An ebselen-quinazoline derivative, preparation method, pharmaceutical composition and application thereof

Abstract

The application discloses an ebselen-quinazoline derivative, a preparation method, a pharmaceutical composition and application thereof. The structural formula of the ebselen-quinazoline derivative is shown as formula I, or a pharmaceutically acceptable salt thereof. The ebselen-quinazoline derivative covalently connects an ebselen pharmacophore and a quinazoline pharmacophore through a reasonable linker, so that the final product is expected to play an antitumor role through a double synergistic mechanism: on the one hand, the redox defense system of tumor cells can be destroyed by inhibiting TrxR, and oxidation stress-mediated apoptosis and chemotherapy sensitization can be induced; on the other hand, the proliferation and survival signal pathways of tumors can be blocked by inhibiting key kinases such as EGFR.

Description

Technical Field

[0001] This invention relates to the field of heterocyclic compound technology, and particularly to an ebuselenline-quinazoline derivative, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] The occurrence and development of malignant tumors are closely related to abnormal redox balance within cells. Thioredoxin reductase (TrxR) is one of the core enzymes maintaining this balance, and it is overexpressed and significantly active in various tumor cells. TrxR regulates several key processes, including tumor cell proliferation, apoptosis resistance, invasion and metastasis, and chemotherapy resistance, by reducing thioredoxin (Trx). Therefore, TrxR has become a highly attractive target for anti-tumor drugs. Selective inhibition of TrxR in tumor cells can effectively disrupt their redox homeostasis and induce tumor-specific apoptosis.

[0003] Ebuselenoline, a classic organoselenium compound, has been identified as a potent human TrxR inhibitor. Its mechanism of action differs from traditional GPx-mimicking activity; instead, it irreversibly inhibits enzyme activity through a covalent interaction between its active selenium center and the selenocysteine ​​residue at the TrxR catalytic site, leading to a rapid accumulation of ROS and activation of apoptosis signaling pathways in tumor cells. However, despite its well-defined target, the antitumor efficacy and selectivity of ebuselenoline as a TrxR inhibitor still require significant improvement. Its single TrxR inhibition mechanism may have limited effectiveness in the complex tumor microenvironment, and its relatively weak cytotoxic activity (IC50) further complicates matters. 50 Its direct application is limited by the fact that it is typically in the range of 10 to 100 µmol / L.

[0004] To enhance the antitumor activity targeting TrxR, current research directions mainly include: introducing phosphate, sulfonic acid, or polyethylene glycol (PEG) groups to synthesize water-soluble prodrugs, improving pharmacokinetic properties and bioavailability; utilizing nanodelivery systems such as lipid nanoparticles and nanomicelles to improve pharmacokinetics and targeting; or developing TrxR inhibitors with other structures (such as aurinophene and nitroaromatic compounds). However, these strategies often face problems such as limited activity enhancement, toxic side effects, or unsatisfactory pharmacokinetic properties. Summary of the Invention

[0005] The purpose of this invention is to disclose an ebuselenline-quinazoline derivative, its preparation method, pharmaceutical composition, and application, which has important scientific value and application prospects for developing a new generation of multi-target, highly effective, and low-toxicity anti-tumor drugs.

[0006] The first aspect of this invention is to provide an ebuselenline-quinazoline derivative. The structural formula of the ebuselenline-quinazoline derivative is shown in Formula I:

[0007] ,

[0008] Or its pharmaceutically acceptable salt;

[0009] Among them, R 1 It is one or a combination of at least two of H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0010] R 2 It is one or a combination of at least two of H, halogen, substituted or substituted C1-C6 alkyl, substituted or substituted C1-C6 alkoxy;

[0011] R 3 It can be H, Me, or -COOH;

[0012] R 4 It can be a mono- or poly-substituted benzoyl group (halogen, -Me, -NO2, -OCH3, -CF3, -OCF3), a mono- or poly-substituted benzenesulfonyl group (halogen, -Me, -NO2, -OCH3, -CF3, -OCF3), an α,β-unsaturated fatty acyl group, a substituted or unsubstituted C1~C6 fatty acyl group, or a substituted or unsubstituted C3~C6 cyclic fatty acyl group.

[0013] The halogen is selected from F, Cl, Br, and I.

[0014] In this invention, the benzene ring connected to R1 can be monosubstituted or polysubstituted, that is, R1 does not only represent that there is only one substituent on the benzene ring, but can also be two or more substituents.

[0015] In this invention, the substituted or unsubstituted C1-C6 alkoxy group can be a substituted or unsubstituted C1, C2, C3, C4, C5 or C6 alkoxy group, specifically a methoxy, ethoxy or propoxy group, etc., preferably a methoxy group.

[0016] The ebuselenline-quinazoline derivative of this invention has the following structure:

[0017] compound structural compound structural I-01 I-02 I-03 I-04 I-05 I-06 I-07 I-08 I-09 I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-20 I-21 I-22 I-23 I-24 I-25 I-26 I-27 I-28 I-29 I-30

[0018] A second aspect of this invention is to provide a method for preparing the ebuselenline-quinazoline derivative described in the first aspect of this invention. The synthetic route is as follows:

[0019] The specific synthesis method includes the following steps:

[0020] (1) Under alkaline and solvent conditions, compound 1 (2,4-dichloro-6,7-dimethoxyquinazoline) undergoes a nucleophilic substitution reaction with intermediate 2 to give intermediate 3.

[0021] ;

[0022] The molar ratio of compound 1 to intermediate 2 is 1:1~2; the base is one or more of triethylamine, DBU or potassium carbonate; the molar ratio of compound 1 to base is 1:1~4; the solvent is one or more of dichloromethane, tetrahydrofuran, methanol, N,N-dimethylformamide; and the reaction temperature is 25~60 °C.

[0023] (2) Under a nitrogen atmosphere, in the presence of alkali, solvent, and catalyst, intermediate 3 and intermediate 4 undergo a Suzuki coupling reaction to obtain intermediate 5.

[0024] ;

[0025] The molar ratio of intermediate 3 to intermediate 4 is 1:1~2. The catalyst is one of tetrakis(triphenylphosphine)palladium or Pd(dppf)Cl2. The molar ratio of intermediate 3 to catalyst is 1:0.02~0.1. The base is one of sodium carbonate, potassium carbonate or cesium carbonate. The solvent is selected from one or more of ethanol, 1,4-dioxane, toluene or water. The reaction temperature is 70~110 ℃.

