3-(Indole-3-selenyl)benzamide compounds, their synthesis methods and applications

Abstract

The present invention discloses a 3-(indole-3-selenyl) benzamide compound, its synthesis method and application. The 3-(indole-3-selenyl) benzamide compound has good biological activity. At a concentration without cytotoxicity when used alone for cancer cell lines showing drug resistance, it shows an obvious sensitization effect when combined with anti-tumor drugs. It can be used as a P-gp inhibitor or a tumor multidrug resistance reversing agent, or a tumor metastasis inhibitor or a biological probe with good biocompatibility, expanding the application prospect of selenium-containing small molecule structures in the aspect of tumor multidrug resistance reversing agents.

Description

(1) Technical Field

[0001] The present invention belongs to the fields of pharmaceutical chemical synthesis and pharmacotherapeutics, and particularly relates to a 3-(indole-3-selenyl)benzamide compound, a preparation method thereof, and an application thereof. (2) Background Art

[0002] Multidrug Resistance (MDR) is a serious problem in the chemotherapy of malignant tumors. As a member of the ATP-binding cassette transporter protein family, the overexpression of the multidrug resistance protein P-gp (P-glycoprotein, ABCB1, MDR1) on tumor cells is one of the main mechanisms leading to MDR. Inhibiting P-gp is a common method for reversing MDR and is also one of the research hotspots in the overcoming of MDR in malignant tumors. However, the first three generations of P-gp inhibitors still have some problems, such as poor selectivity, insufficient inhibitory activity, high toxicity, and the impact on the pharmacokinetics of chemotherapeutic drugs. (3) Summary of the Invention

[0003] The purpose of the present invention is to provide a 3-(indole-3-selenyl)benzamide compound, a preparation thereof, and an application thereof. This compound has good biological activity, excellent MDR reversal effect, and enhanced sensitivity of malignant tumor cells to the antitumor drug doxorubicin hydrochloride. It can be used for the development and utilization of drugs for treating multidrug resistance of malignant tumor cells caused by P-gp protein and is expected to become a potential P-gp inhibitor for treating MDR. In order to explore the influence of different terminal aromatic rings on the drug effect, we selected three reported structures, namely 3,4-dimethoxytetrahydroisoquinoline, 3,4-dimethoxyaniline, and pyridine-2-methylamine, for incorporation. In addition, we also studied the influence of the substitution position (ortho, meta, and para) of indole selenide on the benzene ring on the activity, which is of great significance for adjusting the geometric configuration of the molecule.

[0004] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0005] In the first aspect, the present invention provides a 3-(indole-3-selenyl)benzamide compound represented by formula I:

[0006]

[0007] R1 is selected from one of the following: H, halogen, wherein, Y is C1-C 10 alkyl, phenyl substituted by halogen or C1-C4 alkoxy, or -(CH2) n -N-(CH3)2, wherein n is an integer between 1 and 4.

[0008] R2 is selected from one of the following:

[0009] R3 is H or

[0010] Further, R1 is H, fluorine or wherein, Y is methyl, isopropyl, phenyl substituted by fluorine or methoxy, or -(CH2)2-N-(CH3)2.

[0011] Preferably, the R1 is hydrogen, 5-fluoride group, 7-azaindolyl,

[0012]

[0013] More preferably

[0014] Especially recommended, the 3-(indole-3-selenyl)benzamide compounds shown in formula Ⅰ are one of the following:

[0015]

[0016]

[0017]

[0018] In the second aspect, the present invention also provides a preparation method of two kinds of the 3-(indole-3-selenyl)benzamide compounds. Route 1 is used to investigate the influence of substituted indole on biological activity, and route 2 is used to investigate the influence of amine on biological activity. All compounds can be prepared by route 1 or 2.

[0019] The method of route 1 includes the following steps:

[0020] S1: The compound shown in formula Ⅱ and a basic substance are added into organic solvent A. A solution of 3-nitrobenzoyl chloride is added dropwise at (-20 to 0 °C) (preferably -10 °C). After the addition is completed, the reaction is carried out at 20 to 40 °C for 1 to 4 h (preferably at 25 °C for 2 h). The obtained reaction solution A is purified and separated by A to obtain the intermediate shown in formula Ⅲ. The molar ratio of the compound shown in formula Ⅱ, the basic substance to 3-nitrobenzoyl chloride contained in the 3-nitrobenzoyl chloride solution is 1:1 - 3:1 - 1.5 (preferably 1:3:1);

[0021]

[0022] S2: The intermediate shown in Formula III described in Step S1 undergoes a reduction reaction at 20 - 40°C for 12 - 16 h (preferably at 25°C for 12 h) in a hydrogen atmosphere and organic solvent B under the action of a Pd / C catalyst. The resulting reaction solution B is purified and separated by B to obtain the compound shown in Formula IV; the molar ratio of the Pd loaded on the intermediate shown in Formula III to the Pd / C catalyst is 1:0.1 - 0.5 (preferably 1:0.3);

[0023]

[0024] S3: The compound shown in Formula IV described in Step S2 and hydrochloric acid are added to water. An aqueous sodium nitrite solution is added dropwise at -5 - 5°C (preferably 0°C). After the addition is complete, the pH is adjusted to 5.5 - 6, and an aqueous solution containing potassium selenocyanate and sodium bicarbonate is added. The temperature is (slowly) raised to 40 - 60°C (preferably 55°C) and the reaction is carried out for 0.5 - 1.5 hours (preferably 1 hour). The resulting reaction solution C is separated and purified by C to obtain the intermediate shown in Formula V; the molar ratio of the compound shown in Formula IV, HCl contained in hydrochloric acid, sodium nitrite contained in the aqueous sodium nitrite solution, potassium selenocyanate in the aqueous solution containing potassium selenocyanate and sodium bicarbonate to sodium bicarbonate in the aqueous solution containing potassium selenocyanate and sodium bicarbonate is 1:5 - 8:1 - 1.5:1 - 1.5:0.1 - 0.3 (preferably 1:5.7:1:1:0.25);

[0025]

[0026] In the examples of the present invention, since the diazotization is unstable, during the slow heating process, the temperature is first raised to room temperature at room temperature and then to the reaction temperature.

[0027] S4: The intermediate shown in Formula V described in Step S3 and the compound shown in Formula VI are stirred and reacted at 50 - 120°C for 3 - 8 h (preferably stirred and reacted at 80 - 100°C for 3 - 8 h, particularly preferably stirred and reacted at 100°C for 3 h) in organic solvent C in the presence of a catalyst. The resulting reaction solution D is purified and separated by D to obtain the compound shown in Formula I; the catalyst is tris(pentafluorophenyl)borane or copper(I) iodide (preferably copper(I) iodide); the molar ratio of the intermediate shown in Formula V, the compound shown in Formula VI to the catalyst is 1:1 - 1.5:0.001 - 0.1 (preferably 1:1.2:0.1);

[0028]

[0029] The range of the substituents is as described above.

[0030] Further, the organic solvent A in step S1, the solvent of the 3-nitrobenzoyl chloride solution, the organic solvent B in step S2, and the organic solvent C in step S4 are each independently selected from one or a mixture of two or more of the following: benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether. Preferably, the organic solvent A and the solvent of the 3-nitrobenzoyl chloride solution are dichloromethane, the organic solvent B is 1,2-dichloroethane, and the organic solvent C is 1,2-dichloroethane.

[0031] Furthermore, the volume of the organic solvent A in step S1 is 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula II, preferably 2 mL / mmol.

[0032] Further, the concentration of the 3-nitrobenzoyl chloride solution in step S1 is 0.5 - 2.5 mmol / mL, and in the examples of the present invention, it is 0.5 mmol / mL.

[0033] Further, the basic substance in step S1 is one or a mixture of two or more of pyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene or diazabicycloundecene, sodium hydroxide, sodium ethoxide, trimethylamine or triethylamine; preferably triethylamine.

[0034] In the examples of the present invention, the separation and purification A in step S1 is as follows: The reaction solution A is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (silica gel 200 - 300 mesh, column height 10 cm, diameter 2 cm) using a dichloromethane:methanol eluent with a volume ratio of 200:1. The eluent containing the target compound is collected, and the solvent is evaporated to obtain the intermediate shown in formula III.

[0035] Furthermore, the volume of the organic solvent B in step S2 is 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula III, and in one example of the present invention, it is 4 mL / mmol.

[0036] Further, the active substance loading of the Pd / C catalyst in step S2 is 3 - 10%, and in the examples of the present invention, it is 10%.

[0037] In an embodiment of the present invention, the separation and purification of B in step S2 is as follows: The reaction solution B is filtered with diatomaceous earth, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography using dichloromethane:methanol with a volume ratio of 120:1 as the eluent, and the eluent containing the target compound is collected, and the solvent is evaporated to obtain the compound shown in formula IV. [[ID=..]]

[0038] Further, the concentration of the hydrochloric acid in step S3 is 10 - 12 mol / L, and it is 12 mol / L in the embodiment of the present invention.

[0039] Further, the concentration of the sodium nitrite aqueous solution in step S3 is 0.5 - 1 mol / L, and it is 1 mol / L in the embodiment of the present invention.

