Preparation method and application of a selenoacetylene compound

Abstract

This invention discloses a method for preparing selenoyne compounds and their applications. The method involves an addition reaction of benzisoselenopyrone and alkyne, characterized by mild reaction conditions, simple operation, a green solvent, excellent yield, and 100% atom utilization, conforming to click chemistry principles. The obtained selenoyne compounds are easily separated, and their purity is above 98%. The selenoyne compounds provided by this invention exhibit good anti-liver cancer cells, human breast cancer cells, or human non-small cell lung cancer cells, laying the foundation for the screening and development of anticancer drugs. Therefore, this invention has broad application prospects.

Description

Technical Field

[0001] This invention relates to the field of preparation of selenoyne compounds, and more specifically to a method for preparing selenoyne compounds and their applications. Background Technology

[0002] Click chemistry, a concept proposed by K.B. Sharpless in 2001, describes a highly efficient chemical synthesis method for constructing various functional molecules through the rapid assembly of modular molecules. Since its inception, click chemistry has been widely applied in fields such as chemical biology, medicinal chemistry, materials chemistry, and supramolecular chemistry. Chemical reactions that meet the definition of click chemistry—click reactions generally possess advantages such as mild reaction conditions, simple operation, excellent product yields, a wide range of applicable substrates, and high atom economy. The copper-catalyzed [3+2] cycloaddition reaction of alkynes and azides, namely the CuAAC reaction, is one of the representative click reactions. Using alkynes and azides as modular molecules, the CuAAC reaction can efficiently and rapidly synthesize various types of 1,4-disubstituted triazole compounds under stoichiometric alkaline conditions and copper catalysis, and is currently widely used in new drug development, bioorthogonal synthesis, and other fields.

[0003] Selenium is an essential trace element for the human body, and its deficiency can easily lead to various adverse reactions. Selenium carriers in the human body include selenocysteine, selenomethionine, glutathione peroxidase, and various selenoproteins. These play a crucial role in maintaining redox balance in the body, participating in a series of important physiological metabolisms, and exhibiting antioxidant, anti-inflammatory, neuroprotective, antitumor, antibacterial, and antiviral effects. In recent years, various organoselenium compounds have been found to possess multiple biological activities, including antitumor, antibacterial, and antiviral activity, thus the design and synthesis of selenium-containing small molecules have attracted great interest. As mentioned earlier, click chemistry can efficiently and conveniently prepare various modular functional molecules; therefore, developing novel click chemistry methods to construct selenium-containing compound libraries and using them for the research and development of antitumor drugs has significant social and application value. Summary of the Invention

[0004] In a first aspect, the present invention provides a selenoyne compound as shown in formula (III) and a 5-selenofunctionalized triazole as shown in formula (V):

[0005]

[0006] In formula (Ⅲ),

[0007] R 1 It is one of phenyl, benzyl, substituted phenyl, cyclohexyl, tert-butyl, n-butyl or pyridyl;

[0008] R 2For phenyl, halogenated, C 1-8 Alkyl or C 1-20 Alkoxy-substituted phenyl, pyridyl, thiophene, or C 3-20 One of the alkyl groups;

[0009] In formula (I) or formula (II), R 1 R 2 The definition is the same as in equation (Ⅲ).

[0010] Preferably, the selenoyne compound represented by formula (Ⅲ) is one of the following:

[0011]

[0012]

[0013] In formula (V),

[0014] R 1 R 2 The definition is the same as in equation (Ⅲ), R 3 It is either phenyl or benzyl; in formula (Ⅳ), R 3 The definition is the same as in equation (V).

[0015] Preferably, the selenoyne compound represented by formula (Ⅲ) is one of the following:

[0016]

[0017] Secondly, the present invention provides a method for preparing the selenoyne of formula (III):

[0018] Formulas (I) and (II) are added to the reaction solvent, a copper catalyst is added, and the reaction is carried out at room temperature for 6-24 hours under the action of alkaline substances. After the reaction is completed, the resulting reaction solution is post-treated to obtain the selenyne compound shown in formula (III).

[0019] Furthermore, the organic solvent is preferably isopropanol; and even further, the volume of the organic solvent, in terms of the amount of substance of the benzisoselenozoline compound (Ⅰ), is 6.6 mL / mmol.

[0020] Furthermore, the copper catalyst is preferably cuprous iodide;

[0021] Furthermore, the alkaline substance is preferably potassium carbonate;

[0022] Furthermore, the preferred reaction time is 6 hours;

[0023] Furthermore, the preferred molar ratio of formula (I), formula (II), copper catalyst, and alkaline substance is 1:1:0.05:0.1;

[0024] Further, the post-processing is as follows: after the reaction is completed, dichloromethane is added to dilute the reaction solution, silica gel powder is added and evaporated, and the solution is separated by column chromatography using a mixed solvent of petroleum ether and ethyl acetate as the eluent. The eluent containing the target compound is collected, concentrated, and dried to obtain the selenyne compound shown in formula (Ⅲ).

[0025] Thirdly, this invention provides the preparation of compound (V) using benzisoselenoazole ketone compound (I), terminal alkyne (II), and organic azide compound (IV) as raw materials to synthesize 5-selenofunctionalized triazole (V) in a one-pot reaction. The general reaction formula is:

[0026]

[0027] Benzisoselenozolone compound (Ⅰ), terminal alkyne (Ⅱ) and organic azide compound (Ⅳ) are added to 2 mL of organic solvent (preferably isopropanol), and reacted at room temperature for 18-36 h (preferably 18 h) under a nitrogen atmosphere with the action of a copper catalyst (preferably cuprous iodide). After the reaction is completed, the reaction solution is obtained and 5-selenyl functionalized triazole (Ⅴ) is obtained after post-treatment.

[0028] Furthermore, the preferred molar ratio of formulas (I), (II), (IV), copper catalyst, and alkaline substance is 1:1:1::0.05:1.1;

[0029] Further, the post-treatment is as follows: after the reaction is completed, dichloromethane is added to dilute the reaction solution, silica gel powder is added and evaporated, and column chromatography is performed using a mixed solvent of petroleum ether and ethyl acetate as the eluent. The eluent containing the target compound is collected, concentrated, and dried to obtain 5-selenyl-functionalized triazole as shown in formula (V).

[0030] Fourthly, the present invention also provides the use of the selenoyne compounds represented by formula (III) in the preparation of antitumor drugs.

[0031] Furthermore, the tumor is T47D human breast cancer cells, A549 human non-small cell lung cancer cells, or HEPG2 human liver cancer cells.

[0032] Furthermore, when the tumor is T47D human breast cancer cells, the selenoyne compounds represented by formulas (Ⅲ-1), (Ⅲ-3), (Ⅲ-4), (Ⅲ-6), (Ⅲ-7), (Ⅲ-9), (Ⅲ-11), (Ⅲ-15), (Ⅲ-16), (Ⅲ-17), (Ⅲ-18), (Ⅲ-19), or (Ⅲ-20) exhibit good antitumor activity; when the tumor is A549 human non-small cell lung cancer cells, the selenoyne compounds represented by formulas (Ⅲ-7), (Ⅲ-14), (Ⅲ-16), or (Ⅲ-17) exhibit good antitumor activity; when the tumor is HEPG2 human liver cancer cells, the selenoyne compounds represented by formulas (Ⅲ-3), (Ⅲ-6), (Ⅲ-7), (Ⅲ-16), (Ⅲ-17), (Ⅲ-18), or (Ⅲ-20) exhibit good antitumor activity. Detailed Implementation

[0033] The following examples illustrate the invention in detail, but the invention is not limited thereto.

