4-substituted quinoline compounds, and preparation method and application thereof

Abstract

The application discloses a 4-substituted quinoline compound and a preparation method and application thereof, and has a structure as shown in general formula (I), wherein R is NH, CH2NH, CH2O, CH2S or piperazine, R1 and R2 are halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, phenoxy, nitro, phenyl, benzyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C15 aryl or C6-C10 heteroaryl, respectively. The application has a good inhibiting effect on tumor cells such as PC-3 (human prostate cancer cells), Hela (human cervical cancer cells) and K562 (human chronic myelogenous leukemia cells).

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a 4-substituted quinoline compound, a method for preparing the 4-substituted quinoline compound, and its application in the preparation of anti-prostate cancer, cervical cancer, chronic myeloid leukemia and other tumor drugs. Background Technology

[0002] Quinoline compounds have received continuous attention in the field of medicinal chemistry due to their broad range of biological activities, especially in the research of anti-tumor drugs. Many small molecule anti-tumor drugs targeting DNA methyltransferases (DNMTs) contain quinoline structural units, such as SGI-1027, CM-272, and CM-579.

[0003] Researchers have made significant progress in the design, synthesis, and activity studies of quinoline-based antitumor compounds. Rabal et al. designed and synthesized a series of quinoline analogs targeting DNMT1, histone deacetylase, and optionally G9a. These compounds exhibit simultaneous inhibitory effects: low nanomolar inhibitory concentrations (IC50) against histone deacetylase and medium nanomolar inhibitory concentrations (IC50 < 200 nM) against DNMT1. Compound 26, in particular, demonstrated excellent in vitro activity, with an IC50 of 32 nM, a sufficient therapeutic window (>1 logarithmic unit), and suitable pharmacokinetic characteristics. In in vivo experiments, compound 26 also showed significant antitumor efficacy in a human multiple myeloma xenograft mouse model.

[0004] Lin et al. combined CM-272 with the key pharmacophore of SAHA to synthesize a series of novel quinoline compounds. These compounds can act as dual inhibitors of DNA methyltransferases and histone deacetylases, among which 27 is the most promising candidate compound, with half-maximal inhibitory concentrations (IC50) of 365 nM and 0.20 nM for DNMT1 and HDAC1, respectively. At the cellular activity level, 27 exhibited broad-spectrum anti-proliferative activity in various solid tumor cell lines. Mechanistically, it induces RASSF1A gene demethylation and promotes histone hyperacetylation, thereby triggering apoptosis in breast cancer cells in a dose-dependent manner. In addition, 27 can significantly inhibit the colony formation, migration, and invasion of cancer cells in vitro.

[0005] Zwergel et al. designed and synthesized 21 quinoline-based DNA methyltransferase inhibitors with basic side chains. Their activity was evaluated through various biochemical and cellular experiments. They found that some compounds exhibited potent and selective DNMT inhibition and significant anticancer potential. Compound 28, in particular, showed outstanding performance, with a low half-maximal inhibitory concentration (IC50) of 44 nM against DNMT1, and IC50 values ​​of 0.4 and 1.9 μM against HCT-116 and MDA-MB-231, respectively. This provides new drug candidates for epigenetic anticancer therapy.

[0006] Liang et al. synthesized a series of novel divalent quinoline compounds. By introducing linker chains containing 4-6 methylene units at the 4 and 7 positions of the quinoline core, most of these compounds exhibited significant anti-proliferative activity against human cancer cell lines, with half-maximal inhibitory concentrations (IC50) all below 50 μM. Compound 29 showed the most prominent activity, with IC50 values ​​of 0.26 μM, 2.75 μM, 4.06 μM, 3.71 μM, and 3.08 μM against HCT116, A549, BGC823, HeLa, and MCF-7 cell lines, respectively.

