Method for stereoselectively synthesizing chiral triarylmethane thioether compound with antitumor biological activity

Abstract

The invention discloses a method for stereoselectively synthesizing a chiral triarylmethane thioether compound with antitumor biological activity, and relates to the technical field of medicine synthesis. According to the invention, a seven-membered ring system 3-indolyl [1, 4] sulfur azacycloheptane compound is used as a raw material, an asymmetric Friedel-Crafts alkylation reaction with nucleophilic indole is realized through a new strategy that a spiro chiral phosphonic acid catalyst catalyzes bond breaking of a carbon-nitrogen bond, a high-quality path is provided for synthesis of a chiral triarylmethane thioether compound, and the chiral triarylmethane thioether compound has a wide application prospect. Meanwhile, the reaction has the characteristics of easily available raw materials and mild conditions, and also has the technical advantages of high enantioselectivity and high atom economy. The chiral triarylmethane thioether compound provided by the invention has an obvious inhibition effect on the growth of human cervical cancer cells (HeLa), pancreatic cancer cells (Panc-1) and human bone marrow neuroblastoma cells (Sy5Y), shows good anti-tumor biological activity, and has important positive significance for promoting the research and development of anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for stereoselectively synthesizing chiral triarylmethane sulfide compounds with antitumor bioactivity. Background Technology

[0002] Chiral triarylmethane compounds are an important class of heterocyclic molecules with diverse biological activities and medicinal value. They possess structural properties such as anticancer, antibacterial, and antituberculosis activity, and are frequently developed as organic dyes, novel pH indicators, and fluorescent probes. Examples include vorozole, which inhibits aromatase activity, and sulfatase inhibitors. Furthermore, chiral triarylmethane sulfides contain diaryl sulfide structural units, which are also commonly found in many drug and pesticide molecules, exhibiting promising pharmacological effects in antitumor, antiviral, anti-inflammatory, and analgesic applications.

[0003] Currently, there are numerous reports on the synthesis of chiral triarylmethanes. Synthetic strategies mainly focus on asymmetric 1,4- or 1,6-conjugated addition reactions catalyzed by small organic molecules of quinone methylates, and intramolecular or intermolecular tandem cyclization reactions of functionalized reactants mediated by metal-chiral ligand catalytic systems. While these methods have advanced the construction of chiral triarylmethane compounds, no studies have yet achieved intramolecular fusion of chiral triarylmethanes with diaryl sulfide structural units, and research on the bioactivity of related compounds remains lacking.

[0004] Based on the core principles of combinatorial chemistry and compound structure modification, integrating two types of structural fragments with good biological activity into the same molecule can often synergistically enhance the pharmacological properties of the compound. Therefore, the synthesis of chiral triarylmethane sulfides has significant potential application value and is a research direction that urgently needs to be explored. However, existing technologies lack universal and efficient synthetic routes. How to develop highly atom-economical and highly stereoselective organic asymmetric catalytic systems based on readily available raw materials to achieve the precise synthesis of such compounds has become a key issue that urgently needs to be addressed in this field. Therefore, this invention aims to provide an efficient synthetic method to fill the gap in existing technologies. Summary of the Invention

[0005] The purpose of this invention is to provide a method for stereoselectively synthesizing chiral triarylmethane sulfide compounds with antitumor biological activity, so as to solve the problems existing in the prior art.

[0006] To achieve the above objectives, the present invention provides the following solution: One of the technical solutions of this invention is to provide a chiral triarylmethane sulfide compound with the following general structural formula: ; Among them, R 1 Selected from H, alkyl, or halogen; R 2 Selected from H, alkyl, or halogen; R 3 Selected from H or alkyl groups.

[0007] Furthermore, the chiral triarylmethane sulfide compound is selected from any one of the following structures: .

[0008] The second technical solution of the present invention provides a method for preparing the above-mentioned chiral triarylmethane sulfide compound, comprising the following steps: Using 3-indolyl[1,4]thiazocyclic heptane compounds and indole compounds as raw materials, the chiral triarylmethane sulfide compounds were obtained by reaction under the catalysis of a spirocyclic chiral phosphonic acid catalyst. This invention utilizes a spirocyclic chiral phosphonic acid catalyst to catalyze the carbon-nitrogen bond breaking of a seven-membered ring 3-indolyl[1,4]thiazocyclic heptane compound, thereby achieving an asymmetric Friedel-Crafts reaction with nucleophilic indole to obtain the chiral triarylmethane sulfide compound.

[0009] The structure of the 3-indolyl[1,4]thiazide-heptanane compound is as follows: ; The preparation method of the 3-indolyl[1,4]thiazide-heptanane compound includes the following steps: The nitrogen-sulfur heterocyclic compound and indole were mixed in a solvent, and trifluoroacetic acid was added. The 3-indolyl[1,4]sulfur-sulfur heterocyclic heptane compound was obtained by a second reaction. The structure of the nitrogen-sulfur heterocyclic compound is as follows: ; Among them, R 1 Selected from H, alkyl, or halogen; The structure of the indole compound is as follows: ; Among them, R 2 Selected from H, alkyl, or halogen; R 3 Selected from H or alkyl; The structure of the spirocyclic chiral phosphonic acid catalyst is as follows: .

