Bridged biquinoline compound as well as preparation method and application thereof

Abstract

The invention discloses a bridged biquinoline compound and a preparation method and application thereof.The compound has a certain killing effect on colon cancer cells, lung cancer cells, liver cancer cells, gastric cancer cells, cervical cancer cells and breast cancer cells, the killing effect on the colon cancer cells is especially obvious, and the killing effect on the colon cancer cells is remarkably superior to that of positive control drugs chloroquine and cis-platinum; in addition, the bridged biquinoline compound has small toxic and side effects, solves the problem of large toxic and side effects of traditional platinum antitumor drugs such as cis-platinum and the like, and can be prepared into antitumor drugs for application. The preparation method of the bridged biquinoline compound is simple and efficient, industrial production can be realized, and the bridged biquinoline compound has great application value in tumor resistance.

Description

[0001] This application is a divisional application of a Chinese application with the application number CN202410860305.3, the application date of June 28, 2024, and the invention title of "A Bridged Diquinoline Compound and Its Preparation Method and Application". Technical Field

[0002] The present invention belongs to the technical field of medicinal chemistry, and specifically relates to a bridged diquinoline compound and its preparation method and application. Background Art

[0003] Cancer is one of the leading causes of morbidity and mortality globally, seriously threatening human health. Currently, anti-tumor drugs clinically mainly include alkylating agents, antimetabolites, anti-tumor antibiotics, anti-tumor plant drugs, and immunotherapy drugs, etc. However, many anti-cancer drugs have obvious toxic and side effects on the normal body, such as mutagenicity and genotoxicity, etc. Therefore, the research on anti-tumor drugs has become a hot topic today. Currently, anti-tumor drug structures are complex and diverse, and compounds with various different structures show excellent anti-tumor activities. Finding effective anti-tumor drugs with small toxic and side effects has become a hot spot in the current research and development of new anti-tumor drugs.

[0004] Quinoline compounds have good biological activities and extensive medicinal values. Drugs developed based on the quinoline skeleton include anti-cancer drugs, antibacterial drugs, antifungal drugs, and antiviral drugs. However, currently, quinoline compounds have disadvantages such as insufficient activity and high toxicity in anti-tumor drugs. How to improve quinoline compounds and further develop anti-tumor drugs with high efficiency and small side effects is a problem to be solved. Summary of the Invention

[0005] In order to overcome the problems existing in the above-mentioned prior art, one of the purposes of the present invention is to provide a bridged diquinoline compound. The second purpose of the present invention is to provide a preparation method of the bridged diquinoline compound. The third purpose of the present invention is to provide the application of the bridged diquinoline compound.

[0006] Nowadays, the "multivalent binding theory" has been proposed in research. This theory believes that the binding between biological entities (molecules / surfaces) is an instantaneous multivalent binding of multiple ligands and multiple receptors. This multivalent binding is ubiquitous in biological systems and has many characteristics that monovalent binding does not have. In particular, the binding force of multivalent binding is stronger as a whole. Due to the importance of multivalent binding in biological systems, more and more research is devoted to the exploration and optimization of multivalent binding, and according to the "multivalent binding theory", new strategies for drug design have been provided, which have been widely applied in aspects such as anti-resistant bacteria antibiotics, anti-influenza virus, anti-human immunodeficiency virus (HIV), anti-cholera bacteria, and anti-tumor.

[0007] Bimolecular drugs are a new type of drug based on the "multivalent binding theory". Their basic structure is a dimer formed by covalently bridging active monomers through a non-toxic covalent bond. Based on the multivalent binding theory, the affinity and avidity of bimolecular drugs for receptors can be significantly improved, usually 100 - 1000 times that of monomer molecules, and the toxicity of bimolecular drugs is usually also significantly reduced compared to monomer molecules. The present invention provides a bridged bisquinoline compound, which solves the problems of low activity and high toxicity of current quinoline compounds in anti-tumor drugs.

[0008] To achieve the above object, the technical solution adopted by the present invention is:

[0009] In the first aspect of the present invention, a bridged bisquinoline compound is provided, and its structural formula is shown as formula (A), formula (B) or formula (C):

[0010]

[0011] In formula (A), n = 3 - 9;

[0012] In formula (B), the R1 is alkyl diamino, aryl diamino or non-aromatic azacyclic group; the R2 is alkoxy, substituted or unsubstituted aralkyl ether group;

[0013] In formula (C), the R3 is alkyl diether group; the R4 is substituted or unsubstituted arylamino, substituted or unsubstituted non-aromatic azacyclic group.

[0014] Generally, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen on a group (e.g., a carbon or nitrogen atom) is replaced by an allowable substituent, e.g., a substituent that produces a stable compound upon substitution, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination or other reactions). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents at each position are the same or different. The term "substituted" includes substitution with all allowable substituents of organic compounds (any substituent described herein that results in the formation of a stable compound).

[0015] Preferably, in formula (B), the R1 is --NH-(CH2) m -NH--, where m = 1 - 3, and the dashed line represents the group linking position.

[0016] Preferably, in formula (B), the substituted or unsubstituted aralkyl ether group in the R2 is Among them, x = 1 to 3, Y is a halogen, and the dotted line represents the group linkage position.

[0017] Preferably, in formula (C), the R3 is ---O-(CH2) b -O---; where b = 4 to 7, and the dotted line represents the group linkage position.

[0018] Preferably, in formula (C), the substituted arylamino group in R4 is Among them, Z is a methoxy group, a trifluoromethyl group or a halogen, and the dotted line represents the group linkage position.

[0019] More preferably, the bridged bisquinoline compound is shown in Formulas 1 to 28:

[0020]

[0021]

[0022]

[0023] The second aspect of the present invention provides a preparation method of the bridged bisquinoline compound described in the first aspect. When the bridged bisquinoline compound is shown in formula (A), its preparation method includes the following steps:

[0024] React the compound shown in formula (a) with a dihalide to obtain a bridged bisquinoline compound shown in formula (A); the reaction formula is as follows:

[0025]

[0026] Among them, the K is fluorine, iodine, chlorine, bromine;

[0027] When the bridged bisquinoline compound is shown in formula (B), its preparation method includes the following steps:

[0028] React the compound shown in formula (b) with a compound containing R1 to obtain a bridged bisquinoline compound shown in formula (B); the reaction formula is as follows:

[0029]

[0030] Among them, the Z is fluorine, iodine, chlorine, bromine;

[0031] When the bridged bisquinoline compound is shown in formula (C), its preparation method includes the following steps:

[0032] React the compound shown in formula (c) with a compound containing R3 to obtain a bridged bisquinoline compound shown in formula (C); the reaction formula is as follows:

[0033]

[0034] Among them, X is fluorine, iodine, chlorine, or bromine;

[0035] n, R1, R2, R3, and R4 are as described above.

[0036] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (A), the reaction temperature of the reaction is 40 - 60 °C. More preferably, the reaction temperature of the reaction is 45 - 55 °C.

[0037] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (A), the reaction time of the reaction is 8 - 10 h.

[0038] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (B), the reaction temperature of the reaction is 120 - 140 °C.

[0039] More preferably, the reaction temperature of the reaction is 125 - 135 °C.

[0040] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (B), the reaction time of the reaction is 20 - 48 h.

[0041] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (C), the reaction temperature of the reaction is 40 - 60 °C.

[0042] More preferably, the reaction temperature of the reaction is 45 - 55 °C.

[0043] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (C), the reaction time of the reaction is 4 - 10 h.

[0044] Preferably, the molar ratio of the compound represented by formula (a) to the dihalide is (2 - 3):1.

[0045] Preferably, the molar ratio of the compound represented by formula (b) to the compound containing R1 is (2 - 3):1.

[0046] Preferably, the molar ratio of the compound represented by formula (c) to the compound containing R3 is (2 - 3):1.

[0047] Preferably, the compound represented by formula (b) is prepared by a preparation method including the following steps:

[0048] React the compound represented by formula (b1) with the compound containing R2 to obtain the compound represented by formula (b); the reaction formula is as follows:

[0049]

[0050] Among them, Z and R2 are as described above.

[0051] Preferably, the compound represented by formula (b) is prepared by a preparation method comprising the following steps:

[0052] React the compound represented by formula (c1) with a compound containing R4 to obtain the compound represented by formula (c); the reaction formula is as follows:

[0053]

[0054] Among them, R4 is as described above.

