Preparation and application of 5-aryl substituted 1, 2, 4-triazole iron death inhibitor

Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses a preparation method and application of a 5-aryl substituted 1, 2, 4-triazole iron death inhibitor derivative. The derivative has a structural general formula as shown in the following formula (I), wherein Ar1 and Ar2 substituent groups can be combined at will. The compound can be used for efficiently removing cell lipid peroxides and effectively inhibiting ferroptosis processes of various cells. Particularly, the compound SN26 has optimal ferroptosis inhibitory activity (786-O cell line, EC50 = 62nM), and can effectively improve acute liver injury of mice caused by concanavalin by inhibiting ferroptosis. The research is expected to be used for developing ferroptosis inhibitors and research and development of small molecule drugs for related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method and application of a 5-aryl substituted 1,2,4-triazole ferrocephalostatin derivative. Background Art

[0002] Ferroptosis, first proposed by Dr. Brent R. Stockwell in 2012, is an iron-dependent form of programmed cell death that is different from apoptosis, necrosis, and autophagy. It is characterized by iron ion overload, lipid peroxide accumulation, and increased mitochondrial membrane density. Studies have shown that ferroptosis plays a key role in a variety of pathological conditions, including tissue ischemia-reperfusion injury, neurodegenerative diseases, inflammatory diseases, as well as autoimmunity, infection, and cancer. Therefore, inhibiting the ferroptosis process may provide a new therapeutic approach for these diseases and improve the therapeutic effect. At present, the reported ferroptosis inhibitors are mainly divided into two categories: iron chelators and free radical trapping antioxidants. For example, deferoxamine, as an iron chelator, is widely used in the treatment of traumatic spinal cord injury; Fer-1, as an arylalkylamine free radical trapping antioxidant, can inhibit the accumulation of lipid peroxides in the ferroptosis model in HT-1080 cells. In addition, phenolic compounds are also a class of effective lipid peroxide scavengers and have been shown to inhibit cellular ferroptosis, although their activity may be limited by hydrogen bonds formed with polar phospholipid heads; FSP1 inhibits ferroptosis by catalyzing the conversion of vitamin K into hydroquinone, preventing lipid peroxidation.

[0003] Although research on ferroptosis inhibitors is increasingly abundant, the above-mentioned iron chelators and free radical-trapping antioxidants still have many shortcomings, including weak activity or poor pharmacokinetic properties, which limit their clinical application. Therefore, the development of new ferroptosis inhibitors is of great clinical significance for the treatment of ferroptosis-related diseases, but it also faces many challenges. Summary of the invention

[0004] In order to improve the deficiencies of the above-mentioned technology, the present invention provides a preparation method and use of a 5-aryl substituted 1,2,4-triazole ferroptosis inhibitor derivative. This type of compound can effectively inhibit the ferroptosis process of various cells and exert an inhibitory effect on ferroptosis. In a mouse liver injury model, the compound effectively improved the pathological condition of acute liver injury in mice by inhibiting ferroptosis.

[0005] In order to achieve the above technical effects, the present invention is implemented through the following technical solutions:

[0006] A 5-aryl substituted 1,2,4-triazole derivative having a general structural formula as shown in the following formula (I):

[0007]

[0008] Ar1 can be any of the following substituents. The wavy line indicates the position of the substituent, and the number 5 indicates the site where Ar1 is chemically bonded to 1,2,4-triazole.

[0009]

[0010] Wherein, the Ar2 group can be selected from any of the following substituent groups. The wavy line indicates the position of the substituent.

[0011]

[0012] The above Ar1 and Ar2 substituent groups may be combined arbitrarily.

[0013] Furthermore, the 5-aryl substituted 1,2,4-triazole ferrochlorephate inhibitor is one of compounds NY1-NY28, and Ar1 and Ar2 in NY1-NY28 are shown in the following table.

[0014]

[0015]

[0016] The present invention also provides a method for preparing the above-mentioned 1,2,4-triazole derivative substituted with a 5-aryl group, comprising the following steps:

[0017] The synthesis of compounds NY1-NY28 comprises four steps (see Appendix Figure 1 ), the steps are as follows:

[0018] (1) Synthesis of intermediate (Z)-2-oxo-N-phenylpropanhydrazone chloride 3: A suitable amount of aniline (10 mmol, 1 eq.) was dissolved in 24 mL of 2M HCl, and NaNO2 (10 mmol) was dissolved in 3 mL of H2O, and then added dropwise into the reaction system at 0-5°C to obtain a diazotized aniline solution. Subsequently, the newly prepared diazotized aniline solution was added dropwise at 5-10°C to a precooled mixture (0°C) of a methanol solution (50 mL) of 3-chloropentane-2,4-dione (10 mmol, 1 eq.) and NaOAc (48 mmol, 4.8 eq.). After reacting for 2 hours, the solid was obtained by vacuum filtration and washed with H2O to obtain a light yellow solid compound 3 in a yield of 87%.

[0019] (2) General method for the synthesis of intermediates 6a-zd: K2CO3 (40mmol, 4eq.), TBAI (4mmol, 0.25eq.) and 2-hydroxybenzaldehyde derivatives (4a-f, 20mmol, 2eq.) were added to a stirred solution of benzyl chloride derivatives (5a-y, 10mmol, 1eq.) in DMF (70mL) under N2 protection at room temperature. The mixture was stirred at room temperature for 0.5 hours, then heated to 60°C and stirred for 4 hours. The mixture was cooled, filtered through a celite pad, 10mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10mL*3 times). Washed with saturated brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography eluting with petroleum ether / ethyl acetate to obtain 65%-85% of the target compound 6a-zd as a white solid.

[0020] (3) General method for the synthesis of intermediates 7a-zd: To a 0.32 M solution of 2-(benzyloxy)-3-methoxybenzaldehyde derivative (6a-zd, 1.46 mmol, 1 eq.) in dichloromethane, 4A molecular sieves (1 g / mmol), aniline derivative (1.61 mmol, 1.1 eq.) and pyrrolidine (0.146 mmol, 0.1 eq.) were added. The mixture was stirred at 45°C for 4 hours. After cooling to room temperature, the mixture was filtered and concentrated. The crude product was used directly in the next step.

[0021] (4) General method for the synthesis of NY1-NY28: To a solution of (Z)-4-((2-(benzyloxy)-3-methoxybenzylidene)amino)-N,N-dimethylaniline derivative (7a-zd, 5 mmol, 1 eq.) and intermediate 3 (5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) was added triethylamine (1.4 mL, 10 mmol, 2 eq.) at room temperature. The reaction mixture was refluxed for 8 hours. Deionized water was then added to the mixture, and it was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether / ethyl acetate to give the target compound.