[0040] Further, a weak base is used to adjust the pH in step S3, which is one or a mixture of two of sodium acetate, potassium acetate, potassium carbonate, and sodium carbonate, and preferably sodium acetate.

[0041] Further, in the aqueous solution containing potassium selenocyanate and sodium bicarbonate in step S3, the concentration of potassium selenocyanate is 1 - 3 mol / L, and it is 2.5 mol / L in the embodiment of the present invention, and the concentration of the sodium bicarbonate aqueous solution is 0.5 - 1 mol / L, and it is 0.6 mol / L in the embodiment of the present invention.

[0042] Further, the volume of water in step S3 is 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula IV, and it is 2.4 mL / mmol in an embodiment of the present invention.

[0043] In an embodiment of the present invention, the separation and purification of C in step S3 is as follows: The reaction solution C is extracted with dichloromethane, the organic layers are combined, washed with saturated brine (twice), dried over anhydrous sodium sulfate, the solvent is removed under reduced pressure, and the obtained residue is subjected to silica gel column chromatography using dichloromethane:methanol with a volume ratio of 200:1 as the eluent, and the eluent containing the target compound is collected, and the solvent is evaporated to obtain the intermediate shown in formula V.

[0044] Further, the volume of the organic solvent C in step S4 is 1 - 7 mL / mmol based on the amount of substance of the intermediate shown in formula V, and it is 6.7 mL / mmol in an embodiment of the present invention.

[0045] In an embodiment of the present invention, the separation and purification of D in step S4 is as follows: The reaction solution D is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography purification (silica gel 200 - 300 mesh, column height 10 cm, diameter 2 cm) using petroleum ether:ethyl acetate with a volume ratio of 3:1 as the eluent, and the eluent containing the target compound is collected, and the solvent is evaporated to obtain the compound shown in formula I.

[0046] The method described in Route 2 includes the following steps:

[0047] (1) Methyl 3-aminobenzoate and hydrochloric acid are added to water. An aqueous solution of sodium nitrite is added dropwise at -5 to 5 °C (preferably 0 °C). After the addition is complete, the pH is adjusted to 5.5 - 6. An aqueous solution containing potassium selenocyanate and sodium bicarbonate is added, and the temperature is (slowly) raised to 40 - 60 °C (preferably 55 °C) for reaction for 0.5 - 1.5 hours (preferably 1 hour). The resulting reaction solution E is separated and purified to obtain the intermediate shown in Formula VII; the molar ratio of methyl 3-aminobenzoate, HCl contained in hydrochloric acid, sodium nitrite contained in the aqueous solution of sodium nitrite, potassium selenocyanate in the aqueous solution containing potassium selenocyanate and sodium bicarbonate to sodium bicarbonate in the aqueous solution containing potassium selenocyanate and sodium bicarbonate is 1:5 - 8:1 - 1.5:1 - 1.5:0.1 - 0.3 (preferably 1:5.7:1:1:0.25);

[0048]

[0049] (2) The intermediate shown in Formula VII and the compound shown in Formula VI in step (1) are stirred and reacted in organic solvent D in the presence of a catalyst at 50 - 100 °C for 3 - 8 h (preferably stirred and reacted at 55 °C for 6 h). The resulting reaction solution F is purified and separated to obtain the compound shown in Formula VIII; the catalyst is tris(pentafluorophenyl)borane or copper(I) iodide (preferably tris(pentafluorophenyl)borane); the molar ratio of the intermediate shown in Formula VII, the compound shown in Formula VI to the catalyst is 1:1 - 1.5:0.001 - 0.1 (preferably 1:1.2:0.1);

[0050]

[0051] (3) The compound shown in Formula VIII in step (2) is stirred and an aqueous solution of a basic substance is added in organic solvent E, and the reaction is stirred at 20 - 40 °C for 4 - 8 h (preferably stirred and reacted at 25 °C for 6 h). The organic solvent is removed under reduced pressure, and the pH is adjusted to 2 - 3 with (concentrated hydrochloric acid), filtered, and the obtained filter cake is dried to obtain the compound shown in Formula IX; the molar ratio of the compound shown in Formula VIII to the basic substance in the aqueous solution of the basic substance is 1:50 - 60 (preferably 1:57);

[0052] [[ID=1,8]]

[0053] (4) The compound shown by Formula IX and the compound shown by Formula II in step (3) react in organic solvent F at 20 - 40 °C for 1 - 4 h (preferably react at 25 °C for 4 h) under the action of a basic substance, a catalyst and a condensing agent. The obtained reaction solution G is purified and separated to obtain the compound shown by Formula I; the catalyst is 4-dimethylaminopyridine; the condensing agent is one or a mixture of two or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-benzotriazolyl-N,N,N',N'-tetramethylurea hexafluorophosphate, O-benzotriazolyl-N,N,N',N'-tetramethylurea tetrafluoroborate, triphenylphosphine-polyhalomethane, triphenylphosphine-hexachloroacetone, triphenylphosphine-NBS, 3-acyl-2-thiazoline (preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); the molar ratio of the compound shown by Formula IX, the compound shown by Formula II, the basic substance, the catalyst and the condensing agent is 1:1 - 1.5:1 - 3:0.1:1 - 1.5, preferably 1:1.2:3:0.1:1.5;

[0054]

[0055] The scope of the substituents in the above formula is as described above.

[0056] All the above intermediates or target compounds can be purified by conventional separation techniques such as recrystallization or chromatographic separation.

[0057] Further, the concentration of the hydrochloric acid in step (1) is 10 - 12 mol / L, and in the examples of the present invention, it is 12 mol / L.

[0058] Further, the concentration of the sodium nitrite aqueous solution in step (1) is 0.5 - 1 mol / L, and in the examples of the present invention, it is 1 mol / L.

[0059] Further, in step (1), a weak base is used to adjust the pH, which is one or a mixture of two of sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, and preferably sodium acetate.

[0060] Further, in the aqueous solution containing potassium selenocyanate and sodium bicarbonate in step (1), the concentration of potassium selenocyanate is 1 - 3 mol / L, and in the examples of the present invention, it is 2.5 mol / L, and the concentration of the sodium bicarbonate aqueous solution is 0.5 - 1 mol / L, and in the examples of the present invention, it is 0.6mol / L.

[0061] Further, the volume of water in step (1) is 1 - 5 mL / mmol based on the amount of substance of the compound shown by Formula IV, and in an example of the present invention, it is 2.4 mL / mmol.

[0062] In an embodiment of the present invention, the separation and purification of E in step (1) is as follows: The reaction solution E is extracted with dichloromethane, the organic layers are combined, washed with saturated brine (twice), dried over anhydrous sodium sulfate, the solvent is removed under reduced pressure, and the obtained residue is subjected to silica gel column chromatography using dichloromethane:methanol with a volume ratio of 200:1 as the eluent, the eluate containing the target compound is collected, and the solvent is evaporated to obtain the intermediate shown in Formula VII.

[0063] In steps (2) to (4) of the present invention, the diluents may be the same or different. The organic solvent D in step (2), the organic solvent E in step (3), and the organic solvent F in step (4) are each independently selected from one or a mixture of two or more of the following: benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, or diethylene glycol monoethyl ether. Preferably, the organic solvent D in step (2) is 1,2-dichloroethane, the organic solvent E in step (3) is tetrahydrofuran, and the organic solvent F in step (4) is dichloromethane.

[0064] Furthermore, the volume of the organic solvent D in step (2) is 1 - 7 mL / mmol based on the amount of substance of the intermediate shown in Formula VII, and is 4 mL / mmol in an embodiment of the present invention.

[0065] In an embodiment of the present invention, the separation and purification of F in step (2) is as follows: The reaction solution F is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography purification using petroleum ether:ethyl acetate with a volume ratio of 3:1 as the eluent (silica gel 200 - 300 mesh, column height 10 cm, diameter 2 cm), the eluate containing the target compound is collected, and the solvent is evaporated to obtain the compound shown in Formula VIII.

[0066] Furthermore, the basic substance in the aqueous solution of the basic substance in step (3) is one or a mixture of two or more of potassium hydroxide, lithium hydroxide, and sodium hydroxide, and preferably sodium hydroxide.

[0067] Even further, the concentration of the aqueous solution of the basic substance in step (3) is 1 - 3 mol / L, and preferably 2.9 mol / L.

[0068] Further, the volume of the organic solvent E in step (3) is 1 - 15 mL / mmol based on the amount of substance of the compound represented by formula VIII, and is 10 mL / mmol in one embodiment of the present invention.

[0069] Further, the basic substance in step (4) is one or a mixture of two or more of pyridine, N,N - diisopropylethylamine, N,N - dimethylaniline, N,N - dimethylbenzylamine, N - methylpiperidine, N - methylmorpholine, N,N - dimethylaminopyridine, diazabicyclooctane, diazabicyclononene, or diazabicycloundecene, sodium hydroxide, sodium ethoxide, trimethylamine, and triethylamine. Triethylamine or N,N - diisopropylethylamine is preferred, and N,N - diisopropylethylamine (DIPEA) is particularly preferred.

[0070] Further, the volume of the organic solvent F in step (4) is 1 - 15 mL / mmol based on the amount of substance of the intermediate represented by formula IX, and is 15 mL / mmol in one embodiment of the present invention.

