A tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound and a preparation method and application thereof

Abstract

The application belongs to the technical field of medicine and chemical industry, and discloses a tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound. The cyclic enamine ketone can be used as a carbon attack point or a carbon-nitrogen attack point. The tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound is efficiently prepared through a base-catalyzed cascade cyclization reaction of the cyclic enamine ketone and a 2-halogenated quinoline-3-alpha, beta unsaturated carbonyl compound. The tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound has the characteristics of easy-to-obtain raw materials, simple operation, high atom economy and the like. Meanwhile, the prepared tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound shows in-vitro inhibition effect on human colon cancer cells HT-29 and human non-small cell lung cancer cells A549, and thus has great implementation value and application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine and chemical industry, and particularly relates to a tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound, a synthesis method thereof and an application of the compound in the field of anti-tumor. BACKGROUND

[0002] The benzo-hydronaphthyridine nucleus and the polysubstituted hydrogenated quinoline nucleus are important pharmacophores in drug molecules. Research shows that the polysubstituted benzo-hydronaphthyridine compound and the polysubstituted hydrogenated quinoline compound have certain biological activity. For example, the compound 1 containing the benzo-hydronaphthyridine structure is an acetylcholine self-enzyme inhibitor, and the compound 2 containing the polysubstituted hydrogenated quinoline compound can inhibit the proliferation of HeLa cells and has potential anti-tumor activity (The Lycopodium Alkaloids: chemistry and pharmacology. Vol 45. New York: Academic Press; 1994. p. 233-266).

[0003] At present, there are many reports on the synthesis of the benzo-hydronaphthyridine nucleus and the polysubstituted hydrogenated quinoline nucleus. However, there are few reports on the connection of the benzo-hydronaphthyridine nucleus and the polysubstituted hydrogenated quinoline through the common nitrogen-containing six-membered ring to form the tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound. In view of this, it has great research significance and potential application prospect to study a simple and efficient method for synthesizing the tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound. SUMMARY

[0004] The cyclic enamine ketone can be used as a carbon attack point or a carbon-nitrogen attack point to participate in various cycloaddition reactions in the form of a double nucleophile reagent, and the tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound is efficiently prepared through an alkaline catalytic tandem cyclization reaction with a 2-halogenated quinoline-3-alpha, beta unsaturated carbonyl compound.

[0005] The first object of the application is to provide a tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound, and the structural formula is shown as (I):

[0006]

[0007] wherein, R 1 is selected from naphthyl, phenyl, substituted phenyl, and the substituents in the substituted phenyl are halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, phenyl, phenoxy, nitro and trifluoromethyl; R 2 is selected from hydrogen, C1-6 alkyl, phenyl; R 3 selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, phenyl ring; R 4 selected from phenyl, C 1-6 alkyl, C 1-6 alkoxy.

[0008] A second object of the present application is to provide a synthetic method for preparing the above-mentioned tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound.

[0009] A third object of the present application is to provide the use of the above-mentioned tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound in the preparation of an antitumor drug.

[0010] The technical solution of the present application is as follows:

[0011] A tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound, whose structural formula is shown as (I):

[0012]

[0013] wherein, R 1 selected from naphthyl, phenyl, substituted phenyl, and the substituent in the substituted phenyl is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, phenyl, phenoxy, nitro, trifluoromethyl; R 2 selected from hydrogen, C 1-6 alkyl, phenyl; R 3 selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, phenyl ring; R 4 selected from phenyl, C 1-6 alkyl, C 1-6 alkoxy.

[0014] A preparation method of the above-mentioned tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound, whose reaction formula is shown as follows: 2-halogenated quinoline-3-α,β unsaturated carbonyl compound shown as formula (II), cyclic enamine ketone shown as formula (III) are mixed with a solvent, a base is added, and stirring reaction is carried out at 0℃-120℃ for 0.5-36 hours, to prepare tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound shown as formula (I).

[0015]

[0016] In an embodiment of the present application, the base is triethylamine, triethylenediamine, 4-dimethylaminopyridine, piperidine, sodium carbonate, barium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

[0017] In another embodiment of the present application, the base is preferably cesium carbonate.