[0022] The present invention provides a use of a 5-aryl substituted 1,2,4-triazole ferrocephalosporin derivative, wherein the use is for protecting acute liver injury.

[0023] The 5-aryl substituted 1,2,4-triazole derivative of the present invention exhibits certain activity of inhibiting cell ferroptosis. As a further preferred embodiment, the 5-aryl substituted 1,2,4-triazole derivative is compound NY26.

[0024] Compared with the existing technology, the technical effect of the present invention is embodied in that: the present invention provides a ferroptosis inhibitor with a novel structure, and the compound NY26 exhibits excellent free radical scavenging effect and has a significant ferroptosis inhibitory effect on a variety of cells (see the attached Figure 2 ). BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The preparation process flow chart of compounds NY1-NY28 is shown in FIG.

[0026] Figure 2 The inhibitory effect of compounds NY1-NY28 on ferroptosis of various cells

[0027] Figure 3 The effect of compound NY26 on protecting mice from acute liver injury DETAILED DESCRIPTION

[0028] The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0029] The present invention discloses a 5-aryl substituted 1,2,4-triazole derivative having a general structural formula (I) as shown below. The preparation process flow chart of the structure is shown in the attached specification. Figure 1 :

[0030]

[0031] The present invention adopts the following general characterization method for the following embodiments:

[0032] Product testing conditions in the following examples: The characterization of the examples was performed using 600 Hz nuclear magnetic resonance spectroscopy (Bruker AVANCE III 600), with deuterated chloroform or deuterated dimethyl sulfoxide as solvent; and tetramethylsilane (TMS) as internal standard. The nuclear magnetic resonance data of the example compounds are reported as follows: 1 H NMR chemical shift, in δ; peak shape: s = singlet, d = doublet, t = triplet, m = multiplet, coupling constant J (in Hz); 13 C NMR data are reported as chemical shifts; the example compounds were further verified by high-resolution mass spectrometry HRMS (instrument model Vanquish Flex+Oribit RapExploris 120, Thermo Fisher Scientific, USA).

[0033] Example 1

[0034] Compound NY1 of this example: 1-(5-(2-(2,4-dichlorobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0035] The specific structural formula of compound NY1 is:

[0036] The preparation method of compound NY1 is as follows:

[0037] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(2,4-dichlorobenzyl)oxy)-3-methoxybenzylidene)amino)-N,N-dimethylaniline (7a, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture and extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY1 as a yellow solid (291 mg, yield 51%). Its structural characterization data are as follows: 1 H NMR(600MHz, CDCl3)δ7.40(d,J=8.4Hz,1H),7.28(d,J=1.8Hz,1H),7.24–7.2 0(m,2H),7.18(m,2H),7.14(t,J=8.4Hz,1H),7.10–7.07(m,2H),6.92(dd,J= 7.8,1.2Hz,1H),6.86(t,J=1.2Hz,1H),6.76(s,1H),6.70–6.67(m,2H),6.45 –6.42(m,2H),5.06(d,J=13.2Hz,1H),3.85(s,3H),2.87(s,6H),2.45(s,3H). 13 C NMR (150MHz, CDCl3) δ188.5,152.5,149.5,146.0,146.0,143.5,142.9,133.9,132.5,132.1,131.0,129 .3,127.7,127.5,125.3,121.2,120.7,119.0,113.7,113.1,112.7,111.2,84.1,73.4,55.9,40.7,26.7.

[0038] Example 2

[0039] Compound NY2 of this example: 1-(5-(2-(2,4-dichlorobenzyl)oxy)-3-methylphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0040] The specific structural formula of compound NY2 is:

[0041] The preparation method of compound NY1 is as follows:

[0042] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(2,4-dichlorobenzyl)oxy)-3-methylbenzylidene)amino)-N,N-dimethylaniline (7b, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY2 as a yellow solid (230 mg, yield 42%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.38–7.34(m,2H),7.22–7.17(m,2H),7.08–7.02(m,3H),6.96(d,J=8.4Hz,1H),6.87–6.81(m,3H),6. 74–6.67(m,3H),6.49–6.45(m,2H),5.07(d,J=13.2Hz,1H),4.86(d,J=13.2Hz,1H),2.86(s,6H),2.48(s,3H),2.33(s,3H). 13 C NMR (150MHz, CDCl3) δ188.6,155.8,146.0,142.9,140.9,133.9,133.3,132.7,129.6,129.5,129.2,128.9,127 .4,127.1,125.3,123.0,120.5,113.7,113.2,112.6,83.0,66.8,60.5,40.7,26.8,21.8.HRMS(ESI)calculated for C 32 H 31 Cl2N4O2 + ([M+H] +):573.1819, found 573.1809.

[0043] Example 3

[0044] Compound NY3 of this example: 1-(5-(2-(2,4-dichlorobenzyl)oxy)-4-methylphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0045] The specific structural formula of compound NY3 is:

[0046] The preparation method of compound NY3 is as follows:

[0047] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(2,4-dichlorobenzyl)oxy)-4-methylbenzylidene)amino)-N,N-dimethylaniline (7c, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY3 as a yellow solid (145 mg, yield 25%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.50(dd,J=7.8,1.8Hz,1H),7.35(d,J=2.4Hz,1H),7.31–7.27(m,1H),7.20(m,2H),7.09–6.98(m,4H),6.94(d,J=8.4 Hz,1H),6.91–6.83(m,3H),6.75–6.67(m,2H),6.51–6.44(m,2H),5.10(d,J=13.2Hz,1H),4.88(d,J=13.2Hz,1H),2.86(s,6H),2.49(s,3H). 13CNMR (150MHz, CDCl3) δ188.5,155.9,149.2,146.0,142.8,133.9,133.2,132.7,130.8,130.6,129.7,129.5,1 29.2,128.9,128.2,127.3,127.2,122.2,120.5,113.7,112.5,112.4,66.8,40.6,26.8.HRMS(ESI)calculated for C 31 H 29 Cl2N4O2 + ([M+H] + ):559.1662, found 559.1653.