[0055] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (A), the reaction system of the reaction further comprises an inorganic base. More preferably, the inorganic base is selected from one or more of Cs2CO3, K2CO3, and Na2CO3. More preferably, the concentration of the inorganic base in the reaction system is 0.3 - 1 mol / L.

[0056] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (A), the reaction system of the reaction further comprises an iodide salt. More preferably, the iodide salt is selected from one or more of potassium iodide, sodium iodide, and iodide amine. More preferably, the molar ratio of the iodide salt to the compound represented by formula (a) is 1:(3 - 6).

[0057] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (A), the solvent for the reaction is any one of dimethyl sulfoxide (DMSO), N,N - dimethylformamide (DMF), N,N - dimethylacetamide (DMAC), and acetonitrile (CH3CN).

[0058] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (B), the reaction system of the reaction further comprises an organic base. More preferably, the organic base is selected from one or more of triethylamine, tripropylamine, and tributylamine. More preferably, the concentration of the organic base in the reaction system is 0.3 - 1 mol / L.

[0059] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (B), the solvent for the reaction is ethylene glycol monoethyl ether or ethylene glycol monomethyl ether.

[0060] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (C), the reaction system of the reaction further comprises an iodide salt. More preferably, the iodide salt is selected from one or more of potassium iodide, sodium iodide, and iodide amine. More preferably, the molar ratio of the iodide salt to the compound represented by formula (c) is 1:(3 - 6).

[0061] Preferably, in the preparation of the bridged bisquinoline compound shown in formula (C), the solvent for the reaction is any one of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), and acetonitrile (CH3CN).

[0062] The third aspect of the present invention provides the use of the bridged bisquinoline compound described in the first aspect or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

[0063] Preferably, the pharmaceutically acceptable salts are selected from phosphates, hydrochlorides, sulfates, nitrates, hydrobromides, methanesulfonates, maleates, tartrates, benzoates, and lactates.

[0064] Preferably, the tumors include colon cancer, lung cancer, liver cancer, gastric cancer, cervical cancer, or breast cancer.

[0065] The beneficial effects of the present invention are as follows:

[0066] (1) The present invention provides a bridged bisquinoline compound, which shows a certain killing effect on colon cancer, lung cancer, liver cancer, gastric cancer, cervical cancer, and breast cancer cells. Among them, the killing effect on colon cancer cells is particularly obvious, significantly better than the positive control drugs chloroquine phosphate and cisplatin. In addition, the bridged bisquinoline compound has small toxic and side effects, solves the problem of large toxic and side effects of traditional anti-tumor drugs such as cisplatin, and can be prepared into an anti-tumor drug for application;

[0067] (2) The preparation method of the bridged bisquinoline compound of the present invention is simple and efficient, can realize industrial production, and has great application value in anti-tumor. Detailed implementation manners

[0068] The content of the present invention will be further described in detail through specific examples below. The raw materials used in the following examples, unless otherwise specified, can be obtained from conventional commercial channels or prepared and separated by simple synthesis; the processes used, unless otherwise specified, are all conventional processes in the art.

[0069] Example 1

[0070] This example provides 1-position bridged bisquinoline compounds 9a-9f, and their general synthesis process and synthesis equations are as follows:

[0071]

[0072] Add chloroquine 7a (3 mmol), DMF (15 mL), K2CO3 (10 mmol), KI (0.75 mmol) and dihalide (1.5 mmol) to a 100 mL round-bottom flask, stir and heat at 50 °C for 8 - 10 h, monitor the reaction by TLC (DCM:MeOH = 10:1) until the reaction is complete. After removing most of the solvent by rotary evaporation under reduced pressure, add 100 mL of water, and a solid will precipitate. Extract with ethyl acetate (100 mL × 3), combine the organic phases, wash successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (DCM:MeOH = 100:1, 50:1). Collect the target product and concentrate it to dryness under reduced pressure to obtain a solid. The synthesis of specific compounds 9a - 9f is as follows:

[0073] 1) 1,4-Bis(7-chloro-4-oxoquinoline)butane (9a)

[0074]

[0075] Using chloroquine 7a and 1,4-dibromobutane as raw materials, a white solid was obtained with a yield of 26.7%, mp 69.1 - 70.4 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 9.19 (d, J = 7.0 Hz, 1H, ArH), 8.39 (d, J = 6.4 Hz, 1H, ArH), 8.26 (d, J = 8.0 Hz, 2H, ArH), 8.18 (d, J = 8.8 Hz, 1H, ArH), 7.92 (d, J = 7.4 Hz, 2H, ArH), 7.49 (dd, J = 7.6 Hz, 2H, ArH), 6.31 (d, J = 7.8 Hz, 1H, ArH), 4.63 (t, J = 7.2 Hz, 4H, NCH2), 2.01 (m, 4H, CH2). 13 13C NMR (151 MHz, CD3OD) δ 170.7, 148.7, 142.5, 140.9, 104.5, 131.2, 126.8, 120.7, 104.5, 72.8, 26.7. HR-MS (ESI) calcd for C 22 H 19 Cl2N2O2 [M + H] + : 413.08181, found: 413.08179.

[0076] 2) 1,5-Bis(7-chloro-4-oxoquinoline)pentane (9b)

[0077]

[0078] Using chloroquine 7a and 1,5-dibromopentane as raw materials, a grayish-white solid was obtained with a yield of 14.8% and a melting point of 118.6 - 119.4 °C. 1 HNMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.6 Hz, 2H, ArH), 8.07 (d, J = 7.8 Hz, 2H, ArH), 7.90 (d, J = 2.0 Hz, 2H, ArH), 7.45 (dd, J = 8.6, 1.8 Hz, 2H, ArH), 6.18 (d, J = 7.6 Hz, 2H, ArH), 4.28 (t, J = 7.2 Hz, 4H, CH2-N), 1.77 (t, J = 7.8 Hz, 4H, CH2), 1.36 (m, 2H, CH2). 13 C NMR (101 MHz, DMSO-d6) δ 162.8, 147.4, 126.6, 125.8, 123.2, 121.8, 120.3, 104.1, 69.1, 28.4, 22.5. HR-MS (ESI) calcd for C 23 H 21 Cl2N2O2 [M+H] + : 427.09746, found: 427.09735.

[0079] 3) 1,6-Bis(7-chloro-4-oxoquinoline)hexane (9c)

[0080]

[0081] Using chloroquine 7a and 1,6-dibromohexane as raw materials, a grayish-white solid was obtained with a yield of 53.6% and a melting point of 121 - 122.4 °C. 1 HNMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.8 Hz, 2H, ArH), 8.10 (d, J = 7.8 Hz, 2H, ArH), 7.91 (d, J = 1.8 Hz, 2H, ArH), 7.46 (dd, J = 8.6, 1.7 Hz, 2H, ArH), 6.21 (d, J = 7.6 Hz, 2H, ArH), 4.28 (t, J = 7.4 Hz, 4H, CH2-N), 1.71 (t, J = 8.0 Hz, 4H, CH2), 1.39–1.31 (m, 4H, CH2). 13 C NMR (151 MHz, DMSO-d6) δ 175.4, 146.2, 140.8, 138.0, 128.3, 125.2, 124.7, 116.8, 109.4, 52.7, 28.9, 25.9. HR-MS (ESI) calcd for C 24 H 23Cl2N2O2[M+H] + : 441.11311, found: 441.11295。

[0082] 4) 1,7 - Bis(7 - chloro - 4 - oxoquinoline)heptane (9d)

[0083]

[0084] Using chloroquine N - oxide 7a and 1,7 - dibromoheptane as raw materials, a light - beige solid was obtained, with a yield of 36.3%, mp 149.3 - 150.7 °C. 1 HNMR(400 MHz, CDCl3) δ 8.73(d, J = 5.2 Hz, 1H, ArH), 8.41(d, J = 8.6 Hz, 1H, ArH), 8.16(d, J = 6.8 Hz, 2H, ArH), 7.51(d, J = 8.0 Hz, 2H, ArH), 7.41(d, J = 6.8 Hz, ArH), 6.71(d, J = 5.4 Hz, 1H, ArH), 6.26(d, J = 7.8 Hz, 1H, ArH), 4.14(t, J = 6.8 Hz, 4H, CH2 - N), 1.94(t, J = 6.8 Hz, 4H, CH2), 1.59(t, J = 6.2 Hz, 2H, CH2), 1.48(q, J = 5.6 Hz, 4H, CH2). 13 C NMR(151 MHz, DMSO - d6) δ 161.2, 150.4, 128.2, 125.6, 123.2, 121.7, 108.5, 68.7, 29.4, 29.3, 26.4. HR - MS(ESI) calcd for C 25 H 25 Cl2N2O2[M + H] + : 455.12876, found: 455.12848。

