 H NMR (400MHz, Chloroform-d) δ8.02 (d, J=8.8Hz, 2H), 7.43-7.36 (m, 4H), 7.19 (t, J=7.2Hz, 1H), 7.16-7.05 (m, 4H), 6.94 (d, J=8.8Hz, 2H), 4. 09 (t, J=5.4Hz, 2H), 3.34-3.12 (m, 6H), 2.98-2.87 (m, 2H), 2.29-2.17 (m, 2H), 1.78-1.66 (m, 2H), 1.40-1.28 (m, 8H), 0.86 (t, J=7.2Hz, 3H). 13C NMR (101MHz, Chloroform-d) δ160.14, 159.29, 157.92, 156.70, 155.78, 130.63, 130.26, 128.67, 127.08, 124.76, 12 0.80, 120.00, 118.92, 114.84, 64.75, 49.25, 46.88, 30.04, 25.22, 23.79, 22.33, 13.50, 8.48.HR-ESIMS(m / z):[M+H] + calculated for C 31 H 39 N4O2499.3073, found499.3073.

[0137] Example 2

[0138] The human triple-negative breast cancer cell line SUM149 was cultured using standard methods, and the cell density was adjusted to approximately 3 × 10⁻⁶ cells / year. 4 A single-cell suspension of 100 μL / mL was evenly seeded into each well of a 96-well plate using a pipette. The plates were then incubated at 37°C in a 5% CO2 incubator for 24 hours.

[0139] Cells were removed and the test compounds were added: the experiment consisted of a blank group and different dose groups. The blank group received 100 μL of UMS149 cell culture medium. For each dose group, four concentrations of each compound were tested, with three replicates per concentration. 100 μL of the compound solution at concentrations of 2.5, 5, 10, and 20 μM were added, resulting in final test concentrations of 1.25, 2.5, 5, and 10 μM. Cells were incubated at 37°C in a 5% CO2 incubator for 48 hours. The culture medium was then removed, and freshly prepared MTS reagent was added. Cells were incubated at 37°C for 1-4 hours. The OD value was measured at 490 nm using a microplate reader, and the readings were transferred to GraphpadPrism software to calculate the IC50. 50 Equal values.

[0140] If some compounds IC are found 50 If the value is below 1.25 μM, reduce the concentration and test again using the method described above.

[0141] The experimental results are shown in Table 1, indicating that some azirregular triazole derivatives have a good inhibitory effect on the growth of human triple-negative breast cancer cell line SUM149, with an IC50 score of 1.5%. 50 The values ​​ranged from μM to nM, with the most active KC-37 at 0.220 ± 0.034 μM; the other compounds showed lower cytotoxic activity, with inhibition rates <50% at the maximum tested concentration (10 (M)).

[0142] Table 1. Growth inhibitory effect of azirregular triazole derivatives on human triple-negative breast cancer cell line SUM149

[0143] Comp. <![CDATA[IC 50 (μM)]]> Comp. <![CDATA[IC 50 (μM)]]> Azeliragon 5.292±0.310 KC-44 0.328±0.057 KC-6 6.295±0.474 KC-46 0.487±0.092 KC-36 0.593±0.012 KC-48 0.664±0.005 KC-37 0.220±0.034 KC-49 0.665±0.008 KC-38 0.588±0.035 KC-59 0.538±0.060 KC-40 5.434±0.358 KC-63 7.045±0.248 KC-43 0.267±0.020 KC-65 5.682±0.464

Claims

1. A triazolyl-containing compound of the formula: ###0001### 2. Use of the compound of claim 1 in the preparation of a medicament for the treatment of breast cancer.

3. Use of the compound of claim 1 in the preparation of a medicament for the treatment of triple negative breast cancer.

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