Indole alkaloid compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of chemical medicine synthesis, and particularly relates to an indole alkaloid compound as well as a preparation method and application thereof. The structural formula of the indole alkaloid compound is shown as a formula I, and the indole alkaloid compound is synthesized by taking 7-bromoindole and boric acid ester as initial raw materials. The preparation process is simple and easy to implement, and the prepared indole alkaloid compound or the pharmaceutically acceptable salt thereof has the effect of efficiently inhibiting STEAP1 in a targeted manner; the inhibition on the STEAP1 is realized on the protein level and the cell level, and a good effect of resisting prostate cancer cell proliferation is shown on the animal level.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine technology and organic chemical synthesis, and specifically relates to an indole alkaloid compound and a preparation method and application thereof. Background Art

[0002] Globally, prostate cancer (PCa) is the most common malignancy in men and the second leading cause of cancer-related death. Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer. However, most patients will eventually progress to castration-resistant prostate cancer (CRPC) after receiving ADT. The median survival of CRPC patients has been less than 2 years. In recent years, some new treatments have emerged, and the survival rate of patients has improved, but the overall prognosis is still poor.

[0003] Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a unique and promising therapeutic target. The expression of STEAP1 in tumor cells and normal cells is significantly different. It is highly expressed in many types of tumor cells and low in normal tissues (except prostate tissue). Studies have shown that in androgen-dependent prostate cancer, knocking down STEAP1 can inhibit cell growth and induce apoptosis of LNCaP prostate cancer cells in a DHT-independent manner. Therefore, STEAP1 may be a potential target for the treatment of CRPC. However, there are currently 4 STEAP1 drugs in the clinical stage, involving a variety of therapies such as antibodies, CA RT and ADC, and the highest clinical research progress is clinical phase II. Therefore, the development of STEAP1 small molecule inhibitors is of great clinical significance for the treatment of CRPC. Summary of the invention

[0004] The purpose of the present invention is to provide a preparation method and application of a covalent small molecule inhibitor targeting STEAP1 for treating CRPC, which specifically adopts the following technical scheme:

[0005] An indole alkaloid compound, the structural formula of which is shown in Formula I:

[0006]

[0007] Wherein, R is one of an aromatic ring, a substituted aromatic ring, an aromatic heterocycle, a substituted aromatic heterocycle, a straight-chain alkane and a cyclic alkane.

[0008] In some preferred implementations, the above R is one of an aromatic ring, a substituted aromatic ring, an aromatic heterocycle and a substituted aromatic heterocycle. Further preferably, the structure of the above indole alkaloid compound is one of 8a-8n:

[0009]

[0010] The present invention also provides a method for preparing the above-mentioned indole alkaloid compound, and the preparation route thereof is as follows:

[0011]

[0012] in, It represents one of an aromatic ring, a substituted aromatic ring, an aromatic heterocycle and a substituted aromatic heterocycle.

[0013] Commercially available 7-bromoindole 1 and borate ester 2 are used as starting materials, and compound 3 is generated by Suzuki coupling reaction; compound 3 is deprotected by Boc protection under acidic conditions to generate compound 4, and then compound 6 is obtained by Ullmann reaction catalyzed by cuprous acid; and target compound 8 is then prepared by N-arylation reaction catalyzed by palladium. The preparation method of the present invention has low raw material cost, is easy to prepare, and has good functional group compatibility.

[0014] The above-mentioned indole alkaloid compounds or pharmaceutically acceptable salts thereof can be used to prepare drugs for treating and / or preventing cancer; the above-mentioned cancer can be prostate cancer; in particular, the effect is most prominent when the prostate cancer is castration-resistant prostate cancer and metastatic castration-resistant prostate cancer.

[0015] The present invention also provides a pharmaceutical composition, which includes the above-mentioned indole alkaloid compound or a pharmaceutically acceptable salt thereof as a main active ingredient. In some implementations, the above-mentioned pharmaceutical composition also includes an excipient, which may be at least one of gum arabic, syrup, lanolin and starch; the excipient is stable in nature, has no incompatibility with the main drug, does not produce side effects, does not affect the efficacy, is not easy to deform, crack, mildew, or be worm-eaten at room temperature, is harmless to the human body, has no physiological effect, does not produce chemical or physical effects with the main drug, and does not affect the content determination of the main drug. The dosage form of the above-mentioned pharmaceutical composition may be any pharmaceutically acceptable dosage form.

[0016] The beneficial effects of the present invention are as follows: the novel indole alkaloid compound proposed in the present invention has good anti-tumor activity and can inhibit the activity of various tumor cells, especially castration-resistant prostate cancer. At the same time, the preparation process of the compound is simple and easy, the oral bioavailability is high, and the safety is good. DETAILED DESCRIPTION

[0017] The following will be combined with the embodiments to clearly and completely describe the concept and technical effects of the present invention, so as to fully understand the purpose, scheme and effect of the present invention. It should be noted that the embodiments and features in the embodiments of this application can be combined with each other without conflict.