[0010] Furthermore, the temperature of the first reaction is -10℃ to 0℃, and the time is 64-72h; the preferred reaction solvent is 1,2-dichloroethane.

[0011] Furthermore, the amount of the spirocyclic chiral phosphonic acid catalyst added is 10-15 mol of the molar amount of the 3-indolyl[1,4]thiazide-heptanane compound.

[0012] Furthermore, after the first reaction is completed, a column chromatography separation step is also included; the eluent used for the column chromatography separation is a mixture of petroleum ether and ethyl acetate.

[0013] Furthermore, the volume ratio of petroleum ether to ethyl acetate is 10:1 to 5:1.

[0014] Furthermore, the second reaction is carried out at room temperature for 2-5 hours.

[0015] The amount of trifluoroacetic acid added is 10-15 mol of the molar amount of the seven-membered ring nitrogen-sulfur heterocyclic compound.

[0016] The third technical solution of the present invention provides a pharmaceutical composition, wherein the active ingredient comprises the above-mentioned chiral triarylmethane sulfide compound.

[0017] Furthermore, in the pharmaceutical composition, the concentration of the chiral triarylmethane sulfide compound is 1.1 μmol / L-100 μmol / L.

[0018] The fourth technical solution of the present invention provides the application of the above-mentioned chiral triarylmethane sulfide compound or pharmaceutical composition in the preparation of antitumor drugs.

[0019] Furthermore, the tumors include human cervical cancer, pancreatic cancer, and / or neuroblastoma.

[0020] The present invention discloses the following technical effects: This invention innovatively uses a seven-membered ring system 3-indolyl[1,4]thioazine heptane compound as raw material and, through a novel strategy of carbon-nitrogen bond breaking catalyzed by spirocyclic chiral phosphonic acid, achieves for the first time the molecular fusion of chiral triarylmethane and diaryl sulfide structural units, filling a gap in the existing technology.

[0021] The chiral triarylmethane sulfide compounds provided by this invention have shown clear inhibitory effects on human cervical cancer cells (HeLa), pancreatic cancer cells (Panc-1), and human myeloid neuroblastoma cells (Sy5Y), providing novel active molecules for the development of anti-tumor drugs and having significant implications for advancement.

[0022] The reaction of this invention features readily available raw materials and mild conditions, while also exhibiting high enantioselectivity and high atom economy. The products can be efficiently separated by column chromatography, providing an excellent route for the large-scale preparation of this type of compound and showing broad application prospects. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 The 1H NMR spectrum of compound 3a (400 MHz, CDCl3); Figure 2 The carbon NMR spectrum of compound 3a (100 MHz, CDCl3); Figure 3 The 1H NMR spectrum (400 MHz, CDCl3) of compound 3b is shown. Figure 4 The carbon NMR spectrum of compound 3b (100 MHz, CDCl3); Figure 5 The 1H NMR spectrum of compound 3c (400 MHz, CDCl3); Figure 6 The image shows the carbon NMR spectrum of compound 3c (100 MHz, CDCl3). Figure 7 The 1H NMR spectrum of compound 3d (400 MHz, CDCl3); Figure 8 The image shows the carbon NMR spectrum of compound 3d (100 MHz, CDCl3); Figure 9 The NMR spectrum of compound 3d is shown (100 MHz, CDCl3). Figure 10 The 1H NMR spectrum of compound 3e (400 MHz, CDCl3); Figure 11 The image shows the carbon NMR spectrum of compound 3e (100 MHz, CDCl3); Figure 12 The 1H NMR spectrum of compound 3f (400 MHz, CDCl3); Figure 13 The image shows the carbon NMR spectrum of compound 3f (100 MHz, CDCl3). Figure 14 The 1H NMR spectrum (400 MHz, CDCl3) of 3g of compound is shown. Figure 15 The image shows the carbon NMR spectrum (100 MHz, CDCl3) of compound 3g. Figure 16The 1H NMR spectrum of compound 3h (400 MHz, CDCl3); Figure 17 The carbon NMR spectrum of compound 3h is shown (100 MHz, CDCl3). Figure 18 The 1H NMR spectrum (400 MHz, CDCl3) of compound 3i is shown. Figure 19 The carbon NMR spectrum (100 MHz, CDCl3) of compound 3i is shown below. Figure 20 The 1H NMR spectrum (400 MHz, CDCl3) of compound 3j is shown. Figure 21 The carbon NMR spectrum (100 MHz, CDCl3) of compound 3j is shown below. Figure 22 The 1H NMR spectrum (400 MHz, CDCl3) of compound 3k is shown. Figure 23 The carbon NMR spectrum of compound 3k (100 MHz, CDCl3); Figure 24 This is the high-performance liquid chromatography (HPLC) spectrum of the racemic mixture of compound 3a; Figure 25 The high-performance liquid chromatography (HPLC) spectrum of the chiral target product of compound 3a; Figure 26 This is the high-performance liquid chromatography (HPLC) spectrum of the racemic mixture of compound 3b. Figure 27 The high-performance liquid chromatography (HPLC) spectrum of the chiral target product of compound 3b; Figure 28 This is the high-performance liquid chromatography (HPLC) spectrum of the racemic 3c compound. Figure 29 The high-performance liquid chromatography (HPLC) spectrum of the 3C chiral target product of the compound; Figure 30 This is the high-performance liquid chromatography (HPLC) spectrum of the 3d racemic mixture of compound ; Figure 31 High-performance liquid chromatography (HPLC) spectrum of the 3d chiral target product of the compound; Figure 32 This is the high-performance liquid chromatography (HPLC) spectrum of the racemic mixture of compound 3e; Figure 33 The high-performance liquid chromatography (HPLC) spectrum of the target product of compound 3e chirality; Figure 34 This is the high-performance liquid chromatography (HPLC) spectrum of the racemic 3f compound. Figure 35 The high-performance liquid chromatography (HPLC) spectrum of the target product of compound 3f chirality; Figure 36Here is the high-performance liquid chromatography (HPLC) spectrum of 3g racemic mixture of compound; Figure 37 The high-performance liquid chromatography (HPLC) spectrum of 3g of the chiral target product of compound 3g; Figure 38 The high-performance liquid chromatography (HPLC) spectrum of the 3h racemic mixture of compound; Figure 39 The high-performance liquid chromatography (HPLC) spectrum of the chiral target product of compound 3h; Figure 40 The high-performance liquid chromatography (HPLC) spectrum of the racemic mixture of compound 3i; Figure 41 The high-performance liquid chromatography (HPLC) spectrum of the chiral target product of compound 3i; Figure 42 The high-performance liquid chromatography (HPLC) spectrum of the racemic mixture of compound 3j is shown. Figure 43 The high-performance liquid chromatography (HPLC) spectrum of the chiral target product of compound 3j; Figure 44 This is the high-performance liquid chromatography (HPLC) spectrum of the racemic mixture of compound 3k; Figure 45 The image shows the high-performance liquid chromatography (HPLC) spectrum of the target product of compound 3k. Detailed Implementation

