PI3K / m-TOR Inhibitors and Their Applications

Abstract

This invention relates to PI3K / m-TOR inhibitors and their applications, belonging to the field of targeted antitumor drug technology. The technical problem solved by this invention is to provide a dual-selective PI3K / m-TOR inhibitor. The compounds of this invention have the structural formula shown in Formula I. This invention designs and synthesizes 94 novel compound molecules targeting PI3K / m-TOR. These compounds exhibit superior antitumor activity and biosafety, representing a promising dual-selective PI3K / m-TOR inhibitor with good prospects for treating colorectal cancer, lung cancer, or cervical cancer.

Description

Technical Field

[0001] This invention relates to PI3K / m-TOR inhibitors and their applications, belonging to the field of targeted anti-tumor drug technology. Background Technology

[0002] Cancer has become a global problem, with the number of cancer patients increasing in almost every country worldwide. The global burden of cancer has seriously threatened human health, and cancer treatment has become a major challenge for society today. At the same time, the problem of drug resistance in tumors is becoming increasingly prominent. Numerous studies have shown that alterations in genes related to the PI3K / AKT / m-TOR signaling pathway are closely related to tumor formation. More than 70% of tumors carry mutations or gene amplifications in the PI3K / AKT / m-TOR signaling pathway, making this target a very promising target for developing oncology drugs.

[0003] Currently, most drugs targeting the PI3K / AKT / m-TOR signaling pathway are still in clinical trials, with only a very small number of marketed drugs. These include the pan-PI3K inhibitor copanlisib; the PI3Kδ inhibitor idelalisib; and three m-TOR inhibitors: tamsuloxim, everolimus, and desfolimex. The marketed drugs have certain limitations. For example, pan-PI3K inhibitors have limited inhibitory effects on downstream PI3K pathways, and their inhibitory effects on upstream m-TOR signaling pathways are also very limited, significantly restricting the indications for copanlisib in clinical applications. While the PI3Kδ inhibitor idelalisib selectively acts on PI3Kδ, avoiding cumulative toxicity, its applicability is much more limited compared to dual-selective PI3K / m-TOR inhibitors. In clinical use, idelalisib is often used in combination with other anti-tumor or cytotoxic drugs, which can increase adverse drug reactions in cancer patients, further limiting its clinical application. The marketed m-TOR inhibitors have a negative feedback regulatory effect on PI3K kinase and IRS. While inhibiting the m-TOR pathway, they also activate the upstream PI3K pathway. Therefore, it is difficult to achieve good clinical efficacy when m-TOR inhibitors are used alone. In the treatment of cancer patients, m-TOR inhibitors are generally used in combination with other anti-tumor drugs or cytotoxic drugs.

[0004] Dual-selective PI3K / m-TOR inhibitors possess the characteristics of both PI3K and m-TOR inhibitors. They selectively inhibit the PI3K pathway while simultaneously inhibiting the downstream m-TOR pathway. These inhibitors combine the advantages of individual PI3K and m-TOR inhibitors, offering a broader range of indications and achieving better efficacy when used alone. Currently, although some dual-selective PI3K / m-TOR inhibitors have entered clinical trials and achieved some success, many remain unmarketed due to poor in vivo efficacy, poor solubility, excessively high plasma clearance rates, and poor oral bioavailability. Therefore, addressing the current challenges of dual-selective PI3K / m-TOR inhibitors and developing next-generation inhibitors with higher biological activity and better efficacy is crucial. Summary of the Invention

[0005] To address the above deficiencies, the technical problem solved by this invention is to provide a PI3K / m-TOR dual-selective inhibitor.

[0006] The compound of this invention has the structural formula shown in Formula I:

[0007]

[0008] Formula I

[0009] Where R1 is , , , , , , , , , , , , , , or R4 is a C1-C4 alkyl, C1-C3 alkoxy, hydroxyl, halogen, -CN, -CF3, -NH2, , or ;

[0010] R2 is hydrogen or halogen;

[0011] R3 is a C1-C3 alkyl group. , , , , , , , , , or ;

[0012] R5 is hydrogen, halogen, methoxy, -CF3, -CN, or -CH2CN.

[0013] In one embodiment of the present invention, R2 is hydrogen.

[0014] In one embodiment of the present invention, R1 is or .

[0015] In one embodiment of the present invention, R3 is or R5 is F, methoxy, or .

[0016] The present invention also provides the use of the compounds described herein in the preparation of PI3K / m-TOR inhibitors.

[0017] The compounds of this invention can be used as dual-selective inhibitors of PI3K / m-TOR.

[0018] The present invention also provides the use of the compounds described herein in the preparation of antitumor drugs.

[0019] The compounds of this invention can target the PI3K / AKT / m-TOR signaling pathway and play a role in the treatment of tumors.

[0020] In one embodiment of the present invention, the tumor is colon cancer, lung cancer, or cervical cancer.

[0021] The present invention also provides a pharmaceutical composition.

[0022] The pharmaceutical composition of the present invention comprises an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] This invention designs and synthesizes 94 novel compound molecules targeting PI3K / m-TOR. These compounds exhibit superior antitumor activity and biosafety, and are ideal dual-selective inhibitors of PI3K / m-TOR, showing promising potential in the treatment of colorectal cancer, lung cancer, or cervical cancer. Attached Figure Description

[0025] Figure 1 This diagram shows a simulated binding pattern of compound 14h with the PI3Kα / m-TOR protein. In the diagram, A represents the docking pattern of compound 14h with PI3Kα; B represents the docking pattern of compound 14h with m-TOR.

[0026] Figure 2 The inhibitory activity (IC50) of the compound against different tumor cells over 14 hours. 50 μM)

[0027] Figure 3 The figure shows the colony formation results of compound 14h on SW620 and HeLa plates.

[0028] Figure 4 Tumor volume diagrams showing the effect of compound administration at 14 h in HeLa and SW620 xenograft models. P < 0.1 vs DMSO, P < 0.01 vs DMSO; P < 0.001 vs DMSO.

[0029] Figure 5 Tumor images of mice with HeLa and SW620 xenografts treated with the compound for 14 hours 30 days later.

[0030] Figure 6 This is a schematic diagram showing the weight changes of Hela and SW620 xenograft mice during 30 days of treatment.

[0031] Figure 7 This is a schematic diagram showing the tumor weight in different treatment groups using HeLa and SW620. P < 0.1 vs DMSO, P < 0.01 vs DMSO; P < 0.001 vs DMSO. Detailed Implementation

[0032] The compound of this invention has the structural formula shown in Formula I:

[0033]

[0034] Formula I

[0035] Where R1 is , , , , , , , , , , , , , , or R4 is a C1-C4 alkyl, C1-C3 alkoxy, hydroxyl, halogen, -CN, -CF3, -NH2, , or ;

[0036] R2 is hydrogen or halogen;

[0037] R3 is a C1-C3 alkyl group. , , , , , , , , , or ;

[0038] R5 is hydrogen, halogen, methoxy, -CF3, -CN, or -CH2CN.

[0039] In one embodiment of the present invention, R2 is hydrogen. That is, R1 is... , , , , , , , , , , , , , , or R4 is a C1-C4 alkyl, C1-C3 alkoxy, hydroxyl, halogen, -CN, -CF3, -NH2, , or ;

[0040] R2 is hydrogen;

[0041] R3 is a C1-C3 alkyl group. , , , , , , , , , or ;

[0042] R5 is hydrogen, halogen, methoxy, -CF3, -CN, or -CH2CN.

[0043] In one embodiment of the present invention, R1 is or That is, R1 is or R2 is hydrogen; R3 is a C1-C3 alkyl group. , , , , , , , , , or R5 represents hydrogen, halogen, methoxy, -CF3, -CN, or -CH2CN.

[0044] In one embodiment of the present invention, R3 is or R5 is F, methoxy, or That is, R1 is or That is, R1 is or R2 is hydrogen; R3 is... or R5 is F, methoxy, or .

[0045] In some specific embodiments, the compound of the present invention has any one of the following structural formulas:

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] The present invention also provides the use of the compounds described herein in the preparation of PI3K / m-TOR inhibitors.

[0053] The compounds of this invention can be used as dual-selective inhibitors of PI3K / m-TOR.

[0054] The present invention also provides the use of the compounds described herein in the preparation of antitumor drugs.

[0055] The compounds of this invention can target the PI3K / AKT / m-TOR signaling pathway and play a role in the treatment of tumors.

[0056] In one embodiment of the present invention, the tumor is colon cancer, lung cancer, or cervical cancer.

[0057] The present invention also provides a pharmaceutical composition.

[0058] The pharmaceutical composition of the present invention comprises an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0059] The specific embodiments of the present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the embodiments described herein.