[0007] Although existing technologies have reported a variety of quinoline compounds with antitumor activity, there is still a need to develop novel quinoline derivatives that are structurally sound, easy to synthesize, and highly selective and inhibitory on different tumor cell lines, in order to provide more candidate drugs for cancer treatment. Summary of the Invention

[0008] The purpose of this invention is to solve the above-mentioned problems by providing a 4-substituted quinoline compound that has a good inhibitory effect on tumor cells such as PC-3 (human prostate cancer cells), HeLa (human cervical cancer cells), and K562 (human chronic myeloid leukemia cells).

[0009] Another object of the present invention is to provide a method for preparing the 4-substituted quinoline compounds that has few synthetic steps, readily available raw materials, and a simple synthetic method.

[0010] Another object of the present invention is to provide the application of the 4-substituted quinoline compound in the preparation of anti-prostate cancer, cervical cancer, chronic myeloid leukemia and other tumor drugs.

[0011] To achieve the above objectives and technical effects, the technical solution adopted by this invention is as follows:

[0012] One 4-substituted quinoline compound of the present invention has the structure of general formula (I):

[0013] (I)

[0014] Wherein, R is NH, CH2NH, CH2O, CH2S, or piperazine; in CH2NH, one end of CH2 is attached to the carbonyl carbon of the amide group, and the other end of NH is attached to the benzene ring substituted by R1 and R2; in CH2O, one end of CH2 is attached to the carbonyl carbon of the amide group, and the other end of O is attached to the benzene ring substituted by R1 and R2; in CH2S, one end of CH2 is attached to the carbonyl carbon of the amide group, and the other end of S is attached to the benzene ring substituted by R1 and R2; one N atom of piperazine-1,4-diyl is attached to the carbonyl carbon of the amide group, and the other N atom is attached to R1. The benzene ring substituted by R2; R1 and R2 are respectively halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, phenoxy, nitro, phenyl, benzyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C15 aryl or C6-C10 heteroaryl, wherein R1 is a monosubstituted or one or more identical or different substituents, and when R1 contains an aromatic ring, the aromatic ring is further substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro or trifluoromethyl.

[0015] In the aforementioned 4-substituted quinoline compounds, the halogen is fluorine, chlorine, bromine, or iodine; the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or neopentyl; the C1-C6 alkoxy group is methoxy, ethoxy, propoxy, or butoxy; the C2-C6 alkenyl group is propenyl or allyl; and the C6-C15 aryl group is phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, etc. The C6-C10 heteroaryl group is 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, or 4-trifluoromethylbenzyl.

[0016] In the above-mentioned 4-substituted quinoline compounds: when R1=H, R2 is selected from methyl, trifluoromethyl, fluorine, trifluoromethoxy, bromine, nitro, and chlorine; when R1=CH3, R2 is selected from chlorine, fluorine, and methyl; when R1=chlorine, R2 is selected from chlorine.

[0017] Furthermore, the 4-substituted quinoline compounds specifically include the following compounds:

[0018] A method for preparing a 4-substituted quinoline compound according to the present invention includes the following steps:

[0019] The application of the 4-substituted quinoline compounds of the present invention in the preparation of anti-prostate cancer, cervical cancer, chronic myeloid leukemia and other tumor drugs.

[0020] Compared with the prior art, the present invention has the following obvious beneficial effects as can be seen from the above technical solution:

[0021] 1. Novel structure: The compound of the present invention introduces a series of substituted thiophenol structural fragments at the 4 position of quinoline through an amino group and an acetyl thioether chain, forming a new compound with specific structural features.

[0022] 2. Simple synthesis: The preparation method of the present invention uses readily available raw materials, has few synthesis steps, mild reaction conditions, simple post-processing, and is easy to industrialize.