[0034] Example 1

[0035] In a dry reaction tube, 0.3 mmol (0.0823 g) of ebuselenline, 0.3 mmol (0.0306 g) of phenylacetylene, 0.03 mmol (0.0057 g) of CuI, 0.3 mmol (0.0415 g) of K2CO3, and 2 mL of isopropanol were added. A stir bar was added, and the reaction was stirred at room temperature under air for 6 h. The solvent was removed under reduced pressure, and the mixture was subjected to column chromatography (petroleum ether: ethyl acetate = 4:1). R was collected. f The eluent with a concentration of approximately 0.4 was used to remove the solvent under reduced pressure, and the product was dried to obtain the target compound (Ⅲ-1), a white solid of 0.1108 g, with a yield of 98%, a melting point of 133-134 °C, and a purity of 97.03% (HPLC detection). The purity of all compounds in this invention is above 95%.

[0036]

[0037] 1 H NMR (400MHz, CDCl3) δ8.29(d,J=8.0Hz,1H),7.96(s,1H),7.71(d,J=7.6Hz,1H),7.61-7.49(m,5H),7.40-7.32(m,6H),7.18(t,J=7.3Hz,1H). 13C NMR (101MHz, CDCl3) δ165.67,137.14,135.12,132.45,131.77,130.77,130.69,129.15, 128.51,128.36,126.67,126.19,125.10,123.31,120.67,104.34,73.91; HRMS(ESI)for C 21 H 15 NOSe: calculated for [M+Na] + 400.0211, found 400.0215.

[0038] Examples 2-5

[0039] The base in the reaction was changed, with K2CO3 replaced by Cs2CO3, KHCO3, DIEA, and Et3N, while other steps remained the same as in Example 1. The reaction results are shown in Table 1-1.

[0040] Table 1-1 Effect of different bases on reaction yield

[0041]

[0042] The results showed that the yield was highest when K2CO3 was used.

[0043] Examples 6-9

[0044] The amount of K2CO3 was changed to 0.15 mmol, 0.03 mmol, 0.015 mmol, and 0, respectively, while other parameters remained the same as in Example 1. The reaction results are shown in Table 1-2.

[0045] Table 1-2 Effect of different amounts of alkali on reaction yield

[0046]

[0047] The results showed that the yield could reach 97% when using 0.03 mmol (0.0042 g) of K2CO3.

[0048] Examples 10-16

[0049] The solvent for the reaction was changed, and the amount of K2CO3 was replaced with acetonitrile, DMF (N,N-dimethylformamide), toluene, ethanol, ethyl acetate, isopropanol, and water. Other steps were the same as in Example 1. The reaction results are shown in Tables 1-3.

[0050] Table 1-3 Effect of different solvents on reaction yield

[0051]

[0052] Based on the reaction yield and green chemistry considerations, isopropanol, a green solvent, was ultimately chosen as the reaction solvent.

[0053] Examples 17-20

[0054] The type of copper catalyst was changed, with CuI replaced by Cu (5 μm), CuBr, CuCl, and CuSO4·5H2O, while other aspects remained the same as in Example 1. The reaction results are shown in Tables 1-4.

[0055] Table 1-4 Effect of different copper catalysts on reaction yield

[0056]

[0057] The results showed that the yield was not as high as that when using other copper catalysts as when using CuI, so CuI was chosen to be added to the reaction.

[0058] Examples 21-22

[0059] The amount of CuI was changed from 10% (0.03 mmol) to 0.015 mmol, and other parameters remained the same as in Example 1. The reaction results are shown in Tables 1-5.

[0060] Table 1-5 Effect of different CuI dosages on reaction yield

[0061]

[0062] The results showed that the yield could reach 98% when using 0.003 mmol of CuI, so CuI (0.015 mmol, 0.0029 g) was finally added to the reaction.

[0063] After the above series of condition screenings, the optimal conditions are those used in Example 21, and the specific operations are as follows:

[0064] In a dry reaction tube, add 0.3 mmol (0.0823 g) of ebuselenline, 0.3 mmol (0.0306 g) of phenylacetylene, 0.015 mmol (0.0028 g) of CuI, 0.03 mmol (0.0042 g) of K2CO3 and 2 mL of isopropanol. Add a stir bar and stir the mixture at room temperature under air for 6 h. Remove the solvent under reduced pressure and perform column chromatography (petroleum ether: ethyl acetate = 4:1). Collect R. f The solvent was removed by using an eluent with a pH of approximately 0.4 under reduced pressure, and the mixture was dried to obtain the target compound (Ⅲ-1), a white solid of 0.1115 g, with a yield of 99%, a melting point of 132-134 °C, and a purity of 98.32% (HPLC detection).

[0065] Example 23

[0066] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 34.8 mg (0.3 mmol) of p-methylphenylacetylene, and PE:EA = 5:1 is passed through a column to obtain 111.1 mg of white solid (Ⅲ-2), with a yield of 95% and a melting point of 175-176 °C.

[0067]

[0068] 1 H NMR (400MHz, CDCl3) δ8.27(d,J=7.9Hz,1H),7.96(s,1H),7.69(d,J=7.4Hz,1H),7.58( d,J=7.6Hz,2H),7.50-7.42(m,3H),7.37-7.29(m,3H),7.18-7.14(m,3H),2.36(s,3H). 13 C NMR (101MHz, CDCl3) δ165.69,138.79,137.16,135.26,132.40,131.77,130.77,130.68,129 .13,129.12,126.67,126.13,125.07,120.66,120.23,104.48,72.86,21.54; HRMS(ESI)for C 22 H 17 NOSe: calculated for [M+Na] + 414.0368, found 414.0370.

[0069] Example 24

[0070] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 36.0 mg (0.3 mmol) of p-fluorophenylacetylene, and PE:EA = 5:1 is passed through a column to obtain 113.2 mg of white solid (Ⅲ-3), with a yield of 96% and a melting point of 130-131 °C.

[0071]

[0072] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=7.8Hz,1H),7.96(s,1H),7.70(d,J=7.4Hz,1H),7.58(d,J=7. 6Hz,2H),7.51-7.48(m,3H),7.38-7.31(m,3H),7.17(t,J=7.2Hz,1H),7.04(t,J=8.5Hz,2H). 13C NMR(101MHz, CDCl3)δ165.66,162.63(d,J=250.0Hz),137.11,135.04,133.81(d,J=8.4Hz),132.45,130.75,130.63, 129.16,126.71,126.24,125.13,120.68,119.43(d,J=3.5Hz),115.66(d,J=22.1Hz),103.18,73.65; HRMS(ESI)forC 21 H 14 FNOSe: calculated for [M+Na] + 418.0117, found 418.0123.

[0073] Example 25

[0074] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 41.0 mg (0.3 mmol) of p-chlorophenylacetylene, and PE:EA = 5:1 is passed through a column to obtain 121.9 mg of white solid (Ⅲ-4), with a yield of 99% and a melting point of 167-168 °C.

[0075]

[0076] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=7.9Hz,1H),7.96(s,1H),7.71(d,J=7.5Hz,1H),7.58(d,J=7.7 Hz,2H),7.51(t,J=7.6Hz,1H),7.45(d,J=8.0Hz,2H),7.39-7.31(m,5H),7.18(t,J=7.2Hz,1H). 13 C NMR (101MHz, CDCl3) δ165.63,137.09,134.91,134.49,132.94,132.48,130.72,130.62, 129.17,128.69,126.70,126.28,125.15,121.79,120.68,103.16,75.34; HRMS(ESI)for C 21 H 14 ClNOSe: calculated for [M+Na] + 433.9821, found 433.9824.

