Antitumor applications of a class of fluorine-containing indole compounds

Abstract

The application discloses antitumor application of a fluorine-containing indole compound. The fluorine-containing indole compound has the following structure, wherein R1, R2 and R3 are independently halogen, -CN, -NO2, C 1‑6 alkyl, C 1‑6 alkoxy, C 1‑6 haloalkyl, C 1‑6 acyl. The compound has significant cytotoxic activity on human tumor cells selected from any one or more of human leukemia HL-60 cells, human lung cancer A549 cells, human hepatoma SMMC-7721 cells, human breast cancer MDA-MB-231 cells and human colon cancer SW480 cells.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a class of fluorinated indole compounds, their preparation methods and anti-tumor applications, and particularly to the in vitro cytotoxic activity of the compounds against various tumor cells and their application in the preparation of anti-tumor drugs. Background Technology

[0002] Malignant tumors are a major disease that seriously threatens human health, with their incidence and mortality rates rising year by year, making them a major public health problem worldwide. Currently, most clinically used anti-tumor drugs have drawbacks such as poor targeting, significant toxic side effects, and easy development of drug resistance. Therefore, the development of novel, highly effective, and low-toxicity anti-tumor active compounds has become an urgent need in the field of pharmaceutical research and development.

[0003] Unrestricted proliferation of tumor cells is one of the core characteristics of malignant tumors. Currently, inducing tumor cell death and inhibiting tumor cell proliferation through drugs is one of the core strategies in anti-tumor drug development. The MTS method is a cell activity assay based on the activity of mitochondrial succinate dehydrogenase in live cells. It can accurately quantify the inhibitory effect of drugs on tumor cell proliferation and is a commonly used technique for in vitro screening of anti-tumor active compounds.

[0004] Currently, the antitumor activity of 3a-fluorofurano[3,2-b]dihydroindole compounds has not been disclosed in existing technologies (Org. Lett. 2023, 25, 8666-8671), nor has their in vitro cytotoxic effect on leukemia, lung cancer, liver cancer, breast cancer, and colon cancer cells been disclosed. Developing the antitumor pharmaceutical applications of these compounds could provide new drug options for clinical antitumor treatment. Summary of the Invention

[0005] Technical problems to be solved

[0006] The purpose of this invention is to provide a compound or a pharmaceutically acceptable salt thereof with significant antitumor cytotoxic activity, and its application in the preparation of antitumor drugs, thereby solving the technical problems of insufficient activity, poor targeting, and large toxic side effects of existing antitumor drugs.

[0007] Technical solution

[0008] To achieve the above objectives, the present invention provides an active compound of compound I that significantly inhibits the proliferation of tumor cells, or a pharmaceutically acceptable salt thereof, the general structural formula of which is as follows:

[0009] Ⅰ

[0010] R1, R2, and R3 are independently halogens, -CN, -NO2, and C, respectively.1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Acyl group; preferably methyl, methoxy, trifluoromethyl, fluorine, chlorine, or bromine;

[0011] To facilitate understanding of this invention, the following specific compounds are preferred as examples of compounds with general structural formulas, as shown in Table 1:

[0012] Table 1.

[0013] The aforementioned 3a-fluorofurano[3,2-b] dihydroindole compounds, wherein the salts include hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonate, or methanesulfonate.

[0014] The aforementioned 3a-fluorofurano[3,2-b] dihydroindole compounds or pharmaceutically acceptable salts thereof, wherein the compounds exhibit significant cytotoxic activity against human tumor cells, the human tumor cells being selected from any one or more of human leukemia HL-60 cells, human lung cancer A549 cells, human liver cancer SMMC-7721 cells, human breast cancer MDA-MB-231 cells, and human colon cancer SW480 cells.

[0015] On the other hand, the present invention provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs.

[0016] Furthermore, the tumor cells are selected from any one or more of leukemia, lung cancer, liver cancer, breast cancer, and colon cancer.

[0017] Furthermore, the drug is a drug that inhibits the proliferation of tumor cells, and the tumor cells are selected from any one or more of human leukemia HL-60 cells, human lung cancer A549 cells, human liver cancer SMMC-7721 cells, human breast cancer MDA-MB-231 cells, and human colon cancer SW480 cells.

[0018] Secondly, the present invention can be used to provide an antitumor pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0019] Furthermore, the dosage form of the pharmaceutical composition is any one of injection, tablet, capsule, granule, oral liquid, liposome, and nanoparticle.

[0020] In addition, the present invention provides a method for treating malignant tumors, comprising administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, to a subject in need.

[0021] Furthermore, the malignant tumor is selected from any one or more of leukemia, lung cancer, liver cancer, breast cancer, and colon cancer.

[0022] Furthermore, the administration method is any one of oral, intravenous, intramuscular, intraperitoneal, subcutaneous, or local administration. Beneficial effects

[0023] The beneficial effects of this invention are as follows:

[0024] 1. This invention is the first to discover that 3a-fluorofurano[3,2-b]dihydroindole compounds have significant in vitro cytotoxic activity against human leukemia HL-60 cells, human lung cancer A549 cells, human liver cancer SMMC-7721 cells, human breast cancer MDA-MB-231 cells, and human colon cancer SW480 cells. They can effectively inhibit tumor cell proliferation, with IC50 values ​​reaching 13~22μM, demonstrating excellent antitumor activity.

[0025] 2. The compounds described in this invention can be used to prepare drugs for treating various malignant tumors such as leukemia, lung cancer, liver cancer, breast cancer, and colon cancer, providing new drug candidates for clinical anti-tumor treatment and possessing good development prospects and clinical application value.