[0060] Example 1: Synthesis of the compound

[0061] The synthetic route is as follows:

[0062]

[0063] Reagents and conditions: (a) POCl3, Et3N, 100℃, 3h; (b) R2-NH2, DMF, rt, ovn; (c) Fe, NH4Cl, EtOH / H2O, reflux, 4h; (d) AcOH, CDI, 110℃, ovn; (e) arylboronic acid substitutes, dppf(PdCl2), AcOK, 100℃, ovn.

[0064]

[0065] Reagents and conditions: (a) POCl3, Et3N, 100℃, 3 h; (b) R2-NH2, DMF, rt, ovn; (c) Fe, NH4Cl, EtOH / H2O, reflux, 4 h; (d) AcOH, CDI, 110℃, ovn; (e) arylboronic acid substitutes, dppf(PdCl2), AcOK, 100℃, ovn.

[0066] Synthetic method of intermediate compound 2 (6-bromo-4-chloro-3-nitroquinoline)

[0067]

[0068] Under argon atmosphere, 10 g (37.17 mmol) of 6-bromo-3-nitroquinoline-4-ol was added to a reaction flask, followed by 19.95 g (130.10 mmol) of POCl3 and 18.81 g (185.85 mmol) of triethylamine at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then reacted at 100 °C for 3–5 h. The reaction endpoint was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature and poured into ice water (500 mL). The aqueous phase was adjusted to pH 9–10 with 4N NaOH, extracted twice with ethyl acetate (2 × 400 mL), and the organic phases were combined, washed with brine, and dried over anhydrous MgSO4. The organic layer was removed by rotary evaporation under vacuum, and the product was purified by column chromatography to give 7.66 g of a brownish-black solid. The yield was 71.62%. 1 H NMR (400 MHz, CDCl3)δ 9.20(s, 1H), 8.53 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.96 (dd, J = 9.0, 2.0 Hz,1H). ESI-MS: mass calcd for [M+H] + (C9H4BrClN2O2) 286.91,288.90; found m / z, 286.92, 288.91.

[0069] General Synthesis Method N1 for Intermediate Compound 3

[0070] Intermediate compound 2 (15.00 mmol) was added to aromatic amines with different substituents (15.00 mmol) and dissolved in DMF (20 mL). The mixture was stirred overnight at room temperature, and the reaction endpoint was monitored by TLC. After the reaction was complete, the reaction solution was poured into 200 mL of ice water, and a large amount of solid precipitated. The solid was filtered, the filter cake was washed three times with water, dried, and the crude product was obtained. The crude product, intermediate compound 3, was obtained by column chromatography.

[0071] Synthesis of intermediate compound 3a (6-bromo-N-(4-fluorophenyl)-3-nitroquinoline-4-amine)

[0072]

[0073] It was prepared from compound 2 and 4-fluoroaniline according to general synthetic method N1. Yield: 68.22%, yellow solid. 1 H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 9.45 (s, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.76 (dd, J = 8.9, 2.1 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.21–7.10 (m,4H). ESI-MS: mass calcd for [M+H] + (C 15 H9BrFN3O2) 361.99, 363.98; found m / z,361.01,363.99.

[0074] Synthesis of intermediate compound 3b (6-bromo-N-(4-methoxyphenyl)-3-nitroquinoline-4-amine)

[0075]

[0076] It was prepared from compound 2 and 4-methoxyamine according to general synthetic method N1. Yield 71.13%, yellow-brown solid. 1 H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 9.44 (s, 1H), 7.85 (d, J= 9.4Hz,1H), 7.78–7.67 (m, 2H), 7.19–7.09 (m, 2H), 7.01–6.92 (m, 2H), 3.87 (s, 3H).ESI-MS: mass calcd for [M+H] + (C 16 H 12 BrN3O3) 374.01, 376.00; found m / z,374.02,376.01.

[0077] Synthesis of intermediate compound 3C (2-(4-((6-bromo-3-nitroquinoline-4-yl)amino)phenyl)-2-methylpropionitrile)

[0078]

[0079] It was prepared by general synthetic method N1 from compound 2 and 2-(4-aminophenyl)-2-methylpropionitrile. Yield 68.50%, yellow-brown solid. 1 H NMR (400 MHz, CDCl3) δ 10.54 (s, 1H), 9.47 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.76 (dd, J = 8.9, 2.1 Hz, 1H), 7.63 (d, J = 2.0 Hz,1H),7.58–7.51 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 1.77 (s, 6H). ESI-MS: masscalcd for[M+H] + (C 19 H 15 BrN4O2) 411.14, 413.04; found m / z, 411.15, 413.04.

[0080] General Synthesis Method N2 for Intermediate Compound 4

[0081] Intermediate compound 3 (10.00 mmol) was added to NH4Cl (30.00 mmol) and Fe powder (50.00 mmol), and the mixture was heated to reflux in EtOH / H2O (V1 / V2=2 / 1; 20 mL) for 3–5 h. The reaction endpoint was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the iron powder was removed by filtration of the reaction solution (diatomaceous earth). The filter cake was washed twice with EA, and the solvent was removed by vacuum distillation. 200 mL of EA and 200 mL of deionized water were added to the crude product, and the mixture was extracted twice. The organic layers were combined, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product, intermediate compound 4, was purified by column chromatography.

[0082] Synthesis of intermediate compound 4a (6-bromo-N4-(4-fluorophenyl)quinoline-3,4-diamine)

[0083]

[0084] It was prepared from compound 3a according to general synthetic method N2. Yield 51.35%, brownish-yellow solid. 1 HNMR(400 MHz, CDCl3) δ 10.52(s, 1H), 9.44 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 8.8, 2.2 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.20–7.11 (m, 4H), 5.51(brs, 2H).ESI-MS: mass calcd for [M+H] + (C 15 H 11 BrFN3) 332.01, 334.01; found m / z, 332.02,334.01.

[0085] Synthesis of intermediate compound 4b (6-bromo-N4-(4-methoxyphenyl)quinoline-3,4-diamine)

[0086]

[0087] It was prepared from compound 3b according to general synthetic method N2. Yield: 62.28%, pale yellow solid. 1 HNMR(400 MHz, CDCl3) δ 10.75 (s, 1H), 9.45 (s, 1H), 7.86 (d, J= 9.4 Hz, 1H),7.79–7.66 (m, 2H), 7.22 – 7.11 (m, 2H), 7.02–6.93 (m, 2H), 3.86 (s, 3H). ESI-MS: masscalcd for [M+H] + (C 16 H 14 BrN3O) 344.03, 346.03; found m / z, 344.04,346.04.

[0088] Synthesis of intermediate compound 4C (2-(4-((3-amino-6-bromoquinoline-4-yl)amino)phenyl)-2-methylpropionitrile)

[0089]

[0090] It was prepared from compound 3c according to the general synthetic method N2. Yield 63.39%, brownish-black solid. 1 HNMR(400 MHz, CDCl3) δ 10.54 (s, 1H), 9.48 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.74(dd, J = 8.9, 2.1 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.55– .48 (m, 2H), 7.17 (d, J =8.5 Hz, 2H), 1.78 (s, 6H). ESI-MS: mass calcd for [M+H] + (C 19 H 17 BrN4) 381.06,383.06; found m / z, 381.07, 383.07.

[0091] General Synthesis Method N3 for Intermediate Compound 5

[0092] Intermediate compound 4 (15.00 mmol) was added to CDI (45.00 mmol), and the mixture was heated to reflux in AcOH overnight. The reaction endpoint was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and 300 mL of EA and 300 mL of deionized water were added. The mixture was extracted twice, and the organic layers were combined. The solvent was removed under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the pure product, intermediate compound 5.

[0093] Synthesis of intermediate compound 5a (8-bromo-1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0094]

[0095] It was prepared from compound 4a according to general synthetic method N3. Yield 73.21%, light brownish-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.63 (dd, J = 9.0,2.1 Hz, 1H), 7.52–7.39 (m, 4H), 7.20 (d, J = 2.1 Hz, 1H), 2.49 (s, 3H). ESI-MS: masscalcd for [M+H] + (C15H11BrFN3) 356.01, 358.01; found m / z, 356.02,358.01.

[0096] Synthesis of intermediate compound 5b (8-bromo-1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0097]

[0098] It was prepared from compound 4b according to general synthetic method N3. Yield: 68.29%, light brown solid. 1 HNMR(400 MHz, CDCl3) δ 9.29 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.63 (dd, J = 9.0,2.2 Hz, 1H), 7.40–7.33 (m, 2H), 7.32–7.26 (m, 1H), 7.23–7.16 (m, 2H), 3.98(s,3H), 2.48 (s, 3H). ESI-MS: mass calcd for [M+H] + (C 18 H 14 BrN3O) 368.03,369.03; found m / z, 368.04, 369.04.

