Indole alkaloid compound, preparation method and application thereof

Abstract

This invention belongs to the technical field of chemical drug synthesis, specifically relating to an indole alkaloid compound, its preparation method, and its application. The indole alkaloid compound, whose structural formula is shown in Formula I, is synthesized from 7-bromoindole and a boric acid ester as starting materials. The preparation process is simple and easy, and the resulting indole alkaloid compound or a pharmaceutically acceptable salt thereof exhibits highly effective targeted inhibition of STEAP1, inhibiting STEAP1 at both the protein and cellular levels and demonstrating potent anti-proliferative effects against prostate cancer cells in animals.

Description

Technical Field

[0001] The present invention belongs to the fields 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. Although some new treatments have emerged in recent years, the survival rate of patients has improved, but the overall prognosis remains poor.

[0003] Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a unique and promising therapeutic target. STEAP1 expression differs significantly between tumor cells and normal cells, with high expression in multiple tumor cell types and low expression in normal tissues (except prostate tissue). Studies have shown that knocking down STEAP1 in androgen-dependent prostate cancer inhibits cell growth and induces apoptosis in LNCaP prostate cancer cells in a DHT-independent manner. Therefore, STEAP1 may be a promising target for the treatment of CRPC. However, there are currently four STEAP1 drugs in clinical trials, encompassing a variety of therapies, including antibodies, CART, and ADCs, with the most advanced clinical research progressing to Phase II. Therefore, the development of small molecule STEAP1 inhibitors has important 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 the treatment of CRPC, specifically using the following technical solutions:

[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 linear alkane and a cyclic alkane.

[0008] In some preferred embodiments, 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, 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, undergoing a Suzuki coupling reaction to generate compound 3. Compound 3 is then subjected to removal of the Boc protecting group under acidic conditions to generate compound 4, which is then subjected to a cuprous-catalyzed Ullmann reaction to obtain compound 6. This is followed by a palladium-catalyzed N-arylation reaction to produce the target compound 8. The preparation method of the present invention features low raw material cost, ease of preparation, and 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 comprising the above-mentioned indole alkaloid compound or a pharmaceutically acceptable salt thereof as a main active ingredient. In some embodiments, the pharmaceutical composition further comprises an excipient, which may be at least one of gum arabic, syrup, lanolin, and starch. The excipient is stable, has no incompatibility with the main drug, does not produce side effects, does not affect the efficacy, is not easily deformed, cracked, moldy, or infested by insects at room temperature, is harmless to the human body, has no physiological effects, does not react chemically or physically with the main drug, and does not affect the content determination of the main drug. The pharmaceutical composition may be in any pharmaceutically acceptable dosage form.

[0016] The beneficial effects of the present invention are: the new 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 unless there is a 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, 7-bromoindole 1 (2.0 g, 10.0 mmol, 1.0 eq) was dissolved in a mixture of 1,4-dioxane (50.0 mL) and water (50.0 mL). Boronate 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 sequentially. The mixture was reacted at 90°C overnight. The reaction solution was washed with saturated NaCl solution and extracted with ethyl acetate (3 × 10 mL). The organic phase was dried over 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 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), and trifluoroacetic acid (2.6 g, 22.7 mmol, 3.0 eq) was slowly added to the system under an ice bath. After 2 hours of reaction at room temperature, TLC detected that the raw material reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and the system was adjusted to alkaline. Dichloromethane extraction (3 × 20 mL), the organic phase was dried over 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 detected, and the test results were 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,found211.0984.

[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 sequentially. The reaction system was heated to 110°C and reacted overnight. The reaction was quenched by adding water, extracted with ethyl acetate (3 × 10 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain compound 6.

[0030] The structural formulas of the aryl bromides 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,found370.2022.

[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,found389.0778.

[0042] 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,found288.1240.

[0043] 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.

[0044] 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

[0045] .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): δ160.7,158.9,156.8,151.2,135.3,135.3,131.7,129.3,127.5,126.2,124.9,123.8,123.8,123.3,123.3,12

[0046] 0.9,117.4,117.3,103.1ppm.HRMS(ESI):m / z Calcd.for C 18 H 14 FN4 + [M+H] + 305.1197,f ound 305.1199.

[0047] 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

[0048] .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): δ160.7,156.0,151.2,133.2,131.7,129.3,127.5,126.2,124.9,123.8,123.8,122.3,120.9,11

[0049] 5.0,103.1,55.3ppm.HRMS(ESI):m / z Calcd.for C 19 H 17 N4O + [M+H] + 317.1397,found 3 17.1399.