[0085] 5) 1,8 - Bis(7 - chloro - 4 - oxoquinoline)octane (9e)

[0086]

[0087] Using chloroquine N - oxide 7a and 1,8 - dibromooctane as raw materials, a white solid was obtained, with a yield of 19.5%, mp 131.2 - 132.5 °C. 1HNMR(400MHz,CDCl3)δ8.69(d,J=5.2Hz,2H,ArH),8.12(d,J=3.4Hz,2H,ArH),7.98(d,J=2.2Hz,2H,ArH),7.40(dd,J=9.0,2.2Hz,2H,ArH),6.70(d,J=5.1Hz,2H,ArH),4.17(t,J=6.4Hz,4H,CH2-N),1.93(p,J=6.6Hz,4H,CH2),1.57(t,J=7.6Hz,4H,CH2),1.50–1.42(m,4H,CH2). 13 C NMR(101MHz,CDCl3)δ161.7,152.5,149.6,135.6,127.8,126.4,123.5,119.9,100.9,68.6,40.3,29.2,26.0.HR-MS(ESI)calcd for C 26 H 27 Cl2N2O2[M+H] + :469.14441,found:469.14447。

[0088] 6) 1,9-Bis(7-chloro-4-oxoquinoline) nonane (9f)

[0089]

[0090] Using chloroquine 7a and 1,9-dibromononane as raw materials, a grayish-white solid was obtained with a yield of 41.3% and mp 140.1 - 141.5 °C. 1 HNMR(600MHz,DMSO-d6)δ8.74(d,J=5.2Hz,2H,ArH),8.15(d,J=8.6Hz,2H,ArH),7.58(d,J=2.2Hz,2H,ArH),7.39(dd,J=8.6,1.9Hz,2H,ArH),7.04(d,J=5.4Hz,2H,ArH),4.23(t,J=7.2Hz,4H,CH2-N),1.84(p,J=6.6Hz,4H,CH2),1.72–1.66(m,4H,CH2),1.47(p,J=7.4Hz,2H),1.38–1.31(m,4H,CH2). 13 C NMR(151MHz,DMSO-d6)δ161.4,149.6,140.9,134.9,127.7,125.8,124.1,116.6,102.5,69.0,56.5,55.3,52.3,19.0.HR-MS(ESI)calcd forC27 H 29 Cl2N2O2[M + H] + : 483.16006, found: 483.15994。

[0091] Example 2

[0092] This example provides 4 - bridged bis - quinoline compounds 11a - 11j, and their general synthesis process and synthesis equations are as follows:

[0093] 1. Synthesis of intermediates

[0094] The preparation methods of 4 - chloro - 7 - methoxyquinoline and 4 - chloro - 8 - hydroxyquinoline are as follows:

[0095]

[0096] Synthesis route of intermediates:

[0097]

[0098] General synthesis process of intermediates 10a - d:

[0099] Add DMF (30 mL), intermediate 8 (10 mmol) and 60% NaH (20 mmol) into a 100 mL round - bottom flask, stir at room temperature for 10 min, and the system becomes yellow - green turbid. Then add the corresponding alkyl halide (20 mmol), stir and react at room temperature, and monitor by TLC. After the reaction is completed, mix the reaction mixture with 100 mL of water, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and subject the residue to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 as the mobile phase), collect the target product, and concentrate to dryness under reduced pressure to obtain a pale - yellow solid. The synthesis of intermediates 10a - d is as follows:

[0100] 1) 4 - chloro - 7 - n - butoxyquinoline (10a)

[0101] Synthesized according to the above method, obtained as a white solid, yield 46%. ESI - MS m / z: 236.62[M + H] + 。

[0102] 2) 4 - chloro - 7 - benzyloxyquinoline (10b)

[0103] Synthesized according to the above method, obtained as a pale - yellow solid, yield 58%. ESI - MS m / z: 270.21[M + H] + 。

[0104] 3) 4 - chloro - 7 - (4’ - fluorobenzyl)oxy)quinoline (10c)

[0105] Synthesized according to the literature method to obtain a yellow solid with a yield of 87%. ESI-MS m / z: 288.15 [M+H] + .

[0106] 4) 4-Chloro-7-phenoxypropylquinoline (10d)

[0107]

[0108] Using intermediate 8 and 1-bromo-3-phenylpropane as raw materials, a pale yellow solid was obtained with a yield of 86.8%. mp 108.1 - 109.4 °C. ESI-MS m / z: 298.28 [M+H] + . 1 H NMR (600 MHz, CDCl3) δ 9.01 (d, J = 6.0 Hz, 1H, ArH), 8.27 (d, J = 9.4 Hz, 1H, ArH), 8.11 (d, J = 2.4 Hz, 1H, ArH), 7.81 (d, J = 6.0 Hz, 1H, ArH), 7.51 (dd, J = 9.4, 2.4 Hz, 1H, ArH), 7.25 (t, J = 7.6 Hz, 2H, ArH), 7.18 (d, J = 7.4 Hz, 2H, ArH), 7.16 (d, J = 7.4 Hz, 1H, ArH), 4.25 (t, J = 6.2 Hz, 2H, OCH2), 2.82 (dd, J = 8.6, 6.8 Hz, 2H, CH2), 2.22–2.12 (m, 2H, CH2). 13 C NMR (151 MHz, CDCl3) δ 164.8, 152.3, 142.3, 141.5, 140.8, 128.5, 128.4, 126.6, 126.2, 125.0, 122.7, 119.5, 100.4, 69.12, 34.8, 32.0, 30.3.

[0109] 2. Synthetic route (1) of 4-bridged bisquinoline compounds:

[0110]

[0111] Synthetic route (2) of 4-bridged bisquinoline compounds:

[0112]

[0113] Synthetic route (3) of 4-bridged bisquinoline compounds:

[0114]

[0115] General synthetic process of 4-bridged bisquinoline derivatives 11a - 11c, 11g - 11j:

[0116] Add intermediate 7 or 10a - d (2 mmol), triethylamine (3 mmol), ethylenediamine or anhydrous piperazine (1.5 mmol), and ethylene glycol monoethyl ether (5 mL) successively into a 50 mL round-bottom flask. React at 130 °C for 30 h with stirring, and monitor the reaction by TLC. After the reaction is completed, cool the reaction mixture to room temperature. Add 5 mL of anhydrous ether or ethyl acetate to the mixture to induce precipitation of the product. Stir for 30 min, filter to obtain a solid, then wash the solid with petroleum ether, and perform silica gel column chromatography (200 - 300 mesh, mobile phase dichloromethane:methanol = 100:1, 50:1). Collect the target product and concentrate it under reduced pressure to dryness to obtain a solid.

[0117] General synthetic process of 4-bridged bisquinoline derivatives 11d - 11f:

[0118] Add intermediate 7 or 10c - d (2 mmol), triethylamine (3 mmol), p-phenylenediamine (1.5 mmol), ethylene glycol monomethyl ether (5 mL), and pyridine hydrochloride (1 mmol) successively into a 50 mL round-bottom flask. React at 130 °C for 20 - 48 h with stirring, and monitor the reaction by TLC. After the reaction is completed, cool the reaction mixture to room temperature. Add 5 mL of anhydrous ether or ethyl acetate to the mixture to induce precipitation of the product. Stir for 30 min, filter to obtain a solid, then wash the solid with petroleum ether, and perform silica gel column chromatography (200 - 300 mesh, mobile phase dichloromethane:methanol = 100:1, 50:1). Collect the target product and concentrate it under reduced pressure to dryness to obtain a solid.