[0026] (3) In the presence of alkali and solvent, intermediate 5 and intermediate 6 undergo an amidation reaction to obtain intermediate 7.

[0027] ;

[0028] The molar ratio of intermediate 5 to intermediate 6 is 1:1~2, the base is one or more of triethylamine, DBU, and pyridine, the solvent is one or more of dichloromethane, tetrahydrofuran, and 1,2-dichloroethane, and the reaction temperature is 0~60 ℃.

[0029] (4) Under the conditions of alkali, solvent and catalyst, intermediate 7 reacts with potassium selenocyanate in a selenylation cyclization reaction to obtain intermediate 8.

[0030] ;

[0031] The molar ratio of intermediate 7 to potassium selenocyanate is 1:1~2. The catalyst is cuprous iodide or 1,10-phenanthroline. The molar ratio of intermediate 7 to cuprous iodide is 1:0.5~1.5, and the molar ratio of cuprous iodide to 1,10-phenanthroline is 1:0.8~1.2. The base is one or more of cesium carbonate, sodium carbonate, and potassium carbonate. The solvent is one or more of dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile. The reaction temperature is 25~120 °C.

[0032] (5) After intermediate 8 undergoes deprotection with trifluoroacetic acid, it undergoes N-acylation with an acylation reagent in the presence of a base and solvent to obtain the ebuselenline-quinazoline derivative shown in Formula I.

[0033] ;

[0034] The base is one or more of triethylamine, DBU, and DIPEA; the solvent is one or more of dichloromethane, tetrahydrofuran, and 1,2-dichloroethane; the acylation reagent is selected from substituted benzoyl chloride, substituted benzenesulfonyl chloride, fatty acyl chloride, and cycloalkylformyl chloride; the molar ratio of intermediate 8 to the acylation reagent is 1:1~2; and the reaction temperature is 0~70 ℃.

[0035] On the other hand, the present invention applies the above-mentioned ebuselenline-quinazoline derivative in the preparation of antitumor drugs.

[0036] This synthetic route successfully synthesized 30 novel ebuselenin-quinazoline derivatives. The ebuselenin-quinazoline derivatives of this invention can serve as active ingredient candidates for antitumor drugs and have significant in vitro tumor growth inhibitory activity.

[0037] A third aspect of the present invention is to provide a pharmaceutical composition. The pharmaceutical composition comprises a therapeutically effective amount of the ebuselenline-quinazoline derivative, or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, and at least one of a pharmaceutically acceptable carrier, excipient, or diluent. Detailed Implementation

[0038] The following embodiments further illustrate the content of the present invention, but should not be construed as limiting the present invention. Any modifications and substitutions made to the methods, steps, or conditions of the present invention without departing from the spirit and essence of the present invention are within the scope of the present invention.

[0039] Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0040] Example 1: Preparation of ebuselenline-quinazoline derivative I:

[0041] The synthetic route for the target compound I-01 is shown in the following formula:

[0042]

[0043] (1) Preparation of intermediate 3-1

[0044] Take a 150 mL round-bottom flask, add 18 mmol of 2,4-dichloro-6,7-dimethoxyquinazoline and 22 mmol of intermediate 2-1, add 70 mL of tetrahydrofuran and stir to dissolve, then add triethylamine (55 mmol). Stir the reaction mixture overnight at room temperature. Evaporate the reaction mixture, then add water and sodium chloride, collect the precipitate, wash with water and dry to give a white solid intermediate 3-1 in 97% yield.

[0045] (2) Preparation of intermediate 5-1

[0046] Under a nitrogen atmosphere, intermediate 3 (17.5 mmol), p-aminophenylboronic acid pinacol ester (17 mmol), and tetrakis(triphenylphosphine)palladium (0.17 mmol) were added to a 250 mL two-necked flask, dissolved in 90 mL of 1,4-dioxane, followed by 42.5 mL of a 1 mol / L aqueous solution of sodium carbonate. The mixture was heated at 100 °C for two hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried, and concentrated. The residue was purified by column chromatography to give a white solid intermediate 5-1 in 93% yield.

[0047] (3) Preparation of intermediate 7-1

[0048] Weigh 15.9 mmol of intermediate 5-1 into a 150 mL round-bottom flask, dissolve it in 70 mL of dichloromethane, then add 6.6 mL of triethylamine. Add 23.85 mmol of o-iodobenzoyl chloride in small portions to the flask under ice-water bath conditions. After the addition is complete, stir the mixture at room temperature for two hours. Wash the organic phase 2-3 times with water, dry it with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and purify the residue by column chromatography to give a white solid intermediate 7-1 in 80% yield.

[0049] (4) Preparation of intermediate 8-1

[0050] Intermediate 7-1 (12.8 mmol), potassium selenocyanate (15.36 mmol), cuprous iodide (12.8 mmol), 1,10-phenanthroline (12.8 mmol), and cesium carbonate (35 mmol) were placed in a 100 mL round-bottom flask and dissolved in 30 mL of N,N-dimethylformamide solution. The reaction mixture was stirred at 100 °C for two hours, diluted with water, and extracted with ethyl acetate. The organic phases were combined, washed 2-3 times with water, dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure. The residue was purified by column chromatography to give intermediate 8-1 as a white solid with a yield of 70%.

[0051] (5) Preparation of target compound I-01

[0052] Weigh 9 mmol of intermediate 8-1 into a 100 mL round-bottom flask, dissolve it in 40 mL of dichloromethane, add 18 mL of trifluoroacetic acid dropwise to the mixture, stir the reaction solution at room temperature for two hours, remove the solvent and excess trifluoroacetic acid by vacuum distillation, add 20 mL of dichloromethane and a few drops of triethylamine and stir, slowly add 13.5 mmol of m-fluorobenzoyl chloride dropwise under an ice-water bath, stir the reaction solution at room temperature for two hours, wash the organic phase 2-3 times with water, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and purify the residue by column chromatography to obtain the target compound I-01 in 85% yield.

