CN115806523A - A kind of substituted quinoline compound and its application in the preparation of antitumor drugs - Google Patents

Abstract

The invention belongs to the technical field of medicines, and relates to a substituted quinoline compound and its application in the preparation of antineoplastic drugs. The inhibitor uses mTOR inhibitor PI-103 as a shape questioning molecule, and is obtained by virtual screening from a ChemDiv library. The compound shown in formula (I) or its isomer, tautomer, or pharmaceutically acceptable salt, said formula (I) structure is as follows:

Description

A kind of substituted quinoline compound and its application in the preparation of antitumor drugs

technical field

The invention belongs to the technical field of medicines, and relates to a substituted quinoline compound and its application in the preparation of antitumor medicines.

Background technique

As an important serine-threonine protein kinase downstream of PI3K/Akt, mTOR is involved in the regulation of cell growth, proliferation, survival and autophagy. Activation of the mTOR signaling pathway is closely related to cancer, diabetes, Alzheimer's disease and autoimmune diseases. mTOR includes mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTORC1 fully activates AKT mainly by phosphorylating Ser473, regulates cell growth and energy metabolism, and is sensitive to rapamycin. While mTORC2 is mainly involved in cytoskeleton remodeling and cell survival, it is not sensitive to rapamycin. Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinases (S6Ks) belong to two signaling pathways downstream of mTOR, which are involved in mRNA translation and protein synthesis. Hyperphosphorylated 4EBP1 can release eIF4E, promote the combination of eIF4G and eIF4E, and initiate the translation of related mRNAs. S6Ks protein is another downstream target protein of mTOR pathway, encoded by two cellular genes S6K1 and S6K2. Many studies have shown that S6K1 activates ribosomes involved in protein synthesis by promoting the translation of mRNA, and affects cell growth, differentiation and autophagy. Because the mTOR signaling pathway controls the metabolism, growth, proliferation and survival of cells, excessive activation of mTOR will lead to increased cell metabolism and prolong cell life, which can directly or indirectly induce metabolic diseases, cancer and aging diseases. Inhibiting this state can be effective Delay or treat cancer, cardiovascular damage, and other diseases caused by mTOR overactivation. Therefore, mTOR inhibitors are currently a hot spot in the research of targeted anti-tumor drugs, and a number of mTOR inhibitors (specific structural formulas are shown in Figure 1) have entered clinical trials or been used on the market.

According to the protein pocket, mTOR inhibitors can be divided into allosteric inhibitors and ATP competitive inhibitors. Allosteric mTOR inhibitors are mainly rapamycin and its derivatives (Rapalogs). However, the clinical efficacy of Rapalogs in some cancers has not yet reached expectations, and the negative feedback of mTORC1 to AKT will be activated, which will greatly reduce the efficacy of the drug and easily lead to drug resistance. In addition, Rapalogs also has the disadvantages of unstable structure and difficult synthesis. ATP competitive mTOR inhibitors include PI-103, WAY-001, AZD8055 and PQR620 etc. ATP-competitive mTOR inhibitors regulate the downstream signaling pathway of mTOR by competing with the upstream molecules of mTOR kinase for the ATP binding site on mTOR kinase, and have the advantages of stable chemical structure, high kinase inhibitory activity and good drug-like properties. Although ATP-competitive mTOR inhibitors overcome some of the shortcomings of rapamycin, there are currently no inhibitors that have entered the market, most of which are in clinical trials, and have structural or mechanism-related side effects. Therefore, it is necessary to further develop new ATP competitive inhibitors with novel structure types, high kinase inhibitory activity and selectivity, and good drug-like properties to provide candidate drugs for the research of innovative anti-tumor drugs targeting mTOR. At the same time, it provides a theoretical reference for mTOR-based innovative drug research.

Contents of the invention

Aiming at the deficiencies of the prior art, the invention proposes a substituted quinoline compound and its application in the preparation of antitumor drugs.

Specifically, it is realized through the following technical solutions:

One aspect of the present invention provides a substituted quinoline compound, which is a compound as shown in formula (I) or its isomer, tautomer, or pharmaceutically acceptable salt, said formula (I ) structure is as follows:

Another aspect of the present invention provides a pharmaceutical composition, which comprises at least one pharmaceutically acceptable adjuvant, adjuvant or carrier, and an effective therapeutic dose of at least one of the above-mentioned substituted quinoline compounds.

Another aspect of the present invention provides an application of the above-mentioned substituted quinoline compound or the above-mentioned pharmaceutical composition in the preparation of antitumor drugs.