[0026] 3. The compounds of the present invention can be prepared into various dosage forms with pharmaceutically acceptable carriers to meet different clinical administration needs and have a wide range of applications. Attached Figure Description

[0027] Figure 1 This is the general chemical structural formula of the present invention;

[0028] Figure 2 This is a bar graph showing the single-concentration screening of the in vitro antitumor cytotoxic activity of the present invention (using the MTS method as the detection method, with compounds initially screened at a concentration of 40 μM).

[0029] Figure 3 The results of the single-concentration screening of cisplatin (DDP) and taxol (Taxol) for the in vitro antitumor cytotoxic activity of the present invention are shown (using the MTS method as the detection method, the compounds were initially screened at a concentration of 40 μM).

[0030] Figure 4This report presents the results of the in vitro antitumor cytotoxic activity rescreening report for the positive control compound cisplatin (DDP) and the graded rescreening results for paclitaxel (Taxol) (using the MTS method as the detection method, with compounds rescreened at concentrations of 40 μM, 8 μM, 1.6 μM, 0.32 μM, and 0.064 μM). Detailed Implementation

[0031] The technical solution of the present invention will be described in detail below with reference to specific embodiments. The following embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0032] Example 1: A general method for preparing compounds

[0033] The raw material 3,3-difluoro-2-phenyl-3H-indole (0.05 mmol) and 1-naphthol (0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-triisopropylphenyl]dinaphtho[2,1-d:1′,2′-f]-1,3,2-dioxaphosphepine 4-oxide (2s,4R,11bS)-4-hydroxy-2,6-bis(2,4,6-triisopropylphenyl)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine 4-oxide 0.005 mmol of Silica gel and 0.05 mmol of Silica gel were added sequentially to 0.5 mL of toluene solution, and the reaction was carried out at 60 °C under nitrogen protection for two days to obtain the corresponding compound. .

[0034] Example 2: Specific characterization data of the corresponding compounds

[0035]

[0036] MT-1 (YNMD18) (6bS,11bR)-11b-fluoro-6b-(o-tolyl)-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-1 (YNMD18) is a yellow oily substance obtained by reacting 3,3-difluoro-2-(m-tolyl)-3H-indole (12.6 mg, 0.05 mmol) with 1-naphthol (14.4 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) in 0.5 mL of toluene solution at 60 °C for two days under nitrogen protection. The yield was 90% (17 mg), and the stereoselectivity was 92%.

[0037] 1 H NMR (400 MHz, CDCl3) δ 8.07 – 8.05 (m, 1H), 7.88 – 7.79 (m, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.55 – 7.47 (m, 3H), 7.28 – 7.20 (m, 3H), 7.18 –7.09 (m, 3H), 6.88 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.72 (s,1H), 2.28 (s, 3H).

[0038] 13 C NMR (101 MHz, CDCl3) δ 154.6, 150.7 (d, J = 7.0 Hz), 138.0, 137.1, (d, J = 7.0 Hz), 134.9, 132.1, 129.2, 128.5, 128.3 (d, J = 241.0 Hz), 128.2,127.9, 127.0, 126.1, 125.1, 125.0, 123.5, 122.8, 122.7, 122.2 (d, J = 26.0Hz), 121.7, 120.5, 120.0, ,111.0, 78.9 (d, J = 21.0 Hz), 21.5.

[0039] 19 F NMR (376 MHz, CDCl3) δ -102.5.

[0040] HRMS (ESI) m / z calcd. for C 25 H 19 FNO (M+H)+ : 368.1445, found 368.1437.

[0041] Enantiomeric excess is 92% determined by HPLC (Chiralpak AS-H, Hexane / Isopropanol 95 / 5, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =12.69 min; minor isomer: tr = 9.63 min.

[0042] [α] 20 D = -106 (c = 0.3, CHCl3).

[0043]

[0044] MT-2 (YNMD19) (6bS,11bR)-11b-fluoro-6b-(3-fluorophenyl)-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-2 (YNMD19) is a yellow oily substance obtained by reacting 3,3-difluoro-2-(3-fluorophenyl)-3H-indole (12.4 mg, 0.05 mmol) with 1-naphthol (14.4 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine-4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) in 0.5 mL of toluene solution at 60 °C under nitrogen protection for two days. The yield was 92% (17.2 mg), and the stereoselectivity was 94%. 1H NMR (400 MHz, CDCl3) δ 8.07 – 8.04 (m, 1H), 7.83 – 7.81 (m, 1H),7.58 (d, J = 7.6 Hz, 1H), 7.54 – 7.46 (m, 3H), 7.29 – 7.24 (m, 2H), 7.21 –7.18 (m, 1H), 7.15 – 7.08 (m, 2H), 7.02 – 6.97 (m, 1H), 6.89 (t, J = 7.5 Hz,1H), 6.78 (d, J = 8.0 Hz, 1H), 4.72 (s, 1H)。

[0045] 13 C NMR (100 MHz, CDCl3) δ 164.1, 161.6, 154.7, 150.3 (d, J = 7.0 Hz),140.1 (t, J = 7.0 Hz), 135.0, 129.8, 129.7, 129.6 (t, J = 7.0 Hz), 128.0,127.2, 126.3, 125.0, 123.7 (d, J = 3.0 Hz), 123.1, 122.4(d, J = 31.0 Hz),122.2, 122.1,121.7 (d, J = 250.0 Hz) 121.3, 120.5, 120.32, 120.31,115.2 (dd,J = 21.0 Hz, 5.0 Hz) , 111.2, 78.3 (dd, J = 22.0 Hz, 2.0 Hz)。

[0046] 19 F NMR (376 MHz, CDCl3) δ -103.0, -112.7。

[0047] HRMS (ESI) m / z calcd. for C 24 H 16 F2NO (M+H) + :372.1200, found 372.1205。

[0048] Enantiomeric excess is 94% determined by HPLC (Chiralpak AS-H, Hexane / Isopropanol 98 / 2, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =22.54 min; minor isomer: tr = 17.91 min.