[0053] 1 H NMR (400 MHz, CDCl3, ppm) δ 8.56 (d, J = 8.7 Hz, 2H), 8.13 (d, J =7.8 Hz, 1H), 7.84 – 7.74 (m, 2H), 7.67 (dd, J = 6.2, 1.5 Hz, 2H), 7.51 – 7.41(m, 2H), 7.36 (s, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.22 – 7.14 (m, 2H), 7.11(s, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 3.78 (d, J = 34.1 Hz, 8H); 13C NMR (100MHz, CDCl3, ppm) δ 169.40(d, J = 3.0 Hz), 165.82, 163.98, 161.52, 157.80,154.99, 150.31, 148.91, 141.07, 137.67(d, J= 8.1 Hz), 137.55, 136.62, 132.80,130.68(d, J = 38.4 Hz), 129.53, 129.15, 127.89, 126.75, 124.65, 123.84,122.91(d, J = 3.0 Hz), 117.27(d, J = 21.2 Hz), 114.73 (d, J = 23.2 Hz), 110.28, 108.17, 102.75, 56.46, 56.24, 49.99, 47.44.

[0054] Example 2

[0055] In this embodiment, compounds of formulas I-02 to I-30 are prepared. The preparation method differs from that of compound I-01 in Example 1 in that the derivatives used in step (2) are N-tert-butoxycarbonylpiperazine and (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine, respectively, and the acylation reagents used in step (5) are respectively...

[0056] ,

[0057] Except for the preparation method, it is the same as the preparation method of compound I-01 in Example 1.

[0058] The structural characterization of the prepared compounds of formulas I-02 to I-30 is as follows:

[0059] I-02: 1H NMR (400 MHz, CDCl3, ppm) δ 8.56 (d, J = 8.7 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 7.3 Hz, 2H), 7.50 –7.45 (m, 2H), 7.44 – 7.41 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 6.9Hz, 2H), 7.11 (s, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 3.78 (d, J = 35.0 Hz, 8H); 13 C NMR (100 MHz, CDCl3, ppm) δ 169.29, 165.81, 163.97, 157.78, 154.97,150.30, 148.89, 141.06, 137.55, 137.31, 136.60, 134.91, 132.79, 130.25,130.18, 129.52, 129.14, 127.88, 127.48, 126.75, 125.34, 124.64, 123.84,110.27, 108.15, 102.72, 56.46, 56.24。

[0060] I-03: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.56 (dd, J = 8.7, 2.2 Hz, 2H),8.13 (dd, J = 7.7, 2.6 Hz, 1H), 7.79 (dd, J = 8.7, 2.2 Hz, 2H), 7.70 – 7.65(m, 2H), 7.63 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.52 – 7.44 (m, 1H), 7.40(d, J = 7.7 Hz, 1H), 7.35 (s, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.10 (s, 1H),4.06 (s, 3H), 4.00 (s, 3H), 3.78 (d, J = 33.9 Hz, 8H); 13C NMR (100 MHz,CDCl3, ppm) δ 169.13, 165.80, 163.95, 157.76, 154.96, 150.28, 148.88, 141.06,137.54, 136.57, 133.16, 132.78, 130.40, 130.32, 129.50, 129.13, 127.88,126.73, 125.78, 124.62, 123.84, 122.93, 110.26, 108.14, 102.72, 56.45, 56.23,53.56。

[0061] I-04: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.56 (d, J = 8.6 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.71 – 7.64 (m, 2H), 7.47 (ddd, J= 8.0, 6.7, 1.5 Hz, 1H), 7.35 (s, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.29 (s,1H), 7.25 (d, J = 5.6 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.12 (s, 1H), 4.06(s, 3H), 4.00 (s, 3H), 3.78 (d, J = 32.8 Hz, 8H), 2.40 (s, 3H); 13 C NMR (100MHz, CDCl3, ppm) δ 171.10, 165.80, 164.02, 157.79, 154.91, 150.27, 148.81,141.04, 138.72, 137.57, 136.64, 135.58, 132.75, 130.78, 129.48, 129.12,128.56, 127.86, 126.70, 124.60, 124.14, 123.85, 110.26, 108.13, 102.82,56.43, 56.21, 21.53。

[0062] I-05: 1H NMR (400 MHz, CDCl3, ppm) δ 8.56 (d, J = 8.2 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 10.0 Hz, 2H), 7.48(t, J = 7.3 Hz, 1H), 7.37 (d, J = 10.8 Hz, 3H), 7.11 (s, 1H), 7.01 (s, 2H),4.06 (s, 3H), 4.00 (s, 3H), 3.79 (d, J = 41.4 Hz, 11H); 13 C NMR (100 MHz,CDCl3, ppm) δ 170.62, 165.79, 163.99, 159.87, 157.77, 154.90, 150.27, 148.81,141.03, 137.57, 136.88, 136.61, 132.76, 129.89, 129.48, 129.11, 127.89,126.70, 124.60, 123.85, 119.24, 115.83, 112.67, 110.26, 108.12, 102.76,56.43, 56.20, 55.52。

[0063] I-06: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.55 (d, J = 8.7 Hz, 2H), 8.12 (d,J = 7.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.70 – 7.62 (m, 2H), 7.48 (dt, J =9.4, 7.2 Hz, 2H), 7.40 (d, J = 7.7 Hz, 1H), 7.36 – 7.30 (m, 3H), 7.10 (s,1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.77 (d, J = 35.3 Hz, 8H); 13C NMR (100 MHz,CDCl3, ppm)δ 169.07, 165.80, 163.94, 157.76, 154.99, 150.28, 149.41(d, J =2.1Hz), 148.91, 141.08, 137.54(d, J = 4.0 Hz), 136.55, 132.78, 130.45,129.50, 129.12, 127.88, 126.72, 125.60, 124.61, 123.83, 122.47, 121.79,120.01, 119.23, 110.25, 108.14, 102.72, 56.44, 56.22, 49.96, 47.46。

[0064] I-07: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.55 (d, J = 8.7 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.97 (d, J = 15.3 Hz, 3H), 7.79 (d, J = 8.7 Hz, 2H), 7.67(dd, J = 6.2, 1.5 Hz, 2H), 7.48 (ddd, J = 8.0, 6.2, 2.0 Hz, 1H), 7.37 (s,1H), 7.11 (s, 1H), 4.14 – 3.65 (m, 14H); 13 C NMR (100 MHz, CDCl3, ppm) δ167.64, 165.84, 163.89, 157.81, 155.12, 150.37, 149.05, 141.15, 137.69 (d, J= 16.2 Hz), 136.51, 132.83, 132.65, 132.31, 129.57, 129.16, 127.89, 127.69,126.78, 124.69, 124.34, 123.84, 121.63, 110.28, 108.21, 102.63, 56.50, 56.28,49.86, 47.70。