[0071] In an embodiment of the present invention, the separation and purification G in step (4) is as follows: the reaction solution G is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography using dichloromethane:methanol with a volume ratio of 150:1 as the eluent. The eluate containing the target compound is collected, and the solvent is evaporated to obtain the compound represented by formula I.

[0072] In the third aspect, the present invention also provides an application of the 3 - (indole - 3 - seleno)benzamide compound in the preparation of a multi - drug resistance protein P - gp inhibitor.

[0073] Preferably, the 3 - (indole - 3 - seleno)benzamide compound is one or a mixture of two or more of compound I - 1, I - 13, I - 14, I - 15, and I - 16, and I - 13 is particularly preferred.

[0074] In the fourth aspect, the present invention also provides an application of the 3 - (indole - 3 - seleno)benzamide compound in the preparation of a tumor multi - drug resistance reverser or a tumor metastasis inhibitor.

[0075] The tumor multi - drug resistance or the tumor metastasis is caused by over - expression of the multi - drug resistance protein P - gp.

[0076] Preferably, the 3 - (indole - 3 - seleno)benzamide compound is one or a mixture of two or more of compound I - 1, I - 13, I - 14, I - 15, and I - 16, and I - 13 is particularly preferred.

[0077] In an embodiment of the present invention, the tumor includes the human breast cancer adriamycin - resistant cell line MCF - 7 / ADR. The inhibitor also includes a pharmaceutically acceptable salt.

[0078] Furthermore, the present invention provides a drug for preventing or treating multi-drug resistant tumors, which comprises the above-mentioned 3-(indole-3-selenyl)benzamide compounds and anti-tumor drugs.

[0079] Furthermore, the anti-tumor drugs of the present invention are one or a mixture of two or more of alkylating agents (such as cyclophosphamide or cisplatin), antimetabolites (such as 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (such as camptothecin or topotecan), cell microtubule inhibitors (such as paclitaxel or vinblastine), DNA intercalating agents (such as doxorubicin or daunorubicin), lysine kinase inhibitors (such as gefitinib), etc. (clinical chemotherapy drugs). By combining with anti-tumor drugs for treatment, the sensitivity of multi-drug resistant tumor cells to anti-tumor drugs is enhanced, thereby improving the chemotherapy treatment effect. In the examples of the present invention, the anti-tumor drug is doxorubicin.

[0080] Compared with the prior art, the present invention has the following beneficial effects:

[0081] The present invention provides a 3-(indole-3-selenyl)benzamide compound, which has a simple preparation method and a high yield. The 3-(indole-3-selenyl)benzamide compound has good biological activity. At a concentration without cytotoxicity when used alone for cancer cell lines showing drug resistance, it shows an obvious sensitization effect when combined with anti-tumor drugs, and can be used as a P-gp inhibitor or a tumor multi-drug resistance reversing agent and a tumor metastasis inhibitor or a biological probe with good biocompatibility, expanding the application prospect of selenium-containing small molecule structures in the aspect of tumor multi-drug resistance reversing agents. The combination of 3-(indole-3-selenyl)benzamide compound and doxorubicin hydrochloride can effectively improve the efficacy of doxorubicin hydrochloride against doxorubicin-resistant human breast cancer cell line (MCF-7 / ADR). (IV) BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 MCF-7 and MCF-7 / ADR cells were treated with 0.5, 2.5, 5.0 μM I-13, and the expression level of P-gp protein (A, B) was calculated, which is the relative expression level relative to β-tubulin. The effect of compound I-13 on the accumulation of rhodamine 123 mediated by P-gp in MCF-7 / ADR cells (A) Fluorescence images of rhodamine 123 treated with 10.0 μM verapamil or 0.1, 1.0, 10.0 μM I-13; (B, C) Fluorescence intensity of rhodamine 123 in MCF-7 / ADR cells. Data are expressed as the mean ± SD of three independent experiments. ***p < 0.001, (**)p < 0.01, (*)p < 0.05. Data are expressed as the mean ± SD of three independent experiments. ***p < 0.001 is considered to be statistically significant.

[0083] Figure 2 MCF-7 and MCF-7 / ADR cells were treated with 0.5, 2.5, and 5.0 μM I-13, and the expression level of P-gp protein (A, B) was calculated, which was the relative expression level relative to β-tubulin. The data were expressed as the mean ± SD of three independent experiments. ***p < 0.001 was considered statistically significant. (V) Specific implementation manners

[0084] The present invention will be further explained below with reference to specific embodiments, but the specific embodiments do not impose any limitations on the present invention. Unless otherwise specified, the reagents and methods involved in the embodiments are common reagents and methods in the art.

[0085] The room temperature referred to in the present invention means 25 to 30 °C.

[0086] Route 1:

[0087]

[0088] This route is used to prepare compounds I-1 to I-7.

[0089] Example 1. Preparation of (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(3-((5-fluoro-1H-indol-3-yl)selanyl)phenyl)methanone (I-1)

[0090]

[0091] S1. Add 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (II) (2.88 g, 15.00 mmol), triethylamine (6.26 mL, 45.00 mmol), and 30 mL of dichloromethane to a round-bottom flask, stir and cool to -10 °C, and dropwise add 3-nitrobenzoyl chloride (2.79 g, 15.00 mmol) dissolved in dichloromethane (30 mL) to the system. Control the dropping rate to keep the temperature at -10 °C. After dropping, slowly raise the temperature to room temperature and react at 25 °C for 2 h. Concentrate the solvent under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 200-300 mesh, column height 10 cm, diameter 4 cm), using dichloromethane:methanol with a volume ratio of 200:1 as the eluent, the elution speed was 1 / 10 column retention volume per minute, and 3 column volumes were eluted. Thin layer chromatography was monitored using dichloromethane:methanol with a volume ratio of 50:1 as the developing agent, and the effluent with an Rf of 0.5 was collected. After evaporating the solvent, a yellow solid intermediate shown in formula III (4.41 g, 11.25 mmol, yield 75%) was obtained, namely (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(3-nitrophenyl)methanone, which was used for the next reaction.

[0092] S2. Sequentially add (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(3-nitrophenyl)methanone (Ⅲ) (3.9 g, 10.00 mmol), 10% Pd / C (318 mg, 3 mmol) and 40 mL of dichloromethane into a round-bottom flask. Under a hydrogen atmosphere (1 atm), react at 25 °C for 12 h. Filter the mixture through diatomaceous earth, concentrate the obtained filtrate under reduced pressure, and purify the residue on silica gel (silica gel 200 - 300 mesh, column height 10 cm, diameter 4 cm). Use dichloromethane:methanol with a volume ratio of 120:1 as the eluent, and the elution rate is 1 / 10 of the column retention volume flowing out per minute. Elute for 3 column volumes. Monitor by thin-layer chromatography using dichloromethane:methanol with a volume ratio of 30:1 as the developing agent, collect the effluent with an Rf value of 0.5, evaporate the solvent to obtain the intermediate shown as yellow oil of formula Ⅳ (2.65 g, 8.50 mmol, yield 85%), namely (3-aminophenyl)(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone, for the next reaction.

[0093] S3. Add (3-aminophenyl)(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Ⅳ) (1.56 g, 5.0 mmol), concentrated hydrochloric acid (2.3 mL, 28.80 mmol) and 12 mL of water into a round-bottom flask. Cool the mixture to 0 °C through an ice bath, and add an aqueous sodium nitrite solution (0.35 g, 5.0 mmol, 5 mL). Control the dropping rate to keep the temperature at 0 °C. After the addition is complete, add sodium acetate to adjust the pH to 5.5 - 6, and add an aqueous solution (2 mL) containing potassium selenocyanate (0.72 g, 5.0 mmol) and sodium bicarbonate (0.11 g, 1.25 mmol). Stir at room temperature for 30 minutes, then heat the mixture to 55 °C and continue the reaction for 1 hour. Extract the mixture with dichloromethane several times, combine the organic layers, wash twice with saturated brine, and dry with anhydrous sodium sulfate. Remove the solvent under reduced pressure, and purify the residue on silica gel (silica gel 200 - 300 mesh, column height 10 cm, diameter 2 cm). Use dichloromethane:methanol with a volume ratio of 200:1 as the eluent, and the elution rate is 1 / 10 of the column retention volume flowing out per minute. Elute for 3 column volumes. Monitor by thin-layer chromatography using dichloromethane:methanol with a volume ratio of 50:1 as the developing agent, collect the effluent with an Rf value of 0.5, evaporate the solvent to obtain the intermediate shown as yellow solid of formula Ⅴ (0.88 g, 2.2 mmol, yield 44%), namely (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(3-selenocyanatophenyl)methanone, for the next reaction.