[0025] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0026] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0027] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0028] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0029] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0030] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0031] In this invention, room temperature refers to 25-30℃.

[0032] In the following embodiments of the present invention, a chiral triarylmethane sulfide compound was obtained by reacting a seven-membered ring 3-indolyl[1,4]thiazide-heptanane compound and a substituted indole under the catalysis of a spirocyclic chiral phosphonic acid catalyst. Specifically, the synthetic route of the chiral triarylmethane sulfide compound is as follows: .

[0033] In the following embodiments of the present invention, readily available seven-membered ring 3-indolyl[1,4]thiazocyclic heptane compound 1 and substituted indole 2 were used as initial raw materials. A spirocyclic chiral phosphonic acid catalyst with a molar amount of 10 mol% of 3-indolyl[1,4]thiazocyclic heptane compound was added to dissolve the compound in 1,2-dichloroethane, and the reaction was carried out at 0°C for 72 hours to synthesize a series of novel chiral triarylmethane sulfide compounds 3.

[0034] The synthetic route for the 3-indolyl[1,4]thiazide ring heptane compound is as follows: ; Among them, R 1 Selected from H, alkyl, or halogen; In the following embodiments of the present invention, the 3-indolyl[1,4]thiazide-heptanane compound was prepared by the following steps: Different R 1A substituent seven-membered ring N-sulfur heterocyclic compound (5 mmol, 1.0 equivalent) and indole (11 mmol, 2.2 equivalent) were dissolved in tetrahydrofuran (THF, 20 mL). Then, 10 mol% trifluoroacetic acid of the seven-membered ring N-sulfur heterocyclic compound was added to the reaction mixture, and the mixture was stirred for 3 hours, monitored by thin-layer chromatography. After the seven-membered ring N-sulfur heterocyclic compound was consumed, the reaction mixture was extracted twice with ethyl acetate (EtOAc) and saturated sodium bicarbonate (NaHCO3) solution. The organic layers were combined, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated to obtain the residue, which was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to obtain different R... 1 Substituent-containing seven-membered ring 3-indolyl[1,4]thiazocycloheptanane compounds.