[0077] Example 26

[0078] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 54.3 mg (0.3 mmol) of p-bromophenylacetylene, and PE:EA = 5:1 is passed through a column to obtain 131.7 mg of white solid (Ⅲ-5), with a yield of 96% and a melting point of 168-170 °C.

[0079]

[0080] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=8.0Hz,1H),7.95(s,1H),7.71(d,J=7.6Hz,1H),7 .59(d,J=7.7Hz,2H),7.53-7.47(m,3H),7.40-7.33(m,5H),7.18(t,J=7.3Hz,1H). 13 CNMR(101MHz,CDCl3)δ165.61,137.10,134.89,133.12,132.49,131.61,130.72,130.63, 129.17,126.68,126.29,125.15,122.71,122.25,120.66,103.22,75.59; HRMS(ESI)forC 21 H 14 BrNOSe: calculated for [M+Na] + 477.9316, found 477.9318.

[0081] Example 27

[0082] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 51.0 mg (0.3 mmol) of p-trifluoromethylphenylacetylene, and PE:EA = 6:1 is passed through a column to obtain 110.8 mg of white solid (Ⅲ-6), with a yield of 92% and a melting point of 155-156 °C.

[0083]

[0084] 1 H NMR(400MHz, CDCl3)δ8.25(dd,J=8.1,0.9Hz,1H),7.95(s,1H),7.73(dd,J=7.8,1.2Hz,1H) ,7.64-7.59(m,6H),7.54(td,J=7.8,1.3Hz,1H),7.40-7.35(m,3H),7.19(t,J=7.4Hz,1H). 13C NMR (101MHz, CDCl3) δ165.61,137.09,134.70,132.59,131.74,130.76,130.66,130.13,129.97(d,J=32.6Hz),127 .10,126.72,126.44,125.32(d,J=3.8Hz),125.24,123.91(d,J=272.1Hz),120.70,103.07,77.68; HRMS(ESI)forC 22 H 14 F3NOSe: calculated for [M+Na] + 468.0085, found 468.0096.

[0085] Example 28

[0086] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 48.1 mg (0.3 mmol) of methyl p-acetylenate, and PE:EA = 3:1 is passed through a column to obtain 122.9 mg of white solid (Ⅲ-7), with a yield of 94% and a melting point of 190-191 °C.

[0087]

[0088] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.22(t,J=7.6Hz,2H),7.99(d,J=7.6Hz,2H),7.76-7. 69(m,5H),7.55(t,J=7.4Hz,1H),7.40(t,J=7.4Hz,2H),7.17(t,J=7.2Hz,1H),3.88(s,3H). 13 C NMR(101MHz,DMSO-d6)δ165.81,165.61,138.26,132.96,132.77,131.42,130.62,129.42,129.3 5,129.18,129.06,128.73,127.14,126.63,124.42,121.02,103.25,79.13,52.34; HRMS(ESI)for C 23 H 17 NO3Se: calculated for [M+Na] + 458.0266, found 458.0268.

[0089] Example 29

[0090] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 39.6 mg (0.3 mmol) of p-methoxyphenylacetylene, and PE:EA = 5:1 is passed through a column to give 114.6 mg of white solid (Ⅲ-8), with a yield of 94% and a melting point of 133-134 °C.

[0091]

[0092] 1 H NMR (400MHz, CDCl3) δ8.27(d,J=8.0Hz,1H),7.97(s,1H),7.69(d,J=7.6Hz,1H),7.59(d,J=7.9Hz,2H) ,7.49(d,J=7.9Hz,3H),7.38-7.29(m,3H),7.17(t,J=7.3Hz,1H),6.87(d,J=8.3Hz,2H),3.82(s,3H). 13 C NMR (101MHz, CDCl3) δ165.69,159.89,137.21,135.44,133.59,132.38,130.80,130.69,129 .14,126.66,126.09,125.04,120.65,115.43,113.97,104.27,71.90,55.33; HRMS(ESI)for C 22 H 17 NO2Se: calculated for [M+Na] + 430.0317, found 430.0321.

[0093] Example 30

[0094] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 36.0 mg (0.3 mmol) m-fluorophenylacetylene, and PE:EA = 5:1 is passed through a column to obtain 117.3 mg of white solid (Ⅲ-9), with a yield of 99% and a melting point of 98-99 °C.

[0095]

[0096] 1 H NMR(400MHz, CDCl3)δ8.25(d,J=7.9Hz,1H),8.03-7.90(m,1H),7.71(d,J=7.0 Hz,1H),7.60-7.51(m,3H),7.39-7.31(m,5H),7.25-7.17(m,2H),7.05(s,1H). 13C NMR (101MHz, CDCl3) δ165.65,162.32(d,J=246.7Hz),137.08,134.79,132.51,130.73,130.62,129.94(d,J=8.7Hz),129.16,127.54(d,J= 3.0Hz),126.72,126.32,125.17,125.05,120.70,118.38(d,J=22.8Hz),115.79(d,J=21.2Hz),103.06(d,J=3.4Hz),75.61; HRMS(ESI)for C 21 H 14 FNOSe: calculated for [M+Na] + 418.0117, found 418.0123.

[0097] Example 31

[0098] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 44.1 mg (0.3 mmol) m-nitrophenylacetylene, and PE:EA = 5:1 is passed through a column to obtain 125.1 mg of yellow solid (Ⅲ-10), with a yield of 99% and a melting point of 164-165 °C.

[0099]

[0100] 1 H NMR(400MHz, CDCl3)δ8.36(t,J=1.7Hz,1H),8.25(d,J=8.0Hz,1H),8.19-8.16(m,1H),7.96(s,1H),7.82 (d,J=7.7Hz,1H),7.75(d,J=6.9Hz,1H),7.62-7.51(m,4H),7.39(t,J=8.0Hz,3H),7.20(t,J=7.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ165.57,148.10,137.18,137.05,134.45,132.67,130.68,130.63,129.41, 129.23,126.73,126.53,126.26,125.25,125.12,122.95,120.69,101.88,78.34; HRMS(ESI)for C 21 H 14 N₂O₃Se: calculated for [M + Na] + 445.0062, found 445.0069.

[0101] Example 32

[0102] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 41.0 mg (0.3 mmol) o-chlorophenylacetylene, and PE:EA = 6:1 is passed through a column to obtain 122.1 mg of white solid (Ⅲ-11), with a yield of 99% and a melting point of 111-112 °C.

[0103]

[0104] 1 H NMR (400MHz, CDCl3) δ8.45(dd,J=8.1,0.6Hz,1H),7.97(s,1H),7.70(dd,J=7.7,0.9Hz,1H),7.58(d,J=7.7 Hz,2H),7.55-7.49(m,2H),7.46-7.40(m,1H),7.43-7.41(m,3H),7.27-7.23(m,3H),7.17(t,J=7.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ165.81,137.23,135.61,134.90,133.20,132.61,131.14,130.78,129.39, 129.30,129.28,126.76,126.64,126.44,125.26,123.41,120.83,101.27,80.39; HRMS(ESI)for C 21 H 14 ClNOSe: calculated for [M+Na] + 433.9821, found 433.9832.

[0105] Example 33

[0106] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 48.7 mg (0.3 mmol) of 2,3-dimethoxyphenylacetylene, the reaction is carried out for 12 h, and PE:EA = 4:1 is passed through a column to obtain 130.0 mg of white solid (Ⅲ-12), with a yield of 99% and a melting point of 98-99 °C.