Specifically, it provides an application of the above-mentioned substituted quinoline compound or the above-mentioned pharmaceutical composition in the preparation of drugs for preventing and/or treating proliferative diseases caused by the action of mTOR kinase.

The value range of the IC50 value of the effective therapeutic dose is 8.90±0.09 μM.

Another aspect of the present invention provides a method for obtaining the above-mentioned substituted quinoline compound. PI-103 is an ATP-competitive mTOR kinase inhibitor obtained by Astella through high-throughput screening. Its structure is simple, its molecular weight is small, and it is easy to modify, and its crystal structure with protein 4JT6 (https://www.rcsb.org/) has been solved, so it is beneficial to improve the accuracy of its binding mode comparison and analysis . The compound of the present invention uses the ATP competitive mTOR inhibitor PI-103 as the shape questioning molecule, and is obtained by virtual screening from the ChemDiv library.

Specifically, a method for obtaining the above-mentioned substituted quinoline compounds is to compare the shapes of the molecules in the ChemDiv library with the mTOR inhibitor PI-103, select molecules with a similarity greater than 80%, and compare them with the mTOR kinase protein (protein coding : 4JT6) for high-precision (XP) docking, according to the docking scoring and binding mode analysis, select 10 promising compounds and conduct in vitro kinase inhibition experiments and cell proliferation inhibition experiments, and screen the obtained results through the experimental results.

The substituted quinoline compound is an inhibitor targeting PI3K/mTOR signaling pathway.

In the shape screening of the present invention, the minimum similarity is set to 0.8 to narrow the screening range and reduce the workload of the next step of docking. If the minimum similarity is set to 0.9 or 0.85, the range will be too small, resulting in inaccurate results. The high-precision docking is used instead of the ordinary standard (SP) docking because the high-precision docking can more accurately dock the compound into the protein binding pocket of mTOR kinase, and the docking result is more accurate and reliable.

Beneficial effect:

The compound with the structure of formula (I) obtained in the present invention or its isomer or the pharmaceutical composition comprising the compound of formula (I) has broad-spectrum anti-cancer effects, and is effective against HCT 116, TE-1, 5637 and HepG2, etc. A variety of cancer cell lines have high inhibitory activity and excellent stability, especially in artificial gastrointestinal fluid, rat plasma and rat liver microsomes, are not easy to degrade, and have micromolar levels of mTOR kinase inhibitory activity. The compound of the invention has the characteristics of excellent activity, high selectivity, excellent stability and high safety.

The method of the invention is a virtual screening method, which has the advantages of low cost and fast calculation speed.

Description of drawings

Figure 1: The structural formulas of 9 reported compounds of mTOR kinase inhibitors;

Figure 2: Structural formulas of 10 potential compounds obtained from preliminary screening;

Figure 3: Histogram of inhibition rate of compound L971-0652 on 20 cancer cell lines;

Figure 4: The dose-effect curve of compound L971-0652 on HCT116 cell line;

Figure 5: The dose-effect curve of compound L971-0652 on TE-1 cell line;

Figure 6: The dose-effect curve of compound L971-0652 on 5637 cell line;

Figure 7: The dose-effect curve of compound L971-0652 on HepG2 cell line;

Figure 8: Average remaining percentage-time curve (n=3) of compound L971-0652 in artificial gastrointestinal fluid;

Figure 9: The average remaining percentage of compound L971-0652 in rat plasma-time histogram or line graph (n=3);

Figure 10: Average percentage remaining-time curve of compound L971-0652 in rat liver microsome incubation system (n=3).

Detailed ways

The specific embodiments of the present invention will be described in further detail below, but the present invention is not limited to these embodiments, and any improvement or replacement on the basic spirit of this embodiment still belongs to the scope of protection claimed by the claims of the present invention.

Example 1

A substituted quinoline compound is a compound shown in formula (I), numbered L971-0652:

The method for obtaining the substituted quinoline compound of formula (I) is specifically: using Schrodinger software, comparing the shapes of the molecules in the ChemDiv library with the mTOR inhibitor PI-103, and selecting molecules with a similarity greater than 80%, Then, high-precision (XP) docking was performed with mTOR kinase protein (protein code: 4JT6). According to the docking scoring and binding mode analysis, 10 promising compounds were initially screened out, and in vitro kinase inhibition experiments and cell proliferation inhibition experiments were carried out. Experimental results obtained through screening; the structural formulas of the 10 potential compounds are shown in Figure 2;

1. In vitro mTOR Kinase Inhibition Experiment

The inhibitory effect of these compounds on mTOR kinase was evaluated by the Lance Ultra fluorescence assay method described below.

