5,6,7-trimethoxy-2,3-dihydroquinoline compounds, pharmaceutical compositions and uses

Abstract

The present invention discloses a 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof; further discloses a pharmaceutical composition comprising a therapeutically effective amount of a 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; further discloses the use of the above-mentioned 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof in an anti-tumor drug and in the preparation of a microtubule protein target inhibitor drug. The present invention compound has a significant inhibitory effect on microtubule protein targets, has good anti-tumor cell proliferation activity, and has a potential prospect of drugability in tumor treatment.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof, a method for preparing the compound, a pharmaceutical composition containing the compound, and the use of the compound or the composition in anti-tumor drugs and drugs related to inhibiting tubulin activity or angiogenesis. Background Art

[0002] Tumors, especially malignant tumors, are currently one of the major diseases that affect human life and health. Since the 1980s, the incidence and mortality of malignant tumors in China have been on an upward trend. According to relevant statistics, about a quarter of the deaths are caused by malignant tumors. In recent years, the design of drugs related to cancer treatment has always been a hot topic. Nowadays, anti-tumor drugs based on the molecular mechanisms of cancer occurrence, such as angiogenesis, signal transduction or apoptosis induction, are designed and developed. However, the existing anti-tumor drugs still cannot meet clinical needs in terms of high efficacy and low toxicity. In clinical practice, patients and doctors still need more satisfactory treatment options, so there is still a need to find new low-toxic and high-efficiency anti-tumor drugs.

[0003] Tubulin is an important target for the development of anti-tumor drugs. It plays an important role in cell division, material transport, signal transduction, and maintaining cell morphology. Tumor cells undergo vigorous mitosis, so inhibiting the physiological effects of microtubules in tumor cells can inhibit the occurrence and development of tumors. Drugs that act on tubulin work by changing the dynamics of tubulin, such as changing the polymerization and depolymerization of tubulin. Among these drug molecules, most can bind to tubulin dimers, causing tubulin to be unable to continue normal physiological activities, such as interfering with the mitotic process.

[0004] Based on the structure of tubulin inhibitor CA-4, the present invention studies a class of 5,6,7-trimethoxy-2,3-dihydroquinoline compounds with tubulin polymerization inhibitory activity, which has great application potential in anti-tumor. Summary of the invention

[0005] Purpose of the invention: The technical problem to be solved by the present invention is to provide a 5,6,7-trimethoxy-2,3-dihydroquinoline compound having the structural characteristics of general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and use thereof. The compound has good microtubule polymerization inhibitory activity and good anti-tumor cell proliferation activity.

[0006] Technical solution: The present invention provides a 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof represented by the general formula (I):

[0007]

[0008] Wherein: R1 represents hydrogen, methyl, ethyl, propyl, hydroxymethyl or N,N-dimethylaminomethyl.

[0009] Preferably, in the 5,6,7-trimethoxy-2,3-dihydroquinoline compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, R1 represents hydrogen, methyl or ethyl.

[0010] Furthermore, the present invention provides a 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof represented by the general formula (II):

[0011]

[0012] in:

[0013] X represents carbon atom, nitrogen atom, oxygen atom;

[0014] Y represents a carbon atom, a nitrogen atom, and an oxygen atom;

[0015] n is 1 or 2.

[0016] Preferably, X in the compound of general formula (II) or its pharmaceutically acceptable salt represents an oxygen atom;

[0017] Y represents an oxygen atom; n is 1 or 2.

[0018] Furthermore, the present invention provides a 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof represented by the general formula (III):

[0019]

[0020] in:

[0021] Z represents CO or CH2;

[0022] R2 represents hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxyl or halogen;

[0023] R3 represents hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy or halogen.

[0024] Preferably, in the compound of general formula (II) or a pharmaceutically acceptable salt thereof, Z represents CO or CH2; R2 represents hydrogen, methyl or methoxy; and R3 represents hydrogen, methoxy or hydroxyl.

[0025] Specifically, the 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof represented by general formula (I), (II) or (III) is preferably selected from:

[0026] 1-(1H-indol-3-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0027]

[0028] 1-(1H-indol-4-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0029]

[0030] 1-(1H-indol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0031]

[0032] 1-(1H-indol-6-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0033]

[0034] 5,6,7-trimethoxy-1-(1-methyl-1H-indol-4-yl)-2,3-dihydroquinolin-4(1H)-one,

[0035]

[0036] 5,6,7-trimethoxy-1-(1-methyl-1H-indol-5-yl)-2,3-dihydroquinolin-4(1H)-one,

[0037]

[0038] 5,6,7-trimethoxy-1-(1-methyl-1H-indol-6-yl)-2,3-dihydroquinolin-4(1H)-one,

[0039]

[0040] 1-(1-ethyl-1H-indol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0041]

[0042] 1-(Benzo[d][1,3]dioxazol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0043]

[0044] 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0045]

[0046] 2-methoxy-5-(5,6,7-trimethoxy-3,4-dihydroquinolin-1(2H)-yl)phenol,

[0047]

[0048] 1-(3-Hydroxy-4-methoxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0049]

[0050] 1-(3-Hydroxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0051]

[0052] 5,6,7-trimethoxy-1-(4-methoxyphenyl)-2,3-dihydroquinolin-4(1H)-one,

[0053]

[0054] 5,6,7-trimethoxy-1-(p-phenylmethyl)-2,3-dihydroquinolin-4(1H)-one,

[0055]

[0056] 5,6,7-trimethoxy-1-(3,4,5-trimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one,

[0057]

[0058] 1-(3,4-dimethoxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one,

[0059]

[0060] Furthermore, the present invention also provides a pharmaceutical composition, which is mainly composed of a therapeutically effective amount of an active component and a pharmaceutically acceptable excipient; the active component includes the 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. In the pharmaceutical composition, the excipients used include pharmaceutically acceptable carriers, diluents and / or excipients.