[0107]

[0108] 1H NMR (400MHz, CDCl3) δ8.43(d,J=8.0Hz,1H),8.06(s,1H),7.71(d,J=7.6Hz,1H),7.58(d,J=7.9Hz,2H),7.48(t,J=7.6 Hz,1H),7.37-7.25(m,3H),7.16(t,J=7.2Hz,1H),7.08-6.99(m,2H),6.89(d,J=8.0Hz,1H),3.96(s,3H),3.86(s,3H). 13 C NMR (101MHz, CDCl3) δ165.76,152.68,150.18,137.20,135.03,132.38,130.72,130.69,129.10,126.72 ,126.20,125.04,124.59,124.00,120.73,118.18,112.79,100.50,78.36,61.08,55.92; HRMS(ESI)for C 23 H 19 NO3Se: calculated for [M+Na] + 460.0422, found 460.0421.

[0109] Example 34

[0110] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 30.9 mg (0.3 mmol) of 2-ethynylpyridine, and PE:EA = 1:1 is passed through a column to obtain 109.6 mg of brown solid (Ⅲ-13), with a yield of 97% and a melting point of 199-201 °C.

[0111]

[0112] 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.62(d,J=4.0Hz,1H),8.23(d,J=7.7Hz,2H),7.86(t,J= 7.6Hz,1H),7.77-7.67(m,4H),7.55(t,J=7.4Hz,1H),7.47-7.39(m,3H),7.18(t,J=7.2Hz,1H). 13C NMR(101MHz,DMSO-d6)δ165.74,150.06,142.13,138.18,136.77,132.84,132.52,130.58,12 9.21,129.02,128.66,126.86,126.61,124.37,123.46,120.96,103.91,75.52; HRMS(ESI)for C 20 H 14 N₂OSe: calculated for [M + Na] + 401.0164, found 401.0168.

[0113] Example 35

[0114] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 61.8 mg (0.3 mmol) of 4-ethyl-4'-ethynyl-1,1'-biphenyl, and PE:EA = 4:1 is passed through a column to give 135.0 mg of white solid (Ⅲ-14), with a yield of 94% and a melting point of 180-181 °C.

[0115]

[0116] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.22(d,J=7.8Hz,2H),7.76(d,J=7.8Hz,2H),7.72-7.62(m,7H),7.53(t,J=7.3Hz ,1H),7.40(t,J=7.5Hz,2H),7.32(d,J=7.3Hz,2H),7.17(t,J=7.2Hz,1H),2.65(q,J=6.6Hz,5H),1.21(t,J=7.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ165.82,143.67,140.37,138.33,136.48,133.26,132.83,132.05,130.68,129.30,129.0 2,128.72,128.47,126.66,126.60,126.46,124.37,121.11,120.98,103.86,75.36,27.83,15.55; HRMS(ESI)for C 29 H 23 NOSe: calculated for [M+Na] + 504.0837, found 504.0847.

[0117] Example 36

[0118] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 32.4 mg (0.3 mmol) 2-ethynylthiophene, and PE:EA = 4:1 is passed through a column to obtain 108.4 mg of brown solid (Ⅲ-15), with a yield of 95% and a melting point of 151-152 °C.

[0119]

[0120] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.21(d,J=6.9Hz,1H),8.09(d,J=8.0Hz,1H),7.75(d,J =7.8Hz,2H),7.71-7.65(m,2H),7.54-7.49(m,2H),7.40(t,J=7.9Hz,2H),7.23-7.09(m,2H). 13 C NMR(101MHz,DMSO-d6)δ165.78,138.28,133.90,133.26,132.83,130.65,129.62,129.2 2,129.05,128.73,127.73,126.57,124.40,122.02,120.99,96.64,79.24; HRMS(ESI)for C 19 H 13 NOSSe: calculated for [M+Na] + 405.9775, found 405.9780.

[0121] Example 37

[0122] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 29.4 mg (0.3 mmol) ethyl propynate, and PE:EA = 4:1 is passed through a column to obtain 107.0 mg of white solid (Ⅲ-16), with a yield of 96% and a melting point of 155-157 °C.

[0123]

[0124] 1H NMR (400MHz, CDCl3) δ8.16(d,J=7.6Hz,2H),7.74(d,J=7.5Hz,1H),7.58(d,J=7.7Hz,2H),7.52(t,J =7.7Hz,1H),7.38-7.35(m,3H),7.18(t,J=7.4Hz,1H),4.28(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ165.60,153.06,136.93,132.92,132.67,130.65,130.52,12 9.17,126.97,126.84,125.32,120.81,97.97,79.48,62.08,14.13; HRMS(ESI)for C 18 H 15 NO3Se: calculated for [M+Na] + 396.0109, found 396.0115.

[0125] Example 38

[0126] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 29.5 mg (0.3 mmol) ethynyltrimethylsilane, and PE:EA = 6:1 is passed through a column to obtain 108.5 mg of white solid (Ⅲ-17), with a yield of 97% and a melting point of 129-130 °C.

[0127]

[0128] 1 H NMR (400MHz, CDCl3) δ8.22(d,J=8.1Hz,1H),7.89(br,1H),7.68(d,J=7.7Hz,1H),7.57(d,J =8.3Hz,2H),7.50(t,J=7.7Hz,1H),7.42-7.29(m,3H),7.17(t,J=7.4Hz,1H),0.27(s,9H); 13 C NMR (101MHz, CDCl3) δ165.73,137.28,134.54,132.53,131.14,130.72,129.28,126.78,126.35,125.22,120.76,112.93,89.82,0.16; HRMS(ESI) forC 18 H 19 NOSeSi: calculated for [M+Na] +396.0293, found 396.0298.

[0129] Example 39

[0130] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 30.6 mg (0.3 mmol) of (R)-3-methylpent-1-yn-3-ol, and PE:EA = 2:1 is passed through a column to give 109.9 mg of white solid (Ⅲ-18), with a yield of 98% and a melting point of 114-115 °C.

[0131]

[0132] 1 H NMR (400MHz, CDCl3) δ8.20-8.14(m,1H),8.04(s,1H),7.69(d,J=7.7Hz,1H),7.60-7.55(m,2H),7.53-7.49(m,1H ),7.40-7.27(m,3H),7.20-7.14(m,1H),2.23(s,1H),1.80(q,J=7.4Hz,2H),1.58(s,3H),1.11(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ165.68,137.16,134.73,132.35,130.86,130.40,129.14,126. 74,126.15,125.09,120.69,108.56,69.88,67.59,36.55,29.34,9.15; HRMS(ESI)for C 19 H 19 NO2Se: calculated for [M+Na] + 396.0473, found 396.0475.

[0133] Example 40

[0134] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 33.1 mg (0.3 mmol) 1-octyne, and PE:EA = 10:1 is passed through a column to obtain 106.3 mg of white solid (Ⅲ-19), with a yield of 92% and a melting point of 95-96 °C.

[0135]

[0136] 1H NMR (400MHz, CDCl3) δ8.22(d,J=7.8Hz,1H),7.90(s,1H),7.67(d,J=7.4Hz,1H),7.57(d,J=7.4Hz,2H),7.48(t,J=7. 2Hz,1H),7.37-7.30(m,3H),7.16(t,J=6.9Hz,1H),2.49(t,J=6.7Hz,2H),1.64-1.59(m,2H),1.54-1.40(m,2H),1.40 -1.22(m,4H),0.98-0.82(m,3H). 13 C NMR (101MHz, CDCl3) δ165.67,137.24,135.60,132.17,130.90,130.52,129.12,126.58,125. 91,124.98,120.58,106.07,62.09,31.34,28.76,28.64,22.58,20.62,14.08; HRMS(ESI)for C 21 H 23 NOSe: calculated for [M+Na] + 408.0837, found 408.0841.

