A kind of triphenylene derivatives and its modular synthesis method and application in preparation of anticancer drugs

Abstract

The application discloses a kind of benzo phenanthridine ketone derivatives and modular synthesis method and application in preparation anticancer drug, belong to the technical field of organic chemistry and pharmaceutical chemistry technology cross technology.This application uses cobalt / copper composite catalytic system, by two-step carbon hydrogen bond activation strategy, first realizes halogen retention carbon hydrogen bond activation cyclization reaction, further utilizes the halogen site of retention and carries out modular derivative modification, and quickly constructs a variety of substituted benzo phenanthridine ketone derivative library.The method significantly improves the synthesis efficiency and atom economy, provides efficient, flexible and reliable path for the construction of benzo phenanthridine alkaloid derivatives.The obtained derivative shows good activity in anti-hepatocarcinoma Huh-7 cell activity screening, and the activity of compound 47 is better (IC50=39.4 μM), which provides a new active molecular skeleton and potential target for the development of hepatocarcinoma treatment drugs.

Description

Technical Field

[0001] This invention belongs to the interdisciplinary field of organic chemistry and medicinal chemistry, and particularly relates to a benzophenanthridine ketone derivative, its modular synthesis method, and its application in the preparation of anticancer drugs. Background Technology

[0002] Benzophenidone alkaloids, as a class of natural product derivatives with excellent biological activity, are an important and promising backbone for anticancer drugs, showing great promise for research and development. However, the synthesis of these compounds in current technologies is generally hampered by cumbersome steps, complex processes, and low yields, making it difficult to achieve large-scale and modular preparation, thus limiting their application in drug screening and structural modification. Although C-H bond activation strategies have been used in the construction of heterocyclic compounds, there is still no technical solution that combines two-step C-H bond activation with pharmacophore-directing groups for the efficient synthesis of these derivatives; furthermore, research on structural modification of the critical sites at positions 11 and 12 of benzophenidone derivatives is also relatively scarce.

[0003] While halogen retention strategies are highly attractive, their application in the cyclization of haloalkynes faces significant chemoselectivity challenges. To date, there are few reports of achieving halogenated cyclization of the CH bonds in haloalkynes (especially brominated alkynes) while retaining the halogen atom. In recent years, the Pablo Barrio group at the University of Oviedo, Spain, and others have developed gold-catalyzed intramolecular cyclization reactions of haloalkynes. Through the π-Lewis acidic activation of the alkyne bond by a gold (I) catalyst, intramolecular nucleophiles (such as alkenes, aromatic rings, and C(sp³)-H bonds) are activated to construct halogenated polycyclic skeletons; however, this method requires expensive catalysts. Furthermore, research on the activity of these compounds in anti-liver cancer is still limited, and the lack of highly active candidate molecules that can be directly used for drug development has become a significant technical bottleneck in their transformation into anticancer drugs. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention proposes a benzo[a]phenanthrone derivative, its modular synthetic method, and its application in the preparation of anticancer drugs. This invention addresses the issues of complex, inefficient, and structurally unsustainable synthetic routes for benzo[a]phenanthrone compounds by proposing a modular synthetic method based on a two-step C-H bond activation. First, it achieves a cobalt-catalyzed, halogen-retaining C-H bond activation reaction. Second, it enables the rapid construction of various substituted benzo[a]phenanthrone derivatives, providing a reliable pathway for the construction of a benzo[a]phenanthrone alkaloid derivative library. Furthermore, this invention provides the application of the benzo[a]phenanthrone derivatives prepared by this method in the development of anti-hepatocellular carcinoma Huh-7 cell drugs. Through screening, candidate compounds with good anti-hepatocellular carcinoma activity are obtained, providing new ideas, active molecular skeletons, and potential targets for the development of hepatocellular carcinoma therapeutic drugs.

[0005] To achieve the above objectives, the present invention provides the following technical solution: A benzophenanthridine ketone derivative has the following structural formula: , , , , or .

[0006] A modular synthetic method for benzophenanthridine ketone derivatives includes the following steps: (1) Using a cobalt / copper composite catalytic system, under the action of an oxidant, N-(quinoline-8-yl)benzamide compounds undergo carbon-hydrogen bond activation cyclization reaction with halogen-substituted aryl alkynes, retaining the halogen and generating halogen-containing benzophenanthrene ketone intermediates; (2) Using the halogen-containing benzophenanthrene ketone intermediate as a general intermediate, and utilizing its retained halogen active sites, react with the modified reactants to carry out modular derivatization modification, thereby obtaining the benzophenanthrene ketone derivative. The modified reactants are selected from 2-butyne, carbon monoxide, or 1,4-dimethoxy-2-butyne.

[0007] Beneficial Effects: This invention utilizes a cobalt / copper composite catalytic system to achieve halogen-retaining C-H bond activation, yielding a halogen-containing intermediate. Then, benzo[a]pyridone derivatives are prepared through further C-H bond activation reactions. Specifically, this invention innovatively develops a C-H bond activation reaction between aromatic haloalkynes and benzamide compounds with bioactive directing groups, preparing a halogen-containing intermediate in one step. Further C-H bond activation reactions are then used to prepare benzo[a]pyridone derivatives. This synthetic method enables the batch synthesis of benzo[a]pyridone derivatives, allowing for the editing of individual modules, such as replacing the core of a module with a bioactive heterocycle and its substituents.

[0008] In summary, this invention, through methodological innovation, enables controllable modification of key sites and expands the research on its antitumor activity, providing an important foundation for the study of the structure-activity relationship of this type of alkaloid and the subsequent development of anticancer drugs.

[0009] Optionally, the N-(quinolin-8-yl)benzamide compound is selected from any of the following structural formulas (1a-1v): .

[0010] Optionally, the halogen-substituted aryl alkynes are selected from any of the following structural formulas (2a-2s): .

[0011] Optionally, the molar ratio of the N-(quinoline-8-yl)benzamide compound to the halogenated aryl alkyne compound is 1:1.5.

[0012] Optionally, the cobalt / copper composite catalytic system is a complex of cobalt acetate and copper sulfate; The oxidant is sodium chlorate.

[0013] Optionally, the carbon-hydrogen bond activation cyclization reaction is carried out at a temperature of 80 °C for 3 h.

[0014] Optionally, when the modified reactant is 2-butyne, the specific reaction conditions are as follows: stirring at 110°C for 5 hours under the action of palladium catalyst and cesium carbonate base, followed by dilution, washing, drying, concentration, and purification by silica gel column chromatography to obtain the benzophenanthrene ketone derivative.

[0015] Optionally, when the modified reactant is carbon monoxide, the specific reaction conditions are as follows: under palladium catalyst and cesium neopentanoate base conditions, stirring at 110°C for 16 h, and then obtaining the benzophenanthridine ketone derivative after post-treatment and purification.

[0016] Optionally, when the modified reactant is 1,4-dimethoxy-2-butyne, the specific reaction conditions are as follows: stirring at 110°C for 5 hours under palladium catalyst and cesium carbonate base conditions, followed by post-treatment and purification to obtain the benzophenanthrene ketone derivative.

[0017] The application of the above-mentioned benzophenanthridine ketone derivatives in the preparation of anti-liver cancer drugs.

[0018] Compared with the prior art, the present invention has the following advantages and technical effects: This invention achieves a cobalt-catalyzed halogen-retaining C-H bond activation reaction. By constructing a two-step C-H bond activation reaction system, the synthetic route of benzo[a]phenanthrene ketone derivatives is significantly simplified. This improves atom economy and reaction efficiency while enabling rapid construction of diverse structures, and allows for flexible expansion using modules such as alkynes or carbon monoxide. The resulting compounds exhibit good antitumor activity in Huh-7 hepatocellular carcinoma cells, with compound 47 showing superior activity (IC50). 50 = 39.4 μM), showing potential value for drug development. Attached Figure Description

[0019] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 The structural formulas and corresponding yields of compounds 3-52 prepared in Example 1 of this invention are shown. Detailed Implementation

[0020] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0021] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0022] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0023] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0024] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0025] Unless otherwise specified, "room temperature" in this invention refers to 20-30℃.

[0026] All raw materials used in this invention were commercially available. The human liver cancer cells mentioned in this invention are Huh-7 liver cancer cells, obtained from Qisai Biotechnology (Wuhan) Co., Ltd. Cells were suspended in a complete culture medium containing 10% fetal bovine serum, seeded into culture dishes, gently mixed by pipetting, and cultured at 37 ℃ and 5% CO2 saturated humidity. Unless otherwise specified, all reagents used in this invention can be purchased commercially. DMEM culture medium was purchased from Shanghai Xiaopeng Biotechnology Co., Ltd.; fetal bovine serum and penicillin-streptomycin double antibiotic solution (100×) were purchased from Qisai Biotechnology (Wuhan) Co., Ltd.; phosphate-buffered saline (PBS) was purchased from Cytiva; and the CCK-8 (Cell Counting Kit-8) reagent kit was purchased from Shanghai Beyotime Biotechnology Co., Ltd.

[0027] The technical solution of the present invention will be further illustrated by the following embodiments.

[0028] Example 1 I. (1) Synthesis of raw material N-(quinoline-8-yl)benzamide (1a-1v) (the spheres represent the substituents on number 1a-1v in the figure) Aryl carboxylic acid (1.5 eq) and 8-aminoquinoline (1.0 eq) were added to 5 mL of DMF solution, followed by HATU (1-[(1-(dimethylamino)ethyl)-1H-1,2,3-triazol-5-yl]-1H-1,2,3-triazol-6-amine hexafluorophosphate) (1.2 eq) and DIEA (N,N-diisopropylethylamine, 3.0 eq). The reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the solution was diluted with 50 mL of EA (ethyl acetate), washed three times with 150 mL of saturated sodium chloride, and then concentrated and column filtered.

[0029] (2) Synthesis of halogen-substituted aryl alkynes (2a-2s) Arylalkyne was added to acetone solution, followed by silver nitrate (5 mol%), NBS (N-bromosuccinimide) or NCS (N-chlorosuccinimide) (1.5 equiv.), and reacted at room temperature for 5 hours. After the reaction was completed, the mixture was extracted with 50 mL of DCM (dichloromethane), washed once with 50 mL of saturated sodium chloride solution, and then concentrated and filtered through a column.