[0023] 3. Significant Antitumor Activity: In vitro antitumor activity tests showed that the BD series compounds of this invention had a weak inhibitory effect on the A549 lung cancer cell line, but exhibited significant antitumor activity against the remaining four tumor cell lines, with inhibition rates exceeding 80%. Compound BD-4 showed significant antitumor activity against all five tumor cell lines. The DS series compounds showed good inhibitory effects on the proliferation of various tumor cell lines, particularly K562 (human chronic myeloid leukemia cells), PC-3 (human prostate cancer cells), and HeLa (human cervical cancer cells). Compound DS-9, at a concentration of 10 μM, showed an inhibition rate of up to 99.46% against K562 cells and 97.89% against HeLa cells. Compound DS-19, at a concentration of 10 μM, showed inhibition rates of 98.66%, 88.63%, and 98.21% against K562, PC-3, and HeLa cells, respectively, demonstrating broad-spectrum antitumor activity superior to the positive control drugs imatinib and 5-fluorouracil. Compounds DS-16 and DS-21 also exhibited potent inhibitory effects on HeLa cells exceeding 80%. Most compounds in the DO series showed relatively good antitumor activity against K562, PC-3, and HeLa cells, with inhibition rates almost all exceeding 80%. Notably, among all compounds in the DO series, only DO-1 showed good antitumor activity only against HeLa cells, while exhibiting almost no inhibitory activity against the other four cancer cell lines, with inhibition rates of 30.41%, 31.77%, 26.42%, 84.48%, and 4.92%, respectively.

[0024] 4. Selective inhibition: Some compounds exhibit differentiated inhibitory activity against different tumor cell lines, providing a basis for the subsequent development of selective antitumor drugs. Detailed Implementation

[0025] The following detailed description, in conjunction with preferred embodiments, outlines the specific implementation methods, structure, features, and effects of a 4-substituted quinoline compound, its preparation method, and its applications according to the present invention:

[0026] Example 1:

[0027] A method for preparing a 4-substituted quinoline compound (BD1) includes the following steps:

[0028] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0029] (2) The intermediate DC-Z1 (0.2 g, 850.01 μmol) and 2-methyl isocyanate (0.14 g, 1.02 mmol) were added to a dichloromethane solution (50 mL), followed by the addition of triethylamine (0.12 g, 1.02 mmol). The reaction was carried out at room temperature for about 8 hours. After the reaction was completed, the reaction mixture was poured into water and stirred overnight. The precipitated solid was collected by filtration. The target compound BD1 was purified by dichloromethane recrystallization with a yield of 85%~90%.

[0030] Example 2:

[0031] A method for preparing a 4-substituted quinoline compound (BD2) includes the following steps:

[0032] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0033] (2) The intermediate DC-Z1 (0.2 g, 850.01 μmol) and 3-fluoromethyl isocyanate (0.2 g, 1.02 mmol) were added to a dichloromethane solution (50 mL), followed by the addition of triethylamine (0.12 g, 1.02 mmol). The reaction was carried out at room temperature for about 8 hours. After the reaction was completed, the reaction mixture was poured into water and stirred overnight. The precipitated solid was collected by filtration. The target compound BD2 was purified by dichloromethane recrystallization with a yield of 85%~90%.

[0034] Example 3:

[0035] A method for preparing a 4-substituted quinoline compound (BD3) includes the following steps:

[0036] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0037] (2) The intermediate DC-Z1 (0.2 g, 850.01 μmol) and 2-fluoroisocyanate (0.14 g, 1.02 mmol) were added to a dichloromethane solution (50 mL), followed by the addition of triethylamine (0.12 g, 1.02 mmol) to the system. The reaction was carried out at room temperature for about 8 hours. After the reaction was completed, the reaction mixture was poured into water and stirred overnight. The precipitated solid was collected by filtration. The target compound BD3 was purified by dichloromethane recrystallization with a yield of 85%~90%.

[0038] Example 4:

[0039] A method for preparing a 4-substituted quinoline compound (BD4) includes the following steps:

[0040] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0041] (2) The intermediate DC-Z1 (0.2 g, 850.01 μmol) and 4-methyl isocyanate (0.14 g, 1.02 mmol) were added to a dichloromethane solution (50 mL), followed by the addition of triethylamine (0.12 g, 1.02 mmol) to the system. The reaction was carried out at room temperature for about 8 hours. After the reaction was completed, the reaction mixture was poured into water and stirred overnight. The precipitated solid was collected by filtration. The target compound BD4 was purified by dichloromethane recrystallization with a yield of 85%~90%.