[0119] The synthesis of specific compounds 11a - 11j is as follows:

[0120] 1) 1,2-bis(7-methoxy-4-aminoquinoline)ethane (11a)

[0121]

[0122] Using intermediate 7 and ethylenediamine as raw materials, a grayish-white solid was obtained with a yield of 24.7%, mp > 240 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 5.8 Hz, 2H, ArH), 8.02 (d, J = 9.2 Hz, 2H, ArH), 7.14 (d, J = 2.6 Hz, 2H, ArH), 7.07 (dd, J = 9.2, 2.7 Hz, 2H, ArH), 6.50 (d, J = 5.8 Hz, 2H, ArH), 3.84 (s, 6H, OCH3), 3.61 (s, 4H, CH2). 1313C NMR (151 MHz, DMSO-d6) δ 163.1, 155.6, 142.9, 140.9, 125.7, 118.0, 111.6, 100.9, 98.0, 56.4, 42.0. HRMS (ESI) calcd for C 22 H 23 N4O2 [M+H] + : 375.18155, found: 375.18137。

[0123] 2) 1,2-Bis(7-n-butoxy-4-aminoquinoline)ethane (11b)

[0124]

[0125] Using intermediate 10a and ethylenediamine as raw materials, a white solid was obtained with a yield of 18.6%, mp > 240 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.4 Hz, 2H, ArH), 8.39 (t, J = 8.4 Hz, 4H, ArH), 7.23 (d, J = 12.0 Hz, 2H, ArH), 6.70 (d, J = 6.2 Hz, 2H, ArH), 3.90 (d, J = 6.4 Hz, 4H, CH2), 3.78 (s, 4H, CH2), 2.38–2.30 (m, 2H, CH2), 2.09 (p, J = 8.8, 7.6 Hz, 2H, CH2), 1.03 (s, 6H, OCH3). 13 13C NMR (101 MHz, DMSO-d6) δ 161.8, 154.5, 144.4, 142.8, 125.6, 117.6, 112.0, 102.9, 97.8, 74.7, 41.8, 37.2, 28.0, 19.4. HRMS (ESI) calcd for C 28 H 35 N4O2 [M+H] + : 459.27545, found: 459.27512。

[0126] 3) 1,2-Bis(7-phenoxypropoxy-4-aminoquinoline)ethane (11c)

[0127]

[0128] Using intermediate 10d and ethylenediamine as raw materials, a light yellow solid was obtained with a yield of 36.4%, mp > 240 °C. 11H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 2H, ArH), 8.62 (d, J = 9.4 Hz, 2H, ArH), 8.43 (d, J = 6.8 Hz, 2H, ArH), 7.32 - 7.26 (m, 8H, ArH), 7.20 (t, J = 7.2 Hz, 2H, ArH), 6.86 (d, J = 7.2 Hz, 2H, ArH), 4.13 (t, J = 6.4 Hz, 4H, CH2), 3.90 (s, 4H, CH2), 2.79 (t, J = 7.8 Hz, 4H, CH2), 2.14–2.08 (m, 4H, CH2). 13 13C NMR (151 MHz, DMSO-d6) δ 162.5, 155.8, 142.3, 141.6, 140.4, 128.9, 128.8, 126.4, 126.1, 118.1, 111.5, 100.9, 98.0, 68.1, 36.9, 31.8, 30.4. HRMS (ESI) calcd for C 38 H 39 N4O2 [M + H] + : 583.30675, found: 583.30579。

[0129] 4) 1,4-Bis(7-methoxy-4-ylquinoline)phenylenediamine (11d)

[0130]

[0131] Using intermediate 7 and p-phenylenediamine as raw materials, a yellowish-green solid was obtained with a yield of 85.3% and mp > 240 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 2H, NH), 8.72 (d, J = 9.4 Hz, 2H, ArH), 8.50 (d, J = 6.8 Hz, 2H, ArH), 7.67 (s, 4H, ArH), 7.49 (d, J = 9.4 Hz, 2H, ArH), 7.48 (s, 2H, ArH), 6.86 (d, J = 7.0 Hz, 2H, ArH), 4.00 (s, 6H, OCH3). 13 13C NMR (151 MHz, DMSO-d6) δ 163.7, 154.9, 142.9, 141.1, 136.5, 127.2, 126.0, 119.0, 112.1, 100.5, 99.9, 56.6. HRMS (ESI) calcd for C 26 H 23 N4O2 [M + H] +: 423.18155, found: 423.18118。

[0132] 5) 1,4-Bis(7-benzyloxy-4-ylquinoline)phenylenediamine (11e)

[0133]

[0134] Using intermediate 10b and p-phenylenediamine as raw materials, a grayish-brown solid was obtained with a yield of 46.3% and mp > 240 °C. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 2H, NH), 8.74 (d, J = 9.4 Hz, 2H, ArH), 8.49 (d, J = 7.0 Hz, 2H, ArH), 7.66 (s, 4H, ArH), 7.60–7.50 (m, 8H, ArH), 7.53–7.45 (m, 2H, ArH), 7.48–7.40 (m, 4H, ArH), 7.44–7.36 (m, 2H, ArH), 6.86 (d, J = 7.0 Hz, 2H, ArH), 5.37 (s, 4H, OCH2). 13 C NMR (101 MHz, DMSO-d6) δ 162.6, 154.9, 143.0, 141.0, 136.4, 136.2, 129.1, 128.8, 128.5, 127.1, 126.1, 119.2, 112.2, 101.8, 99.9, 70.60. HRMS (ESI) calcd for C 38 H 31 N4O2 [M+H] + : 575.14415, found: 575.24377。

[0135] 6) 1,4-Bis(7-phenoxypropoxy-4-ylquinoline)phenylenediamine (11f)

[0136]

[0137] Using intermediate 10d and p-phenylenediamine as raw materials, a yellow solid was obtained with a yield of 72.8% and mp > 240 °C. 11H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 2H, NH), 8.73 (d, J = 9.4 Hz, 2H, ArH), 8.50 (d, J = 6.8 Hz, 2H, ArH), 7.67 (s, 4H, ArH), 7.51 (d, J = 9.4 Hz, 2H, ArH), 7.30 (dd, J = 14.2, 6.8 Hz, 8H, ArH), 7.23 (d, J = 5.8 Hz, 2H, ArH), 6.87 (d, J = 6.8 Hz, 2H, ArH), 4.22 (d, J = 6.4 Hz, 4H, OCH2), 2.83 (t, J = 7.8 Hz, 4H, ArCH2), 2.16 (t, J = 7.4 Hz, 4H, CH2). 13 13C NMR (151 MHz, DMSO-d6) δ 162.9, 154.9, 142.9, 141.6, 141.1, 136.5, 128.9, 128.8, 127.1, 126.5, 126.2, 119.0, 112.1, 101.0, 99.8, 68.3, 31.8, 30.4. HRMS (ESI) calcd for C 42 H 39 N4O2 [M + H] + : 631.30675, found: 631.30573。

[0138] 7) 1,4-Bis(7-methoxyquinolin-4-yl)piperazine (11 g)

[0139]

[0140] Using intermediate 7 and anhydrous piperazine as raw materials, a pale yellow solid was obtained with a yield of 82.2% and mp 176.4 - 177.2 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 5.2 Hz, 2H, ArH), 8.04 (d, J = 9.2 Hz, 2H, ArH), 7.36 (d, J = 2.6 Hz, 2H, ArH), 7.23 (dd, J = 9.2, 2.8 Hz, 2H, ArH), 7.00 (d, J = 5.2 Hz, 2H, ArH), 3.92 (s, 6H, OCH3), 3.51 (s, 8H, NCH2). 13 13C NMR (101 MHz, DMSO-d6) δ 162.9, 159.4, 142.3, 141.2, 129.1, 117.5, 112.9, 103.2, 100.4, 56.5, 49.7. HRMS (ESI) calcd for C 24 H 25N4O2[M+H] + : 401.19720, found: 401.19717。

[0141] 8) 1,4 - Bis(7 - benzyloxy - 4 - ylquinoline)piperazine (11h)

[0142]