[0018] In an embodiment of the present application, the solvent is toluene, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, dichloroethane, chlorobenzene, chloroform, ethyl acetate, ethanol, methanol or tert-butanol.

[0019] In an embodiment of the present application, the molar feed ratio of 3-haloquinoline-2-α,β-unsaturated carbonyl compound to cyclic enaminone to base is 1:1-3:1-3.

[0020] The present application also provides the use of the above-mentioned tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound in the preparation of an antitumor drug, specifically in the preparation of an antitumor drug for inhibiting human colon cancer H-29 cells and human non-small cell lung cancer A549 cells.

[0021] Compared with the prior art, the present application has the following advantages:

[0022] The present application is a tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound, a preparation method thereof and an application thereof. The cyclic enaminone compound can be used as a carbon attack point or a carbon-nitrogen attack point. Through base-catalyzed cascade cyclization reaction with 2-haloquinoline-3-α,β-unsaturated carbonyl compound, a tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound is efficiently prepared. The present application has the characteristics of easy availability of raw materials, simple operation and high atom economy. In addition, the prepared tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compound shows in-vitro inhibition effect on human colon cancer HT-29 cells and human non-small cell lung cancer A549 cells, and thus has great implementation value and application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The H NMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2-phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][1,8]naphthyridin-1(2H)-one (Ia) of Example 1 of the present application is as follows: 1 H NMR spectrum

[0024] Figure 2HNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention. 13 CNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention.

[0025] Figure 3 HNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention. 1 CNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention.

[0026] Figure 4 CNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention. 13 HNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention.

[0027] Figure 5 HNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention. 1 CNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention.

[0028] Figure 6 CNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention. 13 HNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention.

[0029] Figure 7 HNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention. 1 CNMR spectrum of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ia) of Example 1 of the present invention.

[0030] Figure 8The 6-(4-methoxyphenyl)-8,8-dimethyl-11-(2-oxo-2-phenylethyl)-7,8,9-11-tetrahydro-[1,3]dioxane[4',5':4,5]benzo[1,2-b]benzo[g][1,8]naphthidium-10(6H)-one-(Id) of Example 9 of the present invention 13 CNMR spectrum;

[0031] Figure 9 The 13-(4-methoxyphenyl)-11,11-dimethyl-8-(2-oxo-2-phenylethyl)-8,11,12,13-tetrahydrobenzo[b]naphtho[2,1-g][1,8]naphthyridine-9(10H)-one (Ie) of Example 10 of the present invention 1 H NMR spectrum;

[0032] Figure 10 The 13-(4-methoxyphenyl)-11,11-dimethyl-8-(2-oxo-2-phenylethyl)-8,11,12,13-tetrahydrobenzo[b]naphtho[2,1-g][1,8]naphthyridine-9(10H)-one (Ie) of Example 10 of the present invention 13 CNMR spectrum. Detailed Implementation

[0033] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0034] Numerous specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0035] The preparation of the 2-haloquinoline-3-α,β-unsaturated carbonyl compounds shown in formula (II) is described in Eur. J. Med. Chem. 2011, 46, 4448-4456; Org. Lett. 2019, 21, 8149-8152. Although some of these compounds have not been reported, they can still be prepared according to the methods described in these documents.

[0036] The preparation of the cyclic enamino ketones shown in formula (III) can be found in Adv. Synth. Catal. 2017, 359, 2202-2208; RSCAdv. 2020, 10, 20552-20557. Some of these compounds, although not reported, can still be prepared according to the methods in these documents.

[0037] Example 1: Preparation of 5-(4-methoxyphenyl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodiben[b,g][l,8]naphthyridin-l(2H)-one (la)

[0038]

[0039] In ethanol (2 mL) as solvent, compound Ila (29.3 mg, 0.1 mmol) and Ilia (29.4 mg, 0.12 mmol) were added, and triethylamine (11.3 mg, 0.12 mmol) was added. After stirring at reflux for 12 hours, the solvent was recovered by concentration under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) was performed to obtain 15 mg of product la as a red oil, with a yield of 30%.