[0048] Example 4

[0049] Compound NY4 of this example: 1-(5-(2-(2,4-dichlorobenzyl)oxy)-5-methylphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0050] The specific structural formula of compound NY4 is:

[0051] The preparation method of compound NY4 is as follows:

[0052] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(2,4-dichlorobenzyl)oxy)-5-methylbenzylidene)amino)-N,N-dimethylaniline (7d, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY3 as a yellow solid (265 mg, yield 36%). Its structural characterization data are as follows: 1H NMR (600MHz, CDCl3) δ7.47(dd,J=7.8,1.8Hz,1H),7.43(s,1H),7.30(d,J=8.4Hz,1H),7.25–7.19(m,4H),7.16–7.09(m,3H),6.87(m,1H),6.7 1(d,J=8.4Hz,2H),6.65(s,1H),6.48(d,J=9.0Hz,2H),4.69(d,J=13.8Hz,1H),4.12(d,J=13.2Hz,1H),2.88(s,6H),2.44(s,3H),2.27(s,3H). 13 CNMR (150MHz, CDCl3) δ188.6,155.3,146.2,143.1,134.2,133.6,133.5,132.7,132.2,131.3,129.3,128.9,128 .6,127.8,127.8,127.2,125.5,120.7,114.6,113.7,112.6,84.0,71.5,40.6,26.7,16.5.HRMS(ESI)calculated for C 32 H 31 Cl2N4O2 + ([M+H] + ):573.1819,found573.1813.

[0053] Example 5

[0054] Compound NY5 of this example: 1-(5-(2-(2,4-dichlorobenzyl)oxy)phenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0055] The specific structural formula of compound NY5 is:

[0056] The preparation method of compound NY5 is as follows:

[0057] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(2,4-dichlorobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7e, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY5 as a yellow solid (265 mg, yield 53%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.35(d,J=1.8Hz,1H),7.32(d,J=1.8Hz,1H),7.25–7.20( m,2H),7.09(m,3H),7.05(dd,J=8.4,2.4Hz,1H),6.92(d,J=8.4Hz,1H),6.90–6. 84(m,2H),6.79(d,J=8.4Hz,1H),6.76–6.69(m,2H),6.52–6.41(m,2H),5.07(d ,J=13.2Hz,1H),4.84(d,J=13.2Hz,1H),2.87(s,6H),2.52(s,3H),2.27(s,3H). 13 C NMR (150MHz, CDCl3) δ188.6,153.7,149.2,146.0,143.0,133.7,133.4,132.6,131.7,131.1,131.0,130.0,129. 3,129.2,128.9,128.1,127.3,127.2,120.6,113.7,112.5,112.5,67.0,40.6,26.8,20.8.HRMS(ESI)calculated forC 32 H 31 Cl2N4O2 + ([M+H] + ):573.1819, found 573.1822.

[0058] Example 6

[0059] Compound NY6 of this example: 1-(5-(4-(2,4-dichlorobenzyl)oxy)-3,5-dimethylphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0060] The specific structural formula of compound NY6 is:

[0061] The preparation method of compound NY6 is as follows:

[0062] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((4-(2,4-dichlorobenzyl)oxy)-3,5-dimethylbenzylidene)amino)-N,N-dimethylaniline (7f, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY6 as a yellow solid (102 mg, yield 18%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.62(d,J=8.4Hz,1H),7.42(d,J=1.8Hz,1H),7.31(dd,J=8.4,2.4Hz,1H),7.25–7.20(m,2H),7.08–7.03(m ,4H),6.91–6.87(m,1H),6.72–6.67(m,2H),6.61–6.56(m,2H),6.08(s,1H),4.88(s,2H),2.92(s,6H),2.56(s,3H),2.24(s,6H). 13 C NMR (150MHz, CDCl3) δ188.7,156.2,149.3,146.1,143.3,136.2,134.2,134.2,133.3,131.7,130.9,129.9,129. 2,129.1,128.2,127.4,127.4,127.3,120.8,114.0,112.7,89.0,70.2,40.7,26.9,16.6.HRMS(ESI)calculated for C 33 H 33 Cl2N4O2 + ([M+H]+ ):587.1975, found 587.1966.

[0063] Example 7

[0064] Compound NY7 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(3-methoxy-2-((4-methylbenzyl)oxy)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0065] The specific structural formula of compound NY7 is:

[0066] The preparation method of compound NY7 is as follows:

[0067] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-N,N-dimethyl-4-((2-((4-methylbenzyl)oxy)benzylidene)amino)aniline (7 g, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrinoyl chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY7 as a yellow solid (285 mg, yield 62%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.20-7.15(m,3H),7.13-7.05(m,7H),6.90(dd,J=12.0,2.4Hz,1H),6.85-6.77(m,4H),6.58 -6.54(m,2H),4.96(d,J=16.2Hz,1H),4.00(d,J=16.2Hz,1H),3.87(s,3H),2.88(s,6H),2.47(s,3H),2.33(s,3H). 13 C NMR (150MHz, CDCl3) δ188.6,152.6,149.6,146.5,146.1,142.8,137.5,134.8,133.9,130.9,129.2,129.0, 128.1,127.9,124.9,121.1,120.5,113.7,112.8,83.3,75.0,55.9,40.7,26.8,21.3.HRMS(ESI)calculated for C 33H 35 N4O3 + ([M+H] + ):535.2704, found 535.2689.

[0068] Example 8

[0069] Compound NY8 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(2-((4-fluorobenzyl)oxy)-3-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0070] The specific structural formula of compound NY8 is:

[0071] The preparation method of compound NY8 is as follows:

[0072] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-((4-fluorobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7h, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY8 as a yellow solid (96 mg, yield 15%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.21–7.10(m,6H),7.08–7.04(m,2H),6.96(t,J=8.4Hz,2H),6.91(dd,J=8.4,1.8Hz,1H),6.83(s,1H),6.78(d, J=9.0Hz,2H),6.73(s,1H),6.58–6.53(m,2H),4.95(d,J=10.8Hz,1H),3.98(d,J=10.8Hz,1H),3.87(s,3H),2.88(s,6H),2.46(s,3H). 13C NMR (150MHz, CDCl3) δ188.4,163.1,161.4,152.3,149.4,146.1,145.9,142.7,133.7,133.4,133.4,130.8,129.5,129.4,129.0,12 7.7,124.9,120.9,120.4,115.0,114.9,113.5,112.7,112.6,83.4,74.0,55.7,40.5,31.4,30.1,29.6,26.5.HRMS(ESI)calculated for C 32 H 32 FN4O3 + ([M+H] + ):539.2442,found539.2449.

