Dehydropeperidine derivatives as topoisomerase i inhibitors and methods of making and medical uses thereof

Abstract

The present application discloses a dehydropegoine derivative as shown in structure I or its pharmaceutically acceptable salt, solvate as a medicine, R is independently selected from hydrogen or methoxy; R1, R2, R3, R4, R5 are independently selected from hydrogen, methyl, ethyl, methoxy, nitro, fluorine, chlorine or bromine, or R2, R3 are connected to each other to form a dioxane ring with two oxygen atoms together with the benzene ring. The dehydropegoine derivative has strong anti-tumor activity and can effectively inhibit the proliferation of tumor cells. The dehydropegoine derivative can play a role by inhibiting DNA topoisomerase I. The present application also discloses the application of the dehydropegoine derivative or its pharmaceutically acceptable salt, solvate in preparing a DNA topoisomerase I inhibitor. The present application discloses the application of the dehydropegoine derivative or its pharmaceutically acceptable salt, solvate in preparing a medicine for treating tumors.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to dehydrocamellia alkaloid derivatives, their preparation methods and pharmaceutical uses; the dehydrocamellia alkaloid derivatives, as topoisomerase I inhibitors, can inhibit the proliferation of tumor cells at the cellular level and inhibit the growth of syngeneic xenograft tumors at the animal level. Background Technology

[0002] Cancer remains one of the leading causes of death worldwide. Lung cancer, breast cancer, and colon cancer are the most common types of malignant tumors. Cancer treatments include surgery, chemotherapy, radiotherapy, hormone therapy, and immunotherapy. However, these traditional therapies suffer from low specificity, dose-limited toxicity, cellular resistance, tumor microenvironment resistance, and significant adverse reactions. Therefore, there is an urgent need for new molecularly targeted therapies.

[0003] Topoisomerase (Topo) is a crucial enzyme involved in DNA topology during DNA synthesis and transcription. It is overexpressed in many proliferating cancer cells and is an important cellular target for many successful chemotherapeutic drugs. Because Topo plays a key role in maintaining and replicating DNA during cancer cell proliferation, Topo inhibitors are a major class of anticancer therapeutics. Drugs targeting topoisomerase I (Topo I) mainly include camptothecin (CPT) and its derivatives. The mechanism by which CPT inhibits Topo I is by stabilizing the Topo I-DNA cleavage complex and preventing DNA breakage and resealing by Topo I toxins.

[0004] Natural products are a rich source of drug discovery, and most anticancer drugs currently used clinically are derived from natural product scaffolds. Harmine, originally isolated from *Phyllostachys edulis*, is a β-carboxin compound used to treat gastrointestinal cancers. The antitumor potential of β-carboxin compounds is linked through multiple mechanisms, such as inhibiting DNA topoisomerase I and II, inserting into DNA, or targeting specific cancer signaling pathways to inhibit cancer cell growth and induce apoptosis. Although harmine has good antitumor activity, its significant toxicity limits its clinical development and application. Humans and animals taking harmine may experience tremors, ataxia, vomiting, and fever, with hepatotoxicity, nephrotoxicity, and neurological toxicity being the most severe. Therefore, it is necessary to improve the antitumor activity of harmine and reduce its toxicity. Summary of the Invention

[0005] The purpose of this invention is to chemically modify and alter the structure of dehydrocamelin, attempting to introduce a chalcone structure containing α,β-enone and exhibiting lower toxicity into the structure of dehydrocamelin, in order to reduce the toxicity of dehydrocamelin and enhance the anticancer activity of the compound. The resulting dehydrocamelin derivatives, as inhibitors of DNA topoisomerase I, can inhibit the proliferation of tumor cells at the cellular level and inhibit the growth of genus-transplanted tumors at the animal level, and can be used to treat various cancers.

[0006] The first objective of this invention is to provide a class of dehydrocamelin derivatives or their pharmaceutically acceptable salts or solvates with the structure shown in I for pharmaceutical use:

[0007]

[0008] In this context, R is independently selected from hydrogen or methoxy; R1, R2, R3, R4, and R5 are independently selected from hydrogen, methyl, ethyl, methoxy, nitro, fluorine, chlorine, or bromine, or R2 and R3 are connected to each other and together with a benzene ring to form a dioxane containing two oxygen atoms.

[0009] Preferably, R is selected from hydrogen or methoxy; R1 is selected from hydrogen, methyl, methoxy, chlorine or bromine; R2 is selected from hydrogen, methyl, methoxy, nitro, fluorine, chlorine, bromine or iodine; R3 is selected from hydrogen, methoxy, nitro, fluorine, chlorine or bromine; or R2 and R3 are interconnected with a benzene ring to form a dioxane containing two oxygen atoms; R4 is selected from hydrogen, methoxy or fluorine; R5 is selected from hydrogen, methyl, methoxy or chlorine; but does not include: R is selected from hydrogen, R1 = R2 = R4 = R5 = H, R3 is selected from methoxy; R is selected from methoxy, R1 = R2 = R4 = R5 = H, R3 is selected from nitro.

[0010] More preferably, R is selected from hydrogen or methoxy, R1 is selected from hydrogen or chlorine, R2 is selected from hydrogen, bromine or iodine, R3 is selected from hydrogen, nitro or bromine, R4 is selected from hydrogen, and R5 is selected from hydrogen; or R is selected from hydrogen or methoxy, R1 is selected from hydrogen, R2 is selected from methyl, methoxy, nitro, or chlorine, R3 is selected from hydrogen, fluorine or chlorine, or R2 and R3 are interconnected with a benzene ring to form a dioxane containing two oxygen atoms, R4 is selected from hydrogen, and R5 is selected from hydrogen or chlorine; or R is selected from hydrogen or methoxy, R1 is selected from methyl R1 is selected from hydrogen, R2 is selected from hydrogen, R3 is selected from hydrogen, R4 is selected from hydrogen, and R5 is selected from methyl or methoxy; or R is selected from hydrogen or methoxy, R1 is selected from hydrogen, methoxy or bromine, R2 is selected from hydrogen, methoxy or fluorine, R3 is selected from hydrogen or methoxy, R4 is selected from hydrogen, methoxy or fluorine, and R5 is selected from hydrogen; but excluding: R is selected from methoxy, R1 = R2 = R4 = R5 = H, R3 is selected from nitro, R is selected from hydrogen, R1 = R2 = R4 = R5 = H, and R3 is selected from methoxy.

[0011] Specifically, the dehydrocamelin derivative is selected from the following compounds:

[0012]

[0013]

[0014] The pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, p-toluenesulfonate, or alkaline metal cation salts.

[0015] The second objective of this invention is to provide a method for preparing the aforementioned dehydrocamelin derivative, the synthetic route of which is as follows:

[0016]

[0017] R, R1, R2, R3, R4, and R5 are as described above.