[0040] Ia was characterized by structure as shown in Figures 1-2 1 H NMR (400 MHz, CDC13): δ 8.02-7.96 (m, 2H), 7.83 (s, 1H), 7.64-7.47 (m, 4H), 7.45-7.38 (m, 3H), 7.30-7.26 (m, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.96 (dd, J = 7.6, 3.6 Hz, 1H), 3.91 (s, 3H), 3.56-3.29 (m, 2H), 2.34-2.21 (m, 2H), 2.16-2.02 (m, 2H), 0.99 (s, 3H), 0.98 (s, 3H). 13 CNMR (100 MHz, CDC13): δ 198.2, 195.4, 159.0, 155.4, 151.0, 145.7, 137.0, 136.2, 132.8, 132.0, 131.1, 128.9, 128.5, 128.2, 128.1, 126.8, 124.4, 122.3, 114.4, 109.7, 55.4, 50.0, 46.6, 42.4, 32.5, 31.7, 29.1, 27.3. HRMS (ESI) m / z calcd for C 33 H 31 N2O3[M+H] + = 503.2329, found = 503.2330.

[0041] ​In Examples 2-6, the present application investigates the influence of solvent, base, temperature, time on the yield of the product, and the optimal conditions for different halogenated quinoline derivatives 2-position bromide type substrate (IIa'), the optimal conditions for 2-position chloride II type substrate are: acetonitrile as solvent, cesium carbonate as base, and the reaction time is about 12 hours at 80°C.

[0042] Example 2: Preparation of Ia

[0043] In ethanol (2 mL) as solvent, add compound IIa (29.3 mg, 0.1 mmol) and IIIa (29.4 mg, 0.12 mmol), and add potassium carbonate (16.6 mg, 0.12 mmol), stir the reaction under reflux for 12 hours, then recover the solvent under reduced pressure, separate by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 38.2 mg of product Ia as red oil, with a yield of 76%.

[0044] Example 3: Preparation of Ia

[0045] In ethanol (2 mL) as solvent, add compound IIa (29.3 mg, 0.1 mmol) and IIIa (29.4 mg, 0.12 mmol), and add cesium carbonate (39.1 mg, 0.12 mmol), stir the reaction under reflux for 12 hours, then recover the solvent under reduced pressure, separate by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 40.2 mg of product Ia as red oil, with a yield of 80%.

[0046] Example 4: Preparation of Ia

[0047] In acetonitrile (2 mL) as solvent, add compound IIa (29.3 mg, 0.1 mmol) and IIIa (29.4 mg, 0.12 mmol), and add cesium carbonate (39.1 mg, 0.12 mmol), stir the reaction at 80°C for 12 hours, then recover the solvent under reduced pressure, separate by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 48.2 mg of product Ia as red oil, with a yield of 96%.

[0048] Example 5: Preparation of Ia

[0049] In acetonitrile (2 mL) as solvent, add compound IIa (29.3 mg, 0.1 mmol) and IIIa (29.4 mg, 0.12 mmol), and add cesium carbonate (39.1 mg, 0.12 mmol), stir the reaction at room temperature for 36 hours, then recover the solvent under reduced pressure, separate by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 30.1 mg of product Ia as red oil, with a yield of 60%.

[0050] Example 6: Preparation of Ia

[0051]

[0052] In acetonitrile (2 mL) as solvent, compound IIa' (33.7 mg, 0.1 mmol) and IIIa (29.4 mg, 0.12 mmol) were added, and cesium carbonate (39.1 mg, 0.12 mmol) was added. After stirring at 80 °C for 12 h, the solvent was recovered by concentration under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) was used to separate the product Ia, which was obtained as a red oil, 46.2 mg, 92% yield.

[0053] Example 7: Preparation of 5-(benzo[d][l,3]dioxol-5-yl)-3,3-dimethyl-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ib)

[0054]

[0055] In acetonitrile (2 mL) as solvent, compound IIa (29.3 mg, 0.1 mmol) and IIIb (31.1 mg, 0.12 mmol) were added, and cesium carbonate (39.1 mg, 0.12 mmol) was added. After stirring at 80 °C for 12 h, the solvent was recovered by concentration under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) was used to separate the product Ib, which was obtained as a red oil, 45.9 mg, 89% yield.