[0030] II. Synthetic methods of benzopyridone derivatives Step A. First-step synthetic method for halogen-containing intermediates (compounds 3-46) of benzopyridone derivatives: Add the following sequentially to a 10 mL Schlenk tube equipped with a magnetic stir bar: N -(quinoline-8-yl)benzamide compounds 1a-1v (0.30 mmol), halogenated aryl alkynes 2a-2s (0.45 mmol, 1.5 equivalents), cobalt acetate Co(OAc)2 (0.06 mmol, 20 mol%), copper sulfate CuSO4 (0.09 mmol, 30 mol%), sodium chlorate NaClO3 (0.60 mmol, 2.0 equivalents), ligands (0.06 mmol, 20 mol%), and 2,2,2-trifluoroethanol (TFE, 4.0 mL). The resulting mixture was stirred in air at 80 °C for 3 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to give the corresponding product 3-46.

[0031] 2. A second-step modular derivatization method for benzopyridone derivatives Using the halogen-containing intermediates (compounds 43-46) prepared in the first step as raw materials, modular derivatization was achieved through three specific reaction pathways to obtain a series of benzo[a]pyridone derivatives (compounds 47-52). The specific pathways are as follows: Step B. Reaction with 2-butyne to prepare compounds 47-50: Under a nitrogen atmosphere, halogenated intermediate (0.20 mmol), 2-butyne (0.80 mmol), tetrakis(triphenylphosphine)palladium Pd(PPh3)4 (0.01 mmol), cesium carbonate Cs2CO3 (0.60 mmol), and [other components] were added sequentially to a 10 mL Schlenk tube equipped with a magnetic stirrer. N , N - Dimethylformamide (DMF) (4.0 mL). The mixture was stirred at 110 °C for 5 hours. The reaction solution was diluted with ethyl acetate (20 mL) and washed with saturated sodium chloride solution (3 × 60 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50 °C, and the residue was purified by silica gel column chromatography to give the corresponding product 47-50.

[0032] Step C. Reaction with carbon monoxide to prepare compound 52: Under a carbon monoxide atmosphere, halogenated intermediate 46 (0.20 mmol), dichlorobis(tricyclohexylphosphine)palladium Pd(PCy3)2Cl2 (0.01 mmol), cesium neopentanoate CsOPiv (3.0 equiv.), and [other components] were added to a 10 mL Schlenk tube equipped with a magnetic stirrer. N , N - Dimethylformamide (DMF) (4.0 mL). The mixture was stirred at 110 °C for 16 hours. The resulting mixture was diluted with ethyl acetate (20 mL) and washed with saturated sodium chloride solution (3 × 60 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50 °C, and the residue was purified by silica gel column chromatography to give the corresponding product 52.

[0033] Step D. Reaction with 1,4-dimethoxy-2-butyne to prepare compound 51: Under nitrogen protection, halogenated intermediate 46 (0.20 mmol), 1,4-dimethoxy-2-butyne (0.80 mmol), bis(triphenylphosphine)palladium dichloride PdCl2(PPh3)2 (0.01 mmol), cesium carbonate Cs2CO3 (0.60 mmol), and other halogenated intermediates were added sequentially to a 10 mL Schlenk tube equipped with a magnetic stirrer. N , N - Dimethylformamide (DMF) (4.0 mL). The mixture was stirred at 110 °C for 5 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated sodium chloride solution (3 × 60 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50 °C, and the residue was purified by silica gel column chromatography to give the corresponding product 51.

[0034] The data characterization of the compounds mentioned above is as follows: 4-Bromo-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(3) Following procedure A, using 1a (74.4 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain colorless solid 3 (80.7 mg, 63%).

[0035] 1 H NMR (600 MHz, CDCl3): δ = 8.90 (d,J = 3.6 Hz, 1H), 8.53 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.2, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 7.3, 1H), 7.40–7.35 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5,1H), 6.91 (d, J = 7.8 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 162.4, 151.0, 144.5, 143.0, 137.5, 136.4, 136.2, 136.1, 133.6, 130.9, 130.1, 129.0, 129.0, 128.9, 128.8, 128.5, 127.8, 127.5, 127.3, 126.9, 126.0, 125.8, 121.8, 102.3. HR-MS (ESI): m / z calcd for C 24 H 15 BrN2O [M+Na] + 449.0261, 451.0240, found449.0260, 451.0239. 4-Bromo-2-(5-methoxyquinoline-8-yl)-3-phenylisoquinoline-1(2 H )-Ketone(4) Following procedure A, using 1b (84.0 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain colorless solid 4 (89.1 mg, 65%).

[0036] 1 H NMR (600 MHz, CDCl3): δ = 8.87 (dd, J = 4.1, 1.8 Hz, 1H), 8.52 (dd, J =8.0, 1.4 Hz, 1H), 8.45 (dd, J = 8.4, 1.8 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.81(ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.38–7.32 (m, 2H), 7.24 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.95(d, J = 7.6 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 3.92 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 162.7, 155.4, 151.1, 144.8, 143.5, 136.5, 133.5, 131.0, 130.8, 130.1, 130.0, 128.9, 128.9, 128.4, 127.7, 127.5, 127.4, 126.8, 126.0, 121.1, 120.8, 103.4, 102.1, 55.9. HR-MS (ESI): m / z calcd for C 25 H 17 BrN2O2[M+Na] +479.0366, 481.0346, found479.0364, 481.0346. 4-Bromo-2-(5-nitroquinoline-8-yl)-3-phenylisoquinoline-1(2 H )-Ketone(5) Following procedure A, using 1c (88.0 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a pale yellow solid 5 (77.9 mg, 55%).

[0037] 1 H NMR (600 MHz, CDCl3): δ = 8.99 (dd, J = 4.1, 1.6 Hz, 1H), 8.92 (dd, J =8.8, 1.6 Hz, 1H), 8.49 (dd, J = 8.0, 1.4 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.14(d, J = 7.9 Hz, 1H), 7.87 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.68–7.61 (m, 2H),7.59 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 6.8 Hz, 1H), 7.21 (td, J = 7.6, 1.3 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.82 (td, J = 7.6, 1.3 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ= 162.2, 152.0, 145.3, 144.5, 143.6, 141.9, 136.3, 135.5, 134.0, 132.3, 130.0, 129.5, 129.1, 129.0, 128.7, 128.2, 128.0, 127.7, 127.1, 125.7, 124.5, 124.1, 121.9, 102.9. HR-MS (ESI): m / z calcd for C 24 H 14 BrN3O3[M+Na] + 494.0111, 496.0091, found494.0109, 496.0092. 4-Bromo-6-methyl-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(6) Following procedure A, using 1d (78.6 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain colorless solid 6 (80.7 mg, 61%).

[0038] 1 H NMR (600 MHz, CDCl3): δ = 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (d, J = 8.2Hz, 1H), 8.05 (dd, J = 8.3, 1.7 Hz, 1H), 7.90 (s, 1H), 7.66 (dd, J = 8.2, 1.4 Hz, 1H), 7.46 (dd, J = 7.3, 1.4 Hz, 1H), 7.41 (dd, J = 8.2, 1.6 Hz, 1H), 7.40–7.34(m, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.90 (d, J= 7.8 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 2.59 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 162.4, 151.0, 144.5, 144.4, 142.9, 137.6, 136.4, 136.3, 136.2, 130.9, 130.1, 129.3, 129.0, 128.9, 128.8, 128.4, 127.5, 127.3, 126.7, 125.8, 123.8, 121.7, 102.2, 22.3. HR-MS (ESI): m / z calcd for C 25 H 17 BrN2O [M+H] + 441.0597, 443.0577, found441.0598, 443.0579. 4-Bromo-6-methoxy-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(7) Following procedure A, using 1e (83.4 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain colorless solid 7 (91.9 mg, 67%).

[0039] 1 H NMR (600 MHz, CDCl3): δ = 8.90 (dd, J = 4.2, 1.7 Hz, 1H), 8.43 (d, J = 8.3Hz, 1H), 8.05 (dd, J = 8.3, 1.7 Hz, 1H), 7.66 (dd, J = 8.3, 2.5 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.46 (dd, J = 7.2, 1.4 Hz, 1H), 7.39–7.35 (m, 2H), 7.23 (d, J=7.8 Hz, 1H), 7.18–7.12 (m, 2H), 7.01 (tt, J = 7.5, 1.4 Hz, 1H), 6.90 (dt, J =7.8, 1.5 Hz, 1H), 6.76 (td, J = 7.6, 1.3 Hz, 1H), 4.00 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 164.0, 162.1, 151.0, 144.5, 143.7, 138.6,137.6, 136.3, 136.1, 131.1, 131.0, 130.0, 129.0, 128.9, 128.8, 128.5, 127.5,127.3, 125.8, 121.7, 119.7, 116.9, 108.5, 102.0, 55.8. HR-MS (ESI): m / z calcd for C 25 H 17 BrN2O2[M+H] + 457.0546, 459.0526, found457.0548, 459.0526. 4-Bromo-6-(methylthio)-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(8) Following procedure A, using 1f (88.2 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a pale yellow solid 8 (63.9 mg, 45%).

[0040] 1 H NMR (600 MHz, CDCl3): δ = 8.90 (d, J = 4.1 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.86 (s, 1H), 7.67 (d, J= 8.2 Hz, 1H), 7.46 (d, J =7.2 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.40–7.34 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 2.64 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 162.2, 151.0, 146.7, 144.4, 143.8, 137.5, 136.8, 136.2, 131.0, 130.0, 129.1, 129.0, 128.9, 128.8, 128.5, 127.6, 127.3, 125.8, 125.3, 122.7, 121.9, 121.8, 101.7, 15.1. HR-MS (ESI): m / z calcd for C 25 H 17 BrN2OS [M+H] + 473.0318, 475.0298, found473.0319, 475.0299. 6-Amino-4-bromo-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(9) Following procedure A, using 1 g (78.9 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain colorless solid 9 (49.1 mg, 37%).

[0041] 1 H NMR (600 MHz, CDCl3): δ = 8.91 (d, J = 3.8 Hz, 1H), 8.29 (d,J = 8.6 Hz, 1H), 8.07 (d, J = 7.1 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H),7.41–7.34 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.14 (t, J =7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.85 (dd, J = 8.6, 2.2 Hz, 1H), 6.75 (t, J = 7.7 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 162.2, 151.6, 150.8, 143.2, 138.4, 137.6, 136.5, 131.3, 131.0, 130.1, 128.9, 128.9, 128.4, 127.5, 127.3, 125.9, 121.7, 117.4, 116.2, 109.2, 102.0. HR-MS (ESI): m / z calcd for C 24 H 16 BrN3O [M+H] + 442.0550, 444.0530, found442.0551, 444.0530. 5-Bromo-6-fluoro-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(10) Following procedure A, using 1h (79.8 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain 10 (72.1 mg, 54%) of colorless solid.