[0049] [α] 20 D = -149 (c = 0.3, CHCl3).

[0050]

[0051] MT-3 (YNMD20) (6bS,11bR)-11b-fluoro-6b-(3-methoxyphenyl)-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-3 (YNMD20) was obtained by reacting 3,3-difluoro-2-(3-methoxyphenyl)-3H-indole (13.0 mg, 0.05 mmol) and 1-naphthol (14.4 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) sequentially in 0.5 mL of toluene solution at 60 °C under nitrogen protection for two days. The yield was 92% (17.6 mg), and the stereoselectivity was 90%.

[0052] 1 H NMR (400 MHz, CDCl3) δ 8.12 – 8.04 (m, 1H), 7.88 – 7.80 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.57 – 7.49 (m, 3H), 7.31 – 7.26 (m, 2H), 7.25 (d,J = 2.4 Hz, 1H), 6.96 – 6.86 (m, 4H), 6.80 (d,J = 8.1 Hz, 1H), 4.73 (s, 1H), 3.74 (s, 3H).

[0053] 13C NMR (100 MHz, CDCl3) δ 158.6, 153.7, 149.6 (d, J = 6.0 Hz), 138.0 (d, J = 7.0 Hz), 133.9, 131.1, 128.3,127.3 (d, J = 241.0 Hz) 126.9, 126.0,125.1, 124.1, 122.4, 121.8, 121.5 (d, J = 31.0 Hz), 121.1, 120.6, 119.6,119.4, 119.0, 113.2, 112.3, 110.0, 77.8 (d, J = 21.0 Hz), 54.2.

[0054] 19 F NMR (376 MHz, CDCl3) δ -103.0.

[0055] HRMS (ESI) m / z calcd. for C 25 H 19 FNO2(M+H) + :384.1394, found 384.1401.

[0056] Enantiomeric excess is 91% determined by HPLC (Chiralpak AS-H,Hexane / Isopropanol 95 / 5, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =24.15 min; minor isomer: tr = 15.85 min.

[0057] [α] 20 D = -107 (c = 0.3, CHCl3).

[0058]

[0059] MT-4 (YNMD21) (6bS,11bR)-11b-fluoro-6b-(4-fluorophenyl)-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-4 (YNMD21) was obtained by reacting 3,3-difluoro-2-(4-fluorophenyl)-3H-indole (12.4 mg, 0.05 mmol) and 1-naphthol (14.4 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) sequentially in 0.5 mL of toluene solution for two days at 60 °C under nitrogen protection. The yield was 83% (15.4 mg), and the stereoselectivity was 96%.

[0060] 1 H NMR (400 MHz, CDCl3) δ 8.10 – 8.08 (m, 1H), 7.87 – 7.85 (m, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.58 – 7.51 (m, 3H), 7.39 – 7.33 (m, 2H), 7.30 (t,J = 7.7 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 8.7 Hz, 2H), 6.93 (t,J = 7.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.74 (s, 1H).

[0061] 13 C NMR (100 MHz, CDCl3) δ 162.7 (d, J = 246.0 Hz), 150.4 (d, J = 6.0Hz), 135.0, 133.1 (dd, J = 6.0 Hz, 3.0 Hz), 129.9, 129.8, 128.0, 127.1,126.3, 125.1, 123.0,122.4 (d, J = 31.0 Hz), 122.1, 121.9 (d, J = 272.0 Hz), 121.3, 120.5, 120.25, 120.24, 115.3, 115.1, 111.1, 78.2 (d, J = 21.0 Hz).

[0062] 19 F NMR (376 MHz, CDCl3) δ -103.0, -114.2.

[0063] HRMS (ESI) m / z calcd. for C 24 H 16 F2NO (M+H) + :372.1194, found 372.1194.

[0064] Enantiomeric excess is 96% determined by HPLC (Chiralpak AS-H, Hexane / Isopropanol 98 / 2, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =24.28 min; minor isomer: tr = 22.23 min.

[0065] [α] 20 D = -167 (c = 0.3, CHCl3).

[0066]

[0067] MT-5 (YNMD22) (6bS,11bR)-11b-fluoro-6b-(p-tolyl)-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-5 (YNMD22) was obtained by reacting 3,3-difluoro-2-(p-tolyl)-3H-indole (12.6 mg, 0.05 mmol) and 1-naphthol (14.4 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) sequentially in 0.5 mL of toluene solution at 60 °C under nitrogen protection for two days. The yield was 62% (11.4 mg), and the stereoselectivity was 96%.

