A bridged bisquinoline compound and its preparation method and application

Abstract

The invention discloses a bridged bisquinoline compound and a preparation method and application thereof. The compound exhibits a certain killing effect on colon cancer, lung cancer, liver cancer, gastric cancer, cervical cancer and breast cancer cells, wherein the killing effect on colon cancer cells is particularly obvious, and is significantly better than positive control drugs chloroquine 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 platinum anti-tumor drugs such as cisplatin, and can be prepared into anti-tumor drugs for application. The preparation method of the bridged bisquinoline compound of the invention is simple and efficient, can realize industrialized production, and has great application value in anti-tumor.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to a bridged bisquinoline compound, a preparation method thereof, and an application thereof. Background Art

[0002] 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, antimetabolic drugs, anti-tumor antibiotics, anti-tumor phytomedicines, 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 nowadays. Currently, anti-tumor drugs have complex and diverse structures, and compounds with different structures show excellent anti-tumor activities. Searching for 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.

[0003] 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 then develop anti-tumor drugs with high efficiency and small side effects is a problem to be solved. Summary of the Invention

[0004] 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 bisquinoline compound. Another purpose of the present invention is to provide a preparation method of the bridged bisquinoline compound. The third purpose of the present invention is to provide an application of the bridged bisquinoline compound.

[0005] 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 effects, and according to the "multivalent binding theory", new strategies have been provided for drug design, which have been widely applied in aspects such as anti-resistant bacteria antibiotics, anti-influenza viruses, anti-HIV, anti-cholera bacteria, and anti-tumor.

[0006] 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 greatly improved, usually 100-1000 times that of monomeric molecules, and the toxicity of bimolecular drugs is usually also significantly reduced compared to monomeric 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.

[0007] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0008] In the first aspect of the present invention, a bridged bisquinoline compound is provided, and its structural formula is shown in formula (A), formula (B) or formula (C):

[0009]

[0010] In formula (A), n = 3 to 9;

[0011] In formula (B), the R 1 is alkyl diamino, aryl diamino or non-aromatic azacyclic group; the R 2 is alkoxy, substituted or unsubstituted arylalkyl ether group;

[0012] In formula (C), the R 3 is alkyl diether group; the R 4 is substituted or unsubstituted arylamino, substituted or unsubstituted non-aromatic azacyclic group.

[0013] 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 a permissible substituent, e.g., a substituent that results in 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 permissible substituents of an organic compound (any substituent described herein that results in the formation of a stable compound).

[0014] Preferably, in formula (B), the R 1 is --NH-(CH 2 ) m -NH--, where m = 1 to 3, and the dashed line represents the group linking position.

[0015] Preferably, in formula (B), the R 2 substituted or unsubstituted arylalkyl ether group in is wherein x = 1-3, Y is a halogen, and the dashed line represents the group linking position.

[0016] Preferably, in formula (C), the R 3 is ---O-(CH 2 ) b -O---; where b = 4-7, and the dashed line represents the group linking position.

[0017] Preferably, in formula (C), the substituted arylamino group in the R 4 is wherein Z is a methoxy group, a trifluoromethyl group or a halogen, and the dashed line represents the group linking position.

[0018] More preferably, the bridged bisquinoline compound is shown in Formulas 1-28:

[0019]

[0020]

[0021]

[0022] In a second aspect of the present invention, a preparation method of the bridged bisquinoline compound described in the first aspect is provided. When the bridged bisquinoline compound is shown in formula (A), the preparation method includes the following steps:

[0023] Reacting the compound shown in formula (a) with a dihalide to obtain the bridged bisquinoline compound shown in formula (A); the reaction formula is as follows:

[0024]

[0025] wherein, the K is fluorine, iodine, chlorine, bromine;

[0026] When the bridged bisquinoline compound is shown in formula (B), the preparation method includes the following steps:

[0027] Reacting the compound shown in formula (b) with a compound containing R 1 to obtain the bridged bisquinoline compound shown in formula (B); the reaction formula is as follows:

[0028]

[0029] wherein, the Z is fluorine, iodine, chlorine, bromine;

[0030] When the bridged diquinoline compound is as shown in formula (C), its preparation method includes the following steps:

[0031] React the compound shown in formula (c) with the compound containing R 3 to obtain the bridged diquinoline compound as shown in formula (C); the reaction formula is as follows:

[0032]

[0033] wherein, X is fluorine, iodine, chlorine, or bromine;

[0034] n, R 1 , R 2 , R 3 , R 4 are as described above.

[0035] Preferably, in the preparation of the bridged diquinoline compound as shown in formula (A), the reaction temperature of the reaction is 40 - 60 °C. More preferably, the reaction temperature of the reaction is 45 - 55 °C.

[0036] Preferably, in the preparation of the bridged diquinoline compound as shown in formula (A), the reaction time of the reaction is 8 - 10 h.

[0037] Preferably, in the preparation of the bridged diquinoline compound as shown in formula (B), the reaction temperature of the reaction is 120 - 140 °C.

[0038] More preferably, the reaction temperature of the reaction is 125 - 135 °C.