[0099] Synthesis of intermediate compound 5c(2-(4-(8-bromo-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0100]

[0101] It was prepared from compound 4c according to general synthetic method N3. Yield: 65.21%, brownish-brown solid. 1 HNMR(400 MHz, CDCl3) δ 9.31 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.89 – 7.82 (m,2H), 7.63 (dd, J = 9.0, 2.2 Hz, 1H), 7.56–7.48 (m, 2H), 7.04 (d, J = 2.1 Hz,1H), 2.53 (s,3H), 1.90 (s, 6H). ESI-MS: mass calcd for [M+H] + (C 21 H 17 BrN4)405.06, 407.06; found m / z, 305.07, 307.06.

[0102] General method for preparing the final product N4

[0103] Intermediate compound 5 (0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.05 mmol), AcOK (1.5 mmol), and various types of boronic ester substitutes (0.60 mmol) were reacted in dioxane / H2O (V1 / V2=9 / 1, 3 mL) with argon purging and then heated to 100 °C overnight. The reaction endpoint was monitored by TLC. After the reaction was completed, the reaction was allowed to cool to room temperature, the solvent was removed by vacuum distillation, and 50 mL of EA and 50 mL of deionized water were added. The mixture was extracted twice with EA, and the organic layers were combined. The crude product was then purified by thin-layer chromatography to obtain the target compound.

[0104] Synthesis of target compound 6a (1-(4-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)phenyl)ethyl-1-one)

[0105] It was prepared by general synthetic method N4 from compound 5a and p-acetylphenylboronic acid. Yield 48.23%, pale white solid. 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.86 (dd, J = 8.8, 2.0 Hz, 1H), 7.59–7.51 (m, 2H), 7.43(ddd, J = 6.3, 5.0, 3.2 Hz, 4H), 7.35 (d, J = 1.8 Hz, 1H), 2.63 (s, 3H), 2.53(s, 3H). 13 C NMR(101 MHz, CDCl3) δ 197.57, 164.72, 162.21, 152.49, 144.87,144.61, 144.23, 137.03,136.54, 136.11, 135.34, 132.96, 132.93, 131.14,130.03, 129.95, 129.04, 126.96,126.17, 117.98, 117.83, 117.60, 117.46, 26.65,14.18. ESI-MS: mass calcd for [M+H] + (C 25 H 18 FN3O) 396.14; found m / z, 396.15.

[0106] Synthesis of target compound 6b (1,8-bis(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0107] It was prepared by general synthesis method N4 from compound 5a and p-fluorophenylboronic acid. Yield 51.02%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.79 (dd, J = 8.8, 2.1 Hz, 1H), 7.55–7.49 (m, 2H), 7.457.38 (m, 2H), 7.34–7.28 (m,2H),7.23 (d, J= 2.0 Hz, 1H), 7.12–7.05 (m, 2H), 2.52 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 144.67, 137.45, 136.53, 136.39, 136.35, 133.10, 133.07, 131.16,130.05,129.97, 128.52, 128.43, 126.19, 117.74, 117.51, 117.29, 116.00,115.79, 14.18. ESI-MS: mass calcd for [M+H] + (C 23 H 15 F2N3) 372.12; found m / z,372.13.

[0108] Synthesis of target compound 6c (8-(4-chlorophenyl)-1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0109] It was prepared by general synthesis method N4 from compound 5a and p-chlorophenylboronic acid. Yield 42.13%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 1.8 Hz, 1H), 7.52 (dd, J = 8.7, 4.7 Hz, 2H), 7.42 (t, J = 8.3 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.25 (dd, J = 8.6, 5.1 Hz, 3H), 2.52 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.68, 162.17, 152.25, 144.78, 144.17, 138.67,137.14, 136.53, 135.16,133.86, 133.06, 133.03, 131.21, 130.04, 129.95,129.12, 128.10, 126.01, 117.76,117.53, 117.49, 117.38, 14.17. ESI-MS: masscalcd for [M+H] + (C 23 H 15 ClFN3) 388.09; found m / z, 388.10.

[0110] Synthesis of target compound 6d (4-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)-N-methylbenzamide)

[0111] It was prepared according to general synthetic method N4, from compound 5a and 4-(N-methylformamide)phenylboronic acid. Yield 45.51%, brown solid. 1 H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.51 (d, J =4.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 8.8, 1.9 Hz, 1H), 7.91 – 7.85(m,4H), 7.66 (t, J = 8.7 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 1.8Hz, 1H), 2.81(d, J = 4.5 Hz, 3H), 2.46 (s, 3H). 13C NMR (101 MHz, DMSO) δ166.42, 164.54,162.07, 153.02, 144.77, 144.09, 142.14, 136.70, 136.65,135.17, 134.09, 133.42,133.39, 131.30, 131.20, 128.31, 126.76, 126.11,117.97, 117.83, 117.75, 117.61, 26.74,14.30. ESI-MS: mass calcd for [M+H] + (C 25 H 19 FN4O) 411.15; found m / z, 411.16.

[0112] Synthesis of target compound 6e (4-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)benzyl nitrile)

[0113] It was prepared by general synthesis method N4 from compound 5a and 4-cyanobenzonic acid. Yield 53.37%, off-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.81(dd, J = 8.8, 2.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.58 – 7.52 (m, 2H), 7.49 –7.42 (m, 4H), 7.30 (d, J = 1.9 Hz, 1H), 2.53 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ164.73, 162.22, 152.53, 145.27, 144.67, 144.50, 136.61, 136.27,135.21, 132.94,132.91, 132.72, 131.48, 130.05, 129.95, 127.45, 125.85,118.63, 118.16, 117.86,117.63, 117.49, 111.31, 14.16. ESI-MS: mass calcd for[M+H] + (C 24 H15 FN4) 379.13;found m / z, 379.14.

[0114] Synthesis of target compound 6f (1-(4-fluorophenyl)-2-methyl-8-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinoline)

[0115] It was prepared by general synthetic method N4 from compound 5a and 4-trifluoromethylphenylboronic acid. Yield 50.08%, brownish solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.8, 2.0 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.57 – 7.50 (m,2H), 7.50 –7.39 (m, 4H), 7.32 (d, J = 1.7 Hz, 1H), 2.53 (s, 3H). 13 C NMR (101MHz, CDCl3) δ164.72, 162.20, 152.44, 145.02, 144.36, 143.69, 136.86, 136.56,135.24, 132.99,132.95, 131.32, 130.03, 129.94, 129.86, 129.54, 127.15,126.13, 125.92, 125.88,125.49, 122.79, 14.16. ESI-MS: mass calcd for [M+H] + (C 24 H 15 F4N3) 422.12;found m / z, 422.13.

[0116] Synthesis of 6g of target compound (1-(4-fluorophenyl)-2-methyl-8-(p-tolyl)-1H-imidazo[4,5-c]quinoline)

[0117] It was prepared by general synthetic method N4 from compound 5a and 4-methylphenylboronic acid. Yield 50.08%, brownish solid. 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.24 (d, J= 8.7 Hz, 1H), 7.82(dd, J = 8.8, 1.9 Hz, 1H), 7.55 – 7.47 (m, 2H), 7.40 (t, J = 8.4 Hz, 2H),7.28 (d, J= 1.9 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 2.50 (s, 3H), 2.38 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.65, 162.14, 152.12,144.34, 143.93, 138.34,137.59, 137.26, 136.43, 135.24, 133.13, 133.09,130.90, 130.04, 129.96, 129.71,126.74, 126.30, 117.72, 117.49, 117.05, 21.06,14.18. ESI-MS: mass calcd for [M+H] + (C 24 H 18 FN3) 368.15; found m / z, 368.16.

[0118] Synthesis of target compound 6h (methyl 4-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinoline-8-yl)benzoate)

[0119] It was prepared by general synthetic method N4 from compound 5a and 4-methoxycarbonylphenylboronic acid. Yield 43.51%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.86 (dd, J = 8.8, 2.0 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.43 (dd, J =11.5, 5.3 Hz, 4H), 7.34 (d, J = 1.8 Hz, 1H), 3.94 (s, 3H), 2.52(s, 3H).13 C NMR (101MHz, CDCl3) δ 166.80, 164.71, 162.20, 152.34, 145.02,144.54, 144.43, 137.10,136.56, 135.24, 133.01, 132.97, 131.27, 130.24,130.04, 129.95, 129.23, 126.78,126.11, 117.97, 117.80, 117.57, 117.48, 52.19,14.17. ESI-MS: mass calcd for [M +H] + (C 25 H 18 FN3O2) 412.14; found m / z, 412.15.

[0120] Synthesis of target compound 6i (4-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinoline-8-yl)phenol)

[0121] It was prepared by general synthetic method N4 from compound 5a and 4-hydroxyphenylboronic acid. Yield 52.72%, light gray solid. 1 H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 9.17 (s, 1H), 8.13 (d, J =8.8Hz, 1H), 7.88 – 7.81 (m, 3H), 7.64 (t, J = 8.7 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 1.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 2.44 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 164.53, 162.06, 157.98, 152.72, 143.94, 143.40, 137.81,136.58, 135.03,133.52, 133.49, 131.28, 131.19, 130.98, 130.53, 128.12,125.82, 117.91, 117.68,116.34, 116.31, 14.28. ESI-MS: mass calcd for [M+H]+ (C 23 H 16 FN3O) 370.13; found m / z, 370.14.