[0018] Specifically, the following steps are included:

[0019] Step (1): Using water as the reaction solvent, under acidic conditions, acetone aldehyde and tryptamine or 5-methoxytryptamine shown in Formula IV undergo a cyclization reaction at room temperature to obtain compound III;

[0020] Step (2): Using N,N-dimethylformamide (DMF) as the reaction solvent, compound III was dissolved in the reaction solvent under an ice-water bath. Then, potassium permanganate was slowly added under an ice-water bath, and the reaction was carried out at room temperature to obtain compound II.

[0021] Step (3): Using anhydrous ethanol as the reaction solvent, under alkaline conditions, compound II reacts with the compound having the structure shown below. The substituted benzaldehyde shown reacts at room temperature to give a dehydrocamellia alkaloid derivative with the structure shown in Formula I.

[0022] In step (1), the molar ratio of acetone aldehyde and tryptamine or 5-methoxytryptamine is 1:1.

[0023] The acidic condition is achieved by adding 0.5 mL of concentrated sulfuric acid to every 50 mL of water.

[0024] The concentrated sulfuric acid has a mass fraction of 98%.

[0025] After the reaction was complete, the pH of the reaction solution was adjusted to 6-7 with 1 mol / L NaOH. A solid precipitated out. The mixture was filtered, and the filter cake was washed with water to obtain compound III.

[0026] In step (2), the molar ratio of compound III to potassium permanganate is 1:2.

[0027] After the reaction was completed, sodium bisulfite was added to the reaction solution to reduce excess potassium permanganate. The mixture was filtered, the filter cake was discarded, water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated under vacuum. The mixture was then subjected to rapid column chromatography to obtain compound II.

[0028] The eluent for the rapid column chromatography is ethyl acetate and petroleum ether in a volume ratio of 3:17, the flow rate is 60 mL / min, and the detection wavelengths are 256 nm and 365 nm.

[0029] After drying the organic phase with anhydrous sodium sulfate and then vacuum drying, it can also be purified using other conventional separation methods in this field to obtain compound II.

[0030] In step (3), the molar ratio of compound II to the substituted benzaldehyde is 1:1.

[0031] The alkaline environment is achieved by adding 15 mL of anhydrous ethanol to 1 mL of 20% sodium hydroxide solution.

[0032] After the reaction was completed, the reaction solution was placed in an ice-water bath, and the pH was adjusted to 4-5 with 1 mol / L hydrochloric acid. The solution was filtered, the filtrate was discarded, and the filter cake was dried to obtain the crude product. The crude product was recrystallized with anhydrous ethanol to obtain the dehydrocamelin derivative with the structure shown in Formula I.

[0033] The recrystallization process involves heating the crude product in anhydrous ethanol at a ratio of 10:1 to 20:1 mg / mL, dissolving the crude product in the ethanol until completely dissolved, cooling in an ice-water bath, and precipitating the solid.

[0034] A third object of the present invention is to provide a pharmaceutical composition comprising a dehydrocamellidine derivative of Formula I or a pharmaceutically acceptable salt, solvate, and pharmaceutically acceptable excipient thereof. Preferably, the pharmaceutically acceptable excipient is selected from one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0035] A fourth object of the present invention is to provide the use of the aforementioned dehydrocamelin derivative or its pharmaceutically acceptable salt, solvate, or pharmaceutical composition in the preparation of DNA topoisomerase I inhibitors.

[0036] A fifth object of the present invention is to provide the use of the aforementioned dehydrocamelin derivative or its pharmaceutically acceptable salt, solvate or pharmaceutical composition in the preparation of a medicament for treating tumors.

[0037] The tumors mentioned are breast cancer, liver cancer, colorectal cancer cells, non-small cell lung cancer, and prostate cancer.

[0038] As a preferred technical solution of the dehydrocamelin derivative of the present invention, the structure of the dehydrocamelin derivative is as follows:

[0039]

[0040] The application of the dehydrocamelin derivative in the preparation of drugs for treating colorectal cancer.

[0041] As another preferred embodiment of the dehydrocamelin derivative of the present invention, the structure of the dehydrocamelin derivative is shown below:

[0042]

[0043] The application of the aforementioned dehydrocamelin derivative in the preparation of drugs for treating prostate cancer.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] The dehydrocamelin derivative of this invention exhibits strong antitumor activity and can effectively inhibit the proliferation of tumor cells. Furthermore, this dehydrocamelin derivative works by inhibiting DNA topoisomerase I, providing a novel DNA topoisomerase I inhibitor for suppressing tumor cell proliferation. Attached Figure Description

[0046] Figure 1 This is an assay of the inhibitory activity of compound G11 against Topo1.

[0047] Figure 2 It is the growth-inhibiting effect of compound G11 on MCF-7 cell xenografts. Detailed Implementation

[0048] The technical solutions of the present invention will be further described in detail below through embodiments, but it should not be construed as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies that can be implemented in the art based on the above content of the present invention should be included in the content of the present invention.

[0049] Example 1

[0050] Preparation of (E)-3-(4-bromophenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G1)

[0051]

[0052] Step (1), cyclization reaction: Add 0.5 mL of concentrated sulfuric acid (98% by mass), acetone aldehyde (10 mmol, 1 equivalent) and tryptamine (compound 1, 10 mmol, 1 equivalent) to 50 mL of water in sequence. Stir the reaction system at room temperature for 12 h. Monitor the reaction by TLC. After the reaction is complete, adjust the pH to 7 with 1 mol / L NaOH. A yellow solid precipitates out. Filter and wash the filter cake three times with water to obtain compound 2, a yellow solid. Compound 2 is used in the next step without purification.

[0053] Step (2), Oxidation reaction: Compound 2 (10 mmol, 1 equivalent) was dissolved in 50 mL of N,N-dimethylformamide (DMF) under an ice-water bath; potassium permanganate (20 mmol, 2 equivalent) was slowly added under an ice bath. The reaction system was stirred at room temperature for 10 hours and the reaction was monitored by TLC. After the reaction was completed, excess potassium permanganate was reduced with sodium bisulfite (NaHSO3), filtered, and the filter cake was discarded. A large amount of water was added to the filtrate to remove DMF. The filtrate was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was dried with anhydrous sodium sulfate, and then vacuum evaporated. The sample was mixed with silica gel and subjected to rapid column chromatography using an automated rapid chromatography system. The eluent was ethyl acetate and petroleum ether in a volume ratio of 3:17, the flow rate was 60 mL / min, and the detection wavelengths were 256 nm and 365 nm. The mobile phase containing the target compound was collected and vacuum evaporated to obtain compound 3, a yellow solid.