[0065] I-08: 1H NMR (400 MHz, CDCl3, ppm) δ 8.56 (d, J = 8.7 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.70 – 7.63 (m, 2H), 7.48 (ddd, J= 8.1, 5.9, 2.3 Hz, 1H), 7.36 (s, 1H), 7.12 (s, 1H), 6.65 (dd, J = 16.8, 10.5Hz, 1H), 6.36 (dd, J = 16.8, 1.9 Hz, 1H), 5.77 (dd, J = 10.5, 1.9 Hz, 1H),4.06 (s, 3H), 4.01 (s, 3H), 3.96 – 3.79 (m, 8H); 13 C NMR (100 MHz, CDCl3, ppm)δ 165.94, 165.83, 163.95, 157.81, 154.95, 150.30, 148.84, 141.05, 137.55,136.69, 132.80, 129.56, 129.17, 128.60, 127.91, 127.41, 126.76, 124.66,123.83, 110.24, 108.16, 102.87, 56.47, 56.25, 50.25, 45.57。

[0066] I-09: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.54 (d, J = 8.2 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.70 – 7.61 (m, 2H), 7.52 – 7.39(m, 2H), 7.34 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.15 (ddd, J = 10.9, 8.5,4.2 Hz, 2H), 7.07 (s, 1H), 4.40 (dd, J = 85.0, 41.0 Hz, 2H), 4.06 (s, 3H),4.00 (s, 3H), 3.90 – 3.31 (m, 5H), 1.44 (d, J = 47.6 Hz, 3H); 13C NMR (100MHz, CDCl3, ppm) δ 165.82, 163.97(d, J = 3.1Hz), 161.50, 157.75, 154.95,150.42, 148.82, 141.01, 137.67(d, J = 8.1Hz), 137.56, 136.71, 132.80, 130.58(d, J = 38.3Hz), 130.01, 129.54, 129.12, 127.88, 126.75, 124.68, 123.84,122.92(d, J = 3.1Hz), 116.97(d, J = 21.1Hz), 114.47(d, J = 23.3Hz), 110.73,108.12, 102.70, 56.46, 56.18, 53.56, 52.06, 44.37, 42.15, 15.56。

[0067] I-10: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.54 (d, J = 8.0 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.72 – 7.61 (m, 2H), 7.50 – 7.32(m, 6H), 7.08 (s, 1H), 4.64 – 4.34 (m, 2H), 4.07 (s, 3H), 4.00 (s, 3H), 3.89– 3.38 (m, 5H), 1.45 (d, J = 47.9 Hz, 3H); 13 C NMR (100 MHz, CDCl3, ppm) δ165.81, 164.05, 157.73, 154.93, 150.98, 150.41, 148.81, 141.01, 137.56,137.37, 136.69, 134.87, 132.78, 130.17, 129.52, 129.12, 127.87, 127.44,126.74, 125.34, 124.66, 123.84, 115.54, 110.71, 108.11, 102.69, 56.45, 56.18,52.35, 44.23, 29.44, 21.61, 15.52。

[0068] I-11:1 H NMR (400 MHz, CDCl3, ppm) δ 8.53 (d, J = 8.2 Hz, 2H), 8.12 (d,J = 7.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.70 – 7.53 (m, 4H), 7.46 (ddd, J= 8.2, 6.8, 1.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 4.0 Hz, 1H),7.30 (d, J = 7.7 Hz, 1H), 7.06 (s, 1H), 4.64 – 4.27 (m, 2H), 4.05 (s, 3H),3.99 (s, 3H), 3.86 – 3.23 (m, 5H), 1.43 (d, J = 43.0 Hz, 3H); 13 C NMR (100MHz, CDCl3, ppm) δ 165.79, 163.98, 157.69, 154.91, 150.37, 148.79, 141.01,137.59, 137.57, 136.64, 133.05, 132.74, 130.37, 130.26, 129.46, 129.08,127.87, 127.16, 126.69, 125.76, 124.61, 123.85, 122.87, 110.67, 108.09,102.69, 56.41, 56.15, 52.14, 46.49, 44.27, 30.94, 15.56。

[0069] I-12: 1H NMR (400 MHz, CDCl3, ppm) δ 8.54 (d, J = 8.7 Hz, 2H), 8.12 (d,J = 7.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.71 – 7.60 (m, 2H), 7.46 (td, J =7.3, 1.4 Hz, 1H), 7.35 – 7.29 (m, 2H), 7.25 – 7.15 (m, 3H), 7.07 (s, 1H),4.67 – 4.29 (m, 2H), 4.05 (s, 3H), 3.99 (s, 3H), 3.68 (dt, J = 85.5, 44.7 Hz,5H), 1.43 (d, J = 50.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3, ppm) δ 165.80,164.06, 157.71, 154.87, 150.34, 148.72, 145.72, 140.99, 138.67, 137.60,136.70, 135.65, 132.73, 130.67, 129.46, 129.10, 128.54, 127.89, 127.80,126.68, 124.61, 124.12, 123.87, 110.66, 108.06, 102.79, 56.41, 56.14, 53.52,44.35, 27.31, 26.00, 21.51, 15.52。

[0070] I-13: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.53 (d, J = 8.2 Hz, 2H), 8.12 (d,J = 7.8 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.71 – 7.59 (m, 2H), 7.50 – 7.42(m, 1H), 7.33 (d, J = 6.7 Hz, 2H), 7.07 (s, 1H), 6.99 (q, J = 7.9 Hz, 3H),4.62 – 4.35 (m, 2H), 4.05 (s, 3H), 3.99 (s, 3H), 3.83 (s, 3H), 3.54 (d, J =68.6 Hz, 4H), 1.44 (d, J = 44.9 Hz, 3H);13 C NMR (100 MHz, CDCl3, ppm) δ165.80, 164.09, 159.85, 157.73, 154.88, 150.39, 148.74, 140.99, 137.58,136.96, 136.73, 132.75, 129.87, 129.48, 129.10, 127.89, 126.70, 124.63,123.86, 119.25, 117.46, 115.72, 112.68, 110.70, 108.10, 102.77, 56.42, 56.15,55.51, 53.55, 47.36, 44.37, 29.42, 15.52。