[0018] Example 1

[0019] Indole alkaloid compounds (Compound 8), the structural formulas of which are shown in 8a-8n:

[0020]

[0021] The synthetic route of the above-mentioned indole alkaloid compound (Compound 8) is as follows:

[0022]

[0023] The specific process is as follows:

[0024] (1) Preparation of Compound 3

[0025] Under argon protection, 7-bromoindole 1 (2.0 g, 10.0 mmol, 1.0 eq) was dissolved in a mixed solvent of 1,4-dioxane (50.0 mL) and water (50.0 mL), and borate ester 2 (4.2 g, 10.0 mmol, 1.0 eq), Na2CO3 (2.1 g, 20.0 mmol, 2.0 eq) and palladium catalyst (0.7 g, 1.0 mmol, 0.1 eq) were added to the system in sequence, and the reaction was carried out overnight at 90°C. The reaction solution was washed with saturated NaCl solution, extracted with ethyl acetate (3×10 mL), and the organic phase was dried with anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to obtain compound 3 (white solid, 3.4 g, yield: 84%). Compound 3 was detected, and the detection results were as follows: mp 190.5-192.4°C. 1 H NMR (400MHz, CDCl3): δ9.12(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.84(dt,J=7.5,1.5H z,1H),7.39(t,J=7.5Hz,1H),7.29(d,J=7.5Hz,1H),6.70(dd,J=7.4,1.5Hz,1H),1.48(s,18H).ppm. 13C NMR (100MHz, CDCl3): δ155.8,151.6,149.8,131.7,129.3,127.7,127.5,124.9,123.8,123.8,120.9,103.1,83.4,27.8ppm.HRMS(ESI):m / z Calcd.for C 22 H 27 N4O4 + [M+H] + 411.2027, found 411.2031.

[0026] (2) Preparation of Compound 4

[0027] Compound 3 (3.1 g, 7.6 mmol, 1.0 eq) was dissolved in dichloromethane (20.0 mL), trifluoroacetic acid (2.6 g, 22.7 mmol, 3.0 eq) was slowly added to the system under an ice bath, and the reaction was complete after TLC detection at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution and the system was adjusted to alkalinity. Dichloromethane extraction (3×20 mL), the organic phase was dried with anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain compound 4 (colorless oil, 1.2 g, yield: 76%). Compound 4 was tested, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ8.83(s,2H),8.23(s,1H),7.97(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.5,1.5 Hz,1H),7.37(t,J=7.5Hz,1H),7.27(d,J=7.5Hz,1H),6.68(dd,J=7.5,1.6Hz,1H),1.79(s,2H)ppm. 13 C NMR (100MHz, CDCl3): δ163.0,149.9,131.7,129.3,127.5,124.9,124.3,123.8,123.8,120.9,103.1ppm.HRMS (ESI): m / z Calcd.for C 12 H 11 N4 + [M+H] + 211.0978, found 211.0984.

[0028] (3) Preparation of Compound 6

[0029] Under argon protection, compound 4 (1.0 mmol, 1.0 eq) was dissolved in DMSO (10.0 mL), and the corresponding aryl bromide 5 (1.2 mmol, 1.2 eq), cuprous iodide (0.1 mmol, 0.1 eq), BTMPO (0.1 mmol, 0.1 eq) and potassium phosphate (2.0 mmol, 2.0 eq) were added in sequence, and the reaction system was heated to 110 ° C and reacted overnight. Water was added to quench the reaction, and ethyl acetate was extracted (3×10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 6.

[0030] The structural formulas of the aryl bromide 5 used are as follows:

[0031]

[0032] The corresponding compounds 6a-6n were obtained as follows:

[0033]

[0034] Compound 6a was detected and the detection results were as follows: mp 201-202°C. 1 H NMR (400MHz, CDCl3): δ8.86(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.7Hz,1H),7.82(dt,J=7.5,1.5Hz,1H),7.41–7.34(m,3H),7.28(d,J =7.5Hz,1H),6.75–6.71(m,2H),6.69(dd,J=7.5,1.5Hz,1H),4.79(s,1H),3.20(t,J=5.2Hz,4H),2.98(t,J=5.2Hz,4H),2.60(s,3H)ppm. 13 C N R(100MHz, CDCl3): δ160.7,151.2,149.5,131.7,129.3,127.5,126.7,126.2,124. 9,123.8,123.8,123.7,120.9,117.8,103.1,55.0,50.1,44.7ppm.HRMS(ESI):m / z Calcd.for C 23 H 25 N6 + [M+H] + 385.2135, found 385.2139.

[0035] Compound 6b was detected and the detection results were as follows: mp 195-196°C. 1H NMR (400MHz, CDCl3): δ8.86(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.7Hz,1H),7.82(dt,J=7.5,1.5Hz,1H),7.40–7.32(m,3H),7.2 8(d,J=7.4Hz,1H),6.77–6.71(m,2H),6.69(dd,J=7.5,1.5Hz,1H),4.79(s,1H),3.74(t,J=4.7Hz,4H),3.15(t,J=4.7Hz,4H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,147.0,131.7,129.3,127.5,126.7,126.2, 124.9,123.8,123.8,123.7,120.9,117.8,103.1,66.6,48.5ppm.HRMS(ESI):m / z Calcd.for C 22 H 22 N5O + [M+H] + 372.1819, found 372.1823.