[0073] Example 9

[0074] Compound NY9 of this example: 4-(2-(3-acetyl-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-yl)-6-methoxyphenoxy)methyl)benzonitrile

[0075] The specific structural formula of compound NY9 is:

[0076] The preparation method of compound NY9 is as follows:

[0077] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-(2-((4-(dimethylamino)phenyl)imino)methyl)phenoxy)methyl)benzonitrile (7i, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrinoyl chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). . The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY9 as a yellow solid (135 mg, yield 39%). Its structural characterization data are as follows: 1H NMR (600MHz, CDCl3) δ7.59–7.53(m,2H),7.29(d,J=7.8Hz,2H),7.20(m,2H),7.18–7.12(m,2H),7.05(m,2H),6.93(dd,J=7.2,2.4Hz,1H),6.85(s,1 H),6.76–6.70(m,2H),6.66(s,1H),6.51(d,J=8.4Hz,2H),5.06(d,J=12.0 Hz,1H),4.14(m,1H),3.85(s,3H),2.88(s,6H),2.40(s,3H),1.55(s,4H). 13 C NMR (150MHz, CDCl3) δ188.5,152.5,149.5,146.0,146.0,143.5,142.9,133.9,132.1,131.0,129.3,127.7,127. 5,125.3,121.2,120.7,119.0,113.7,113.1,112.7,111.2,84.1,73.4,55.9,40.7,26.7.HRMS(ESI)calculated for C 33 H 32 N5O3 + ([M+H] + ):546.2500,found546.2489.

[0078] Example 10

[0079] Compound NY10 of this example: 1-(5-(2-((4-chlorobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0080] The specific structural formula of compound NY10 is:

[0081] The preparation method of compound NY10 is as follows:

[0082] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-((4-chlorobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7j, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY10 as a yellow solid (65 mg, yield 6%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.26–7.22(m,2H),7.21–7.14(m,3H),7.12(m,3H),7.07–7.04(m,2H),6.91(dd,J=8.4,1.8Hz,1H),6.83(m,1H),6. 78–6.74(m,2H),6.71(s,1H),6.55–6.52(m,2H),4.97(d,J=10.8Hz,1H),4.04(d,J=10.8Hz,1H),3.86(s,3H),2.88(s,6H),2.45(s,3H). 13 C NMR (150MHz, CDCl3) δ188.6,152.5,149.6,146.2,146.1,142.9,136.4,133.9,133.4,131.0,129.2,129.1,128.4,12 7.8,125.1,121.1,120.6,113.7,113.0,112.8,83.7,74.0,55.9,40.7,31.6,30.3,29.8,26.7.HRMS(ESI)calculated for C 32 H 32 ClN4O3 + ([M+H] + ):555.2157, found 555.2145.

[0083] Embodiment 11

[0084] Compound NY11 of this example: 1-(5-(2-((4-bromobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0085] The specific structural formula of compound NY11 is:

[0086] The preparation method of compound NY11 is as follows:

[0087] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-((4-bromobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7k, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY11 as a yellow solid (100 mg, yield 25%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.40 (d, J = 7.8Hz, 2H), 7.2 -7.15(m,3H),7.12(t,J=7.8Hz,1H),7.06(d,J=7.8Hz,4H),6.91(dd,J=8.4,1.8Hz,1H),6.84(t,J=7.8Hz,1H),6.7 9-6.73(m,2H),6.71(s,1H),6.53(d,J=9.0Hz,2H),4.96(d,J=10.8Hz,1H),3.86(s,3H),2.88(s,6H),2.44(s,3H). 13 C NMR (150MHz, CDCl3) δ188.6,147.2,142.9,136.9,133.9,132.0,131.4,129.6,129.3,129.2,128.5,127.8,125.8,125.1,124. 6,124.5,124.1,123.6,121.2,120.6,119.2,117.5,113.7,113.0,112.8,55.9,40.7,31.6,30.3,29.8.HRMS(ESI)calculated for C 32 H 32 BrN4O3 + ([M+H] + ):599.1652,found599.1647.

[0088] Example 12

[0089] Compound NY12 of this example: methyl 4-((2-(3-acetyl-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-yl)-6-methoxyphenoxy)methyl)benzoate

[0090] The specific structural formula of compound NY12 is:

[0091] The preparation method of compound NY12 is as follows:

[0092] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-((4-(dimethylamino)phenyl)imino)methyl)phenoxy)methyl)benzoic acid ethyl ester (7l, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrinoyl chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY12 as a yellow solid (135 mg, yield 54%). Its structural characterization data are as follows: 1 HNMR(600MHz, CDCl3)δ7.98–7.93(m,2H),7.27(s,1H),7.22–7.15(m,3H),7. 13(t,J=7.8Hz,1H),7.09–7.04(m,2H),6.92(dd,J=7.8,1.2Hz,1H),6.84(m,1 H),6.78–6.65(m,4H),6.55–6.48(m,2H),5.06(d,J=12.0Hz,1H),4.12(m,1H ),3.91(s,3H),3.85(s,3H),2.88(s,6H),2.42(s,3H),2.04(d,J=6.0Hz,1H). 13 C NMR (150MHz, CDCl3) δ188.5,167.0,152.4,149.4,146.1,146.0,143.1,142.8,133.8,130.8,129.5,129.2,129.1,127 .7,126.9,125.1,121.0,120.5,113.6,112.9,112.6,83.7,73.9,55.8,52.1,40.6,29.7,26.6.HRMS(ESI)calculated forC 34 H35 N4O5 + ([M+H] + ):579.2602, found 579.2590.

[0093] Embodiment 13

[0094] Compound NY13 of this example: 1-(5-(2-((4-(tert-butyl)benzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0095] The specific structural formula of compound NY13 is:

[0096] The preparation method of compound NY13 is as follows:

[0097] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-((4-(tert-butyl)benzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7m, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY13 as a yellow solid (99 mg, yield 14%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.34–7.30(m,2H),7.21–7.06(m,8H),6.90(dd,J=8.4,1.8Hz,1H),6.84–6.78(m ,4H),6.59–6.55(m,2H),4.92(d,J=10.8Hz,1H),3.86(s,3H),2.88(s,6H),2.46(s,3H),1.31(s,9H). 13C NMR (101MHz, CDCl3) δ188.5,152.6,150.8,149.6,146.6,146.1,142.9,134.9,134.0,130.9,129.2,127. 9,127.9,125.3,124.9,121.1,120.5,113.8,112.9,112.8,55.9,40.7,31.5,26.8.HRMS(ESI)calculated for C 36 H 41 N4O3 + ([M+H] + ):577.3173, found 577.3163.

[0098] Embodiment 14

[0099] Compound NY14 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(3-methoxy-2-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0100] The specific structural formula of compound NY14 is:

[0101] The preparation method of compound NY14 is as follows:

[0102] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-N,N-dimethyl-4-((2-((4-(trifluoromethyl)benzyl)oxy)benzylidene)amino)aniline (7n, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY14 as a yellow solid (105 mg, yield 26%). Its structural characterization data are as follows: 1H NMR(600MHz, CDCl3) δ7.53(d,J=7.8Hz,2H),7.30(d,J=8.4Hz,2H),7.23–7.12(m,4H),7.08–7.05(m,2H),6.93(dd,J=7.8,1.8Hz,1H),6.87– 6.83(m,1H),6.76–6.73(m,2H),6.70(s,1H),6.55–6.50(m,2H),5.06( d,J=12.0Hz,1H),4.12(m,1H),3.86(s,3H),2.88(s,6H),2.41(s,3H). 13 CNMR (101MHz, CDCl3) δ188.8,152.6,146.2,142.9,129.3,127.8,127.4,125.2,125.2, 125.1,121.2,120.7,113.7,113.1,73.7,55.8,31.6,29.8,26.7.HRMS(ESI)calculated for C 33 H 32 F3N4O3 + ([M+H] + ):589.2421, found 589.2408.