[0071] I-14: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.53 (d, J = 8.3 Hz, 2H), 8.11 (d,J = 7.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.70 – 7.60 (m, 2H), 7.47 (q, J =7.1 Hz, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7.35 – 7.27 (m, 3H), 7.06 (s, 1H),4.62 – 4.29 (m, 2H), 4.05 (s, 3H), 3.99 (s, 3H), 3.61 (d, J = 83.8 Hz, 5H),1.44 (d, J = 46.6 Hz, 3H); 13 C NMR (100 MHz, CDCl3, ppm) δ 165.82, 164.02,157.72, 154.95, 150.41, 149.37, 149.35, 148.83, 141.02, 137.57(d, J = 3.9Hz),136.68, 132.77, 130.46, 129.49, 129.10, 127.86, 126.71, 125.58, 124.65,123.85, 122.38, 121.79, 119.96, 119.23, 110.70, 108.11, 102.68, 56.42, 56.16,53.23, 46.49, 44.28, 29.42, 15.48。

[0072] I-15: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.53 (d, J = 8.2 Hz, 2H), 8.12 (d,J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.93 (s, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.70 –7.61 (m, 2H), 7.47 (ddd, J = 8.1, 6.3, 1.9 Hz, 1H), 7.35 (s, 1H), 7.06 (s,1H), 4.66 – 4.27 (m, 2H), 4.06 (s, 3H), 4.00 (s, 3H), 3.86 – 3.29 (m, 5H),1.47 (d, J = 40.6 Hz, 3H); 13 C NMR (100 MHz, CDCl3, ppm) δ 165.82, 163.97,157.73, 155.06, 150.46, 148.96, 141.10, 137.74, 137.54, 136.57, 132.80,132.60, 132.26, 131.93, 129.53, 129.10, 127.87, 127.66(d, J = 38.4Hz),126.74, 124.67, 124.33, 123.84, 121.61, 110.73, 108.16, 102.57, 56.47, 56.19,51.84, 47.47, 44.29, 29.43, 15.73。

[0073] I-16: 1H NMR (400 MHz, CDCl3, ppm) δ 8.56 (d, J = 8.7 Hz, 1H), 8.13 (d,J = 7.8 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.71 – 7.60 (m, 2H), 7.48 (ddd, J= 8.1, 6.5, 1.7 Hz, 1H), 7.36 (s, 1H), 7.08 (s, 1H), 6.71 – 6.56 (m, 1H),6.37 (dd, J = 16.7, 1.9 Hz, 1H), 5.77 (d, J = 10.6 Hz, 1H), 4.55 (d, J = 17.6Hz, 2H), 4.06 (s, 3H), 4.00 (s, 3H), 3.70 (dt, J = 37.8, 7.7 Hz, 4H), 3.32(s, 1H), 1.42 (d, J = 4.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3, ppm) δ 165.83,164.05, 157.73, 154.92, 150.33, 148.77, 143.57, 141.04, 137.57, 136.68,132.80, 129.55, 129.16, 128.61, 127.91, 127.23, 126.75, 124.67, 123.86,110.63, 108.08, 102.83, 56.48, 56.20, 53.49, 52.29, 44.75, 29.83, 15.42。

[0074] I-17: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.47 (d, J = 6.8 Hz, 2H), 8.12 (d,J = 7.9 Hz, 1H), 7.76 (dd, J = 8.7, 1.8 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H),7.59 (d, J = 7.0 Hz, 1H), 7.56 – 7.44 (m, 3H), 7.34 – 7.27 (m, 2H), 7.02 –6.93 (m, 1H), 4.03 (s, 3H), 3.96 (s, 3H), 3.84 (s, 4H), 3.30 (s, 4H); 13C NMR(100 MHz, CDCl3, ppm) δ 165.83, 163.64(d, J = 3.1Hz), 161.39, 157.72, 155.00,150.35, 148.89, 141.05, 138.12(d, J = 8.0Hz), 137.54, 136.55, 132.82, 131.30(d, J = 38.4Hz), 129.55, 129.10, 127.87, 126.77, 124.65, 123.84, 123.57(d, J= 3.1Hz), 120.63(d, J = 21.3Hz), 115.28(d, J = 23.1Hz), 110.09, 108.16,102.70, 56.44, 56.32, 49.25, 45.65。

[0075] I-18: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.48 (d, J = 8.4 Hz, 2H), 8.13 (d,J = 7.9 Hz, 1H), 7.78 (d, J = 8.9 Hz, 3H), 7.67 (q, J = 7.9 Hz, 3H), 7.60 –7.54 (m, 1H), 7.49 (q, J = 7.0 Hz, 2H), 7.31 (s, 1H), 6.99 (s, 1H), 4.04 (s,3H), 3.97 (s, 3H), 3.85 (s, 4H), 3.31 (s, 4H); 13 C NMR (100 MHz, CDCl3, ppm) δ165.83, 163.64, 157.72, 155.01, 150.34, 148.90, 141.06, 137.84, 137.54,136.53, 135.68, 133.43, 132.83, 130.74, 129.56, 129.11, 127.87, 127.81,126.78, 125.88, 124.66, 123.84, 110.09, 108.15, 102.69, 56.46, 56.33, 49.24,45.65。

[0076] I-19: 1H NMR (400 MHz, CDCl3, ppm) δ 8.49 (d, J = 8.2 Hz, 2H), 8.14 (d,J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.84 – 7.65 (m, 6H), 7.45 (d, J = 13.7 Hz,2H), 7.33 (s, 1H), 7.00 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 3.87 (s, 4H),3.32 (s, 4H); 13 C NMR (100 MHz, CDCl3, ppm) δ 165.81, 163.62, 157.70, 154.99,150.32, 148.88, 141.04, 137.82, 137.52, 136.51, 135.66, 133.40, 132.81,130.72, 129.54, 129.09, 127.85, 127.79, 126.76, 125.86, 124.64, 123.82,110.07, 108.13, 102.67, 56.44, 56.31, 49.22, 45.63。