[0036] Compound 6c was detected and the detection results were as follows: mp 198-199°C. 1 H NMR (400MHz, CDCl3): δ8.86(s,2H),8.23(s,1H),7.99(dd,J=7.4,1.6Hz,1H),7.82(dt,J=7.5,1.6Hz,1H),7.40–7.33(m,3H), 7.28(d,J=7.5Hz,1H),6.77–6.72(m,2H),6.69(dd,J=7.5,1.4Hz,1H),4.80(s,1H),3.52–3.41(m,4H),1.68–1.56(m,6H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,148.8,131.7,129.3,127.5,126.7,126.2,124 .9,123.8,123.8,123.7,120.9,117.8,103.1,49.5,25.5,24.6ppm.HRMS(ESI):m / z Calcd.for C 23 H 24 N5 + [M+H] + 370.2026, found 370.2022.

[0037] Compound 6d was detected and the detection results were as follows: mp 177-178°C. 1 H NMR (400MHz, CDCl3): δ8.86(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.5,1.5Hz,1H),7.41–7.33(m,3H), 7.28(d,J=7.5Hz,1H),6.69(dd,J=7.4,1.4Hz,1H),6.65–6.58(m,2H),4.74(s,1H),3.42–3.25(m,4H),2.41–2.26(m,4H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,148.0,131.7,129.3,127.5,126.6,126.2, 124.9,124.2,123.8,123.8,120.9,117.2,103.1,47.7,25.2ppm.HRMS(ESI):m / z Calcd.for C 22 H 22 N5 + [M+H] + 356.1870,fo und356.1875.

[0038] Compound 6e was detected and the detection results were as follows: mp 172-173°C. 1 H NMR (400MHz, CDCl3): δ8.86(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.5,1.5Hz,1H),7.41– 7.33(m,3H),7.28(d,J=7.5Hz,1H),6.69(dd,J=7.5,1.6Hz,1H),6.65–6.59(m,2H),4.74(s,1H),3.02(s,6H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,147.9,131.7,129.3,127.5,126.6,126. 2,124.9,123.8,123.8,122.6,120.9,114.3,103.1,40.4ppm.HRMS(ESI):m / z Calcd.for C 20 H 20 N5 + [M+H]+ 330.1713, found 330.1710.

[0039] Compound 6f was detected and the detection results were as follows: mp 184-185°C. 1 H NMR (400MHz, CDCl3): δ8.87(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.5,1.6Hz,1H),7.77–7.68(m, 2H),7.38(t,J=7.5Hz,1H),7.34–7.24(m,3H),7.03(tt,J=7.5,2.0Hz,1H),6.69(dd,J=7.5,1.5Hz,1H),4.90(s,1H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,139.6,131.7,129.3,128.6,127.5,126.2,124.9,123.8,123.8,123.5,121.1,120.9,103.1ppm.HRMS(ESI):m / z Calcd.for C 18 H 15 N4 + [M+H] + 287.1291, found 287.1295.

[0040] Compound 6g was detected and the detection results were as follows: mp 189-190°C. 1 H NMR (400MHz, CDCl3): δ8.87(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.5,1.6Hz,1H),7.56–7.48 (m,2H),7.38(t,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),7.20–7.12(m,2H),6.69(dd,J=7.4,1.5Hz,1H),4.89(s,1H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,137.2,131.7,129.3,128.7,127.8,127.5,126.2,124.9,123.8,123.8,121.9,120.9,103.1pp m.HRMS(ESI):m / z Calcd.for C 18 H 14 ClN4+ [M+H] + 321.0902, found 321.0906.

[0041] Compound 6h was detected and the detection results were as follows: mp 212-213°C. 1 H NMR (400MHz, CDCl3): δ8.88(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.83(dt,J=7.6,1.6Hz,1H),7.62–7.58(m,1H),7.56(dd ,J=7.5,2.0Hz,1H),7.51(d,J=7.5Hz,1H),7.38(t,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),6.69(dd,J=7.4,1.5Hz,1H),4.93(s,1H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,141.7,141.7,141.7,141.7,131.7,129.3,128.9,128.9,128.9,128.6,127. 5,127.5,126.2,124.9,123.8,123.8,122.8,121.8,120.9,116.1,116.1,116.1,116.0,103.1ppm.HRMS(ESI):m / z Calcd.for C 19 H 13 ClF3N4 + [M+H] + 389.0775, found 389.0778.

[0043] Compound 6i was detected and the detection results were as follows: mp 152-153°C. 1 H NMR (400MHz, CDCl3): δ9.03(s,2H),9.00(d,J=1.3Hz,1H),8.26–8.20(m,2H),7.99(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.5,1. 5Hz,1H),7.38(t,J=7.5Hz,1H),7.31–7.25(m,2H),7.17(dt,J=8.0,1.3Hz,1H),6.69(dd,J=7.4,1.5Hz,1H),4.87(s,1H)ppm. 13C NMR (100MHz, CDCl3): δ160.7,151.2,144.7,140.5,138.8,131.7,129.3,127. 5,126.2,124.9,123.8,123.8,123.7,122.9,120.9,103.1ppm.HRMS(ESI):m / z Calcd.for C 17 H 14 N5 + [M+H] + 288.1244, found 288.1240.