[0042] 1 H NMR(600 MHz, CDCl3): δ = 8.90 (dd, J = 4.1, 1.7 Hz, 1H), 8.53 (dd, J =8.8, 5.8 Hz, 1H), 8.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.77 (dd, J = 10.3, 2.5 Hz,1H), 7.68 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.43–7.33 (m, 2H), 7.28(td, J = 8.5, 2.5 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.02(t, J = 7.4 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H). 13 C NMR(150 MHz, CDCl3): δ = 166.3 (d, 1 J C– F = 253.3 Hz), 161.8, 151.1,144.5, 144.3, 139.2, 139.1, 137.3, 136.2, 135.9, 132.3 (d, 3 J C–F = 10.1 Hz),130.9, 129.9, 129.2, 128.9, 128.7 (d, 3 J C–F = 10.5 Hz), 127.6, 127.4, 125.9,122.5 (d, 4 J C–F = 1.6 Hz), 121.9, 116.3 (d, 2 J C–F= 23.4 Hz), 112.6 (d, 2 J C–F = 24.9Hz), 101.2 (d, J = 3.1 Hz). 19 F NMR (565 MHz, CDCl3): δ = -104.41. HR-MS (ESI): m / z calcd for C 24 H 14 BrFN2O [M+H] + 445.0346, 447.0326, found445.0346, 447.0325. 4-Bromo-6-chloro-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(11) Following procedure A, using 1i (84.6 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain colorless solid 11 (77.6 mg, 56%).

[0043] 1 H NMR (600 MHz, CDCl3): δ = 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (d, J = 8.5Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.68 (dd, J =8.2, 1.4 Hz, 1H), 7.53 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 (dd, J = 7.3, 1.4 Hz, 1H),7.41–7.35 (m, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.02 (t, J=7.5 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.77 (t, J = 8.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 161.8, 151.1, 144.4, 144.3, 140.4, 137.8, 137.2, 136.2, 135.9, 130.8, 130.7, 129.9, 129.2, 128.8, 128.7, 128.7, 128.3, 127.6, 127.4, 126.5, 125.8, 124.3, 121.8, 100.9. HR-MS (ESI): m / z calcd for C 24 H 14 BrClN2O [M+H] + 461.0051, 463.0031, found461.0053, 463.0031. 4,6-Dibromo-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2 H )-Ketone(12) Following procedure A, using 1j (97.8 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain colorless solid 12 (82.0 mg, 54%).

[0044] 1 H NMR (600 MHz, CDCl3): δ = 8.87 (d, J = 4.3, 1.6 Hz, 1H), 8.36 (d, J = 8.5Hz, 1H), 8.30 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.70–7.64 (m, 2H), 7.46 (d, J =7.0 Hz, 1H), 7.39–7.34 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.15 (t, J= 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 162.0, 151.0, 144.7, 144.6, 138.1, 137.6, 136.1, 136.1, 131.1, 130.9, 130.7, 130.0, 129.7, 129.1, 129.1, 129.1, 129.0, 128.7, 127.6, 127.3, 125.8, 125.0, 121.8, 100.5. HR-MS (ESI): m / z calcd for C 24 H 14 Br2N2O [M+H] + 504.9546, 506.9526, found504.9547, 506.9526. 4-Bromo-6-iodo-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(13) Following procedure A, using 1k (112.2 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain a pale yellow solid 13 (96.2 mg, 58%).

[0045] 1 H NMR (600 MHz, CDCl3): δ = 8.89 (dd, J = 4.3, 1.8 Hz, 1H), 8.50 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.45 (d, J= 7.0 Hz, 1H), 7.41–7.35 (m, 2H), 7.22 (d, J = 7.7Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 162.2, 151.0, 144.5, 137.9, 137.5, 136.9, 136.2, 136.1, 135.9, 131.0, 130.3, 130.0, 129.1, 129.0, 128.7, 127.6, 127.4, 125.8, 125.5, 121.8, 101.6, 100.3. HR-MS (ESI): m / z calcd for C 24 H 14 BrIN2O [M+H] + 552.9407, 554.9387, found552.9408, 554.9386. 4-Bromo-3-phenyl-2-(quinolin-8-yl)-6-(trifluoromethyl)isoquinolin-1(2) H )-Ketone(14) Following procedure A, using 1L (94.8 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain colorless solid 14 (98.0 mg, 66%).

[0046] 1 H NMR (600 MHz, CDCl3): δ = 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.64 (d, J = 8.3Hz, 1H), 8.40 (s, 1H), 8.07 (dd, J= 8.3, 1.7 Hz, 1H), 7.80 (dd, J = 8.3, 1.7 Hz,1H), 7.69 (dd, J = 8.3, 1.4 Hz, 1H), 7.47 (dd, J = 7.3, 1.4 Hz, 1H), 7.43–7.35(m, 2H), 7.24 (dt, J = 8.1, 1.6 Hz, 1H), 7.18 (td, J = 7.6, 1.3 Hz, 1H), 7.04(tt, J = 7.5, 1.3 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.78 (td, J = 7.7, 1.3 Hz,1H). 13 C NMR(150 MHz, CDCl3): δ = 161.6, 151.1, 144.6, 144.2, 137.1, 136.8,136.2, 135.7, 135.2 (q, 2 J = 32.6 Hz), 130.7, 130.0, 129.9, 129.3, 128.9,128.8, 128.7, 128.2, 127.7, 127.4, 125.8, 124.5 (q, 3 J = 4.2 Hz), 123.8 (q, 1 J =273.3 Hz), 123.8 (q, 3 J = 3.4 Hz), 121.9, 101.5. 19 F NMR(565 MHz, CDCl3): δ = -62.90. HR-MS(ESI): m / z calcd for C 25 H 14 BrF3N2O [M+H] + 495.0314, 497.0294, found495.0316, 497.0294. 4-Bromo-6-nitro-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(15) Following procedure A, using 1m (87.9 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 15 (56.6 mg, 40%) of pale yellow solid.

[0047] 1 H NMR (400 MHz, d 6-DMSO): δ = 8.21 (dd, J = 4.3, 1.7 Hz, 1H), 8.12 (d, J =2.3 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.2Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 6.85 (dd, J = 8.3, 4.3Hz, 1H), 6.80 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 6.53 (t, J = 7.6 Hz, 1H), 6.38 (t, J = 7.6 Hz, 1H), 6.13 (dt, J = 13.8, 7.7 Hz, 2H). 13 C NMR (101 MHz, d 6-DMSO): δ = 159.8, 150.7, 150.7, 145.7, 143.2, 136.4, 136.1, 136.0, 134.9, 130.8, 130.4, 129.5, 128.9, 128.7, 128.5, 128.0, 127.7, 127.4, 126.8, 125.4, 121.7, 121.3, 121.3, 99.1. HR-MS (ESI): m / z calcd for C 24 H 14 BrN3O3[M+H] + 472.0291, 474.0271, found472.0291, 474.0273. 4-Bromo-1-oxo-3-phenyl-2-(quinolin-8-yl)-1,2-dihydroisoquinolin-6-carboxynitrile (16) Following procedure A, using 1n (81.9 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain colorless solid 16 (70.5 mg, 52%).

[0048] 1 H NMR (600 MHz, CDCl3): δ = 8.88 (d, J = 4.2 Hz, 1H), 8.60 (d, J = 8.2 Hz,1H), 8.46 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.70 (d, J =8.2 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.42–7.36 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ= 161.3, 151.2, 145.3, 144.1, 136.9, 136.2,135.5, 131.8, 130.6, 130.0, 129.8, 129.6, 129.4, 128.9, 128.9, 128.7, 128.4,127.7, 127.5, 125.9, 122.0, 118.3, 117.2, 100.6. HR-MS (ESI): m / z calcd for C 25 H 14 BrN3O [M+Na] + 474.0212, 476.0192, found474.0214, 476.0194. 4-Bromo-1-oxo-3-phenyl-2-(quinolin-8-yl)-1,2-dihydroisoquinoline-6-carboxylic acid methyl ester (17) Following procedure A, using 1o (91.8 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain colorless solid 17 (72.8 mg, 50%).

[0049] 1 H NMR (600 MHz, CDCl3): δ = 8.91 (d, J = 4.0 Hz, 1H), 8.79 (d, J = 1.6 Hz, 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.20 (dd, J = 8.2, 1.6 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.48 (dd, J = 7.4, 1.3 Hz, 1H), 7.44–7.36 (m, 2H), 7.24 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.93(d, J= 7.6 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 4.03 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 166.5, 161.9, 150.9, 143.8, 137.0, 136.5, 135.9, 134.6, 131.1, 130.0, 129.3, 129.2, 128.9, 128.8, 128.8, 128.7, 127.9, 127.6, 127.5, 126.1, 121.9, 102.3, 52.8. HR-MS (ESI): m / z calcd for C 26 H 17 BrN2O3[M+H] + 485.0495, 487.0475, found485.0496, 487.0476. 6-Acetyl-4-bromo-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(18) Following procedure A, using 1p (87.0 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain colorless solid 18 (77.4 mg, 55%).

[0050] 1 H NMR (600 MHz, CDCl3): δ = 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (d, J = 1.6Hz, 1H), 8.59 (d, J = 8.3 Hz, 1H), 8.11 (dd, J = 8.3, 1.6 Hz, 1H), 8.07 (dd, J =8.3, 1.6 Hz, 1H), 7.69 (dd, J = 8.2, 1.4 Hz, 1H), 7.47 (dd, J= 7.3, 1.4 Hz, 1H),7.43–7.34 (m, 2H), 7.25 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.03 (t, J =7.5 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.78 (td, J = 7.6, 1.3 Hz, 1H), 2.80 (s,3H). 13 C NMR (150 MHz, CDCl3): δ = 197.9, 161.8, 151.1, 144.2, 144.0, 140.8, 137.2, 136.6, 136.3, 135.8, 130.8, 130.0, 129.6, 129.2, 128.9, 128.8, 128.7, 127.6, 127.6, 127.4, 126.4, 125.9, 121.9, 102.2, 27.3. HR-MS (ESI): m / z calcd for C 26 H 17 BrN2O2[M+H] + 469.0546, 471.0526, found469.0547, 471.0526. 4-Bromo-1-oxo-3-phenyl-2-(quinolin-8-yl)-1,2-dihydroisoquinolin-6-carboxaldehyde (19) Following procedure A, using 1q (82.8 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain colorless solid 19 (62.8 mg, 46%).