[0068] 1H NMR (400 MHz, CDCl3) δ 8.09 – 8.07 (m, 1H), 7.85 – 7.83 (m, 1H),7.60 (d, J = 7.6 Hz, 1H), 7.56 – 7.48 (m, 3H), 7.29 – 7.24 (m, 4H), 7.15 (d,J = 8.1 Hz, 2H), 6.90 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.74 (s,1H), 2.34 (s, 3H)。

[0069] 13 C NMR (100 MHz, CDCl3) δ 154.7, 150.7 (d, J = 6.0 Hz), 138.2, 134.9,134.2 (d, J = 7.0 Hz), 132.1, 129.1, 128.5 (d, J = 241.0 Hz), 127.9, 127.8,126.9, 126.1, 125.1, 123.5, 122.8, 122.6, 122.2 (d, J = 28 Hz), 121.7, 120.5,119.96, 1, 78.8 (d, J = 21.0 Hz), 21.1。

[0070] 19 F NMR (376 MHz, CDCl3) δ -102.5。

[0071] HRMS (ESI) m / z calcd. for C 25 H 19 FNO (M+H) + :368.1445, found 368.1441。

[0072] Enantiomeric excess is 96% determined by HPLC (Chiralpak AS-H,Hexane / Isopropanol 95 / 5, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =13.55 min; minor isomer: tr = 12.10 min。

[0073] [α] 20 D= -154 (c = 0.2, CHCl3).

[0074]

[0075] MT-6 (YNMD23) (6bS,11bR)-6b-(4-chlorophenyl)-11b-fluoro-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-6 (YNMD23) was obtained by reacting 2-(4-chlorophenyl)-3,3-difluoro-3H-indole (13.2 mg, 0.05 mmol) and 1-naphthol (14.4 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) sequentially in 0.5 mL of toluene solution for two days at 60 °C under nitrogen protection. The yield was 78% (15.2 mg), and the stereoselectivity was 96%.

[0076] 1 H NMR (400 MHz, CDCl3) δ 8.16 – 8.02 (m, 1H), 7.88 – 7.84 (m, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.58 – 7.50 (m, 3H), 7.38 – 7.26 (m, 5H), 7.21 (d,J = 8.4 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.81 (d,J = 8.1 Hz, 1H), 4.73 (s,1H).

[0077] 13C NMR (100 MHz, CDCl3) δ 154.7, 150.4 (d, J = 6.0 Hz), 135.6 (d, J =7.0 Hz), 135.0, 134.3, 132.2, 129.4, 128.4, 128.3 (d, J = 241.0 Hz) 128.0,127.2, 126.3, 125.1, 123.1, 122.4 (d, J = 31.0 Hz), 122.1, 121.2, 120.5,120.32, 120.31, 111.2, 78.2 (d, J = 21.0 Hz).

[0078] 19 F NMR (376 MHz, CDCl3) δ -102.9.

[0079] HRMS (ESI) m / z calcd. for C 24 H 16 ClFNO (M+H) + :388.0899, found 388.0892.

[0080] Enantiomeric excess is 96% determined by HPLC (Chiralpak AS-H, Hexane / Isopropanol 98 / 2, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =24.97 min; minor isomer: tr = 22.43 min.

[0081] [α] 20 D = -154 (c = 0.3, CHCl3).

[0082]

[0083] MT-8 (YNMD25) (6bS,11bR)-11,11b-difluoro-6b-phenyl-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-8 (YNMD25) was obtained by reacting 3,3,4-trifluoro-2-phenyl-3H-indole (12.3 mg, 0.05 mmol) and 1-naphthol (14.4 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) sequentially in 0.5 mL of toluene solution at 60 °C under nitrogen protection for two days. The yield was 89% (16.6 mg), and the stereoselectivity was 96%.

[0084] 1 H NMR (400 MHz, CDCl3) δ 8.18 – 8.09 (m, 1H), 7.91 – 7.83 (m, 1H), 7.59 – 7.52 (m, 3H), 7.36 (s, 5H), 7.26 – 7.20 (m, 2H), 6.73 – 6.26 (m, 2H),4.91 (s, 1H).

[0085] 13 C NMR (100 MHz, CDCl3) δ 161.5, 159.0, 154.7, 152.8 (dd, J = 7.0 Hz, 2.0Hz), 136.7 (d, J = 7.0 Hz), 135.0, 134.0 (d, J = 9.0 Hz), 128.5, 128.4,127.9, 127.24 (d, J = 242.0 Hz), 127.17, 126.3, 123.0, 122.8, 122.2, 121.4,120.6, 106.6 (d, J = 20.0 Hz), 106.52, 106.48, 79.8 (d, J = 21.0 Hz).

[0086] 19 F NMR (376 MHz, CDCl3) δ -101.5 (t, J = 2.0 Hz), -116.8 (d, J = 1.0Hz).

[0087] HRMS (ESI) m / z calcd. for C 24 H 16 F2NO (M+H) +:372.1194, found 372.1204.

[0088] Enantiomeric excess is 96% determined by HPLC (Chiralpak AS-H, Hexane / Isopropanol 97 / 3, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =27.04 min; minor isomer: tr = 24.17 min.

[0089] [α] 20 D = -108 (c = 0.3, CHCl3).

[0090]

[0091] MT-9 (YNMD26) (6bS,11bR)-11b-fluoro-10-methyl-6b-phenyl-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-9 (YNMD26) was obtained by reacting 3,3-difluoro-5-methyl-2-phenyl-3H-indole (12.2 mg, 0.05 mmol) and 1-naphthol (14.4 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) sequentially in 0.5 mL of toluene solution at 60 °C under nitrogen protection for two days. The yield was 98% (18.2 mg), and the stereoselectivity was 90%.