[0035] In the following embodiments of the present invention, the structure of the product chiral triarylmethane sulfide compound is as follows: Example 1 Synthesis of chiral triarylmethane sulfide compound 3a 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1 = H, 0.033 mmol, 11 mg) and substituted indole 2a (R 2 = H, R 3 Using Me (0.0363 mmol, 4.8 mg) as the initial raw material, 10 mol% of a spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide heptane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE). The reaction was carried out at 0 °C for 72 hours, and the reaction was monitored by TLC until the reaction of starting material 1a was complete. Subsequently, the reaction mixture was separated by column chromatography using a gradient eluent to obtain chiral triarylmethane sulfide compound 3a (pale yellow oil; 15 mg; yield 98%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0036] (S)-2-((2-((1H-indol-3-yl)(2-methyl-1H-indol-3-yl)methyl)phenyl)thio) aniline (3a) 1 H NMR (400 MHz, CDCl3): δ7.88 (br, 1H), 7.77 (br, 1H), 7.39–7.33 (m,2H), 7.28–7.25 (m, 2H), 7.24–7.23 (m, 1H), 7.19–7.14 (m, 3H), 7.05–6.97 (m,4H), 6.88–6.84 (m, 2H), 6.73–6.71 (m, 1H), 6.69–6.64 (m, 1H), 6.61 (s, 1H), 6.25 (s, 1H), 3.83 (br, 2H), 2.25 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 148.4,141.2, 137.3, 136.8, 135.8, 135.2, 132.6, 130.6, 129.6, 128.6, 127.2, 127.1,126.9, 125.3, 124.2, 122.0, 120.6, 119.9, 119.3, 119.1, 118.6, 115.5, 115.3,112.0, 111.1, 110.1, 37.4, 12.5;HRMS(ESI-TOF + ): m / z calcd for C 30 H 26 N3S + [(M + H) + ], 460.1842 found, 460.1843. 91% ee [HPLC condition: Chiralpak OD-H column, n -hexane / i -propanol = 75:25, flow rate = 0.9 mL / min, wavelength = 254 nm, t R =10.275 min (major), t R = 21.712 min (minor)]. [α] D 25 + 24.8 (c 1.0, CHCl3). Example 2 Synthesis of chiral triarylmethane sulfide compound 3b 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1= H, 0.033 mmol, 11 mg) and substituted indole 2b (R 2 = H, R 3 = Et, 0.0363 mmol, 5.4 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction was carried out at C for 72 hours, and the reaction was monitored by TLC until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography using a gradient elution of the eluent to obtain chiral triarylmethane sulfide compound 3b (light yellow oil; 15 mg; yield 95%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0037] (S)-2-((2-((2-ethyl-1H-indol-3-yl)(1H-indol-3-yl)methyl)phenyl)thio) aniline (3b) 1 H NMR (400 MHz, CDCl3): δ 7.83–7.87 (m, 2H), 7.29–7.32 (m, 2H), 7.19–7.23 (m, 3H), 7.07–7.11 (m, 3H), 6.90–6.99 (m, 4H), 6.76–6.79 (m, 2H), 6.59–6.66 (m, 3H), 6.22 (s, 1H), 3.79 (br, 2H), 2.59–2.75 (m, 2H), 1.06 (t, J = 7.6Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 148.4, 141.3, 138.1, 137.4, 136.8, 135.8,135.2, 130.6, 129.6, 128.5, 127.2, 127.0, 126.9, 125.3, 124.1, 122.0, 120.6,119.9, 119.5, 119.3, 119.1, 118.9, 118.5, 115.5, 115.3, 111.2, 111.0, 110.2,37.3, 19.8, 13.7;HRMS(ESI-TOF + ): m / z calcd for C 31 H 28 N3S + [(M + H)+ ], 474.1998found, 474.1996. 90% ee [HPLC condition: Chiralpak OD-H column, n -hexane / i -propanol = 75:25, flow rate = 0.9 mL / min, wavelength = 254 nm, t R = 8.778 min(major), t R = 13.207 min (minor)]. [α] D 25 +36.2 (c 1.0, CHCl3). Example 3 Synthesis of chiral triarylmethane sulfide compound 3c 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1 = H, 0.033 mmol, 11 mg) and substituted indole 2c (R 2 = 6-Me, R 3 = Me, 0.0363 mmol, 5.4 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction was carried out at C for 72 hours, and the reaction was monitored by TLC until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography with gradient elution of the eluent to obtain chiral triarylmethane sulfide compound 3c (pale yellow oil; 15.1 mg; yield 96%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0038] (S)-2-((2-((2,6-dimethyl-1H-indol-3-yl)(1H-indol-3-yl)methyl)phenyl) thio)aniline (3c) 1 H NMR (400 MHz, CDCl3): δ7.94 (br, 1H), 7.70 (s, 1H), 7.40–7.36 (m,2H), 7.28–7.25 (m, 2H), 7.19–7.15 (m, 2H), 7.08–7.06 (m, 2H), 7.01–6.97 (m,3H), 6.86–6.83 (m, 1H), 6.73–6.66 (m, 4H), 6.23 (s, 1H), 3.87 (br, 2H), 2.39 (s, 3H), 2.26 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 148.4, 141.3, 137.4, 136.8,135.8, 135.6, 131.8, 130.6, 130.3, 129.6, 127.1, 126.9, 126.4, 125.3, 124.1,122.0, 120.7, 119.9, 119.3, 119.0, 118.7, 118.5, 115.6, 115.3, 111.8, 111.0,110.1, 37.4, 21.6, 12.4;HRMS(ESI-TOF + ): m / z calcd for C 31 H 28 N3S + [(M + H) + ],474.1998 found, 474.1999. 93% ee [HPLC condition: Chiralpak OD-H column, n -hexane / i -propanol = 75:25, flow rate = 0.9 mL / min, wavelength = 254 nm, t R =9.355 min (major), t R = 25.015 min (minor)]. [α] D 25 +25.9 (c 1.0, CHCl3). Example 4 Synthesis of chiral triarylmethane sulfide compound 3d 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1= H, 0.033 mmol, 11 mg) and substituted indole 2d (R 2 = 4-F, 5-OMe, R 3 = Me, 0.0363 mmol, 6.5 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction was carried out at C for 72 hours, and the reaction was monitored by TLC until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography with gradient elution of the eluent to obtain chiral triarylmethane sulfide compound 3d (light yellow oil; 15.7 mg; yield 93%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0039] (S)-2-((2-((4-fluoro-5-methoxy-2-methyl-1H-indol-3-yl)(1H-indol-3-yl) methyl)phenyl)thio)aniline (3d) 1 H NMR (400 MHz, CDCl3): δ 7.92 (br, 1H), 7.62 (br, 1H), 7.41–7.38 (m,1H), 7.35–7.33 (m, 2H), 7.25 (s, 3H), 7.19–7.12 (m, 3H), 7.03–6.93 (m, 2H), 6.90–6.88 (m, 1H), 6.84–6.67 (m, 3H), 6.53 (s,1H), 3.84 (s, 5H), 1.84 (s,3H); 13 C NMR (100 MHz, CDCl3): δ 148.6, 145.2, 141.5, 140.4, 140.3, 137.6, 136.8, 136.2, 134.3, 132.7, 132.6, 130.6, 129.2, 127.4, 127.0, 126.8, 125.2, 123.7, 122.0, 119.8, 119.3, 119.0, 118.4, 115.7, 115.3, 111.0, 110.9, 110.7, 105.1, 58.7, 37.7, 12.8; 19 F NMR (376 MHz, CDCl3): δ -144.6;HRMS(ESI-TOF + ): m / z calcd forC31 H 27 FN3OS + [(M + H) + ], 508.1853 found, 508.1855. 