[0042] Example 5:

[0043] A method for preparing a 4-substituted quinoline compound (BD5) includes the following steps:

[0044] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0045] (2) The intermediate DC-Z1 (0.2 g, 850.01 μmol) and 2-trifluoromethoxyisocyanate (0.21 g, 1.02 mmol) were added to a dichloromethane solution (50 mL), followed by the addition of triethylamine (0.12 g, 1.02 mmol). The reaction was carried out at room temperature for about 8 hours. After the reaction was completed, the reaction mixture was poured into water and stirred overnight. The precipitated solid was collected by filtration. The target compound BD5 was purified by dichloromethane recrystallization with a yield of 85%~90%.

[0046] Example 6:

[0047] A method for preparing a 4-substituted quinoline compound (BD6) includes the following steps:

[0048] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0049] (2) The intermediate DC-Z1 (0.2 g, 850.01 μmol) and 2,6-dimethyl isocyanate (0.15 g, 1.02 mmol) were added to a dichloromethane solution (50 mL), followed by the addition of triethylamine (0.12 g, 1.02 mmol). The reaction was carried out at room temperature for about 8 hours. After the reaction was completed, the reaction mixture was poured into water and stirred overnight. The precipitated solid was collected by filtration. The target compound BD6 was purified by dichloromethane recrystallization with a yield of 85% to 90%.

[0050] The physicochemical properties and NMR (1H and 1C) spectra of the synthesized 4-substituted quinoline derivatives are shown in Table 1. Table 1 shows the physicochemical properties and NMR data of the target compounds.

[0051] Table 1

[0052] Example 7:

[0053] A method for preparing a 4-substituted quinoline compound (DS1) includes the following steps:

[0054] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0055] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0056] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.16 g of 3-methoxythiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.41 g of the target compound DS1 by recrystallization from dichloromethane.

[0057] Example 8

[0058] A method for preparing a 4-substituted quinoline compound (DS2) includes the following steps:

[0059] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0060] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0061] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.15 g of 4-fluorothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.4 g of the target compound DS2 by recrystallization from dichloromethane.

[0062] Example 9

[0063] A method for preparing a 4-substituted quinoline compound (DS3) includes the following steps:

[0064] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0065] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0066] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.17 g of 4-bromothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.42 g of the target compound DS3 by recrystallization from dichloromethane.

[0067] Example 10

[0068] A method for preparing a 4-substituted quinoline compound (DS4) includes the following steps:

[0069] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0070] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0071] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.22 g of 4-bromothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.47 g of the target compound DS4 by recrystallization from dichloromethane.

[0072] Example 11

[0073] A method for preparing a 4-substituted quinoline compound (DS5) includes the following steps:

[0074] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0075] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0076] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.18 g of 4-nitrobenzenethiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.43 g of the target compound DS5 by recrystallization from dichloromethane.

[0077] Example 12

[0078] A method for preparing a 4-substituted quinoline compound (DS6) includes the following steps:

[0079] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0080] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0081] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.14 g of 4-methylthiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.4 g of the target compound DS6 by recrystallization from dichloromethane.

[0082] Example 13

[0083] A method for preparing a 4-substituted quinoline compound (DS7) includes the following steps:

[0084] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0085] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0086] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.15 g of 3-fluorothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.4 g of the target compound DS7 by recrystallization from dichloromethane.

[0087] Example 14

[0088] A method for preparing a 4-substituted quinoline compound (DS8) includes the following steps:

[0089] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0090] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0091] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.17 g of 2-chlorothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.42 g of the target compound DS8 by recrystallization from dichloromethane.

[0092] Example 15

[0093] A method for preparing a 4-substituted quinoline compound (DS9) includes the following steps:

[0094] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0095] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0096] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.22 g of 2-bromothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.47 g of the target compound DS9 by recrystallization from dichloromethane.

[0097] Example 16

[0098] A method for preparing a 4-substituted quinoline compound (DS10) includes the following steps:

[0099] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0100] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0101] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.22 g of 4-trifluoromethoxythiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.47 g of the target compound DS10 by recrystallization from dichloromethane.

