Triazole compounds

Abstract

The invention mainly relates to a triazole compound, belongs to the technical field of medicines, and particularly relates to synthesis of an advanced glycosylation end product receptor inhibitor and application of the advanced glycosylation end product receptor inhibitor in the aspect of breast cancer resistance. The preparation method comprises the following steps: carrying out skeleton transition on an azilrepel structure, replacing diazole of the original structure with 1, 2, 4-triazole, and then carrying out structure derivation. An in-vitro pharmacological activity experiment result shows that part of the derivatives have a good growth inhibition effect on a human triple negative breast cancer cell line SUM149, the IC50 value is in the level of mu M to nM, and the compound with the best activity is 0.220 + / -0.034 mu M; the other compounds have low cytotoxic activity, and the inhibition rate at the maximum test concentration (10 [mu] M) is less than 50%.

Description

[0001] This application is a divisional application with an application date of June 28, 2021, application number 202110716283.X, and invention name "Azireg triazole derivatives and their use in anti-breast cancer". Technical Field

[0002] The invention belongs to the technical field of medicines and mainly relates to triazole compounds. Background Art

[0003] The receptor for advanced glycation end products (RAGE) is an immunoglobulin on the cell membrane and belongs to the pattern recognition receptor. RAGE is widely present in a variety of cells and is commonly expressed in tissues such as mononuclear macrophages, vascular endothelial cells, tumor cells, renal mesangial cells, nerve cells and smooth muscle cells. At present, there are many literatures proving that RAGE is closely related to the occurrence, development and metastasis of breast cancer. With the growth, metastasis and recurrence of breast cancer, the marker signal of RAGE increases significantly. The results of the clinical trial on the relationship between RAGE-related receptors and breast cancer (NCT02103387) showed that there is a strong correlation between the two. It can be seen that 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 codenamed PF-04494700 or TTP488, CAS No.: 603148-36-3), with the structural formula shown below, is a RAGE inhibitor currently in clinical trials.

[0005]

[0006] Azireg's R&D company applied for patent protection, among which patent WO200307592 applied for patents for the following compounds:

[0007]

[0008] In the formula, R1 is -hydrogen, -aryl, -heterocyclyl, -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 a heterocyclylene group, an arylene group, an alkylene group, a cycloalkylene group, a heteroarylene group, and a direct bond;

[0010] G is alkylene, -O-, -C(O), -CO 2 -, or direct key; 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)-Y 4 -NR 23 R 24 ; e)-Y 4 -NH-C(=NR 25 )NR 23 R 24 .

[0016] Patent WO2011041198 applied for the following compound patents:

[0017]

[0018] In the formula, R1 and R2 are independently selected from the following group: -CH 3 , -CH 2 CH 3 ,-CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 ;

[0019] Q1 is selected from: -CH 2 OCH 2 CH 3 or -CH 2 CH 2 CH 2 CH 3 .

[0020] Hudson et al. found that compounds such as Azirig have anti-breast cancer activity and applied for related patents (WO2019094613A1). Through preliminary experiments and computer-aided drug design, our research group found that the structure of Azirig can be subjected to skeleton transition, replacing the diazole of the original structure with 1,2,4-triazole, and then the structure is derived, as shown below. The calculation results of software such as molecular docking show that the skeleton transition has a stronger affinity for RAGE. Therefore, it may still have good anti-breast cancer activity.

[0021] Summary of the invention

[0022] The purpose of the present invention is to synthesize triazole derivatives of azireg, an advanced glycation end product receptor inhibitor, to explore drugs or lead compounds that may become anti-breast cancer drugs and to provide triazole compounds.

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

[0024] First, according to the following synthetic method, 1,2,4-triazole is used to replace the diazole in the center of the azirrig structure to obtain the skeleton transition product KC-6.

[0025]

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

[0027]

[0028]

[0029] DETAILED DESCRIPTION

[0030] The present invention will be further described below in conjunction with the 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), and the mixture was heated under reflux for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and 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 distillation under reduced pressure to obtain a colorless oily liquid (4.6 g, yield 97.9%).