[0061] According to the therapeutic purpose, the pharmaceutical composition can be prepared into various types of dosage unit forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., preferably tablets, capsules, liquids, suspensions and injections (solutions and suspensions). In order to shape the pharmaceutical composition in the form of tablets, pills or suppositories, any excipients known and widely used in the art can be used.

[0062] In order to prepare the pharmaceutical composition in the form of injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol) and made into an injection with an osmotic pressure equal to that of blood. When preparing the injection, any commonly used carrier in the art can also be used, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, etc. In addition, common solvents and buffers can also be added.

[0063] The content of the compound provided by the present invention in the pharmaceutical composition is not particularly limited and can be selected within a wide range, usually 1-50% by mass.

[0064] There is no particular limitation on the administration method of the pharmaceutical composition provided by the present invention, and various dosage forms of preparations can be selected for administration according to the patient's age, gender, and other conditions and symptoms.

[0065] In addition to the above, the present invention also provides the use of 5,6,7-trimethoxy-2,3-dihydroquinoline compounds or pharmaceutically acceptable salts thereof in anti-tumor drugs and in the preparation of microtubule protein target inhibitor drugs; and the use of pharmaceutical compositions in anti-tumor drugs and in the preparation of microtubule protein target inhibitor drugs. Among them, tumors include but are not limited to colon cancer, leukemia, liver cancer, breast cancer, gastric cancer or pancreatic cancer.

[0066] Beneficial effects: Compared with the prior art, the significant advantages of the present invention are: the 5,6,7-trimethoxy-2,3-dihydroquinoline compounds are a class of compounds with a brand-new skeleton structure, which innovatively introduces aromatic rings or heterocyclic rings with or without substituents into the nitrogen atom of the skeleton 5,6,7-trimethoxy-2,3-dihydroquinoline, and for the first time realizes the role of this type of skeleton structure in inhibiting the in vivo and in vitro polymerization of tubulin, thereby producing the effect of inhibiting microtubule targets.

[0067] Pharmacological experiments show that the 5,6,7-trimethoxy-2,3-dihydroquinoline compounds have a significant inhibitory effect on the microtubule protein target. Further pharmacological experiments found that the compound 1-(1-ethyl-1H-indol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinoline-4(1H)-one (i.e., compound 8) has a better cell proliferation inhibition effect in human chronic myeloid leukemia K562 cells than the positive control compound CA-4, IC 50 It reaches nanomolar levels and therefore has potential drugability in tumor treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 This is an experimental characterization diagram of the in vitro anti-microtubule polymerization activity of the compound of the present invention, 1-(1-ethyl-1H-indol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (ie, compound 8). DETAILED DESCRIPTION

[0069] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments.

[0070] Example 1

[0071] 1-(1H-indol-3-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 1), the structural formula is shown below:

[0072]

[0073] The synthesis process is as follows:

[0074]

[0075] 1.1 Synthesis of 5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one

[0076]

[0077] Dissolve 3,4,5-trimethoxyaniline (3.0 g, 16.37 mmol, 1.0 eq) in DCM (200 mL), add anhydrous K2CO3 (2.72 g, 19.65 mmol, 1.2 eq). Add 20 mL DCM solution of bromopropionyl chloride (1.96 mL, 19.65 mmol, 1.2 eq) dropwise into the above solution under ice bath, and stir at room temperature for 3 h. After the reaction is completed, monitor the reaction by TLC (PE:EA=1:1), and add water (200 mL) to quench. Add DCM to extract (250 mL×3), combine the organic layers, wash with water, wash with saturated brine, and dry with anhydrous sodium sulfate. The solvent is dried under reduced pressure to obtain the product, and 5.13 g of light yellow solid 3-bromo-N-(3,4,5-trimethoxyphenyl) acrylamide is obtained, with a yield of 98.4%. 1 H NMR (300MHz, DMSO-d6) δ10.01 (s, 1H), 6.99 (s, 2H), 3.77–3.68 (m, 8H), 3.61 (s, 3H), 2.92 (t, J = 6.3Hz, 2H).

[0078] The product of the previous step (5.13g, 16.12mmol, 1.0eq) was dissolved in DMF (50mL), and the above solution was added to a DMF solution (150mL) of sodium tert-butoxide (1.55g, 16.12mmol, 1.0eq) under ice bath, and stirred at room temperature overnight. TLC monitoring (PE:EA=2:1) After the reaction is completed, water (100mL) was added to quench, EA extraction (200mL×3), the organic layer was washed with water 3 times, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was dried under reduced pressure to obtain the product, and 3.43g of dark yellow solid 1-(3,4,5-trimethoxyphenyl)azetidine-2-one was obtained, with a yield of 89.7%. 1 H NMR (300MHz, DMSO-d6) δ6.66 (s, 2H), 3.76 (s, 6H), 3.66–3.57 (m, 5H), 3.06 (t, J = 4.5Hz, 2H).

[0079] Dissolve the product of the previous step (3.43g, 14.46mmol, 1.0eq) in DCM (150mL) under ice bath, and add trifluoromethanesulfonic acid (2.54mL, 31.81mmol, 2.2eq) in 50mL DCM solution dropwise. Stir at room temperature for 2h. Monitor the reaction on TLC plate (PE:EA=2:1). Add saturated NaHCO3 (100mL) to quench, extract with DCM (200mL), wash with water, wash with saturated brine and dry with anhydrous sodium sulfate. Spin dry the organic layer to obtain a crude product. Add an appropriate amount of EA:PE=1:1 mixed solution to suspend the product, filter, wash the filter cake with EA:PE=1:2, and vacuum dry to obtain the product, 1.78g of yellow granular solid 5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, yield 51.9%. 1 H NMR (300MHz, DMSO-d6) δ6.68(s,1H),6.09(s,1H),3.75(s,3H),3.67(s,3H),3.58(s,3H),3.37–3.26(m,2H),2.37(t,J=7.0Hz,2H).