87% ee [HPLC condition: Chiralpak OD-H column, n -hexane / i -propanol = 75:25, flow rate = 0.9 mL / min, wavelength = 254 nm, t R = 10.526 min (major), t R = 16.540 min (minor)]. [α] D 25 +33.4 (c 1.0, CHCl3). Example 5 Synthesis of chiral triarylmethane sulfide compound 3e 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1 = H, 0.033 mmol, 11 mg) and substituted indole 2e (R 2 = 6-Cl, R 3 = Me, 0.0363 mmol, 6.0 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction was carried out at C for 72 hours, and the reaction was monitored by TLC until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography with gradient elution of the eluent to obtain chiral triarylmethane sulfide compound 3e (pale yellow oil; 15.3 mg; yield 93%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0040] (S)-2-((2-((6-chloro-2-methyl-1H-indol-3-yl)(1H-indol-3-yl)methyl) phenyl)thio)aniline (3e) 1 H NMR (400 MHz, CDCl3): δ7.97 (br, 1H), 7.83 (br, 1H), 7.38–7.36 (m,2H), 7.26–7.16 (m, 5H), 7.04–6.98 (m, 4H), 6.86–6.80 (m, 2H), 6.74–6.67 (m,2H), 6.61 (s, 1H), 6.21 (s, 1H), 3.87 (br, 2H), 2.26 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 148.4, 140.9, 137.3, 136.8, 135.8, 135.5, 133.4, 130.7, 129.7, 129.5,127.1, 126.4, 125.4, 124.0, 122.1, 120.1, 119.8, 119.4, 118.7, 118.3, 115.4,115.3, 112.2, 111.2, 110.1, 37.3, 12.4;HRMS(ESI-TOF + ): m / z calcd for C 30 H 25 ClN3S + [(M + H) + ], 494.1452 found, 494.1454. 94% ee [HPLC condition: Chiralpak OD-Hcolumn, n -hexane / i -propanol = 75:25, flow rate = 0.9 mL / min, wavelength = 254nm, t R = 9.594 min (major), t R = 23.727 min (minor)]. [α] D 25 +11.8 (c 1.0, CHCl3). Example 6 Synthesis of chiral triarylmethane sulfide compound 3f 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1 = H, 0.033 mmol, 11 mg) and substituted indole 2f (R 2 = 6-Br, R 3= Me, 0.0363 mmol, 7.6 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction was carried out at C for 72 hours, and the reaction was monitored by TLC until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography using a gradient elution of the eluent to obtain chiral triarylmethane sulfide compound 3f (pale yellow oil; 17 mg; yield 95%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0041] (S)-2-((2-((6-bromo-2-methyl-1H-indol-3-yl)(1H-indol-3-yl)methyl) phenyl)thio)aniline (3f) 1 H NMR (400 MHz, CDCl3): δ 7.93 (br, 1H), 7.78 (s, 1H), 7.37–7.34 (m,3H), 7.26–7.15 (m, 4H), 7.04–6.92 (m, 5H), 6.86–6.84 (m, 1H), 6.73–6.67 (m,2H), 6.60–6.59 (m, 1H), 6.21 (s, 1H), 3.86 (br, 2H), 2.23 (s, 3H); 13 C NMR (100MHz, CDCl3): δ 148.4, 140.9, 137.3, 136.8, 136.0, 135.8, 133.4, 130.7, 129.5,127.4, 127.1, 125.4, 124.0, 122.4, 122.1, 120.5, 119.8, 119.4, 118.7, 118.3,115.4, 114.1, 113.0, 112.3, 111.2, 37.3, 12.4;HRMS(ESI-TOF + ): m / z calcd forC 30 H 24 BrN3NaS + [(M + Na) + ], 560.0767 found, 560.0766. 90% ee [HPLC condition: Chiralpak OD-H column, n -hexane / i -propanol = 75:25, flow rate = 0.9 mL / min, wavelength = 254 nm, t R = 9.413 min (major), t R = 22.906 min (minor)]. [α] D 25 +15.2 (c 1.0, CHCl3). Example 7 Synthesis of 3g of chiral triarylmethane sulfide compound 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1 = H, 0.033 mmol, 11 mg) and substituted indole 2g (R 2 = 4-Me, R 3 = H, 0.0363 mmol, 4.8 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction was carried out at C for approximately 72 hours, monitored by TLC, until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography using a gradient eluent to obtain 3 g of chiral triarylmethane sulfide compound (pale yellow oil; 14.5 mg; yield 95%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0042] (S)-2-((2-((1H-indol-3-yl)(4-methyl-1H-indol-3-yl)methyl)phenyl)thio) aniline (3g) 1 H NMR (400 MHz, CDCl3): δ 7.89 (br, 2H), 7.43–7.38 (m, 3H), 7.25 (s,3H), 7.20–7.16 (m, 5H), 7.08–6.97 (m, 1H), 6.88–6.86 (m, 1H), 6.81–6.79 (m,2H), 6.74–6.68 (m, 1H), 6.53–6.49 (m, 2H), 4.00 (br, 2H), 2.50 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ148.6, 142.4, 137.6, 137.2, 136.8, 135.5, 131.6, 130.8,129.1, 126.9, 126.8, 125.9, 125.4, 124.4, 122.1, 122.0, 119.9, 119.5, 119.4,118.7, 115.3, 115.1, 111.1, 109.0, 38.2, 19.8;HRMS(ESI-TOF + ): m / z calcd forC 30 H 26 N3S + [(M + H) + ], 460.1842 found, 460.1843. 