[0122] Synthesis of target compound 6j (1-(4-fluorophenyl)-8-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0123] It was prepared by general synthetic method N4 from compound 5a and 4-methoxyphenylboronic acid. Yield 55.17%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.23 ​​(d, J = 8.8 Hz, 1H), 7.80 (dd, J = 8.8, 2.0 Hz, 1H), 7.56 – 7.47 (m, 2H), 7.46 – 7.37 (m, 2H), 7.29 (t, J =2.5 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 6.96 – 6.89 (m, 2H), 3.84 (s, 3H), 2.51 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.64, 162.14, 159.47, 152.09,144.22, 143.76, 138.04,136.43, 135.17, 133.15, 133.11, 132.62, 130.91,130.06, 129.97, 127.95, 126.14,117.70, 117.53, 117.47, 116.63, 114.43, 55.36,14.18. ESI-MS: mass calcd for [M+H] + (C 24 H 18 FN3O) 384.14; found m / z, 384.14.

[0124] Synthesis of target compound 6k ((5-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)-2-methoxyphenyl)methanol)

[0125] It was prepared according to general synthetic method N4, from compound 5a and (3-hydroxymethyl-4-methoxyphenyl)boronic acid. Yield 50.02%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.19 (d, J =8.8Hz, 1H), 7.76 (dd, J = 8.8, 1.8 Hz, 1H), 7.47 (dd, J = 8.7, 4.8 Hz, 2H), 7.40(t, J =8.4 Hz, 2H), 7.31 (s, 1H), 7.27 – 7.24 (m, 1H), 7.20 (d, J = 1.6 Hz, 1H), 6.88 (d, J =8.5 Hz, 1H), 4.74 (s, 2H), 3.88 (s, 3H), 2.49 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ164.66, 162.16, 157.15, 152.10, 144.20, 143.71, 137.79,136.40, 135.26, 133.14,133.11, 132.37, 130.83, 130.08, 129.99, 129.85,127.05, 126.92, 125.98, 117.78,117.55, 117.49, 116.65, 110.65, 61.67, 55.52,14.15. ESI-MS: mass calcd for [M+H] + (C 25 H 20 FN3O2) 414.15; found m / z, 414.16.

[0126] Synthesis of target compound 6l (8-(3,5-bis(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0127] It was prepared by general synthetic method N4 from compound 5a and 3,5-bis(trifluoromethyl)phenylboronic acid. Yield 47.23%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.34 (d, J= 8.7Hz,1H), 7.92 – 7.78 (m, 4H), 7.57 (dd, J = 8.6, 4.6 Hz, 2H), 7.45 (t, J = 8.2Hz, 2H), 7.32 (d, J = 1.8 Hz, 1H), 2.56 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ164.93, 162.41,152.56, 145.47, 144.51, 142.04, 136.70, 135.26, 134.93,132.87, 132.80, 132.77,132.54, 132.21, 131.88, 131.72, 130.04, 129.96,126.80, 126.78, 125.21, 124.58,121.87, 121.18, 121.15, 121.11, 118.30,117.92, 117.69, 117.53, 14.12. ESI-MS: mass calcd for [M+H] + (C 25 H 14 F7N3)490.11; found m / z, 490.12.

[0128] Synthesis of target compound 6m (1-(4-fluorophenyl)-2-methyl-8-(3,4,5-trifluorophenyl)-1H-imidazo[4,5-c]quinoline)

[0129] It was prepared according to general synthetic method N4 from compound 5a and 3,4,5-trifluorophenylboronic acid. Yield 42.33%, grayish-black solid. 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.71 (dd, J = 8.7, 1.6 Hz, 1H), 7.55 (dd, J = 8.6, 4.7 Hz, 2H), 7.46 (t, J =8.3 Hz, 2H), 7.18 (s, 1H), 6.98 – 6.89 (m, 2H), 2.54 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.80,162.29, 152.49, 145.16, 144.30, 136.63, 135.26, 135.15,131.44, 130.04, 129.95,125.46, 117.88, 117.65, 117.60, 117.41, 110.92,110.86, 110.76, 110.70, 14.13. ESI-MS: mass calcd for [M+H] + (C 23 H 13 F4N3)408.10; found m / z, 408.11.

[0130] Synthesis of target compound 6n (8-(3,5-dimethylphenyl)-1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0131] It was prepared by general synthetic method N4 from compound 5a and 3,5-dimethylphenylboronic acid. Yield 53.78%, light gray solid. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 8.8, 1.5 Hz, 1H), 7.52 (dd, J = 8.5, 4.7 Hz, 2H), 7.42 (t, J =8.3 Hz, 2H),7.26 (s, 1H), 6.98 (d, J = 3.9 Hz, 3H), 2.53 (s, 3H), 2.34 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 164.71, 162.20, 152.01, 144.33, 143.98, 139.83,138.56, 138.24, 136.37,135.37, 133.20, 133.16, 130.75, 130.18, 130.10,129.29, 126.13, 124.76, 117.73,117.50, 117.43, 117.38, 21.31, 14.13. ESI-MS:mass calcd for [M+H] + (C25 H 20 FN3)382.16; found m / z, 382.17.

[0132] Synthesis of target compound 6o(4-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)aniline)

[0133] It was prepared by general synthesis method N4 from compound 5a and 4-aminophenylboronic acid. Yield 51.36%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.78(dd, J = 8.8, 2.0 Hz, 1H), 7.55–7.45 (m, 2H), 7.39 (t, J = 8.4 Hz, 2H), 7.20(d, J= 1.9 Hz, 1H), 7.17–7.12 (m, 2H), 6.72 – 6.64 (m, 2H), 2.50 (s, 3H). 13 CNMR (101MHz, CDCl3) δ 164.61, 162.11, 152.02, 146.34, 143.85, 143.52, 138.41,136.35,135.16, 133.16, 133.12, 130.70, 130.15, 130.06, 129.98, 127.81,125.96, 117.65,117.55, 117.42, 116.00, 115.41, 14.16. ESI-MS: mass calcd for[M+H] + (C 23 H 17 FN4)369.14; found m / z, 369.15.

[0134] Synthesis of the target compound 6p(5-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-amine)

[0135] It was prepared by general synthetic method N4 from compound 5a and pinacol ester of 2-aminopyrimidine-5-boronic acid. Yield 48.78%, light brown solid. 1H NMR (400 MHz, DMSO) δ 9.19 (s, 1H), 8.29 (s, 2H), 8.16(d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.8, 2.0 Hz, 1H), 7.85 (dd, J = 8.8, 4.9Hz, 2H), 7.64 (t, J = 8.7 Hz, 2H), 7.10 (d, J = 1.7 Hz, 1H), 6.89 (s, 2H), 2.45 (s, 3H). 13 C NMR(101 MHz, DMSO) δ 163.45, 156.17, 152.92, 144.19, 143.52,136.64, 134.88, 133.42,132.92, 131.34, 131.24, 124.84, 121.65, 117.91,117.73, 117.68, 115.15, 14.28. ESI-MS: mass calcd for [M+H] + (C 21 H 15 FN6)371.13; found m / z, 371.14.

[0136] Synthesis of target compound 6q (5-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)pyridine-2-amine)

[0137] It was prepared by general synthetic method N4 from compound 5a and pinacol ester of 2-aminopyridine-5-boronic acid. Yield 50.19%, brown solid. 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 8.12 (d, J =8.8 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.85 (dt, J = 6.7, 4.8 Hz, 3H), 7.65 (t, J =8.7Hz, 2H), 7.45 (dd, J = 8.6, 2.2 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.50(d, J= 8.6 Hz,1H), 6.19 (s, 2H), 2.45 (s, 3H). 13 C NMR (101 MHz, DMSO) δ164.49, 162.02, 159.90,152.73, 146.18, 143.83, 143.32, 136.59, 135.74,135.47, 134.89, 133.52, 133.49,131.29, 131.20, 131.10, 125.20, 123.38,117.89, 117.75, 117.66, 115.17, 115.17,108.49, 14.27. ESI-MS: mass calcd for[M+H] + (C 22 H 16 FN5) 370.15; found m / z,370.15.