[0092] 1 H NMR (400 MHz, CDCl3) δ 8.16 – 7.97 (m, 1H), 7.94 – 7.78 (m, 1H), 7.59 – 7.48 (m, 3H), 7.43 (s, 1H), 7.40 – 7.34 (m, 5H), 7.29 – 7.26 (m, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.75 – 6.73 (m, 1H), 4.62 (s, 1H), 2.33 (s, 3H).

[0093] 13 C NMR (100 MHz, CDCl3) δ 154.7, 148.5 (d, J = 6.0 Hz), 137.4 (d, J =7.0 Hz), 134.9, 132.9, 132.9, 128.7 (d, J = 243.0 Hz), 128.28, 128.25,127.94, 127.90, 126.9, 126.1, 125.1, 123.6, 122.8, 122.7 (d, J = 31.0 Hz),122.1, 121.7, 120.5, 111.1, 79.1 (d, J = 21.0 Hz), 20.7.

[0094] 19 F NMR (376 MHz, CDCl3) δ -102.7.

[0095] HRMS (ESI) m / z calcd. for C 25 H 19 FNO (M+H) + :368.1445, found 368.1446.

[0096] Enantiomeric excess is 90% determined by HPLC (Chiralpak AS-H,Hexane / Isopropanol 98 / 2, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =15.07 min; minor isomer: tr = 14.00 min.

[0097] [α] 20 D = -108 (c = 0.3, CHCl3).

[0098]

[0099] MT-10 (YNMD27) (6bS,11bR)-9-chloro-11b-fluoro-6b-phenyl-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-10 (YNMD27) was obtained by reacting 3,3-difluoro-2-phenyl-5-(trifluoromethyl)-3H-indole (14.9 mg, 0.05 mmol) and 1-naphthol (14.4 mg, 0.1 mmol) with catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol) and Silicagel (3 mg, 0.05 mmol) in 0.5 mL of toluene solution at 60 °C under nitrogen protection for two days. The yield was 55% (11.5 mg), and the stereoselectivity was 92%.

[0100] 1 H NMR (400 MHz, CDCl3) δ 8.18 – 8.02 (m, 1H), 7.92 – 7.83 (m, 1H), 7.58 – 7.50 (m, 4H), 7.36 (s, 5H), 7.24 (d, J = 8.4 Hz, 1H), 6.87 (dd, J =8.1, 1.6 Hz, 1H), 6.79 – 6.78 (m, 1H), 4.85 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 154.6, 151.6 (d, J = 7.0 Hz), 138.0, 136.6(d, J = 7.0 Hz), 135.0, 128.5, 128.4, 128.0, 127.8, 127.4 (d, J = 241.0 Hz),127.1, 126.3, 126.0, 123.0, 122.9, 122.0, 121.5, 121.0 (d, J = 32.0 Hz), 120.5, 120.1, 110.9, 79.5 (d, J = 21.0 Hz).

[0101] 19 F NMR (376 MHz, CDCl3) δ -102.7.

[0102] HRMS (ESI) m / z calcd. for C 25 H 16 F4NO (M+H) + :422.1163, found 422.1172.

[0103] Enantiomeric excess is 92% determined by HPLC (Chiralpak AS-H,Hexane / Isopropanol 97 / 3, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =20.70 min; minor isomer: tr = 15.26 min.

[0104] [α] 20 D = -94 (c = 0.3, CHCl3).

[0105]

[0106] MT-11 (YNMD28) (6bS,11bR)-11b-fluoro-9-methyl-6b-phenyl-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-11 (YNMD28) was obtained by reacting 3,3-difluoro-6-methyl-2-phenyl-3H-indole (12.2 mg, 0.05 mmol) and 1-naphthol (14.4 mg, 0.1 mmol) with catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphtho[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine-4-oxide (12.6 mg, 0.005 mmol) and Silica gel (3 mg, 0.05 mmol) in 0.5 mL of toluene solution at 60 °C under nitrogen protection for two days. The yield was 78% (14.3 mg); the stereoselectivity was 90%.

[0107] 1 H NMR (400 MHz, CDCl3) δ 8.11 – 8.07 (m, 1H), 7.87 – 8.02 (m, 1H), 7.55 – 7.48 (m, 4H), 7.40 – 7.31 (m, 5H), 7.26 – 7.22 (m, 1H), 6.74 (d, J =7.7 Hz, 1H), 6.63 (s, 1H), 4.69 (s, 1H), 2.32 (s, 3H).

[0108] 13C NMR (100 MHz, CDCl3) δ 154.7, 151.0 (d, J = 7.0 Hz), 142.7, 137.4 (d, J = 7.0 Hz), 134.9, 128.4 (d, J = 241.0 Hz), 128.3, 127.9, 126.9, 126.1,124.74, 124.73, 123.5, 122.7, 122.1, 121.7, 121.18, 121.17, 120.6, 119.9 (d,J = 31.0 Hz), 111.5, 79.1 (d, J = 21.0 Hz), 21.8.

[0109] 19 F NMR (376 MHz, CDCl3) δ -102.3.

[0110] HRMS (ESI) m / z calcd. for C 25 H 19 FNO (M+H) + :368.1445, found 368.1451.

[0111] Enantiomeric excess is 90% determined by HPLC (Chiralpak AS-H, Hexane / Isopropanol 98 / 2, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =19.72 min; minor isomer: tr = 13.64 min.

[0112] [α] 20 D = -67 (c = 0.3, CHCl3).