[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 the addition, the reaction mixture was stirred at 0°C for 1.5 hours, and then a stannous chloride solution (4.7 g, 25 mmol, dissolved in 25 mL of 12N concentrated hydrochloric acid) was added dropwise. After the addition, the mixture was stirred at room temperature for another 2.5 hours, and then the pH was adjusted to 7 with an ice-cold aqueous sodium hydroxide solution. 200 mL of ethyl acetate was added, and the precipitate formed was filtered off, the organic layer was washed with water, the liquid was separated, the organic layer was dried, and the crude product was concentrated under reduced pressure, which was purified by a rapid silica gel column, eluted 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 of 4-(3-(diethylamino)propoxy)benzaldehyde (2.3 g, 10 mmol) dissolved in 20 mL of anhydrous ethanol. The mixture was stirred at room temperature for 2 hours and the solvent was removed in vacuo to obtain a crude product, which was 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 I 2 (5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added to a solution of 3-(4-((2-(4-(4-chlorophenoxy)phenyl)hydrazine)methyl)phenoxy)-N,N-diethylpropane-1-amine (90 mg, 0.2 mmol) and n-pentylamine (94 μL, 0.8 mmol) in acetonitrile (10 mL). 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 flash silica gel column eluting with petroleum ether: ethyl acetate (6: 1) to give the purified product as a light 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). 13 C 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 C1N 4 O 2 533.2683, found 533.2682.

[0045]

[0046] 1-(4-Bromobenzylidene)-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 solution of 4-bromobenzaldehyde (1.85 g, 10 mmol) in 20 mL of anhydrous ethanol. The mixture was stirred for 2 hours and the solvent was removed in vacuo to give a crude product which was 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 I 2(5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added to a solution of 1-(4-bromobenzylidene)-2-(4-(4-chlorophenoxy)phenyl)hydrazine (80 mg, 0.2 mmol) and n-pentylamine (94 μL, 0.8 mmol) in acetonitrile (10 mL). The crude product was obtained according to the synthetic method of KC-6 and purified by flash silica gel column, eluted with petroleum ether: ethyl acetate (6: 1) to obtain the purified product as a brown oil (70 mg, yield 73%).

[0051] 1 H 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), and (4-methoxyphenyl)boronic acid (91.2 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol) and 2M aqueous potassium carbonate solution (276 mg, 2.05 mmol) were added in sequence. The solution was degassed with an argon stream for 3 minutes, and then the reaction vessel was sealed into a sealed tube and stirred at 90°C for 12 hours to obtain a black mixture, which 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 in vacuo to obtain the crude product. Purification by silica gel column eluting with petroleum ether:ethyl acetate (10:1) gave the title compound as a brown oil (119 mg, yield 57%).

[0055] 1 H 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 C1N 3 O 2 510.1948, found 510.1948.

[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, the reaction mixture was stirred at 0°C for 1.5 hours, and then a stannous chloride solution (4.7 g, 25 mmol, dissolved in 25 mL of 12M concentrated hydrochloric acid) was added dropwise, and the resulting mixture was stirred at room temperature for another 2.5 hours. After the reaction was completed, an ice-cold aqueous sodium hydroxide solution was added dropwise to adjust the pH to >7. 200 mL of ethyl acetate was added, the precipitate formed was filtered out, the filtrate was separated into an organic layer, dried, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography using petroleum ether: ethyl acetate (4:1) as eluent. The purified product was obtained as a yellow solid (1.1 g, 59% yield).

[0059]

[0060] 3-(4-((2-(4-bromophenyl)hydrazine)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 solution of 4-(3-(diethylamino)propoxy)benzaldehyde (2.3 g, 10 mmol) in 20 mL of absolute ethanol. The mixture was stirred for 2 hours and the solvent was removed in vacuo to give a crude product which was 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 I 2 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 and washed with water. The organic layer was dried, concentrated, and purified by flash silica gel column eluting with petroleum ether: ethyl acetate (8: 1) to give the purified product as a brown oil (82 mg, 84% yield).

[0065] 1H 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), and (4-(trifluoromethyl)phenyl)boric acid (114 mg, 0.6 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol) and 2M potassium carbonate aqueous solution (276 mL) were added in sequence. The solution was degassed with an argon stream for 3 minutes, and then the reaction vessel was sealed and stirred at 90°C for 20 hours to give a black mixture, which 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 in vacuo to give a crude product. Purification by flash silica gel column eluting with dichloromethane: methanol (10: 1) gave the purified product as a colorless oil (82 mg, 38% yield).