[0056] Ib was characterized by structure as shown in Figures 3-4 1 H NMR (400 MHz, CDC13): δ 8.01-7.94 (m, 2H), 7.83 (s, 1H), 7.65-7.57 (m, 2H), 7.53-7.39 (m, 4H), 7.31-7.27 (m, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.91-6.82 (m, 2H), 6.11 (dd, J = 7.2, 1.2 Hz, 2H), 4.94 (dd, J = 7.3, 3.6 Hz, 1H), 3.55-3.30 (m, 2H), 2.35-2.22 (m, 2H), 2.22-2.10 (m, 2H), 1.01 (s, 3H), 0.99 (s, 3H). 13 ​CNMR (100 MHz, CDC13): δ 198.1, 195.4, 155.2, 151.0, 147.3, 145.7, 137.0, 136.2, 133.1, 132.9, 129.0, 128.5, 128.2, 128.1, 126.8, 126.3, 124.5, 122.4, 109.8, 108.3f, 101.7, 50.1, 46.6, 42.2, 32.5, 31.7, 29.2, 27.3. HRMS (ESI) m / z calculated for C 33 H 29 N2O4[M+H] + = 517.2122, found = 517.2129.

[0057] Example 8: Preparation of 3,3-dimethyl-5-(naphthalen-l-yl)-12-(2-oxo-2- phenylethyl)-3,4,5,12-tetrahydrodibenzo[b,g][l,8]naphthyridin-l(2H)-one (Ic)

[0058]

[0059] In acetonitrile (2 mL) as solvent, compound Ila (29.3 mg, 0.1 mmol) and IIIc (31.8 mg, 0.12 mmol) were added, and cesium carbonate (39.1 mg, 0.12 mmol) was added. After stirring at 80 °C for 12 h, the solvent was recovered by concentration under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) was used to separate the product Ic, which was obtained as a red oil, 48.0 mg, 92% yield.

[0060] The structural characterization of Ic is shown in Figures 5-6 : 1 H NMR (600 MHz, CDC13): δ 8.32-8.10 (m, 1H), 8.06-7.97 (m, 3H), 7.92-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.64-7.28 (m, 9H), 7.26-7.20 (m, 2H), 5.17-5.03 (m, 1H), 3.75-3.40 (m, 2H), 2.34-2.23 (m, 2H), 2.13-1.76 (m, 2H), 0.90 (d, J = 1.8 Hz, 3H), 0.87 (s, 3H). 13CNMR (150 MHz, CDC13): δ 198.3, 198.2, 195.6, 195.5, 155.5, 155.3, 151.0, 150.7, 145.8, 145.7, 137.1, 137.0, 137.0, 136.2, 136.1, 135.7, 134.5, 134.2, 133.0, 132.9, 132.3, 132.0, 129.0, 128.9, 128.8, 128.71, 128.66, 128.6, 128.53, 128.46, 128.43, 128.41, 128.3, 128.2, 128.1, 127.4, 127.2, 126.9, 126.79, 126.77, 126.5, 126.38, 126.35, 126.3, 126.0, 125.4, 124.5, 124.4, 123.4, 122.6, 122.2, 122.1, 109.9, 109.6, 50.3, 50.2, 47.2, 46.9, 42.1, 41.0, 32.5, 32.2, 32.0, 31.9, 29.7, 28.3, 27.8, 26.2. HRMS (ESI) m / z calculated for C 36 H 31 N2O2[M+H] + = 523.2380, found = 523.2398.

[0061] Example 9: Preparation of 6-(4-methoxyphenyl)-8,8-dimethyl-11-(2-oxo-2- phenylethyl)-7,8,9-11-tetrahydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[g][1,8] naphthyridin-10(6H)-one (Id)

[0062]

[0063] In acetonitrile (2 mL) as solvent, compound Ila (33.7 mg, 0.1 mmol) and Ilia (29.4 mg, 0.12 mmol) were added, and cesium carbonate (39.1 mg, 0.12 mmol) was added. After stirring at 80 °C for 12 hours, the solvent was recovered by concentration under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) was performed to obtain 45.8 mg of product Id as a red oil, with a yield of 84%.