[0039] Preferably, in the preparation of the bridged diquinoline compound as shown in formula (B), the reaction time of the reaction is 20 - 48 h.

[0040] Preferably, in the preparation of the bridged diquinoline compound as shown in formula (C), the reaction temperature of the reaction is 40 - 60 °C.

[0041] More preferably, the reaction temperature of the reaction is 45 - 55 °C.

[0042] Preferably, in the preparation of the bridged diquinoline compound as shown in formula (C), the reaction time of the reaction is 4 - 10 h.

[0043] Preferably, the molar ratio of the compound shown in formula (a) to the dihalide is (2 - 3):1.

[0044] Preferably, the molar ratio of the compound shown in formula (b) to the compound containing R 1 is (2 - 3):1.

[0045] Preferably, the molar ratio of the compound shown in formula (c) to the compound containing R3 The molar ratio of the compounds is (2 - 3):1.

[0046] Preferably, the compound represented by the formula (b) is prepared by a preparation method including the following steps:

[0047] React the compound represented by the formula (b1) with the R-containing 2 compound to obtain the compound represented by the formula (b); the reaction formula is as follows:

[0048]

[0049] wherein, the Z, R 2 are as described above.

[0050] Preferably, the compound represented by the formula (b) is prepared by a preparation method including the following steps:

[0051] React the compound represented by the formula (c1) with the R-containing 4 compound to obtain the compound represented by the formula (c); the reaction formula is as follows:

[0052]

[0053] wherein, the R 4 are as described above.

[0054] Preferably, in the preparation of the bridged bisquinoline compound represented by the formula (A), the reaction system of the reaction further includes an inorganic base. More preferably, the inorganic base is selected from one or more of Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 . More preferably, the concentration of the inorganic base in the reaction system is 0.3 - 1 mol / L.

[0055] Preferably, in the preparation of the bridged bisquinoline compound represented by the formula (A), the reaction system of the reaction further includes 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 the formula (a) is 1:(3 - 6).

[0056] Preferably, in the preparation of the bridged bisquinoline compound represented by the formula (A), the solvent for the reaction is any one of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), and acetonitrile (CH 3 CN).

[0057] 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.

[0058] 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.

[0059] 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).

[0060] Preferably, in the preparation of the bridged bisquinoline compound represented by formula (C), the solvent for the reaction is any one of dimethyl sulfoxide (DMSO), N,N - dimethylformamide (DMF), N,N - dimethylacetamide (DMAC), and acetonitrile (CH 3 CN).

[0061] 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.

[0062] Preferably, the pharmaceutically acceptable salt is selected from phosphate, hydrochloride, sulfate, nitrate, hydrobromide, mesylate, maleate, tartrate, benzoate, and lactate.

[0063] Preferably, the tumors include colon cancer, lung cancer, liver cancer, gastric cancer, cervical cancer, or breast cancer.

[0064] The beneficial effects of the present invention are as follows:

[0065] (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 superior to 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;

[0066] (2) The preparation method of the bridged bisquinoline compound described in the present invention is simple and efficient, can realize industrial production, and has great application value in anti - tumor treatment. Specific embodiments

[0067] The content of the present invention will be further described in detail through specific embodiments below. The raw materials used in the following embodiments can be obtained from conventional commercial channels or prepared and separated by simple synthesis, unless otherwise specified; the processes adopted, unless otherwise specified, are all conventional processes in the art.

[0068] Example 1

[0069] This example provides 1-bridged bisquinoline compounds 9a - 9f, and their general synthesis process and synthesis equations are as follows:

[0070]

[0071] Add chloroquine 7a (3 mmol), DMF (15 mL), K 2 CO 3 (10 mmol), KI (0.75 mmol) and dihalide (1.5 mmol) into 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 reduced pressure distillation, add 100 mL of water, and a solid precipitates. 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, subject the residue to silica gel column chromatography (DCM:MeOH = 100:1, 50:1), collect the target product, and concentrate to dryness under reduced pressure to obtain a solid. The synthesis of specific compounds 9a - 9f is as follows:

[0072] 1) 1,4-Bis(7-chloro-4-oxoquinoline)butane (9a)

[0073]

[0074] 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 HNMR(600MHz,DMSO-d 6 )δ9.19(d,J = 7.0Hz,1H,ArH),8.39(d,J = 6.4Hz,1H,ArH),8.26(d,J = 8.0Hz,2H,ArH),8.18(d,J = 8.8Hz,1H,ArH),7.92(d,J = 7.4Hz,2H,ArH),7.49(dd,J = 7.6Hz,2H,ArH),6.31(d,J = 7.8Hz,1H,ArH),4.63(t,J = 7.2Hz,4H,NCH 2 ),2.01(m,4H,CH 2 ). 1313C NMR (151 MHz, CD 3 OD) 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 Cl 2 N 2 O 2 [M + H] + : 413.08181, found: 413.08179。

[0075] 2) 1,5-Bis(7-chloro-4-oxoquinoline)pentane (9b)

[0076]

[0077] Using chloroquine 7a and 1,5-dibromopentane as raw materials, a grayish-white solid was obtained with a yield of 14.8% and mp 118.6 - 119.4 °C. 1 1H NMR (400 MHz, DMSO-d 6 ) 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, CH 2 -N), 1.77 (t, J = 7.8 Hz, 4H, CH 2 ), 1.36 (m, 2H, CH 2 ). 13 13C NMR (101 MHz, DMSO-d 6 ) 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 Cl 2 N 2 O 2 [M + H] + : 427.09746, found: 427.09735.