[0054] Step (3), condensation reaction: Compound 3 (1 mmol, 1 equivalent) and 4-bromobenzaldehyde (1 mmol, 1 equivalent) were added to 15 mL of anhydrous ethanol and stirred. The reaction system was a pale yellow transparent liquid. 1 mL of 20% sodium hydroxide solution was added dropwise to the reaction system, and the reaction system turned reddish-brown. The mixture was stirred at room temperature for 12 hours. The reaction process was monitored by TLC. After the reaction was completed, the reaction system was placed in an ice-water bath and the pH was adjusted to 4 with 1 mol / L hydrochloric acid. A yellow solid precipitated out. The mixture was filtered, the filtrate was discarded, and the filter cake was dried to obtain crude compound G1. 70 mg of crude G1 was dissolved in 5 mL of anhydrous ethanol at 60 °C. After complete dissolution, the mixture was cooled in an ice-water bath, and a yellow solid precipitated out to obtain pure compound G1 as a yellow powder with a yield of 37%.

[0055] 1 H NMR (600MHz, DMSO-d6) δ12.07(s,1H),8.61-8.54(m,2H),8.48(d,J=4.9Hz,1H),8.32(d,J=7.8H z,1H),7.90-7.82(m,4H),7.68(d,J=8.4Hz,2H),7.61(d,J=16.1Hz,1H),7.32(t,J=7.4Hz,1H).13 C NMR(151MHz,DMSO-d6)δ190.22,142.30,141.76,138.06,136.54,135.48,134.54,132.54,131 .57,131.07,129.47,124.44,122.61,122.34,120.77,120.43,120.08,113.62.HRMS(ESI):m / z calcd for C 20 H 13 BrN2O[M+H] + :377.02097; found377.0284.

[0056] Example 2

[0057] Preparation of (E)-3-(4-nitrophenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G2)

[0058]

[0059] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 4-nitrobenzaldehyde, to obtain compound G2, a yellow powder, with a yield of 15.3%.

[0060] 1 H NMR (600MHz, DMSO-d6) δ12.09(s,1H),8.66(d,J=16.2Hz,1H),8.60(d,J=4.9Hz,1H),8.48(d,J=4.9Hz,1H),8.31(d,J=7.8Hz,1H),8.2 9-8.25(m,2H),8.13-8.08(m,2H),7.95(d,J=16.2Hz,1H),7.84(d,J=8.2Hz,1H),7.61(ddd,J=8.2,7.0,1.2Hz,1H),7.34-7.28(m,1H). 13 C NMR(151MHz,DMSO-d6)δ189.99,148.47,142.32,141.62,140.22,138.10,136.30,135.53,13 1.65,130.12,129.51,125.73,124.54,122.34,120.83,120.42,113.63.HRMS(ESI):m / zcalcd for C 20 H 13 N3O3[M+H] +:344.09569; found344.10297.

[0061] Example 3

[0062] Preparation of (E)-3-(3-bromophenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)propyl-2-en-1-one (compound G3)

[0063]

[0064] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 3-bromobenzaldehyde, to obtain compound G3, a light yellow powder, with a yield of 31.8%.

[0065] 1 H NMR (500MHz, DMSO-d6) δ12.07(s,1H),8.62-8.53(m,2H),8.48(d,J=4.9Hz,1H),8.32(d,J=7.9Hz,1H),8.08(t,J=1.6Hz,1H) ,7.92-7.83(m,3H),7.66(dd,J=8.9,1.0Hz,1H),7.61(ddd,J=8.3,7.1,1.1Hz,1H),7.45(t,J=7.9Hz,1H),7.35-7.30(m,1H). 13 C NMR (126MHz, DMSO-d6) δ190.21,142.31,141.38,138.07,137.81,136.52,135.51,133.53,131.73,131.61 ,131.58,129.47,127.80,123.46,122.87,122.33,120.78,120.44,120.10,113.62.HRMS(ESI):m / zcalcd for C 20 H 13 BrN2O[M+H] + :377.02113; found377.0284.

[0066] Example 4

[0067] Preparation of (E)-3-(3-iodophenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)propyl-2-en-1-one (compound G4)

[0068]

[0069] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 3-iodobenzaldehyde, to obtain compound G4, a yellow powder, with a yield of 35.5%.

[0070] 1 H NMR(500MHz,DMSO-d6)δ12.07(s,1H),8.60(d,J=4.9Hz,1H),8.57-8.47(m,2H),8.33(d,J=7.8Hz,1H), 8.24(s,1H),7.91(d,J=7.9Hz,1H),7.87-7.81(m,3H),7.64-7.59(m,1H),7.31(dt,J=13.4,7.8Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ190.19,142.31,141.46,139.44,138.08,137.69,137.52,136.54,135.51 ,131.60,129.47,128.19,123.16,122.34,120.79,120.44,120.10,113.62,95.99.HRMS(ESI):m / z calcd for C 20 H 13 IN2O[M+H] + :425.00726; found 425.01453.

[0071] Example 5

[0072] Preparation of (E)-3-(2-chlorophenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G5)

[0073]

[0074] The preparation method is the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 is replaced with 2-chlorobenzaldehyde to obtain compound G5, a light yellow powder with a yield of 15.0%.

[0075] 1H NMR (500MHz, DMSO-d6) δ12.09(s,1H),8.63-8.54(m,2H),8.49(d,J=4.9Hz,1H),8.32(d,J=7.9Hz,1H),8.23(d,J=16.1H z,1H),8.09(dd,J=7.2,2.3Hz,1H),7.84(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.54-7.45(m,2H),7.32(t,J=7.9Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ190.05,142.34,138.08,137.93,136.34,135.59,134.81,132.92,132.48,131.66 ,130.62,129.54,128.81,128.45,124.58,122.36,120.83,120.43,120.18,113.59.HRMS(ESI):m / zcalcd for C 20 H 13 ClN2O[M+H] + :333.07164; found 333.07892.

[0076] Example 6

[0077] Preparation of (E)-3-(4-methoxyphenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G6)

[0078]

[0079] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 4-methoxybenzaldehyde to obtain compound G6, a yellow powder with a yield of 41.8%.

[0080] 1 H NMR (500MHz, DMSO-d6) δ12.03(s,1H),8.58(d,J=4.9Hz,1H),8.47-8.40(m,2H),8.31(d,J=7.9Hz,1H),7.89(d,J=1 6.1Hz,1H),7.84(dd,J=10.1,8.5Hz,3H),7.63-7.58(m,1H),7.33-7.29(m,1H),7.05(d,J=8.8Hz,2H),3.83(s,3H). 13C NMR (126MHz, DMSO-d6) δ190.27,161.89,143.17,142.25,137.98,136.89,135.44,131.46,131.06,12 9.37,127.91,122.28,120.67,120.45,119.77,119.36,115.08,113.59,55.87.HRMS(ESI):m / zcalcd for C 21 H 16 N₂O₂[M+H] + :329.12118; found 329.12845.