[0069] 1H 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), and 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (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) were added in sequence. The crude product was obtained according to the synthesis method of KC-36, and purified by flash silica gel column, eluted with dichloromethane: methanol (10: 1), to obtain the purified product as a brown oil (121 mg, yield 57%).

[0073] 1H 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 C1N 4 O 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), and (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) were added in sequence. The crude product was obtained according to the synthesis method of KC-36, and purified by flash silica gel column, eluted with dichloromethane: methanol (10: 1), to obtain the purified product as a yellow oil (107 mg, yield 51%).

[0077] 1H 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 41 N 4 O 2 513.32230, found 513.3227.

[0078]

[0079] 4'-(5-butyl-3-(4-(3-(diethylamino)propoxy)phenyl)-1H-1,2,4-triazol-1-yl)-[1,1'-biphenyl]-4-carbonitrile (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), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were added in sequence. The crude product was obtained according to the synthesis method of KC-36, and purified by flash silica gel column, eluted with dichloromethane: methanol (10: 1), to obtain the purified product as a yellow oil (131 mg, yield 63%).

[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). 13 C 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 N 5 O 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 in sequence. The crude product was obtained according to the synthesis method of KC-36, and purified by flash silica gel column, eluted with dichloromethane: methanol (10: 1), to obtain the purified product as a yellow oil (92 mg, yield 45%).

[0085] 1 H 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 N 4 O 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), and (4-(ethoxycarbonyl)phenyl)boric 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) were added in sequence. The crude product was obtained according to the synthesis method of KC-36 and purified by flash silica gel column eluting with dichloromethane: methanol (10: 1) to obtain the purified product as a brown oil (116 mg, yield 51%).

[0089] 1 H 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 N 4O 3 555.3335, 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), and (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) were added in sequence. The crude product was obtained according to the synthesis method of KC-36, and purified by flash silica gel column, eluted with dichloromethane: methanol (10: 1), to obtain the purified product as a brown oil (104 mg, yield 47%).

[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). 13C 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 N 4 O 3 543.3335, 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), and (4-(trifluoromethoxy)phenyl)boric 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) were added in sequence. The crude product was obtained according to the synthesis method of KC-36, and purified by flash silica gel column, eluted with dichloromethane: methanol (10: 1), to obtain the purified product as a yellow oil (116 mg, yield 50%).

[0097] 1H 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 F 3 N 4 O 2 567.2947, 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), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan)-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) were added in sequence. The crude product was obtained according to the synthetic method of KC-36, and purified by flash silica gel column, eluted with dichloromethane: methanol (10: 1), to obtain the purified product as a brown oil (104 mg, yield 52%).

[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 N 6 O 487.3185, found 487.3184.

[0102]

[0103] 4-((2-(4-(4-chlorophenoxy)phenyl)hydrazino)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 solution of 4-hydroxybenzaldehyde (1.2 g, 10 mmol) in 20 mL of anhydrous ethanol. The mixture was stirred at room temperature for 6 hours and the solvent was removed in vacuo to give a crude product which was 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 (I 2) (5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added sequentially to a solution of 4-((2-(4-(4-chlorophenoxy)phenyl)hydrazine)methyl)phenol (68 mg, 0.2 mmol) and n-pentylamine (94 μL, 0.8 mmol) in acetonitrile (10 mL). The mixture was stirred at room temperature for 3 hours, after which the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, separated, and the organic layer was dried and concentrated under reduced pressure to obtain a crude product, which was purified by flash silica gel column eluting with petroleum ether: ethyl acetate (8: 1) to obtain a purified product as a brown oil (72 mg, yield 86%).

[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). 13 C 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 C1N 3 O 2 420.1479, found 420.1484.

[0109]

[0110] 5-Butyl-1-(4-(4-chlorophenoxy)phenyl)-3-(4-(oxiran-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 to 10 mL of N,N-dimethylformamide. The reactants were refluxed at 80°C for 12 hours, and saturated aqueous ammonium chloride solution was added to quench the reaction. The aqueous layer was extracted with ethyl acetate, separated, and the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column eluted with petroleum ether: ethyl acetate (6: 1) to obtain the purified product as a light yellow oil (82 mg, yield 75%).