[0051] 1 H NMR (600 MHz, CDCl3): δ = 10.28 (s, 1H), 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.65 (d, J = 8.1 Hz, 1H), 8.60 (d,J = 1.5 Hz, 1H), 8.11–8.03 (m, 2H), 7.70 (dd, J = 8.3, 1.4 Hz, 1H), 7.48 (dd, J = 7.3, 1.4 Hz, 1H), 7.45–7.37 (m, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.18 (td, J = 7.6, 1.3 Hz, 1H), 7.04 (tt, J = 7.5, 1.3 Hz, 1H), 6.90 (dt, J = 7.5, 1.5 Hz, 1H), 6.78 (td, J = 7.6, 1.3 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 192.0, 161.8, 151.1, 144.4, 144.2, 139.7, 137.1, 137.1, 136.2, 135.7, 130.7, 130.4, 130.0, 129.9, 129.6, 129.3, 128.9, 128.8, 128.8, 127.7, 127.4, 126.3, 125.9, 121.9, 101.8. HR-MS (ESI): m / z calcd for C 25 H 15 BrN2O2[M+H] + 455.0390, 457.0370, found455.0390, 457.0371. 4-Bromo-6,7-dimethoxy-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2H)-one (20) Following procedure A, using 1r (92.4 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain colorless solid 20 (58.4 mg, 40%).

[0052] 1 H NMR (600 MHz, CDCl3):δ = 8.90 (dd, J = 4.3, 1.7 Hz, 1H), 8.06 (dd, J =8.3, 1.7 Hz, 1H), 7.92 (s, 1H), 7.66 (dd, J = 8.2, 1.4 Hz, 1H), 7.49 (s, 1H), 7.44 (dd, J = 7.3, 1.3 Hz, 1H), 7.40–7.33 (m, 2H), 7.25 (d, J = 7.1 Hz, 1H), 7.16(t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.76 (t, J =7.6 Hz, 1H), 4.09 (s, 3H), 4.01 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 161.7, 154.3, 151.1, 149.8, 144.6, 141.5, 137.8, 136.3, 136.1, 131.9, 130.8, 130.3, 129.0, 128.9, 128.8, 128.4, 127.5, 127.3, 125.8, 121.7, 119.6, 108.8, 107.6, 101.9, 56.4, 56.4. HR-MS (ESI): m / z calcd for C 26 H 19 BrN2O3[M+H] + 487.0652, 489.0632, found487.0653, 489.0633. 4-Bromo-8-methoxy-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(21) Following procedure A, using 1s (83.4 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain colorless solid 21 (76.8 mg, 56%).

[0053] 1 H NMR (600 MHz, CDCl3): δ = 8.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.03 (d, J = 8.2Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 7.1 Hz, 1H), 7.38–7.32 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.14(t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.94 (d, J =7.6 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 3.95 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 161.7, 160.8, 150.9, 143.9, 139.2, 137.9, 136.5, 136.1, 134.1, 131.2, 129.9, 128.8, 128.8, 128.7, 128.4, 127.5, 127.2, 125.8, 121.6, 119.1, 115.4, 109.5, 101.6, 56.4. HR-MS (ESI): m / z calcd for C 25 H 17 BrN2O2[M+H] +457.0546, 459.0526, found457.0546, 459.0525. 5-Bromo-5-phenyl-6-(quinolin-8-yl)furano[2,3-c]pyridine-7(6) H )-Ketone(22) Following procedure A, using 1t (71.4 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:2:1) to obtain colorless solid 22 (65.1 mg, 52%).

[0054] 1 H NMR (600 MHz, CDCl3): δ = 8.90 (dd, J = 4.2, 1.6 Hz, 1H), 8.05 (dd, J =8.4, 1.7 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 8.2, 1.4 Hz, 1H), 7.46(dd, J = 7.3, 1.4 Hz, 1H), 7.40–7.35 (m, 2H), 7.17 (d, J = 7.8 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.01 (tt, J = 7.5, 1.4 Hz, 1H), 6.90–6.83 (m, 2H), 6.76 (t, J =7.6 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 153.4, 151.1, 148.6, 144.3, 143.4, 142.1, 136.8, 136.2, 135.2, 135.0, 131.1, 130.2, 129.3, 129.1, 128.9, 128.6, 127.6, 127.3, 125.8, 121.8, 108.8, 94.6. HR-MS (ESI): m / z calcd for C 22 H13 BrN2O2[M+H] + 417.0233, 419.0213, found417.0235, 419.0213. 7-Bromo-6-phenyl-5-(quinolin-8-yl)furano[3,2-c]pyridine-4(5 H )-Ketone(23) Following procedure A, using 1u (71.4 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:2:1) to obtain colorless solid 23 (50.0 mg, 40%).

[0055] 6 (dd, J = 8.2, 1.6 Hz, 1H), 7.68 (dd, J = 8.2, 1.4 Hz, 1H), 7.65 (d, J =2.1 Hz, 1H), 7.44 (dd, J = 7.4, 1.4 Hz, 1H), 7.41–7.35 (m, 2H), 7.19 (dt, J =7.8, 1.6 Hz, 1H), 7.17–7.12 (m, 2H), 7.02 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 7.7Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 159.3, 157.4, 151.1, 144.9, 144.4, 144.0, 137.2, 136.2, 134.5, 131.0, 130.1, 129.2, 129.0, 128.8, 128.8, 127.6, 127.4, 125.8, 121.8, 115.7, 109.1, 89.6. HR-MS (ESI): m / z calcd for C 22 H 13 BrN2O2[M+H] +417.0233, 419.0213, found417.0234, 419.0213. 4-Bromo-3-phenyl-2-(quinolin-8-yl)-2,6-naphthidine-1(2 H )-Ketone(24) Following procedure A, using 1v (74.7 mg, 0.30 mmol) and 2a (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 24 (32.1 mg, 25%) of colorless solid.

[0056] 1 H NMR (600 MHz, CDCl3): δ = 9.51 (s, 1H), 8.88 (dd, J = 4.2, 1.7 Hz, 1H),8.84 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.07 (dd, J = 8.3, 1.7 Hz, 1H), 7.69 (dd, J = 8.2, 1.4 Hz, 1H), 7.45 (dd, J = 7.3, 1.4 Hz, 1H), 7.41–7.37 (m, 2H), 7.23(dt, J = 7.7, 1.6 Hz, 1H), 7.18 (td, J = 7.6, 1.3 Hz, 1H), 7.04 (tt, J = 7.5, 1.3Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.78 (td, J = 7.6, 1.3 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 161.3, 151.1, 150.3, 147.5, 144.8, 144.1, 136.9, 136.2, 135.2, 131.1, 130.6, 130.0, 129.4, 128.9, 128.9, 128.8, 127.7, 127.5, 125.8, 122.0, 120.2, 99.1. HR-MS (ESI): m / z calcd for C 23 H 14 BrN3O [M+Na] + 450.0212, 452.0192, found450.0212, 452.0193. 4-Chloro-3-phenyl-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(25) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2b (61.7 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain 25 (80.4 mg, 70%) of colorless solid.

[0057] 1 H NMR (600 MHz, CDCl3): δ = 8.90 (dd, J = 4.2, 1.7 Hz, 1H), 8.54 (dd, J =8.0, 1.4 Hz, 1H), 8.10 (dd, J = 8.2, 1.0 Hz, 1H), 8.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.85 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.68 (dd, J = 8.2, 1.4 Hz, 1H), 7.62 (t, J =7.6, 1H), 7.47 (dd, J = 7.3, 1.4 Hz, 1H), 7.41–7.35 (m, 2H), 7.26 (d, J = 7.6,1H), 7.16 (td, J = 7.6, 1.4 Hz, 1H), 7.02 (tt, J = 7.5, 1.3 Hz, 1H), 6.93 (dt, J =7.8, 1.6 Hz, 1H), 6.78 (td, J = 7.7, 1.3 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ = 162.2, 151.1, 144.5, 141.3, 137.3, 136.1, 135.6, 134.2, 133.4, 130.9, 130.2, 129.1, 129.0, 128.9, 128.9, 128.5, 127.8, 127.6, 127.4, 126.0, 125.8, 124.2, 121.8, 111.4. HR-MS (ESI): m / z calcd for C 24 H 15 ClN2O [M+Na] + 405.0765, 407.0736, found405.0765, 407.0735. 4-Bromo-2-(quinolin-8-yl)-3-(p-tolyl)isoquinolin-1(2) H )-Ketone(26) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2c (87.5 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain 26 (83.3 mg, 63%) of colorless solid.

[0058] 1 H NMR (600 MHz, CDCl3): δ = 8.89 (d, J = 3.8 Hz, 1H), 8.52 (d, J = 7.9 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H),7.41–7.35 (m, 2H), 7.13 (d, J = 7.8, 1H), 6.96 (d, J= 7.8 Hz, 1H), 6.78 (d, J =7.9, 1H), 6.57 (d, J = 7.9 Hz, 1H), 2.12 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 162.5, 151.0, 144.5, 143.1, 138.3, 137.7, 136.5, 136.1, 133.5, 133.3, 130.8, 130.0, 128.9, 128.9, 128.8, 128.7, 128.3, 128.0, 127.7, 126.9, 126.0, 125.9, 121.7, 102.5, 21.3. HR-MS (ESI): m / z calcd for C 25 H 17 BrN2O [M+Na] + 463.0416, 465.0396, found463.0416, 465.0396. 4-Bromo-3-(4-methoxyphenyl)-2-(quinolin-8-yl)isoquinolin-1(2 H )-Ketone(27) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2d (94.5 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 27 (60.3 mg, 44%) of colorless solid.

[0059] 1 H NMR (600 MHz, CDCl3): δ = 8.89 (dd, J = 4.1, 1.7 Hz, 1H), 8.51 (d, J = 7.9Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.07 (dd, J = 8.3, 1.7 Hz, 1H), 7.82 (t, J = 7.6Hz, 1H), 7.69 (dd, J= 8.2, 1.4 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.46 (dd, J =7.2, 1.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.37 (dd, J = 8.3, 4.1 Hz, 1H), 7.15(dd, J = 8.5, 2.3 Hz, 1H), 6.83 (dd, J = 8.6, 2.2 Hz, 1H), 6.68 (dd, J = 8.5, 2.7Hz, 1H), 6.29 (dd, J = 8.6, 2.7 Hz, 1H), 3.62 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 162.5, 159.3, 151.0, 144.5, 142.9, 137.7, 136.5, 136.2, 133.5, 131.4, 130.8, 130.3, 129.0, 128.9, 128.8, 128.7, 127.7, 126.9, 126.0, 125.9, 121.7, 112.9, 112.7, 102.9, 55.1. HR-MS (ESI): m / z calcd for C 25 H 17 BrN2O2[M+Na] + 479.0366, 481.0346, found479.0364, 481.0347. 4-Bromo-3-(4-methoxyphenyl)-2-(quinolin-8-yl)isoquinolin-1(2H)-one (28) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2e (101.0 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 28 (80.5 mg, 57%) of colorless solid.