[0138] Synthesis of target compound 6r (1-(4-fluorophenyl)-8-(6-methoxypyridin-3-yl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0139] It was prepared by general synthetic method N4 from compound 5a and 2-methoxy-5-pyridineboronic acid. Yield 48.38%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.19 (d, J = 8.8Hz, 1H), 7.76 (dd, J = 8.8, 1.8 Hz, 1H), 7.47 (dd, J = 8.7, 4.8 Hz, 2H), 7.40 (t, J = 8.4Hz, 2H), 7.31 (s, 1H), 7.27 – 7.24 (m, 1H), 7.20 (d, J = 1.6 Hz, 1H), 6.88 (d, J = 8.5Hz, 1H), 4.74 (s, 2H), 3.88 (s, 3H), 2.49 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.66,162.16, 157.15, 152.10, 144.18, 143.71, 137.79,136.40, 135.26, 133.14, 133.11,132.37, 130.83, 130.08, 129.99, 129.85,127.05, 126.92, 125.98, 117.78, 117.55,117.49, 116.65, 110.65, 61.67, 55.52,14.15. ESI-MS: mass calcd for [M+H] + (C 23 H 17 FN4O) 385.14; found m / z, 385.15.

[0140] Synthesis of the target compound 6S (4-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)-3,5-dimethylisoxazole)

[0141] It was prepared according to general synthetic method N4, from compound 5a and 3,5-dimethylisoxazole-4-boronic acid. Yield 45.66%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.28 (d, J =8.7 Hz,1H), 7.59–7.48 (m, 3H), 7.40 (t, J = 8.3 Hz, 2H), 7.05 (d, J = 1.6 Hz, 1H), 2.49 (s, 3H), 2.27 (s, 3H), 2.12 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.37,164.58,162.06, 158.31, 152.52, 144.96, 143.73, 136.57, 134.76, 133.04,133.01, 131.21,129.82, 129.73, 128.14, 127.76, 119.54, 117.96, 117.73,117.48, 116.11, 14.17, 11.64,10.80. ESI-MS: mass calcd for [M+H] + (C 22 H17 FN4O)373.14; found m / z, 373.15.

[0142] Synthesis of target compound 6t (1-(4-fluorophenyl)-2-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinoline)

[0143] It was prepared by general synthetic method N4 from compound 5a and 1-methyl-1H-pyrazole-4-boronic acid. Yield 51.57%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.17 (d, J = 8.7Hz, 1H), 7.66 (dd, J = 8.7, 1.9 Hz, 1H), 7.56 – 7.49 (m, 2H), 7.42 (dd, J = 16.8, 7.3 Hz, 4H), 7.15 (d, J = 1.8 Hz, 1H), 3.91 (s, 3H), 2.51 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 164.63, 162.12, 152.07, 143.99, 143.59, 136.51, 136.48, 134.82,133.13,133.09, 131.12, 130.13, 130.12, 130.03, 126.97, 125.14, 122.60,117.67, 117.45,114.85, 39.17, 14.16. ESI-MS: mass calcd for [M+H] + (C 21 H 16 FN5)358.14; foundm / z, 358.14.

[0144] Synthesis of target compound 6u (1-(4-fluorophenyl)-2-methyl-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline)

[0145] It was prepared according to general synthetic method N4 from compound 5a and quinoline-3-boronic acid. Yield 51.57%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.92 (d, J= 2.0 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 10.2, 5.0 Hz, 2H), 7.95 (dd, J = 8.7, 1.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.63 – 7.53 (m, 3H), 7.44 (t, J = 8.3Hz, 3H), 2.53 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.74,162.22, 152.46, 149.25,147.39, 145.09, 144.33, 136.65, 135.13, 135.03,133.28, 132.98, 132.94, 132.80,131.63, 130.03, 129.94, 129.76, 129.21,127.96, 127.91, 127.30, 126.12, 117.91,117.87, 117.68, 117.66, 14.19. ESI-MS: mass calcd for [M+H] + (C 26 H 17 FN4)405.14; found m / z, 405.15.

[0146] Synthesis of target compound 6v (1-(4-fluorophenyl)-2-methyl-8-(naphth-2-yl)-1H-imidazo[4,5-c]quinoline)

[0147] It was prepared from compound 5a and 2-naphthoboric acid according to general synthetic method N4. Yield 48.78%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.8, 1.8 Hz, 1H), 7.88 – 7.77 (m, 4H), 7.55 – 7.39 (m, 8H), 2.53 (s, 3H). 13C NMR(101 MHz, CDCl3) δ 164.73, 162.22, 152.21, 144.49, 144.04, 138.11,137.21, 136.44,135.33, 133.63, 133.12, 133.09, 132.70, 130.99, 130.13,130.05, 128.67, 128.15,127.62, 126.61, 126.39, 126.33, 125.86, 124.78,117.77, 117.72, 117.54, 14.16. ESI-MS: mass calcd for [M+H] + (C 27 H 18 FN3)404.15; found m / z, 404.16.

[0148] Synthesis of target compound 6w (4-(5-(1-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-yl)morpholine)

[0149] It was prepared by general synthetic method N4 from compound 5a and 2-morpholinylpyrimidine-5-ylboronic acid. Yield 51.71%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.33 (s, 2H), 8.26(d, J = 8.7 Hz, 1H), 7.70 (dd, J = 8.7, 1.9 Hz, 1H), 7.56 – 7.50 (m, 2H),7.43 (t, J = 8.3Hz, 2H), 7.20 (d, J = 1.8 Hz, 1H), 3.85 (d, J = 5.2 Hz, 4H), 3.79 (d, J = 5.1 Hz, 4H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.64,162.13, 160.99, 155.77, 152.41,144.52, 143.84, 136.53, 134.87, 133.03,132.94, 132.91, 131.49, 129.93, 129.84,125.06, 122.44, 117.85, 117.71,117.62. 115.63, 44.36, 14.18. ESI-MS: mass calcd for[M+H] + (C 25 H 21 FN6O) 441.18;found m / z, 441.18.

[0150] Synthesis of target compound 6x (1-(4-fluorophenyl)-2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0151] It was prepared by general synthetic method N4 from compound 5a and pinacol 7-azaindole-5-boronic acid. Yield 49.82%, brown solid. 1 H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 9.21 (s, 1H), 8.22 (t, J = 5.7 Hz, 2H), 8.02 – 7.97 (m, 2H), 7.88 (dd, J = 8.8, 4.9 Hz, 2H), 7.66(t, J= 8.7 Hz, 2H), 7.58 – 7.53 (m, 1H), 7.26 (d, J = 1.8 Hz, 1H), 6.49 (dd, J = 3.3, 1.7 Hz,1H), 2.47 (s, 3H). 13C NMR (101 MHz, DMSO) δ 164.54, 162.08,152.88, 148.55,144.22, 143.55, 142.16, 141.56, 136.69, 136.62, 135.05,133.49, 133.46, 131.33,131.24, 131.22, 127.84, 127.75, 126.47, 126.43,120.24, 117.95, 117.72, 117.27,100.62, 14.28. ESI-MS: mass calcd for [M+H] + (C 24 H 16 FN5) 394.14; found m / z,394.15.

[0152] Synthesis of target compound 6y (1-(4-fluorophenyl)-8-(1H-indol-5-yl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0153] It was prepared by general synthetic method N4 from compound 5a and 5-indoleboric acid. Yield 45.31%, light brown solid. 1 H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 9.18 (s, 1H), 8.16 (d, J =8.7Hz, 1H), 7.96 (dd, J = 8.8, 1.8 Hz, 1H), 7.87 (dd, J = 8.7, 4.9 Hz, 2H), 7.66 (t, J = 8.7Hz, 2H), 7.58 (s, 1H), 7.42 (dd, J = 10.2, 5.6 Hz, 2H), 7.26(d, J = 1.5 Hz, 1H), 7.15(d, J = 8.4 Hz, 1H), 6.46 (s, 1H), 2.46 (s, 3H). 13CNMR (101 MHz, DMSO) δ 164.58,162.12, 152.65, 143.83, 143.38, 139.39, 136.56,136.08, 135.10, 133.61, 133.58,131.32, 131.23, 130.89, 130.78, 128.84,126.90, 126.40, 120.42, 118.69, 117.94,117.72, 116.99, 112.38, 101.94, 14.28.ESI-MS: mass calcd for [M+H] + (C 25 H 17 FN4)393.14; found m / z, 393.14.

[0154] Synthesis of target compound 7a (1-(4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)phenyl) ethyl-1-one)

[0155] It was prepared by general synthetic method N4 from compound 5b and p-acetylphenylboronic acid. Yield 51.27%, light gray solid. 1 H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.96(d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.48 – 7.40 (m, 5H), 7.21 (d, J = 8.6Hz, 2H), 3.98 (s, 3H), 2.63 (s, 3H), 2.53 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 197.70,161.07, 152.94, 144.79, 144.70, 144.18, 136.69, 136.29,136.00, 135.56, 130.92,129.18, 129.08, 128.95, 127.00, 125.96, 118.30,117.65, 115.69, 55.94, 29.27, 26.66,14.09. ESI-MS: mass calcd for [M+H] + (C26 H 21 N3O2) 408.16; found m / z, 408.17.