[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). 13 C 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 to 10 mL of N,N-dimethylformamide in sequence. The target compound was obtained according to the synthetic method of KC-63 and purified by flash silica gel column, eluted with petroleum ether: ethyl acetate (6: 1) to obtain the purified product as a light yellow oil (92 mg, yield 81%).

[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). 13 C 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 C1N 3 O 3 492.2054, 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 synthetic method of KC-63 and purified by flash silica gel column, eluted with dichloromethane: methanol (30: 1) to obtain the purified product as a light yellow oil (97 mg, yield 80%).

[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). 13 C 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 C1N 4 O 2 531.2527, found 531.2528.

[0121]

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

[0123] Iodine I 2 (5 mg, 0.02 mmol) and TBHP (70% aqueous solution, 114 μL, 0.8 mmol) were added to a solution of 4-((2-(4-phenoxyphenyl)hydrazine)methyl)phenol (61 mg, 0.2 mmol) and n-pentylamine (94 μL, 0.8 mmol) in acetonitrile (10 mL). 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, the organic layer was dried, concentrated, and purified by flash silica gel column 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). 13 CNMR (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 N 3 O 2 386.1869, 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 to 10 mL of acetonitrile in sequence. The reactants were refluxed at 80° C. for 12 hours. After the reaction was completed, the product was cooled to room temperature and filtered. The solvent of the filtrate was evaporated under reduced pressure. The residue was dissolved in 30 mL of ethyl acetate, washed with water, separated, and the organic layer was dried and concentrated under reduced pressure to obtain a crude product, which was purified by a rapid silica gel column and eluted with petroleum ether: ethyl acetate (4:1) to obtain a purified product as a light 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). 13 C 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 N 3 O 2 428.2338, found 428.2343.

[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 to 10 mL of acetonitrile in sequence. The target compound was obtained according to the synthesis method of KC-57 and purified by flash silica gel column, eluted with petroleum ether: ethyl acetate (4: 1) to obtain the purified product as a light yellow oil (84 mg, yield 85%).

[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). 13 C 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 N 3 O 2 428.2338, 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 added to 10 mL of N,N-dimethylformamide in sequence. The target compound was obtained according to the synthetic method of KC-63 and purified by flash silica gel column, eluted with dichloromethane: methanol (30: 1) to obtain the purified product as a light yellow oil (92 mg, yield 80%).

[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). 13 C 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 N 4 O 2 499.3073, found 499.3073.

[0137] Example 2

[0138] The human triple-negative breast cancer cell line SUM149 was cultured according to conventional methods and the cell density was adjusted to approximately 3×10 4 / mL single cell suspension was pipetted and evenly inoculated into a 96-well plate, 100 μL per well. 2 Incubate incubator for 24 hours.

[0139] Remove the cells and add the test compound: the test is divided into a blank group and different dose groups. The blank group is added with 100 μL SUM149 cell culture medium; each compound in the different dose groups is tested at 4 concentrations, and 3 parallel wells are set for each concentration. 100 μL of compound solution with concentrations of 2.5, 5, 10, and 20 μM is added respectively, that is, the final test concentration is 1.25, 2.5, 5, and 10 μM. Place at 37°C and 5% CO 2 Incubate for 48 hours, remove the culture medium, add freshly prepared MTS reagent, place in a 37°C incubator for 1-4 hours, measure the OD value at 490nm on a microplate reader, and transfer the reading to GraphpadPrism software to calculate IC 50 Equal values.

[0140] If some compounds are found to be IC 50 If the value is lower than 1.25 μM, reduce the concentration and test again according to the above method.

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

[0142] Table 1 Growth inhibition of triazole derivatives of azireg 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 triazole compound of general formula B: In the formula R2 is selected from phenyl or 4-halophenyl; R3 is selected from N,N-diethyl-3-propylamino, oxiranemethyl or piperidine-2-ethyl.

2. The compound according to claim 1, characterized in that The structure of the compound is shown below:

3. The compound according to claim 1, characterized in that The structure of the compound is shown below:

4. The compound according to claim 1, characterized in that The structure of the compound is shown below:

5. The compound according to claim 1, characterized in that The structure of the compound is shown below:

6. Use of the compound according to claims 1-5 in the preparation of anti-breast cancer drugs.

7. Use of the compound according to claims 1-5 in the preparation of an anti-triple-negative breast cancer drug.

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