82% ee [HPLC condition: ChiralpakOD-H column, n -hexane / i -propanol = 75:25, flow rate = 1.0 mL / min,, wavelength= 254 nm, t R = 10.385 min (minor), t R = 12.193 min (major)]. [α] D 25 44.0 (c 1.0, CHCl3). Example 8 Synthesis of chiral triarylmethane sulfide compound 3h 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1 = H, 0.033 mmol, 11 mg) and substituted indole 2h (R 2 = 6-Me, R 3 = H, 0.0363 mmol, 4.8 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction mixture was subjected to a reaction at C for 72 hours, and TLC monitoring was performed until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography using a gradient eluent to obtain a chiral triarylmethane sulfide compound 3h (a light yellow oil; 14 mg; yield 92%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0043] (S)-2-((2-((1H-indol-3-yl)(6-methyl-1H-indol-3-yl)methyl)phenyl)thio) aniline (3h) 1 H NMR (400 MHz, CDCl3): δ 7.88 (br, 1H), 7.78 (br, 1H), 7.42–7.40 (m,2H), 7.35–7.26 (m, 3H), 7.19–9.14 (m, 4H), 7.03–6.98 (m, 3H), 6.93–6.91 (m,1H), 6.86–6.84 (m, 1H), 6.75–6.68 (m, 2H), 6.64–6.63 (m, 1H), 6.56–6.55 (m,1H), 6.42 (s, 1H), 4.04 (br, 1H), 2.44 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 148.5, 141.8, 137.4, 136.7, 135.5, 131.8, 130.6, 129.2, 127.3, 127.1, 127.0,126.9, 125.7, 125.0, 124.0, 123.4, 122.0, 121.1, 120.0, 119.6, 119.3, 118.8,118.7, 118.6, 115.6, 115.4, 111.1, 37.1, 21.8;HRMS(ESI-TOF + ): m / z calcd forC 30 H 26 N3S + [(M + H) + ], 460.1842 found, 460.1843. 87% ee [HPLC condition: ChiralpakOD-H column, n -hexane / i -propanol = 85:15, flow rate = 0.9 mL / min, wavelength =254 nm, t R = 12.550 min (major), t R = 14.917 min (minor)]. [α] D 25+21.3 (c 1.0, CHCl3). Example 9 Synthesis of chiral triarylmethane sulfide compound 3i 1b(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1 = 4'-Me, 0.033 mmol, 11.3 mg) and substituted indole 2a (R 2 = H, R 3 = Me, 0.0363 mmol, 4.8 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction was carried out at C for 72 hours, and the reaction was monitored by TLC until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography using a gradient eluent to obtain chiral triarylmethane sulfide compound 3i (light yellow oil; 14.9 mg; yield 95%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0044] (S)-2-((2-((1H-indol-3-yl)(2-methyl-1H-indol-3-yl)methyl)-4- methylphenyl)thio)aniline (3i) 1 H NMR (400 MHz, CDCl3): δ 7.92 (br, 1H), 7.79 (s, 1H), 7.37–7.35 (m,2H), 7.29–7.25 (m, 2H), 7.22–7.14 (m, 3H), 7.12–1.09 (m, 1H), 7.06–7.04 (m,1H), 7.02–6.97 (m, 1H), 6.89–6.84 (m, 2H), 6.81–6.79 (m, 1H), 6.71–6.69 (m,1H), 6.68–6.64 (m, 2H), 6.27 (s, 1H), 3.86 (br, 2H), 2.24 (s, 3H), 2.13 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ148.1, 141.5, 136.8, 135.2, 135.1, 132.5, 132.1,130.2, 128.6, 127.9, 127.8, 127.3, 124.0, 121.9, 120.6, 119.9, 119.3, 119.1,118.8, 118.5, 116.4, 115.3, 112.2, 111.0, 110.0, 37.3, 21.3, 12.5;HRMS (ESI-TOF + ): m / z calcd for C 31 H 28 N3S + [(M + H) + ], 474.1998 found, 474.2002. 96% ee [HPLCcondition: Chiralpak OD-H column, n -hexane / i -propanol = 75:25, flow rate = 1.0mL / min, wavelength = 254 nm, t R = 8.428 min (major), t R = 19.708 min (minor)].[α] D 25 +22.3 (c 1.0, CHCl3). Example 10 Synthesis of chiral triarylmethane sulfide compound 3j 1c(R) of seven-membered ring 3-indolyl[1,4]thiazide-heptanane compounds 1 = 4'-Br, 0.033 mmol, 13.4 mg) and substituted indole 2a (R 2 = H, R 3 = Me, 0.0363 mmol, 4.8 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. oThe reaction was carried out at C for 72 hours, and the reaction was monitored by TLC until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography with gradient elution of the eluent to obtain chiral triarylmethane sulfide compound 3j (light yellow oil; 16.6 mg; yield 93%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0045] (S)-2-((2-((1H-indol-3-yl)(2-methyl-1H-indol-3-yl)methyl)-4- bromophenyl)thio)aniline (3j) 1 H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.85 (s, 1H), 7.39–7.36 (m,3H), 7.29–7.12 (m, 4H), 7.09–7.00 (m, 2H), 6.94–6.90 (m, 1H), 6.74–6.66 (m,4H), 6.23 (m, 1H), 3.86 (br, 1H), 2.24 (s, 3H), 1.58 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 148.4, 143.3, 137.4, 136.8, 135.4, 135.1, 132.8, 132.1, 131.0, 130.0,128.5, 128.3, 127.0, 124.1, 122.2, 120.8, 119.6, 119.5, 119.4, 119.0, 118.7,117.8, 115.4, 114.6, 111.3, 111.2, 110.2, 37.0, 12.5;HRMS(ESI-TOF + ): m / z calcdfor C 30 H 25 BrN3S + [(M + H) + ], 538.0947 found, 538.0949. 85% ee [HPLC condition: Chiralpak OD-H column, n -hexane / i -propanol = 75:25, flow rate = 1.0 mL / min, wavelength = 254 nm, t R = 8.663 min (major), t R= 19.405 min (minor)]. [α] D 25 +16.2 (c 1.0, CHCl3). Example 11 Synthesis of chiral triarylmethane sulfide compound 3k 1a(R) of a seven-membered ring system 3-indolyl[1,4]thiazide-heptanane compound 1 = H, 0.033 mmol, 11 mg) and substituted indole 2i (R 2 = 5- , R 3 = Me, 0.0363 mmol, 16.2 mg) as the initial raw material, 10 mol% of spirocyclic chiral phosphonic acid catalyst (2.8 mg) of 3-indolyl[1,4]thiazide-heptanane compound 1a was dissolved in 0.3 mL of 1,2-dichloroethane (DCE), and the solution was heated at 0°C. o The reaction was carried out at C for 72 hours, and the reaction was monitored by TLC until the reactant 1a was completely reacted. Subsequently, the reaction mixture was separated by column chromatography using a gradient eluent to obtain chiral triarylmethane sulfide compound 3k (pale yellow oil; 20.6 mg; yield 80%). The eluent used was a mixture of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1).