[0060] 1H NMR(600 MHz, CDCl3, compound exists as a mixture of rotamers): δ =8.89 (td, J = 4.2, 1.6 Hz, 2H), 8.50 (d, J = 7.9 Hz, 2H), 8.12–8.08 (m, 4H), 7.82(td, J = 7.7, 1.4 Hz, 2H), 7.75–7.71 (m, 2H), 7.59 (t, J = 7.6 Hz, 2H), 7.48–7.41(m, 4H), 7.39 (dt, J = 7.9, 3.7 Hz, 2H), 6.75–6.67 (m, 2H), 6.60 (d, J = 8.0 Hz,1H), 6.43–6.37 (m, 2H), 6.20 (d, J = 8.1 Hz, 1H), 5.87 (s, 1H), 5.84 (s, 1H),5.76 (s, 1H), 5.67 (s, 1H). 13 C NMR(151 MHz, CDCl3): δ = 162.4, 151.2, 151.1, 147.5, 147.4, 146.9,146.6, 144.6, 144.4, 142.4, 142.4, 137.6, 137.5, 136.4, 136.4, 136.2, 136.2,133.6, 130.9, 130.6, 129.9, 129.7, 129.1, 129.1, 128.9, 128.9, 128.8, 127.8,126.9, 126.9, 126.0, 126.0, 125.9, 124.3, 123.1, 121.9, 121.8, 110.5, 109.8,107.6, 107.4, 102.9, 101.2, 101.0. HR-MS(ESI): m / z calcd for C 25 H 15 BrN2O3[M+Na] +493.0158, 495.0138, found493.0157, 495.0138. 3-([1,1'-biphenyl]-4-yl)-4-bromo-2-(quinolin-8-yl)isoquinolin-1(2 H )-Ketone(29) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2f (115.2 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain 29 (105.6 mg, 70%) of colorless solid.

[0061] 1 H NMR (600 MHz, CDCl3): δ = 8.92 (d, J = 4.0 Hz, 1H), 8.54 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.43–7.39 (m, 4H), 7.38 (d, J = 4.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 2H), 7.31 (t, J = 7.9Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ= 162.4, 151.1, 144.5, 142.8, 140.9, 140.1, 137.5, 136.5, 136.2, 135.1, 133.6, 130.9, 130.6, 129.4, 129.1, 128.9, 128.8, 128.8, 127.8, 127.7, 127.0, 126.9, 126.1, 126.0, 125.9, 125.8, 121.8, 102.4. HR-MS (ESI): m / z calcd for C 30 H 19 BrN2O [M+Na] + 525.0573, 527.0553, found525.0573, 527.0553. 4-Bromo-3-(4-fluorophenyl)-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(30) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2g (89.1 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain 30 (93.5 mg, 70%) of colorless solid.

[0062] 1 H NMR (600 MHz, CDCl3): δ = 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.52 (d, J = 8.0Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.3, 1.7 Hz, 1H), 7.83 (ddd, J =8.4, 7.2, 1.4 Hz, 1H), 7.71 (dd, J = 8.2, 1.5 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.38 (dd, J= 8.3, 4.1 Hz, 1H),7.21 (ddd, J = 8.2, 5.3, 2.3 Hz, 1H), 6.94 (ddd, J = 8.2, 5.4, 2.3 Hz, 1H), 6.84(td, J = 8.6, 2.7 Hz, 1H), 6.47 (td, J = 8.6, 2.7 Hz, 1H). 13 C NMR(150 MHz, CDCl3): δ = 162.4, 162.3 (d, 1 J C–F = 248.9 Hz), 151.1,144.3, 142.0, 137.4, 136.3, 136.2, 133.7, 132.2 (d, 4 J C–F = 3.7 Hz), 132.0 (d, 3 J C–F = 8.3 Hz), 131.1, 131.1 (d, 3 J C–F = 8.3 Hz), 129.2, 128.9, 128.8, 128.0,126.9, 126.1, 125.9, 121.9, 114.8 (d, 2 J C–F = 22.0 Hz), 114.5 (d, 2 J C–F = 21.6 Hz),102.7. 19 F NMR(565 MHz, CDCl3): δ = -111.91 (tq, J = 9.0, 5.3 Hz). HR-MS(ESI): calcd for C 24 H 14 BrFN2O [M+Na] + 467.0166, 469.0146, found467.0166, 469.0147. 4-Bromo-3-(4-chlorophenyl)-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(31) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2h (96.5 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain colorless solid 31 (99.8 mg, 72%).

[0063] 1 H NMR (600 MHz, CDCl3): m / z = 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.52 (d, J = 8.0Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.3, 1.7 Hz, 1H), 7.83 (t, J = 7.7Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (dd, J = 7.2, 1.4Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 8.3, 4.2 Hz, 1H), 7.17 (dd, J =8.3, 2.1 Hz, 1H), 7.13 (dd, J = 8.3, 2.2 Hz, 1H), 6.89 (dd, J = 8.3, 2.1 Hz, 1H), 6.76 (dd, J = 8.3, 2.2 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ= 162.3, 151.1, 144.4, 141.8, 137.3, 136.3, 136.3, 134.6, 134.5, 133.7, 131.5, 130.8, 130.5, 129.3, 129.0, 128.8, 128.0, 127.9, 127.7, 126.9, 126.1, 125.9, 121.9, 102.5. HR-MS (ESI): δ calcd for C 24 H 14 BrClN2O [M+Na] + 482.9870, 484.9850, found482.9867, 484.9848. 4-Bromo-3-(4-Bromophenyl)-2-(quinolin-8-yl)isoquinolin-1(2 H )-Ketone(32) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2i (116.0 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain a pale yellow solid 32 (112.3 mg, 74%).

[0064] 1 H NMR (600 MHz, CDCl3): m / z = 8.88 (dd, J = 4.1, 1.7 Hz, 1H), 8.51 (dd, J =8.0, 1.5 Hz, 1H), 8.13–8.07 (m, 2H), 7.83 (ddd, J = 8.4, 7.2, 1.5 Hz, 1H), 7.73(dd, J = 8.2, 1.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.52–7.45 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 8.3, 4.1 Hz, 1H ), 7.29 (dd, J = 8.2, 2.1 Hz, 1H), 7.11 (dd, J= 8.3, 2.0 Hz, 1H), 6.92 (dd, J = 8.3, 1.9 Hz, 1H), 6.83 (dd, J = 8.2, 2.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 162.3, 151.1, 144.4, 141.8, 137.3, 136.3, 136.3, 135.1, 133.7, 131.7, 130.9, 130.8, 130.8, 130.6, 129.4, 129.0, 128.9, 128.1, 126.9, 126.1, 125.9, 122.9, 121.9, 102.4. HR-MS (ESI): δ calcd for C 24 H 14 Br2N2O [M+Na] + 526.9365, 528.9345, found526.9364, 528.9344. 4-Bromo-2-(quinolin-8-yl)-3-(4-(trifluoromethyl)phenyl)isoquinolin-1-(2-) H )-Ketone(33) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2j (111.6 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3:1:1) to obtain colorless solid 33 (102.5 mg, 69%).

[0065] 1 H NMR (600 MHz, CDCl3): m / z = 8.89 (d, J = 4.2 Hz, 1H), 8.53 (d, J = 7.9 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.63 (t,J = 7.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.45–7.35 (m, 4H), 7.09 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 162.3, 151.2, 144.3, 141.5, 139.6, 137.1,136.3, 136.2, 133.8, 130.8, 130.5 (q, 2 J C–F = 32.7 Hz), 129.7, 129.5, 129.0,128.9, 128.2, 126.9, 126.1, 125.9, 124.6 (q, 3 J C–F = 3.8 Hz), 124.3 (q, 3 J C–F = 3.6Hz), 123.7 (q, 1 J C–F = 272.0 Hz), 122.8, 122.0, 102.3. 19 F NMR (565 MHz, CDCl3) δ -62.93. HR-MS (ESI): δ calcd for C 25 H 14 BrF3N2O [M+Na] + 517.0134, 519.0114, found517.0132, 519.0113. 4-(4-bromo-1-oxo-2-(quinolin-8-yl)-1,2-dihydroisoquinolin-3-yl)benzonitrile (34) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2k (93.0 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain a colorless solid 34 (81.4 mg, 60%).

[0066] 1 H NMR (600 MHz, CDCl3): m / z = 8.88 (dd, J = 4.0, 1.7 Hz, 1H), 8.52 (d, J = 7.9Hz, 1H), 8.13–8.06 (m, 2H), 7.85 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.73 (dd, J =8.2, 1.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 6.0 Hz, 1H), 7.45–7.38(m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 162.1, 151.2, 144.2, 140.9, 140.5, 136.9,136.4, 136.0, 133.8, 131.4, 131.1, 131.0, 130.9, 130.2, 129.6, 129.0, 128.9,128.4, 127.0, 126.2, 125.9, 122.1, 118.2, 112.4, 102.1. HR-MS (ESI): δ calcd for C 25 H 14 BrN3O [M+Na] + 474.0212, 476.0192, found474.0213, 476.0191. 4-Bromo-3-(4-nitrophenyl)-2-(quinolin-8-yl)isoquinolin-1(2 H )-Ketone(35) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2l (102.0 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 35 (85.0 mg, 60%) of colorless solid.