[0050] Compound 6m was detected, and the detection results were as follows: mp 201-202°C. 1 H 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

[0051] .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, 129.3,127.5,126.2,125.4,124.9,123.8,123.8,123.3,121.2,121.2,121.1,120.9,119.5,119.5,11

[0052] 9.4,119.4,119.0,103.1ppm.HRMS(ESI):m / z Calcd.for C 18 H 13 F3N5 + [M+H] + 356.1118, found 356.1123.

[0053] 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. 13C 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

[0054] 0.9,103.1,54.5ppm.HRMS(ESI):m / z Calcd.for C 18 H 16 N5O + [M+H] + 318.1349, found 318.1352.

[0055] (4) Preparation of Compound 8 (8a-8n)

[0056] Under argon, the corresponding compound 6 (1.0 mmol, 1.0 eq), i.e., 6a-6n, was dissolved in N,N-dimethylformamide (10.0 mL). 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. The reaction system was heated to 100°C and reacted overnight. The reaction was quenched by water and extracted with ethyl acetate (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography to obtain compound 8, i.e., 8a-8n.

[0057] 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.

[0058] 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,

[0059] J=5.2Hz,4H),2.60(s,3H)ppm. 13 C 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

[0060] 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

[0061] / z Calcd.for C 32 H 31 N6O + [M+H] + 515.2554, found 515.2557.

[0062] 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

[0063] ),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 (

[0064] 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,found502.2240.

[0065] 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.

[0066] 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

[0067] .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 +

[0068] [M+H] + 500.2445,found 500.2449.

[0069] 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): δ19 3.7,162.3,152.1,147.9,135.3,135.1,133.0,131.8,130.8,129.9,128.5,127.0,126.8,1

[0070] 26.6,126.2,125.5,125.3,124.2,124.2,123.1,121.9,120.6,117.2,105.1,47.7,25.2ppm.HRMS(ESI):m / z Calcd.for C 31 H 28 N5O + [M+H] + 486.2288, found 486.2291.

[0071] 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

[0072] –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.

[0073] 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 (100 MHz, DMSO-d6): δ 19

[0074] 1.5,161.2,155.0,139.6,137.8,136.1,134.0,132.8,130.8,129.9,129.6,128.6,127.0,126 .8,126.2,125.5,125.3,124.2,123.5,123.1,121.9,121.1,120.6,105.1ppm.HRMS(ESI):m / z Calcd.for C 27 H 21 N4O + [M+H] + 417.1710, found 417.1714.

[0075] 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

[0076] 00MHz, DMSO-d6): δ193.1,162.5,152.9,138.2,137.3,137.1,134.1,132.4,131.3,129.9,12 9.1,128.7,127.8,127.0,126.8,126.2,125.5,125.3,124.2,123.1,121.9,121.9,120.6,10

[0077] 5.1ppm.HRMS(ESI):m / z Calcd.for C 27 H 20 ClN4O + [M+H] + 451.1320,found451.1326.

[0078] Compound 8h was detected, and the detection results were as follows: mp 281-282°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

[0079] 00MHz, DMSO-d6): δ193.1,162.5,152.9,138.2,137.3,137.1,134.1,132.4,131.3,129.9,12 9.1,128.7,127.8,127.0,126.8,126.2,125.5,125.3,124.2,123.1,121.9,121.9,120.6,10 5.1ppm.HRMS(ESI):m / z Calcd.for C 28 H 19 ClF3N4O + [M+H] + 519.1194, found 519.1197.

[0080] 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

[0081] .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): δ190.9,160.9,151.0,144.7,140.5,138.8,136.8,1 36.1,133.0,131.8,130.8,129.9,129.1,127.0,126.8,126.2,125.5,125.3,

[0082] 124.2,123.7,123.1,122.9,121.9,120.6,105.1ppm.HRMS(ESI):m / z Calcd.forC 26 H 20 N5O + [M+H] + 418.1662, found 418.1666.

[0083] 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

[0084] 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

[0085] .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,

[0086] 13.8Hz,1H),4.85(s,1H)ppm. 13C NMR (100MHz, DMSO-d6): δ190.9,160.9,151.0,148.0,144.4,136.8,136.1,133.0,131.8,130.8,129.9,129.1,127.0,126.8,126.2,125.5,12

[0087] 5.3,124.2,123.1,121.9,120.6,112.9,105.1ppm.HRMS(ESI):m / z Calcd.forC 26 H 20 N5O

[0088] + [M+H] + 418.1662, found 418.1668.