Detection principle: Lance Ultra fluorescence assay is a homogeneous non-radioactive detection method, which quantitatively measures the activity of purified kinase by detecting the ATP content in the system after the kinase reaction. The determination of ATP content was quantified by the light intensity generated by the oxidation of Mg ²⁺ , ATP and oxygen-catalyzed beetle luciferin. Add a certain amount of ATP to the reaction system, the kinase reaction needs to consume ATP, and the remaining ATP can react with the firefly luciferase in the Kinase Glo reagent and then emit light, so that the amount of remaining ATP can be quantitatively detected, and the reaction kinase can be indirectly determined. active.

Detection method: first prepare 1×kinase buffer, which contains 50mM HEPES, PH 7.5, 1mMEGTA, 0.01% Tween-20; dissolve the compound with 100% DMSO and perform gradient dilution, transfer 10nL of the diluted compound to the detection plate, At the same time, a control group without compounds and a blank control group without kinases were prepared. Add 1×kinasebuffer to mTOR to prepare kinase solution, take 5μL and add it to the detection plate and vortex to mix. In addition, prepare 1 × kinase reaction buffer containing 4E-BP1 (Thr 37/46, PE) polypeptide and ATP substrate, take 5 μL and add it to the well plate to start the reaction. After reacting for 1 hour at room temperature, put EDTA and Eu-anti-P - 10 μL of 4E-BP1 (Thr 37/46, PE) antibody PBS buffer was added to the well plate, incubated at room temperature for 60 min, the well plate was read and statistical data were used to calculate the inhibitory rate of the compound on mTOR kinase. The inhibition rate and the corresponding concentration were substituted into the GraphPad Prism software for curve fitting, and the IC ₅₀ value was calculated. The experimental results are shown in Table 1;

Table 1 Kinase inhibitory activity of PI-103 and 10 purchased compounds

Compounds IC₅₀(uM) PI-103 0.005±0.00 4229-0124 38.19±0.18 D337-1379 >100 E130-0745 >100 F043-0262 >100 L971-0652 8.90±0.09 8018-9599 >100 6197-5126 29.87±0.23 E130-0641 46.98±0.96 F167-0048 >100 Y503-0661 >100

From the kinase activity data in Table 1, it can be seen that compound L971-0652 has the best kinase inhibitory activity. Therefore, the compound formula (I) of the present invention has positive and predictable anti-proliferative diseases, especially the clinical application value of anti-tumor, and has good development prospects; the compound of the present invention inhibits mTOR kinase activity, thereby inhibiting Transduction of cell signaling pathways, thereby affecting the cell cycle and cell proliferation.

2. Cell Proliferation Inhibition Experiment

The Cell Counting Kit (CCK-8) method was used to evaluate the inhibitory activity of the compound on cell proliferation, and the IC ₅₀ value of the half inhibitory concentration was determined through single-concentration activity preliminary screening and multi-concentration.

Detection principle: CCK-8 reagent contains WST-8, which is dehydrogenase in the mitochondria of the cell under the action of the electron carrier 1-methoxy-5-methylphenazine dimethyl sulfate (1-Methoxy PMS). Reduction to a highly water-soluble yellow formazan product (Formazan). The amount of formazan produced is directly proportional to the number of viable cells.

Detection method: (1) Cell inoculation: Cells were made into a single cell suspension with culture medium containing 10% fetal bovine serum, and 90 μL of 5×10 ⁴ /mL adherent cells and 9×10 ⁴ cells were inoculated in each well of a 96-well plate. /mL suspension cells were pre-cultured for 24 hours under the condition of 5% CO ₂ and 37°C. (2) Add the sample solution to be tested: add 10 μL sample solution to each hole, set 1 concentration for each sample in the primary screening of activity, and set up 3 duplicate holes; IC ₅₀ measures 8 concentrations (including 0 concentration), each concentration is set 3 duplicate wells; cultured in an incubator for 48 hours. The experiment set up a blank group (Blank), a control group (Control) and a drug group (Drug). (3) Color development: Adherent cells suck out the old medium and drug solution (add 10 μL CCK-8 solution directly to the suspension cells), add 100 μL CCK-8 solution diluted ten times to each well, and store at 37 ° C, 5% CO ₂ Continue to cultivate for 1-4h (operation in dark, real-time observation). (4) Detection: Measure the absorbance at 450 nm with a microplate reader, and record the original data results. (5) Excel software was used to standardize the original data, and the OD value of each well was used to calculate the inhibition rate of cell proliferation (formula = (ODControl-ODDrug)/(ODControl-ODBlank) × 100%) for primary screening, and the inhibition rate was calculated. IC ₅₀ was calculated by GraphPadPrism 8 (version 8.0.2, GraphPad Software Inc), and the experimental results were expressed as ±SD.