[0137] Example 41

[0138] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 37.3 mg (0.3 mmol) of 1-ethynylcyclohexane-1-ol, and PE:EA = 2:1 is passed through a column to obtain 113.9 mg of white solid (Ⅲ-20), with a yield of 95% and a melting point of 163-164 °C.

[0139]

[0140] 1 H NMR (400MHz, CDCl3) δ8.20(d,J=8.0Hz,1H),8.02(s,1H),7.72(d,J=7.6Hz,1H),7.60(d,J=7.8Hz,2H),7.50(t,J=7.6H z,1H),7.40-7.32(m,3H),7.19(t,J=7.2Hz,1H),2.24(s,1H),2.12-2.04(m,2H),1.77-1.58(m,8H),1.33-1.28(m,1H). 13C NMR (101MHz, CDCl3) δ165.62,137.17,134.93,132.38,130.88,130.46,129.18,126.6 2,126.15,125.10,120.61,108.71,69.84,68.34,39.96,25.18,23.31; HRMS(ESI)for C 21 H 21 NO₂Se: calculated for [M + Na] + 422.0630, found 422.0636.

[0141] Example 42

[0142] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 76.8 mg (0.3 mmol) pendimethalin, the reaction is carried out for 12 h, and PE:EA = 2:1 / 1:1 column chromatography yields 157.5 mg of white solid (Ⅲ-21), with a yield of 99% and a melting point of 185-186 °C.

[0143]

[0144] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.71(s,1H),8.32(d,J=7.9Hz,1H),8.15(d,J=7.6Hz,1H),7.92(d,J=1.8Hz,2H),7.81(t,J=1.7 Hz,1H),7.73(d,J=7.8Hz,2H),7.60(t,J=7.2Hz,1H),7.49(t,J=7.4Hz,1H),7.38(t,J=7.9Hz,2H),7.15(t,J=7.4Hz,1H),1.73(s,6H); 13 C NMR(101MHz,DMSO-d6)δ166.27,163.66,138.83,138.32,134.65,134.04,132.89,131.15,130.0 4,129.27,129.15,126.83,126.71,124.74,121.37,109.09,64.72,48.87,29.46; HRMS(ESI)for C 25 H 20 Cl2N2O2Se:calculated for[M+Na] + 552.9959, found 552.9963.

[0145] Example 43

[0146] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 93.7 mg (0.3 mmol) of ethinyleneprogesterone, and PE:EA = 1:1 is passed through a column to obtain 170.1 mg of white solid (Ⅲ-22), with a yield of 95% and a melting point of 147-151 °C.

[0147]

[0148] 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 8.14 (t, J = 7.2Hz, 2H), 7.73-7.71 (m, 2H), 7.64-7.53 ( m,1H),7.59-7.55(m,1H),7.38(t,J=7.9Hz,2H),7.15(t,J=7.4Hz,1H),5.62(s,1H),5.58(s ,1H),2.43-2.36(m,2H),2.25-2.12(m,3H),1.99-1.92(m,2H),1.82-1.79(m,1H),1.71-1.5 8(m,6H),1.51-1.44(m,1H),1.40-1.29(m,2H),1.16(s,3H),0.95-0.85(m,2H),0.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ198.45,171.30,166.19,138.82,134.11,132.66,131.37,129.67,129.37,129.16,126.79,124.76,123.64,121.34,1 10.34,79.84,68.12,53.82,50.48,47.23,38.69,36.10,35.59,34.10,33.14,32.41,31.90,25.26,23.34,20.82,17.42,13.34; HRMS(ESI)for C 34 H 37 NO3Se: calculated for [M+Na] + 610.1831, found 610.1834.

[0149] Example 44

[0150] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 129.0 mg (0.3 mmol) of icotinib hydrochloride and potassium carbonate is used with 45.6 mg (0.33 mmol). The DCM:CH3OH = 40:1 column chromatography yields 198.3 mg of white solid (Ⅲ-23), with a yield of 99% and a melting point of 118-120 °C.

[0151]

[0152] 1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H),9.52(s,1H),8.53(s,1H),8.22-8.15(m,1H),8.08-8.07(m, 1H),7.94(dd,J=8.3,1.1Hz,1H),7.89(s,1H),7.75(dd,J=8.5,0.9Hz,1H),7.70(t,J=7.0Hz,1H), 7.53(t,J=7.0Hz,1H),7.46(t,J=7.9Hz,1H),7.42-7.38(m,1H),7.33(d,J=7.7Hz,1H),7.24(s,1H ),7.17(t,J=7.4Hz,1H),4.32-4.29(m,4H),3.81-3.74(m,4H),3.38(s,3H),3.36(d,J=4.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ165.82,156.13,153.68,152.80,148.15,147.01,13 9.87,138.32,133.20,132.83,131.29,130.71,129.25,129.05,129.01,128 .74,126.52,126.20,124.50,124.40,122.58,122.46,120.99,108.21,103. 93,103.15,74.56,70.13,70.06,68.38,68.06,58.42,58.36; HRMS(ESI)forC 35 H 32 N4O5Se: calculated for [M+H] + 669.1611, found 669.1622.

[0153] Example 45

[0154] The other operations are the same as in Example 21, except that phenylacetylene is replaced with 35.4 mg (0.15 mmol) of diethyl 2,2-dipropynyl malonate. After reacting for 18 h, PE:EA = 2:1 is passed through a column to obtain 109.5 mg of white solid (Ⅲ-24), with a yield of 93% and a melting point of 91-92 °C.

[0155]

[0156] 1 H NMR (400MHz, CDCl3) δ8.16(d,J=6.1Hz,2H),8.07-7.98(m,2H),7.66(d,J=7.2Hz2H),7.61-7.51(m,4H),7. 50-7.45(m,2H),7.34-7.33(m,4H),7.20-7.10(m,2H),4.28-4.18(m,4H),3.36(s,4H),1.28-1.20(m,6H). 13 C NMR (101MHz, CDCl3) δ168.94,165.74,137.18,134.88,132.38,130.79,130.62,129.10,1 26.67,126.11,125.05,120.71,99.47,67.09,62.19,56.83,25.15,14.11; HRMS(ESI)for C 39 H 34 N₂O₆Se₂: calculated for [M + Na] + 809.0640, found 809.0650.

[0157] Example 46

[0158] The other operations are the same as in Example 21, except that epuxenline is replaced with 105.9 mg (0.3 mmol) of 2-(2-bromophenyl)benzo[d][1,2]selenozol-3(2H)-one, and PE:EA = 5:1 is passed through a column to give 127.3 mg of white solid (Ⅲ-25), with a yield of 93% and a melting point of 140-141 °C.

[0159]

[0160] 1H NMR (400MHz, CDCl3) δ8.54(br,1H),8.49(dd,J=8.3,1.5Hz,1H),8.32(dd,J=8.1,0.9Hz,1H),7 .80(dd,J=7.8,1.1Hz,1H),7.64-7.49(m,4H),7.46-7.31(m,5H),7.05(td,J=7.8,1.5Hz,1H); 13 C NMR (101MHz, CDCl3) δ165.26,135.67,135.19,132.72,132.32,131.80,130.82,130.36,128.59, 128.54,128.36,126.69,126.41,125.76,123.28,121.97,114.02,104.53,73.78; HRMS(ESI)for C 21 H 14 BrNOSe: calculated for [M+Na] + 477.9316, found 477.9324.