[0080] 1.2 Synthesis of 1-(1H-indol-3-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one

[0081]

[0082] Under ice bath, 60% NaH (24 mg, 612.10 μmol, 1.2 eq) was dissolved in anhydrous THF, and 3-bromoindole (100 mg, 510.08 μmol, 1.0 eq) in anhydrous THF solution was added dropwise under argon protection, and stirred under ice bath for 20 min. Under ice bath, triisopropylsilyl chloride (150 μL, 663.11 μmol, 1.3 eq) in anhydrous THF solution was added dropwise, and after the addition was completed, the mixture was moved to room temperature to react for 2 h until TLC detection of the reaction was complete (PE: EA = 15: 1). Saturated ammonium chloride was added to quench, and the mixture was extracted with anhydrous ether and washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried. Sand making was purified by column chromatography (PE) to obtain 155 mg of light yellow liquid 3-bromo-1-(triisopropylsilyl)-1H-indole, with a yield of 86.23%.

[0083] Under argon protection, 5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (150 mg, 632.23 μmol, 1.0 eq), sodium tert-butoxide (92 mg, 948.34 μmol, 1.5 eq), 2-(di-tert-butylphosphino)biphenyl (15 mg, 50.58 μmol, 8 mol%), Pd2dba3 (12 mg, 12.64 μmol, 2 mol%) and 3-bromo-1-(triisopropylsilyl)-1H-indole (311 mg, 885.12 μmol, 1.4 eq) were added to a three-necked flask. After suspension was added with anhydrous toluene, the mixture was reacted at 100°C for 24 h and detected by TLC (PE:EA=1:1). After cooling, diatomaceous earth was used to filter out insoluble matter, the filtrate was dried, diluted with water, and extracted with EA (2×100mL), the organic layers were combined and washed with water, washed with saturated brine, and then dried. After sand making, column chromatography purification (PE:EA=8:1 to 2:1) was performed to obtain the intermediate 5,6,7-trimethoxy-1-(1-(triisopropylsilyl)-1H-indol-3-yl)-2,3-dihydroquinoline-4(1H)-one. The intermediate of the previous step was then dissolved in THF, and 1N tetrabutylammonium fluoride THF solution (140μL, 140μmol, 1.1eq) was added. After stirring at room temperature for 1h, TLC detection (DCM:MeOH=20:1) showed that the reaction was complete. After the reaction solution was dried, water was added, extracted with EA, washed with water, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After vacuum drying, the residue was sanded and purified by column chromatography (DCM:MeOH=60:1) to obtain 26 mg of yellow solid as compound 1. The two-step yield was 12%. 1 H NMR (300MHz, DMSO-d6) δ11.23(s,1H),7.49(d,J=2.6Hz,1H),7.43(d,J=8.1Hz,1H),7.31(d,J=7.8Hz,1H),7.18–7. 10(m,1H),7.01(t,J=7.5Hz,1H),5.82(s,1H),3.83–3.73(m,5H),3.60(s,3H),3.34(s,3H),2.67(t,J=6.8Hz,2H). 13 C NMR(75MHz,DMSO-d6)δ189.9,158.0,154.5,150.6,135.0,133.9,122.8,121.8,121.6, 121.5,119.2,118.1,112.3,107.3,93.4,61.1,60.8,55.2,51.2.HR-MS(ESI)m / z:calcd for C 20 H 20 N2O4[M+H] +353.1496, found353.1501. HPLC retention time 5.162min, 96.698% pure.

[0084] Example 2

[0085] 1-(1H-indol-4-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 2)

[0086]

[0087] Referring to the synthesis process of Example 1, a yellow solid was obtained with a yield of 15%. 1 H NMR(400MHz,Chloroform-d)δ8.64(s,1H),7.37(dt,J=8.2,1.0Hz,1H),7.28–7.19(m,2H),7.00(dd,J=7.5,0.9Hz,1 H),6.37(ddd,J=3.2,2.1,1.0Hz,1H),5.75(s,1H),3.99–3.91(m,5H),3.79(s,3H),3.42(s,3H),2.84–2.78(m,2H). 13 C NMR(75MHz,Chloroform-d)δ191.6,158.6,155.2,150.1,138.3,137.6,135.1,124.7,122 .9,116.8,109.9,108.4,101.2,94.7,61.6,61.4,55.6,50.7,40.0.HR-MS(ESI)m / z:calcd for C 20 H 20 N2O4[M+H] + 353.1496, found 353.1498.HPLCretention time 5.931min, 98.857% pure.

[0088] Example 3

[0089] 1-(1H-indol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 3)

[0090]

[0091] Referring to the synthesis process of Example 1, a yellow solid was obtained with a yield of 16%. 1H NMR (300MHz, DMSO-d6) δ11.24(s,1H),7.52–7.44(m,2H),7.41(t,J=2.7Hz,1H),7.02(dd,J=8.6,2.0Hz,1H ),6.46(t,J=2.5Hz,1H),5.67(s,1H),3.79–3.70(m,5H),3.59(s,3H),3.39(s,3H),2.63(t,J=6.8Hz,2H). 13 C NMR(75MHz,DMSO-d6)δ189.9,157.8,154.4,151.2,137.8,134.4,133.9,128.6,126.5, 120.2,117.9,112.7,107.4,101.6,93.5,61.1,60.8,55.2,51.0.HR-MS(ESI)m / z:calcd for C 20 H 20 N2O4[M+H] + 353.1496, found 353.1508. HPLC retention time 6.214min, 99.761% pure.