[0156] Synthesis of target compound 7b (8-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0157] It was prepared by general synthesis method N4 from compound 5b and p-fluorophenylboronic acid. Yield 51.32%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.77(dd, J = 8.8, 2.0 Hz, 1H), 7.44 – 7.39 (m, 2H), 7.32 (ddd, J = 10.7, 7.0, 2.0 Hz,3H),7.22 – 7.17 (m, 2H), 7.06 (t, J = 8.6 Hz, 2H), 3.97 (s, 3H), 2.52 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 163.81, 161.35, 160.97, 152.61, 144.60, 143.95,137.05, 136.44,136.42, 135.44, 130.93, 129.44, 129.15, 128.54, 128.46,125.88, 117.68, 117.57,115.84, 115.62, 55.89, 14.12. ESI-MS: mass calcd for[M+H] + (C 24 H 18 FN3O) 384.14; found m / z, 384.15.

[0158] Synthesis of target compound 7c (8-(4-chlorophenyl)-1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0159] It was prepared by general synthesis method N4 from compound 5b and p-chlorophenylboronic acid. Yield 43.07%, light brown solid. 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.77(dd, J = 8.8, 2.0 Hz, 1H), 7.40 (t, J = 5.9 Hz, 2H), 7.36 – 7.26 (m, 5H), 7.19 (d, J = 8.8Hz, 2H), 3.97 (s, 3H), 2.52 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.99,152.69,144.67, 144.05, 138.73, 136.77, 136.42, 135.45, 133.70, 130.96,129.37, 129.12,128.98, 128.14, 125.75, 117.67, 117.65, 115.63, 55.91, 14.11.ESI-MS: mass calcd for[M+H] + (C 24 H 18 ClN3O) 400.11; found m / z, 400.11.

[0160] Synthesis of target compound 7d (4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)-N-methylbenzamide)

[0161] It was prepared from compound 5b and 4-(N-methylformamide)phenylboronic acid according to general synthetic method N4.

[0162] Yield 43.23%, grayish-brown solid. 1 H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 8.52 (d, J= 4.4 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.88(d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.48 (d, J= 8.2 Hz, 2H), 7.37– 7.31 (m, 3H), 3.97 (s,3H), 2.82 (d, J = 4.4 Hz, 3H), 2.46 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 166.47,160.99, 153.16, 144.72, 144.05, 142.10, 136.63,136.38, 135.35, 134.06, 131.18,129.96, 129.46, 128.25, 126.72, 125.93,117.90, 117.71, 116.04, 56.38, 26.74, 14.24.ESI-MS: mass calcd for [M+H] + (C 26 H 22 N4O2) 423.17; found m / z, 423.18.

[0163] Synthesis of target compound 7e (4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)benzyl nitrile)

[0164] It was prepared by general synthesis method N4 from compound 5b and 4-cyanobenzonic acid. Yield 54.31%, grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.80(d, J = 8.7 Hz, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.49 – 7.42 (m, 4H), 7.36 (s,1H),7.22 (d, J = 8.8 Hz, 2H), 3.99 (s, 3H), 2.54 (s, 3H). 13C NMR (101 MHz, CDCl3) δ161.08, 152.94, 145.23, 144.74, 144.43, 136.56, 135.87, 135.53,132.60, 131.29,129.25, 129.12, 127.47, 125.55, 118.73, 118.50, 117.68,115.69, 111.14, 55.95, 14.11.ESI-MS: mass calcd for [M+H] + (C 25 H 18 N4O) 391.15; found m / z, 391.16.

[0165] Synthesis of target compound 7f (1-(4-methoxyphenyl)-2-methyl-8-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinoline)

[0166] It was prepared by general synthesis method N4 from compound 5b and 4-trifluoromethylphenylboronic acid. Yield 52.71%, brownish solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 2.5 Hz, 1H), 8.30 (dd, J =8.7, 2.8 Hz, 1H), 7.86 – 7.78 (m, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.50 – 7.40(m, 4H),7.38 (d, J = 2.0 Hz, 1H), 7.24 – 7.17 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.05,152.94, 144.80, 144.10, 143.74, 136.52, 136.47, 135.61,130.97, 129.27, 129.10,127.18, 125.90, 125.78, 125.74, 118.26, 117.65,115.68, 55.90, 14.12. ESI-MS: masscalcd for [M+H] + (C 25 H 18 F3N3O) 434.14; foundm / z, 434.15.

[0167] Synthesis of 7g of target compound (1-(4-methoxyphenyl)-2-methyl-8-(p-tolyl)-1H-imidazo[4,5-c]quinoline)

[0168] It was prepared by general synthetic method N4 from compound 5b and 4-methylphenylboronic acid. Yield 55.13%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.82 (dd, J = 8.7, 1.4 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.36 (s, 1H), 7.29 – 7.24 (m,2H), 7.17(dd, J = 8.4, 3.6 Hz, 4H), 3.97 (s, 3H), 2.51 (s, 3H), 2.37 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.93, 152.64, 144.13, 143.70, 138.02, 137.47,137.26, 136.32, 135.59,130.57, 129.59, 129.43, 129.11, 126.78, 126.11,117.68, 117.30, 115.63, 55.88, 21.07,14.14. ESI-MS: mass calcd for [M+H] + (C 25 H 21 N3O) 380.17; found m / z, 360.18.

[0169] Synthesis of target compound 7h (methyl 4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline-8-yl)benzoate)

[0170] It was prepared by general synthetic method N4 from compound 5b and 4-methoxycarbonylphenylboronic acid. Yield 48.32%, light brown solid. 1 H NMR 1H NMR (400 MHz, CDCl3) δ 9.31 (d, J = 1.3 Hz, 1H), 8.28 (d, J= 8.7Hz, 1H), 8.06 – 8.01 (m, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.46 – 7.40 (m,5H), 7.20 (d, J= 8.7 Hz, 2H), 3.96 (d, J = 13.5 Hz, 6H), 2.53 (s, 3H). 13 C NMR(101 MHz, CDCl3) δ166.87, 161.04, 152.76, 144.98, 144.64, 144.37, 136.72,136.49, 135.52, 131.08,130.13, 129.32, 129.11, 126.80, 125.87, 118.27,117.68, 115.66, 55.93, 52.19, 14.12.ESI-MS: mass calcd for [M+H] + (C 26 H 21 N3O3)424.16; found m / z, 424.17.

[0171] Synthesis of target compound 7i (4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline-8-yl)phenol)

[0172] It was prepared by general synthetic method N4 from compound 5b and 4-hydroxyphenylboronic acid. Yield 49.37%, light gray solid. 1 H NMR 1 H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 9.15 (s, 1H), 8.11 (d, J =8.8 Hz, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.32(d, J = 8.8Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 1.9 Hz, 1H), 6.79(d, J = 8.6 Hz, 2H), 3.95 (s, 3H), 2.45 (s, 3H). 13C NMR (101 MHz, DMSO) δ160.97, 157.95, 152.87,143.90, 143.36, 137.53, 136.51, 135.23, 130.86,130.46, 129.99, 129.59, 128.10,125.59, 117.78, 116.40, 116.27, 116.03, 56.32,14.23. ESI-MS: mass calcd for [M +H]+ (C 24 H 19 N3O2) 382.15; found m / z, 382.15.

[0173] Synthesis of target compound 7j (1,8-bis(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0174] It was prepared by general synthetic method N4 from compound 5b and 4-methoxyphenylboronic acid. Yield 57.81%, light brown solid. 1 H NMR 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.23 ​​(d, J = 8.8 Hz, 1H), 7.80 (dd, J = 8.8, 2.0 Hz, 1H), 7.44 – 7.38 (m, 2H), 7.34 – 7.29 (m, 3H), 7.21 – 7.16(m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.96 (s, 3H), 3.84 (s, 3H), 2.51 (s, 3H). 13 C NMR(101 MHz, CDCl3) δ 160.92, 159.37, 152.48, 144.22,143.73, 137.67, 136.39, 135.44,132.75, 130.75, 129.53, 129.16, 128.00,125.86, 117.74, 116.92, 115.61, 114.30, 55.88,55.37, 14.14. ESI-MS: masscalcd for [M+H] + (C 25 H 21 N3O2) 396.16; found m / z,396.17.