[0081] Example 7

[0082] Preparation of (E)-3-(4-ethylphenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G7)

[0083]

[0084] The preparation method is the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 is replaced with 4-ethylbenzaldehyde, to obtain compound G7, a light yellow powder, with a yield of 31.0%.

[0085] 1 H NMR(500MHz,DMSO-d6)δ12.04(s,1H),8.59(d,J=4.9Hz,1H),8.54-8.45(m,2H),8.32(d,J=7.9Hz,1H),7.93-7.83(m,2H), 7.78(d,J=8.1Hz,2H),7.61(ddd,J=8.2,7.2,1.1Hz,1H),7.36-7.29(m,3H),2.66(q,J=7.6Hz,2H),1.21(t,J=7.6Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ190.33,143.24,142.28,138.02,136.73,135.46,132.80,129.42,12 9.30,129.03,122.32,120.81,120.71,120.44,119.93,113.61,28.61,15.75.HRMS(ESI):m / z calcd for C 22 H 18 N₂O[M+H] + :327.14191; found 327.14919.

[0086] Example 8

[0087] Preparation of (E)-3-(4-fluoro-3-methoxyphenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)propyl-2-en-1-one (compound G8)

[0088]

[0089] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 3-methoxy-4-fluorobenzaldehyde, to obtain compound G8, a light yellow powder with a yield of 16.6%.

[0090] 1 H NMR(500MHz,DMSO-d6)δ12.06(s,1H),8.61(d,J=4.9Hz,1H),8.54-8.47(m,2H),8.33(d,J=7.8Hz,1H),7.93-7.83(m,2 H),7.68(dd,J=8.4,1.8Hz,1H),7.65-7.59(m,1H),7.48(ddd,J=8.5,4.5,2.0Hz,1H),7.36-7.30(m,2H),3.98(s,3H). 13 C NMR (126MHz, DMSO-d6) δ190.35,152.42,148.10,142.54,142.29,138.03,136.68,135.49,132.43,131 .54,129.44,122.32,121.95,120.75,120.44,119.98,116.97,116.82,114.10,56.69.HRMS(ESI):m / z calcd for C 21 H 15 FN2O2[M+H] + 347.11176; found 347.11903.

[0091] Example 9

[0092] Preparation of (E)-3-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G9)

[0093]

[0094] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 2,3-dihydrobenzo[b][1,4]dioxane-6-benzaldehyde, to obtain compound G9, a light yellow powder, with a yield of 58.1%.

[0095] 1 H NMR (500MHz, DMSO-d6) δ12.02(s,1H),8.58(d,J=4.9Hz,1H),8.46(d,J=4.9Hz,1H),8.39(d,J=16.0Hz,1H),8.31(d,J=7.8Hz, 1H),7.87-7.78(m,2H),7.61(t,J=8.2Hz,1H),7.40-7.34(m,2H),7.33-7.28(m,1H),6.97(d,J=8.2Hz,1H),4.34-4.28(m,4H). 13 CNMR(126MHz,DMSO-d6)δ190.23,146.38,144.16,143.05,142.25,138.00,136.85,135.43,131.47,129.38,12 8.79,122.77,122.29,120.68,120.45,119.99,119.80,118.20,117.82,113.59,64.91,64.47.HRMS(ESI):m / z calcd for C 22 H 16 N₂O₃[M+H] + :357.11609; found 357.12337.

[0096] Example 10

[0097] Preparation of (E)-3-(2,5-dichlorophenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G10)

[0098]

[0099] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 2,5-dichlorobenzaldehyde, to obtain compound G10, a light yellow powder with a yield of 27.2%.

[0100] 1H NMR (500MHz, DMSO-d6) δ12.11(s,1H),8.62-8.57(m,2H),8.50(d,J=4.9Hz,1H),8.33(d,J=7.8Hz,1H),8.15(d,J=2.5Hz, 1H), 8.11 (d, J = 16.1Hz, 1H), 7.84 (d, J = 8.2Hz, 1H), 7.65-7.60 (m, 2H), 7.56 (dd, J = 8.6, 2.5Hz, 1H), 7.33 (t, J = 7.5Hz, 1H). 13 C NMR (126MHz, DMSO-d6) δ190.03,142.33,138.16,136.54,136.27,135.62,134.81,133.27,133.11,132.20 ,131.92,131.64,129.54,128.31,126.25,122.37,120.86,120.44,120.30,113.60.HRMS(ESI):m / zcalcd for C 20 H 12 Cl2N2O[M+H] + 367.03267; found 367.03994.

[0101] Example 11

[0102] Preparation of (E)-3-(4-chloro-3-nitrophenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G11)

[0103]

[0104] The preparation method is the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 is replaced with 3-nitro-4-chlorobenzaldehyde, to obtain compound G11, a light yellow powder, with a yield of 35.5%.

[0105] 1 H NMR(500MHz,DMSO-d6)δ12.09(s,1H),8.68-8.58(m,3H),8.50(d,J=4.9Hz,1H),8.32(d,J=7.8Hz,1H),8.21 (dd,J=8.4,2.0Hz,1H),7.94(d,J=16.2Hz,1H),7.88-7.83(m,2H),7.65-7.60(m,1H),7.33(t,J=7.8Hz,1H). 13C NMR(151MHz,DMSO-d6)δ190.02,148.60,142.31,139.47,138.07,136.30,135.93,135.52,133 .63,132.62,131.63,129.50,125.66,125.02,122.36,120.82,120.41,113.64.HRMS(ESI):m / z calcd for C 20 H 12 ClN3O3[M+H] + 378.05672; found 378.064.

[0106] Example 12

[0107] Preparation of (E)-3-(2,6-dimethoxyphenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G12)

[0108]

[0109] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 2,6-dimethoxybenzaldehyde, to obtain compound G12, a light yellow powder with a yield of 28.5%. 1 H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.77(d,J=16.4Hz,1H),8.57(d,J=4.9Hz,1H),8.44(d,J=4.9Hz,1H),8.36-8.25(m,2H),7.8 3(d,J=8.2Hz,1H),7.60(ddd,J=8.2,7.2,1.1Hz,1H),7.41(t,J=8.4Hz,1H),7.36-7.23(m,1H),6.78(d,J=8.4Hz,2H),3.95(s,6H). 13 C NMR (126MHz, DMSO-d6) δ191.79,160.53,142.18,138.06,137.25,135.50,134.19,132.74,131.33 ,129.32,124.08,122.27,120.62,120.48,119.59,113.51,112.49,104.76,56.65.HRMS(ESI):m / z calcd forC 22 H 18 N₂O₃[M+H] + :359.13174; found 359.13902.