[0046] (S)-3-((2-((2-aminophenyl)thio)phenyl)(1H-indol-3-yl)methyl)-2- methyl-1H-indol-5-yl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate (3k) 1 H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.95 (s, 1H), 7.73–7.65 (m,4H), 7.40–7.21 (m, 5H), 7.16–7.09 (m, 4H), 6.96–6.79 (m, 5H), 6.70–6.62 (m,5H), 6.49–6.48 (m, 1H), 6.17 (s, 1H), 3.85 (br, 2H), 2.24 (s, 3H), 1.75 (m,6H); 13 C NMR (100 MHz, CDCl3): δ 194.8, 173.2, 159.6, 148.5, 143.4, 141.0, 138.6, 137.2, 136.8, 136.2, 135.8, 134.4, 133.2, 132.2, 131.3, 130.7, 130.2, 129.4, 128.8, 128.6, 127.1, 127.0, 126.9, 125.2, 124.0, 121.9, 119.6, 119.2, 118.5, 117.9, 117.1, 115.4, 115.1, 113.8, 112.5, 111.2, 110.9, 110.5, 37.2, 25.4,12.4;HRMS(ESI-TOF + ): m / z calcd for C 47 H 39 ClN3SO4 + [(M + H) + ], 776.2344 found,776.2347. 87% de [HPLC condition: Chiralpak AD-H column, n -hexane / i -propanol =75:25, flow rate = 1.0 mL / min, wavelength = 254 nm, t R = 18.480 min (major), t R = 47.454 min (minor)]. [α] D 25 +13.8 (c 1.0, CHCl3). The compounds prepared in the embodiments of the present invention were subjected to antitumor bioactivity testing and analysis: The inhibitory effects of target compounds with concentrations ranging from 0 to 100 μmol / L on the growth of human cervical cancer cells (HeLa), pancreatic cancer cells (Panc-1), and human myeloma cells (Sy5y) were detected using the MTT assay. The specific steps are as follows: 1. Cell culture preparation: Cells were cultured using Duchenne modified Eagle medium (DMEM medium), which contains 5% glutamine, 5% penicillin / streptomycin solution and 10% fetal bovine serum. Cells were seeded at a density of 7 × 10³ cells / well in 96-well plates and incubated overnight in an incubator containing 5% CO2 at 37°C.