[0045] Compound 6j was detected and the detection results were as follows: mp 171-172°C. 1 H NMR (400MHz, CDCl3): δ9.03 (s, 2H), 8.44 (d, J = 5.1Hz, 2H), 8.23 ​​(s, 1H), 7.99 (dd, J = 7.5, 1.5Hz, 1H), 7.83 (dt, J = 7.6, 1.5 Hz,1H),7.38(t,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),6.69(dd,J=7.5,1.6Hz,1H),6.54(d,J=5.0Hz,2H),4.99(s,1H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,148.0,144.4,131.7,129.3,127.5,126.2,124.9,123.8,123.8,120.9,112.9,103.1ppm.HRMS(ESI):m / z Calcd.for C 17 H 14 N5 + [M+H] + 288.1244, found 288.1241.

[0046] Compound 6k was detected and the detection results were as follows: mp 181-182°C. 1 H NMR (400MHz, CDCl3): δ8.87(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.6,1.6Hz,1H),7

[0047] .67–7.58(m,2H),7.38(t,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),7.11–6.99(m,2H),6.69(dd,J=7.5,1.5Hz,1H),4.86(s,1H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,158.9,156.8,151.2,135.3,135.3,131.7,129.3,127.5,1 26.2,124.9,123.8,123.8,123.3,123.3,120.9,117.4,117.3,103.1ppm.HRMS(ESI):m / z Calcd.for C 18 H 14 FN4 + [M+H] + 305.1197, front 305.1199.

[0049] Compound 61 was detected and the detection results were as follows: mp 181-182°C. 1 H NMR (400MHz, CDCl3): δ8.87(s,2H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.5,1.5Hz,1H),7

[0050] .69–7.61(m,2H),7.38(t,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),6.97–6.89(m,2H),6.69(dd,J=7.4,1.5Hz,1H),4.82(s,1H),3.80(s,3H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,156.0,151.2,133.2,131.7,129.3,127.5,126. 2,124.9,123.8,123.8,122.3,120.9,115.0,103.1,55.3ppm.HRMS(ESI):m / z Calcd.for C 19 H 17 N4O + [M+H] + 317.1397, found 317.1399.

[0053] Compound 6m was detected and the detection results were as follows: mp 201-202°C. 1H NMR (400MHz, CDCl3): δ9.03(d,J=2.5Hz,3H),8.23(s,1H),7.99(dd,J=7.5,1.5Hz,1H),7.83(dt, J=7.5,1.5Hz,1H),7.48–7.41(m,1H),7.38(t,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),6.86(dd,J=8

[0054] .1,1.3Hz,1H),6.69(dd,J=7.5,1.5Hz,1H),4.94(s,1H)ppm. 13 C NMR (100MHz, CDCl3): δ160.7,151.2,145.3,145.0,144.8,144.5,142.4,142.4,142.3,140.6,131.7,129.3,127.5,126.2,1 25.4,124.9,123.8,123.8,123.3,121.2,121.2,121.1,120.9,119.5,119.5,119.4,119.4,119.0,103.1ppm.HRMS(ESI):m / z Calcd.for C 18 H 13 F3N5 + [M+H] + 356.1118, found 356.1123.

[0056] Compound 6n was detected and the detection results were as follows: mp 222-223°C. 1 H NMR (400MHz, CDCl3): δ9.03(s,2H),8.27–8.21(m,2H),7.99(dd,J=7.5,1.5Hz,1H),7.82(dt,J=7.5,1.5Hz,1H),7.38(t, J=7.5Hz,1H),7.30–7.23(m,2H),6.69(dd,J=7.5,1.6Hz,1H),6.64(dd,J=8.0,5.0Hz,1H),5.03(s,1H),3.99(s,3H)ppm. 13 C NMR (100MHz, CDCl3): δ160.6,151.1,146.9,146.0,135.1,131.7,129.3,127.5,126.2,124.9,124.5,123.8,123.8,121.8,12

[0057] 0.9,103.1,54.5ppm.HRMS(ESI):m / z Calcd.for C 18 H 16 N5O + [M+H] + 318.1349, found 318.1352.

[0059] (4) Preparation of Compound 8 (8a-8n)

[0060] Under argon protection, the corresponding compound 6 (1.0 mmol, 1.0 eq), i.e., 6a-6n, was dissolved in N,N-dimethylformamide (10.0 mL), and compound 7 (1.2 mmol, 1.2 eq), palladium acetate (0.1 mmol, 0.1 eq), SIPr (0.1 mmol, 0.1 eq) and sodium hydroxide (2.0 mmol, 2.0 eq) were added to the system, and the reaction system was heated to 100°C for overnight reaction. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3×10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 8, i.e., 8a-8n.

[0061] Compound 8a was detected and the detection results were as follows: mp 252-253°C. 1 H NMR (400MHz, DMSO-d6): δ8.90(s,2H),8.42(t,J=2.0Hz,1H),8.13(dd,J=7.5,1.5Hz,1H),8.07(dt,J=7.5,1.5Hz,1H),7.87–7.81(m,2H),7.69 (dt,J=7.5,2.0Hz,1H),7.42–7.33(m,4H),7.22(dd,J=16.8,10.0Hz,1H),6.84(dd,J=7.5,1.5Hz,1H),6.76–6.70(m,2H),6.50(dd,J=13.7,10.