[0078] 3) 1,6-Bis(7-chloro-4-oxoquinoline)hexane (9c)

[0079]

[0080] 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(400MHz, DMSO-d 6 ) δ 8.19 (d, J = 8.8Hz, 2H, ArH), 8.10 (d, J = 7.8Hz, 2H, ArH), 7.91 (d, J = 1.8Hz, 2H, ArH), 7.46 (dd, J = 8.6, 1.7Hz, 2H, ArH), 6.21 (d, J = 7.6Hz, 2H, ArH), 4.28 (t, J = 7.4Hz, 4H, CH 2 -N), 1.71 (t, J = 8.0Hz, 4H, CH 2 ), 1.39–1.31 (m, 4H, CH 2 ). 13 C NMR(151MHz, DMSO-d 6 ) 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 23 Cl 2 N 2 O 2 [M + H] + : 441.11311, found: 441.11295.

[0081] 4) 1,7-Bis(7-chloro-4-oxoquinoline)heptane (9d)

[0082]

[0083] Using chloroquine 7a and 1,7-dibromoheptane as raw materials, a cream-colored solid was obtained with a yield of 36.3% and a melting point of 149.3 - 150.7 °C. 1 H NMR(400MHz, CDCl 3 ) δ 8.73 (d, J = 5.2Hz, 1H, ArH), 8.41 (d, J = 8.6Hz, 1H, ArH), 8.16 (d, J = 6.8Hz, 2H, ArH), 7.51 (d, J = 8.0Hz, 2H, ArH), 7.41 (d, J = 6.8Hz, ArH), 6.71 (d, J = 5.4Hz, 1H, ArH), 6.26 (d, J = 7.8Hz, 1H, ArH), 4.14 (t, J = 6.8Hz, 4H, CH 2-N), 1.94 (t, J = 6.8 Hz, 4H, CH 2 ), 1.59 (t, J = 6.2 Hz, 2H, CH 2 ), 1.48 (q, J = 5.6 Hz, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 Cl 2 N 2 O 2 [M + H] + : 455.12876, found: 455.12848。

[0084] 5) 1,8-Bis(7-chloro-4-oxoquinoline)octane (9e)

[0085]

[0086] Using chloroquine 7a and 1,8-dibromooctane as raw materials, a white solid was obtained with a yield of 19.5% and mp 131.2 - 132.5 °C. 1 HNMR (400 MHz, CDCl 3 ) δ 8.69 (d, J = 5.2 Hz, 2H, ArH), 8.12 (d, J = 3.4 Hz, 2H, ArH), 7.98 (d, J = 2.2 Hz, 2H, ArH), 7.40 (dd, J = 9.0, 2.2 Hz, 2H, ArH), 6.70 (d, J = 5.1 Hz, 2H, ArH), 4.17 (t, J = 6.4 Hz, 4H, CH 2 -N), 1.93 (p, J = 6.6 Hz, 4H, CH 2 ), 1.57 (t, J = 7.6 Hz, 4H, CH 2 ), 1.50–1.42 (m, 4H, CH 2 ). 13 C NMR (101 MHz, CDCl 3 ) δ 161.7, 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 Cl 2N 2 O 2 [M+H] + : 469.14441, found: 469.14447。

[0087] 6) 1,9-bis(7-chloro-4-oxoquinoline)nonane (9f)

[0088]

[0089] 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 H NMR (600 MHz, DMSO-d 6 ) δ 8.74 (d, J = 5.2 Hz, 2H, ArH), 8.15 (d, J = 8.6 Hz, 2H, ArH), 7.58 (d, J = 2.2 Hz, 2H, ArH), 7.39 (dd, J = 8.6, 1.9 Hz, 2H, ArH), 7.04 (d, J = 5.4 Hz, 2H, ArH), 4.23 (t, J = 7.2 Hz, 4H, CH 2 -N), 1.84 (p, J = 6.6 Hz, 4H, CH 2 ), 1.72–1.66 (m, 4H, CH 2 ), 1.47 (p, J = 7.4 Hz, 2H), 1.38–1.31 (m, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) δ 161.4, 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 for C 27 H 29 Cl 2 N 2 O 2 [M+H] + : 483.16006, found: 483.15994。

[0090] Example 2

[0091] This example provides 4-position bridged bisquinoline compounds 11a - 11j, and their general synthesis process and synthesis equations are as follows:

[0092] 1. Synthesis of intermediates

[0093] The preparation methods of 4-chloro-7-methoxyquinoline and 4-chloro-8-hydroxyquinoline are as follows:

[0094]

[0095] Synthetic route of the intermediate:

[0096]

[0097] General synthetic process of intermediates 10a-d:

[0098] 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, the system becomes yellowish-green and 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, subject the residue to silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 as the mobile phase), collect the target product, concentrate to dryness under reduced pressure to obtain a pale yellow solid. The synthesis of intermediates 10a-d is as follows:

[0099] 1) 4-chloro-7-butoxyquinoline (10a)

[0100] Synthesized according to the above method to obtain a white solid with a yield of 46%. ESI-MS m / z: 236.62 [M+H] + 。

[0101] 2) 4-chloro-7-benzyloxyquinoline (10b)

[0102] Synthesized according to the above method to obtain a pale yellow solid with a yield of 58%. ESI-MS m / z: 270.21 [M+H] + 。

[0103] 3) 4-chloro-7-(4'-fluorobenzyloxy)quinoline (10c)

[0104] Synthesized according to the literature method to obtain a yellow solid with a yield of 87%. ESI-MS m / z: 288.15 [M+H] + 。

[0105] 4) 4-chloro-7-phenylpropoxyquinoline (10d)

[0106]

[0107] 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, CDCl 3 ) 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, OCH 2 ), 2.82 (dd, J = 8.6, 6.8 Hz, 2H, CH 2 ), 2.22–2.12 (m, 2H, CH 2 ). 13 C NMR (151 MHz, CDCl 3 ) 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。

[0108] 2. Synthetic route (I) of 4-bridged bisquinoline compounds:

[0109]

[0110] Synthetic route (II) of 4-bridged bisquinoline compounds:

[0111]

[0112] Synthetic route (III) of 4-bridged bisquinoline compounds:

[0113]

[0114] General synthetic process of 4-bridged bisquinoline derivatives 11a - 11c, 11g - 11j:

[0115] In a 50 mL round-bottom flask, successively 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). React at 130 °C for 30 h with stirring, and monitor the reaction by TLC. After the reaction is complete, 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 (mobile phase dichloromethane:methanol = 100:1, 50:1) with 200 - 300 mesh silica gel. Collect the target product, concentrate it under reduced pressure to dryness to obtain a solid.

[0116] General synthetic process for 4-bridged bisquinoline derivatives 11d - 11f:

[0117] In a 50 mL round-bottom flask, successively 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). React at 130 °C for 20 - 48 h with stirring, and monitor the reaction by TLC. After the reaction is complete, 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 (mobile phase dichloromethane:methanol = 100:1, 50:1) with 200 - 300 mesh silica gel. Collect the target product, concentrate it under reduced pressure to dryness to obtain a solid.

[0118] The synthesis of specific compounds 11a - 11j is as follows:

[0119] 1) 1,2-bis(7-methoxy-4-aminoquinoline)ethane (11a)

[0120]

[0121] Using intermediate 7 and ethylenediamine as raw materials, a grayish-white solid was obtained with a yield of 24.7% and mp > 240 °C. 1 H NMR (400 MHz, DMSO-d 6 ) 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, OCH 3 ), 3.61 (s, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6)δ163.1,155.6,142.9,140.9,125.7,118.0,111.6,100.9,98.0,56.4,42.0.HRMS(ESI)calcd for C 22 H 23 N 4 O 2 [M+H] + :375.18155,found:375.18137。

[0122] 2) 1,2-Bis(7-n-butoxy-4-aminoquinoline)ethane (11b)

[0123]

[0124] Using intermediate 10a and ethylenediamine as raw materials, a white solid was obtained with a yield of 18.6% and mp > 240 °C. 1 H NMR(400MHz,DMSO-d 6 )δ8.72(d,J = 8.4Hz,2H,ArH),8.39(t,J = 8.4Hz,4H,ArH),7.23(d,J = 12.0Hz,2H,ArH),6.70(d,J = 6.2Hz,2H,ArH),3.90(d,J = 6.4Hz,4H,CH 2 ),3.78(s,4H,CH 2 ),2.38–2.30(m,2H,CH 2 ),2.09(p,J = 8.8,7.6Hz,2H,CH 2 ),1.03(s,6H,OCH 3 ). 13 C NMR(101MHz,DMSO-d 6 )δ161.8,154.5,144.4,142.8,125.6,117.6,112.0,102.9,97.8,74.7,41.8,37.2,28.0,19.4.HRMS(ESI)calcd for C 28 H 35 N 4 O 2 [M+H] + :459.27545,found:459.27512。

[0125] 3) 1,2-Bis(7-phenoxypropoxy-4-aminoquinoline)ethane (11c)

[0126]

[0127] Using intermediate 10d and ethylenediamine as raw materials, a pale yellow solid was obtained with a yield of 36.4% and mp > 240 °C. 1 H NMR (400 MHz, DMSO-d 6 ) 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, CH 2 ), 3.90 (s, 4H, CH 2 ), 2.79 (t, J = 7.8 Hz, 4H, CH 2 ), 2.14–2.08 (m, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 N 4 O 2 [M + H] + : 583.30675, found: 583.30579.