[0161] Example 47

[0162] The other operations are the same as in Example 21, except that epuxenol is replaced with 86.5 mg (0.3 mmol) of 2-benzylbenzo[d][1,2]selenozol-3(2H)-one, and PE:EA = 6:1 column chromatography yields 115.9 mg of white solid (Ⅲ-26), with a yield of 99% and a melting point of 92-93 °C.

[0163]

[0164] 1 H NMR (400MHz, CDCl3) δ8.26(d,J=8.0Hz,1H),7.56-7.51(m,3H),7.51-7.42(m,1H),7.40-7.22(m,9H),6.55(br,1H),4.63(d,J=5.6Hz,2H); 13 C NMR (101MHz, CDCl3) δ167.27,137.58,134.82,132.21,131.75,130.42,130.18,128.85,128 .44,128.34,127.95,127.80,126.52,126.01,123.39,104.19,74.32,44.24; HRMS(ESI)for C 22 H 17NOSe: calculated for [M+Na] + 414.0368, found 414.0373.

[0165] Example 48

[0166] The other operations were the same as in Example 21, except that epuxenline was replaced with 84.1 mg (0.3 mmol) of 2-cyclohexylbenzo[d][1,2]selezol-3(2H)-one. After reacting for 12 h, PE:EA = 5:1 column chromatography yielded 113.6 mg of white solid (Ⅲ-27), with a yield of 99% and a melting point of 153-155 °C.

[0167]

[0168] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=8.0Hz,1H),7.62-7.50(m,3H),7.45(t,J=7.7Hz,1H),7.38-7.31(m,3H),7.31-7.23(m,2H),6.14 (br,1H),4.03-3.90(m,1H),2.04(d,J=11.1Hz,2H),1.81-1.70(m,2H),1.68-1.60(m,1H),1.47-1.37(m,2H),1.30-1.15(m,3H); 13 C NMR (101MHz, CDCl3) δ166.52,134.60,131.95,131.74,130.68,130.37,128.38,128.3 3,126.30,125.92,123.46,104.01,74.62,49.10,33.15,25.49,24.90; HRMS(ESI)forC 21 H 21 NOSe: calculated for [M+Na] + 406.0681, found 406.0683.

[0169] Example 49

[0170] The other operations were the same as in Example 21, except that epuxenline was replaced with 76.3 mg (0.3 mmol) of 2-(tert-butyl)benzo[d][1,2]selezol-3(2H)-one. After reacting for 12 h, PE:EA = 6:1 column chromatography yielded 105.7 mg of white solid (Ⅲ-28), with a yield of 99% and a melting point of 120-121 °C.

[0171]

[0172] 1 H NMR (400MHz, CDCl3) δ8.25 (d, J = 7.4Hz, 1H), 7.58-7.53 (m, 2H), 7.52-7.43 (m, 2H), 7.42-7.34 (m, 3H), 7.32-7.24 (m, 1H), 6.06 (br, 1H), 1.51 (s, 9H); 13 C NMR (101MHz, CDCl3) δ167.06,133.95,132.04,131.75,131.72,130.37,128.37 ,128.32,126.28,125.93,123.48,103.80,74.53,52.11,28.85; HRMS(ESI)for C 19 H 19 NOSe: calculated for [M+Na] + 380.0524, found 380.0526.

[0173] Example 50

[0174] The other operations were the same as in Example 21, except that epuxenline was replaced with 76.3 mg (0.3 mmol) of 2-butylbenzo[d][1,2]selezol-3(2H)-one. After reacting for 24 h, PE:EA = 5:1 / 4:1 was passed through a column to obtain 104.8 mg of colorless oil (Ⅲ-29), with a yield of 98%.

[0175]

[0176] 1 H NMR (400MHz, CDCl3) δ8.24 (d, J = 8.1Hz, 1H), 7.58-7.51 (m, 3H), 7.49-7.42 (m, 1H), 7.39-7.32 (m, 3H), 7.31-7.27 (m,1H),6.29(s,1H),3.46(dd,J=13.1,7.1Hz,2H),1.70-1.53(m,2H),1.46-1.36(m,2H),0.96(t,J=7.3Hz,3H); 13 C NMR (101MHz, CDCl3) δ167.39,134.58,132.01,131.74,130.57,130.38,128.40,128.3 4,126.33,125.96,123.45,104.06,74.51,40.01,31.64,20.15,13.78; HRMS(ESI)for C19 H 19 NOSe: calculated for [M+Na] + 380.0524, found 380.0529.

[0177] Example 51

[0178] The other operations were the same as in Example 21, except that epuxenline was replaced with 82.6 mg (0.3 mmol) of 2-(pyridin-2-yl)benzo[d][1,2]selezol-3(2H)-one, and 45.9 mg (0.45 mmol) of phenylacetylene was added instead of 30.6 mg (0.3 mmol) of phenylacetylene. After reacting for 9 h, PE:EA = 6:1 column chromatography yielded 110.3 mg of yellow solid (Ⅲ-30), with a yield of 97% and a melting point of 104-105 °C.

[0179]

[0180] Example 52

[0181] In a dry reaction tube, 0.3 mmol (0.0823 g) of ebuselenline, 0.3 mmol (0.0306 g) of phenylacetylene, 0.3 mmol (0.0399 g) of benzyl azide, 0.015 mmol (0.0028 g) of CuI, 0.33 mmol (0.0456 g) of K2CO3, and 2 mL of isopropanol were added. A stir bar was added, and the reaction was stirred at room temperature for 18 h under nitrogen atmosphere. The solvent was removed under reduced pressure, and the mixture was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1). R was collected. f The solvent was removed by reducing the pressure of the eluent with a concentration of approximately 0.3, and the mixture was dried to obtain the target compound (V-1), a white solid of 140.2 mg, with a yield of 92%, a melting point of 181-183 °C, and a purity of 98.72% (HPLC detection).

[0182]

[0183] 1 H NMR (400MHz, CDCl3) δ8.04 (d, J = 7.2Hz, 2H), 7.66 (d, J = 7.8Hz, 3H), 7.52-7.06 (m, 13H), 7.04-6.88 (m, 1H), 6.43 (d, J = 7.9Hz, 1H), 5.66 (s, 2H); 13C NMR (101MHz, CDCl3) δ165.83,152.20,137.27,135.07,134.68,132.32,131.30,130.63,129.26,129.06,128 .51,128.49,128.25,128.05,127.21,127.10,126.00,125.22,120.76,120.63,119.94,53.14; HRMS(ESI)for C 28 H 22 N4OSe: calculated for [M+Na] + 533.0851, found 533.0856.

[0184] Example 53

[0185] The other operations are the same as in Example 52, except that phenylacetylene is replaced with 39.6 mg (0.3 mmol) of p-methoxyphenylacetylene, and PE:EA = 3:1 / 2:1 is passed through a column to obtain 155.2 mg of white solid (V-2), with a yield of 96% and a melting point of 163-164 °C.