[0102] Example 17

[0103] A method for preparing a 4-substituted quinoline compound (DS11) includes the following steps:

[0104] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0105] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0106] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.15 g of difluorothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.4 g of the target compound DS11 by recrystallization from dichloromethane.

[0107] Example 18

[0108] A method for preparing a 4-substituted quinoline compound (DS12) includes the following steps:

[0109] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0110] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0111] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.22 g of 3-bromothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.47 g of the target compound DS12 by recrystallization from dichloromethane.

[0112] Example 19

[0113] A method for preparing a 4-substituted quinoline compound (DS13) includes the following steps:

[0114] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0115] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0116] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.14 g of 2-methylthiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.4 g of the target compound DS13 by recrystallization from dichloromethane.

[0117] Example 20

[0118] A method for preparing a 4-substituted quinoline compound (DS14) includes the following steps:

[0119] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0120] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0121] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.14 g of 3-methylthiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.4 g of the target compound DS14 by recrystallization from dichloromethane.

[0122] Example 21

[0123] A method for preparing a 4-substituted quinoline compound (DS15) includes the following steps:

[0124] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0125] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0126] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.19 g of 2-chloro-4-fluorothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.44 g of the target compound DS15 by recrystallization from dichloromethane.

[0127] Example 22

[0128] A method for preparing a 4-substituted quinoline compound (DS16) includes the following steps:

[0129] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0130] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0131] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.17 g of 4-chlorothiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.42 g of the target compound DS16 by recrystallization from dichloromethane.

[0132] Example 23

[0133] A method for preparing a 4-substituted quinoline compound (DS17) includes the following steps:

[0134] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0135] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0136] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.16 g of 2-methoxythiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.42 g of the target compound DS17 by recrystallization from dichloromethane.

[0137] Example 24

[0138] A method for preparing a 4-substituted quinoline compound (DS18) includes the following steps:

[0139] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0140] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0141] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.16 g of 4-methoxythiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.42 g of the target compound DS18 by recrystallization from dichloromethane.

[0142] Example 25

[0143] A method for preparing a 4-substituted quinoline compound (DS19) includes the following steps:

[0144] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0145] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0146] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.21 g of 2-trifluoromethylthiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour. Then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.45 g of the target compound DS19 by recrystallization from dichloromethane.

[0147] Example 26

[0148] A method for preparing a 4-substituted quinoline compound (DS20) includes the following steps:

[0149] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0150] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0151] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.21 g of 3-trifluoromethylthiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.45 g of the target compound DS20 by recrystallization from dichloromethane.

[0152] Example 27

[0153] A method for preparing a 4-substituted quinoline compound (DS21) includes the following steps:

[0154] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0155] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0156] (3) Weigh 0.07 g of potassium hydroxide (1.15 mmol) and 0.21 g of 4-trifluoromethylthiophenol (1.15 mmol) into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol and mix for half an hour, then add 0.3 g of intermediate DC-Z2 (962.25 μmol) and react at room temperature for about 6 hours. After the reaction is complete, pour the reaction mixture into water, stir overnight, filter and collect the precipitated solid; purify 0.45 g of the target compound DS21 by recrystallization from dichloromethane.

[0157] The physicochemical properties and NMR (1H and 1C) spectra of the synthesized 4-substituted quinoline derivatives are shown in Table 2. Table 2 shows the physicochemical properties and NMR data of the target compounds.

[0158] Table 2

[0159] Example 28

[0160] A method for preparing a 4-substituted quinoline compound (DO1) includes the following steps:

[0161] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0162] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0163] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.2 g of 2-bromophenol (1.15 mmol) and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO1.

[0164] Example 29

[0165] A method for preparing a 4-substituted quinoline compound (DO2) includes the following steps:

[0166] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0167] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0168] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.2 g of 4-bromophenol (1.15 mmol) and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO2.