[0077] I-20: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.49 (d, J = 8.4 Hz, 2H), 8.13 (d,J = 7.9 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 5.1 Hz, 2H), 7.60 (s,2H), 7.51 – 7.38 (m, 3H), 7.31 (s, 1H), 7.00 (s, 1H), 4.04 (s, 3H), 3.96 (s,3H), 3.86 (s, 4H), 3.28 (s, 4H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ165.83, 163.65, 157.74, 154.94, 150.33, 148.80, 141.03, 139.60, 137.53,136.60, 135.75, 134.11, 132.83, 129.56, 129.23, 129.12, 128.14, 127.88,126.78, 125.03, 124.64, 123.84, 110.06, 108.13, 102.81, 56.45, 56.31, 49.24,45.68, 21.58。

[0078] I-21: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.49 (d, J = 8.4 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.76 (t, J = 9.1 Hz, 3H), 7.67 (d, J = 5.8 Hz, 3H), 7.62 (t,J = 8.0 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.32 (s, 1H), 6.98 (s, 1H), 4.04(s, 3H), 3.96 (s, 3H), 3.84 (s, 4H), 3.31 (s, 4H); 13 C NMR (100 MHz, CDCl3,ppm) δ 169.08, 165.81, 163.95, 157.77, 155.00, 150.29, 149.42, 149.40,148.92, 141.09, 137.55(d, J = 4.1Hz), 136.56, 132.79, 130.46, 129.51, 129.13,127.89, 126.73, 125.61, 124.62, 123.84, 122.48, 120.02, 110.26, 108.15,102.73, 56.45, 56.23, 53.55, 49.98。

[0079] I-22: 1H NMR (400 MHz, CDCl3, ppm) δ 8.49 (d, J = 8.2 Hz, 2H), 8.24 (s,2H), 8.13 (d, J = 9.0 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.67 (s, 2H), 7.49(d, J = 7.4 Hz, 1H), 7.32 (s, 1H), 6.98 (s, 1H), 4.04 (s, 3H), 3.96 (s, 3H),3.87 (s, 4H), 3.37 (s, 4H); 13 C NMR (100 MHz, CDCl3, ppm) δ 165.83, 163.55,157.71, 155.08, 150.39, 149.01, 141.13, 139.46, 137.53(d, J = 4.0Hz), 136.40,133.84, 133.49, 133.15, 132.83, 129.54, 129.06, 127.89, 126.77, 124.65,123.83, 121.16, 120.33, 110.10, 108.19, 102.48, 56.46, 56.23, 49.23, 45.62。

[0080] I-23: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.57 (d, J = 8.5 Hz, 1H), 8.46 (d,J = 8.6 Hz, 2H), 8.41 (d, J = 8.7 Hz, 1H), 8.28 (dd, J = 7.4, 1.3 Hz, 1H),8.13 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 6.3 Hz, 2H),7.60 – 7.52 (m, 2H), 7.47 (ddd, J = 8.0, 6.1, 2.0 Hz, 1H), 7.30 (s, 1H), 7.18(d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 4.03 (s, 3H), 3.94 (s, 3H), 3.76 (s, 4H),3.49 (s, 4H), 2.85 (s, 6H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.79, 163.84,157.75, 154.93, 151.97, 150.26, 148.84, 141.01, 137.52, 136.58, 132.80,132.68, 131.16, 130.99, 130.49, 130.24, 129.55, 129.11, 128.31, 127.92,126.75, 124.59, 123.82, 123.28, 119.65, 115.49, 110.18, 108.12, 102.73,56.43, 56.24, 49.50, 45.54, 45.18。

[0081] I-24: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.46 (d, J = 8.7 Hz, 2H), 8.17 –8.09 (m, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.67 (dd, J = 6.2, 1.5 Hz, 2H), 7.59– 7.43 (m, 4H), 7.29 (d, J = 6.1 Hz, 2H), 6.99 (s, 1H), 4.52 (dt, J = 7.1,3.5 Hz, 1H), 4.14 – 4.06 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 3.75 (ddd, J =19.9, 11.1, 6.2 Hz, 2H), 3.54 – 3.45 (m, 1H), 2.89 (td, J = 11.3, 3.5 Hz,2H), 1.56 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.83, 163.78(d, J = 3.2Hz), 161.36, 157.65, 154.96, 150.42, 148.81, 141.00, 138.19(d, J =8.3Hz), 137.55, 136.62, 132.81, 131.19(d, J = 38.3Hz), 129.53, 129.07,127.85, 126.75, 124.65, 123.84, 123.43(d, J = 3.1Hz), 120.54(d, J = 21.4Hz),115.17(d, J = 23.0Hz), 110.56, 108.08, 102.65, 56.43, 56.23, 52.31, 50.20,45.61, 43.88, 15.73。

[0082] I-25: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.46 (d, J = 8.4 Hz, 2H), 8.13 (d,J = 7.9 Hz, 1H), 7.77 (d, J = 9.0 Hz, 3H), 7.66 (q, J = 7.8 Hz, 3H), 7.55 (d,J = 8.1 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.30 (s, 1H), 6.99 (s, 1H), 4.52(d, J = 7.9 Hz, 1H), 4.10 (d, J = 13.9 Hz, 1H), 4.04 (s, 3H), 3.97 (s, 3H),3.74 (q, J = 11.2 Hz, 2H), 3.51 (d, J = 11.5 Hz, 1H), 2.87 (d, J = 12.0 Hz,2H), 1.56 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.83, 163.79,157.67, 154.96, 150.42, 148.82, 141.00, 137.90, 137.54, 136.63, 135.63,133.34, 132.82, 130.72, 129.55, 129.08, 127.86, 127.71, 126.77, 125.75,124.67, 123.84, 110.56, 108.08, 102.63, 56.45, 56.24, 52.31, 50.19, 45.62,43.85, 15.75。

[0083] I-26: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.46 (d, J = 8.7 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.91 (s, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.74 – 7.63 (m, 4H),7.48 (ddd, J = 8.1, 6.1, 2.2 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.30 (s, 1H),6.99 (s, 1H), 4.59 – 4.43 (m, 1H), 4.11 (d, J = 13.6 Hz, 1H), 4.04 (s, 3H),3.98 (s, 3H), 3.75 (dt, J = 20.4, 6.8 Hz, 2H), 3.50 (d, J = 11.2 Hz, 1H),2.95 – 2.80 (m, 2H), 1.57 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ165.84, 163.82, 157.69, 155.00, 150.44, 148.85, 141.02, 138.09, 137.54,136.26, 135.71, 132.83, 130.94, 130.54, 129.58, 129.11, 127.89, 126.79,126.19, 124.70, 123.84, 123.45, 110.59, 108.11, 102.66, 56.46, 56.26, 52.33,50.20, 45.64, 43.89, 15.77。