[0143] Using intermediate 10b and anhydrous piperazine as raw materials, a pinkish - white solid was obtained, with a yield of 41.2%, mp 237.6 - 238.5 °C. 1 H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 5.0 Hz, 2H, ArH), 8.02 (d, J = 9.2 Hz, 2H, ArH), 7.56–7.50 (m, 6H, ArH), 7.43 (t, J = 7.2 Hz, 4H, ArH), 7.40–7.33 (m, 2H, ArH), 7.31–7.24 (m, 2H, ArH), 6.89 (d, J = 5.0 Hz, 2H, ArH), 5.25 (s, 4H, NCH2), 3.53 (s, 8H, OCH2). 13 C NMR (101 MHz, CDCl3) δ 159.5, 156.7, 151.4, 151.3, 136.4, 128.7, 128.2, 127.7, 124.8, 118.7, 118.4, 109.3, 107.6, 70.2, 52.3. HRMS(ESI) calcd for C 36 H 33 N4O2[M+H] + : 553.25980, found: 553.25958。

[0144] 9) 1,4 - Bis(7 - (4 - fluorobenzyloxy) - 4 - ylquinoline)piperazine (11i)

[0145]

[0146] Using intermediate 10c and anhydrous piperazine as raw materials, a light - yellow solid was obtained, with a yield of 31.8%, mp 210.2 - 213.4 °C. 1 H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 5.0 Hz, 2H, ArH), 8.02 (d, J = 9.2 Hz, 2H, ArH), 7.54–7.46 (m, 8H, ArH), 7.12 (t, J = 8.6 Hz, 4H, ArH), 6.90 (d, J = 5.2 Hz, 2H, ArH), 5.21 (s, 4H, CH2), 3.54 (s, 8H, NCH2).13 C NMR (151 MHz, DMSO-d6) δ 163.3, 161.8, 161.7, 159.3, 142.1, 141.3, 132.4, 131.0, 131.0, 129.2, 117.7, 116.0, 115.9, 113.0, 103.2, 101.6, 69.8, 49.7. HRMS (ESI) calcd for C 36 H 31 F2N4O2 [M+H] + : 589.24096, found: 589.24036。

[0147] 10) 1,4-Bis(7-phenoxy-4-ylquinoline)piperazine (11j)

[0148]

[0149] Using intermediate 10d and anhydrous piperazine as raw materials, a light yellow solid was obtained with a yield of 51.3%, mp 146.4 - 148.0 °C. 1 H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 5.0 Hz, 2H, ArH), 8.00 (d, J = 9.2 Hz, 2H, ArH), 7.42 (d, J = 2.6 Hz, 2H, ArH), 7.36–7.28 (m, 2H, ArH), 7.28–7.17 (m, 8H, ArH), 6.89 (d, J = 5.2 Hz, 2H, ArH), 4.16 (t, J = 6.4 Hz, 4H, OCH2), 3.55 (s, 8H, NCH2), 2.89 (t, J = 7.6 Hz, 4H, CH2), 2.23 (t, J = 6.4 Hz, 4H, CH2). 13 C NMR (151 MHz, DMSO-d6) δ 162.2, 159.4, 142.3, 141.6, 141.2, 129.1, 128.9, 128.8, 126.5, 117.7, 112.8, 103.1, 101.0, 68.3, 49.7, 31.8, 30.4. HRMS (ESI) calcd for C 40 H 41 N4O2 [M+H] + : 609.32240, found: 609.32147。

[0150] Example 3

[0151] This example provides 7-bridged bisquinoline compounds 13a - 13l, and their general synthesis process and synthesis equations are as follows:

[0152] 1. Synthesis of Intermediate

[0153]

[0154] Synthesis process of 7-hydroxy-4-(4-methoxypiperazinyl)quinoline 12a:

[0155] Add intermediate 8 (10 mmol), methylpiperazine (15 mmol), ethylene glycol monoethyl ether (30 mL) and triethylamine (5 mL) into a 100 mL round-bottom flask. React under reflux with stirring and monitor by TLC. After the reaction is completed, cool the reaction mixture to room temperature, evaporate the solvent under reduced pressure. Add 100 mL of water to the residue, adjust the pH to 9 with 10% sodium hydroxide solution. A large amount of solid precipitates in the reaction solution. Filter, dry, and recrystallize with acetone to obtain a yellow solid with a yield of 73.7%, mp 104.3 - 105.8 °C. ESI-MS m / z: 244.21 [M + H] + . 1 H NMR (600 MHz, DMSO-d6) δ 15.07 (s, 1H, OH), 11.74 (s, 1H, ArH), 11.60 (s, 1H, ArH), 8.64 (d, J = 6.8 Hz, 1H, ArH), 8.03 (d, J = 9.4 Hz, 1H, ArH), 7.49 (d, J = 2.4 Hz, 1H, ArH), 7.28 (dd, J = 9.4, 2.4 Hz, 1H, ArH), 7.16 (d, J = 6.8 Hz, 1H, ArH), 4.17 (s, 2H, NCH2), 3.81 (s, 2H, NCH2), 3.54 (s, 2H, NCH2), 2.85 (s, 3H, NCH3). 13 C NMR (151 MHz, DMSO-d6) δ 162.5, 161.0, 142.3, 142.1, 128.4, 119.6, 113.7, 105.8, 102.7, 52.2, 48.7, 42.5.

[0156] General synthesis process of intermediates 12b - 12d:

[0157] Add intermediate 8 (10 mmol), corresponding aniline (15 mmol), ethylene glycol monomethyl ether (30 mL) and pyridine hydrochloride (2 mmol) into a 100 mL round-bottom flask. React under reflux with stirring for 3 - 4 h and monitor by TLC. After the reaction is completed, cool the reaction mixture to room temperature, evaporate the solvent under reduced pressure. Add 100 mL of water to the residue, adjust the pH to 9 with 10% sodium hydroxide solution. A large amount of solid precipitates in the reaction solution. Filter, dry, and recrystallize with acetone to obtain a solid, which can be directly used for the next reaction without purification. The synthesis of intermediates 12b - 12d is as follows:

[0158] 1) 7-Hydroxy-4(3-methoxyanilino)quinoline (12b)

[0159] Synthesized by the above method, using intermediate 8 and 3-methoxyaniline as raw materials, to obtain a yellow solid with a yield of 66.5%. ESI-MS m / z: 267.29 [M+H] + .

[0160] 2) 7-Hydroxy-4(3-trifluoromethylanilino)quinoline (12c)

[0161]

[0162] Synthesized by the above method, using intermediate 8 and 3-(trifluoromethyl)aniline as raw materials, to obtain a pale yellow solid with a yield of 54.9%, mp 112.2 - 113.5 °C. ESI-MS m / z: 305.14 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H, OH), 11.47 (s, 1H, NH), 10.98 (s, 1H, ArH), 8.69 (d, J = 9.4 Hz, 1H, ArH), 8.40 (d, J = 6.8 Hz, 1H, ArH), 7.86 (s, 1H, ArH), 7.85–7.72 (m, 2H, ArH), 7.41 (d, J = 2.6 Hz, 1H, ArH), 7.32 (d, J = 9.2 Hz, 1H, ArH), 6.73 (d, J = 6.4 Hz, 1H, ArH). 13 C NMR (151 MHz, DMSO-d6) δ 162.9, 154.7, 142.7, 141.2, 139.0, 131.5, 129.6, 126.3, 123.9, 122.4, 122.3, 119.5, 111.3, 102.6, 99.2.

[0163] 3) 7-Hydroxy-4(3-fluoroanilino)quinoline (12d)

[0164] Synthesized by the above method, using intermediate 8 and 3-fluoroaniline as raw materials, to obtain a yellow solid with a yield of 48.7%. ESI-MS m / z: 255.23 [M+H] + .

[0165] 2. Synthetic route of 7-position bridged bisquinoline compounds:

[0166]

[0167] General synthetic process of 7-position bridged bisquinoline derivatives 13a - 13l:

[0168] Add intermediate 12a-d (2 mmol), dihaloalkane (1 mmol), DMF (10 mL) and KI (0.5 mmol) into a 100 mL round-bottom flask, stir and react at 50 °C for 4 - 10 h, monitor the reaction by TLC. After the reaction is completed, cool the reaction solution to room temperature, pour the reaction mixture into 100 mL of water, extract with dichloromethane (100 mL × 3), combine the organic phases, wash with water and saturated brine, dry the organic phase with anhydrous sodium sulfate for 6 h, filter, concentrate the filtrate under reduced pressure to dryness, and subject the residue to silica gel column chromatography (200 - 300 mesh, eluting successively with mobile phases DCM:MeOH = 100:1, DCM:MeOH = 50:1, DCM:MeOH = 20:1), collect the target product, and concentrate under reduced pressure to obtain a solid.