[0169] Example 30

[0170] A method for preparing a 4-substituted quinoline compound (DO3) includes the following steps:

[0171] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0172] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0173] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.19 g of 3-trifluoromethylphenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO3.

[0174] Example 31

[0175] A method for preparing a 4-substituted quinoline compound (DO4) includes the following steps:

[0176] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0177] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0178] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.15 g of 2-fluoro,4-methylphenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO4.

[0179] Example 32

[0180] A method for preparing a 4-substituted quinoline compound (DO5) includes the following steps:

[0181] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0182] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0183] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.15 g of 2-fluoro,3-methylphenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO5.

[0184] Example 33

[0185] A method for preparing a 4-substituted quinoline compound (DO6) includes the following steps:

[0186] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0187] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0188] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.16 g of 3-chloro-4-methylphenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO6.

[0189] Example 34

[0190] A method for preparing a 4-substituted quinoline compound (DO7) includes the following steps:

[0191] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0192] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0193] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.15 g of 4-fluoro-3-methylphenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO7.

[0194] Example 35

[0195] A method for preparing a 4-substituted quinoline compound (DO8) includes the following steps:

[0196] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0197] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0198] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.13 g of 4-fluorophenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO8.

[0199] Example 36

[0200] A method for preparing a 4-substituted quinoline compound (DO9) includes the following steps:

[0201] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0202] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0203] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.29 g of 2,5-dibromophenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO9.

[0204] Example 37

[0205] A method for preparing a 4-substituted quinoline compound (DO10) includes the following steps:

[0206] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0207] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0208] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.15 g of 2,4-dibromophenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO10.

[0209] Example 38

[0210] A method for preparing a 4-substituted quinoline compound (DO11) includes the following steps:

[0211] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0212] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0213] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.19 g of 3,4-dichlorophenol (1.15 mmol), and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO11.

[0214] Example 39

[0215] A method for preparing a 4-substituted quinoline compound (DO12) includes the following steps:

[0216] (1) p-Phenylenediamine (3.97 g, 36.67 mmol) was added to a solution of 4-chloroquinoline (5 g, 30.56 mmol) and 1,4-dioxane (100 mL), and the mixture was heated at 110 °C for 14 hours. After the reaction was complete, the precipitate was filtered and washed successively with 1,4-dioxane and ethyl acetate to obtain intermediate DC-Z1, with a yield of 90%~95%.

[0217] (2) Intermediate DC-Z1 (3 g, 12.75 mmol) and triethylamine (1.55 g, 15.30 mmol) were added to a dichloromethane solution (50 mL) and reacted in an ice bath for 30 minutes. Then, chloroacetyl chloride (2.16 g, 19.13 mmol) was added to the system, and the reaction was continued at room temperature for about 4 hours. After the reaction was completed, the intermediate DC-Z2 was obtained by filtration, with a yield of 85%~90%.

[0218] (3) Weigh 0.3 g of intermediate DC-Z2 (0.962 mmol) and 0.065 g of potassium hydroxide (1.15 mmol) into a 25 mL round-bottom flask, and then add 10 mL of 1,4-dioxane as a solvent. After stirring at room temperature for 0.5 h, add 0.15 g of 3-chlorophenol (1.15 mmol) and then reflux at 80 °C. After the reaction is complete, pour into water and stir overnight, then filter and wash with dichloromethane to obtain DO12.

[0219] The physicochemical properties and NMR (1H and 1C) spectra of the synthesized 4-substituted quinoline derivatives are shown in Table 3. Table 3 shows the physicochemical properties and NMR data of the target compounds.

[0220] Table 3

[0221] Experimental Example 1: Antitumor Activity Test.

[0222] The MTT assay is used to test the antitumor activity of target compounds. MTT, short for 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (thiazolium blue), is a yellow dye. The MTT colorimetric assay is a method for detecting cell viability and growth. Its principle is that succinate dehydrogenase in the mitochondria of living cells reduces exogenous MTT to water-insoluble blue-violet formazan crystals, which are deposited in the cells. Dead cells lack this function. Dimethyl sulfoxide (DMSO) dissolves the formazan in the cells, and the absorbance is measured at 490 nm using an enzyme-linked immunosorbent assay (ELISA) reader, indirectly reflecting the number of living cells. Within a certain cell number range, the amount of MTT crystals formed is directly proportional to the cell number.