[0084] I-27: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.46 (d, J = 8.7 Hz, 2H), 8.13 (d,J = 7.6 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.70 – 7.63 (m, 2H), 7.57 (dt, J =3.9, 1.9 Hz, 2H), 7.48 (ddd, J = 8.0, 6.1, 2.1 Hz, 1H), 7.44 – 7.35 (m, 2H),7.30 (s, 1H), 7.00 (s, 1H), 4.53 (dt, J = 7.4, 3.6 Hz, 1H), 4.11 (dt, J =14.2, 3.3 Hz, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 3.80 – 3.66 (m, 2H), 3.50 (d,J = 11.1 Hz, 1H), 2.84 (td, J = 12.0, 3.6 Hz, 2H), 2.41 (s, 3H), 1.57 (d, J =6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.82, 163.76, 157.65, 154.89,150.36, 148.71, 140.97, 139.54, 137.54, 136.65, 135.81, 134.03, 132.81,129.54, 129.19, 129.08, 128.02, 127.86, 126.76, 124.89, 124.63, 123.85,110.47, 108.03, 102.75, 56.43, 56.22, 52.33, 50.26, 45.68, 43.85, 21.56,15.80。

[0085] I-28: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.47 (d, J = 8.6 Hz, 2H), 8.13 (d,J = 7.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.73 – 7.57 (m, 5H), 7.51 – 7.40(m, 2H), 7.30 (s, 1H), 6.98 (s, 1H), 4.52 (dt, J = 7.4, 3.4 Hz, 1H), 4.10 (d,J = 14.0 Hz, 1H), 4.03 (s, 3H), 3.96 (s, 3H), 3.75 (td, J = 12.8, 3.2 Hz,2H), 3.51 (d, J = 11.8 Hz, 1H), 2.88 (td, J = 11.2, 3.4 Hz, 2H), 1.56 (d, J =6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.83, 163.77, 157.68, 154.99,150.44, 149.55, 148.85, 141.04, 138.32, 137.54(d, J = 3.9Hz), 136.60, 132.83,131.14, 129.57, 129.08, 127.88, 126.78, 125.87, 125.54, 124.66, 123.84,121.70, 120.29, 110.56, 108.11, 102.60, 56.45, 56.17, 52.29, 50.22, 45.64,43.85, 15.65。

[0086] I-29: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.46 (d, J = 8.5 Hz, 2H), 8.20 (d,J = 5.3 Hz, 2H), 8.16 – 8.06 (m, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.70 – 7.62(m, 2H), 7.52 – 7.41 (m, 1H), 7.30 (s, 1H), 6.97 (s, 1H), 4.59 – 4.48 (m,1H), 4.13 – 4.08 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 3.79 (d, J = 8.5 Hz,2H), 3.57 (d, J = 11.7 Hz, 1H), 2.94 (d, J = 12.9 Hz, 2H), 1.57 (d, J = 6.4Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.80, 163.69, 157.65, 155.04,150.49, 148.93, 141.09, 139.66, 137.53(d, J = 4.2Hz), 136.47, 133.44, 133.10,132.80, 129.52, 129.01, 127.86, 127.76, 126.74, 124.63, 123.87, 123.83,121.15, 110.55, 108.14, 102.47, 56.44, 56.16, 52.20, 50.10, 45.52, 43.72,15.58。

[0087] I-30: 1 H NMR (400 MHz, CDCl3, ppm) δ 8.55 (d, J = 8.5 Hz, 1H), 8.43(dd, J = 8.7, 7.0 Hz, 3H), 8.24 (dd, J = 7.4, 1.3 Hz, 1H), 8.16 – 8.09 (m,1H), 7.74 (d, J = 8.6 Hz, 2H), 7.65 (q, J = 8.6 Hz, 2H), 7.54 (q, J = 8.5 Hz,2H), 7.46 (ddd, J = 8.0, 6.7, 1.6 Hz, 1H), 7.28 (s, 1H), 7.17 (d, J = 7.6 Hz,1H), 6.98 (s, 1H), 4.47 (dt, J = 7.2, 3.5 Hz, 1H), 4.02 (s, 3H), 3.99 (d, J =3.3 Hz, 1H), 3.94 (s, 3H), 3.77 (d, J = 11.4 Hz, 1H), 3.64 (dd, J = 32.5,12.7 Hz, 2H), 3.15 (td, J = 11.4, 3.2 Hz, 2H), 2.84 (s, 6H), 1.41 (d, J = 6.5Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.77, 163.83, 157.63, 154.83,151.90, 150.31, 148.69, 140.93, 137.54, 136.63, 132.76, 132.75, 131.02,130.80, 130.45, 130.14, 129.47, 129.05, 128.21, 127.87, 126.69, 124.54,123.84, 123.23, 119.66, 115.42, 110.55, 108.02, 102.69, 56.38, 56.14, 52.46, 49.73, 45.48, 45.24, 43.91, 15.47.

[0088] Example 3: Antitumor Activity Test

[0089] Detection method: MTS is an MTT analog, its full name being 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetraazonium. Succinate dehydrogenase in the mitochondria of living cells can metabolize and reduce MTS to generate a soluble formazan compound. The optical density (OD) value (490 nm) of this compound is directly proportional to the number of living cells. Cisplatin and paclitaxel were used as positive controls. The IC50 of the compound... 50 The values ​​were determined by calculation using concentration-effect growth curves, and the results are shown in Table 1.

[0090]

[0091] Note: a The concentration of the compound at which the inhibitory activity reaches 50%

[0092] b The average of three experiments, with a time duration of 48 hours.