[0128] 4) 1,4-Bis(7-methoxy-4-ylquinoline)phenylenediamine (11d)

[0129]

[0130] 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 H NMR (400 MHz, DMSO-d 6 ) 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, OCH 3 ). 1313C NMR (151 MHz, DMSO-d 6 ) 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 N 4 O 2 [M + H] + : 423.18155, found: 423.18118。

[0131] 5) 1,4-Bis(7-benzyloxy-4-ylquinoline)phenylenediamine (11e)

[0132]

[0133] Using intermediate 10b and p-phenylenediamine as raw materials, a grayish-brown solid was obtained with a yield of 46.3%, mp > 240 °C. 1 1H NMR (400 MHz, DMSO-d 6 ) 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, OCH 2 ). 13 13C NMR (101 MHz, DMSO-d 6 ) 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 N 4 O 2 [M + H] + : 575.14415, found: 575.24377。

[0134] 6) 1,4-Bis(7-phenoxypropyl-4-ylquinoline)phenylenediamine (11f)

[0135]

[0136] Using intermediate 10d and p-phenylenediamine as raw materials, a yellow solid was obtained with a yield of 72.8% and mp > 240 °C. 1 H NMR (400 MHz, DMSO-d 6 ) 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, OCH 2 ), 2.83 (t, J = 7.8 Hz, 4H, ArCH 2 ), 2.16 (t, J = 7.4 Hz, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 N 4 O 2 [M + H] + : 631.30675, found: 631.30573.

[0137] 7) 1,4-Bis(7-methoxyquinolin-4-yl)piperazine (11g)

[0138]

[0139] 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 HNMR (400 MHz, DMSO-d 6)δ8.67(d, J = 5.2Hz, 2H, ArH), 8.04(d, J = 9.2Hz, 2H, ArH), 7.36(d, J = 2.6Hz, 2H, ArH), 7.23(dd, J = 9.2, 2.8Hz, 2H, ArH), 7.00(d, J = 5.2Hz, 2H, ArH), 3.92(s, 6H, OCH 3 ), 3.51(s, 8H, NCH 2 ). 13 C NMR(101MHz, DMSO-d 6 )δ162.9, 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 25 N 4 O 2 [M + H] + : 401.19720, found: 401.19717。

[0140] 8) 1,4 - Bis(7 - benzyloxy - 4 - ylquinoline) piperazine (11h)

[0141]

[0142] Using intermediate 10b and anhydrous piperazine as raw materials, a pink - white solid was obtained with a yield of 41.2%, mp 237.6 - 238.5 °C. 1 H NMR(400MHz, CDCl 3 )δ8.74(d, J = 5.0Hz, 2H, ArH), 8.02(d, J = 9.2Hz, 2H, ArH), 7.56–7.50(m, 6H, ArH), 7.43(t, J = 7.2Hz, 4H, ArH), 7.40–7.33(m, 2H, ArH), 7.31–7.24(m, 2H, ArH), 6.89(d, J = 5.0Hz, 2H, ArH), 5.25(s, 4H, NCH 2 ), 3.53(s, 8H, OCH 2 ). 13 C NMR(101MHz, CDCl 3 )δ159.5, 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 H33 N 4 O 2 [M+H] + : 553.25980, found: 553.25958。

[0143] 9) 1,4-Bis(7-(4-fluorobenzyloxy)-4-ylquinoline)piperazine (11i)

[0144]

[0145] Using intermediate 10c and anhydrous piperazine as raw materials, a pale yellow solid was obtained with a yield of 31.8% and mp 210.2 - 213.4 °C. 1 H NMR (400 MHz, CDCl 3 ) 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, CH 2 ), 3.54 (s, 8H, NCH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 F 2 N 4 O 2 [M+H] + : 589.24096, found: 589.24036。

[0146] 10) 1,4-Bis(7-phenoxypropyl-4-ylquinoline)piperazine (11j)

[0147]

[0148] Using intermediate 10d and anhydrous piperazine as raw materials, a pale yellow solid was obtained with a yield of 51.3% and mp 146.4 - 148.0 °C. 1 H NMR (400 MHz, CDCl 3)δ8.73(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, OCH 2 ), 3.55(s, 8H, NCH 2 ), 2.89(t, J = 7.6 Hz, 4H, CH 2 ), 2.23(t, J = 6.4 Hz, 4H, CH 2 ). 13 C NMR(151 MHz, DMSO-d 6 )δ162.2, 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 N 4 O 2 [M + H] + : 609.32240, found: 609.32147。

[0149] Example 3

[0150] This example provides 7-bridged bisquinoline compounds 13a - 13l, and their general synthesis process and synthesis equations are as follows:

[0151] 1. Synthesis of intermediates

[0152]

[0153] Synthesis process of 7-hydroxy-4(4-methoxypiperazinyl)quinoline 12a:

[0154] 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, reflux the reaction with stirring, 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 1H NMR (600 MHz, DMSO-d 6 ) 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, NCH 2 ), 3.81 (s, 2H, NCH 2 ), 3.54 (s, 2H, NCH 2 ), 2.85 (s, 3H, NCH 3 ). 13 13C NMR (151 MHz, DMSO-d 6 ) 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。

[0155] General synthetic process of intermediates 12b - 12d:

[0156] Add intermediate 8 (10 mmol), the corresponding aniline (15 mmol), ethylene glycol monomethyl ether (30 mL) and pyridine hydrochloride (2 mmol) into a 100 mL round-bottom flask. Stir and reflux 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. It can be directly used for the next reaction without purification. The synthesis of intermediates 12b - 12d is as follows:

[0157] 1) 7-Hydroxy-4-(3-methoxyanilino)quinoline (12b)

[0158] Synthesized according to 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] + .