[0103] Embodiment 15

[0104] Compound NY15 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(3-methoxy-2-((4-methoxybenzyl)oxy)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0105] The specific structural formula of compound NY15 is:

[0106] The preparation method of compound NY15 is as follows:

[0107] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-((4-methoxybenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7o, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY15 as a yellow solid (112 mg, yield 48%). Its structural characterization data are as follows: 1 H NMR (400MHz, CHCl3) δ7.21–7.15(m,3H),7.13(dd,J=8.4,4.4Hz,3H),7.08(dt,J=8.8,2.4Hz,2H),6.91(dd,J=8.0,2.0Hz,1H),6.84–6.78 (m,6H),6.60–6.56(m,2H),4.93(d,J=10.4Hz,1H),3.98(d,J=10.4Hz,1H),3.88(s,3H),3.80(s,3H),2.88(s,6H),2.49(d,J=1.2Hz,3H). 13 C NMR (150MHz, CDCl3) δ188.6,159.4,152.6,149.6,146.1,142.9,134.0,131.0,130.0,129.7,129.2,127.9,12 4.9,121.1,120.5,113.8,113.7,112.8,83.3,74.9,55.9,55.4,40.7,29.8,26.8,22.8.HRMS(ESI)calculated for C 33 H 35 N4O4 + ([M+H] + ):551.2653, found 551.2642.

[0108] Example 16

[0109] Compound NY16 of this example: 2-(2-(3-acetyl-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-yl)-6-methoxyphenoxy)methyl)benzonitrile

[0110] The specific structural formula of compound NY16 is:

[0111] The preparation method of compound NY16 is as follows:

[0112] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-2-(2-(((4-(dimethylamino)phenyl)imino)methyl)phenoxy)methyl)benzonitrile (7p, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY16 as a yellow solid (175 mg, yield 31%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.59–7.50(m,3H),7.34(m,1H),7.22(m,2H),7.19–7.12(m,2H),7.11–7.07(m,2H),6.93(dd,J=8.4,1.8Hz,1H),6.86( m,1H),6.79(s,1H),6.71–6.67(m,2H),6.45–6.40(m,2H),5.35–5.25( m,1H),4.24(d,J=12.6Hz,1H),3.87(s,3H),2.87(s,6H),2.45(s,3H). 13 C NMR (150MHz, CDCl3) δ188.5,152.4,149.4,146.1,145.6,143.0,141.8,133.6,132.9,132.4,130.2,129.3,127.8,127. 7,127.5,125.5,120.9,120.7,117.1,113.6,112.8,112.4,110.1,83.4,71.6,55.8,40.5,26.8.HRMS(ESI)calculated for C 33 H 32 N5O3 + ([M+H] + ):546.2500,found546.2485.

[0113] Embodiment 17

[0114] Compound NY17 of this example: 1-(5-(2-(2-chlorobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0115] The specific structural formula of compound NY17 is:

[0116] The preparation method of compound NY17 is as follows:

[0117] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(2-chlorobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7q, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY17 as a yellow solid (266 mg, yield 65%). Its structural characterization data are as follows: 1 H NMR(600MHz, CDCl3)δ7.50(dd,J=7.2,1.8Hz,1H),7.29–7.26(m,2H),7.24–7.16(m,5H),7.16–7.08(m,3H),6.91(dd,J=7.8,1.2Hz,1H),6 .84(m,2H),6.73–6.68(m,2H),6.47–6.42(m,2H),5.10(d,J=12.6Hz,1H),4.18(d,J=13.2Hz,1H),3.84(s,3H),2.86(s,6H),2.45(s,3H). 13 C NMR (150MHz, CDCl3) δ188.5,152.5,146.1,146.0,143.0,135.9,133.9,131.7,129.3,129.0,128.3,128.1,127 .7,126.8,125.3,121.0,120.6,113.7,112.8,112.6,83.1,71.6,55.9,40.6,26.8,14.3.HRMS(ESI)calculated for C 32 H 32 ClN4O3 + ([M+H]+ ):555.2146, found 555.2155.

[0118] Embodiment 18

[0119] Compound NY18 of this example: 1-(5-(2-((3-bromobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0120] The specific structural formula of compound NY18 is:

[0121] The preparation method of compound NY18 is as follows:

[0122] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(3-bromobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7r, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY18 as a yellow solid (185 mg, yield 31%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.41–7.37(m,1H),7.36–7.34(m,1H),7.22–7.15(m,5H ),7.13(t,J=7.8Hz,1H),7.09–7.04(m,2H),6.92(dd,J=8.4,1.8Hz,1H),6.8 4(m,1H),6.79–6.75(m,2H),6.72(s,1H),6.57–6.53(m,2H),4.97–4.92(d,J =11.4Hz,1H),3.97(d,J=11.4Hz,1H),3.86(s,3H),2.89(s,6H),2.45(s,3H). 13CNMR (101MHz, CDCl3) δ188.6,152.6,149.6,146.2,146.1,140.2,134.0,130.9,130.7,130.7,129.3,1 27.9,125.2,122.3,121.2,120.6,113.7,112.9,112.8,83.8,55.9,27.0,26.7.HRMS(ESI)calculated for C 32 H 32 BrN4O3 + ([M+H] + ):599.1652, found 599.1645.

[0123] Embodiment 19

[0124] Compound NY19 of this example: 1-(5-(2-((3-chlorobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0125] The specific structural formula of compound NY19 is:

[0126] The preparation method of compound NY19 is as follows:

[0127] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(3-chlorobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7s, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY19 as a yellow solid (255 mg, yield 62%). Its structural characterization data are as follows: 1H NMR (600MHz, CDCl3) δ7.24–7.15(m,6H),7.12(t,J=8.4Hz,2H),7.06(dt,J=7.8,1.2Hz,2H),6.92(dd,J=8.4,1.8Hz,1H),6.84(s,1H),6. 79–6.76(m,2H),6.72(s,1H),6.57–6.52(m,2H),4.95(d,J=10.8Hz,1H),3.98(d,J=11.4Hz,1H),3.86(s,3H),2.89(s,6H),2.45(s,3H). 13 C NMR (150MHz, CDCl3) δ188.6,152.6,146.2,146.0,142.9,139.9,134.1,133.9,129.6,129.2,127.9,127.8 ,127.7,125.6,125.2,121.1,120.6,113.7,113.0,83.8,73.9,55.9,40.8,26.7.HRMS(ESI)calculatedfor C 32 H 32 ClN4O3 + ([M+H] + ):555.2157, found 555.2149.