[0113]

[0114] MT-12 (YNMD29) (6bS,11bR)-5,11b-difluoro-6b-phenyl-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-12 (YNMD29) was obtained by reacting 3,3-difluoro-2-phenyl-3H-indole (11.5 mg, 0.05 mmol) and 4-fluoronaphthyl-1-ol (16.2 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) in 0.5 mL of toluene solution at 60 °C for two days under nitrogen protection. The yield was 70% (13 mg); the stereoselectivity was 94%.

[0115] 1 H NMR (400 MHz, CDCl3) δ 8.10 – 8.06 (m, 2H), 7.62 – 7.56 (m, 3H), 7.37 (s, 5H), 7.31 (t, J = 7.7 Hz, 1H), 6.98 – 6.90 (m, 2H), 6.83 (d, J = 8.0Hz, 1H), 4.75 (s, 1H).

[0116] 13 C NMR (100 MHz, CDCl3) δ 154.6 (d, J = 245.0 Hz), 150.5 (d, J = 6.0Hz), 150.4 (d, J = 3.0 Hz), 136.7 (d, J = 7.0 Hz), 132.2, 128.5, 128.43,128.42 (d, J = 242.0 Hz), 127.8, 127.3, 127.2, 125.1, 124.6 (d, J = 19.0 Hz), 122.5, 122.2, 122.1, 121.6 (dd, J = 235.0 Hz, 9Hz), 121.2, 121.1, 120.2, 111.0, 79.2 (dd, J = 21.0 Hz, 2Hz).

[0117] 19 F NMR (376 MHz, CDCl3) δ -101.9, -128.2.

[0118] HRMS (ESI) m / z calcd. for C 24 H 16 F2NO (M+H) +:372.1194, found 372.1204.

[0119] Enantiomeric excess is 94% determined by HPLC (Chiralpak AS-H,Hexane / Isopropanol 95 / 5, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =11.64 min; minor isomer: tr = 9.79 min.

[0120] [α] 20 D = -97 (c = 0.3, CHCl3).

[0121]

[0122] MT-13 (YNMD30) (6bS,11bR)-5-chloro-11b-fluoro-6b-phenyl-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-13 (YNMD30) was obtained by reacting 3,3-difluoro-2-phenyl-3H-indole (11.5 mg, 0.05 mmol) and 4-chloronaphthyl-1-ol (17.8 mg, 0.1 mmol), catalyst (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol), and Silica gel (3 mg, 0.05 mmol) in 0.5 mL of toluene solution at 60 °C for two days under nitrogen protection. The yield was 86% (16.7 mg), and the stereoselectivity was 86%.

[0123] 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.2 Hz, 1H), 8.16 – 8.08 (m,1H), 7.67 – 7.57 (m, 3H), 7.46 – 7.34 (m, 6H), 7.31 (t, J = 7.7 Hz, 1H), 6.96– 6.90 (m, 1H), 6.85 – 6.80 (m, 1H), 3.64 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 153.8, 150.5 (d, J = 7.0 Hz), 136.6 (d, J =7.0 Hz), 132.3, 131.7, 128.6, 128.5, 128,4 (d, J = 243.0 Hz), 128.1, 127.8,127.0, 125.4, 125.1, 124.9, 123.6, 122.6, 122.1 (d, J = 31.0 Hz), 121.9,121.3, 120.2, 111.0, 79.9 (d, J = 22.0 Hz).

[0124] 19 F NMR (376 MHz, CDCl3) δ -102.1.

[0125] HRMS (ESI) m / z calcd. for C 24 H 16 ClFNO (M+H) + :388.0899, found 388.0908.

[0126] Enantiomeric excess is 86% determined by HPLC (Chiralpak AS-H, Hexane / Isopropanol 98 / 2, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =17.61 min; minor isomer: tr = 13.77 min.

[0127] [α] 20 D = -123 (c = 0.4, CHCl3).

[0128]

[0129] MT-14 (YNMD14) (6bS,11bR)-11b-fluoro-5-methyl-6b-phenyl-6b,11b-dihydro-7H-naphtho[2',1':4,5]furano[3,2-b]indole MT-14 (YNMD14) is a yellow oily substance obtained by reacting 3,3-difluoro-2-phenyl-3H-indole (11.5 mg, 0.05 mmol) and 4-methylnaphthyl-1-ol (15.8 mg, 0.1 mmol) with 3,3-difluoro-2-phenyl-3H-indole (11.5 mg, 0.05 mmol) and 4-methylnaphthyl-1-ol (15.8 mg, 0.1 mmol) as catalyst, followed by (11bR)-4-hydroxy-2,6-bis[2,4,6-tris(isopropyl)phenyl]dinaphthalo[2,1-d:1′,2′-f]-1,3,2-dioxaphosphine 4-oxide (12.6 mg, 0.005 mmol) and Silica gel (3 mg, 0.05 mmol) in 0.5 mL of toluene solution at 60 °C for two days under nitrogen protection. The yield was 87% (16 mg); the stereoselectivity was 96%.

[0130] 1 H NMR (400 MHz, CDCl3) δ 8.16 – 8.09 (m, 1H), 7.99 – 7.97 (m, 1H), 7.63 – 7.52 (m, 3H), 7.43 – 7.34 (m, 5H), 7.29 (t, J = 7.7 Hz, 1H), 7.12 (s,1H), 6.92 (t, J = 7.5 Hz, 1H), 6.84 – 6.79 (m, 1H), 3.63 (s, 1H), 2.65 (s,3H).