(6) Positive control: doxorubicin hydrochloride (Dox).

The compound L971-0652 with the best in vitro kinase inhibitory activity was selected for the cell proliferation inhibition experiment, and the experimental results are shown in Table 2 and Figure 3;

Table 2 Inhibition rate of L971-0652 on 20 cancer cell lines

Celllines Dox L971-0652 A549 70.03%±0.94% 32.50%±0.60% MKN-45 75.65%±0.08% 68.99%±0.54% HCT116 84.45%±0.17% 94.28%±0.17% He La 7.98%±0.39% 58.83%±0.98% K-562 77.64%±0.23% 56.11%±1.04% 786-O 92.98%±0.43% 83.15%±0.94% TE-1 73.98%±1.30% 93.48%±0.88% 5637 98.81%±0.45% 90.95%±1.25% GBC-SD 77.12%±0.64% 64.99%±0.32% LO2 98.98%±0.44% 62.97%±1.30% MCF7 41.88%±1.46% 70.49%±1.27% HepG2 86.56%±2.02% 89.80%±0.92% SF126 87.56%±1.71% 60.86%±1.31% DU145 72.86%±0.54% 32.74%±0.78% CAL-62 92.63%±0.69% 80.01%±1.75% PATU8988T 98.54%±1.19% 85.59%±1.19% HOS 94.52%±1.47% 14.32%±0.62% A-375 95.22%±1.35% 85.24%±1.15% A-673 99.33%±0.46% 92.74%±2.12% 293T 88.02%±0.19% 94.24%±1.18%

It can be seen from Table 2 and Figure 3 that the compound L971-0652 has a strong inhibitory effect on various cancer cell lines such as HCT 116, TE-1, 5637, HepG2, A-673 and 293T.

The IC50 values of compound L971-0652 on HCT 116, TE-1, 5637 and HepG2 cell lines are shown in Table 3, and the dose-effect curves are shown in Figures 4-7.

IC50 values of table 3 compound L971-0652 to HCT 116, TE-1, 5637 and HepG2 cell lines

Note: Doxorubicin hydrochloride (Dox) was determined at a concentration of 10 μM, and L971-0652 was determined at a concentration of 20 μM;

It can be seen from Table 3 and Figure 4-Figure 7 that selective mTOR inhibitors can be used in anti-tumor research.

3. In vitro stability test of L971-0652

Use Agilent 1290Infinity II type ultra-high performance liquid chromatography (USA), Agilent EclipsePlus C18 chromatographic column (2.1mm * 50mm, 1.8μm, USA); Column temperature 40 ℃; Mobile phase is 0.1% formic acid water-0.1% formic acid acetonitrile; The injection volume is 2 μL; the injection time is 5.0 min; the gradient elution program is shown in Table 4 below:

Table 4 Gradient of mobile phase

Use Agilent 6470 triple quadrupole mass spectrometer (USA); ESI ion source; positive ion mode scan; capillary voltage: 4.0kV; drying gas temperature: 300°C; drying gas flow rate: 5.0L/min; ℃; sheath gas flow rate: 11.0L/min; monitoring mode is multiple reaction monitoring (MRM), Fragmentor is 210V, Precursor ion (m/z) is 469.23, Product ion (m/z) is 346.1, Collision Energy is 41V.

1 Stability of artificial gastrointestinal fluid in vitro

1.1 Preparation of solution

1.1.1 Preparation of artificial gastrointestinal juice

Preparation of artificial gastric juice: According to "Chinese Pharmacopoeia" (2020 edition), take 16.4mL of dilute hydrochloric acid, add 800mL of water and 10g of pepsin, shake well to dissolve, adjust the pH value to 1.3, add ultrapure water to 1000mL, that is For artificial gastric juice. Preparation of blank gastric juice: artificial gastric juice without adding pepsin is blank gastric juice. Artificial intestinal juice: Take 6.8g of potassium dihydrogen phosphate, add 500mL of ultrapure water to mix and dissolve, adjust the pH value to 6.8 with 0.1mol/L sodium hydroxide solution: take another 10g of trypsin and add appropriate amount of water to dissolve, mix the two liquids , add ultrapure water to 1000mL, which is artificial intestinal juice. Blank intestinal juice: artificial intestinal juice without trypsin is blank intestinal juice.