[0094] S4. Add (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(3-selenocyanatophenyl)methanone (V) (60 mg, 0.15 mmol), 5-fluoroindole (VI) (24 mg, 0.18 mmol), copper(I) iodide (2.9 mg, 0.015 mmol) and 1 mL of 1,2-dichloroethane into a test tube in sequence. The mixture is stirred at 100 °C for 3 h, and the solvent is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel 200 - 300 mesh, column height 10 cm, diameter 2 cm), using petroleum ether:ethyl acetate with a volume ratio of 5:1 as the eluent, and the elution speed is 1 / 10 of the column retention volume flowing out per minute. Elute for 3 column volumes. Thin layer chromatography is monitored using petroleum ether:ethyl acetate with a volume ratio of 2:1 as the developing agent, and the effluent with an Rf value of 0.4 is collected. After evaporating the solvent, a white solid of formula I-1 (47 mg, 0.09 mmol, yield 61%) is obtained, namely (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(3-((5-fluoro-1H-indol-3-yl)selanyl)phenyl)methanone. 1 H NMR (500 MHz, DMSO-d6) δ 11.64 (s, 1H), 7.78 (s, 1H), 7.52 (dd, J = 9.0, 4.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.16 (s, 1H), 7.12 (dd, J = 9.5, 2.5 Hz, 1H), 7.01 (td, J = 9.0, 2.5 Hz, 1H), 6.67 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.47 (s, 2H), 2.60–2.46 (m, 2H). 13 C NMR (1**25** MHz, DMSO-d6) δ 168.30, 157.46 (d, J = 232.5 Hz), 147.55 (d, J = 3.3 Hz), 136.69, 134.34, 133.41, 133.07, 129.91, 129.82, 129.87 (d, J = 10.0 Hz), 125.86 (d, J = 14.5 Hz), 124.60, 124.01, 113.02 (d, J = 9.5 Hz), 112.48, 110.31, 110.07, 109.86, 103.26, 103.07, 94.81 (d, J = 4.8 Hz), 55.57, 55.56, 27.28.

[0095] Route 2:

[0096]

[0097] This route is used for the preparation of Compounds I-8 to I-21.

[0098] Preparation of 3-((1H-Indol-3-yl)selanyl)-N-(3,4-dimethoxyphenyl)benzamide (I-8) in Example 2

[0099]

[0100] (1) Add methyl 3-aminobenzoate (755 mg, 5.0 mmol), concentrated hydrochloric acid (2.3 mL, 28.8 mmol) and 12 mL of water to a round-bottom flask. Cool the mixture to 0 °C in an ice bath, and dropwise add an aqueous sodium nitrite solution (345 mg, 5.0 mmol, 5 mL). Control the dropping rate to keep the temperature at 0 °C. After dropping, add sodium acetate to adjust the pH to 5.5 - 6, and add an aqueous solution (2 mL) containing potassium selenocyanate (720 mg, 5.0 mmol) and sodium bicarbonate (105 mg, 1.25 mmol). Stir the mixture at room temperature for 30 minutes, then heat the mixture to 55 °C and continue the reaction for 1 hour. Extract the mixture with dichloromethane several times, combine the organic layers, wash twice with saturated brine, and dry with anhydrous sodium sulfate. Remove the solvent under reduced pressure, and purify the residue on silica gel (silica gel 200 - 300 mesh, column height 10 cm, diameter 2 cm) using dichloromethane:methanol with a volume ratio of 200:1 as the eluent. The elution rate is 1 / 10 column retention volume per minute, and elute for 3 column volumes. Monitor by thin-layer chromatography using dichloromethane:methanol with a volume ratio of 50:1 as the developing agent, and collect the effluent with an Rf value of 0.4. After evaporating the solvent, a yellow solid intermediate shown in Formula VII (411 mg, 1.7 mmol, yield 34%), namely methyl 3-selenocyanatobenzoate, is obtained for the next reaction.

[0101] (2) Sequentially add methyl 3-selenocyanatobenzoate (VII) (241 mg, 1.0 mmol), indole (VI) (140 mg, 1.2 mmol), tris(pentafluorophenyl)borane (51 mg, 0.1 mmol) and 1,2-dichloroethane (4 mL) to a test tube. Stir the mixture at 55 °C for 6 h, concentrate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (silica gel 200 - 300 mesh, column height 10 cm, diameter 2 cm) using petroleum ether:ethyl acetate with a volume ratio of 3:1 as the eluent. The elution rate is 1 / 10 column retention volume per minute, and elute for 3 column volumes. Monitor by thin-layer chromatography using petroleum ether:ethyl acetate with a volume ratio of 1:1 as the developing agent, and collect the effluent with an Rf value of 0.3. After evaporating the solvent, a brown solid intermediate shown in Formula VIII (228 mg, 0.69 mmol, yield 69%), namely methyl 3-((1H-indol-3-yl)selanyl)benzoate, is obtained for the next reaction.

[0102] (3) Add methyl 3-((1H-indol-3-yl)seleno)benzoate (Ⅷ) (165 mg, 0.5 mmol) and 5 mL of tetrahydrofuran to a round-bottom flask. While stirring, add an aqueous sodium hydroxide solution (1144 mg, 28.6 mmol, 10 mL). Stir at room temperature for 6 h. Remove tetrahydrofuran under reduced pressure. Adjust the pH of the solution to 2 - 3 with concentrated hydrochloric acid. Filter the residue and dry it to obtain the compound shown in formula Ⅸ, namely 3-((1H-indol-3-yl)seleno)benzoic acid, which can be directly used for the next reaction.

[0103] (4) Add 3-((1H-indol-3-yl)seleno)benzoic acid (Ⅸ) (63 mg, 0.2 mmol), EDCI (58 mg, 0.3 mmol), DMAP (2.4 mg, 0.02 mmol), 3,4-dimethoxyaniline (Ⅱ) (37 mg, 0.24 mmol) and 3 mL of dichloromethane to a round-bottom flask in sequence. While stirring, add DIPEA (0.1 mL, 0.6 mmol). React at room temperature for 4 h. Concentrate the solvent under reduced pressure. Purify the residue by silica gel column chromatography (silica gel 200 - 300 mesh, column height 10 cm, diameter 2 cm), using dichloromethane:methanol with a volume ratio of 150:1 as the eluent, and the elution rate is 1 / 10 of the column retention volume per minute. Elute for 3 column volumes. Monitor by thin-layer chromatography using dichloromethane:methanol with a volume ratio of 30:1 as the developing agent. Collect the effluent with an Rf value of 0.4. After evaporating the solvent, a pale yellow solid of formula Ⅰ-8 (64 mg, 0.14 mmol, yield 71%) is obtained, namely 3-((1H-indol-3-yl)selenoalkyl)-N-(3,4-dimethoxyphenyl)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.08 (s, 1H), 7.81 (d, J = 10.0 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.55–7.36 (m, 3H), 7.34–7.22 (m, 3H), 7.19 (s, 1H), 7.08 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.74 (s, 6H). 13 C NMR (150 MHz, DMSO-d6) δ 164.48, 148.38, 145.17, 136.67, 135.75, 134.25, 133.01, 132.52, 130.85, 129.39, 128.99, 127.21, 124.74, 122.08, 120.12, 118.91, 112.27, 112.20, 111.83, 105.46, 94.64, 55.69, 55.37.

[0104] According to the methods similar to those of Examples 1 and 2, R1, R2 and R3 in the compounds shown in Formula II and Formula VI were replaced to obtain the corresponding compounds shown in Formula I.

[0105]

[0106] According to the method described in Example 1, except that Formula VI was N-methyl-1H-indole-5-carboxamide (31 mg, 0.18 mmol) and the catalyst was tris(pentafluorophenyl)borane (7.6 mg, 0.015 mmol), a pale yellow solid I-2 (40 mg, yield 48%, liquid phase purity 99%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.12 (q, J = 4.5 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 2.0 Hz 1H), 7.74 (dd, J = 8.5, 1.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.18 (dt, J = 7.5, 1.5 Hz, 1H), 7.13 (s, 1H), 6.66 (s, 2H), 4.45 (s, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.45 (s, 2H), 2.80 (d, J = 4.5 Hz, 3H), 2.51–2.40 (m, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 168.43, 167.19, 147.62, 147.57, 137.96, 136.72, 133.89, 133.84, 129.06, 128.85, 128.82, 126.94, 125.90, 125.71, 124.63, 123.98, 121.18, 118.39, 112.53, 111.40, 110.39, 95.90, 55.65, 27.33, 25.86.

[0107]

[0108] According to the method described in Example 1, except that Formula II was pyridine-2-methylamine (1.62 g, 15.00 mmol) and Formula VI was N-methyl-1H-indole-5-carboxamide (31 mg, 0.18 mmol), a white solid I-3 (45 mg, yield 65%, liquid phase purity 99%) was obtained. 11H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.09 (t, J = 6.0 Hz, 1H), 8.49 (d, J = 4.0 Hz, 1H), 8.35 (q, J = 4.4 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.75–7.68 (m, 3H), 7.67 (dt, J = 7.2, 1.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.32–7.21 (m, 4H), 4.51 (d, J = 6.0 Hz, 2H), 2.75 (d, J = 4.4 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 167.23, 165.78, 158.58, 148.78, 138.13, 136.66, 134.96, 134.54, 134.20, 130.69, 129.11, 129.04, 127.04, 126.86, 124.49, 122.02, 121.40, 120.80, 118.67, 111.72, 95.80, 44.63, 26.26.