[0131] 13 C NMR (100 MHz, CDCl3) δ 153.4, 150.6 (d, J = 7.0 Hz), 137.3 (d, J =6.0 Hz), 133.7, 132.04, 132.02, 129.2, 128.3, 128.2 (d, J = 241.0 Hz), 127.9,126.8, 125.9, 125.1, 124.6, 122.9, 122.7, 122.6, 121.8, 120.6, 120.1, 111.1,79.1 (d, J = 21.0 Hz), 19.4.

[0132] 19 F NMR (376 MHz, CDCl3) δ -102.7.

[0133] HRMS (ESI) m / z calcd. for C 25 H 19 FNO (M+H) + :368.1445, found 368.1453.

[0134] Enantiomeric excess is 96% determined by HPLC (Chiralpak AS-H, Hexane / Isopropanol 97 / 3, flow rate = 1.0 mL / min, 254 nm): major isomer: tr =11.84 min; minor isomer: tr = 10.51 min.

[0135] [α] 20 D = -142 (c = 0.4, CHCl3).

[0136] Example 3: Single-concentration screening report of the in vitro antitumor cytotoxic activity of the compound

[0137] 1. Experimental Materials

[0138] 1.1 Test compounds: 3aa (MT-1), YNMD19~32 (MT-2~15), purity ≥95%, dissolved in DMSO to prepare stock solutions, and diluted with culture medium to the required concentration during the experiment, with a final DMSO concentration ≤0.1% (v / v).

[0139] 1.2 Cell lines: human leukemia HL-60 cells, human lung cancer A549 cells, human liver cancer SMMC-7721 cells, human breast cancer MDA-MB-231 cells, and human colon cancer SW480 cells.

[0140] 1.3 Reagents: DMEM culture medium, RPMI 1640 culture medium, fetal bovine serum (FBS), and MTS detection reagent.

[0141] 1.4 Instruments: Multifunctional microplate reader (MULTISKAN FC), CO2 cell incubator, and clean bench.

[0142] 2. Experimental Methods

[0143] 2.1 Cell Culture: Human leukemia HL-60 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, and the remaining cells were cultured in DMEM medium containing 10% fetal bovine serum. The culture conditions were 37℃, 5% CO2, and saturated humidity.

[0144] 2.2 Cell seeding: Seed cells in the logarithmic growth phase into 96-well plates, with 3000-15000 adherent cells per well and a volume of 100 μL per well. Pre-culture for 12-24 h after seeding.

[0145] 2.3 Drug treatment: The test compounds were diluted with culture medium and screened at a concentration of 40 μM. The final volume of each well was 200 μL, and each treatment was set up in 3 replicates. The mixture was added to a 96-well plate with a final volume of 200 μL per well. Each concentration was set up in 3 replicates. At the same time, a blank control group (a mixture of 20 μL of MTS solution and 100 μL of culture medium) and a negative control group (equal volumes of cell culture medium and DMSO solution for the two positive compounds, cisplatin (DDP) and paclitaxel (Taxol)).

[0146] 2.4 Colorimetric Detection: After culturing at 37℃ for 48 h, for adherent cells, discard the culture medium in each well and add 20 μL of MTS solution and 100 μL of culture medium to each well; for suspended cells, discard 100 μL of culture supernatant and add 20 μL of MTS solution to each well; set up 3 blank replicates (a mixture of 20 μL MTS solution and 100 μL culture medium). After continuing incubation for 2-4 h to allow the reaction to proceed fully, measure the absorbance value. Use a multi-mode microplate reader to detect the absorbance value (OD value) of each well at a wavelength of 492 nm.

[0147] 2.5 Data Processing: Cell viability (%) = (OD value of drug-treated group - OD value of blank group) / (OD value of negative control group - OD value of blank group) × 100%. A multi-functional microplate reader (MULTISKAN FC) was used to read the absorbance values ​​of each well at a wavelength of 492 nm, and the results were recorded.

[0148] 3. Experimental Results

[0149] The cell inhibition rates of the tested compounds at a concentration of 40 μM against five tumor cell lines are shown in the table below: .

[0150] in conclusion: At a concentration of 40M: (1) Compounds YNMD19, 21~23, 25, and 27 exhibit half-maximal inhibitory activity against in vitro tumor growth of leukemia HL-60, lung cancer A549, liver cancer SMMC-7721, breast cancer MDA-MB-231, and colon cancer SW480.

[0151] (2) Compound YNMD18 has half-maximal inhibitory activity against the in vitro tumor growth of leukemia HL-60 and liver cancer SMMC-7721.

[0152] (3) Compounds YNMD20, 28, and 31 have half-maximal inhibitory activity against the in vitro tumor growth of liver cancer SMMC-7721.

[0153] (4) Compound YNMD26 has half-maximal inhibitory activity against in vitro tumor growth of leukemia HL-60, liver cancer SMMC-7721, breast cancer MDA-MB-231 and colon cancer SW480.

[0154] (5) Compound YNMD29 has half-maximal inhibitory activity against the in vitro tumor growth of cancer SMMC-7721, breast cancer MDA-MB-231 and colon cancer SW480.

[0155] (6) Compound YNMD30 has half-maximal inhibitory activity against the in vitro tumor growth of leukemia HL-60, lung cancer A549, liver cancer SMMC-7721 and colon cancer SW480.

[0156] The results showed that the compound of the present invention had a significant inhibitory effect on the proliferation of five types of tumor cells, among which the inhibitory activity against human liver cancer SMMC-7721 cells was the strongest, and it had excellent in vitro antitumor cytotoxic activity.