[0159] 2) 7-Hydroxy-4-(3-trifluoromethylanilino)quinoline (12c)

[0160]

[0161] Synthesized by the above method, using intermediate 8 and 3-(trifluoromethyl)aniline as raw materials, a pale yellow solid was obtained with a yield of 54.9% and mp 112.2 - 113.5 °C. ESI-MS m / z: 305.14 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) 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。

[0162] 3) 7-Hydroxy-4(3-fluoroanilino)quinoline (12d)

[0163] Synthesized by the above method, using intermediate 8 and 3-fluoroaniline as raw materials, a yellow solid was obtained with a yield of 48.7%. ESI-MS m / z: 255.23 [M+H] + 。

[0164] 2. Synthetic route of 7-position bridged bisquinoline compounds:

[0165]

[0166] General synthetic process of 7-position bridged bisquinoline derivatives 13a - 13l:

[0167] 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.

[0168] The synthesis of specific compounds 13a - 13l is as follows:

[0169] 1) 1,4-Bis(4-(3-methoxyanilino)-7-oxoquinolin-3-yl)butane (13a)

[0170]

[0171] 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-d 6 ) 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, OCH 2 ), 3.77 (d, J = 2.6 Hz, 6H, OCH 3 ), 2.02 (s, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 N 4 O4 [M+H] + : 587.26528, found: 587.26471。

[0172] 2) 1,5 - Bis(4-(3 - methoxyanilino)-7 - oxyquinoline) pentane (13b)

[0173]

[0174] 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 - d 6 ) 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, OCH 2 ), 3.77 (d, J = 3.2 Hz, 6H, OCH 3 ), 1.90 (d, J = 7.6 Hz, 4H, CH 2 ), 1.70 (s, 2H, CH 2 ). 13 C NMR (151 MHz, DMSO - d 6 ) 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 N 4 O 4 [M + H] + : 601.28093, found: 601.28000。

[0175] 3) 1,6 - Bis(4-(3 - methoxyanilino)-7 - oxyquinoline) hexane (13c)

[0176]

[0177] Using intermediate 12b and 1,6-dibromohexane as raw materials, a yellow solid with a yield of 59.1% and mp 159.7 - 160.5 °C. 1 H NMR(400MHz,DMSO-d 6 )δ8.95(s,2H,NH),8.39(d,J=5.4Hz,2H,ArH),8.27(d,J=9.2Hz,2H,ArH),7.31(t,J=8.2Hz,2H,ArH),7.25(dd,J=6.8,2.6Hz,2H,ArH),7.19(dd,J=9.2,2.6Hz,2H,ArH),6.94(d,J=8.4Hz,2H,ArH),6.90(d,J=2.4Hz,2H,ArH),6.71(dd,J=8.2,2.6Hz,2H,ArH),5.77(s,2H,ArH),4.16(t,J=6.4Hz,4H,OCH 2 ),3.77(s,6H,OCH 3 ),1.85(s,4H,CH 2 ),1.54(d,J=35.6Hz,4H,CH 2 ). 13 C NMR(151MHz,DMSO-d 6 )δ162.8,160.8,154.9,142.6,141.1,138.9,131.1,126.2,118.8,117.8,113.3,111.8,111.6,101.0,99.8,68.9,55.9,28.7,25.6.HRMS(ESI)calcd for C 38 H 39 N 4 O 4 [M+H] + :615.29858,found:615.29808。

[0178] 4) 1,4-bis(4-(3-trifluoromethylphenylamino)-7-oxoquinoline)butane (13d)

[0179]

[0180] Using intermediate 12c and 1,4-dibromobutane as raw materials, a light yellow solid was obtained with a yield of 48.3% and mp 206.2 - 207.8 °C. 1 H NMR(400MHz,DMSO-d 6) 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, OCH 2 ), 2.04 (d, J = 4.8 Hz, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 F 6 N 4 O 2 [M + H] + : 663.21892, found: 663.21790。

[0181] 5) 1,5-Bis(4-(3-trifluoromethylphenylamino)-7-oxoquinoline)pentane (13e)

[0182]

[0183] Using intermediate 12c and 1,5-dibromopentane as raw materials, a pale yellow solid was obtained with a yield of 23.6% and mp 170.7 - 172.8 °C. H NMR (400 MHz, DMSO-d 6 ) 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, OCH 2 ), 1.91 (t, J = 8.4 Hz, 4H, CH 2 ), 1.71 (d, J = 7.4 Hz, 2H, CH 2). 13 C NMR (101 MHz, DMSO-d 6 ) 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 F 6 N 4 O 2 [M + H] + : 677.23457, found: 677.23328.