[0175] Synthesis of target compound 7k ((2-methoxy-5-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)phenyl)methanol)

[0176] It was prepared according to general synthetic method N4, from compound 5b and (3-hydroxymethyl-4-methoxyphenyl)boronic acid. Yield 51.72%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.19 (d, J =8.8 Hz, 1H), 7.77 (dd, J = 8.8, 2.1 Hz, 1H), 7.39 – 7.31 (m, 3H), 7.26 (dd, J = 8.0,1.7Hz, 2H), 7.21 – 7.15 (m, 2H), 6.87 (d, J = 8.5 Hz, 1H), 4.71 (s, 2H), 3.97(s, 3H), 3.89(s, 3H), 2.50 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.86, 157.07,152.48, 144.09,143.61, 137.44, 136.26, 132.37, 130.59, 129.93, 129.46,129.14, 127.06, 126.93,125.68, 117.66, 116.90, 115.67, 110.52, 61.54, 55.89,55.50, 14.07. ESI-MS: masscalcd for [M+H] + (C 26 H 23 N3O3) 426.17; found m / z,426.18.

[0177] Synthesis of target compound 7l (8-(3,5-bis(trifluoromethyl)phenyl)-1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0178] It was prepared by general synthetic method N4 from compound 5b and 3,5-bis(trifluoromethyl)phenylboronic acid. Yield 43.25%, brown solid. 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.8, 2.1 Hz, 1H), 7.82 (s, 3H), 7.44 (dd, J = 5.5, 3.3 Hz,3H), 7.24 –7.19 (m, 2H), 3.95 (s, 3H), 2.54 (s, 3H). 13 C NMR (101 MHz, CDCl3)δ 161.26, 153.12,145.38, 144.42, 142.20, 136.58, 135.50, 134.72, 132.41,132.08, 131.52, 129.00,128.95, 126.86, 126.83, 125.14, 124.64, 121.08,121.04, 121.00, 118.52, 117.76,115.58, 55.53, 14.09. ESI-MS: mass calcd for[M+H] + (C 26 H 17 F6N3O) 502.13;found m / z, 502.14.

[0179] Synthesis of target compound 7m (1-(4-methoxyphenyl)-2-methyl-8-(3,4,5-trifluorophenyl)-1H-imidazo[4,5-c]quinoline)

[0180] It was prepared by general synthetic method N4 from compound 5b and 3,4,5-trifluorophenylboronic acid. Yield 45.07%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.71(dd, J = 8.8, 2.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.22 (dd, J = 10.7, 5.3 Hz, 3H), 6.96(dd, J = 8.7, 6.5 Hz, 2H), 4.00 (s, 3H), 2.55 (s, 3H). 13CNMR (101 MHz, CDCl3) δ161.23, 152.89, 145.04, 144.15, 136.51, 135.55, 134.74,131.16, 129.14, 125.05,117.91, 117.57, 115.73, 110.83, 110.77, 110.67,110.61, 55.87, 14.06. ESI-MS: masscalcd for [M+H] + (C 24 H 16 F3N3O) 420.12; foundm / z, 420.13.

[0181] Synthesis of target compound 7n (8-(3,5-dimethylphenyl)-1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0182] It was prepared by general synthetic method N4 from compound 5b and 3,5-dimethylphenylboronic acid. Yield 50.18%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.23 ​​(d, J = J = 8.7 Hz, 1H), 7.85 (dd, J = J = 8.7, 1.5 Hz, 1H), 7.41 (d, J = J = 8.7 Hz, 2H), 7.36 (d, J = 1.3 Hz, 1H), 7.19(d, J = 8.7 Hz, 2H), 7.01 (s, 2H), 6.96 (s, 1H), 3.95 (s, 3H), 2.52 (s, 3H), 2.33 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 160.91, 152.44,144.34, 143.98, 139.90, 138.38, 137.89,136.34, 135.61, 130.62, 129.54,129.21, 129.16, 125.90, 124.81, 117.69, 117.62,115.55, 55.68, 21.29, 14.10.ESI-MS: mass calcd for [M+H] + (C 26 H 23 N3O) 394.18; found m / z, 394.19.

[0183] Synthesis of target compound 7o (4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)aniline)

[0184] It was prepared by general synthesis method N4 from compound 5b and 4-aminophenylboronic acid. Yield 48.78%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 8.8, 1.5 Hz, 1H), 7.52 (dd, J = 8.5, 4.7 Hz, 2H), 7.42 (t, J = 8.3Hz, 2H),7.26 (s, 1H), 6.98 (d, J = 3.9 Hz, 3H), 2.53 (s, 3H), 2.34 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 164.71, 162.20, 152.01, 144.33, 143.98, 139.83,138.56, 138.24, 136.37,135.37, 133.20, 133.16, 130.75, 130.18, 130.10,129.29, 126.13, 124.76, 117.73,117.50, 117.43, 117.38, 21.31, 14.13. ESI-MS:mass calcd for [M+H] + (C 23H 17 FN4)381.16; found m / z, 381.17.

[0185] Synthesis of the target compound 7p(5-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-amine)

[0186] It was prepared by general synthetic method N4 from compound 5b and pinacol ester of 2-aminopyrimidine-5-boronic acid. Yield 50.03%, brown solid. 1 H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 8.29 (s, 2H), 8.14 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.8, 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.31(d, J = 8.8 Hz, 2H), 7.18 (d, J = 1.8 Hz, 1H), 6.89 (s, 2H), 3.93 (s, 3H), 2.44 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 163.43, 160.94, 156.19, 153.11,144.16, 143.49,136.59, 135.02, 132.77, 131.26, 129.99, 124.72, 121.63,117.86, 115.98, 115.18, 56.34,14.26. ESI-MS: mass calcd for [M+H] + (C 22 H 18 N6O)383.15; found m / z, 383.16.

[0187] Synthesis of target compound 7q (5-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)pyridine-2-amine)

[0188] It was prepared by general synthetic method N4 from compound 5b and pinacol ester of 2-aminopyridine-5-boronic acid. Yield 48.75%, light brown solid. 1H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 8.10 (d, J= 8.8 Hz,1H), 7.98 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.8, 1.9 Hz, 1H), 7.65 (d, J =8.8Hz, 2H), 7.41 (dd, J = 8.6, 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.17(d, J = 1.7 Hz, 1H), 6.49 (d, J = 8.6 Hz, 1H), 6.18 (s, 2H), 3.94 (s, 3H), 2.43 (s, 3H). 13 C NMR (101MHz, DMSO) δ 160.92, 159.86, 152.93, 146.24, 143.77,143.27, 136.50, 135.56,135.44, 135.05, 130.98, 129.95, 129.54, 125.05,123.36, 117.86, 115.98, 115.27,108.48, 56.32, 14.22. ESI-MS: mass calcd for[M+H] + (C 23 H 19 N5O) 382.16; found m / z, 382.17.

[0189] Synthesis of target compound 7r (1-(4-methoxyphenyl)-8-(6-methoxypyridin-3-yl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0190] It was prepared by general synthetic method N4 from compound 5b and 2-methoxy-5-pyridineboronic acid. Yield 46.12%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.22 (dd, J = 26.6, 5.3Hz, 2H), 7.74 (dd, J = 8.7, 1.5 Hz, 1H), 7.54 (dd, J= 8.6, 2.3 Hz, 1H), 7.42(d, J =8.7 Hz, 2H), 7.27 (d, J = 1.2 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 6.75(d, J = 8.6 Hz, 1H), 3.97 (d, J = 4.2 Hz, 6H), 2.52 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 163.70,160.99, 152.72, 145.07, 144.50, 143.83, 137.12, 136.41,135.32, 134.98, 131.04,129.31, 129.28, 129.09, 125.58, 117.76, 117.09,115.70, 110.87, 55.90, 53.60, 14.11.ESI-MS: mass calcd for [M+H] + (C 24 H 20 N4O2)397.16; found m / z, 397.17.

[0191] Synthesis of the target compound 7S (4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)-3,5-dimethylisoxazole)

[0192] It was prepared according to general synthetic method N4, from compound 5b and 3,5-dimethylisoxazole-4-boronic acid. Yield 43.21%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.28 (d, J = 8.7Hz, 1H), 7.49 (dd, J = 8.7, 1.9 Hz, 1H), 7.44 – 7.36 (m, 2H), 7.15 (dd, J = 11.2,5.2Hz, 3H), 3.95 (s, 3H), 2.48 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.39, 160.87, 158.44, 153.01, 144.91, 143.61, 136.51,135.01, 131.00,129.30, 128.84, 127.91, 127.56, 119.80, 117.68, 116.18,115.73, 55.79, 29.29, 14.14,11.71, 10.87. ESI-MS: mass calcd for [M+H] + (C 23 H 20 N4O2) 385.16; found m / z,385.17.

[0193] Synthesis of target compound 7t (1-(4-methoxyphenyl)-2-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinoline)

[0194] It was prepared by general synthetic method N4 from compound 5b and 1-methyl-1H-pyrazole-4-boronic acid. Yield 51.29%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.65 (dd, J = 8.7, 2.0 Hz, 1H), 7.45 – 7.37 (m, 4H), 7.25 – 7.19 (m,3H), 3.99 (s,3H), 3.91 (s, 3H), 2.51 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ160.94, 152.50, 143.98,143.54, 136.57, 136.43, 135.11, 130.95, 129.85,129.47, 129.21, 127.04, 124.89,122.74, 117.88, 115.53, 115.16, 55.89, 39.14,14.13. ESI-MS: mass calcd for [M+H] + [M+H] + (C 22 H 19 N5O) 370.16; found m / z,370.17.