[0157] Screening of active compounds (Ic50 detection).

[0158] Example 4: Report on the in vitro antitumor cytotoxic activity rescreening of the compound

[0159] 1. Experimental Materials

[0160] 1.1 Test compounds: YNMD (18~23) (MT-1~6), YNMD25~31 (MT-8~14), with a purity ≥95%, were prepared into stock solutions by dissolving in DMSO and diluted with culture medium to the required concentration during the experiment. The final concentration of DMSO was ≤0.1% (v / v).

[0161] 1.2 Cell lines: human leukemia HL-60 cells, human lung cancer A549 cells, human liver cancer SMMC-7721 cells, human breast cancer MDA-MB-231 cells, and human colon cancer SW480 cells.

[0162] 1.3 Reagents: DMEM culture medium, RMPI1640 culture medium, fetal bovine serum (FBS), MTS detection reagent.

[0163] 1.4 Instruments: Multifunctional microplate reader (MULTISKAN FC), CO2 cell incubator, and clean bench.

[0164] 2. Experimental Methods

[0165] 2.1 Cell Culture: Human leukemia HL-60 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, and the remaining cells were cultured in DMEM medium containing 10% fetal bovine serum. The culture conditions were 37℃, 5% CO2, and saturated humidity.

[0166] 2.2 Cell seeding: Seed cells in 96-well plates, with 3000-15000 adherent cells per well and a volume of 100 μL per well. Pre-culture for 12-24 h after seeding.

[0167] 2.3 Drug treatment: The test compounds were diluted with culture medium to five concentration gradients of 40 μM, 8 μM, 1.6 μM, 0.32 μM, and 0.064 μM, and added to 96-well plates with a final volume of 200 μL per well. Each concentration was set up in 3 replicates. A blank control group (containing only culture medium and MTS solution) and a negative control group (containing equal volumes of cell culture medium and DMSO solution for the two positive compounds, cisplatin (DDP) and paclitaxel (Taxol)) were also set up.

[0168] 2.4 Colorimetric Detection: After culturing at 37℃ for 48 h, for adherent cells, discard the culture medium in each well and add 20 μL of MTS solution and 100 μL of culture medium to each well; for suspended cells, discard 100 μL of culture supernatant and add 20 μL of MTS solution to each well; the blank control group was treated simultaneously. After further incubation for 2–4 h, the absorbance (OD value) of each well was measured at a wavelength of 492 nm using a multi-functional microplate reader.

[0169] 2.5 Data Processing: Cell growth curves were plotted with compound concentration on the x-axis and cell viability on the y-axis. The Reed-Muench two-point method was used to calculate the half-maximal inhibitory concentration (IC50) of the compound for each cell line.

[0170] 3. Experimental Results .

[0171] in conclusion: (1) The in vitro tumor growth half-inhibitory concentrations of compounds YNMD19, 21~23, 25, and 27 against leukemia HL-60, lung cancer A549, liver cancer SMMC-7721, breast cancer MDA-MB-231, and colon cancer SW480 are shown in the table above.

[0172] (2) The in vitro tumor growth half-inhibitory concentrations of compound YNMD18 against leukemia HL-60 and liver cancer SMMC-7721 are shown in the table above.

[0173] (3) The in vitro tumor growth half-inhibitory concentrations of compounds YNMD20, 28 and 31 against liver cancer SMMC-772 are shown in the table above.

[0174] (4) The in vitro tumor growth half-inhibitory concentrations of compound YNMD26 against leukemia HL-60, liver cancer SMMC-7721, breast cancer MDA-MB-231 and colon cancer SW480 are shown in the table above.

[0175] (5) The in vitro tumor growth half-inhibitory concentrations of compound YNMD29 against cancer SMMC-7721, breast cancer MDA-MB-231 and colon cancer SW480 are shown in the table above.

[0176] (6) The in vitro tumor growth half-inhibitory concentrations of compound YNMD30 against leukemia HL-60, lung cancer A549, liver cancer SMMC-7721 and colon cancer SW480 are shown in the table above.

[0177] The results showed that the compound described in this invention had a significant inhibitory effect on the proliferation of five types of tumor cells, among which the inhibitory activity against human liver cancer SMMC-7721 cells was the strongest, with an IC50 value of 6.151±0.249μM, demonstrating excellent in vitro antitumor cytotoxic activity.

Claims

1. The use of a class of fluorinated indole compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs, characterized in that, The general structural formula of the fluorine-containing indole compound is as follows: Among them, R1, R2, and R3 are independently selected from halogens, -CN, -NO2, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Acyl group.

2. The application according to claim 1, characterized in that, R1, R2, and R3 are independently selected from methyl, methoxy, trifluoromethyl, fluorine, chlorine, and bromine.

3. The application according to claim 1 or 2, characterized in that, The fluorinated indole compound has the following structure: 。 4. The application according to any one of claims 1-3, characterized in that, The tumor is selected from any one or more of leukemia, lung cancer, liver cancer, breast cancer, and colon cancer.

5. The application according to claim 4, characterized in that, The tumor was selected from liver cancer.

6. An antitumor pharmaceutical composition comprising a therapeutically effective amount of a fluorinated indole compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, and a pharmaceutically acceptable carrier.

7. The antitumor composition according to claim 6, characterized in that, The dosage form of the pharmaceutical composition is any one of injection, tablet, capsule, granule, oral liquid, liposome, and nanoparticle.

8. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonate, or methanesulfonate.

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