[0047] 2. Sample and control treatment: The next day, 1 μL of different concentrations of the compound (stock solution concentrations of 10 μmol / L, 3.3 μmol / L, 1.1 μmol / L, 0.33 μmol / L, and 0.11 μmol / L) were added to each well to bring the final concentrations of the compound in the wells to 100 μmol / L, 33 μmol / L, 11 μmol / L, 3.3 μmol / L, and 1.1 μmol / L, respectively. Positive control (cisplatin) and blank control (adding an equal volume of dimethyl sulfoxide (DMSO)) were set up, and each treatment group had 3 replicates.

[0048] 3. MTT reaction and detection: After culturing for another 48 hours, 20 μL of 5 mg / mL MTT solution was added to each well, and the cells were cultured for another 4 hours. Then the culture medium was removed, 150 μL of DMSO was added, and the cells were shaken on a low speed shaker for 10 minutes until the purple crystals were fully dissolved. The absorbance of each well was measured at a wavelength of 570 nm to assess cell viability and metabolic status. The experiment was repeated three times.

[0049] 4. Data Analysis: Let AC represent the absorbance of the control group and AS represent the absorbance of the test sample. SPSS 26 software was used for data analysis, and the growth inhibition rate of the compound against cancer cells was calculated using the following formula: Inhibition rate (%) = (AC-AS) / AC×100%.

[0050] The inhibition rate data are shown in Table 1.

[0051] Table 1 The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A chiral triarylmethane sulfide compound, characterized in that, The general structural formula is as follows: ； Among them, R 1 Selected from H, alkyl, or halogen; R 2 Selected from H, alkyl, or halogen; R 3 Selected from H or alkyl groups.

2. The chiral triarylmethane sulfide compound according to claim 1, characterized in that, Choose any one of the following structures: 。 3. The method for preparing the chiral triarylmethane sulfide compound according to any one of claims 1-2, characterized in that, Includes the following steps: Using 3-indolyl[1,4]thiazocyclic heptane compounds and indole compounds as raw materials, the chiral triarylmethane sulfide compounds were obtained through a first reaction under the catalysis of a spirocyclic chiral phosphonic acid catalyst. The structure of the 3-indolyl[1,4]thiazide-heptanane compound is as follows: ； The preparation method of the 3-indolyl[1,4]thiazide-heptanane compound includes the following steps: The nitrogen-sulfur heterocyclic compound and indole were mixed in a solvent, and trifluoroacetic acid was added. The 3-indolyl[1,4]sulfur-sulfur heterocyclic heptane compound was obtained by a second reaction. The structure of the nitrogen-sulfur heterocyclic compound is as follows: ； Among them, R 1 Selected from H, alkyl, or halogen; The structure of the indole compound is as follows: ； Among them, R 2 Selected from H, alkyl, or halogen; R 3 Selected from H or alkyl; The structure of the spirocyclic chiral phosphonic acid catalyst is as follows: 。 4. The preparation method according to claim 3, characterized in that, The temperature of the first reaction is -10℃ to 0℃, and the time is 64-72h; the temperature of the second reaction is room temperature, and the time is 2-5h.

5. The preparation method according to claim 3, characterized in that, The amount of the spirocyclic chiral phosphonic acid catalyst added is 10-15 mol of the molar amount of the 3-indolyl[1,4]thiazide-heptanane compound.

6. The preparation method according to claim 3, characterized in that, After the first reaction is completed, a column chromatography separation step is also included; the eluent used for the column chromatography separation is a mixture of petroleum ether and ethyl acetate.

7. A pharmaceutical composition, characterized in that, The active ingredient includes the chiral triarylmethane sulfide compound as described in any one of claims 1-2.

8. The pharmaceutical composition according to claim 7, characterized in that, In the pharmaceutical composition, the concentration of the chiral triarylmethane sulfide compound is 1.1 μmol / L-100 μmol / L.

9. The use of the chiral triarylmethane sulfide compound according to any one of claims 1-2 or the pharmaceutical composition according to claim 7 in the preparation of a therapeutic antitumor drug.

10. The application according to claim 9, characterized in that, The tumors include human cervical cancer, pancreatic cancer, and / or neuroblastoma.

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