[0109]

[0110] According to the method described in Example 1, except that Formula II is 2-pyridinemethanamine (1.62 g, 15.00 mmol) and Formula VI is N-methyl-1H-indole-7-carboxamide (31 mg, 0.18 mmol), white solid I-4 (34 mg, yield 49%, liquid phase purity 99%) was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ 12.01 (d, J = 2.4 Hz, 1H), 9.09 (t, J = 6.0 Hz, 1H), 8.49 (dt, J = 4.0, 2.0 Hz, 1H), 8.39 (q, J = 4.4 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.81 (t, J = 1.6 Hz, 1H), 7.72 (td, J = 7.6, 2.0 Hz, 1H), 7.67 (dt, J = 6.8, 2.0 Hz, 1H), 7.58 (dd, J = 8.4, 1.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.31–7.21 (m, 4H), 4.51 (d, J = 6.0 Hz, 2H), 2.80 (d, J = 4.4 Hz, 3H). 1313C NMR (125 MHz, DMSO-d6) δ 167.28, 165.77, 158.58, 148.79, 136.65, 136.10, 135.30, 134.97, 133.93, 131.42, 130.91, 129.08, 128.76, 127.26, 124.57, 122.02, 120.82, 119.10, 118.40, 111.75, 94.96, 44.63, 26.32.

[0111]

[0112] According to the method described in Example 1, except that Formula VI is N-(4-fluorophenyl)-1H-indole-5-carboxamide (46 mg, 0.18 mmol), and the catalyst is tris(pentafluorophenyl)borane (7.6 mg, 0.015 mmol), to obtain yellow solid I-5 (61 mg, yield 65%, liquid phase purity 99%). 1 1H NMR (500 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.06 (s, 1H), 8.20 (d, J = 1.5 Hz, 1H), 7.88 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (s, 1H), 7.81–7.73 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.22–7.08 (m, 4H), 6.73–6.61 (m, 2H), 4.46 (s, 2H), 3.74 (s, 3H), 3.69 (s, 3H), 3.45 (s, 2H), 2.50–2.41 (m, 2H). 13 13C NMR (125 MHz, DMSO-d6) δ 168.35, 165.77, 158.87, 156.96, 147.56, 147.53, 138.25, 136.74, 135.49, 135.47, 134.14, 133.73, 129.09, 128.83, 126.80, 125.84, 124.59, 123.98, 122.17, 122.10, 121.56, 119.12, 114.54, 114.36, 112.47, 111.52, 110.35, 96.07, 55.58, 27.35.

[0113]

[0114] According to the method described in Example 1, except that Formula VI is N-(2-(dimethylamino)ethyl)-1H-indole-5-carboxamide (42 mg, 0.18 mmol), a pale yellow solid I-6 (36 mg, yield 38%, liquid phase purity 99%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.06 (s, 1H), 8.20 (d, J = 1.5 Hz, 1H), 7.88 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (s, 1H), 7.81–7.73 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.22–7.08 (m, 4H), 6.73–6.61 (m, 2H), 4.46 (s, 2H), 3.74 (s, 3H), 3.69 (s, 3H), 3.45 (s, 2H), 2.50–2.41 (m, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 168.35, 165.77, 158.87, 156.96, 147.56, 147.53, 138.25, 136.74, 135.49, 135.47, 134.14, 133.73, 129.09, 128.83, 126.80, 125.84, 124.59, 123.98, 122.17, 122.10, 121.56, 119.12, 114.54, 114.36, 112.47, 111.52, 110.35, 96.07, 55.58, 27.35.

[0115]

[0116] According to the method described in Example 1, except that Formula VI is N-isopropyl-1H-indole-5-carboxamide (36 mg, 0.18 mmol), a pale yellow solid I-7 (48 mg, yield 56%, liquid phase purity 99%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.04 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.74 (dd, J = 8.5, 1.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.17 (dt, J = 7.5, 1.5 Hz, 1H), 7.12 (s, 1H), 6.65 (s, 2H), 4.45 (s, 2H), 4.11 (dp, J = 8.0, 6.5 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.44 (s, 2H), 2.51–2.39 (m, 2H), 1.17 (d, J = 6.5 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d6) δ 168.33, 165.85, 147.57, 147.53, 137.85, 136.70, 133.90, 133.81, 128.95, 128.78, 128.73, 127.27, 125.84, 125.71, 124.60, 123.91, 121.28, 118.50, 112.49, 111.15, 110.37, 95.78, 55.60, 40.62, 27.31, 21.95.

[0117]

[0118] According to the method described in Example 2, except that Formula II is pyridine-2-methylamine (26 mg, 0.24 mmol), a light yellow solid I-9 (59 mg, yield 73%, liquid phase purity 99%) was obtained. 1 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.51 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.65 (td, J = 7.6, 2.0 Hz, 1H), 7.58 (dd, J = 12.4, 8.0 Hz, 2H), 7.55–7.48 (m, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.29–7.22 (m, 2H), 7.23–7.12 (m, 4H), 4.67 (d, J = 4.8 Hz, 2H). 1313C NMR (150 MHz, CDCl3) δ 167.06, 156.02, 148.80, 136.98, 136.49, 134.93, 134.84, 131.72, 131.58, 129.75, 129.03, 127.27, 124.28, 122.91, 122.47, 122.25, 120.86, 120.11, 111.52, 97.43, 44.65.

[0119]

[0120] According to the method described in Example 2, except that Formula VI is 7-azaindolyl (142 mg, 1.2 mmol), a light gray solid I-10 (24 mg, yield 29%, liquid phase purity 99%) was obtained. 1 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.51 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.65 (td, J = 7.6, 2.0 Hz, 1H), 7.58 (dd, J = 12.4, 8.0 Hz, 2H), 7.55–7.48 (m, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.29–7.22 (m, 2H), 7.23–7.12 (m, 4H), 4.67 (d, J = 4.8 Hz, 2H). 13 13C NMR (150 MHz, CDCl3) δ 167.06, 156.02, 148.80, 136.98, 136.49, 134.93, 134.84, 131.72, 131.58, 129.75, 129.03, 127.27, 124.28, 122.91, 122.47, 122.25, 120.86, 120.11, 111.52, 97.43, 44.65.

[0121]

[0122] According to the method described in Example 2, except that Formula II is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (46 mg, 0.24 mmol) and Formula VI is N-(4-methoxyphenyl)-1H-indole-5-carboxamide (319 mg, 1.2 mmol), a white solid I-11 (64 mg, yield 50%, liquid phase purity 99%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 9.87 (s, 1H), 8.20 (d, J = 1.5 Hz, 1H), 7.88 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.69–7.62 (m, 2H), 7.60 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.21–7.15 (m, 2H), 6.94–6.87 (m, 2H), 6.71–6.60 (m, 2H), 4.47 (s, 2H), 3.75 (d, J = 8.0 Hz, 6H), 3.70 (s, 3H), 3.46 (s, 2H), 2.53–2.44 (m, 2H). 13 13C NMR (125 MHz, DMSO-d6) δ 168.35, 165.46, 155.26, 147.54, 147.54, 138.12, 136.74, 134.03, 133.75, 132.29, 129.08, 128.82, 128.80, 127.13, 125.83, 124.59, 123.96, 121.95, 121.53, 119.00, 113.43, 112.46, 111.43, 110.34, 96.07, 55.58, 55.56, 54.99, 54.96, 54.94, 27.36.

[0123]

[0124] According to the method described in Example 2, except that Formula VI is N-(4-methoxyphenyl)-1H-indole-5-carboxamide (319 mg, 1.2 mmol), white solid I-12 (64 mg, yield 53%, liquid phase purity 99%) was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ 12.04 (d, J = 2.8 Hz, 1H), 10.09 (d, J = 2.8 Hz, 2H), 8.14 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.88–7.78 (m, 2H), 7.70 (dt, J = 7.2, 1.6 Hz, 1H), 7.65 (d, J = 2.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.37–7.23 (m, 3H), 6.93–6.84 (m, 3H), 3.75–3.70 (m, 9H). 1313C NMR (150 MHz, DMSO-d6) δ 165.71, 164.44, 155.29, 148.37, 145.16, 138.36, 135.83, 134.80, 134.19, 132.50, 130.75, 129.08, 127.20, 127.12, 124.81, 122.04, 121.82, 119.34, 113.58, 112.27, 111.82, 105.46, 95.92, 55.67, 55.35, 55.11.

[0125]

[0126] According to the method described in Example 2, except that Formula II is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (46 mg, 0.24 mmol) and Formula VI is 5-(1-methyl-1H-pyrazol-4-yl)-1H-indole (236 mg, 1.2 mmol), light brown solid I-13 (54 mg, yield 47%, liquid phase purity 99%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 15 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.42–7.36 (m, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 7.5 Hz, 2H), 6.71–6.52 (m, 2H), 4.44 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 3.69 (s, 3H), 3.43 (s, 2H), 2.51–2.38 (m, 2H). 13 13C NMR (125 MHz, DMSO-d6) δ 168.38, 147.55, 147.52, 136.66, 135.30, 133.95, 132.85, 129.72, 129.07, 128.71, 126.70, 125.84, 124.83, 124.59, 123.85, 122.78, 120.20, 114.59, 112.45, 112.17, 110.35, 55.58, 38.02, 27.29.