[0110] Example 13

[0111] Preparation of (E)-1-(9H-pyrido[3,4-b]indol-1-yl)-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one (compound G13)

[0112]

[0113] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 2,3,4-trimethoxybenzaldehyde, to obtain compound G13, a light yellow powder with a yield of 26.4%. 1 H NMR (500MHz, DMSO-d6) δ12.04(s,1H),8.58(d,J=4.7Hz,1H),8.47(d,J=16.1Hz,2H),8.31(d,J=7.8Hz,1H),8.09(d,J=16.2Hz,1H ),7.84(d,J=8.1Hz,1H),7.71-7.57(m,2H),7.31(t,J=7.4Hz,1H),6.95(d,J=8.8Hz,1H),3.91(s,3H),3.88(s,3H),3.80(s,3H). 13 C NMR (126MHz, DMSO-d6) δ190.47,156.26,153.70,142.41,142.25,138.02,137.90,136.93,135.50,131.44,129.3 8,123.85,122.29,121.73,120.67,120.46,120.40,119.76,113.55,109.15,62.00,60.98,56.54.HRMS(ESI):m / z calcd for C 23 H 20 N₂O₄[M+H] + :389.14231; found 389.14958.

[0114] Example 14

[0115] Preparation of (E)-3-(2-bromo-4,5-dimethoxyphenyl)-1-(9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G14)

[0116]

[0117] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 2-bromo-4,5-dimethoxybenzaldehyde, to obtain compound G14, an orange-yellow powder with a yield of 25.9%. 1 H NMR(500MHz,DMSO-d6)δ12.13(s,1H),8.60(d,J=5.0Hz,1H),8.54-8.42(m,2H),8.33(d,J=7.9Hz,1H),8.18(d,J=15.8Hz,1H),7 .83(d,J=8.2Hz,1H),7.62(ddd,J=8.3,7.2,1.1Hz,1H),7.57(s,1H),7.35-7.31(m,1H),7.29(s,1H),3.93(s,3H),3.86(s,3H). 13 C NMR (126MHz, DMSO-d6) δ189.82,152.28,149.21,142.48,141.44,137.57,136.14,135.52,131.90,129.67,12 6.38,122.44,122.23,120.86,120.38,120.00,118.23,116.29,113.58,110.55,56.62,56.49.HRMS(ESI):m / z calcd for C 22 H 17 BrN2O3[M+H] + :437.04226; found 437.04953.

[0118] Example 15

[0119] Preparation of (E)-1-(9H-pyrido[3,4-b]indol-1-yl)-3-(3,4,5-trifluorophenyl)prop-2-en-1-one (compound G15)

[0120]

[0121] The preparation method was the same as in Example 1, except that the amount of 4-bromobenzaldehyde and other substances in Example 1 was replaced with 3,4,5-trifluorobenzaldehyde, to obtain compound G15, a light yellow powder with a yield of 25.3%. 1H NMR(500MHz,DMSO-d6)δ12.06(s,1H),8.59(d,J=4.9Hz,1H),8.56-8.48(m,2H),8.32(d,J=7.8Hz, 1H),7.94(dd,J=8.9,6.9Hz,2H),7.87-7.79(m,2H),7.62(t,J=7.7Hz,1H),7.33(t,J=7.9Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ190.18,142.31,140.04,138.07,136.39,135.52,131.61,129.49,129.46 ,122.34,120.82,120.44,120.19,113.86,113.82,113.72,113.69,113.62.HRMS(ESI):m / zcalcd for C 20 H 11 F3N2O[M+H] + :353.08235; found 353.08962.

[0122] Example 16

[0123] Preparation of (E)-3-(4-bromophenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G16)

[0124]

[0125] The preparation method was the same as in Example 1, except that the tryptamine in Example 1 was replaced with 5-methoxytryptamine, to obtain compound G16, a yellow powder, with a yield of 15.5%. 1 H NMR(500MHz,Chloroform-d)δ10.40(s,1H),8.63-8.52(m,2H),8.14(d,J=4.0Hz,1H),7.90(d,J=15.9 Hz,1H),7.65(d,J=7.6Hz,2H),7.60(s,1H),7.57(d,J=7.4Hz,2H),7.52(d,J=8.5Hz,2H),3.95(s,3H). 13C NMR(151MHz,Chloroform-d)δ194.90,159.25,146.42,142.20,141.81,141.30,140.61,139.31,137.26 ,136.25,135.84,129.15,127.37,125.60,124.93,124.20,119.24,108.91,60.85.HRMS(ESI):m / zcalcd for C 21 H 15 BrN2O2[M+H] + :407.03169; found407.03897.

[0126] Example 17

[0127] Preparation of (E)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one (compound G17)

[0128]

[0129] The preparation method is the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 is replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances is replaced with 4-nitrobenzaldehyde, to obtain compound G17, a reddish-brown powder with a yield of 13.4%. 1 HNMR (600MHz, DMSO-d6) δ11.94(s,1H),8.67(d,J=16.2Hz,1H),8.52(dd,J=51.0,4.8Hz,2H),8.29(d,J=8.7Hz,2H),8.13(d, J=8.7Hz,2H),7.96(d,J=16.2Hz,1H),7.88(d,J=2.1Hz,1H),7.74(d,J=8.8Hz,1H),7.26(dd,J=8.8,2.4Hz,1H),3.88(s,3H). 13 C NMR (151MHz, DMSO-d6) δ189.93,154.55,148.49,141.68,140.13,137.52,137.08,136.33,135.92,131. 59,130.14,125.78,124.57,120.85,120.40,119.41,114.47,104.21,56.10.HRMS(ESI):m / zcalcdforC 21 H 15 N3O4[M+H] +:374.10626; found374.11353.

[0130] Example 18

[0131] Preparation of (E)-3-(3-bromophenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G18)

[0132]

[0133] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 3-bromobenzaldehyde, to obtain compound G18, an orange powder with a yield of 39.3%. 1 H NMR (500MHz, DMSO-d6) δ11.93(s,1H),8.57(dd,J=10.4,5.5Hz,2H),8.48(d,J=4.7Hz,1H),8.09(s,1H),7. 89(t,J=12.9Hz,3H),7.72(dd,J=40.1,8.0Hz,2H),7.47(t,J=7.7Hz,1H),7.32-7.20(m,1H),3.90(s,3H). 13 C NMR(126MHz,DMSO-d6)δ190.13,154.52,141.25,137.83,137.46,137.07,136.52,135.89,133.50,131.71 ,131.61,131.50,127.78,123.46,122.86,120.86,120.20,119.35,114.44,104.24,56.13.HRMS(ESI):m / z calcd forC 21 H 15 BrN2O2[M+H] + 407.03169; found 407.03897.