[0223] Test cell lines

[0224] 5637 (human bladder cancer cell line, adherent cell);

[0225] A549 (human non-small cell lung cancer cells, adherent cells).

[0226] PC-3 (human prostate cancer cells, adherent cells);

[0227] Hela (human cervical cancer cells);

[0228] K562 (human chronic myeloid leukemia cells, suspension cells).

[0229] Cell Count

[0230] First, soak the cell counting chamber and blood coverslips in anhydrous ethanol. Take 10 μL of cell suspension and add it to the edge of the blood coverslip, ensuring the suspension fills the space between the coverslip and the counting chamber without overflowing the coverslip or into the glass troughs on either side. Observe the number of cells in the four large squares (each large square contains 16 smaller squares) of the counting chamber under a 10× objective lens. Only count the cells on the left and top edges of the large squares, excluding the right and bottom edges. Calculate the cell density using the formula: (sum of cell counts in the four large squares / 4) × 10⁴ cells / mL.

[0231] Dilute the cell suspension to the required cell concentration for the experiment, seed 100 μL into each well of a 96-well culture plate, set up a negative control group and a blank control group, observe, and then place in an incubator.

[0232] Cellular drug delivery

[0233] (1) Preparation of drug stock solution (10000 μmol / L): Accurately weigh the compound (molecular weight M) mg in a clean bench and put it into a 1.5 mL centrifuge tube. Add m / M × 108 μL DMSO in a biosafety cabinet.

[0234] For example, if 0.0035 g of compound A with M = 249 is weighed, the volume of DMSO added is 0.0035 / 249 × 10⁸ = 1406 μL.

[0235] (2) Cell seeding plate (5000 / well): Open 96 wells in a biosafety cabinet, add 200 μL of sterile distilled water around the perimeter, and add 100 μL of cell suspension (1 × 105 cells / mL) to the remaining wells to adjust the cell density to 5000 / well; incubate at 37°C for 24 h with 5% CO2.

[0236] (3) Initial drug screening (10 μmol / L): Take a 1.5 mL sterile centrifuge tube, add 500 μL serum-free culture medium and 1 μL 10000 μmol / L compound stock solution to prepare a 20 μmol / L solution. After shaking and mixing, add 100 μL to each well of a 96-well plate (do not remove the previous 100 μL culture medium) to make the final concentration of the compound 10 μmol / L; repeat each concentration 5 times; incubate at 37℃ for 48 h with 5% CO2.

[0237] MTT testing

[0238] After 48 hours of drug treatment, the 96-well plate was disinfected with 75% alcohol and then placed in the biosafety cabinet.

[0239] Add 20 μL of MTT solution (5 mg / mL, i.e., 0.5% MTT) to each well and continue culturing for 4 h;

[0240] Terminate the culture and carefully aspirate the culture medium from the wells (if the cells are in suspension, centrifuge at 3500 rpm for 30 min and then carefully aspirate the culture medium); add 150 μL of DMSO to each well and shake on a shaker at low speed for 15 min to fully dissolve the crystals. Measure the absorbance of each well at OD 490 nm using an ELISA reader.

[0241] Control group setup and inhibition rate calculation

[0242] Blank group: Cellless wells used for zeroing absorbance (subtracting a small amount of the absorbance of the 96-well plate itself).

[0243] Negative control group: Wells containing cells with an administration concentration of 0; the cell viability of this group was considered as 100% in the experiment.

[0244] Drug treatment groups: Different concentrations of drug treatment groups

[0245] Positive control: refers to using a known effective drug that is similar to the test sample as a control.