[0169] The synthesis of specific compounds 13a - 13l is as follows:

[0170] 1) 1,4 - Bis(4-(3 - methoxyanilino)-7 - oxoquinolinyl)butane (13a)

[0171]

[0172] Using intermediate 12b and 1,4 - dibromobutane as raw materials, a yellow solid was obtained with a yield of 64.8%, mp 176.0 - 177.4 °C. 1 H NMR (400 MHz, DMSO - d6) δ 8.95 (s, 2H, NH), 8.39 (d, J = 5.0 Hz, 2H, ArH), 8.28 (d, J = 9.2 Hz, 2H, ArH), 7.30 (s, 2H, ArH), 7.20 (d, J = 9.2 Hz, 2H, ArH), 6.94 (d, J = 8.4 Hz, 2H, ArH), 6.90 (s, 4H, ArH), 6.71 (d, J = 8.4 Hz, 2H, ArH), 5.77 (s, 2H, ArH), 4.24 (s, 4H, OCH2), 3.77 (d, J = 2.6 Hz, 6H, OCH3), 2.02 (s, 4H, CH2). 13 C NMR (151 MHz, DMSO - d6) δ 162.7, 160.7, 154.9, 142.5, 141.0, 139.0, 131.1, 126.3, 118.7, 117.8, 113.3, 111.9, 111.6, 101.0, 99.8, 68.7, 55.9, 25.6. HRMS (ESI) calcd for C 36 H 35 N4O4[M + H] + : 587.26528, found: 587.26471.

[0173] 2) 1,5-Bis(4-(3-methoxyanilino)-7-oxoquinolin-1-ium)pentane (13b)

[0174]

[0175] Using intermediate 12b and 1,5-dibromopentane as raw materials, a yellow solid was obtained with a yield of 33.3% and mp 144.3 - 145.1 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 2H, NH), 8.39 (d, J = 5.0 Hz, 2H, ArH), 8.27 (d, J = 9.2 Hz, 2H, ArH), 7.31 (t, J = 9.6 Hz, 2H, ArH), 7.20 (d, J = 9.2 Hz, 2H, ArH), 6.94 (d, J = 8.0 Hz, 2H, ArH), 6.89 (d, J = 7.8 Hz, 4H, ArH), 6.71 (d, J = 8.4 Hz, 2H, ArH), 5.77 (s, 2H, ArH), 4.18 (s, 4H, OCH2), 3.77 (d, J = 3.2 Hz, 6H, OCH3), 1.90 (d, J = 7.6 Hz, 4H, CH2), 1.70 (s, 2H, CH2). 13 C NMR (151 MHz, DMSO-d6) δ 162.8, 160.8, 154.9, 142.5, 141.0, 138.9, 131.1, 126.2, 118.7, 117.8, 113.3, 111.9, 111.6, 101.0, 99.8, 68.9, 55.9, 28.5, 22.5. HRMS (ESI) calcd for C 37 H 37 N4O4 [M + H] + : 601.28093, found: 601.28000.

[0176] 3) 1,6-Bis(4-(3-methoxyanilino)-7-oxoquinolin-1-ium)hexane (13c)

[0177]

[0178] Using intermediate 12b and 1,6-dibromohexane as raw materials, a yellow solid was obtained with a yield of 59.1% and mp 159.7 - 160.5 °C. 11H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 2H, NH), 8.39 (d, J = 5.4 Hz, 2H, ArH), 8.27 (d, J = 9.2 Hz, 2H, ArH), 7.31 (t, J = 8.2 Hz, 2H, ArH), 7.25 (dd, J = 6.8, 2.6 Hz, 2H, ArH), 7.19 (dd, J = 9.2, 2.6 Hz, 2H, ArH), 6.94 (d, J = 8.4 Hz, 2H, ArH), 6.90 (d, J = 2.4 Hz, 2H, ArH), 6.71 (dd, J = 8.2, 2.6 Hz, 2H, ArH), 5.77 (s, 2H, ArH), 4.16 (t, J = 6.4 Hz, 4H, OCH2), 3.77 (s, 6H, OCH3), 1.85 (s, 4H, CH2), 1.54 (d, J = 35.6 Hz, 4H, CH2). 13 13C NMR (151 MHz, DMSO-d6) δ 162.8, 160.8, 154.9, 142.6, 141.1, 138.9, 131.1, 126.2, 118.8, 117.8, 113.3, 111.8, 111.6, 101.0, 99.8, 68.9, 55.9, 28.7, 25.6. HRMS (ESI) calcd for C 38 H 39 N4O4 [M + H] + : 615.29858, found: 615.29808。

[0179] 4) 1,4-Bis(4-(3-trifluoromethylanilino)-7-oxyquinoline)butane (13d)

[0180]

[0181] Using intermediate 12c and 1,4-dibromobutane as raw materials, a pale yellow solid was obtained with a yield of 48.3% and mp 206.2 - 207.8 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 2H, NH), 8.48 (d, J = 5.4 Hz, 2H, ArH), 8.26 (d, J = 9.4 Hz, 2H, ArH), 7.70–7.57 (m, 6H, ArH), 7.42 (d, J = 7.6 Hz, 2H, ArH), 7.34 (d, J = 2.6 Hz, 2H, ArH), 7.25 (dd, J = 9.2, 2.6 Hz, 2H, ArH), 6.96 (d, J = 5.4 Hz, 2H, ArH), 4.26 (s, 4H, OCH2), 2.04 (d, J = 4.8 Hz, 4H, CH2).13 C NMR (151 MHz, DMSO-d6) δ 159.94, 149.25, 142.6, 130.9, 130.7, 124.8, 123.0, 119.4, 117.8, 117.6, 115.2, 108.9, 102.0, 67.9, 25.9. HRMS (ESI) calcd for C 36 H 29 F6N4O2 [M+H] + : 663.21892, found: 663.21790。

[0182] 5) 1,5-Bis(4-(3-(trifluoromethyl)anilino)-7-oxoquinolin-1-ium-1-yl)pentane (13e)

[0183]

[0184] Using intermediate 12c and 1,5-dibromopentane as raw materials, a pale yellow solid was obtained with a yield of 23.6%, mp 170.7 - 172.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 2H, NH), 8.47 (d, J = 5.4 Hz, 2H, ArH), 8.25 (d, J = 9.2 Hz, 2H, ArH), 7.63 (m, 6H, ArH), 7.42 (d, J = 7.6 Hz, 2H, ArH), 7.32 (d, J = 2.6 Hz, 2H, ArH), 7.24 (dd, J = 9.2, 2.6 Hz, 2H, ArH), 6.96 (d, J = 5.4 Hz, 2H, ArH), 4.20 (t, J = 6.4 Hz, 4H, OCH2), 1.91 (t, J = 8.4 Hz, 4H, CH2), 1.71 (d, J = 7.4 Hz, 2H, CH2). 13 C NMR (101 MHz, DMSO-d6) δ 163.0, 154.7, 143.1, 141.1, 138.8, 131.6, 131.2, 130.8, 129.6, 126.1, 124.1, 122.4, 119.2, 112.1, 101.1, 99.9, 68.9, 28.5, 22.5. HRMS (ESI) calcd for C 37 H 31 F6N4O2 [M+H] + : 677.23457, found: 677.23328.。

[0185] 6) 1,6-Bis(4-(3-(trifluoromethyl)anilino)-7-oxoquinolin-1-ium-1-yl)hexane (13f)

[0186]

[0187] Using intermediate 12c and 1,6-dibromohexane as raw materials, a pale yellow solid was obtained with a yield of 26.0% and mp 220.1 - 223.6 °C. 1 HNMR(400MHz, DMSO-d6) δ 8.48(d, J = 5.6Hz, 2H, ArH), 8.31(d, J = 9.2Hz, 2H, ArH), 7.73–7.61(m, 6H, ArH), 7.49(d, J = 7.6Hz, 2H, ArH), 7.34–7.25(m, 4H, ArH), 6.94(d, J = 5.6Hz, 2H, ArH), 5.77(s, 2H, ArH), 4.19(t, J = 6.4Hz, 4H, OCH2), 1.88(s, 4H, CH2), 1.61(d, J = 6.2Hz, 4H, CH2). 13 C NMR(151MHz, DMSO-d6) δ 160.3, 150.6, 150.3, 147.8, 142.2, 131.0, 130.8, 130.5, 125.3, 124.2, 119.9, 118.1, 118.0, 114.8, 108.1, 101.8, 68.2, 29.0, 25.8. HRMS(ESI) calcd for C 38 H 33 F6N4O2[M + H] + : 691.25022, found: 691.24902.