[0134] Example 19

[0135] Preparation of (E)-3-(3-iodophenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G19)

[0136]

[0137] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 3-iodobenzaldehyde, to obtain compound G19, a light orange powder with a yield of 37.3%. 1 H NMR(500MHz,DMSO-d6)δ11.91(s,1H),8.57-8.49(m,2H),8.46(d,J=4.9Hz,1H),8.23(s,1H),7.92-7.86(m,2 H),7.85-7.80(m,2H),7.74(d,J=8.9Hz,1H),7.29(t,J=7.8Hz,1H),7.25(dd,J=8.9,2.5Hz,1H),3.88(s,3H). 13 C NMR (126MHz, DMSO-d6) δ190.11,154.52,141.30,139.40,137.70,137.48,137.45,137.08,136.54,135.89 ,131.58,131.50,128.16,123.15,120.86,120.18,119.35,114.44,104.24,95.98,56.13.HRMS(ESI):m / z calcd forC 21 H 15 IN₂O₂[M+H] + :455.01782; found 455.0251.

[0138] Example 20

[0139] Preparation of (E)-3-(2-chlorophenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G20)

[0140]

[0141] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 2-chlorobenzaldehyde, to obtain compound G20, a yellow powder with a yield of 36.7%. 1H NMR (500MHz, DMSO-d6) δ11.93(s,1H),8.60-8.52(m,2H),8.46(d,J=5.0Hz,1H),8.21(d,J=16.1Hz,1H),8.09(dd,J=7.2,2.3Hz,1 H),7.87(d,J=2.5Hz,1H),7.74(d,J=8.9Hz,1H),7.60(dd,J=7.0,2.2Hz,1H),7.52-7.44(m,2H),7.27-7.24(m,1H),3.88(s,3H). 13 C NMR(126MHz,DMSO-d6)δ190.01,154.55,137.75,137.09,136.40,135.99,134.79,132.95,131.53 ,130.61,128.79,128.43,124.61,120.87,120.27,119.37,114.41,104.28,56.13.HRMS(ESI):m / z calcd for C 21 H 15 ClN2O2[M+H] + 363.08221; found 363.08948.

[0142] Example 21

[0143] Preparation of (E)-3-(4-fluoro-3-methoxyphenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G21)

[0144]

[0145] The preparation method is the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 is replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances is replaced with 3-methoxy-4-fluorobenzaldehyde, to obtain compound G21, a yellow powder, 39.3%. 1HNMR(500MHz,DMSO-d6)δ11.89(s,1H),8.56(d,J=4.9Hz,1H),8.52-8.45(m,2H),7.91-7.86(m,2H),7.75(d,J=8.8Hz,1H),7.67(dd,J= 8.4,1.9Hz,1H),7.47(ddd,J=8.3,4.4,1.9Hz,1H),7.32(dd,J=11.2,8.4Hz,1H),7.26(dd,J=8.9,2.5Hz,1H),3.97(s,3H),3.88(s,3H). 13 CNMR(126MHz,DMSO-d6)δ190.28,154.50,152.40,148.09,142.41,137.42,137.06,136.69,135.88,132.45,13 1.46,122.59,121.94,120.86,120.07,119.33,116.82,114.44,114.07,104.23,56.68,56.13.HRMS(ESI):m / z calcd for C 22 H 17 FN2O3[M+H] + :377.12232; found 377.1296.

[0146] Example 22

[0147] Preparation of (E)-3-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G22)

[0148]

[0149] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 2,3-dihydrobenzo[b][1,4]dioxane-6-benzaldehyde, to obtain compound G22, a yellow powder with a yield of 54.4%. 1H NMR (500MHz, DMSO-d6) δ11.85(s,1H),8.53(d,J=4.9Hz,1H),8.43(d,J=4.9Hz,1H),8.38(d,J=16.1Hz,1H),7.87(d,J=2.5Hz,1H),7.80(d,J =16.0Hz,1H),7.74(d,J=8.9Hz,1H),7.39-7.34(m,2H),7.25(dd,J=8.9,2.5Hz,1H),6.96(d,J=8.2Hz,1H),4.34-4.28(m,4H),3.88(s,3H). 13 C NMR (126MHz, DMSO-d6) δ190.17,154.46,146.34,144.15,142.91,137.38,137.03,136.86,135.84,131.38,128.8 1,122.73,120.86,120.02,119.88,119.27,118.19,117.79,114.41,104.20,64.90,64.47,56.12.HRMS(ESI):m / z calcd for C 23 H 18 N₂O₄[M+H] + :387.12666; found 387.13393.

[0150] Example 23

[0151] Preparation of (E)-3-(2,5-dichlorophenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G23)

[0152]

[0153] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 2,5-dichlorobenzaldehyde, to obtain compound G23, a yellow powder with a yield of 43.3%. 1HNMR(500MHz,DMSO-d6)δ11.95(s,1H),8.64-8.55(m,2H),8.49(d,J=4.9Hz,1H),8.18-8.08(m,2H),7.89(d,J=2.5Hz,1 H),7.74(d,J=8.8Hz,1H),7.64(d,J=8.6Hz,1H),7.57(dd,J=8.6,2.5Hz,1H),7.26(dd,J=8.9,2.5Hz,1H),3.88(s,3H). 13 C NMR(126MHz,DMSO-d6)δ189.96,154.58,137.56,137.09,136.42,136.28,136.00,134.85,133.26,133.11 ,132.21,131.91,131.58,128.31,126.29,120.88,120.41,119.42,114.43,104.30,56.14.HRMS(ESI):m / z calcd for C 21 H 14 Cl2N2O2[M+H] + :397.04323; found 397.05051.

[0154] Example 24

[0155] Preparation of (E)-3-(4-chloro-3-nitrophenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G24)

[0156]

[0157] The preparation method is the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 is replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances is replaced with 3-nitro-4-chlorobenzaldehyde, to obtain compound G24, an orange-yellow powder with a yield of 73.6%. 1HNMR (500MHz, DMSO-d6) δ11.94(s,1H),8.65(d,J=16.2Hz,1H),8.62(d,J=2.0Hz,1H),8.57(d,J=4.9Hz,1H),8.49(d,J=4.9Hz,1H),8.21(dd,J=8.5 ,2.0Hz,1H),7.93(d,J=16.2Hz,1H),7.89(d,J=2.4Hz,1H),7.87(d,J=8. 4Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.27 (dd, J=8.9, 2.5Hz, 1H), 3.90 (s, 3H). 13 C NMR (126MHz, DMSO-d6) δ189.98,154.56,148.63,139.35,137.47,137.09,136.34,135.99,135.92,133.59 ,132.60,131.56,126.43,125.64,125.10,120.86,120.35,119.39,114.46,104.25,56.12.HRMS(ESI):m / z calcd forC 21 H 14 ClN3O4[M+H] + :408.06728; found 408.07456.