[0093] The test results are shown in Table 1. Using cisplatin as a positive control, the 30 synthesized ebuselin derivatives were preliminarily evaluated for antitumor activity in human non-small cell lung cancer cell line A549, human colon cancer cell line HCT116, human breast cancer cell line MDA-MB-231, and human non-small cell lung cancer cell line PC-9. The results showed that compounds I-01, I-02, I-03, I-04, I-05, I-06, I-08, I-09, I-10, I-12, I-13, I-14, I-16, and I-25 could inhibit the activity of all four cancer cell lines to a certain extent. Among them, I-02 (IC50) showed the highest activity. 50 =12.1 μmol / L) and I-08 (IC 50 The antitumor activity of cisplatin (IC50) at 10.92 μmol / L in A549 cells was similar to that of cisplatin (IC50). 50 =11.72 μmol / L) equivalent; I-03 (IC 50 =13.45 μmol / L) and I-12 (IC 50 The antitumor activity of cisplatin (IC50) at 12.33 μmol / L in HCT116 cells was similar to that of cisplatin (IC50). 50 =12.38 μmol / L) equivalent; I-04 (IC 50 =7.13 μmol / L) and I-09 (IC 50 =7.16 μmol / L) had slightly lower antitumor activity in MDA-MB-231 cells than cisplatin (IC50). 50 =2.04 μmol / L); I-10 (IC50) 50 =1.59 μmol / L) and I-25 (IC 50 The antitumor activity of 2.76 μmol / L cisplatin in PC-9 cells was superior to that of cisplatin (IC50). 50 The concentration of 3.08 μmol / L indicates that these compounds can serve as promising lead compounds in this series, providing an important theoretical basis for further in-depth structure-activity relationship studies and structural optimization.

[0094] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. An ebuselenline-quinazoline derivative, characterized in that, The structural formula is shown in Formula I: Or its pharmaceutically acceptable salt; Among them, R 1 It is one or a combination of at least two of H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 2 It is one or a combination of at least two of H, halogen, substituted or substituted C1-C6 alkyl, substituted or substituted C1-C6 alkoxy; R 3 It can be H, Me, or -COOH; R 4 It can be a mono- or poly-substituted benzoyl group (halogen, -Me, -NO2, -OCH3, -CF3, -OCF3), a mono- or poly-substituted benzenesulfonyl group (halogen, -Me, -NO2, -OCH3, -CF3, -OCF3), an α,β-unsaturated fatty acyl group, a substituted or unsubstituted C1~C6 fatty acyl group, or a substituted or unsubstituted C3~C6 cyclic fatty acyl group.

2. The ebuselenline-quinazoline derivative according to claim 1, characterized in that: Its structure is as shown in any of the following compounds:

3. The method for preparing the ebuselenline-quinazoline derivative according to claim 1 or 2, characterized in that, Including the following steps: (1) Under the presence of a base and a solvent, 2,4-dichloro-6,7-dimethoxyquinazoline is reacted with intermediate 2 via a nucleophilic substitution reaction to give intermediate 3; intermediate 2 is shown in Formula II, R 3 It can be H, Me, or -COOH. #imgpt31#; (2) Under a nitrogen atmosphere, in the presence of a base, solvent, and catalyst, intermediate 3 and intermediate 4 undergo a Suzuki coupling reaction to obtain intermediate 5; intermediate 4 is shown in Formula III, R 2 It is one or a combination of at least two of H, halogen, substituted or substituted C1-C6 alkyl, substituted or substituted C1-C6 alkoxy. #imgpt32#; (3) In the presence of a base and a solvent, intermediate 5 and intermediate 6 undergo an amidation reaction to obtain intermediate 7, wherein intermediate 6 is shown in Formula IV. #imgpt33#; (4) In the presence of alkali, solvent and catalyst, intermediate 7 reacts with potassium selenocyanate in a selenylation cyclization reaction to obtain intermediate 8; (5) After intermediate 8 undergoes deprotection reaction with trifluoroacetic acid, it undergoes N-acylation reaction with acylation reagent in the presence of alkali and solvent to obtain the ebuseline-quinazoline derivative shown in Formula I.

4. The preparation method according to claim 3, characterized in that: In step (1), the molar ratio of 2,4-dichloro-6,7-dimethoxyquinazoline to intermediate 2 is 1:1~2; the base is one or more of triethylamine, DBU or potassium carbonate; the molar ratio of 2,4-dichloro-6,7-dimethoxyquinazoline to the base is 1:1~4; the solvent is one or more of dichloromethane, tetrahydrofuran, methanol, N,N-dimethylformamide; and the reaction temperature is 25~60 ℃.

5. The preparation method according to claim 4, characterized in that: In step (2), the molar ratio of intermediate 3 to intermediate 4 is 1:1~2, the catalyst is one of tetrakis(triphenylphosphine)palladium or Pd(dppf)Cl2, the molar ratio of intermediate 3 to catalyst is 1:0.02~0.1, the base is one of sodium carbonate, potassium carbonate or cesium carbonate, the solvent is selected from one or more of ethanol, 1,4-dioxane, toluene or water, and the reaction temperature is 70~110 ℃.

6. The preparation method according to claim 4, characterized in that: In step (3), the molar ratio of intermediate 5 to intermediate 6 is 1:1~2, the base is one or more of triethylamine, DBU, and pyridine, the solvent is one or more of dichloromethane, tetrahydrofuran, and 1,2-dichloroethane, and the reaction temperature is 0~60 ℃.

7. The preparation method according to claim 4, characterized in that: In step (4), the molar ratio of intermediate 7 to potassium selenocyanate is 1:1~2, the catalyst is cuprous iodide or 1,10-phenanthroline, the molar ratio of intermediate 7 to cuprous iodide is 1:0.5~1.5, the molar ratio of cuprous iodide to 1,10-phenanthroline is 1:0.8~1.2, the base is one or more of cesium carbonate, sodium carbonate, and potassium carbonate, the solvent is one or more of dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile, and the reaction temperature is 25~120 ℃.

8. The preparation method according to claim 4, characterized in that: In step (5), the base is one or more of triethylamine, DBU, and DIPEA, the solvent is one or more of dichloromethane, tetrahydrofuran, and 1,2-dichloroethane, the acylation reagent is selected from substituted benzoyl chloride, substituted benzenesulfonyl chloride, fatty acyl chloride, and cycloalkylformyl chloride, the molar ratio of intermediate 8 to acylation reagent is 1:1~2, and the reaction temperature is 0~70 ℃.

9. An antitumor drug composition, characterized in that, The product comprises a therapeutically effective amount of the ebuselenline-quinazoline derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, and at least one pharmaceutically acceptable carrier, excipient or diluent.

10. The use of the ebuselenline-quinazoline derivative according to any one of claims 1 to 3 in the preparation of antitumor drugs.

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