[0128] Embodiment 20

[0129] Compound NY20 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(3-methoxy-2-((3-formylbenzyl)oxy)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0130] The specific structural formula of compound NY20 is:

[0131] The preparation method of compound NY20 is as follows:

[0132] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(3-methoxybenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7t, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY20 as a yellow solid (185 mg, yield 43%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.23–7.16(m,4H),7.12(t,J=7.8Hz,1H),7.08(d,J=7.8Hz,2H),6.91(dd,J=8.4,1.8Hz,1H),6.85–6.75( m,7H),6.56–6.53(m,2H),4.96(d,J=10.8Hz,1H),3.98(d,J=11.4Hz,1H),3.87(s,3H),3.78(s,3H),2.88(s,6H),2.46(s,3H). 13 C NMR (150MHz, CDCl3) δ188.6,159.7,152.6,149.5,146.4,146.0,142.9,139.4,134.0,130.9,129.3,129.2,127.8,1 25.0,121.1,120.5,120.0,113.7,113.4,113.1,112.9,112.8,74.8,55.9,55.3,40.7,26.8.HRMS(ESI)calculated for C 33 H 35 N4O4 + ([M+H] + ):551.2653, found 551.2640.

[0133] Embodiment 21

[0134] Compound NY21 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(2-(2,6-dimethylbenzyl)oxy)-3-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0135] The specific structural formula of compound NY21 is:

[0136] The preparation method of compound NY21 is as follows:

[0137] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(2,6-dimethylbenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7u, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY21 as a yellow solid (123 mg, yield 36%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.21–7.04(m,7H),6.99(d,J=7.8Hz,2H),6.91(dd,J=7.8,1.2Hz,1H),6.84(s,1H),6.82–6.76(m,3H) ,6.53(d,J=8.4Hz,2H),5.05(d,J=10.2Hz,1H),4.36(d,J=10.8Hz,1H),3.87(s,3H),2.86(s,6H),2.51(s,3H),2.29(s,6H). 13 C NMR (150MHz, CDCl3) δ188.5,152.3,146.0,142.7,138.5,133.9,129.3,128.5,128.4,127.8, 125.1,121.1,120.5,113.6,112.6,82.3,70.5,55.6,40.7,26.9,20.1.HRMS(ESI)calculated for C 34 H 37 N4O3 + ([M+H] + ):549.2860,found549.2852.

[0138] Embodiment 22

[0139] Compound NY22 of this example: 1-(5-(2-(2,6-difluorobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0140] The specific structural formula of compound NY22 is:

[0141] The preparation method of compound NY22 is as follows:

[0142] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(2,6-difluorobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7v, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrinoyl chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY22 as a yellow solid (124 mg, yield 27%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.28(m,1H),7.22(dd,J=7.8,1.2Hz,1H),7.17(m,2H),7.13(s,1H),7.10(dd,J=9.0,1.2Hz,1H),6.92(s,1H),6 .90–6.85(m,3H),6.84–6.79(m,3H),6.56–6.53(m,2H),4.95(d,J=10.2Hz,1H),4.13(m,1H),3.86(s,3H),2.85(s,6H),2.53(s,3H). 13 C NMR (150MHz, CDCl3) δ188.5,162.9,162.9,161.3,161.2,152.4,149.5,146 .1,145.7,142.8,134.1,130.6,130.5,130.4,130.3,129.2,128.0,125.3, 120.9,120.4,113.7,112.7,112.7,111.5,111.5,111.4,111.3,82.3,62.7,62.7,62.7,56.0,55.8,40.7,40.6,40.2,26.9.HRMS(ESI)calculatedfor C 32 H 31 F2N4O3 + ([M+H] + ):557.2359, found 557.2344.

[0143] Embodiment 23

[0144] Compound NY23 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(3-methoxy-2-((2,4,6-trimethylbenzyl)oxy)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0145] The specific structural formula of compound NY23 is:

[0146] The preparation method of compound NY23 is as follows:

[0147] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-N,N-dimethyl-4-((2-(2,4,6-trimethylbenzyl)oxy)benzylidene)amino)aniline (7w, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrinoyl chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY23 as a yellow solid (133 mg, yield 27%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.22–7.18(m,1H),7.18–7.10(m,3H),7.08–7.04(m,2H),6.90(dd,J=7.8,1.2Hz,1H),6.87–6.76(m,6H),6 .57–6.50(m,2H),5.01(d,J=10.0Hz,1H),4.25(d,J=10.2Hz,1H),3.88(s,3H),2.86(s,6H),2.54(s,3H),2.25(d,J=10.8Hz,9H). 13C NMR (150MHz, CDCl3) δ188.5,152.4,147.2,146.0,142.6,138.4,138.1,131.0,129.2,129.2,127.8,125.0,124.6,12 4.1,121.0,120.5,119.2,113.7,112.7,82.2,70.2,55.6,31.6,30.3,29.8,26.8,21.1,20.0.HRMS(ESI)calculated for C 35 H 39 N4O3 + ([M+H] + ):563.3017,found 563.3000.

[0148] Embodiment 24

[0149] Compound NY24 of this example: 1-(5-(2-(3,4-dimethoxybenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0150] The specific structural formula of compound NY24 is:

[0151] The preparation method of compound NY24 is as follows:

[0152] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(3,4-dimethoxybenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7x, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY24 as a yellow solid (102 mg, yield 15%). Its structural characterization data are as follows: 1H NMR (400MHz, CDCl3) δ7.12–7.06(m,3H),7.06–6.97(m,3H),6.82(dd,J=8.0,2.0Hz,1H),6.78–6.66(m,6H),6.65(dd,J=8.4,2.0Hz,1 H),6.51–6.45(m,2H),4.84(d,J=10.4Hz,1H),3.97(d,J=10.4Hz,1H),3.78(d,J=3.6Hz,6H),3.75(s,3H),2.79(s,6H),2.38(s,3H). 13 C NMR (150MHz, CDCl3) δ188.6,152.6,149.4,148.8,148.7,146.3,146.0,142.8,131.1,130.4,129.2,127.7,125.0,121 .1,120.5,120.5,113.7,112.8,112.8,111.4,110.9,83.5,75.0,56.0,55.9,55.8,40.7,26.8.HRMS(ESI)calculated for C 34 H 37 N4O5 + ([M+H] + ):581.2758,found581.2746.