[0064] The structural characterization of Id is shown in Figures 7-8 1 ​H NMR (400 MHz, CDC13): δ 8.01 (d, J = 7.2 Hz, 2H), 7.61 (s, 1H), 7.54-7.48 (m, 1H), 7.46-7.37 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.86 (s, 2H), 5.95 (d, J = 3.2 Hz, 2H), 4.90 (t, J = 5.2 Hz, 1H), 3.90 (s, 3H), 3.45-3.23 (m, 2H), 2.35-2.19 (m, 2H), 2.15-1.96 (m, 2H), 0.98 (s, 7H). 113 CNMR (100 MHz, CDC13): δ 198.4, 195.3, 159.0, 155.3, 150.2, 149.7, 146.3, 143.5, 137.0, 135.3, 132.8, 132.1, 128.5, 128.3, 122.6, 119.6, 114.3, 109.4, 105.1, 102.3, 101.3, 55.4, 50.1, 46.7, 42.3, 32.5, 31.7, 29.1, 27.3. HRMS (ESI) m / z calculated for C 34 H 31 N2O5[M+H] + = 547.2233, found = 547.2239.

[0065] Example 10: Preparation of 13-(4-methoxyphenyl)-11,11-dimethyl-8-(2-oxo-2- phenylethyl)-8,11,12,13-tetrahydrobenzo[b]naphtho[2,1-g][1,8]naphthyridin-9(10H)- one (Ie)

[0066]

[0067] In acetonitrile (2 mL) as solvent, compound Ila (34.3 mg, 0.1 mmol) and Ilia (29.4 mg, 0.12 mmol) were added, and cesium carbonate (39.1 mg, 0.12 mmol) was added. After stirring at 80 °C for 12 hours, the solvent was recovered by concentration under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) was performed to obtain 46.9 mg of product Ie as a red oil, with a yield of 85%.

[0068] The structural characterization of Ie is shown as follows: Figures 9-10 1 ​H NMR (600 MHz, CDC13): δ 8.41 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 2H), 7.86 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.54-7.48 (m, 3H), 7.48-7.41 (m, 3H), 7.36 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H), 5.02 (dd, J = 7.8, 3.6 Hz, 1H), 3.98 (s, 3H), 3.53-3.33 (m, 2H), 2.36-2.25 (m, 2H), 2.17 (s, 2H), 1.02 (s, 6H). 13 C{ 1 H} NMR (150 MHz, CDC13): δ 198.3, 195.4, 159.1, 155.3, 150.2, 143.4, 137.1, 136.4, 133.6, 132.8, 132.2, 130.9, 128.5, 128.3, 127.5, 127.4, 126.4, 125.5, 124.7, 124.1, 123.7, 121.6, 114.4, 109.4, 55.55, 50.2, 46.8, 42.3, 32.5, 31.7, 29.2, 27.4. HRMS (ESI) m / z calcd for C 37 H 33 N2O5[M+H] + = 553.2491, found = 553.2498.

[0069] Examples 11-49:

[0070] In Examples 11-49, the present application also prepared the substituent R 1 , R 2 , R 3 and R 4 Various changes of tetrahydrodibenzo[b,g][1,8]naphthyridin-1-one compounds, as shown in Table 1. The reaction conditions are as follows:

[0071] In a Schlenk tube (15 mL), a 2-chloroquinoline-3-α,β-unsaturated carbonyl compound (0.1 mmol) represented by formula (II) and a cyclic enaminone represented by formula (III) (0.12 mmol) were added as solvents with acetonitrile (2 mL), and cesium carbonate (0.12 mmol) was added. After stirring at 80°C for 12 hours, the solvent was recovered by concentration under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) was used to separate the target product represented by formula (I), as shown in Table 1.