[0067] 1 H NMR (600 MHz, CDCl3): m / z = 8.90 (dd, J = 4.2, 1.7 Hz, 1H), 8.53 (d, J = 7.9Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.3, 1.7 Hz, 1H), 8.01 (dd, J =8.5, 2.4 Hz, 1H), 7.86 (ddd, J = 8.2, 7.9, 1.4 Hz, 1H), 7.72 (dd, J = 8.2, 1.4Hz, 1H), 7.68–7.62 (m, 2H), 7.52 (dd, J = 7.3, 1.4 Hz, 1H), 7.45–7.39 (m, 3H), 7.21 (dd, J = 8.5, 1.9 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ = 162.1, 151.3, 147.5, 144.2, 142.3, 140.6, 136.9, 136.4, 136.0, 133.9, 131.3, 130.9, 130.6, 129.7, 129.0, 128.9, 128.5, 127.0, 126.2, 126.0, 122.8, 122.6, 122.1, 102.2. HR-MS (ESI): δ calcd for C 24 H 14 BrN3O3[M+Na] +494.0111, 496.0091, found494.0112, 496.0091. Methyl 4-(4-bromo-1-oxo-2-(quinolin-8-yl)-1,2-dihydroisoquinolin-3-yl)benzoate (36) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2m (107.0 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 36 (107.7 mg, 74%).

[0068] 1 H NMR (600 MHz, CDCl3): m / z = 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.52 (dd, J =8.0, 1.4 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.05 (dd, J = 8.2, 1.7 Hz, 1H), 7.86–7.81 (m, 2H), 7.68 (dd, J = 8.2, 1.4 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.48 (dd, J = 7.3, 1.4 Hz, 1H), 7.46 (dd, J = 8.2, 1.8 Hz, 1H), 7.40–7.36 (m, 2H), 7.33(dd, J = 8.0, 1.8 Hz, 1H), 7.04 (dd, J = 8.1, 1.8 Hz, 1H), 3.80 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ= 166.5, 162.3, 151.2, 144.3, 141.9, 140.5, 137.2, 136.2, 136.2, 133.7, 130.8, 130.3, 130.0, 129.4, 129.3, 128.9, 128.9, 128.8, 128.6, 128.1, 126.9, 126.1, 125.9, 121.9, 52.3. HR-MS (ESI): δ calcd for C 26 H 17 BrN2O3[M+Na] + 507.0315, 509.0295, found507.0316, 509.0296. 3-(4-acetylphenyl)-4-bromo-2-(quinolin-8-yl)isoquinolin-1(2 H )-Ketone(37) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2n (100.0 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain a colorless solid 37 (85.8 mg, 61%).

[0069] 1 H NMR (600 MHz, CDCl3): m / z = 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.52 (d, J = 7.9Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.84 (t, J = 7.7Hz, 1H), 7.75 (dd, J = 8.0, 1.9 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 7.6Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.41–7.34 (m, 4H), 7.07 (dd, J= 8.1, 1.8 Hz,1H), 2.43 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 197.5, 162.2, 151.2, 144.3, 141.8, 140.6, 137.2, 136.6, 136.3, 136.2, 133.7, 130.8, 130.5, 129.5, 129.4, 128.9, 128.9, 128.1, 127.6, 127.3, 126.9, 126.1, 125.9, 121.9, 102.1, 26.6. HR-MS (ESI): calcd for C 26 H 17 BrN2O2[M+Na] + 491.0366, 493.0346, found491.0365, 493.0348. 5-(4-bromo-1-oxo-2-(quinolin-8-yl)-1,2-dihydroisoquinolin-3-yl)benzaldehyde (38) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2o (93.6 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 38 (105.1 mg, 77%).

[0070] 1 H NMR (600 MHz, CDCl3): δ = 9.78 (s, 1H), 8.90 (dd, J = 3.2, 1.1 Hz, 1H), 8.53 (d, J = 7.9 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.85(t, J = 7.7 Hz, 1H), 7.71–7.65 (m, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.3Hz, 1H), 7.43 (d,J = 7.9 Hz, 1H), 7.41–7.36 (m, 2H), 7.30 (dd, J = 8.0, 2.0 Hz, 1H), 7.16 (dd, J = 8.0, 1.7 Hz, 1H). 13 C NMR (150 MHz, CDCl3): m / z = 191.6, 162.2, 151.2, 144.3, 141.9, 141.6, 137.1, 136.3, 136.1, 135.8, 133.8, 131.0, 130.9, 130.0, 129.5, 129.0, 128.9, 128.8, 128.6, 128.2, 126.9, 126.1, 125.9, 122.0, 102.0. HR-MS (ESI): δ calcd for C 25 H 15 BrN2O2[M+Na] + 477.0209, 479.0189, found477.0208, 479.0191. 4-Bromo-3-(naphth-2-yl)-2-(quinolin-8-yl)isoquinoline-1(2) H )-Ketone(39) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2p (103.5 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 2:1:1) to obtain a colorless solid 39 (97.3 mg, 68%).

[0071] 1 H NMR(600 MHz, CDCl3, compound exists as a mixture of rotamers): δ =8.97 (dd, J = 4.3, 1.6 Hz, 1H), 8.93 (dd, J = 4.2, 1.6 Hz, 1H), 8.55 (d, J = 8.0Hz, 2H), 8.14 (d, J= 8.3, 4.5 Hz, 2H), 8.00 (dd, J = 8.4, 1.7 Hz, 1H), 7.94 (dd, J = 8.3, 1.7 Hz, 1H), 7.84 (t, J = 7.7 Hz, 2H), 7.77–7.73 (m, 2H), 7.66–7.60 (m,4H), 7.57 (t, J = 8.7 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 7.1, 3.3 Hz,2H), 7.46 (s, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.39 (d, J = 7.0 Hz, 1H), 7.38–7.30(m, 5H), 7.30–7.26 (m, 2H), 7.26–7.23 (m, 2H), 7.01 (dd, J = 8.5, 1.7 Hz, 1H). 13 C NMR(151 MHz, CDCl3): m / z = 162.5, 162.4, 151.1, 151.0, 144.6, 144.5,142.9, 137.6, 137.5, 136.5, 136.2, 133.8, 133.6, 133.4, 132.7, 132.7, 132.3,132.1, 130.9, 130.5, 130.0, 129.2, 129.0, 128.9, 128.8, 128.2, 128.1, 127.9,127.7, 127.6, 127.3, 127.3, 126.9, 126.9, 126.7, 126.6, 126.4, 126.3, 126.1,126.1, 126.0, 125.8, 125.8, 121.8, 121.7, 102.6, 102.6. HR-MS(ESI): δ calcd for C 28 H 17 BrN2O [M+Na] +499.0416, 501.0396, found499.0414, 501.0397. 4-Bromo-3-(pyridin-3-yl)-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(40) Prepared according to the general procedureAusing1a(81.9 mg, 0.30mmol) and2q(81.5 mg, 0.45 mmol), purification by column chromatography onsilica gel (petroleum ether / EtOAc / DCM = 1:1:1) yielded40(30.8 mg, 24%) as acolorless solid. Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2q (81.5 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 40 (30.8 mg, 24%) of colorless solid.

[0072] 1 H NMR(600 MHz, CDCl3, compound exists as a mixture of rotamers): δ =8.89 (td, J = 4.6, 1.6 Hz, 2H), 8.53 (d, J = 7.9 Hz, 2H), 8.50 (s, 1H), 8.29 (s,1H), 8.27–8.18 (m, 2H), 8.11 (d, J = 8.2 Hz, 2H), 8.07 (dd, J = 8.3, 1.7 Hz, 1H), 8.04 (dd, J = 8.4, 1.7 Hz, 1H), 7.85 (t, J = 7.7 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 2H), 7.58–7.49 (m, 3H), 7.43 (q,J = 8.0 Hz, 2H), 7.38 (td, J = 8.8, 4.2 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.8, 4.9 Hz, 1H), 6.74 (dd, J = 7.9, 4.8 Hz, 1H). 13 C NMR (151 MHz, CDCl3): m / z = 162.3, 162.2, 151.4, 151.2, 150.4, 149.9, 149.4, 149.3, 144.2, 144.0, 139.8, 139.7, 137.4, 137.1, 137.0, 136.5, 136.3, 136.2, 136.1, 133.8, 132.5, 132.2, 131.0, 130.7, 129.5, 129.4, 129.1, 129.0, 128.9, 128.3, 127.0, 127.0, 126.3, 126.2, 125.7, 122.2, 122.1, 122.0, 103.2. HR-MS (ESI): δ calcd for C 23 H 14 BrN3O [M+Na] + 450.0212, 452.0192, found450.0210, 452.0191. 4-Bromo-3-(pyrimidin-5-yl)-2-(quinolin-8-yl)isoquinolin-1(2 H )-Ketone(41) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2r (82.4 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 41 (38.6 mg, 30%).

[0073] 1 H NMR (600 MHz, CDCl3): δ = 8.88 (dd, J= 4.2, 1.7 Hz, 1H), 8.79 (s, 1H), 8.55 (d, J = 2.9 Hz, 1H), 8.53 (dd, J = 8.0, 1.4 Hz, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.3, 1.7 Hz, 1H), 7.87 (ddd, J = 8.4, 7.3,1.4 Hz, 1H), 7.77 (dd, J = 8.1, 1.2 Hz, 1H), 7.69–7.60 (m, 2H), 7.51 (t, J = 7.8Hz, 1H), 7.40 (dd, J = 8.3, 4.1 Hz, 1H). 13 C NMR (150 MHz, CDCl3): m / z = 162.1, 157.9, 157.0, 157.0, 151.5, 143.7, 136.7, 136.5, 136.4, 135.7, 133.9, 130.9, 130.8, 130.0, 129.2, 129.0, 128.8, 127.1, 126.4, 126.2, 122.3, 103.9. HR-MS (ESI): δ calcd for C 22 H 13 BrN4O [M+Na] + 451.0165, 453.0145, found451.0164, 453.0145, 453.0145. 4-Bromo-2-(quinolin-8-yl)-3-(thiophen-3-yl)isoquinolin-1(2) H )-Ketone(42) Following procedure A, using 1a (81.9 mg, 0.30 mmol) and 2s (83.7 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:2:1) to obtain 42 (87.0 mg, 67%) of colorless solid.

[0074] 1 H NMR (600 MHz, CDCl3, compound exists as a mixture of rotamers): δ =8.89 (d, J = 5.0 Hz, 2H), 8.51 (d, J = 7.9 Hz, 2H), 8.11 (d, J = 7.9 Hz, 4H), 7.82(t, J = 7.7 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.60 (t, J = 7.6 Hz, 2H), 7.48 (d, J =7.1 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.39 (dd, J = 8.4, 4.2 Hz, 2H), 7.18 (s,1H), 7.03 (s, 1H), 6.95 (s, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 6.44 (s, 1H). 13 C NMR (151 MHz, CDCl3): m / z = 162.4, 151.1, 144.5, 138.6, 137.6, 136.3, 136.2, 135.5, 133.6, 130.6, 130.1, 129.1, 128.9, 128.8, 128.2, 127.9, 127.1, 126.9, 126.1, 126.0, 126.0, 124.5, 124.3, 121.8, 103.2. HR-MS (ESI): δ calcd for C 22 H 13 BrN2OS [M+Na] + 454.9824, 456.9804, found454.9824, 456.9804. 5-(benzo[d][1,3]dioxolane-5-yl)-4-bromo-6-(quinolin-8-yl)furan[2,3-c]pyridine-7(6H )-Ketone(43) Following procedure A, using 1t (81.4 mg, 0.30 mmol) and 2e (101.3 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:2:1) to obtain a colorless solid 43 (69.2 mg, 50%).