[0127]

[0128] According to the method described in Example 2, except that Formula II is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (46 mg, 0.24 mmol) and Formula VI is 1-(4-methoxybenzyl)-1H-indole (284 mg, 1.2 mmol), white solid I-14 (104 mg, yield 85%, liquid phase purity 99%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.38 (dt, J = 8.0, 1.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.24–7.15 (m, 4H), 7.15–7.08 (m, 2H), 6.85–6.79 (m, 2H), 6.64 (s, 2H), 5.40 (s, 2H), 4.42 (s, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 3.69 (s, 3H), 3.43 (s, 2H), 2.52-2.35 (m, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 168.42, 158.57, 147.62, 147.60, 136.71, 136.48, 135.56, 133.70, 129.89, 129.18, 129.14, 128.82, 128.17, 125.89, 124.60, 124.08, 122.00, 120.12, 119.08, 113.83, 112.54, 110.59, 110.33, 94.58, 55.66, 55.63, 54.81, 48.77, 27.35.

[0129]

[0130] According to the method described in Example 2, except that Formula VI is 5-(1-methyl-1H-pyrazol-4-yl)-1H-indole (236 mg, 1.2 mmol), white solid I-15 (67 mg, yield 63%, liquid phase purity 99%) was obtained. 11H NMR (400 MHz, DMSO-d6) δ 11.73 (d, J = 2.4 Hz, 1H), 10.09 (s, 1H), 8.06–8.00 (m, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.69 (dt, J = 6.8, 2.0 Hz, 1H), 7.57–7.52 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.45–7.36 (m, 2H), 7.34–7.24 (m, 3H), 6.90 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.72 (d, J = 1.2 Hz, 6H). 13 13C NMR (150 MHz, DMSO-d6) δ 164.45, 148.38, 145.16, 135.73, 135.64, 135.43, 134.41, 133.58, 132.51, 130.84, 129.99, 129.02, 127.22, 127.18, 125.00, 124.73, 122.89, 120.43, 114.68, 112.59, 112.28, 111.82, 105.46, 94.59, 55.68, 55.35, 38.47.

[0131]

[0132] According to the method described in Example 2, except that Formula VI is 1-(4-methoxybenzyl)-1H-indole (284 mg, 1.2 mmol), white solid I-16 (102 mg, yield 89%, liquid phase purity 99%) was obtained. 1 1H NMR (400 MHz, CDCl3) δ 7.64 (t, J = 1.6 Hz, 1H), 7.63–7.54 (m, 2H), 7.53 (s, 1H), 7.41 (s, 1H), 7.41–7.33 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.30–7.14 (m, 3H), 7.11 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.88–6.76 (m, 4H), 5.30 (s, 2H), 3.86 (m, 6H), 3.73 (s, 3H). 1313C NMR (150 MHz, CDCl3) δ 165.10, 159.32, 149.03, 145.97, 137.09, 135.65, 135.20, 135.06, 131.58, 131.47, 130.56, 129.23, 128.44, 128.36, 126.47, 124.28, 122.71, 120.77, 120.33, 114.31, 111.92, 111.30, 110.35, 104.90, 95.91, 56.09, 55.91, 55.21, 49.99.

[0133]

[0134] According to the method described in Example 2, except that Formula II is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (46 mg, 0.24 mmol), a pale yellow solid I-17 (65 mg, yield 66%, liquid phase purity 99%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ 11.52 (s, 1H), 7.69 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.22–7.12 (m, 3H), 7.09 (t, J = 7.5 Hz, 1H), 6.72–6.62 (m, 2H), 4.45 (s, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 3.45 (s, 2H), 2.53–2.42 (m, 2H). 13 13C NMR (125 MHz, DMSO-d6) δ 168.32, 147.55, 147.52, 136.60, 136.45, 133.81, 132.34, 129.12, 129.08, 128.66, 125.84, 124.59, 123.86, 121.65, 119.70, 118.56, 112.49, 111.75, 110.32, 94.73, 55.59, 27.27.

[0135]

[0136] According to the method described in Example 2, except that the starting compound is methyl 4-aminobenzoate (755 mg, 5.0 mmol) and Formula II is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (46 mg, 0.24 mmol), a white solid I-18 (85 mg, yield 86%, liquid phase purity 99%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.54–7.49 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.29–7.20 (m, 4H), 7.19 (t, J = 7.5 Hz, 1H), 7.13–7.06 (m, 1H), 6.71 (s, 2H), 4.54 (s, 2H), 3.78–3.65 (m, 6H), 3.61 (s, 2H), 2.72 (t, J = 6.0 Hz, 2H). 13 13C NMR (125 MHz, DMSO-d6) δ 168.73, 147.56, 147.54, 136.43, 135.71, 133.29, 132.39, 129.22, 127.61, 127.20, 126.00, 124.79, 121.68, 119.73, 118.60, 112.53, 111.76, 110.37, 94.51, 55.57, 27.50.

[0137]

[0138] According to the method described in Example 2, except that the starting compound was methyl 4-aminobenzoate (755 mg, 5.0 mmol), brown solid I-19 (52 mg, yield 58%, liquid phase purity 99%) was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ 11.76 (d, J = 2.8 Hz, 1H), 9.96 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.29–7.23 (m, 3H), 7.20 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.09 (td, J = 8.0, 7.2, 1.2 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.72 (d, J = 2.8 Hz, 6H). 13 13C NMR (150 MHz, DMSO-d6) δ 164.64, 148.39, 145.06, 138.69, 136.71, 133.05, 132.67, 132.23, 129.30, 128.09, 127.37, 122.12, 120.16, 118.89, 112.22, 112.19, 111.87, 105.41, 94.18, 55.68, 55.34.

[0139]

[0140] According to the method described in Example 2, except that the starting compounds were methyl 4-aminobenzoate (755 mg, 5.0 mmol) and pyridine-2-methanamine of formula II (26 mg, 0.24 mmol), brown solid I-20 (39 mg, yield 48%, liquid phase purity 99%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.51 (dt, J = 4.8, 1.2 Hz, 1H), 7.65 (td, J = 7.6, 2.0 Hz, 1H), 7.64–7.53 (m, 4H), 7.47 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.26–7.22 (m, 2H), 7.22–7.18 (m, 2H), 7.18–7.13 (m, 1H), 4.71 (d, J = 4.8 Hz, 2H). 13 C NMR (150 MHz, CDCl3) δ 167.16, 156.09, 148.85, 139.47, 136.89, 136.53, 131.62, 131.27, 129.70, 128.02, 127.46, 122.99, 122.44, 122.21, 120.92, 120.09, 111.56, 96.89, 44.62.

[0141]

[0142] According to the method described in Example 2, except that the starting compounds were methyl 2-aminobenzoate (755 mg, 5.0 mmol) and pyridine-2-methanamine of formula II (26 mg, 0.24 mmol), white solid I-21 (33 mg, yield 41%, liquid phase purity 99%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.58 (dt, J = 4.8, 1.2 Hz, 1H), 7.70 (td, J = 7.6, 2.0 Hz, 1H), 7.66–7.60 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.50–7.43 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.29–7.19 (m, 2H), 7.18–7.07 (m, 2H), 7.07–6.96 (m, 2H), 4.84 (d, J = 4.8 Hz, 2H). 1313C NMR (150 MHz, CDCl3) δ 168.35, 156.09, 148.95, 137.55, 136.90, 136.70, 132.28, 131.99, 131.03, 130.27, 129.49, 127.23, 124.75, 122.78, 122.48, 122.32, 120.69, 120.50, 111.40, 99.36, 44.80.

[0143] Example 3 Cytotoxicity of 3-(Indole-3-selenyl)benzamide Compounds Shown in Formula I against MCF-7 / ADR

[0144] Cell line: MCF-7 / ADR (human breast cancer adriamycin-resistant cell line).

[0145] Sample test concentration: 5 μM.

[0146] Positive control drugs: verapamil, cyclosporin, tariquidar.

[0147] Test method: The MTT (tetramethyl thiazolyl tetrazolium) method was used to conduct the cell proliferation activity test of the compounds.

[0148] MCF-7 / ADR cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% double antibody under the conditions of 37 °C and 5% CO2 saturated humidity. Cells in the logarithmic growth phase were taken and inoculated into 96-well culture plates at a density of 1×10 5 / mL, 100 μL per well, and cultured under the conditions of 37 °C and 5% CO2 saturated humidity. They were divided into a blank control group, a test compound group, and a positive control group. The test compounds and positive control drugs were prepared into solutions with a concentration of 10 mM using dimethyl sulfoxide (DMSO) and reserved. Different test compound solutions were added to the test compound group and diluted with RPMI 1640 medium containing 10% fetal bovine serum, and the final concentration was 5 μmol / L; the positive control group was added with the positive control drug solution and diluted with RPMI 1640 medium containing 10% fetal bovine serum and 1% double antibody, and the final concentration was 5 μmol / L; the blank control group was given an equal volume of PBS. After culturing for 48 hours, MTT solution was added. After 4 hours, the culture medium was aspirated, 100 μL of DMSO was added to each well to dissolve, and then the absorbance was measured at a wavelength of 570 nm on an enzyme-linked immunosorbent assay (ELISA) reader to calculate the effect of the compounds on the cell survival rate.