[0072]

[0073] Table 1

[0074]

[0075]

[0076] Example 49: Anti-tumor biological activity test method

[0077] The above compound (I) is tested for anti-tumor activity. The specific test method is as follows: after each group of solid compounds is calculated in molar units, it is dissolved in DMSO to prepare a final concentration of 40 mM, and then it is diluted in proportion to prepare a concentration of 8 / 1.6 / 0.32 mM / L, which is stored at -20°C in the dark. Cells are seeded in a 96-well plate at a quantity of 3000-5000 per well, and after the cells adhere, the compounds are administered, and the administration concentration of each compound is 40 / 8 / 1.6 / 0.32 nM. Incubation is performed in an incubator for 72 h. Each experiment is repeated three times. The 96-well plate is taken, and the culture solution is discarded, 100 ul of 15% TCA solution is added to each well, and it is fixed at 4°C for 4-6 h, then it is taken out, the TCA solution is discarded, and it is inverted and dried in a 37°C oven. After drying, 40 ul of SRB solution (0.8 g of SRB powder is dissolved in 200 ml of 1% acetic acid to prepare) is added to each well under dark conditions, and it is dyed at room temperature for 30 min in the dark. The dye solution is discarded, and the excess dye is washed away with 1% acetic acid, and it is inverted and dried at 37°C. 80 ul of 10 mM Tris solution is added to each well, and the absorbance at 515 nm is measured, and the IC 50 The experimental results show that most of the products have good inhibitory activity on human colorectal cancer cells HT-29 and human non-small cell lung cancer cells A549. The present application only lists the active products, and the inhibitory activity is shown in Table 2.

[0078] Table 2 Anti-tumor activity of some compounds I

[0079]

[0080]

[0081]

[0082] As can be seen from the above table, most of the target compounds obtained by the present application exhibit good in vitro proliferation inhibition on human colon cancer cells HT-29 and human non-small cell lung cancer cells A549, and thus have great implementation value and application prospect.

[0083] The preferred embodiments of the application disclosed above are only to facilitate the elucidation of the application. The preferred embodiments do not describe all the details of the application and limit the application to the specific embodiments described. Obviously, many modifications and variations can be made in light of the teachings above. The description is chosen and described in order to best explain the principles of the application and its practical application to thereby enable others skilled in the art to best utilize the application and get the best results from the application. The application is only limited by the claims and their full scope and equivalents.

Claims

1. A tetrahydrodibenzo[ b , g ][1,8]naphthyridin-1-one compound, having a structural formula as shown in (I): （I） wherein, R 1 selected from naphthyl, phenyl, substituted phenyl, the substituents in substituted phenyl being halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, phenyl, phenoxy, nitro, trifluoromethyl; R 2 selected from hydrogen, C 1-6 alkyl, phenyl; R 3 selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, phenyl ring; R 4 selected from phenyl, C 1-6 alkyl, C 1-6 alkoxy.

2. A tetrahydrodibenzo[a] as described in claim 1 b , g The method for preparing [1,8]naphthidine-1-one compounds is characterized in that, The reaction formula is shown as follows: A 2-halogenated quinoline-3-α,β unsaturated carbonyl compound shown in formula (II), a cyclic enaminone shown in formula (III) are mixed with a solvent, a base is added, and the reaction is stirred at 0-120℃ for 0.5-36 hours to prepare a tetrahydrodibenzo[ b , g ][1,8]naphthyridin-1-one compound shown in formula (I).

3. The tetrahydrodibenzo[ b , g ]azepine compound according to claim 2, wherein the tetrahydrodibenzo[ The base is triethylamine, triethylenediamine, 4-dimethylaminopyridine, piperidine, sodium carbonate, barium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

4. The tetrahydrodibenzo[ b , g ][1,8]naphthyridin-1-one compound according to claim 2, wherein The base is cesium carbonate.

5. The tetrahydrodibenzo[ b , g ]azepine compound according to claim 2, wherein the tetrahydrodibenzo[ The solvent is toluene, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, dichloroethane, chlorobenzene, chloroform, ethyl acetate, ethanol, methanol or tert-butanol.

6. The tetrahydrodibenzo[ b , g ][1,8]naphthyridin-1-one compound according to claim 2, wherein The molar feed ratio of the 3-haloquinoline-2-α,β unsaturated carbonyl compound to the base is 1:1~3:1~3.

7. The tetrahydrodibenzo[ b , g ][1,8]naphthyridin-1-one compound for use in the preparation of an antitumor drug for inhibiting human colon cells H-29 and human non-small cell lung cancer A549.

Images