1.1.2 Preparation of standard solution

Precisely weigh an appropriate amount of compound L971-0652, dissolve it in methanol and constant volume to make a stock solution with a concentration of 500 μg/mL, and store it at 4°C for later use.

1.2 Stability test of artificial gastrointestinal fluid in vitro

Take an appropriate amount of L971-0652 stock solution under item "1.1.2", dilute it with methanol to 100μg/mL, accurately measure 50μL and add it to four 10mL centrifuge tubes, add blank gastric juice, artificial gastric juice, blank intestinal juice, Artificial intestinal juice 4950μL. Immediately after mixing, divide into 1.5mL EP tubes (4 groups, 6 tubes/group), 200μL per tube. At 0, 1, 2, 4, 6, and 8 hours, 400 μL of ice methanol was added to terminate the reaction, and each system was operated 3 times in parallel. Vortex and mix for 10 minutes, centrifuge at 13,000 rpm for 10 minutes, take 200 μL of supernatant for detection, record the peak area, take the drug content after incubation for 0 h as 100%, and calculate the remaining percentage of L971-0652 incubated in artificial gastrointestinal fluid for different times.

2 In vitro plasma stability

Take an appropriate amount of L971-0652 stock solution under "1.1.2", dilute it with methanol to 50μg/mL, add 2μL/tube into a 1.5mLEP tube, then add 198μL/tube of rat plasma, make 3 parallel portions, shake and mix Incubate in a water bath at 37°C for 0, 0.5, 1, 2, and 3 h, add 400 μL of ice methanol to terminate the reaction, vortex for 5 min, centrifuge at 13,000 rpm at 4°C for 10 min, take the supernatant and dry it under N2, redissolve in 200 μL of methanol, 4 After centrifugation at 13,000 rpm for 10 min at °C, the supernatant was taken for detection, and the peak area was recorded. Taking the drug content at 0 h of incubation as 100%, the remaining percentage of L971-0652 incubated in rat plasma for different times was calculated.

3 Metabolic stability of liver microsomes in vitro

3.1 Preparation of solution

3.1.1 Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme solution

Liquid A: Weigh 200 mg of nicotinamide adenine dinucleotide disodium phosphate (NADP-Na2), 200 mg of glucose-6-phosphate-disodium (G-6-P-Na2), and 133 mg of magnesium chloride, dissolve in water and set Make up to 10mL; solution B: Weigh 44mg of sodium citrate and 1000U of glucose-6-phosphate dehydrogenase (G-6-P-DH) respectively, dissolve in water and make up to 25mL; store them at -20°C for later use. Before use, mix liquid A and liquid B at a volume ratio of 5:1 to obtain a coenzyme solution with a concentration of 1 mmol/L (based on NADPH).

3.1.2 Dilution of liver microsomes

20 mg/mL liver microsomes were diluted to 5 mg/mL with 80% PBS buffer (0.01M) and 20% glycerol mixture, and stored at -80°C after aliquoting.

3.2 Metabolic stability experiment in rat liver microparticles

Take 20 μL of rat liver microsomes (final concentration 0.5 mg/mL), and add 150 μL of diluted L971-0652 solution. After the above solution was preheated in a 37°C water bath for 5 min, 30 μL of NADPH solution was added to start the reaction. The total volume of the incubation system is 200 μL, the mass concentration of L971-0652 is 500 ng/mL, the final concentration of NADPH is 1 mmol/L, and the organic solvent does not exceed 1%. The above incubation system was continued to be placed in a 37°C water bath, and 400 μL of ice methanol was added at 0, 5, 15, 30, 45, and 60 min to terminate the reaction, and three parallel replicates were performed at each time point. After vortex mixing the above mixture for 5 min, centrifuge at 13,000 rpm for 10 min at 4°C, collect the supernatant and dry it under N2 at 37°C, redissolve the residue in 200 μL of methanol, centrifuge at 13,000 rpm for 10 min, take the supernatant for detection, and record Peak area.

3.3 Data processing

(1) Percent remaining rate = Ct/C0×100%

(2) Half-life: T1/2＝﹣0.693/k

(3) Intrinsic clearance rate: CLint＝0.693/T1/2×V/0.1

In the formula: Ct is the remaining concentration of the drug at different incubation times; C0 is the concentration of the drug at 0 time; k is the slope obtained by linear regression of the natural logarithm of the percentage remaining rate of the drug at each time point to the incubation time; V is the total concentration of the incubation solution. Volume (mL); 0.1 is the content (mg) of liver microsomes in the incubation system.