[0092] Example 4

[0093] 1-(1H-Indol-6-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 4)

[0094]

[0095] Referring to the synthesis process of Example 1, a yellow solid was obtained with a yield of 11%. 1 H NMR (300MHz, DMSO-d6) δ11.18(s,1H),7.61(d,J=8.3Hz,1H),7.39(t,J=2.7Hz,1H),7.35–7.29(m,1H),6.95(dd,J=8.4,1. 9Hz,1H),6.50–6.42(m,1H),5.76(s,1H),3.82–3.76(m,2H),3.75(s,3H),3.60(s,3H),3.42(s,3H),2.64(t,J=6.8Hz,2H). 13CNMR(75MHz,DMSO-d6)δ190.0,157.9,154.5,150.8,139.8,136.5,134.2,126.4,126.2,12 1.2,118.1,109.2,107.7,101.3,93.7,61.1,60.8,55.3,50.9,39.3.HR-MS(ESI)m / z:calcd for C 20 H 20 N2O4[M+H] + 353.1496, found353.1493. HPLC retention time 4.698min, 95.124% pure.

[0096] Example 5

[0097] 5,6,7-Trimethoxy-1-(1-methyl-1H-indol-4-yl)-2,3-dihydroquinolin-4(1H)-one (Compound 5)

[0098]

[0099] The synthesis process is as follows:

[0100]

[0101] Under argon protection, 5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (100 mg, 421.49 μmol, 1.0 eq), sodium tert-butoxide (61 mg, 948.34 μmol, 1.5 eq), 2-(di-tert-butylphosphino)biphenyl (10 mg, 50.58 μmol, 8 mol%), Pd2dba3 (8 mg, 12.64 μmol, 2 mol%) and 4-bromo-1-methyl-1H-indole (124 mg, 590 μmol, 1.4 eq) were added to a three-necked flask. After adding anhydrous toluene for suspension, the mixture was reacted at 100°C for 24 h and detected by TLC (PE:EA=1:1). After cooling, diatomaceous earth was used to filter out insoluble matter, the filtrate was dried, diluted with water and extracted with EA (2×100 mL), the organic layers were combined and washed with water, washed with saturated brine and dried. After sand making, column chromatography purification (PE:EA=8:1 to 2:1) was performed to obtain 61 mg of yellow solid 5,6,7-trimethoxy-1-(1-methyl-1H-indol-4-yl)-2,3-dihydroquinolin-4(1H)-one, with a yield of 39%. 1HNMR(300MHz,DMSO-d6)δ7.41(d,J=8.2Hz,1H),7.35(d,J=3.1Hz,1H),7.23(t,J=7.8Hz,1H),7.03–6.98(m,1H), 6.27–6.21(m,1H),5.70(s,1H),3.90–3.79(m,5H),3.76(s,3H),3.60(s,3H),3.32(s,3H),2.65(t,J=6.7Hz,2H). 13 CNMR(75MHz,DMSO-d6)δ190.0,157.8,154.5,149.4,138.1,137.5,134.2,130.0,124.4,122. 0,116.2,108.5,107.7,98.7,94.0,61.1,60.8,55.2,50.0,39.4,32.8.HR-MS(ESI)m / z:calcd for C 21 H 22 N2O4[M+H] + 367.1652, found 367.1652. HPLC retention time 10.567min, 98.838% pure.

[0102] Example 6

[0103] 5,6,7-Trimethoxy-1-(1-methyl-1H-indol-5-yl)-2,3-dihydroquinolin-4(1H)-one (Compound 6)

[0104]

[0105] Referring to the synthesis process of Example 5, a yellow solid was obtained with a yield of 32%. 1 H NMR(300MHz,Chloroform-d)δ7.49(d,J=2.1Hz,1H),7.37(d,J=8.7Hz,1H),7.16–7.04(m,2H),6.49 (d,J=3.1Hz,1H),5.71(s,1H),3.93(s,3H),3.86–3.74(m,8H),3.49(s,3H),2.76(t,J=6.9Hz,2H). 13CNMR(75MHz,Chloroform-d)δ191.1,158.4,155.1,151.6,138.4,135.3,134.6,130.1,129.3,12 0.8,118.9,110.6,108.0,101.2,93.9,61.4,61.3,55.5,51.6,39.7,33.1.HR-MS(ESI)m / z:calcd for C 21 H 22 N2O4[M+H] + 367.1652, found 367.1653. HPLC retention time 5.640min, 99.003% pure.

[0106] Example 7

[0107] 5,6,7-Trimethoxy-1-(1-methyl-1H-indol-6-yl)-2,3-dihydroquinolin-4(1H)-one (Compound 7)

[0108]

[0109] Referring to the synthesis process of Example 5, a yellow solid was obtained with a yield of 32%. 1 H NMR(300MHz,Chloroform-d)δ7.66(d,J=8.3Hz,1H),7.21(d,J=1.8Hz,1H),7.13(d,J=3.2Hz,1H),7.00(dd,J=8.4,1.9Hz,1H),6 .56–6.48(m,1H),5.79(s,1H),3.94(s,3H),3.86(t,J=7.0Hz,2H),3.80(s,3H),3.78(s,3H),3.51(s,3H),2.78(t,J=6.9Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ191.2,158.5,155.2,151.3,140.8,137.4,134.9,130.0,127.1,122 .2,118.7,108.3,107.4,101.2,94.1,61.6,61.4,55.7,51.6,39.8,33.1.HR-MS(ESI)m / z:calcd forC 21 H 22 N2O4[M+H] +367.1652, found367.1645. HPLC retention time 6.368min, 98.527% pure.