[0062] 1Hz,1H),5.93(dd,J=16.8,13.8Hz,1H),4.65(s,1H),3.20(t,J=5.2Hz,4H),2.98(t,

[0063] J=5.2Hz,4H),2.60(s,3H)ppm. 13C NMR (100MHz, DMSO-d6): δ191.0,161.0,151.1,149.6,136.8,136.2,133.1,131.8,130.9,129.9,129.2,127.0,126.8,126.7,126.2,125.6,12

[0064] 5.4,124.2,123.7,123.2,122.0,120.7,117.8,105.1,55.0,50.1,44.7ppm.HRMS(ESI):m

[0065] / z Calcd.for C 32 H 31 N6O + [M+H] + 515.2554, found 515.2557.

[0066] Compound 8b was detected and the detection results were as follows: mp 275-277°C. 1 H NMR (400MHz, DMSO-d6): δ8.91(s,2H),8.24(t,J=2.0Hz,1H),8.12(dd,J=7.5,1.5Hz,1H),8.07(dt ,J=7.6,1.6Hz,1H),7.85(d,J=7.5Hz,1H),7.80(dt,J=7.5,2.0Hz,1H),7.76(dt,J=7.5,2.0Hz,1H

[0067] ),7.41(t,J=7.5Hz,1H),7.38–7.33(m,3H),7.09(dd,J=16.8,10.0Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.77–6.72(m,2H), 6.51(dd,J=13.8,10.0Hz,1H),5.94(dd,J=16.7,13.8Hz,1H),4.44(s,1H),3.74(t,J=4.7Hz,4H),3.15(t,J=4.7Hz,4H)ppm. 13 C NMR (

[0068] 100MHz, DMSO-d6): δ190.9,160.9,151.0,147.0,136.8,136.1,133.0,131.8,130.8,129.9,129.1,127.0,126. 8,126.7,126.2,125.5,125.3,124.2,123.7,123.1,121.9,120.6,117.8,105.1,66.6,48.5ppm.HRMS(ESI):m / z Calcd.for C 31 H 28 N5O2 + [M+H] + 502.2238, found 502.2240.

[0069] Compound 8c was detected and the detection results were as follows: mp 235-236°C. 1 H NMR (400MHz, DMSO-d6): δ8.90(s,2H),8.42(t,J=2.1Hz,1H),8.13(dd,J=7.5,1.4Hz,1H),8.07(dt,J=7.4,1.5Hz,1H),7.87–7.81(m,2H),7.69 (dt,J=7.5,2.0Hz,1H),7.41–7.33(m,4H),7.22(dd,J=16.8,10.0Hz,1H),6.84(dd,J=7.5,1.5Hz,1H),6.78–6.71(m,2H),6.50(dd,J=13.7,10.

[0070] 1Hz,1H),5.93(dd,J=16.8,13.8Hz,1H),4.66(s,1H),3.53–3.39(m,4H),1.69–1.57(m,6H)ppm. 13 C NMR (100MHz, DMSO-d6): δ192.2,161.6,153.0,148.8,136.8,135.8,134

[0071] .0,131.8,131.2,129.6,129.1,126.7,126.8,126.7,126.2,125.5,125.3,124.2 ,123.7,123.1,121.9,120.6,117.8,105.1,49.5,25.5,24.6ppm.HRMS(ESI):m / z Calcd.forC 32 H 30 N5O +

[0072] [M+H] + 500.2445, found 500.2449.

[0073] Compound 8d was detected and the detection results were as follows: mp 252-253°C. 1 H NMR (400MHz, DMSO-d6): δ8.91(s,2H),8.27(t,J=2.0Hz,1H),8.12(dd,J=7.5,1.4Hz,1H),8.07(dt,J=7. 5,1.5Hz,1H),7.88(d,J=7.5Hz,1H),7.84(dd,J=7.5,2.0Hz,2H),7.42(t,J=7.5Hz,1H),7.35(dd,J=7.8 ,6.6Hz,3H),7.17(dd,J=16.7,10.0Hz,1H),6.83(dd,J=7.5,1.6Hz,1H),6.66–6.61(m,2H),6.49(dd,J= 13.7,10.1Hz,1H),5.92(dd,J=16.7,13.8Hz,1H),4.61(s,1H),3.36–3.28(m,4H),2.41–2.32(m,4H)ppm. 13 C NMR (100MHz, DMSO-d6): δ193.7,162.3,152.1,147.9,135.3,135.1,133.0,131.8,130.8,129.9,128.5,127.0,12 6.8,126.6,126.2,125.5,125.3,124.2,124.2,123.1,121.9,120.6,117.2,105.1,47.7,25.2ppm.HRMS(ESI):m / z Calcd.for C 31 H 28 N5O + [M+H] + 486.2288, found 486.2291.

[0076] Compound 8e was detected and the detection results were as follows: mp 219-220°C. 1H NMR (400MHz, DMSO-d6): δ8.91(s,2H),8.40(t,J=2.0Hz,1H),8.13(dd,J=7.5,1.5Hz,1H),8.07(dt,J=7.5,1.5Hz,1H),7.83(dd,J=7.5,1.6Hz ,2H),7.68(dt,J=7.3,1.9Hz,1H),7.40(d,J=7.5Hz,1H),7.38–7.33(m,3H),7.22(dd,J=16.8,10.0Hz,1H),6.83(dd,J=7.4,1.5Hz,1H),6.65

[0077] –6.58(m,2H),6.50(dd,J=13.8,10.0Hz,1H),5.94(dd,J=16.8,13.8Hz,1H),4.58(s,1H),3.02(s,6H)ppm. 13 C NMR (100MHz, DMSO-d6): δ192.9,161.6,152.1,146.6,136.8,136.5,133.0,131.8,130.8,129.9,129.5,127.0,126. 8,126.6,126.2,125.5,125.3,124.2,123.1,122.6,121.9,120.6,114.3,105.1,40.4ppm.HRMS(ESI):m / zCalcd.for C 29 H 26 N5O + [M+H] + 460.2132, found 460.2137.