[0184] 6) 1,6-Bis(4-(3-trifluoromethylanilino)-7-oxoquinolin-2-yl)hexane (13f)

[0185]

[0186] Using intermediate 12c and 1,6-dibromohexane as raw materials, a pale yellow solid was obtained, with a yield of 26.0%, mp 220.1 - 223.6 °C. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.48 (d, J = 5.6 Hz, 2H, ArH), 8.31 (d, J = 9.2 Hz, 2H, ArH), 7.73–7.61 (m, 6H, ArH), 7.49 (d, J = 7.6 Hz, 2H, ArH), 7.34–7.25 (m, 4H, ArH), 6.94 (d, J = 5.6 Hz, 2H, ArH), 5.77 (s, 2H, ArH), 4.19 (t, J = 6.4 Hz, 4H, OCH 2 ), 1.88 (s, 4H, CH 2 ), 1.61 (d, J = 6.2 Hz, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 F 6 N 4 O2 [M+H] + : 691.25022, found: 691.24902。

[0187] 7) 1,4-Bis(4-(3-fluoroanilino)-7-oxoquinolin-2-yl)butane (13 g)

[0188]

[0189] Using intermediate 12d and 1,4-dibromobutane as raw materials, a white solid was obtained with a yield of 54.6%, mp 236.9 - 238.1 °C. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.03 (s, 2H, NH), 8.46 (d, J = 5.4 Hz, 2H, ArH), 8.24 (d, J = 9.2 Hz, 2H, ArH), 7.41 (q, J = 7.8 Hz, 2H, ArH), 7.32 (d, J = 2.6 Hz, 2H, ArH), 7.25–7.10 (m, 6H, ArH), 6.98 (d, J = 5.4 Hz, 2H, ArH), 6.92 (s, 2H, ArH), 4.25 (t, J = 4.8 Hz, 4H, OCH 2 ), 2.03 (s, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 F 2 N 4 O 2 [M+H] + : 563.22531, found: 563.22485。

[0190] 8) 1,5-Bis(4-(3-fluoroanilino)-7-oxoquinolin-2-yl)pentane (13 h)

[0191]

[0192] 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. 11H NMR (400 MHz, DMSO-d 6 ) 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, OCH 2 ), 1.92 (q, J = 7.6 Hz, 4H, CH 2 ), 1.70 (t, J = 8.0 Hz, 2H, CH 2 ). 13 13C NMR (151 MHz, DMSO-d 6 ) 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 F 2 N 4 O 2 [M + H] + : 577.24096, found: 577.24048。

[0193] 9) 1,6-Bis(4-(3-fluoroanilino)-7-oxoquinolinyl)hexane (13i)

[0194]

[0195] 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-d 6)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, OCH 2 ), 1.85 (q, J = 6.4 Hz, 4H, CH 2 ), 1.58 (q, J = 6.6 Hz, 4H, CH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 F 2 N 4 O 2 [M + H] + : 591.25661, found: 591.25574。

[0196] 10. 1,4 - Bis(4-(4 - methylpiperazinyl)-7 - oxyquinoline)butane (13j)

[0197]

[0198] Using intermediate 12a and 1,4 - dibromobutane as raw materials, a pale yellow solid was obtained with a yield of 48.9%, mp 146.1 - 147.3 °C. ESI - MS m / z: 541.58 [M + H] + . 1 H NMR (400 MHz, DMSO - d 6 ) 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, NCH 2 ), 4.21 (q, J = 13.8 Hz, 4H, CH 2), 3.84 (t, J=13.2 Hz, 4H, NCH 2 ), 2.86 (s, 6H, NCH 3 ), 2.05 (t, J=4.8 Hz, 4H, OCH 2 ). 13 C NMR (151 MHz, DMSO-d 6 ) 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 N 6 O 2 [M + H] + : 541.32764, found: 541.32855。

[0199] 11) 1,5-Bis(4-(4-methylpiperazinyl)-7-oxoquinoline)pentane (13k)

[0200]

[0201] Using intermediate 12a and 1,5-dibromopentane as raw materials, a pale yellow solid was obtained with a yield of 43.2%, mp 163.3 - 164.7 °C. 1 H NMR (400 MHz, DMSO-d 6 ) 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, NCH 2 ), 3.84 (t, J=13.4 Hz, 4H, NCH 2 ), 3.57 (q, J=12.2 Hz, 4H, CH 2 ), 2.85 (s, 6H, NCH 3 ), 1.92 (q, J=7.2 Hz, 4H, CH 2 ), 1.69 (t, J=7.8 Hz, 2H, OCH 2 ). 13 C NMR (101 MHz, DMSO-d 6)δ162.5,160.8,142.5,142.1,128.3,119.1,114.5,106.4,101.1,69.0,52.1,48.6,42.4,28.4,22.5.HR-MS(ESI)calcd for C 33 H 43 N 6 O 2 [M + H] + :555.34420,found:555.34412。