[0110] Example 8

[0111] 1-(1-Ethyl-1H-indol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 8)

[0112]

[0113] The synthetic process of reference example 5 is different in that a yellow solid is obtained from 5-bromo-1-ethyl-1H-indole (1.4 eq) with a yield of 36%. 1 H NMR(300MHz,Chloroform-d)δ7.50(d,J=2.0Hz,1H),7.40(d,J=8.6Hz,1H),7.20(d,J=3.1Hz,1H),7.08(dd,J=8.7,2.0Hz,1H),6.54–6.4 6(m,1H),5.73(s,1H),4.21(q,J=7.2Hz,2H),3.94(s,3H),3.85–3.75(m,5H),3.50(s,3H),2.76(t,J=6.9Hz,2H),1.51(t,J=7.2Hz,3H). 13 CNMR(75MHz,Chloroform-d)δ191.2,158.5,155.2,151.6,138.5,134.7,134.4,129.6,128.3,120.8 ,119.1,110.6,108.2,101.4,94.1,61.5,61.4,55.7,51.7,41.3,39.8,15.6.HR-MS(ESI)m / z:calcd for C 22 H 24 N2O4[M+H] + 381.1809, found 381.1810. HPLC retention time 6.696min, 99.500% pure.

[0114] Example 9

[0115] 1-(Benzo[d][1,3]dioxazol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 9)

[0116]

[0117] Referring to the synthesis process of Example 5, a yellow solid was prepared from 4-bromo-1,2-methylenedioxybenzene (1.4 eq) with a yield of 45%. 1 H NMR(300MHz,Chloroform-d)δ6.85(d,J=8.1Hz,1H),6.71(d,J=9.2Hz,2H),6.02(s,2H),5.73 (s,1H),3.91(s,3H),3.76(s,3H),3.71(t,J=6.8Hz,2H),3.62(s,3H),2.72(t,J=6.9Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ191.0,158.5,155.3,150.7,148.8,146.2,140.5,135.3,120 .1,109.1,108.6,107.9,101.8,94.0,61.5,61.4,55.8,51.3,39.7.HR-MS(ESI)m / z:calcd for C 19 H 19 NO6[M+H] + 358.1285, found358.1286. HPLC retention time 7.350min, 97.697% pure.

[0118] Example 10

[0119] 1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 10)

[0120]

[0121] The synthetic process of reference example 5 was different in that a yellow solid was obtained from 6-bromo-1,4-benzodioxane (1.4 eq) with a yield of 33%. 1 H NMR(400MHz,Chloroform-d)δ6.91(d,J=8.5Hz,1H),6.77(d,J=2.4Hz,1H),6.75(dd,J=8.5,2.5H z,1H),4.30(s,4H),3.92(s,3H),3.78(s,3H),3.76–3.70(m,2H),3.63(s,3H),2.77–2.69(m,2H). 13CNMR(75MHz,Chloroform-d)δ191.0,158.5,155.3,150.6,144.4,142.1,139.9,135.2,119.8 ,118.2,115.4,108.6,94.1,64.5,64.4,61.5,61.4,55.8,51.1,39.7.HR-MS(ESI)m / z:calcd for C 20 H 21 NO6[M+H] + 372.1442, found372.1444. HPLC retention time 5.954min, 99.159% pure.

[0122] Embodiment 11

[0123] 2-Methoxy-5-(5,6,7-trimethoxy-3,4-dihydroquinolin-1(2H)-yl)phenol (Compound 11)

[0124]

[0125] The synthetic route of the compound is as follows:

[0126]

[0127] LiAlH4 (240 mg, 6.32 mmol, 3.0 eq) was dissolved in anhydrous THF under ice bath. 5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (500 mg, 2.11 mmol, 1.0 eq) was dissolved in anhydrous THF and added to the above solution. The reaction was carried out under ice bath for 5 min. After TLC detection (PE:EA=2:1) ​​showed new spots, AlCl3 (421 mg, 3.16 mmol, 1.5 eq) was added and stirred under ice bath until the reaction was complete. EA and water were added under ice bath to quench, EA / water was extracted, the organic phase was washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was spin-dried and sanded, and the product was purified by column chromatography (PE:EA=8:1), 370 mg of light yellow liquid, and the yield was 78.63%.

[0128] Take the product of the previous step (100 mg, 447.88 μmol, 1.0 eq), BINAP (28 mg, 44.79 μmol, 10 mol%), Pd (OAc) 2 (10 mg, 44.79 μmol, 10 mol%), cesium carbonate (292 mg, 895.77 μmol, 2.0 eq) and 3-benzyloxy-4-methoxybromobenzene (171 mg, 582.25 μmol, 1.3 eq) and add them to a three-necked flask, dissolve in anhydrous dioxane under argon protection, and reflux overnight. After the solvent is dried, EA and water are added for extraction, washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate. After the organic phase is dried, sand is made, and column chromatography purification (PE: EA = 6: 1) is performed to obtain 69 mg of the product with a yield of 35.37%.