[0186]

[0187] 1 H NMR (400MHz, CDCl3) δ8.15(br,1H),7.98(d,J=8.7Hz,2H),7.70-7.65(m,3H),7.39(t,J=7.8Hz,2H),7.22-7.19(m,3 H),7.16-7.04(m,4H),6.95(t,J=7.7Hz,1H),6.85(d,J=8.8Hz,2H),6.42(d,J=8.1Hz,1H),5.62(s,2H),3.75(s,3H); 13 C NMR (101MHz, CDCl3) δ165.88,159.78,152.05,137.31,135.02,134.67,132.24,131.30,129.19,128.95,128.49 ,128.44,128.21,128.00,127.23,125.94,125.14,123.15,120.68,119.08,113.92,55.21,53.09; HRMS(ESI)for C 29 H 24 N4O2Se: calculated for [M+Na] + 563.0957, found 563.0958.

[0188] Example 54

[0189] The other operations are the same as in Example 52, except that phenylacetylene is replaced with 36.0 mg (0.3 mmol) of p-fluorophenylacetylene, and PE:EA = 3:1 is passed through a column to obtain 156.1 mg of white solid (V-3), with a yield of 99% and a melting point of 159-160 °C.

[0190]

[0191] 1 H NMR (400MHz, CDCl3) δ8.08(br,1H),8.06-7.97(m,2H),7.70(d,J=7.1Hz,1H),7.66(d,J=7.7Hz,2H ),7.40(t,J=7.9Hz,2H),7.24-7.08(m,7H),7.06-6.92(m,3H),6.39(d,J=8.0Hz,1H),5.64(s,2H); 13 C NMR (101MHz, CDCl3) δ165.80,162.91(d,J=248.1Hz),151.37,137.23,134.88,134.61,132.34,131.30,129.26,129.03(d,J=8.2Hz),128 .91,128.51,128.26,128.10,127.17,126.84(d,J=3.2Hz),126.08,125.27,120.68,119.79,115.49(d,J=21.6Hz),53.19; HRMS(ESI)for C 28 H 21 FN4OSe: calculated for [M+Na] + 551.0757, found 551.0766.

[0192] Example 55

[0193] The other operations are the same as in Example 52, except that phenylacetylene is replaced with 41.0 mg (0.3 mmol) o-chlorophenylacetylene, the reaction is carried out at 50 °C, PE:EA = 2:1 column chromatography to give 148.1 mg of white solid (V-4), yield 91%, melting point 182-183 °C.

[0194]

[0195] 1H NMR (400MHz, DMSO-d6) δ10.50(br,1H),8.00(d,J=7.6Hz,1H),7.72(d,J=8.3Hz,2H),7.55(dd,J=7.9,0.9Hz,1H),7.50-7.46(m,1H),7.43(t d,J=7.7,1.8Hz,1H),7.40-7.34(m,3H),7.32(t,J=7.5Hz,1H),7.26-7.18(m,6H),7.14(t,J=7.4Hz,1H),6.47(d,J=7.9Hz,1H),5.64(s,2H); 13 C NMR(101MHz,DMSO-d6)δ166.41,151.41,138.92,135.62,134.15,133.61,132.81,132.55,132.02,131.15,130.41,13 0.07,129.52,129.16,129.01,128.73,128.41,128.28,127.51,126.42,124.71,123.81,121.20,52.98; HRMS(ESI)for C 28 H 21 ClN4OSe: calculated for [M+Na] + 567.0461, found 567.0462.

[0196] Example 56

[0197] The other operations are the same as in Example 52, except that phenylacetylene is replaced with 32.4 mg (0.3 mmol) 2-ethynylthiophene, and PE:EA = 2:1 is passed through a column to obtain 137.4 mg of white solid (V-5), with a yield of 89% and a melting point of 181-182 °C.

[0198]

[0199] 1 H NMR (400MHz, DMSO-d6) δ10.60(br,1H),8.07(d,J=7.6Hz,1H),7.80(d,J=7.9Hz,2H),7.53(dd,J=5.0,1.3Hz,2H),7.41(t ,J=7.9Hz,2H),7.34(t,J=7.5Hz,1H),7.26-7.13(m,7H),7.06(dd,J=5.0,3.7Hz,1H),6.42(d,J=8.0Hz,1H),5.71(s,2H); 13CNMR(101MHz,DMSO-d6)δ166.52,147.51,139.02,135.76,133.91,132.74,132.69,132.44,129.68,12 9.20,129.02,128.38,128.19,127.28,126.56,125.55,124.74,121.23,120.31,52.89; HRMS(ESI)for C 26 H 20 N4OSSe: calculated for [M+Na] + 539.0415, found 539.0426.

[0200] Example 57

[0201] The other operations are the same as in Example 52, except that phenylacetylene is replaced with 29.4 mg (0.3 mmol) ethyl propynate, and PE:EA = 2:1 is passed through a column to obtain 132.0 mg of pale yellow solid (V-6), with a yield of 87% and a melting point of 150-151 °C.

[0202]

[0203] 1 H NMR (400MHz, CDCl3) δ8.40(br,1H),7.69(d,J=7.5Hz,1H),7.64(d,J=7.7Hz,2H),7.37(t,J=7.9Hz,2H),7.28-7.0 8(m,7H),7.01(t,J=7.6Hz,1H),6.43(d,J=8.0Hz,1H),5.72(s,2H),4.29(q,J=7.1Hz,2H),1.25(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3) δ165.96,160.60,143.60,137.44,134.23,133.80,132.54,131.90,129.91,129 .12,128.76,128.44,128.21,127.35,126.48,125.04,120.64,61.39,53.40,14.10; HRMS(ESI)forC 25 H 22 N4O3Se: calculated for [M+Na] + 529.0749, found 529.0760.

[0204] Example 58

[0205] The other operations are the same as in Example 52, except that phenylacetylene is replaced with 33.1 mg (0.3 mmol) 1-octyne, and PE:EA = 3:1 is passed through a column to obtain 155.3 mg of colorless oil (V-7), with a yield of 97%.

[0206]

[0207] 1 H NMR (400MHz, CDCl3) δ8.24(br,1H),7.72(d,J=7.7Hz,1H),7.67(d,J=7.7Hz,2H),7.39(t,J=7.9Hz,2H),7.22-7.06(m,7H),7.03-6 .93(m,1H),6.29(d,J=8.0Hz,1H),5.55(s,2H),2.68(t,J=7.7Hz,2H),1.95-1.40(m,2H),1.34-1.06(m,6H),0.80(t,J=6.8Hz,3H); 13 C NMR (101MHz, CDCl3) δ165.96,155.12,137.37,135.29,134.78,131.91,131.42,129.15,128.86,128.46,128.22, 128.01,127.24,125.81,125.10,120.92,120.70,53.06,31.47,29.44,28.97,25.96,22.48,14.03; HRMS(ESI)for C 28 H 30 N4OSe: calculated for [M+Na] + 541.1477, found 541.1487.

[0208] Example 59

[0209] The other operations are the same as in Example 52, except that phenylacetylene is replaced with 76.8 mg (0.3 mmol) of pendimethalin, and PE:EA = 2:1 is passed through a column to obtain 181.4 mg of white solid (V-8), with a yield of 91% and a melting point of 210-214 °C.

[0210]

[0211] 1H NMR (400MHz, DMSO-d6) δ10.37(br,1H),8.75(br,1H),8.02(dd,J=7.8,0.9Hz,1H),7.74(d,J=7.6Hz,2H),7.59(t,J=1.9Hz,1H),7.54(d,J=1 .9Hz,2H),7.38(t,J=7.9Hz,2H),7.24-7.19(m,3H),7.19-7.06(m,4H),7.05-6.97(m,1H),6.30(d,J=7.6Hz,1H),5.48(s,2H),1.75(s,6H); 13 C NMR(101MHz,DMSO-d6)δ166.21,163.44,157.50,138.96,138.57,135.86,135.04,134.05,132.29,131.07,130.3 8,129.08,128.87,128.22,128.11,126.53,125.87,124.64,121.33,119.48,52.84,52.20,28.83; HRMS(ESI)forC 32 H 27 Cl2N5O2Se:calculated for[M+Na] + 686.0599, found 686.0602.