[0078] Compound 8f was detected and the detection results were as follows: mp 215-216°C. 1H NMR (400MHz, DMSO-d6): δ8.92(s,2H),8.39(t,J=2.0Hz,1H),8.13(dd,J=7.5,1.5Hz,1H),8.07(dt,J=7.5 ,1.6Hz,1H),7.83(ddd,J=7.5,4.8,2.8Hz,2H),7.76–7.71(m,2H),7.68(dt,J=7.5,2.0Hz,1H),7.38(dt, J=17.8,7.5Hz,2H),7.30(t,J=7.4Hz,2H),7.22(dd,J=16.8,10.0Hz,1H),7.03(tt,J=7.5,2.0Hz,1H),6. 83(dd,J=7.3,1.5Hz,1H),6.50(dd,J=13.8,10.0Hz,1H),5.94(dd,J=16.8,13.8Hz,1H),4.73(s,1H)ppm. 13 C NMR (100MHz, DMSO-d6): δ191.5,161.2,155.0,139.6,137.8,136.1,134.0,132.8,130.8,129.9,129.6,128.6,12 7.0,126.8,126.2,125.5,125.3,124.2,123.5,123.1,121.9,121.1,120.6,105.1ppm.HRMS(ESI):m / zCalcd.for C 27 H 21 N4O + [M+H] + 417.1710, found 417.1714.

[0080] Compound 8g was detected and the detection results were as follows: mp 251-252°C. 1H NMR (400MHz, DMSO-d6): δ8.92(s,2H),8.38(t,J=2.0Hz,1H),8.13(dd,J=7.5,1.7Hz,1H) ,8.07(dt,J=7.5,1.6Hz,1H),7.83(ddd,J=7.4,4.7,2.7Hz,2H),7.67(dt,J=7.5,2.0Hz,1 H),7.55–7.47(m,2H),7.38(dt,J=19.3,7.5Hz,2H),7.27–7.15(m,3H),6.83(dd,J=7.4,1 .5Hz,1H),6.50(dd,J=13.7,10.1Hz,1H),5.94(dd,J=16.7,13.8Hz,1H),4.78(s,1H)ppm. 13 C NMR (1

[0081] 00MHz, DMSO-d6): δ193.1,162.5,152.9,138.2,137.3,137.1,134.1,132.4,131.3,129.9,129.1,128.7, 127.8,127.0,126.8,126.2,125.5,125.3,124.2,123.1,121.9,121.9,120.6,105.1ppm.HRMS(ESI):m / z Calcd.for C 27 H 20 ClN4O + [M+H] + 451.1320, found 451.1326.

[0083] Compound 8h was detected and the detection results were as follows: mp 281-282°C. 1 H NMR (400MHz, DMSO-d6): δ8.92(s,2H),8.38(t,J=2.0Hz,1H),8.13(dd,J=7.5,1.7Hz,1H) ,8.07(dt,J=7.5,1.6Hz,1H),7.83(ddd,J=7.4,4.7,2.7Hz,2H),7.67(dt,J=7.5,2.0Hz,1 H),7.55–7.47(m,2H),7.38(dt,J=19.3,7.5Hz,2H),7.27–7.15(m,3H),6.83(dd,J=7.4,1 .5Hz,1H),6.50(dd,J=13.7,10.1Hz,1H),5.94(dd,J=16.7,13.8Hz,1H),4.78(s,1H)ppm.13 C NMR (100MHz, DMSO-d6): δ193.1,162.5,152.9,138.2,137.3,137.1,134.1,132.4,131.3,129.9,129.1,128 .7,127.8,127.0,126.8,126.2,125.5,125.3,124.2,123.1,121.9,121.9,120.6,105.1ppm.HRMS(ESI):m / z Calcd.for C 28 H 19 ClF3N4O + [M+H] + 519.1194, found 519.1197.

[0087] Compound 8i was detected and the detection results were as follows: mp 263-264°C. 1 H NMR (400MHz, DMSO-d6): δ9.09(s,2H),9.00(d,J=1.2Hz,1H),8.29(t,J=2.0Hz,1H),8.24(dd,J=4.9,1.3Hz,1H),8.12(dd,J=7.5,1.5Hz,1H), 8.07(dt,J=7.5,1.5Hz,1H),7.92–7.79(m,3H),7.43(t,J=7.5Hz,1H),7.35(t,J=7.5Hz,1H),7.28(dd,J=8.0,5.0Hz,1H),7.22–7.11(m,2H),6

[0088] .83(dd,J=7.4,1.5Hz,1H),6.50(dd,J=13.7,10.1Hz,1H),5.92(dd,J=16.7,13.8Hz,1H),4.71(s,1H)ppm. 13 C NMR (100MHz, DMSO-d6): δ190.9,160.9,151.0,144.7,140.5,138.8,136.8,136.1,133.0,131.8,130.8,129.9,129.1 ,127.0,126.8,126.2,125.5,125.3,124.2,123.7,123.1,122.9,121.9,120.6,105.1ppm.HRMS(ESI):m / zCalcd.for C 26 H 20 N5O + [M+H] +418.1662, found 418.1666.