[0202] 12) 1,6 - Bis(4-(4 - methylpiperazinyl)-7 - oxyquinoline) hexane (13l)

[0203]

[0204] 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 H NMR(400MHz,DMSO - d 6 )δ8.73(d,J = 6.8Hz,2H,ArH),8.10(d,J = 9.6Hz,2H,ArH),7.58(d,J = 2.6Hz,2H,ArH),7.36(dd,J = 9.6,2.6Hz,2H,ArH),7.25(d,J = 6.8Hz,2H,ArH),4.20(t,J = 6.8Hz,8H,NCH 2 ),3.83(t,J = 12.8Hz,4H,NCH 2 ),3.57(q,J = 12.8Hz,4H,CH 2 ),2.87(s,6H,NCH 3 ),1.91–1.83(m,4H,CH 2 ),1.56(t,J = 6.8Hz,4H,OCH 2 ). 13 C NMR(101MHz,DMSO - d 6 )δ162.6,160.9,142.3,142.0,128.3,119.3,114.4,106.4,100.9,69.0,52.1,48.6,42.4,28.6,25.5.HRMS(ESI)calcd for C 34 H 45 N 6 O 2 [M + H] +: 569.35985, found: 569.35956。

[0205] Experimental test

[0206] 1. In vitro anti-tumor activity test

[0207] Pharmacological research on 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 test, and the clinically commonly used anti-tumor drugs - chloroquine phosphate and cisplatin were used as positive control drugs.

[0208] 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), MCF-7 (human breast cancer cell line) were respectively selected, and the inhibitory activity of the bisquinoline compound against human cancer cell lines was evaluated by the MTT method. The tumor cells were inoculated on a 96-well plate at a concentration of 1×10 6 cells / mL and cultured in a CO 2 incubator at 37°C until the logarithmic phase. The fresh medium was replaced, and then the sterilized bisquinoline compound was added. Each compound was set with 6 - 8 dose groups, and each group was set with at least three parallel wells. 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 mixture was oscillated for about 10 min to dissolve the precipitate. Then, the optical density value (OD) was measured at a wavelength of 570 nm with an enzyme-linked immunosorbent assay reader. 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:

[0209] Survival rate % = average OD value of the sample group / average OD value of the control group × 100%.

[0210] 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:

[0211] Table 1 In vitro anti-tumor activity results of the bisquinoline compound

[0212]

[0213]

[0214] 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-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-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-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.

[0215] 2. Acute toxicity test in mice

[0216] 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 normal 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 reaction of the mice after administration was observed. The dead animals were dissected for observation, and the surviving animals were observed for another two weeks, and the death of the animals within two weeks was 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.

[0217] 3. Anti-tumor test in vivo

[0218] 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 in 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 (subcultured and maintained by the Cell Molecular Biology Research Laboratory of the School of Life Sciences of Wuhan University); the solvents used were normal 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 scheme 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 the 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, and administer the drug according to the experimental design plan the next day. 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:

[0219] 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%.

[0220] The test results are shown in Table 2 below:

[0221] Table 2 Results of acute toxicity and in vivo anti-tumor activity tests of bisquinoline compounds in mice

[0222]

[0223] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to 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. A bridged bisquinoline compound, the structural formula of which is shown in formula (B): In formula (B), R1 is The R2 is a methoxy group, a substituted or unsubstituted arylalkyl ether group; the substituted or unsubstituted arylalkyl ether group is in, x=1-3, Y is a halogen, and the dotted line represents the linking position of the group.

2. The bridged bisquinoline compound according to claim 1, characterized in that The bridged bisquinoline compound is shown in Formula 10 to Formula 16:

3. The method for preparing the bridged bisquinoline compound according to any one of claims 1 to 2, characterized in that: The steps include: The compound represented by formula (b) is reacted with a compound containing R1 to obtain a bridged bisquinoline compound represented by formula (B); the reaction formula is as follows: Wherein, Z is fluorine, iodine, chlorine or bromine.

4. The method for preparing a bridged bisquinoline compound according to claim 3, characterized in that: In the preparation of the bridged bisquinoline compound as shown in formula (B), the reaction temperature of the reaction is 120-140°C; And / or, in the preparation of the bridged bisquinoline compound as shown in formula (B), the reaction time of the reaction is 20-48 hours.

5. The method for preparing a bridged bisquinoline compound according to claim 3, characterized in that: The molar ratio of the compound represented by formula (b) to the compound containing R1 is (2-3):

1.

6. The method for preparing a bridged bisquinoline compound according to claim 3, characterized in that: The compound represented by formula (b) is prepared by a preparation method comprising the following steps: The compound represented by formula (b1) is reacted with a compound containing R2 to obtain a compound represented by formula (b); the reaction formula is as follows: Wherein, Z and R2 are as described in claim 3.

7. Use of the bridged bisquinoline compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the preparation of antitumor drugs.

8. The use according to claim 7, characterized in that The tumor is selected from colon cancer, lung cancer, liver cancer, stomach cancer, cervical cancer or breast cancer.

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