[0129] The raw material (69 mg, 158.43 μmol) of the previous step was dissolved in 6 mL of methanol, and 10% Pd / C (7 mg) was added under argon atmosphere. After replacing the hydrogen, the mixture was stirred at room temperature for 1 h. The reaction was completed by TLC plate monitoring (PE: EA = 1: 1). Pd / C was removed by diatomaceous earth filtration and methanol was dried by spin drying. After sand making, column chromatography purification (PE: EA = 4: 1) was performed to obtain 31 mg of a white solid with a yield of 56.65%. 1 H NMR (300MHz, DMSO-d6) δ9.04(s,1H),6.89(d,J=8.5Hz,1H),6.63(d,J=2.6Hz,1H),6.58(dd,J=8.5,2.6Hz,1H),5.89(s,1 H),3.75(s,3H),3.74(s,3H),3.63(s,3H),3.48(s,3H),3.44–3.31(m,2H),2.62(t,J=6.5Hz,2H),1.85(p,J=6.4Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ151.1,151.0,147.1,144.7,141.6,141.1,133.8,115.9,112. 9,112.9,109.2,95.9,60.5,60.0,55.8,55.6,51.0,21.5,21.0.HR-MS(ESI)m / z:calcd for C 19 H 23 NO5[M+H] + 346.1649, found346.1653. HPLC retention time 7.446min, 95.757% pure.

[0130] Example 12

[0131] 1-(3-Hydroxy-4-methoxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 12)

[0132]

[0133] The synthetic route of the compound is as follows:

[0134]

[0135] Dissolve 3-hydroxy-4-methoxybromobenzene (4.0g, 19.70mmol, 1.0eq) in DCM, add anhydrous potassium carbonate (2.72g, 19.70mmol, 1.0eq) and benzyl bromide (2.81mL, 23.64mmol, 1.2eq) in an ice bath, stir at room temperature for 4h until the reaction is completely monitored by TLC plate (PE:EA=4:1). Add appropriate amount of water to quench the reaction, add DCM extraction (200mL), wash with water, wash with saturated brine, dry with anhydrous sodium sulfate and spin dry, add appropriate amount of PE:EA=2:1 solution to the crude product, filter the solid and use appropriate amount of PE to wash the filter cake. Dry the product to obtain 4.80g of white solid with a yield of 83.11%. 1 H NMR (400MHz, DMSO-d6) δ7.47–7.35(m,4H),7.38–7.30(m,1H),7.21(d,J=2.4Hz,1 H),7.08(dd,J=8.6,2.3Hz,1H),6.94(d,J=8.6Hz,1H),5.10(s,2H),3.75(s,3H).

[0136] Then, the method in Example 11 was used to obtain 1-(3-(benzyloxy)-4-methoxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (72 mg, yellow solid). The raw material from the previous step (72 mg, 160.18 μmol) was dissolved in 10 mL of methanol, and 10% Pd / C (7 mg) was added under an argon atmosphere. After replacing the hydrogen, the mixture was stirred at room temperature for 3 h. The reaction was completed as monitored by TLC plate (PE:EA=1:1). Pd / C was removed by diatomaceous earth filtration and methanol was dried by spin drying. After sand making, column chromatography purification (PE:EA=2:1) ​​was performed to obtain 31 mg of a yellow solid, with a two-step yield of 34%. 1H NMR (300MHz, DMSO-d6) δ9.25 (s, 1H), 7.02–6.94 (m, 1H), 6.71 (dd, J = 6.4, 2.6Hz, 2H), 5.77 (s, 1H), 3.79(s,3H),3.72(s,3H),3.66(t,J=6.8Hz,2H),3.60(s,3H),3.52(s,3H),2.59(t,J=6.8Hz,2H). 13 C NMR(75MHz,DMSO-d6)δ190.3,158.3,154.9,150.7,147.9,146.6,139.4,134.7,117.4 ,114.1,113.4,108.2,94.1,61.5,61.2,56.2,55.8,50.9,41.7.HR-MS(ESI)m / z:calcd for C 19 H 21 NO6[M+H] + 360.1442,found 360.1445.HPLCretention time 5.571min,>99.5% pure.

[0137] Example 13

[0138] 1-(3-Hydroxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 13)

[0139]

[0140] The synthetic process of Reference Example 12 was different in that a yellow solid was obtained from 3-benzyloxybromobenzene (1.3 eq) with a yield of 39%. 1 H NMR(400MHz,Chloroform-d)δ7.23–7.14(m,2H),7.02–6.93(m,2H),5.70(s,1H),3.93 (s,3H),3.85(s,3H),3.78(s,3H),3.77–3.71(m,2H),3.59(s,3H),2.79–2.71(m,2H). 13 C NMR(100MHz,Chloroform-d)δ191.0,158.5,158.1,155.3,150.9,139.2,135.1,12 8.0,115.3,108.5,93.8,61.5,61.4,55.7,55.6,51.2,39.7.HR-MS(ESI)m / z:calcd for C 19 H21 NO5[M+H] + 344.1492, found 360.1496. HPLC retention time 4.963min, 99.044% pure.

[0141] Embodiment 14

[0142] 5,6,7-Trimethoxy-1-(4-methoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (Compound 14)

[0143]

[0144] The synthetic process of Reference Example 5 was different in that a yellow solid was obtained from 4-methoxybromobenzene (1.4 eq) with a yield of 39%. 1 H NMR(400MHz,Chloroform-d)δ7.23–7.14(m,2H),7.02–6.93(m,2H),5.70(s,1H),3.93 (s,3H),3.85(s,3H),3.78(s,3H),3.77–3.71(m,2H),3.59(s,3H),2.79–2.71(m,2H). 13 C NMR(100MHz,Chloroform-d)δ191.0,158.5,158.1,155.3,150.9,139.2,135.1,12 8.0,115.3,108.5,93.8,61.5,61.4,55.7,55.6,51.2,39.7.HR-MS(ESI)m / z:calcd for C 19 H 21 NO5[M+H] + 344.1492, found 360.1496. HPLC retention time 4.963min, 99.044% pure.