[0188] 7) 1,4-Bis(4-(3-fluoroanilino)-7-oxoquinoline)butane (13 g)

[0189]

[0190] Using intermediate 12d and 1,4-dibromobutane as raw materials, a white solid was obtained with a yield of 54.6% and mp 236.9 - 238.1 °C. 1 H NMR(400MHz, DMSO-d6) δ 9.03(s, 2H, NH), 8.46(d, J = 5.4Hz, 2H, ArH), 8.24(d, J = 9.2Hz, 2H, ArH), 7.41(q, J = 7.8Hz, 2H, ArH), 7.32(d, J = 2.6Hz, 2H, ArH), 7.25–7.10(m, 6H, ArH), 6.98(d, J = 5.4Hz, 2H, ArH), 6.92(s, 2H, ArH), 4.25(t, J = 4.8Hz, 4H, OCH2), 2.03(s, 4H, CH2). 13CNMR(151MHz, DMSO-d6) δ 163.8, 162.8, 162.2, 154.7, 142.8, 141.1, 139.7, 139.6, 132.0, 131.9, 126.2, 121.7, 119.0, 114.4, 114.3, 113.0, 112.8, 112.1, 101.1, 100.0, 68.9, 25.5. HRMS(ESI) calcd for C 34 H 29 F2N4O2 [M+H] + : 563.22531, found: 563.22485。

[0191] 8) 1,5-Bis(4-(3-fluoroanilino)-7-oxoquinolin-1-ium)pentane (13h)

[0192]

[0193] Using intermediate 12d and 1,5-dibromopentane as raw materials, a white solid was obtained with a yield of 17.3%, mp 211.4 - 213.1 °C. 1 H NMR(400MHz, DMSO-d6) δ 8.45 (d, J = 5.6 Hz, 2H, ArH), 8.30 (d, J = 9.2 Hz, 2H, ArH), 7.44 (t, J = 8.2 Hz, 2H, ArH), 7.30 (s, 2H, ArH), 7.26 (d, J = 9.2 Hz, 2H, ArH), 7.20 (t, J = 10.4 Hz, 4H, ArH), 6.95 (dd, J = 8.2, 4.2 Hz, 4H, ArH), 5.77 (s, 2H, ArH), 4.19 (t, J = 6.8 Hz, 4H, OCH2), 1.92 (q, J = 7.6 Hz, 4H, CH2), 1.70 (t, J = 8.0 Hz, 2H, CH2). 13 C NMR(151MHz, DMSO-d6) δ 162.9, 162.2, 154.7, 142.9, 141.1, 139.7, 139.6, 132.0, 131.9, 126.2, 121.7, 121.7, 119.0, 114.5, 114.3, 113.0, 112.8, 112.1, 101.1, 100.0, 68.9, 28.4, 22.5. HRMS(ESI) calcd for C 35 H 31 F2N4O2 [M+H] + : 577.24096, found: 577.24048。

[0194] 9) 1,6-bis(4-(3-fluoroanilino)-7-oxoquinolin-1-ium)hexane (13i)

[0195]

[0196] Using intermediate 12d and 1,6-dibromohexane as raw materials, a white solid was obtained with a yield of 31.4% and mp 220.0 - 223.8 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 5.6 Hz, 2H, ArH), 8.27 (d, J = 9.2 Hz, 2H, ArH), 7.43 (d, J = 7.8 Hz, 2H, ArH), 7.29 (d, J = 2.6 Hz, 2H, ArH), 7.26 (t, 6H, ArH), 6.95 (dd, J = 8.0, 3.8 Hz, 4H, ArH), 4.17 (t, J = 6.4 Hz, 4H, OCH2), 1.85 (q, J = 6.4 Hz, 4H, CH2), 1.58 (q, J = 6.6 Hz, 4H, CH2). 13 13C NMR (151 MHz, DMSO-d6) δ 163.0, 162.2, 154.7, 142.9, 141.1, 139.6, 132.0, 132.0, 126.1, 121.8, 121.7, 119.1, 114.5, 114.4, 113.0, 112.8, 112.0, 101.0, 100.0, 68.9, 28.7, 25.6. HRMS (ESI) calcd for C 36 H 33 F2N4O2[M + H] + : 591.25661, found: 591.25574.

[0197] 10. 1,4-bis(4-(4-methylpiperazin-1-ium)-7-oxoquinolin-1-ium)butane (13j)

[0198]

[0199] Using intermediate 12a and 1,4-dibromobutane as raw materials, a pale yellow solid was obtained with a yield of 48.9% and mp 146.1 - 147.3 °C. ESI-MS m / z: 541.58 [M + H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 6.8 Hz, 2H, ArH), 8.11 (d, J = 9.5 Hz, 2H, ArH), 7.62 (d, J = 2.6 Hz, 2H, ArH), 7.37 (dd, J = 9.4, 2.6 Hz, 2H, ArH), 7.25 (d, J = 6.8 Hz, 2H, ArH), 4.30 (t, J = 5.0 Hz, 4H, NCH2), 4.21 (q, J = 13.8 Hz, 4H, CH2), 3.84 (t, J = 13.2 Hz, 4H, NCH2), 2.86 (s, 6H, NCH3), 2.05 (t, J = 4.8 Hz, 4H, OCH2). 13 13C NMR (151 MHz, DMSO-d6) δ 162.5, 160.8, 142.4, 142.0, 128.3, 119.2, 114.5, 106.4, 101.0, 68.8, 52.1, 48.6, 42.4, 25.5. HRMS (ESI) calcd for C 32 H 41 N6O2 [M+H] + : 541.32764, found: 541.32855。

[0200] 11) 1,5-Bis(4-(4-methylpiperazinyl)-7-oxyquinoline) pentane (13k)

[0201]

[0202] Using intermediate 12a and 1,5-dibromopentane as raw materials, a pale yellow solid was obtained with a yield of 43.2% and mp 163.3 - 164.7 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 6.8 Hz, 2H, ArH), 8.11 (d, J = 9.4 Hz, 2H, ArH), 7.61 (s, 2H, ArH), 7.36 (dd, J = 9.6 Hz, 2.5 Hz, 2H, ArH), 7.25 (d, J = 6.8 Hz, 2H, ArH), 4.22 (t, J = 9.8 Hz, 8H, NCH2), 3.84 (t, J = 13.4 Hz, 4H, NCH2), 3.57 (q, J = 12.2 Hz, 4H, CH2), 2.85 (s, 6H, NCH3), 1.92 (q, J = 7.2 Hz, 4H, CH2), 1.69 (t, J = 7.8 Hz, 2H, OCH2). 1313C NMR (101 MHz, DMSO-d6) δ 162.5, 160.8, 142.5, 142.1, 128.3, 119.1, 114.5, 106.4, 101.1, 69.0, 52.1, 48.6, 42.4, 28.4, 22.5. HR-MS (ESI) calcd for C 33 H 43 N6O2 [M+H] + : 555.34420, found: 555.34412。

[0203] 12) 1,6-Bis(4-(4-methylpiperazinyl)-7-oxyquinoline)hexane (13l)

[0204]

[0205] Using intermediate 12a and 1,6-dibromohexane as raw materials, a pale yellow solid was obtained with a yield of 21.1%, mp 151.7 - 152.5 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 6.8 Hz, 2H, ArH), 8.10 (d, J = 9.6 Hz, 2H, ArH), 7.58 (d, J = 2.6 Hz, 2H, ArH), 7.36 (dd, J = 9.6, 2.6 Hz, 2H, ArH), 7.25 (d, J = 6.8 Hz, 2H, ArH), 4.20 (t, J = 6.8 Hz, 8H, NCH2), 3.83 (t, J = 12.8 Hz, 4H, NCH2), 3.57 (q, J = 12.8 Hz, 4H, CH2), 2.87 (s, 6H, NCH3), 1.91–1.83 (m, 4H, CH2), 1.56 (t, J = 6.8 Hz, 4H, OCH2). 13 13C NMR (101 MHz, DMSO-d6) δ 162.6, 160.9, 142.3, 142.0, 128.3, 119.3, 114.4, 106.4, 100.9, 69.0, 52.1, 48.6, 42.4, 28.6, 25.5. HRMS (ESI) calcd for C 34 H 45 N6O2 [M+H] + : 569.35985, found: 569.35956。

[0206] Experimental tests

[0207] 1. In vitro anti-tumor activity test

[0208] Pharmacological study of the bisquinoline compound of the present invention as a drug for treating cancer. All the tested compounds were prepared in the form of hydrochloride before the experiment, and the clinically commonly used anti-tumor drugs - chloroquine phosphate and cisplatin were used as positive control drugs.