[0246]

[0247]

[0248] Formula 1: Formula for calculating cell viability and inhibition rate

[0249] Table 4. Antitumor activity of compounds BD1-BD6

[0250]

[0251] Table 5. Antitumor activity of compounds DS1-DS23

[0252]

[0253] Table 6. Antitumor activity of compounds DO1-DO12

[0254]

[0255] a,b,c Reference drugs: 5-F: 5-fluorouracil, DOX: doxorubicin, Ima: imatinib

[0256] " / " indicates inactivity

[0257] In an in vitro cell antitumor activity assay, using broad-spectrum antitumor drugs imatinib, 5-fluorouracil, and doxorubicin as positive controls, compounds were screened for antitumor activity. The BD series showed weak inhibitory activity against the A549 lung cancer cell line, but exhibited significant antitumor activity against the remaining four tumor cell lines, with inhibition rates exceeding 80%. Compound BD4 showed significant antitumor activity against all five tumor cell lines. The DS series showed weak inhibitory activity against the A549 lung cancer cell line and 5637 bladder cancer cells, with inhibition rates generally below 20%, indicating no inhibitory effect on these two specific cell lines. Conversely, compounds DS-9, DS-16, DS-19, and DS-21 showed significant inhibitory effects on the remaining cancer cell lines, with inhibition rates exceeding 80%. Notably, compound DS-19 showed significant antitumor activity against the remaining three tumor cell lines, and its inhibitory activity was superior to the positive control drugs. Most compounds in the DO series exhibited relatively good antitumor activity against K562, PC-3, and HeLa cells, with inhibition rates almost all exceeding 80%. Notably, among all the DO series compounds, only DO-1 showed good antitumor activity against HeLa cells while exhibiting almost no inhibitory activity against the other four cancer cell lines, with inhibition rates of 30.41%, 31.77%, 26.42%, 84.48%, and 4.92%, respectively.

[0258] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made based on the content of the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A 4-substituted quinoline compound, the structure of which is given by general formula (Ⅰ): （Ⅰ） in, R can be NH, CH2NH, CH2O, CH2S, or piperazine. In CH2NH, one end of the CH2 group is attached to the carbonyl carbon of the amide group, and the other end of the NH group is attached to the benzene ring substituted by R1 and R2. In CH2O, one end of the CH2 group is attached to the carbonyl carbon of the amide group, and the other end of the O group is attached to the benzene ring substituted by R1 and R2. In CH2S, one end of the CH2 group is attached to the carbonyl carbon of the amide group, and the other end of the S group is attached to the benzene ring substituted by R1 and R2. In the piperazine-1,4-diyl group, one N atom is attached to the carbonyl carbon of the amide group, and the other N atom is attached to R1 and R2. The substituted benzene ring is 2; R1 and R2 are respectively halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, phenoxy, nitro, phenyl, benzyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C15 aryl or C6-C10 heteroaryl, wherein R1 is a monosubstituted or one or more identical or different substituents, and when R1 contains an aromatic ring, the aromatic ring is further substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro or trifluoromethyl.

2. The 4-substituted quinoline compound as described in claim 1, characterized in that, The halogen is fluorine, chlorine, bromine, or iodine; the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or neopentyl; the C1-C6 alkoxy group is methoxy, ethoxy, propoxy, or butoxy; the C2-C6 alkenyl group is propenyl or allyl; the C6-C15 aryl group is phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, or 3-methylbenzyl. Benzyl or 4-methylbenzyl; the C6-C10 heteroaryl group is 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl or 4-trifluoromethylbenzyl.

3. The 4-substituted quinoline compound as described in claim 1 or 2, characterized in that, When R1=H, R2 is selected from methyl, trifluoromethyl, fluorine, trifluoromethoxy, bromine, nitro, and chlorine; when R1=CH3, R2 is selected from chlorine, fluorine, and methyl; when R1=chlorine, R2 is selected from chlorine.

4. The 4-substituted quinoline compound as described in claim 1 or 2, characterized in that, Specifically, the following compounds: 。 5. A method for preparing a 4-substituted quinoline compound, comprising the following steps: 。 6. Application of a 4-substituted quinoline compound in the preparation of anti-prostate cancer, cervical cancer, chronic myeloid leukemia and other tumor drugs.

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