[0090] Compound 8j was detected and the detection results were as follows: mp 277-278°C. 1 H NMR (400MHz, DMSO-d6): δ9.09 (s, 2H), 8.45 (d, J = 5.1Hz, 2H), 8.29 (t, J = 2.0Hz, 1H), 8.12 (dd, J = 7. 4,1.6Hz,1H),8.07(dt,J=7.5,1.6Hz,1H),7.88(d,J=7.5Hz,1H),7.83(tt,J=7.3,2.0Hz,2H),7.4

[0091] 2(t,J=7.5Hz,1H),7.36(t,J=7.5Hz,1H),7.17(dd,J=16.7,10.0Hz,1H),6.83(dd,J=7.5,1.5Hz,1H), 6.54(d,J=5.1Hz,2H), 6.50(dd,J=13.7,10.1Hz,1H), 5.93(dd,J=16.7,13.8Hz,1H), 4.85(s,1H)ppm. 13 C NMR (100MHz, DMSO-d6): δ190.9,160.9,151.0,148.0,144.4,136.8,136.1,133.0,131.8,130.8,129.9, 129.1,127.0,126.8,126.2,125.5,125.3,124.2,123.1,121.9,120.6,112.9,105.1ppm.HRMS(ESI):m / z Calcd.forC 26 H 20 N5O + [M+H] + 418.1662, found 418.1668.

[0097] Compound 8k was detected and the detection results were as follows: mp 272-273°C. 1H NMR (400MHz, DMSO-d6): δ8.92(s,2H),8.38(t,J=2.0Hz,1H),8.13(dd,J=7.5,1.7Hz,1H),8.07(d t,J=7.5,1.5Hz,1H),7.83(ddd,J=7.5,4.8,2.8Hz,2H),7.67(dt,J=7.5,2.0Hz,1H),7.65–7.57( m,2H),7.38(dt,J=19.1,7.5Hz,2H),7.22(dd,J=16.8,10.1Hz,1H),7.10–7.00(m,2H),6.83(dd, J=7.5,1.5Hz,1H),6.50(dd,J=13.7,10.1Hz,1H),5.94(dd,J=16.8,13.7Hz,1H),4.75(s,1H)ppm. 13 C NMR (100MHz, DMSO-d6): δ193.1,162.5,152.9,138.2,137.3,137.1,134.1,132.4,131.3,129.9,129.1,128 .7,127.8,127.0,126.8,126.2,125.5,125.3,124.2,123.1,121.9,121.9,120.6,105.1ppm.HRMS(ESI):m / z Calcd.for C 27 H 20 FN4O + [M+H] + 435.1616, found 435.1619.

[0101] Compound 81 was detected and the detection results were as follows: mp 272-273°C. 1H NMR (400MHz, DMSO-d6): δ8.92(s,2H),8.42(t,J=2.0Hz,1H),8.14(dd,J=7.5,1.5Hz,1H),8.07(dt,J=7. 5,1.5Hz,1H),7.85(d,J=7.5Hz,1H),7.82(dt,J=7.5,2.0Hz,1H),7.71(dt,J=7.5,2.0Hz,1H),7.67–7.60 (m,2H),7.37(dt,J=14.9,7.5Hz,2H),7.23(dd,J=16.8,10.0Hz,1H),6.96–6.89(m,2H),6.84(dd,J=7.4 ,1.6Hz,1H),6.52(dd,J=13.7,10.1Hz,1H),5.95(dd,J=16.9,13.7Hz,1H),4.32(s,1H),3.80(s,3H)ppm. 13 C NMR (100MHz, DMSO-d6): δ192.3,161.1,157.3,153.1,137.8,136.7 135.2,134.2,132.8,131.8,129.9,129.1,127.9,126.8,126.2,125.5,1 25.3,124.2,123.1,122.3,121.9,120.6,115.0,105.1,55.3ppm.HRMS(E SI):m / z Calcd.for C 28 H 23 N4O2 + [M+H] + 447.1816, found 447.1819.

[0107] Compound 8m was detected and the detection results were as follows: mp 256-257°C. 1H NMR (400MHz, DMSO-d6): δ9.07(s,2H),9.03(d,J=1.2Hz,1H),8.39(t,J=2.0Hz,1H),8.13(dd,J=7.5 ,1.5Hz,1H),8.07(dt,J=7.5,1.6Hz,1H),7.84(ddd,J=7.5,4.7,2.7Hz,2H),7.68(dt,J=7.5,2.0Hz ,1H),7.47–7.42(m,1H),7.38(dt,J=17.3,7.5Hz,2H),7.20(dd,J=16.8,10.1Hz,1H),6.85(ddd,J= 9.2,7.7,1.4Hz,2H),6.49(dd,J=13.8,10.0Hz,1H),5.94(dd,J=16.8,13.7Hz,1H),4.79(s,1H)ppm. 13 C NMR (100MHz, DMSO-d6): δ192.2,161.5,152.1,145.3(q,J=32.4Hz),143.3(d,J=3.1Hz),142.2,137.3,136.6,134.2,132.5,131.7,129.3,129.1, 127.0,126.8,126.2,125.5,125.3,124.2,123.3,123.1,121.9,121.2(d ,J=3.1Hz),121.1,120.6,119.4(q,J=3.8Hz),105.1ppm.HRMS(ESI):m / z Calcd.for C 27 H 19 F3N5O + [M+H] + 486.1536, found 486.1539.