[0153] Embodiment 25

[0154] Compound NY25 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(3-methoxy-2-((3,4,5-trimethoxybenzyl)oxy)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0155] The specific structural formula of compound NY25 is:

[0156] The preparation method of compound NY25 is as follows:

[0157] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-N,N-dimethyl-4-((2-(3,4,5-trimethoxybenzyl)oxy)benzylidene)amino)aniline (7y, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrazone chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY25 as a yellow solid (141 mg, yield 27%). Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.20–7.15(m,3H),7.12(t,J=7.8Hz,1H),7.10–7.07(m,2H),6.93(dd,J=7.8,1.8Hz,1H),6.83(m,1H),6.77(d,J=9.0Hz ,2H),6.73(s,12H),6.56–6.53(m,2H),6.50(s,2H),4.92(d,J=10.8Hz ,1H),3.87(s,3H),3.83(s,3H),3.82(s,7H),2.87(s,6H),2.43(s,3H). 13 CNMR (150MHz, CDCl3) δ187.4,152.0,151.6,148.3,145.2,144.8,141.7,136.3,133.0,132.5,130.0,128.0,126.3,123.9 ,120.0,119.4,115.6,114.8,112.6,111.8,111.5,103.5,73.8,59.8,55.0,54.7,40.1,39.5,25.6.HRMS(ESI)calculated for C 35 H 39 N4O6 + ([M+H] + ):611.2864, found 611.2854.

[0158] Embodiment 26

[0159] Compound NY26 of this example: 1-(5-(2-(3,4-difluorobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0160] The specific structural formula of compound NY26 is:

[0161] The preparation method of compound NY26 is as follows:

[0162] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(3,4-difluorobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7z, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY26 as a yellow solid (137 mg, yield 43%). Its structural characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.18(m,4H),7.10–6.99(m,4H),6.92(d,J=8.0Hz,2H),6.85(m,1H),6.80–6.75(m,2H),6.70(d,J=3.2Hz,1H),6.56(dd, J=8.8,2.8Hz,3H),4.95(dd,J=11.2,3.2Hz,1H),4.00(d,J=11.2Hz,1H),3.86(d,J=3.2Hz,3H),2.89(d,J=3.2Hz,6H),2.48(d,J=3.2Hz,3H). 13 CNMR (150MHz, CDCl3) δ188.6,152.5,149.6,146.1,142.9,134.0,131.0,129.3,127.9,125.2,121.2,120 .6,117.0,116.9,116.8,116.7,113.7,113.0,112.8,73.5,55.9,40.7,29.8,26.8.HRMS(ESI)calculated for C 32 H 31 F2N4O3 + ([M+H] + ):557.2348, found 557.2355.

[0163] Embodiment 27

[0164] Compound NY27 of this example: 1-(5-(2-(3,5-dichlorobenzyl)oxy)-3-methoxyphenyl)-4-(4-(dimethylamino)phenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0165] The specific structural formula of compound NY27 is:

[0166] The preparation method of compound NY27 is as follows:

[0167] Triethylamine (TEA) (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(3,5-dichlorobenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7za, 5 mmol, 1 eq.) and (Z)-2-oxo-N-phenylpropanhydrine chloride (3,5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 h. 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10 mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound NY27 as a yellow solid (132 mg, yield 37%). Its structural characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.25 (t, J = 2.0Hz, 1H), 7.23-7.18 (m, 2H), 7.18-7.11 (m, 2H), 7.09 (d ,J=2.0Hz,2H),7.05(m,2H),6.92(dd,J=7.2,2.0Hz,1H),6.85(tt,J=7.2,1.2Hz,1H),6.79 -6.75(m,2H),6.68(s,1H),6.57-6.53(m,2H),4.91(dq,J=11.6,0.8Hz,1H),3.90(d,J=11.6Hz,1H),3.86(s,3H),2.90(s,6H),2.46(s,3H). 13 C NMR (101MHz, CDCl3) δ188.8,152.5,146.1,145.9,141.3,134.8,134.0,130.8,129.3,128.0,127.7,1 25.8,125.4,121.2,120.7,113.7,112.9,112.7,84.0,73.1,55.9,40.6,26.7.HRMS(ESI)calculated for C 32 H 31Cl2N4O3 + ([M+H] + ):589.1768, found 589.1755.

[0168] Embodiment 28

[0169] Compound NY28 of this example: 1-(4-(4-(dimethylamino)phenyl)-5-(2-((4-fluoro-3-methoxybenzyl)oxy)-3-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethan-1-one

[0170] The specific structural formula of compound NY28 is:

[0171] The preparation method of compound NY28 is as follows:

[0172] To a solution of (Z)-4-((2-((4-fluoro-3-methoxybenzyl)oxy)benzylidene)amino)-N,N-dimethylaniline (7zb, 5mmol, 1eq.) and (Z)-2-oxo-N-phenylpropanhydrinoyl chloride (3,5mmol, 1eq.) in tetrahydrofuran (THF) (40mL) was added triethylamine (TEA) (1.4mL, 10mmol, 2eq.) at room temperature. The reaction mixture was refluxed for 8h. 10mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10mL*3 times). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether=

[0173] 1 / 3), the target compound NY28 was obtained as a yellow solid (101 mg, yield 23%). Its structural characterization data are as follows: 1 H NMR

[0174] (400MHz, CDCl3) δ7.22–7.11(m,4H),7.10–7.05(m,2H),7.01–6.90(m,3H),6.83(s,1H),

[0175] 6.79–6.74(m,2H),6.71(s,1H),6.58–6.51(m,2H),4.95(d,J=10.8Hz,1H), 4.07(d,J=10.8Hz,1H),3.87(s,3H),3.84(s,3H),2.87(s,6H),2.45(s,3H). 13 C NMR (101MHz,CDCl3)δ188.6,

[0176] 152.6,150.7,149.5,147.4,146.2,146.0,142.9,134.2,134.2,134.0,131.1,129.2,127.6,125.1,121.1,

[0177] 120.6,120.1,120.0,115.8,115.6,113.7,112.9,112.9,112.9,112.7,83.8,56.3,55.8,40.7,

[0178] 26.7.HRMS(ESI)calculated for C 33 H 34 FN4O4 + ([M+H] + ):569.2559,found569.2544.