[0145] Embodiment 15

[0146] 5,6,7-Trimethoxy-1-(p-phenylmethyl)-2,3-dihydroquinolin-4(1H)-one (Compound 15)

[0147]

[0148] The synthetic process of reference example 5 is different in that a yellow solid is obtained from 4-methylbromobenzene (1.4 eq) with a yield of 40%. 1H NMR(400MHz,Chloroform-d)δ7.23(d,J=8.1Hz,2H),7.17–7.10(m,2H),5.81(s,1 H),3.92(s,3H),3.83–3.74(m,5H),3.59(s,3H),2.77–2.70(m,2H),2.38(s,3H). 13 C NMR(75MHz,Chloroform-d)δ191.0,158.4,155.3,150.4,143.7,136.0,135.2,130 .6,126.0,108.7,94.0,61.5,61.3,55.6,50.8,39.6,21.1.HR-MS(ESI)m / z:calcd forC 19 H 21 NO4[M+H] + 328.1543, found328.1545. HPLC retention time 10.087min, 98.460% pure.

[0149] Example 16

[0150] 5,6,7-Trimethoxy-1-(3,4,5-trimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (Compound 16)

[0151]

[0152] The synthetic process of Reference Example 5 was different in that a yellow solid was obtained from 3,4,5-trimethoxybromobenzene (1.4 eq) with a yield of 45%. 1 H NMR (300MHz, Chloroform-d) δ6.49(s,2H),5.86(s,1H),3.93(s,3H),3.89(s,3H),3.85(s,6H),3.82–3.77(m,5H),3.63(s,3H),2.79–2.72(m,2H). 13 C NMR(100MHz,Chloroform-d)δ190.9,158.5,155.4,154.3,150.2,142.2,136.5,135.5 ,108.9,103.6,94.2,61.6,61.4,61.1,56.4,55.9,51.1,39.8.HR-MS(ESI)m / z:calcd for C 21 H 25 NO7[M+H] +404.1704, found 404.1699. HPLC retention time 6.768min, 95.133% pure.

[0153] Embodiment 17

[0154] 1-(3,4-Dimethoxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one (Compound 17)

[0155]

[0156] The synthetic process of Reference Example 5 was different in that a yellow solid was obtained from 3,4-dimethoxybromobenzene (1.4 eq) with a yield of 46%. 1 H NMR (300MHz, DMSO-d6) δ7.03(d,J=8.5Hz,1H),6.94(d,J=2.4Hz,1H),6.85(dd,J=8.5,2.5Hz,1H),5.77 (s,1H),3.78(s,3H),3.75(s,3H),3.74–3.69(m,5H),3.60(s,3H),3.52(s,3H),2.61(t,J=6.8Hz,2H). 13 C NMR(75MHz,DMSO-d6)δ189.8,157.8,154.5,150.2,149.5,147.1,138.8,134.3,118.1 ,112.4,110.5,107.7,93.5,61.0,60.7,55.7,55.6,55.4,50.4.HR-MS(ESI)m / z:calcd for C 20 H 23 NO6[M+H] + 374.1598, found374.1600. HPLC retention time 5.546min, 96.610% pure.

[0157] Pharmacological Experiment 1 Antiproliferation Experiment

[0158] 1. Experimental Materials

[0159] K562 cells, A549 cells, HepG2 cells, and MDA-MB-231 cells were purchased from Jiangsu KeyGen Biotech Co., Ltd.

[0160] CA-4 was purchased from Sigma, USA.

[0161] 2. Experimental methods

[0162] (1) Cell digestion, counting, and preparation of a concentration of 5×10 4 100 μl of cell suspension (5×10 cells / mL) was added to each well of a 96-well plate. 3 cells)

[0163] (2) The 96-well plate was placed in a 37°C, 5% CO2 incubator for 24 hours;

[0164] (3) Dilute the drug to the desired concentration with complete culture medium and add 100 μL of the corresponding drug-containing culture medium to each well;

[0165] (4) The 96-well plate was placed in a 37°C, 5% CO2 incubator for 72 hours;

[0166] (5) MTT method:

[0167] 1) The 96-well plate was stained with MTT at λ=490 nm and the OD value was measured.

[0168] 2) Add 20 μL MTT (5 mg / mL) to each well and continue culturing in the incubator for 4 hours;

[0169] 3) The culture medium was discarded, 150 μL DMSO was added to each well for dissolution, and the mixture was gently mixed on a shaker for 10 minutes; λ = 490 nm, and the OD value of each well was read using an enzyme-labeled instrument.

[0170] (6) Calculate the inhibition rate.

[0171] Cell inhibition rate = (OD value of negative control group - OD value of compound group) / OD value of negative control group × 100% The results obtained using the above experimental method are shown in Table 1 below.

[0172] Table 1 IC of antiproliferative activity of human cancer cell lines 50 Value (μM)

[0173]

[0174] It can be seen from Table 1 that Examples 3-15 have strong inhibitory effects on the four tumor cell lines, and Example 8 has the best activity. Its activity on K562 cells, A549 cells, MDA-MB-231 cells and HepG2 cells is better than that of the positive control compound CA-4, which fully demonstrates that the compound has a significant inhibitory effect on the growth of tumor cells. Compound 8 was selected to carry out the following in vitro anti-microtubule polymerization activity experiment.