[0149] Cell survival rate = (average OD value of the test group / average OD value of the control group) × 100%

[0150] The cytotoxicity of the test compounds against MCF-7 / ADR cells was determined by the MTT method, and the results are shown in Table 1. It can be seen from the data that the 3-(indole-3-selenyl)benzamide compounds shown in Formula I have much lower growth inhibition on cells than the control drug and have no obvious cytotoxicity.

[0151] Table 1 Inhibition rate of the compounds described in Formula I on MCF-7 / ADR cells at a test concentration of 5 μM

[0152]

[0153] Example 4 Study on the multidrug resistance reversal activity of the 3-(indole-3-selenyl)benzamide compounds shown in Formula I against MCF-7 / ADR cells.

[0154] Cell line: MCF-7 / ADR (human breast cancer adriamycin-resistant cell line).

[0155] Sample test concentration: 5 μM.

[0156] Positive control drugs: verapamil, cyclosporin, tariquidar.

[0157] Test method: The MTT (tetramethyl azo salt) method was used to conduct a cell proliferation activity test for the combined use of the compound and adriamycin.

[0158] MCF-7 / ADR cells were cultured in RPMI 1640 medium containing 10% calf serum under the conditions of 37 °C and 5% CO2 saturated humidity. Cells in the logarithmic growth phase were taken and seeded at 1×10 5Inoculate at a density of / mL into a 96-well culture plate, 100 μL per well, and culture under the conditions of 37 °C and 5% CO₂ saturated humidity. It is divided into a blank control group, a test compound group, and a positive control group. The test compound, positive control drug, and doxorubicin are respectively prepared into solutions with a concentration of 10 mM using dimethyl sulfoxide (DMSO) and reserved. Add different test compound solutions and doxorubicin solutions to the test compound group, dilute with RPMI 1640 medium containing 10% fetal bovine serum. The test compounds are all 5 μmol / L, and the final concentration of doxorubicin is 0 μmol / L, 0.001 μmol / L, 0.01 μmol / L, 0.1 μmol / L, 1 μmol / L, 10 μmol / L. Add the positive control drug solution and doxorubicin solution to the positive control group, dilute with RPMI 1640 medium containing 10% fetal bovine serum. The final concentrations of the positive control drug and doxorubicin are both 5 μmol / L; the blank control group is given an equal volume of PBS. Culture for another 48 hours, add MTT solution. After 4 hours, aspirate the culture medium, add 100 μL of DMSO to each well to dissolve, gently shake to fully dissolve the crystals, and then read the optical density at a wavelength of 570 nm on an enzyme-linked immunosorbent assay (ELISA) reader to calculate the inhibitory concentration (IC) of doxorubicin on the anti-proliferative activity of MCF-7 / ADR cells when co-administered with the compound described in Formula I at 5 μM 50 (μM) and the multidrug resistance reversal fold (RF), and investigate the effect of the compound on the cell viability.

[0159] Table 2 Results of the multidrug resistance reversal activity of the compound shown in Formula I at 5 μM against MCF-7 / ADR cells

[0160]

[0161] a IC of doxorubicin in combination with the test compound (5 μM) 50 value. b Reversal fold = IC 50 (ADR) / IC 50 (P-gp inhibitor + ADR). c IC of doxorubicin alone 50 (ADR, 12.66 μM).

[0162] As can be seen from Table 2, the meta - substituted indole selenides, Compounds I - 17, I - 8, and I - 9, exhibited stronger reversal activity than the ortho - substituted Compound I - 21 and the para - substituted Compounds I - 18, I - 19, and I - 20. These preliminary results indicate that meta - substituted indole selenides are more favorable for inhibiting P - gp than ortho - and para - substituted ones. For the amide group, C - 5 - substituted I - 2 and I - 3 were more effective than the C - 7 - substituted analog I - 4. Notably, the reversal activity of the C - 5 - fluoro - substituted Compound I - 1 (RF = 95.1) was 23 - fold higher than that of I - 17 (RF = 4.1), and it was also more effective than the positive controls verapamil (RF = 12.5) and cyclosporine (RF = 43.9).

[0163] Example 5. Mode of action of Compound I - 13 in reversing P - gp - mediated MDR.

[0164] To further evaluate P - gp - mediated substrate accumulation, such as Rhodamine 123 (Rh123), is a widely recognized method for assessing the efficacy of P - gp modulators in overcoming MDR. After treatment with verapamil or I - 13, a significant increase in intracellular accumulation of Rh123 was observed in MCF - 7 / ADR cells, as shown in Figure 1 (A) - (C). This indicates that I - 13 has the potential to hinder the P - gp - mediated efflux function in MCF - 7 / ADR cells. Notably, at a concentration of 10 μM, I - 13 was comparable to verapamil in its ability to increase the level of Rh123 in MCF - 7 / ADR cells. In addition, with the increase in the concentration of I - 13, the accumulation of Rh123 in MCF - 7 / ADR cells increased in a dose - dependent manner, indicating that I - 13 can inhibit the P - gp - mediated efflux activity in a concentration - dependent manner.

[0165] To further clarify the mechanistic basis for the efficacy of 3 - (indol - 3 - ylseleno) benzamides in reversing P - gp - mediated MDR, we performed Western blot analysis using I - 13 to evaluate the effect of I - 13 on the expression level of P - gp in MCF - 7 / ADR cells. As shown in Figure 2 (A) - (B), overexpression of P - gp was observed in doxorubicin - resistant MCF - 7 / ADR cells, while I - 13 had no significant effect on the expression level of P - gp. These findings emphasize that the multidrug - resistance reversal potential of I - 13 stems from its efficacy in inhibiting the P - gp efflux function rather than regulating the expression of P - gp.

[0166] In addition, the compounds shown in Formula I generally have good activities in reversing multidrug resistance of tumor cells. Among them, I-13 has the strongest potency, and its reversing activity exceeds that of the control drug Tariquidar (RF: 271.7 vs 261.6). At the same time, its toxicity to the cell lines MCF-7 (inhibition rate: 21.1% vs 36.9%) and MCF-7 / ADR (inhibition rate: 33.7% vs 45.1%) is lower than that of tariquidar. In summary, these results indicate that I-13 is worthy of being used as a starting point for developing novel selenium-containing P-gp inhibitors for clinical applications.

Claims

1. A 3-(indol-3-ylseleno)benzamide compound represented by Formula I: R1 is selected from one of the following: H, halogen, wherein, Y is C1-C 10 alkyl, phenyl substituted by halogen or C1-C4 alkoxy, or -(CH2) n -N-(CH3)2, where n is an integer between 1 and 4; R2 is selected from one of the following: R3 is H or 2. The 3-(indole-3-selenyl)benzamide compound represented by Formula I as described in Claim 1, wherein: R1 is H, fluorine or wherein Y is methyl, isopropyl, phenyl substituted by fluorine or methoxy, or -(CH2)2-N-(CH3)2.

3. The 3-(indole-3-selenyl)benzamide compound represented by Formula I as described in Claim 2, wherein: The 3-(indol-3-ylseleno)benzamide compound represented by Formula I is one of the following:

4. The preparation method of the 3-(indole-3-selenyl)benzamide compounds according to claim 1, characterized in that The method includes the following steps: S1: The compound represented by Formula II and a basic substance are added to organic solvent A, and a 3-nitrobenzoyl chloride solution is added dropwise at -20 to 0 °C. After the addition is complete, the reaction is carried out at 20 to 40 °C for 1 to 4 h. The resulting reaction solution A is purified and separated by A to obtain an intermediate represented by Formula III; the molar ratio of the compound represented by Formula II, the basic substance to 3-nitrobenzoyl chloride in the 3-nitrobenzoyl chloride solution is 1:1 - 3:1 - 1.5; S2: The intermediate represented by Formula III obtained in Step S1 is subjected to a reduction reaction at 20 to 40 °C for 12 to 16 h in a hydrogen atmosphere and in organic solvent B under the action of a Pd / C catalyst. The resulting reaction solution B is purified and separated by B to obtain a compound represented by Formula IV; the molar ratio of the intermediate represented by Formula III to Pd loaded on the Pd / C catalyst is 1:0.1 - 0.5; S3: The compound represented by Formula IV obtained in Step S2 and hydrochloric acid are added to water, and a sodium nitrite aqueous solution is added dropwise at -5 to 5 °C. After the addition is complete, the pH is adjusted to 5.5 - 6, and an aqueous solution containing potassium selenocyanate and sodium bicarbonate is added. The temperature is raised to 40 to 60 °C and the reaction is carried out for 0.5 - 1.5 h. The resulting reaction solution C is separated and purified by C to obtain an intermediate represented by Formula V; the molar ratio of HCl in the compound represented by Formula IV, hydrochloric acid, sodium nitrite in the sodium nitrite aqueous solution, potassium selenocyanate in the aqueous solution containing potassium selenocyanate and sodium bicarbonate to sodium bicarbonate in the aqueous solution containing potassium selenocyanate and sodium bicarbonate is 1:5 - 8:1 - 1.5:1 - 1.5:0.1 - 0.3; S4: The intermediate represented by Formula V obtained in Step S3 and the compound represented by Formula VI are stirred and reacted at 50 to 120 °C for 3 to 8 h in organic solvent C in the presence of a catalyst. The resulting reaction solution D is purified and separated by D to obtain a compound represented by Formula I; the catalyst is tris(pentafluorophenyl)borane or copper iodide; the molar ratio of the intermediate represented by Formula V, the compound represented by Formula VI to the catalyst is 1:1 - 1.5:0.001 - 0.1; Among them, R1 is selected from one of the following: H, halogen, Among them, Y is C1-C 10 alkyl, phenyl substituted by halogen or C1-C4 alkoxy, or -(CH2) n -N-(CH3)2, where n is an integer between 1 and 4; R2 is selected from one of the following: R3 is H or 5. The preparation method of the 3-(indol-3-ylseleno)benzamide compound according to claim 4, characterized in that: The organic solvent A in Step S1, the solvent of the 3-nitrobenzoyl chloride solution, the organic solvent B in Step S2, and the organic solvent C in Step S4 are each independently selected from one of the following or a mixture of two or more: benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether; The volume of the organic solvent A described in step S1 is 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula II; The concentration of the 3-nitrobenzoyl chloride solution described in step S1 is 0.5 - 2.5 mmol / mL; The basic substance described in step S1 is one or a mixture of two or more of pyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene, or diazabicycloundecene, sodium hydroxide, sodium ethoxide, trimethylamine, or triethylamine; The separation and purification A described in step S1 is as follows: The reaction solution A is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography using dichloromethane:methanol with a volume ratio of 200:1 as the eluent. The eluate containing the target compound is collected, and the solvent is evaporated to obtain the intermediate shown in formula III; The volume of the organic solvent B described in step S2 is 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula III; The active substance loading of the Pd / C catalyst described in step S2 is 3 - 10%; The separation and purification B described in step S2 is as follows: The reaction solution B is filtered through diatomaceous earth, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography using dichloromethane:methanol with a volume ratio of 120:1 as the eluent. The eluate containing the target compound is collected, and the solvent is evaporated to obtain the compound shown in formula IV; The concentration of the hydrochloric acid described in step S3 is 10 - 12 mol / L; The concentration of the aqueous sodium nitrite solution described in step S3 is 0.5 - 1 mol / L; In the aqueous solution containing potassium selenocyanate and sodium bicarbonate described in step S3, the concentration of potassium selenocyanate is 1 - 3 mol / L, and the concentration of the aqueous sodium bicarbonate solution is ​ ​ ​ ​ 6. The preparation method of the 3-(indole-3-selenyl)benzamide compounds as claimed in claim 1, wherein ​ (1) Methyl 3-aminobenzoate and hydrochloric acid are added to water. An aqueous solution of sodium nitrite is added dropwise at -5 to 5 °C. After the addition is complete, the pH is adjusted to 5.5 - 6. An aqueous solution containing potassium selenocyanate and sodium bicarbonate is added, and the temperature is raised to 40 - 60 °C for reaction for 0.5 - 1.5 hours. The obtained reaction solution E is separated and purified to obtain the intermediate shown in Formula VII; the molar ratio of methyl 3-aminobenzoate, HCl contained in hydrochloric acid, sodium nitrite contained in the aqueous solution of sodium nitrite, potassium selenocyanate in the aqueous solution containing potassium selenocyanate and sodium bicarbonate to sodium bicarbonate in the aqueous solution containing potassium selenocyanate and sodium bicarbonate is 1:5 - 8:1 - 1.5:1 - 1.5:0.1 - 0.3; (2) The intermediate shown in Formula VII and the compound shown in Formula VI in step (1) are stirred and reacted in organic solvent D in the presence of a catalyst at 50 - 100 °C for 3 - 8 h. The obtained reaction solution F is purified and separated to obtain the compound shown in Formula VIII; the catalyst is tris(pentafluorophenyl)borane or copper iodide; the molar ratio of the intermediate shown in Formula VII, the compound shown in Formula VI to the catalyst is 1:1 - 1.5:0.001 - 0.1; (3) The compound shown in Formula VIII in step (2) is stirred and an aqueous solution of a basic substance is added in organic solvent E, and the reaction is stirred at 20 - 40 °C for 4 - 8 h. The organic solvent is removed under reduced pressure, the pH is adjusted to 2 - 3, filtered, and the obtained filter cake is dried to obtain the compound shown in Formula IX; the molar ratio of the compound shown in Formula VIII to the basic substance in the aqueous solution of the basic substance is 1:50 - 60; (4) The compound shown in Formula IX and the compound shown in Formula II in step (3) are reacted in organic solvent F in the presence of a basic substance, a catalyst and a condensing agent at 20 - 40 °C for 1 - 4 h. The obtained reaction solution G is purified and separated to obtain the compound shown in Formula I; the catalyst is 4-dimethylaminopyridine; the condensing agent is one or a mixture of two or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate, triphenylphosphine-polyhalomethane, triphenylphosphine-hexachloroacetone, triphenylphosphine-NBS, 3-acyl-2-thiazoline; the molar ratio of the compound shown in Formula IX, the compound shown in Formula II, the basic substance, the catalyst to the condensing agent is 1:1 - 1.5:1 - 3:0.1:1 - 1.5; Among them, R1 is selected from one of the following: H, halogen, Among them, Y is C1-C 10 alkyl, phenyl substituted by halogen or C1-C4 alkoxy, or -(CH2) n -N-(CH3)2, where n is an integer between 1 and 4; R2 is selected from one of the following: R3 is H or 7. The preparation method of the 3-(indole-3-selenyl)benzamide compounds according to claim 6, characterized in that: The concentration of the hydrochloric acid in step (1) is 10 - 12 mol / L; The concentration of the aqueous solution of sodium nitrite in step (1) is 0.5 - 1 mol / L; In step (1), the pH is adjusted using a weak base, which is one or a mixture of two of sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide; In the aqueous solution containing potassium selenocyanate and sodium bicarbonate in step (1), the concentration of potassium selenocyanate is 1 - 3 mol / L, and the concentration of the sodium bicarbonate aqueous solution is 0.5 - 1 mol / L; In step (1), the volume of water is 1 - 5 mL / mmol based on the amount of substance of the compound shown in formula Ⅳ; The separation and purification in step (1) is as follows: The reaction solution E is extracted with dichloromethane, the organic layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent is removed under reduced pressure, and the obtained residue is subjected to silica gel column chromatography using dichloromethane: methanol with a volume ratio of 200:1 as the eluent, the eluate containing the target compound is collected, and the solvent is evaporated to obtain the intermediate shown in formula Ⅶ; The organic solvent D in step (2), the organic solvent E in step (3), and the organic solvent F in step (4) are each independently selected from one or a mixture of two or more of the following: benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, 1,2 - dichloroethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N - dimethylformamide, N,N - dimethylacetamide, N - methyl - formanilide, N - methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n - propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether; In step (2), the volume of the organic solvent D is 1 - 7 mL / mmol based on the amount of substance of the intermediate shown in formula Ⅶ; The separation and purification in step (2) is as follows: The reaction solution F is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography purification using petroleum ether: ethyl acetate with a volume ratio of 3:1 as the eluent, the eluate containing the target compound is collected, and the solvent is evaporated to obtain the compound shown in formula Ⅷ; In the aqueous solution of the basic substance in step (3), the basic substance is one or an aqueous solution of two or more of potassium hydroxide, lithium hydroxide, and sodium hydroxide; In step (3), the concentration of the aqueous solution of the basic substance is 1 - 3 mol / L; In step (3), the volume of the organic solvent E is 1 - 15 mL / mmol based on the amount of substance of the compound shown in formula Ⅷ; In step (4), the basic substance is one or a mixture of two or more of pyridine, N,N - diisopropylethylamine, N,N - dimethylaniline, N,N - dimethylbenzylamine, N - methylpiperidine, N - methylmorpholine, N,N - dimethylaminopyridine, diazabicyclooctane, diazabicyclononene, or diazabicycloundecene, sodium hydroxide, sodium ethoxide, trimethylamine, and triethylamine; In step (4), the volume of the organic solvent F is 1 - 15 mL / mmol based on the amount of substance of the intermediate shown in formula Ⅸ; The separation and purification in step (4) is as follows: The reaction solution G is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography using dichloromethane: methanol with a volume ratio of 150:1 as the eluent, the eluate containing the target compound is collected, and the solvent is evaporated to obtain the compound shown in formula Ⅰ.

8. Use of the 3-(indole-3-selenyl)benzamide compound according to any one of claims 1-3 in the preparation of a multi-drug resistance protein P-gp inhibitor.

9. Use of the 3-(indole-3-selenyl)benzamide compound according to any one of claims 1-3 in the preparation of a tumor multi-drug resistance reversing agent or a tumor metastasis inhibitor.

10. The application according to claim 9, wherein The tumor multi-drug resistance reversing agent or the tumor metastasis inhibitor comprises the 3-(indole-3-selenyl)benzamide compound and an anti-tumor drug; The anti-tumor drug is one or a mixture of two or more of an alkylating agent, an anti-metabolite, a topoisomerase inhibitor, a cell microtubule inhibitor, a DNA intercalator, and a lysine kinase inhibitor.

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