[0179] Embodiment 29

[0180] In this example, the ferroptosis inhibition activity of compounds NY1-NY28 obtained in the above examples 1-28 was tested. The detailed process is as follows. After cell counting, the cells were counted at 1.5×10^ 6 / plate at a density of 1 μM in a black 96-well plate and cultured overnight. After 24 hours, the cells were completely attached to the wall, and a 1,2,4-triazole compound at a concentration of 1 μM or DFO at a concentration of 100 μM (as a positive control) was prepared to treat the cells under normal cell culture conditions for 7 hours. After 7 hours, the cells were washed 3 times with PBS, and then 50 μL of serum-free DMEM culture medium containing 1 μM ferrous ion fluorescent probe (FerroOrange, purchased from DOJINDO, item number: F374) was added to the cells, and the cells continued to be incubated at 37°C in a cell culture incubator. After 30 minutes, the cells were taken out and the fluorescence signal was measured with an enzyme reader (Ex=543nm, Em=580nm). The test results are attached to the instruction manual. Figure 2 .

[0181] Embodiment 30

[0182] In this example, the compounds NY15 and NY26 obtained in the above examples 23 and 26 were studied for their protective effects on acute liver injury induced by concanavalin in mice. The specific process is as follows: 8-week-old male C57BL / 6 mice were purchased from Beijing Weitong Lihua Co., Ltd. and adaptive transition feeding was carried out at the Animal Experiment Center of Chongqing Medical University. Pre-drug administration was carried out one day before modeling, and NY-15 and NY-26 were selected from 1,2,4-triazole compounds, each with a dose of 10 mg / kg. The drug was administered again after 24 hours, and both administrations were intraperitoneal injections. Acute liver injury modeling was started one hour after the second administration of the triazole compound, and ConA was injected into the mice by tail vein injection at a dose of 15 mg / kg. After another 24 hours, mouse serum samples and liver samples were collected, and relevant biochemical tests were performed at Wuhan Seville Biotechnology Co., Ltd. The drug preparation method is as follows: ConA is directly dissolved in physiological saline; NY-15 and NY-26 are prepared according to the ratio of "10% DMSO + 30% PEG300 + 5% Tween 80 + 55% PBS". ConA was purchased from Sigma (Cat. No.: L7647-25MG), PEG300 and Tween 80 were purchased from MCE (Cat. No.: HY-Y0873, HY-Y1891). The experimental results are shown in the attached manual. Figure 3 .

Claims

1. A 5-aryl substituted 1,2,4-triazole iron death inhibitor derivative, characterized in that: The derivative has the general structural formula shown in the following formula (I): Ar1 can be any of the following substituents. The wavy line indicates the position of the substituent, and the number 5 indicates the site where Ar1 is chemically bonded to 1,2,4-triazole. Wherein, the Ar2 group can be selected from any of the following substituent groups. The wavy line indicates the position of the substituent. The above Ar1 and Ar2 substituent groups may be combined arbitrarily.

2. A 5-aryl substituted 1,2,4-triazole iron death inhibitor derivative, characterized in that: One of the following compounds:

3. The method for preparing a 5-aryl substituted 1,2,4-triazole iron death inhibitor derivative according to claim 1, characterized in that The steps include: (1) Synthesis of intermediate (Z)-2-oxo-N-phenylpropanhydrazone chloride 3: A suitable amount of aniline (10 mmol, 1 eq.) was dissolved in 24 mL of 2M HCl, and NaNO2 (10 mmol) was dissolved in 3 mL of H2O, and then added dropwise to the reaction system at 0-5°C to obtain a diazoaniline solution. Subsequently, the newly prepared diazoaniline solution was added dropwise to a precooled mixture (0°C) of a methanol solution (50 mL) of 3-chloropentane-2,4-dione (10 mmol, 1 eq.) and NaOAc (48 mmol, 4.8 eq.) at 5-10°C. After reacting for 2 hours, the solid was obtained by vacuum filtration and washed with H2O to obtain a light yellow solid compound 3 in a yield of 87%. (2) General method for the synthesis of intermediates 6a-zd: K2CO3 (40mmol, 4eq.), TBAI (4mmol, 0.25eq.) and 2-hydroxybenzaldehyde derivatives (4a-f, 20mmol, 2eq.) were added to a stirred solution of benzyl chloride derivatives (5a-y, 10mmol, 1eq.) in DMF (70mL) under N2 protection at room temperature. The mixture was stirred at room temperature for 0.5 hours, then heated to 60°C and stirred for 4 hours. The mixture was cooled, filtered through a celite pad, 10mL of water was added to dilute the mixture, and then extracted with ethyl acetate (10mL*3 times). Washed with saturated brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography eluting with petroleum ether / ethyl acetate to obtain 65%-85% of the target compound 6a-zd as a white solid. (3) General method for the synthesis of intermediates 7a-zd: To a 0.32 M solution of 2-(benzyloxy)-3-methoxybenzaldehyde derivative (6a-zd, 1.46 mmol, 1 eq.) in dichloromethane, 4A molecular sieves (1 g / mmol), aniline derivative (1.61 mmol, 1.1 eq.) and pyrrolidine (0.146 mmol, 0.1 eq.) were added. The mixture was stirred at 45°C for 4 hours. After cooling to room temperature, the mixture was filtered and concentrated. The crude product was used directly in the next step. (4) General method for the synthesis of NY1-NY28: Triethylamine (1.4 mL, 10 mmol, 2 eq.) was added to a solution of (Z)-4-((2-(benzyloxy)-3-methoxybenzylidene)amino)-N,N-dimethylaniline derivative (7a-zd, 5 mmol, 1 eq.) and intermediate 3 (5 mmol, 1 eq.) in tetrahydrofuran (THF) (40 mL) at room temperature. The reaction mixture was refluxed for 8 hours. Deionized water was then added to the mixture, and it was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether / ethyl acetate to afford the title compound.

4. The method for preparing a 5-aryl substituted 1,2,4-triazole iron death inhibitor derivative according to claim 3, characterized in that: Step: The compounds NY1-NY28 are separated and purified by silica gel column chromatography, and the eluent is petroleum ether / ethyl acetate with a gradient volume ratio of 3:1 to 1:

1.

5. The method for preparing a 5-aryl substituted 1,2,4-triazole iron death inhibitor derivative according to claim 3, wherein the synthesized intermediate 6a-zd is characterized in that: The product was separated and purified by silica gel column chromatography, using petroleum ether / ethyl acetate in a gradient volume ratio of 5:1 to 3:1 as the eluent.

6. The method for preparing a 5-aryl substituted 1,2,4-triazole iron death inhibitor derivative according to claim 3, wherein the synthesized intermediate 7a-zd is characterized in that: No separation or purification is required.

7. The use of a 5-aryl substituted 1,2,4-triazole iron death inhibitor derivative according to claim 1, characterized in that: The use is for protection against acute liver damage.

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