[0113] Compound 8n was detected and the detection results were as follows: mp 258-259°C. 1H NMR (400MHz, DMSO-d6): δ9.02(s,2H),8.27(dd,J=5.1,1.3Hz,1H),8.11–7.98(m,4H),7.82(d,J=7 .5Hz,1H),7.76(dt,J=7.5,2.0Hz,1H),7.53(t,J=7.5Hz,1H),7.34(t,J=7.5Hz,1H),7.26(dd,J=8 .0,1.2Hz,1H),7.04(dd,J=16.8,10.0Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.62(dd,J=8.1,5.0Hz ,1H),6.43(dd,J=13.8,10.0Hz,1H),5.75(dd,J=16.8,13.8Hz,1H),4.89(s,1H),4.00(s,3H)ppm. 13 C NMR (100MHz, DMSO-d6): δ192.7,162.8,152.6,145.7,144.0,137.8,136.6,135.1,132.0,131.8,130.6,128.3,128 .1,127.0,126.8,126.1,125.5,125.3,124.5,124.2,123.1,121.9,121.8,120.6,105.1,54.5ppm.HRMS(ESI):m / z Calcd.forC 27 H 22 N5O2 + [M+H] + 448.1768, found 448.1768.

[0118] Compound performance test

[0119] 1. Determination of compound cell activity

[0120] The in vitro antiproliferative activity of the 14 indole alkaloid compounds in Example 1 on prostate cancer cell lines PC3 and DU145 was evaluated by CCK-8 assay. The highest concentration was set to 10 μM, and the lowest concentration was 0 μM, with a total of 10 concentration gradients. PC-3 and DU145 cells were incubated for 72 h, respectively. The activity of the cells was detected by CCK-8, and the data were processed using GraphPad Prism 9 to calculate the IC 50 The results are shown in Table 1 (the positive control group was docetaxel).

[0121] Table 1 Determination of cell activity of compounds

[0122]

[0123] Among them, +:>1000nM; ++:1000-100nM; +++:<100nM.

[0124] 2. Determination of compound inhibition of STEAP1 activity

[0125] Western Blot experiments were performed to evaluate the inhibitory effects of a series of molecules in Example 1 on STEAP1 protein in PC3 cells. The levels of STEAP1 protein in cells were detected by Western Blot experiments, and the results are shown in Table 2. The indole alkaloid compounds of the present invention have good inhibitory ability on STEAP1 protein.

[0126] Table 2 Determination of compound inhibition of STEAP1 activity

[0127]

[0128] Among them, +++: >80%; ++: 50%-80%; +: <50%.

[0129] 3. Compound animal tumor inhibition experiment

[0130] To evaluate the anti-tumor ability of active indole derivative molecules in vivo, animal experiments were conducted on two xenograft tumor models in mice (PC3, DU145). The results are shown in Table 3. Compound 81 showed slightly better in vivo anti-tumor activity than the first-line clinical drug docetaxel, and had a more obvious inhibitory effect on the PC-3 model.

[0131] Table 3 Animal tumor inhibition experiments of compounds

[0132]

[0133] The above is only a preferred embodiment of the present invention. The present invention is not limited to the above implementation. As long as the technical effect of the present invention is achieved by the same means, it should belong to the protection scope of the present invention. Within the protection scope of the present invention, its technical scheme and / or implementation method can have various modifications and changes.

Claims

1. An indole alkaloid compound, characterized in that: Its structural formula is shown in Formula I: Wherein, R is one of an aromatic ring, a substituted aromatic ring, an aromatic heterocycle, a substituted aromatic heterocycle, a straight-chain alkane and a cyclic alkane.

2. The indole alkaloid compound according to claim 1, characterized in that The R is one of an aromatic ring, a substituted aromatic ring, an aromatic heterocycle and a substituted aromatic heterocycle.

3. The indole alkaloid compound according to claim 1 or 2, characterized in that: Its structure is one of 8a-8n:

4. A method for preparing an indole alkaloid compound according to any one of claims 2 or 3, characterized in that: The preparation route is as follows: in, It represents one of an aromatic ring, a substituted aromatic ring, an aromatic heterocycle and a substituted aromatic heterocycle.

5. Use of the indole alkaloid compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a drug for treating and / or preventing cancer.

6. The use according to claim 5, characterized in that: The cancer is prostate cancer.

7. The use according to claim 6, characterized in that: The prostate cancer is castration-resistant prostate cancer and metastatic castration-resistant prostate cancer.

8. A pharmaceutical composition, characterized in that The indole alkaloid compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutical composition includes an excipient.

10. The pharmaceutical composition according to claim 9, characterized in that The excipient is at least one of gum arabic, syrup, lanolin and starch.

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