[0175] Pharmacological experiment 2 In vitro anti-microtubule polymerization activity experiment

[0176] The polymerization activity experimental steps are as follows:

[0177] (1) Tubulin was resuspended in PEM buffer [80 mM PIPES (pH 6.9), 0.5 mM EGTA, 2 mM MgCl2 and 15% glycerol] at a concentration of 2 mg / mL, and then pre-incubated on ice with compound 8 (5 μM, 10 μM) or CA-4 (10 μM) at a final concentration of 5 μM or 10 μM for 5 minutes. PEG (containing GTP at a concentration of 3 mg / mL) was added before detecting tubulin polymerization. The absorbance was measured at 340 nm every 5 minutes for 60 minutes using a Berthold LB941 microplate multifunctional microplate reader. After the experiment, an inhibition curve was drawn with time as the horizontal axis and absorbance as the vertical axis based on the results.

[0178] (2) 2 mg / mL tubulin (cytoskeleton) was resuspended in PEM buffer [80 mM PIPES (pH 6.9), 0.5 mM EGTA, 2 mM MgCl2 and 15% glycerol] and then pre-incubated on ice with (0.1 μM, 0.5 μM, 1 μM, 5 μM, 10 μM) compound 8, CA-4 or 0.1% DMSO solvent for 5 minutes. PEG (containing GTP at a concentration of 3 mg / mL) was added before detecting tubulin polymerization. The absorbance was measured at 340 nm after 30 minutes using a Berthold LB941 microplate multifunctional microplate reader.

[0179] Inhibition rate (%) = (OD ctrl –OD 检测 ) / OD ctrl *100%

[0180] IC calculation using Graphpad Prism 9 50 .

[0181] (3) Using radiolabeled 3 H] colchicine competitive scintillation proximity assay (SPA) was used to detect the competitive binding activity of inhibitors. 3 H] Colchicine was treated with compound 8 or CA-4 (0 μM, 1 μM, 5 μM) and biotinylated tubulin (0.5 μg) in 100 μL of a buffer containing 80 mM PIPES (pH 6.8), 1 mM EGTA, 10% glycerol, 1 mM MgCl2 and 1 mM GTP at 37°C for 2 hours. Then 80 μg of streptavidin-labeled SPA beads were added to each mixture. Radioactivity counts were directly measured using a scintillation counter.

[0182] The results obtained from the in vitro anti-microtubule polymerization activity experiment are shown in Table 2 and Figure 1 shown.

[0183] Table 2 Results of in vitro anti-microtubule polymerization experiment of compound 8

[0184]

[0185]

[0186] As shown in Table 2, the IC of compound 8 against microtubule polymerization in vitro 50 The inhibitory effect of compound 8 on microtubule polymerization in vitro was 1.06 μM, which was similar to the in vitro anti-microtubule polymerization effect of the positive control CA-4. In the 1 μM and 5 μM colchicine binding competition experiment, the inhibition rate of compound 8 was also similar to that of CA-4. Figure 1 It shows that compound 8 can reduce the absorbance of the test material at concentrations of 5 μM and 10 μM, which shows that compound 8 has a significant anti-microtubule polymerization effect.

Claims

1. A 5,6,7-trimethoxy-2,3-dihydroquinoline compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: R1 represents hydrogen, methyl, ethyl, propyl, hydroxymethyl or N,N-dimethylaminomethyl.

2. The 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R1 represents hydrogen, methyl or ethyl.

3. A 5,6,7-trimethoxy-2,3-dihydroquinoline compound represented by general formula (II) or a pharmaceutically acceptable salt thereof: in: X represents oxygen atom; Y represents an oxygen atom; n is 1 or 2.

4. A 5,6,7-trimethoxy-2,3-dihydroquinoline compound represented by general formula (III) or a pharmaceutically acceptable salt thereof: in: Z represents CO or CH2; R2 represents hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxyl or halogen; R3 represents hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy or halogen.

5. The 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: Z represents CO or CH2; R2 represents hydrogen, methyl or methoxy; R3 represents hydrogen, methoxy or hydroxy.

6. A 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof, characterized in that: The 5,6,7-trimethoxy-2,3-dihydroquinoline compound is selected from: Compound 2: 1-(1H-indol-4-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, Compound 3: 1-(1H-indol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, Compound 4: 1-(1H-indol-6-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, Compound 5: 5,6,7-trimethoxy-1-(1-methyl-1H-indol-4-yl)-2,3-dihydroquinolin-4(1H)-one, Compound 6: 5,6,7-trimethoxy-1-(1-methyl-1H-indol-5-yl)-2,3-dihydroquinolin-4(1H)-one, Compound 7: 5,6,7-trimethoxy-1-(1-methyl-1H-indol-6-yl)-2,3-dihydroquinolin-4(1H)-one, Compound 8: 1-(1-ethyl-1H-indol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, Compound 9: 1-(Benzo[d][1,3]dioxazol-5-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, Compound 10: 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, Compound 11: 2-methoxy-5-(5,6,7-trimethoxy-3,4-dihydroquinolin-1(2H)-yl)phenol, Compound 12: 1-(3-hydroxy-4-methoxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, Compound 13: 1-(3-hydroxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, Compound 14: 5,6,7-trimethoxy-1-(4-methoxyphenyl)-2,3-dihydroquinolin-4(1H)-one, Compound 15: 5,6,7-trimethoxy-1-(p-phenylmethyl)-2,3-dihydroquinolin-4(1H)-one, Compound 17: 1-(3,4-dimethoxyphenyl)-5,6,7-trimethoxy-2,3-dihydroquinolin-4(1H)-one, 7. A pharmaceutical composition, which is mainly composed of a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprises the 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

8. Use of the 5,6,7-trimethoxy-2,3-dihydroquinoline compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of an anti-tumor drug.

9. Use of the pharmaceutical composition according to claim 7 in the preparation of anti-tumor drugs.

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