[0075] 1 H NMR (600 MHz, CDCl3, compound exists as a mixture of rotamers): δ =8.89 (td, J = 4.4, 1.7 Hz, 2H), 8.09 (ddd, J = 7.9, 5.8, 1.7 Hz, 2H), 7.84 (d, J =2.0 Hz, 2H), 7.73 (ddd, J = 7.6, 4.6, 1.8 Hz, 2H), 7.50–7.42 (m, 4H), 7.38 (dt, J = 7.9, 3.8 Hz, 2H), 6.84 (d, J = 2.0 Hz, 2H), 6.66–6.63 (m, 2H), 6.58 (d, J =8.0 Hz, 1H), 6.36–6.33 (m, 2H), 6.19 (d, J = 8.1 Hz, 1H), 5.85 (d, J = 1.4 Hz, 1H), 5.82 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.4 Hz, 1H), 5.66 (d, J = 1.4 Hz, 1H). 13 C NMR (151 MHz, CDCl3): m / z= 153.4, 151.2, 151.1, 148.6, 147.6, 147.5,146.9, 146.6, 144.5, 144.3, 142.8, 142.8, 142.1, 142.1, 136.9, 136.8, 136.3,136.3, 135.1, 131.1, 130.8, 129.4, 129.0, 128.9, 128.7, 128.5, 125.9, 125.9,124.5, 123.4, 121.9, 121.8, 110.6, 109.8, 108.8, 108.8, 107.6, 107.4, 101.3, 101.1, 95.1. HR-MS (ESI): δ calcd for C 23 H 13 BrN2O4[M+Na] + 482.9951, 484.9931, found482.9949, 484.9930. 4-(4-bromo-6,7-dimethoxy-1-oxo-2-(quinolin-8-yl)-1,2-dihydroisoquinolin-3-yl)benzonitrile (44) Following procedure A, using 1r (92.4 mg, 0.30 mmol) and 2k (92.7 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 44 (76.8 mg, 50%) of colorless solid.

[0076] 1 H NMR (600 MHz, CDCl3): δ = 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.08 (dd, J =8.4, 1.7 Hz, 1H), 7.90 (s, 1H), 7.72 (dd, J = 8.2, 1.4 Hz, 1H), 7.48 (dd, J =7.3, 1.4 Hz, 1H), 7.44 (s, 1H), 7.43 (dd, J = 8.3, 1.5 Hz, 1H), 7.42–7.35 (m,3H), 7.08 (dd, J= 8.0, 1.7 Hz, 1H), 7.06 (dd, J = 8.0, 1.7 Hz, 1H), 4.09 (s, 3H), 4.01 (s, 3H). 13 C NMR (150 MHz, CDCl3): = 161.4, 154.4, 151.2, 150.2, 144.2, 140.6, 139.4, 137.1, 136.3, 131.4, 131.3, 131.2, 131.1, 130.9, 130.2, 129.5, 128.9, 125.9, 122.0, 119.8, 118.3, 112.3, 108.8, 107.6, 101.6, 56.5, 56.4. HR-MS (ESI): m / z calcd for C 27 H 18 BrN3O3[M+Na] + 534.0424, 536.0404, found534.0425, 536.0406. 4-Bromo-6,7-dimethoxy-2-(quinolin-8-yl)-3-(4-(trifluoromethyl)phenyl)isoquinolin-1(2 H )-Ketone(45) Following procedure A, using 1r (92.4 mg, 0.30 mmol) and 2j (112.1 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 45 (99.9 mg, 60%) of colorless solid.

[0077] 1 H NMR (600 MHz, CDCl3): δ = 8.90 (dd, J = 4.2, 1.7 Hz, 1H), 8.08 (dd, J =8.3, 1.7 Hz, 1H), 7.92 (s, 1H), 7.70 (dd, J = 8.2, 1.4 Hz, 1H), 7.47 (s, 1H), 7.46 (dd, J= 7.4, 1.5 Hz, 1H), 7.44–7.34 (m, 4H), 7.06 (d, J = 8.1 Hz, 1H), 7.03 (dd, J = 8.2, 1.7 Hz, 1H), 4.10 (s, 3H), 4.01 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 161.6, 154.4, 151.2, 150.1, 144.4, 140.0,139.8, 137.4, 136.3, 131.6, 130.8, 130.8, 130.4 (q, 2 J C–F = 33.0 Hz), 129.7,129.4, 128.9, 125.9, 124.6 (q, 3 J C–F = 3.7 Hz), 124.3 (q, 3 J C–F = 3.4 Hz), 123.7 (q, 1 J C–F = 272.5 Hz), 121.9, 119.8, 108.9, 107.7, 101.8, 56.5, 56.4. 19 F NMR (565 MHz, CDCl3) δ -62.92. HR-MS (ESI): m / z calcd for C 27 H 18 BrF3N2O3[M+Na] + 577.0345, 579.0325, found577.0346, 579.0326. 3-(benzo[d][1,3]dioxacyclopenten-5-yl)-4-bromo-6,7-dimethoxy-2-(quinolin-8-yl)isoquinolin-1(2) H )-Ketone(46) Following procedure A, using 1r (92.4 mg, 0.30 mmol) and 2e (101.3 mg, 0.45 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 46 (95.6 mg, 60%).

[0078] 1 H NMR (600 MHz, CDCl3, compound exists as a mixture of rotamers): δ =8.89 (s, 2H), 8.12–8.07 (m, 2H), 7.90 (d, J = 1.4 Hz, 2H), 7.74–7.70 (m, 2H),7.48 (d, J = 1.5 Hz, 2H), 7.46 (dd, J = 7.4, 3.1 Hz, 1H), 7.45–7.41 (m, 3H), 7.41–7.36 (m, 2H), 6.74 (d, J = 1.6 Hz, 1H), 6.72 (dd, J = 8.0, 1.7 Hz, 1H), 6.61(d, J = 8.0 Hz, 1H), 6.39 (s, 1H), 6.37 (d, J = 8.4 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 5.87 (d, J = 1.4 Hz, 1H), 5.84 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.5 Hz, 1H), 5.67 (d, J = 1.5 Hz, 1H), 4.09 (s, 6H), 4.00 (s, 6H). 13 C NMR (151 MHz, CDCl3): δ= 161.7, 154.3, 151.2, 151.1, 149.9, 147.4,147.3, 146.9, 146.6, 144.6, 141.0, 140.9, 137.9, 137.8, 136.2, 131.9, 131.9,130.9, 130.6, 130.1, 129.9, 129.0, 129.0, 128.9, 128.9, 126.0, 125.9, 124.5,123.2, 121.8, 121.7, 119.7, 110.7, 109.8, 108.8, 107.7, 107.7, 107.6, 107.4, 102.4, 101.2, 101.0, 56.4, 56.4. HR-MS (ESI): m / z calcd for C 27 H 19 BrN2O5[M+Na] + 553.0370, 555.0350, found553.0370, 555.0350. 11,12-Dimethyl-6-(quinolin-8-yl)-[1,3]dioxacyclopentene[4',5':5,6]benzo[1,2-h]furan[2,3-c]quinolin-7(6 H )-Ketone(47) Following procedure B, using 43 (92.2 mg, 0.20 mmol) and 2-butyne (43.2 mg, 0.80 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 47 (38.2 mg, 44%).

[0079] 1 H NMR (600 MHz, CDCl3): δ = 8.96 (d, J = 4.5 Hz, 1H), 8.25 (d, J = 8.3 Hz,1H), 7.87 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 8.3, 4.5 Hz, 1H), 7.43(t, J = 8.1 Hz, 1H), 7.35 (s, 1H), 7.23 (d,J = 7.4 Hz, 1H), 7.14 (dd, J = 9.1, 1.8Hz, 1H), 6.32 (dd, J = 9.1, 1.8 Hz, 1H), 5.98 (d, J = 19.0 Hz, 2H), 2.84 (s, 3H), 2.82 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 154.3, 151.3, 147.8, 145.4, 144.1, 143.1, 141.9, 141.8, 136.7, 136.6, 130.5, 130.4, 129.7, 129.1, 128.7, 126.5, 125.8, 121.9, 121.7, 121.1, 120.5, 115.2, 110.5, 107.5, 100.6, 18.9, 17.6. HR-MS (ESI): m / z calcd for C 27 H 18 N₂O₄[M+Na] + 457.1159, found 457.1157. 8,9-Dimethoxy-11,12-dimethyl-6-oxo-5-(quinolin-8-yl)-5,6-dihydrobenzo[ c ]Phenanthridine-2-carboxynitrile (48) Following procedure B, using 44 (102.4 mg, 0.20 mmol) and 2-butyne (43.2 mg, 0.80 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 48 (77.8 mg, 80%).

[0080] 1 H NMR (600 MHz, CDCl3): δ = 8.99 (d, J = 4.1 Hz, 1H), 8.32 (s, 1H), 8.31(d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.91 (d, J= 8.2 Hz, 1H), 7.55 (s, 1H), 7.52(dd, J = 8.3, 4.1 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.22(d, J = 7.4 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 4.06 (s, 3H), 4.02 (s, 3H), 3.02(s, 3H), 2.71 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 162.4, 152.3, 151.7, 149.8, 145.5, 141.5, 136.8, 135.1, 131.7, 130.8, 129.9, 129.6, 129.5, 129.3, 129.0, 128.4, 126.7, 126.1, 124.5, 123.9, 122.1, 121.7, 121.0, 119.4, 109.3, 109.2, 108.7, 56.4, 56.3, 22.5, 15.4. HR-MS (ESI): m / z calcd for C 31 H 23 N3O3[M+Na] + 508.1632, found 508.1632. 8,9-Dimethoxy-11,12-dimethyl-5-(quinolin-8-yl)-2-(trifluoromethyl)benzo[c]phenanthrene-anthradinone-6(5 H )-Ketone(49) Following procedure B, using 45 (111.0 mg, 0.20 mmol) and 2-butyne (43.2 mg, 0.80 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 49 (52.9 mg, 50%).