[0089] Compound 8k was detected, and the detection results were as follows: mp 272-273°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(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

[0090] .2,123.1,121.9,121.9,120.6,105.1ppm.HRMS(ESI):m / z Calcd.for C 27 H 20 FN4O +[M+

[0091] H] + 435.1616, found 435.1619.

[0092] Compound 81 was detected, and the detection results were as follows: mp 272-273°C. 1 H 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

[0093] ),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–

[0094] 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=1

[0095] 6.9,13.7Hz,1H),4.32(s,1H),3.80(s,3H)ppm. 13 C NMR (100 MHz, DMSO-d6): δ 19

[0096] 2.3,161.1,157.3,153.1,137.8,136.7 135.2,134.2,132.8,131.8,129.9,129.1,127.9,126.8

[0097] ,126.2,125.5,125.3,124.2,123.1,122.3,121.9,120.6,115.0,105.1,55.3ppm.HRMS(E SI):m / z Calcd.for C 28 H 23 N4O2 + [M+H] + 447.1816, found 447.1819.

[0098] 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)

[0099] ,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

[0100] .3(q,J=32.4Hz),143.3(d,J=3.1Hz),142.2,137.3,136.6,134.2,132.5,131.7,129.3,12

[0101] 9.1,127.0,126.8,126.2,125.5,125.3,124.2,123.3,123.1,121.9,121.2(d,J=3.1Hz),121.1

[0102] ,120.6,119.4(q,J=3.8Hz),105.1ppm.HRMS(ESI):m / z Calcd.for C 27 H 19 F3N5O + [M+

[0103] H] + 486.1536, found 486.1539.

[0104] 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

[0105] .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): δ192.7,162.8,152.6,145.7,1

[0106] 44.0,137.8,136.6,135.1,132.0,131.8,130.6,128.3,128.1,127.0,126.8,126.1,125.5,125

[0107] .3,124.5,124.2,123.1,121.9,121.8,120.6,105.1,54.5ppm.HRMS(ESI):m / zCalcd.for C 27 H 22 N5O2 + [M+H] + 448.1768,found 448.1768.

[0108] Compound performance test

[0109] 1. Determination of compound cell activity

[0110] The in vitro antiproliferative activity of the 14 indole alkaloid compounds in Example 1 against 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. A total of 10 concentration gradients were used. PC-3 and DU145 cells were co-incubated for 72 h. Cell activity was detected by CCK-8 assay. GraphPad Prism 9 was used for data processing to calculate IC 50The results are shown in Table 1 (the positive control group was docetaxel).

[0111] Table 1 Determination of cell activity of compounds

[0112]

[0113] Among them, +:>1000nM; ++:1000-100nM; +++:<100nM.

[0114] 2. Determination of Compound Inhibition of STEAP1 Activity

[0115] Western Blot experiments were performed to evaluate the inhibitory effects of the 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.

[0116] Table 2 Determination of compound inhibition of STEAP1 activity

[0117]

[0118] Among them, +++: >80%; ++: 50%-80%; +: <50%.

[0119] 3. Animal tumor inhibition experiments of compounds

[0120] To evaluate the anti-tumor activity of active indole derivatives in vivo, animal studies were conducted using two mouse xenograft tumor models (PC3 and DU145). The results, shown in Table 3, indicate that compound 81 exhibited slightly superior in vivo anti-tumor activity to that of the clinically effective first-line drug docetaxel, with a particularly pronounced inhibitory effect against the PC-3 model.

[0121] Table 3 Animal tumor inhibition experiments of compounds

[0122]

[0123] The above description is merely a preferred embodiment of the present invention. The present invention is not limited to the above-described embodiments. As long as the technical effects of the present invention are achieved by the same means, they shall fall within the scope of protection of the present invention. Within the scope of protection of the present invention, various modifications and variations of the technical solutions and / or implementation methods may be made.

Claims

1. An indole alkaloid compound, characterized in that Its structure is one of 8a-8n: 。 2. A method for preparing the indole alkaloid compound according to claim 1, characterized in that: The preparation route is as follows: ； in, The corresponding structures in 8a-8n.

3. Use of the indole alkaloid compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for treating and / or preventing cancer, wherein the cancer is prostate cancer.

4. The use according to claim 3, characterized in that The prostate cancer is castration-resistant prostate cancer and metastatic castration-resistant prostate cancer.

5. A pharmaceutical composition, characterized in that The invention comprises the indole alkaloid compound or a pharmaceutically acceptable salt thereof according to claim 1.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition includes an excipient.

7. The pharmaceutical composition according to claim 6, characterized in that The excipient is at least one of gum arabic, syrup, lanolin and starch.

Images