[0158] Example 25

[0159] Preparation of (E)-3-(4-chloro-3-methylphenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G25)

[0160]

[0161] The preparation method is the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 is replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances is replaced with 3-methyl-4-chlorobenzaldehyde, to obtain compound G25, a yellow powder with a yield of 20.2%. 1 HNMR(500MHz,DMSO-d6)δ11.88(s,1H),8.54(d,J=4.9Hz,1H),8.51-8.42(m,2H),7.85(dd ,J=15.8,2.8Hz,3H),7.74(d,J=8.9Hz,2H),7.28-7.20(m,2H),3.88(s,3H),2.31(s,3H). 13CNMR(126MHz,DMSO-d6)δ190.21,161.51,154.50,142.06,137.39,137.06,136.67,135.88,132.28,131.45,12 9.18,125.77,121.52,120.86,120.03,119.31,116.24,116.06,114.42,104.22,56.12,14.52.HRMS(ESI):m / z calcd for C 22 H 17 ClN2O2[M+Na] + 399.09786; found 399.08994.

[0162] Example 26

[0163] Preparation of (E)-3-(2,6-dimethoxyphenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G26)

[0164]

[0165] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 2,6-dimethoxybenzaldehyde, to obtain compound G26, a yellow powder with a yield of 44.1%. 1 HNMR (500MHz, DMSO-d6) δ11.84(s,1H),8.76(d,J=16.4Hz,1H),8.53(d,J=4.9Hz,1H),8.42(d,J=4.9Hz,1H),8.30(d,J=16.4Hz,1H),7.87( d,J=2.4Hz,1H),7.73(d,J=8.9Hz,1H),7.40(t,J=8.4Hz,1H),7.25(dd,J=8.9,2.5Hz,1H),6.78(d,J=8.4Hz,2H),3.94(s,6H),3.88(s,3H). 13 C NMR(126MHz,DMSO-d6)δ191.73,160.50,154.43,137.44,137.27,136.97,135.91,134.05,132.69,13 1.24,124.13,120.89,119.68,119.20,114.34,112.50,104.75,104.23,56.64,56.13.HRMS(ESI):m / z calcd for C23 H 20 N₂O₄[M+H] + :389.1431; found 389.14958.

[0166] Example 27

[0167] Preparation of (E)-3-(2,6-dimethylphenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G27)

[0168]

[0169] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 2,6-dimethylbenzaldehyde, to obtain compound G27, an orange powder with a yield of 42.1%. 1 HNMR(500MHz,DMSO-d6)δ11.94(s,1H),8.52(d,J=4.9Hz,1H),8.44(d,J=5.3Hz,1H),8.17-8.03(m,2H),7.88(d ,J=2.5Hz,1H),7.74(d,J=8.9Hz,1H),7.26(dd,J=8.9,2.5Hz,1H),7.21-7.14(m,3H),3.88(s,3H),2.43(s,6H). 13 C NMR (126MHz, DMSO-d6) δ190.25,154.52,140.96,137.54,137.31,137.08,136.63,136.00,134.52,13 1.45,129.02,128.91,127.18,120.87,120.08,119.33,114.39,104.28,56.14,21.41.HRMS(ESI):m / z calcd forC 23 H 20 N₂O₂[M+H] + 357.15248; found 357.15975.

[0170] Example 28

[0171] Preparation of (E)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one (compound G28)

[0172]

[0173] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 2,3,4-trimethoxybenzaldehyde, to obtain compound G28, a yellow powder with a yield of 29.4%. 1 H NMR (500MHz, DMSO-d6) δ11.88(s,1H),8.54(d,J=4.9Hz,1H),8.50-8.41(m,2H),8.07(d,J=16.2Hz,1H),7.87(d,J=2.5Hz,1H),7.73 (d,J=8.8Hz,1H),7.66(d,J=8.8Hz,1H),7.25(dd,J=8.9,2.5Hz,1H),6.95(d,J=8.9Hz,1H),3.91(s,3H),3.88(s,6H),3.80(s,3H). 13 CNMR(126MHz,DMSO-d6)δ190.41,156.23,154.47,153.67,142.39,137.76,137.40,137.02,136.93,135.91,131.36,1 23.81,121.74,120.87,120.41,119.86,119.27,114.36,109.13,104.23,61.99,60.97,56.53,56.13.HRMS(ESI):m / z calcd for C 24 H 22 N₂O₅[M+H] + :419.15287; found419.16015.

[0174] Example 29

[0175] Preparation of (E)-3-(2-bromo-4,5-dimethoxyphenyl)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)prop-2-en-1-one (compound G29)

[0176]

[0177] The preparation method was the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 was replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances was replaced with 2-bromo-4,5-dimethoxybenzaldehyde, to obtain compound G29, a yellow powder with a yield of 39.4%. 1H NMR (500MHz, DMSO-d6) δ11.93(s,1H),8.56(d,J=4.9Hz,1H),8.47-8.41(m,2H),8.18(d,J=15.9Hz,1H),7.88(d,J=2.5Hz, 1H),7.73(d,J=8.8Hz,1H),7.55(s,1H),7.30(s,1H),7.26(dd,J=8.9,2.5Hz,1H),3.93(s,3H),3.88(s,3H),3.86(s,3H). 13 C NMR (126MHz, DMSO-d6) δ190.19,154.51,152.20,149.21,141.12,137.44,137.05,136.69,135.97,131.43,126.4 3,122.31,120.87,120.07,119.33,118.13,116.30,114.36,110.51,104.27,56.62,56.46,56.14.HRMS(ESI):m / z calcd for C 23 H 19 BrN2O4[M+H] + :467.05282; found 467.0601.

[0178] Example 30

[0179] Preparation of (E)-1-(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)-3-(3,4,5-trifluorophenyl)prop-2-en-1-one (compound G30)

[0180]

[0181] The preparation method is the same as in Example 1, except that the amount of tryptamine and other substances in Example 1 is replaced with 5-methoxytryptamine, and the amount of 4-bromobenzaldehyde and other substances is replaced with 3,4,5-trifluorobenzaldehyde, to obtain compound G30, an orange-yellow powder with a yield of 49.0%. 1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),8.56-8.45(m,3H),7.93(dd,J=8.9,6.9Hz,1H),7.88(d,J=2.3H z,1H),7.81(dd,J=16.1,5.8Hz,1H),7.74(d,J=8.9Hz,1H),7.26(dd,J=8.9,2.5Hz,1H),3.88(s,3H). 13C NMR(126MHz,DMSO-d6)δ190.11,154.55,139.92,137.46,137.07,136.53,136.40,135.91,131.53,12 4.66,123.37,120.87,120.29,120.18,119.38,114.45,113.84,104.25,56.13,15.77.HRMS(ESI):m / z calcd for C 21 H 13 F3N2O2[M+H] + :383.09291; found383.10019.