[0212] Example 60

[0213] The other operations are the same as in Example 52, except that phenylacetylene is replaced with 93.7 mg (0.3 mmol) of ethinyleneprogesterone, the reaction is carried out for 36 h, and PE:EA = 1:1 column chromatography yields 153.1 mg of white solid (V-9), with a yield of 71% and a melting point of 170-174 °C.

[0214]

[0215] 11H NMR (400 MHz, CDCl3) δ 8.27 (br, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.17 - 7.06 (m, 6H), 6.95 (t, J = 7.6 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 5.65 (s, 1H), 5.53 (s, 2H), 3.57 (br, 1H), 2.71 - 2.57 (m, 1H), 2.44 - 2.21 (m, 3H), 2.13 (d, J = 13.5 Hz, 1H), 2.09 - 1.98 (m, 1H), 1.98 - 1.86 (m, 2H), 1.75 (d, J = 12.7 Hz, 1H), 1.67 (d, J = 12.3 Hz, 1H), 1.58 - 1.46 (m, 2H), 1.45 - 1.35 (m, 2H), 1.31 - 1.20 (m, 1H), 1.12 (s, 3H), 1.01 (s, 3H), 0.89 - 0.82 (m, 1H), 0.68 - 0.55 (m, 1H), 0.50 (td, J = 11.7, 4.1 Hz, 1H), 0.41 (td, J = 12.4, 4.1 Hz, 1H); 13 13C NMR (101 MHz, CDCl3) δ 199.65, 171.65, 165.70, 157.48, 137.22, 135.43, 134.34, 132.28, 131.12, 129.66, 129.24, 128.48, 128.26, 128.13, 127.01, 126.17, 125.27, 123.60, 120.72, 120.22, 83.72, 52.96, 49.18, 48.04, 38.51, 36.21, 36.16, 35.59, 33.92, 33.42, 32.77, 31.27, 24.31, 20.69, 17.35, 14.64; HRMS (ESI) for C 41 H 44 N4O3Se: calculated for [M + Na] + 743.2471, found 743.2472.

[0216] Example 61:

[0217] T47D ductal carcinoma cells, A549 non-small cell lung cancer cells, and HEPG2 liver cancer cells were used as research subjects. Cisplatin was used as a positive control drug. The MTT assay was used to perform cell inhibition experiments on the prepared compound III. Experimental steps: Sample preparation: First, the target compound was prepared into a 10.0 μmol / mL solution using biological grade DMSO. Then, the prepared solution was used to prepare a culture medium with a drug concentration of 60.0 μmol / L.

[0218] 1. Cell culture:

[0219] 1.1) Preparation of culture medium: Each 1000 mL of culture medium contains 800,000 units of penicillin, 1.0 g of streptomycin, and 10% inactivated penicillin.

[0220] Fetal bovine serum.

[0221] 1.2) Cell culture: Tumor cells were seeded in culture medium and cultured in a 37°C, 5% CO2 incubator for 3-5 days.

[0222] 5D inheritance.

[0223] 2. Determine the inhibitory effect of the sample on tumor cell growth:

[0224] Cells were digested with EDTA-trypsin digestion solution and diluted with culture medium to 10 μmol / mL. 100 μL was added to each well of a 96-well cell culture plate and incubated at 37°C in a 5% CO2 incubator. 24 h after inoculation, 100 μL of the sample diluted with culture medium was added to each well (3 wells per concentration), and the plates were incubated at 37°C in a 5% CO2 incubator. After 72 h, 10 μL of 5 mg / mL MTT was added to each well, and the plates were incubated at 37°C for 4 h. Then, 150 μL of DMSO was added to each well, and the plates were shaken to completely dissolve the formazan. The cells were then measured at 490 nm using a microplate reader. Cells cultured under the same conditions using medium containing the same concentration of DMSO but without the sample were used as a control. For drugs with an inhibition rate greater than 50%, a gradient test was required with concentrations of 60 μmol / L, 30 μmol / L, 15 μmol / L, 7.5 μmol / L, and 3.75 μmol / L. The IC50 of the sample against tumor cells was calculated. 50 The results are shown in Table 1.

[0225] Table 1 shows the inhibitory activity (IC50) of a total of 31 compounds III against T47D breast duct carcinoma cells, A549 non-small cell lung cancer cells, and HEPG2 liver cancer cells. 50 (μmol / L)

[0226]

[0227]

Claims

1. A process for the preparation of 5-seleno-functionalized triazoles, characterized in that, The method comprises the following steps: b) using the benzisoselenazolone compound (I), the terminal alkyne (II) and the organic azide compound (IV) as raw materials, adding a solvent and a copper catalyst, and reacting under the action of an alkaline substance for 18-30 hours; after the reaction is completed, the obtained reaction liquid is treated to obtain the 5-selenium functionalized triazole shown in formula (V); R in formula (I) is one of phenyl, benzyl, substituted phenyl, cyclohexyl, t-butyl, n-butyl or pyridyl. 1 R in formula (I) is one of phenyl, benzyl, substituted phenyl, cyclohexyl, t-butyl, n-butyl or pyridyl. R in formula (II) is phenyl, phenyl substituted by halogen, C 2 alkyl or C 1-8 alkoxy, pyridyl, thienyl or C 1-20 alkyl; and 3-20 alkyl; and In formula (V), R 1 is one of phenyl, benzyl, substituted phenyl, cyclohexyl, t-butyl, n-butyl or pyridyl, R 2 is one of phenyl, benzyl, substituted phenyl, cyclohexyl, t-butyl, n-butyl or pyridyl, R 1-8 is one of phenyl, benzyl, substituted phenyl, cyclohexyl, t-butyl, n-butyl or pyridyl, R 1-20 is one of phenyl, benzyl, substituted phenyl, cyclohexyl, t-butyl, n-butyl or pyridyl, R 3-20 is one of phenyl, benzyl, substituted phenyl, cyclohexyl, t-butyl, n-butyl or pyridyl, R 3 is one of phenyl or benzyl; In formula (IV), R 3 is the same as in formula (V).

2. The method for preparing 5-selenyl-functionalized trinitrogen as described in claim 1, characterized in that, In step b), the solvent is one or more of dichloromethane, acetonitrile, N,N-dimethylformamide, toluene, ethanol, isopropanol or water; The copper catalyst is cuprous iodide, Cu, cuprous chloride, cuprous bromide or copper sulfate pentahydrate; The alkaline substance is one or more of cesium carbonate, potassium carbonate, potassium bicarbonate, N,N-diisopropyl ethylamine or triethylamine; The molar ratio of the benzisoselenazolone compound (I), the terminal alkyne (II), the organic azide compound (IV), the copper catalyst and the alkaline substance is 1:1:1:0.05:1.

1.

3. The method for preparing 5-selenyl-functionalized trinitrogen as described in claim 1, characterized in that, In step b), after the reaction is completed, dichloromethane is added to dilute the reaction liquid, silica gel powder is added and spun dry, a mixed solvent of petroleum ether and ethyl acetate is used as an eluent for column chromatography separation, the eluent containing the target compound is collected, concentrated and dried to obtain the 5-selenium functionalized triazole shown in formula (V).

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