[0081] 1 H NMR (600 MHz, CDCl3): δ = 9.01 (d, J= 4.2 Hz, 1H), 8.31 (d, J = 8.5 Hz,1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.52(dd, J = 8.5, 4.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 7.21(d, J = 7.3 Hz, 1H), 6.85 (d, J = 9.2 Hz, 1H), 4.06 (s, 3H), 4.02 (s, 3H), 3.02(s, 3H), 2.74 (s, 3H). 13 C NMR(150 MHz, CDCl3): δ = 162.6, 152.2, 151.7, 149.6, 145.7, 141.9,136.8, 135.2, 131.8, 130.1 (q, 2 J C–F = 33.5 Hz), 129.8, 129.5, 129.3, 128.9,128.8, 126.8, 126.1 (q, 3 J C–F = 3.4 Hz), 124.4 (q, 3 J C–F = 3.4 Hz), 123.7 (q, 1 J C–F =273.5 Hz), 122.1, 121.5, 120.9, 120.9, 119.0, 117.2, 109.3, 109.2, 56.4,56.3, 22.5, 15.5. 19 F NMR(565 MHz, CDCl3) δ -62.35. HR-MS(ESI): m / z calcd for C 31 H 23 F3N2O3[M+Na]+ 551.1553, found 551.1552. 9,10-Dimethoxy-12,13-dimethyl-6-(quinolin-8-yl)-[1,3]dioxane[4',5':5,6]benzo[1,2- c ]Phenanthroline-7(6H)-one(50) Following procedure B, using 46 (106.2 mg, 0.20 mmol) and 2-butyne (43.2 mg, 0.80 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain 50 (45.4 mg, 45%) of colorless solid.

[0082] 1 H NMR (600 MHz, CDCl3): δ = 9.05 (d, J = 4.1 Hz, 1H), 8.29 (d, J = 8.3 Hz,1H), 7.91 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.52 (dd, J = 8.3, 4.1 Hz, 1H), 7.48(s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1H), 6.34 (d, J = 9.1 Hz, 1H), 6.00 (d, J = 1.5 Hz, 2H), 4.04 (s, 3H), 3.99 (s, 3H), 2.89 (s, 3H), 2.81 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ= 162.8, 152.2, 151.5, 148.9, 144.0, 142.6,141.7, 136.1, 130.3, 129.3, 129.3, 129.1, 128.4, 126.7, 125.7, 121.9, 120.9,120.4, 120.2, 120.0, 118.6, 109.1, 108.9, 107.7, 100.6, 56.3, 56.2, 21.6,17.2. HR-MS (ESI): m / z calcd for C 31 H 24 N₂O₅[M+Na] + 527.1577, found 527.1576. 9,10-Dimethoxy-12,13-bis(methoxymethyl)-6-(quinolin-8-yl)-[1,3]dioxacyclopentene[4',5':5,6]benzo[1,2- c ]Phenanthroline-7(6 H )-Ketone(51) Following procedure D, using 46 (106.2 mg, 0.20 mmol) and 1,4-dimethoxy-2-butyne (91.2 mg, 0.80 mmol) as raw materials, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 51 (45.1 mg, 40%).

[0083] 1 H NMR (600 MHz, CDCl3): δ = 9.01 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.07(d, J = 2.0 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 9.1, 4.1 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.41 (dd,J = 9.1, 1.9 Hz, 1H), 6.08 (s, 1H), 6.04 (s, 1H), 5.31(d, J = 10.0 Hz, 1H), 4.99 (d, J = 10.9 Hz, 1H), 4.89–4.82 (m, 2H), 4.08 (s, 3H), 4.00 (s, 3H), 3.74 (s, 3H), 3.54 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ = 162.8, 153.2, 151.5, 149.3, 145.6, 144.4, 142.2, 141.8, 138.0, 136.8, 130.6, 129.9, 129.7, 129.1, 128.6, 128.4, 126.6, 121.9, 121.3, 120.6, 119.9, 119.8, 117.6, 109.1, 108.9, 108.3, 101.0, 71.4, 68.3, 59.2, 58.7, 56.3, 56.1. HR-MS (ESI): m / z calcd for C 33 H 28 N₂O₇[M+Na] + 587.1789, found 587.1788. 9,10-Dimethoxy-6-(quinolin-8-yl)-6H-[1,3]dioxacyclopentene[4',5':4,5]indeno[1,2-c]isoquinolin-7,12-dione (52) Following procedure C, using 46 (106.2 mg, 0.20 mmol) as the starting material, the reaction was carried out under a CO atmosphere and purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 1:1:1) to obtain a colorless solid 52 (86.0 mg, 90%).

[0084] 1 H NMR (400 MHz, d 6-DMSO): δ = 8.80 (d, J = 4.2 Hz, 1H), 8.56 (d, J= 8.4 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 7.3 Hz, 1H), 8.06 (s, 1H), 7.89 (t, J =7.8 Hz, 1H), 7.61 (dd, J = 8.4, 4.1 Hz, 1H), 7.52 (s, 1H), 6.25 (d, J = 7.9 Hz,1H), 6.09 (s, 2H), 4.63 (d, J = 7.9 Hz, 1H), 3.97 (s, 3H), 3.85 (s, 3H). 13 C NMR (101 MHz, d 6-DMSO): δ = 186.5, 161.5, 154.6, 151.8, 151.4, 148.7, 146.0, 143.9, 143.5, 136.3, 134.7, 130.2, 130.0, 128.6, 128.6, 127.9, 126.3, 122.2, 116.8, 115.9, 113.6, 108.4, 108.1, 106.5, 103.2, 103.0, 55.6, 55.4. HR-MS (ESI): m / z δ δ m / z calcd for C 28 H 18 N₂O₆[M+Na] + 501.1057 was found; 501.1056 was also found. Effect verification: Detection of anti-hepatocellular carcinoma activity of benzo[a]pyridone derivatives. Experimental procedure: (1) Remove human liver cancer cells from liquid nitrogen and quickly place them in a 37 ℃ water bath. Gently shake the cryovial to thaw the cryopreservation solution. (2) After dissolving, transfer the cells to a centrifuge tube containing 5 ml of culture medium, centrifuge to collect the cells, centrifuge at 1000 rpm for 5 min at room temperature, and discard the supernatant; (3) Suspend the cells in a complete culture medium containing 10% fetal bovine serum, inoculate them into a culture dish, gently pipette to mix, and culture at 37°C and 5% CO2 saturated humidity. (4) Take cells in the logarithmic growth phase and in good growth condition, and use 4×10 3Cells were seeded per well in a 96-well cell culture plate and incubated overnight at 37°C in a 5% CO2 incubator (100 μL of sterile PBS was added to the wells around the cells). (5) The compound samples were subjected to high temperature and high pressure steam sterilization. After sterilization, the sample concentrations were set at 100 μM, 50 μM, 25 μM, 5 μM and 1 μM. (6) Take the 96-well plate that was seeded with cells the day before and put the samples of each concentration into it for co-culture with the cells; (7) The experiment was set up with three groups: experimental group (with cells, culture medium and drug), control group (with cells, culture medium and no drug) and blank control group (without cells, with culture medium and no drug). The well plates were placed in a cell culture incubator and cultured for 24 h before detection.

[0085] The experimental results are shown in Table 1. As can be seen from Table 1, compounds 17-52 exhibited good antitumor activity in Huh-7 liver cancer cells, among which compound 47 showed superior activity (IC50). 50 = 39.4 μM), showing potential value for drug development.

[0086] Table 1 The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A benzophenanthridine ketone derivative, characterized in that, The structure is as follows: 、 、 、 、 or .

2. A modular synthesis method for benzophenanthrene ketone derivatives as described in claim 1, characterized in that, Includes the following steps: (1) Using a cobalt / copper composite catalytic system, under the action of an oxidant, N-(quinoline-8-yl)benzamide compounds undergo a carbon-hydrogen bond activation cyclization reaction with halogen-substituted aryl alkynes to generate halogen-containing benzophenanthrene ketone intermediates; (2) The halogen-containing benzophenanthrene ketone intermediate is reacted with the modified reactant to obtain the benzophenanthrene ketone derivative; The modified reactants are selected from 2-butyne, carbon monoxide, or 1,4-dimethoxy-2-butyne.

3. The modular synthesis method for benzophenanthrene ketone derivatives according to claim 2, characterized in that, The N-(quinolin-8-yl)benzamide compounds are selected from any one of the following structural formulas 1a-1v: 。 4. The modular synthesis method for benzophenanthrene ketone derivatives according to claim 2, characterized in that, The halogen-substituted aryl alkynes are selected from any one of the following structural formulas 2a-2s: 。 5. The modular synthesis method for benzophenanthrene ketone derivatives according to claim 2, characterized in that, The molar ratio of the N-(quinoline-8-yl)benzamide compound to the halogenated aryl alkyne compound is 1:1.

5.

6. The modular synthesis method for benzophenanthrene ketone derivatives according to claim 2, characterized in that, In step (1), the cobalt / copper composite catalytic system is a complex of cobalt acetate and copper sulfate; The oxidant is sodium chlorate; The carbon-hydrogen bond activation cyclization reaction was carried out at a temperature of 80 °C for 3 h.

7. The modular synthesis method for benzophenanthrene ketone derivatives according to claim 2, characterized in that, When the modified reactant is 2-butyne, the specific reaction conditions are as follows: under the action of palladium catalyst and cesium carbonate base, the mixture is stirred at 110°C for 5 hours, and then diluted, washed, dried, concentrated, and purified by silica gel column chromatography to obtain the benzophenanthrene ketone derivative.

8. The modular synthesis method for benzophenanthrene ketone derivatives according to claim 2, characterized in that, When the modified reactant is carbon monoxide, the specific reaction conditions are as follows: under palladium catalyst and cesium neopentanoate base conditions, stirring at 110°C for 16 h, and then obtaining the benzophenanthridine ketone derivative after post-treatment and purification.

9. The modular synthesis method for benzophenanthrene ketone derivatives according to claim 2, characterized in that, When the modified reactant is 1,4-dimethoxy-2-butyne, the specific reaction conditions are as follows: under palladium catalyst and cesium carbonate base conditions, stirring at 110°C for 5 h, and then obtaining the benzophenanthrene ketone derivative after post-treatment and purification.

10. The use of the benzophenanthridine ketone derivatives as described in claim 1 in the preparation of anti-hepatocellular carcinoma drugs.

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