[0209] The tumor cell lines HCT116 (human colon cancer cell line), A549 (human non-small cell lung cancer cell line), HepG2 (human liver cancer cell line), BGC-823 (human gastric cancer cell line), Hela (human cervical cancer cell line), and MCF-7 (human breast cancer cell line) were selected respectively, and the inhibitory activity of the bisquinoline compound against human cancer cell lines was evaluated by the MTT method. Tumor cells were inoculated on 96-well plates at a concentration of 1×10 6 cells / mL, and cultured in a CO2 incubator at 37°C until the logarithmic phase. The fresh medium was replaced, and the sterilized bisquinoline compound was added. Each compound was set with 6 - 8 dose groups, and at least three parallel wells were set in each group. After continuing to culture for 48 h, the supernatant was discarded. 200 μL of medium containing 50 μg / mL MTT was added to each well, and the culture was continued for 4 h. After removing the upper clear liquid in the well plate, 200 μL of DMSO was added to each well, and the precipitate was dissolved by shaking for about 10 min. Then the optical density value (OD) was measured at a wavelength of 570 nm with an enzyme-labeled instrument. The tumor cells treated with the solvent were used as the control group, and the cell survival rate at each sample concentration was calculated by the following formula:

[0210] Survival rate % = average OD value of the sample group / average OD value of the control group × 100%.

[0211] The cell survival rate was plotted against the logarithm of the drug concentration, and the IC 50 value of each sample was obtained by the plotting method. The results are shown in Table 1 below:

[0212] Table 1 Results of in vitro anti-tumor activity of bisquinoline compounds

[0213]

[0214]

[0215] The bridged bisquinoline compounds of the present invention exhibit certain killing effects on colon cancer cells, lung cancer cells, liver cancer cells, gastric cancer cells, cervical cancer cells, and breast cancer cells. Among the 1-position bridged bisquinoline compounds, 9a has a particularly strong killing effect on liver cancer cells, and 9c-9f have particularly obvious killing effects on colon cancer cells. Among the 4-position bridged bisquinoline compounds, 11a, 11b, 11d, 11e, and 11f exhibit high killing effects on various cancer cells and are broad-spectrum anti-tumor drugs. Among the 7-position bridged bisquinoline compounds, 13b, 13c, 13e, 13h, 13i, and 13k exhibit high killing effects on various cancer cells and are broad-spectrum anti-tumor drugs. The bridged bisquinoline compounds of the present invention are superior to the positive control drugs chloroquine phosphate and cisplatin.

[0216] 2. Acute toxicity test in mice

[0217] Kunming mice (provided by the Experimental Animal Center of Wuhan University), weighing 19-20 g, with an equal number of males and females. Each group consisted of 10 mice. The solvents used were physiological saline and 0.5% CMC-Na solution. According to the preliminary test results, five dose levels were designed for each sample, with a dose interval of 0.8 times. After weighing each sample, a small amount of Tween 80 was added during the experiment to assist dissolution, and then 0.5% CMC-Na solution was gradually added to the required concentration. The experimental volume was 0.5 mL / 20 g of mice. Single intraperitoneal administration was used. Kunming mice were randomly grouped by gender, and each group was intraperitoneally administered according to the dose settings. The immediate reactions of the mice after administration were observed. The dead animals were dissected for observation, and the surviving animals were observed for another two weeks, and the deaths of the animals within two weeks were recorded. After two weeks, the surviving animals were dissected to observe the lesions of the parenchymal organs, and the organs with parenchymal lesions were subjected to pathological examination. According to the number of dead animals in each group, the median lethal dose (LD 50 value) of the drug was calculated by the Bliss method, and the results are shown in Table 2.

[0218] 3. Anti-tumor test in vivo

[0219] Kunming mice (provided by the Experimental Animal Center of Wuhan University), with a body weight of 18-20 g, either male or female, and the same gender was used for each batch of experiments. For the anti-tumor experiment, 8-10 C57BL / 6 mice and Kunming mice were in one group, and there were two groups for the negative control. The tumor sources were mouse Lewis lung cancer and S180 sarcoma (passaged and maintained by the Cell Molecular Biology Research Laboratory of the School of Life Sciences, Wuhan University); the solvents used were physiological saline and 0.5% CMC-Na solution; the test drugs were set at high and low dose groups, and the LD 50Based on 1 / 5 of the value; Weigh each test sample, add a small amount of Tween-80 during the experiment to moisten and assist dissolution, and gradually add 0.5% CMC-Na solution to the required concentration. The experimental volume is 0.5 mL / 20 g of mice. Administer the drug intraperitoneally once a day for 10 consecutive days, for a total of 10 administrations. The negative control is given an equal volume of the corresponding solvent, and the administration protocol is by the intraperitoneal route, once a day for 10 consecutive days. The positive control CTX is administered at a dose of 30 mg / kg once a day for 7 consecutive days. An in vivo anti-tumor axillary subcutaneous inoculation model is used: Under sterile conditions, take a vigorously growing tumor source, and prepare it into a cell suspension of about 1×10 7 / mL by homogenization method. Inoculate 0.2 mL / mouse subcutaneously in the axilla of the corresponding host. The next day, administer the drug according to the experimental design plan. Sacrifice the animals in each group about three weeks later, dissect and weigh the tumors, and calculate the tumor inhibition rate according to the following formula:

[0220] Tumor inhibition rate % = [(Average tumor weight of the negative control group - Average tumor weight of the drug administration group) / Average tumor weight of the negative control group] × 100%.

[0221] The test results are shown in Table 2 below:

[0222] Table 2 Results of acute toxicity and in vivo anti-tumor activity tests of bisquinoline compounds in mice

[0223]

[0224] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. Bridged bisquinoline compound, characterized in that, Its structural formula is shown in formula (C): In formula (C), R3 is an alkyldiether group; R4 is a substituted or unsubstituted arylamino group or a substituted or unsubstituted non-aromatic nitrogen heterocyclic group.

2. The bridged bisquinoline compound according to claim 1, wherein In formula (C), the R3 is ---O-(CH2) b -O---; where b = 2 - 10; The substituted arylamino group in R4 is wherein Z is a methoxy group, a trifluoromethyl group or a halogen, and the dotted line represents the group linking position.

3. The bridged bisquinoline compound according to claim 2, wherein The bridged bisquinoline compound is shown in formulas 17 - 28:[[]]END]] 4. A method for preparing the bridged bisquinoline compound according to any one of claims 1 to 3, characterized in that, Comprising the following steps: Reacting the compound shown in formula (c) with a compound containing R3 to obtain a bridged bisquinoline compound shown in formula (C); the reaction formula is as follows: Wherein, X is fluorine, iodine, chlorine or bromine; The definitions of R3 and R4 are as described in any one of claims 1 to 3.

5. The preparation method of the bridged bisquinoline compound according to claim 4, characterized in that, The reaction temperature of the reaction is 40 - 60 °C; And / or, the reaction time of the reaction is 4 - 10 h.

6. The preparation method of the bridged bisquinoline compound according to claim 4, wherein The molar ratio of the compound shown in formula (c) to the compound containing R3 is (2 - 3):

1.

7. The preparation method of the bridged bisquinoline compound according to claim 4, characterized in that, The compound shown in formula (c) is prepared by a preparation method comprising the following steps: Reacting the compound shown in formula (c1) with a compound containing R4 to obtain a compound shown in formula (c); the reaction formula is as follows: Wherein, R4 is as described in claim 4.

8. Use of the bridged bisquinoline compound according to any one of claims 1 - 3 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

9. The application according to claim 8, characterized in that The tumors include colon cancer, lung cancer, liver cancer, gastric cancer, cervical cancer or breast cancer.

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