L971-0652 in vitro stability test results

1 Stability of artificial gastrointestinal fluid in vitro

Taking the concentration of incubation 0h as 100%, the remaining percentage of L971-0652 at different times was calculated, and the results are shown in Table 5 and Figure 8. After incubation for 8 hours, the remaining rates of L971-0652 in blank gastric juice, artificial gastric juice, blank intestinal juice, and artificial intestinal juice were 100.36%, 88.36%, 90.37%, and 98.13%, respectively, indicating that L971-0652 was stable in artificial gastrointestinal juice and not easily degradation.

(Note: greater than 100% is due to operation and detection errors, within the allowable range)

Table 5 The remaining percentage of L971-0652 in artificial gastrointestinal fluid (Mean±SD, n=3)

2 In vitro plasma stability

Taking the concentration of incubation 0h as 100%, the remaining percentage of L971-0652 at different times was calculated, and the results are shown in Table 6 and Figure 9 . After incubation in rat plasma for 3 hours, 98.78% of L971-0652 remained, indicating that L971-0652 was stable in rat plasma and not easily degraded.

Table 6 The remaining percentage of L971-0652 in plasma (Mean±SD, n=3)

time/h Remaining percentage (%) 0 100.00±0.00 0.5 99.82±10.83 1 93.58±1.70 2 95.63±9.78 3 98.78±13.27

3 Metabolic stability of liver microsomes

The remaining rate of L971-0652 incubated in rat liver microsomes for 60 minutes, the enzyme kinetic parameters half-life (T1/2), and in vitro intrinsic clearance rate (CLint) are shown in Table 7 and Figure 10 below. The basis for determining metabolic stability is T1/2, T1/2<30min indicates that the metabolism of the test substance is unstable; 30min<T1/2<90min indicates that the metabolic stability of the test substance is moderate; T1/2>90min indicates that the metabolism of the test substance is Good stability. The half-life T1/2 of L971-0652 in rat liver microsomes is 277.20min, indicating that it has good stability in rat liver microsomes and is not easily metabolized.

Table 7 Metabolic stability of L971-0652 in rat liver microsomes (Mean±SD, n=3)

compound species Residual rate (%) T_1/2(min) CL_int(mL/min/mg) L971-0652 the rat 83.01±5.55 277.20 0.005

The compound L971-0652 obtained by the screening method of the present invention has targeting mTOR kinase inhibitory activity, has micromolar concentration anti-proliferation activity on various tumor cells, and has good stability in vitro. Compound L971-0652 is a lead compound with novel structure and targeted inhibitory effect on mTOR kinase, which has laid a solid foundation for subsequent transformation to obtain new high-activity mTOR kinase inhibitors.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (7)

1. A substituted quinoline compound, characterized in that it is a compound or its isomers, tautomers or pharmaceutically acceptable salts thereof as shown in formula (I), said formula (I) structure as follows:

2. A pharmaceutical composition comprising at least one pharmaceutically acceptable adjuvant, adjuvant or carrier, and at least one substituted quinoline compound according to claim 1 at an effective therapeutic dose. 3. The application of a substituted quinoline compound as claimed in claim 1 or a pharmaceutical composition as claimed in claim 2 in the preparation of antitumor drugs. 4. The application of a substituted quinoline compound as claimed in claim 1 or the pharmaceutical composition as claimed in claim 2 in the preparation of a medicament for preventing and/or treating proliferative diseases where mTOR kinase acts. 5. A method for obtaining a substituted quinoline compound as claimed in claim 1, wherein the mTOR inhibitor PI-103 is used as a shape query molecule and obtained through virtual screening from the ChemDiv library. 6. A method for obtaining substituted quinoline compounds as claimed in claim 5, characterized in that, the molecules in the ChemDiv library are compared with the mTOR inhibitor PI-103 in shape, and after selecting the molecules whose similarity is greater than 80%, It was docked with high precision (XP), and 10 potential compounds were screened out according to the docking scoring and binding mode analysis, and the in vitro kinase inhibition experiment and cell proliferation inhibition experiment were carried out, and the obtained results were screened through the experimental results. 7. A substituted quinoline compound as claimed in claim 1, wherein the substituted quinoline compound is an inhibitor targeting PI3K/mTOR signaling pathway.

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