[0182] Example 31

[0183] Antiproliferative experiment on tumor cells

[0184] The antiproliferative activity of compounds G1-G30 of this invention against tumor cells was tested.

[0185] Tumor cells: Breast cancer cells MCF-7 (DMEM complete medium), breast cancer cells MDA-MB-231 (DMEM complete medium), liver cancer cells HepG2 (DMEM complete medium), colorectal cancer cells HT29 (1640 complete medium), non-small cell lung cancer cells A549 (DMEM complete medium), prostate cancer cells PC-3 (1640 complete medium), and breast cancer 4T1 cells (1640 complete medium).

[0186] Methods: Cells were digested, counted, and prepared to a concentration of 5×10⁻⁶. 4 Add 100 μL of cell suspension per well to each well of a 96-well plate (3 × 10⁶ cells / mL). 3 -5×10 3 (cells). Incubate the 96-well plate at 37°C in a 5% CO2 incubator for 24 hours. Dilute the drug to the desired concentration with complete culture medium, adding 100 μL of the corresponding drug-containing medium to each well. Incubate the 96-well plate at 37°C in a 5% CO2 incubator for 48 hours. Add 20 μL of MTT (5 mg / mL) to each well and continue incubating for 4 hours. Discard the culture medium, add 150 μL of DMSO to each well to dissolve, and gently mix by shaking for 10 minutes. Read the OD value of each well using a microplate reader at λ = 570 nm. Analyze the results using Graphpad Prism 8.0.2.

[0187] The results of the antiproliferative activity test of compounds G1-G30 against tumor cells are shown in Table 1.

[0188] Table 1. Anti-cell proliferation activity of compounds

[0189]

[0190]

[0191] The results showed that, except for compounds G6, G7, and G17, the remaining compounds of this invention had significant inhibitory effects on tumor cells, and their effects were superior to those of the positive control drug, Harmine, which can be used to treat cancer.

[0192] Example 32

[0193] DNA topoisomerase I inhibition assay

[0194] Compound G11, which has good anti-cell proliferation activity, was selected, and its inhibitory activity against DNA topoisomerase I (Topo1) was tested.

[0195] The inhibitory activity of compounds against Topo1 is generally determined by the DNA relaxation assay. The reaction system for the DNA relaxation assay is 10 μL, and the experiment consists of six lanes. Lane 1 contains 5 μL of 0.1 μg / μL pBR322 DNA and 5 μL of nuclease-free water. Lane 2 contains 5 μL of 0.1 μg / μL pBR322 DNA, 1 μL of 10× Reaction Buffer, 0.05 μL of 10 U / μL Vaccinia DNATopoisomerase I, and 3.95 μM nuclease-free water. The other four lanes contain 5 μL of 0.1 μg / μL pBR322 DNA, 1 μL of 10× Reaction Buffer, and 0.05 μL of 10 U / μL Vaccinia DNATopoisomerase I, respectively. I and the corresponding compounds (final CPT concentration of 100 μM in lane 3, and final concentrations of compound G11 of 25 μM, 50 μM, and 100 μM in lanes 4, 5, and 6, respectively) were added, and the reaction mixture was brought to 10 μL with Nuclease-free water. The reaction mixture was incubated at 37 °C for 90 min, and 2 μL of InstantView red fluorescent DNA loading buffer was added. After vortexing, the sample was loaded and electrophoresed in a horizontal electrophoresis tank. The sample was developed on a 1% agarose gel and electrophoresed in TAE buffer at 105 V for 35 min. Finally, the gel was imaged and developed under UV light.

[0196] The results are as follows Figure 1As shown in the diagram, the addition of Topo1 (lane 2) causes the supercoiled DNA to relax, resulting in a decrease in electrophoretic mobility. The addition of the positive control drug CPT (lane 3) shows that CPT can reduce the degree of DNA relaxation by inhibiting Topo1. According to lanes 4, 5, and 6, compound G11 can also inhibit the relaxation of supercoiled DNA by inhibiting Topo1, and this inhibition is concentration-dependent.

[0197] Example 33

[0198] Compound G11 inhibits the growth of 4T1 breast cancer cell allogeneic xenografts.

[0199] An allogeneic breast cancer mouse model was constructed using 4T1 cells to evaluate the in vivo antitumor effect of compound G11.

[0200] 4-5 week old female BALB / c mice (purchased from Jiangsu Huachuang Xinno Pharmaceutical Technology Co., Ltd. (Jiangsu, China)). The fur on the dorsal side of the mice was shaved and depilatory cream was applied to facilitate inoculation and observation of tumor size. Logarithmic growth phase 4T1 cells were resuspended in PBS and subcutaneously injected into the dorsal side of the BALB / c mice, with approximately 5 × 10⁶ cells per mouse. 5 200 μL of cells were inoculated. After inoculation, when the average tumor volume reached 100 mm², [further action was taken]. 3 Drug administration could begin immediately. Mice were randomly divided into five groups: a model group, a positive control group, and three experimental groups with different doses, each containing six mice. Mice in the positive control group received intraperitoneal injections of 10 mg / kg irinotecan (irinotecan dissolved in a solvent, 200 μL per mouse per injection; the solvent was a mixture of DMSO, Tween 80, and physiological saline in a volume ratio of 1:1:8, the same below), once daily for 14 days. Mice in the three experimental groups received intraperitoneal injections of 5 mg / kg, 10 mg / kg, and 20 mg / kg of compound G11 (compound G11 dissolved in a solvent, 200 μL per mouse per injection), respectively, once daily for 14 days. Mice in the model group received an equal volume of solvent intraperitoneally, once daily for 14 days. Tumor volume was measured every two days. After 14 days, mice were sacrificed, tumors were removed, and weighed. The tumor growth inhibition rate (%) was calculated, and the results were analyzed using GraphPad Prism 8.0.2. Statistical analysis between groups was performed using the t-test.

[0201] Experimental results are as follows Figure 2 As shown, compound G11 effectively inhibits the growth of autologous tumors in vivo, significantly reducing tumor volume. At a dose of 20 mg / kg, compound G11 achieved a tumor inhibition rate of 63.87%.

Claims

1. Dehydrocamelin derivatives or pharmaceutically acceptable salts thereof with the following structure: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 2. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the dehydrocamelin derivative of claim 1 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

3. The use of the dehydrocamelin derivative of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of DNA topoisomerase I inhibitors.

4. The use of the dehydrocamelin derivative of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a medicament for treating tumors.

5. The application according to claim 4, characterized in that: The tumors mentioned are breast cancer, liver cancer, colorectal cancer cells, non-small cell lung cancer, and prostate cancer.

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