[0195] Synthesis of target compound 7u (1-(4-methoxyphenyl)-2-methyl-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline)

[0196] It was prepared by general synthesis method N4 from compound 5b and quinoline-3-boronic acid. Yield 48.31%, grayish-brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.34(d, J = 8.7 Hz, 1H), 8.16 – 8.07 (m, 2H), 7.95 (dd, J = 8.7, 2.0 Hz, 1H), 7.81(d, J =8.1 Hz, 1H), 7.76 – 7.70 (m, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.51 –7.42 (m, 3H), 7.22(dd, J = 9.4, 2.7 Hz, 2H), 3.96 (s, 3H), 2.54 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ161.09, 152.87, 149.44, 147.37, 145.03, 144.23, 136.57,135.44, 134.73, 133.24,132.92, 131.39, 129.63, 129.28, 129.21, 129.13,127.95, 127.91, 127.17, 125.83,118.25, 117.85, 115.73, 55.89, 14.15. ESI-MS:mass calcd for [M+H] + (C 27 H 20 N4O)417.16; found m / z, 417.17.

[0197] Synthesis of target compound 7v (1-(4-methoxyphenyl)-2-methyl-8-(naphth-2-yl)-1H-imidazo[4,5-c]quinoline)

[0198] It was prepared from compound 5b and 2-naphthoboric acid according to general synthetic method N4. Yield 53.28%, brown solid. 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 8.8, 2.0 Hz, 1H), 7.87 – 7.78 (m, 4H), 7.56 – 7.46 (m, 4H), 7.46 – 7.41 (m,2H),7.25 – 7.18 (m, 2H), 3.95 (s, 3H), 2.54 (s, 3H). 13 C NMR (101 MHz, CDCl3)δ 161.01,152.61, 144.49, 143.98, 137.76, 137.33, 136.40, 135.64, 133.66,132.69, 130.82,129.49, 129.23, 128.49, 128.12, 127.61, 126.46, 126.22,126.13, 125.88, 124.95,118.05, 117.75, 115.67, 55.85, 14.13. ESI-MS: masscalcd for [M+H] + (C 28 H 21 N3O) 416.17; found m / z, 416.17.

[0199] Synthesis of target compound 7w (4-(5-(1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-yl)morpholine)

[0200] It was prepared by general synthetic method N4 from compound 5b and 2-morpholinylpyrimidine-5-ylboronic acid. Yield 56.51%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.35 (s, 2H), 8.26(d, J = 8.7 Hz, 1H), 7.69 (dd, J = 8.7, 1.9 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.25 (d, J= 1.7 Hz, 1H), 7.20 (d, J= 8.8 Hz, 2H), 3.99 (s, 3H), 3.88 –3.82 (m, 4H), 3.81 – 3.77(m, 4H), 2.51 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ160.99, 155.81, 152.82, 144.49,143.77, 136.47, 135.16, 132.72, 131.29,129.29, 129.06, 124.79, 122.57, 117.91,115.97, 115.73, 66.79, 55.93, 44.36,14.14. ESI-MS: mass calcd for [M+H] + (C 26 H 24 N6O2) 453.20; found m / z, 453.21.

[0201] Synthesis of target compound 7x (1-(4-methoxyphenyl)-2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0202] It was prepared by general synthetic method N4 from compound 5b and pinacol 7-azaindole-5-boronic acid. Yield: 52.18%, light brown solid. 1 H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 9.20 (s, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.8, 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.57 – 7.52 (m, 1H), 7.32 (dd, J =8.4, 5.3 Hz, 3H), 6.47 (dd, J = 3.3, 1.7 Hz, 1H), 3.95 (s, 3H), 2.47 (s, 3H). 13C NMR(101 MHz, DMSO) δ 160.99, 153.02, 148.58, 144.19, 143.53,142.17, 141.67, 136.57,135.24, 131.12, 130.03, 129.56, 127.83, 127.70,126.35, 126.21, 120.24, 117.85,117.34, 116.05, 100.53, 56.33, 14.24. ESI-MS:mass calcd for [M+H] + (C 25 H 19 N5O)406.16; found m / z, 406.17.

[0203] Synthesis of target compound 7y (8-(1H-indol-5-yl)-1-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinoline)

[0204] It was prepared by general synthetic method N4 from compound 5b and 5-indoleboric acid. Yield 48.11%, brown solid. 1 H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 9.16 (s, 1H), 8.14 (d, J = 8.7Hz, 1H), 7.96 (dd, J = 8.8, 1.9 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.56 (s, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.33 (dd, J = 9.4, 5.3 Hz, 3H), 7.18 (d, J = 8.5 Hz, 1H), 6.44 (s, 1H), 3.96 (s, 3H), 2.46 (s, 3H). 13C NMR (101 MHz, DMSO) δ160.99, 152.79, 143.79,143.34, 139.15, 136.50, 136.11, 135.29, 130.78,130.70, 130.01, 129.67, 128.82,126.91, 126.21, 120.45, 118.61, 117.85,117.05, 116.03, 112.34, 101.83, 56.31, 14.24.ESI-MS: mass calcd for [M+H] + (C 26 H 20 N4O) 405.16; found m / z, 405.17.

[0205] Synthesis of target compound 8a (2-(4-(8-(4-acetylphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0206] It was prepared by general synthetic method N4 from compound 5c and p-acetylphenylboronic acid. Yield 53.38%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.85 (dd, J = 12.9, 5.2 Hz, 3H), 7.60 (d, J = 8.4 Hz, 2H), 7.39(d, J = 8.3 Hz, 2H), 7.24 (d, J = 1.8 Hz, 1H), 2.60 (s, 3H), 2.56 (s, 3H), 1.90 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 197.47, 152.11, 145.00,144.59, 144.42, 144.38, 136.79,136.61, 136.60, 136.10, 135.20, 131.25,128.94, 128.73, 127.49, 126.88, 125.94,123.70, 118.08, 117.41, 37.23, 29.14,26.61, 14.20. ESI-MS: mass calcd for [M+H] + (C 29 H 24 N4O) 445.20; found m / z,445.21.

[0207] Synthesis of target compound 8b (2-(4-(8-(4-fluorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0208] It was prepared by general synthesis method N4 from compound 5c and p-fluorophenylboronic acid. Yield 46.88%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.78 (dd, J = 8.8, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.29– 7.24(m, 2H), 7.12 (d, J = 1.9 Hz, 1H), 7.04 (t, J = 8.6 Hz, 2H), 2.55 (s, 3H), 1.88 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 163.87, 161.40, 151.94, 144.63,144.30, 144.02, 137.21,136.71, 136.56, 136.33, 136.30, 135.15, 131.14,128.76, 128.44, 128.36, 127.41,126.02, 123.68, 117.42, 117.30, 115.90,115.69, 37.28, 29.18, 14.21. ESI-MS: masscalcd for [M+H] + (C 27 H 21 FN4) 421.18;found m / z, 421.19.

[0209] Synthesis of the target compound 8c(2-(4-(8-(4-chlorophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0210] It was prepared by general synthesis method N4 from compound 5c and p-chlorophenylboronic acid. Yield 42.58%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.78 (dd, J = 8.8, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.31(d, J =8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 1.9 Hz, 1H), 2.55(s, 3H), 1.89 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 152.01, 144.77, 144.34,144.18, 138.61, 136.93,136.68, 136.59, 135.15, 133.92, 131.23, 129.03,128.73, 128.02, 127.43, 125.89,123.67, 117.44, 117.38, 37.29, 29.20, 14.22.ESI-MS: mass calcd for [M+H] + (C 27 H 21 ClN4) 437.15; found m / z, 437.16.

[0211] Synthesis of target compound 8d (4-(1-(4-(2-cyanopropan-2-yl)phenyl)-2-methyl-1H-imidazo[4,5-c]quinoline-8-yl)-N-methylbenzamide)

[0212] It was prepared according to general synthetic method N4 from compound 5c and 4-(N-methylformamide)phenylboronic acid. Yield 46.01%, grayish-brown solid. 1 H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.47 (d, J =4.2 Hz, 1H), 8.2 (d, J = 8.7 Hz, 1H), 7.98 (dd, J = 15.5, 8.7 Hz, 3H), 7.86 (dd, J =8.4, 1.9 Hz, 4H), 7.43 (d, J = 8.1 Hz, 2H), 7.24 (s, 1H), 2.81 (d, J = 4.1Hz, 3H), 2.48(s, 3H), 1.87 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 166.46,152.77, 144.76, 144.44,144.12, 141.96, 136.75, 136.49, 136.46, 135.13,134.17, 131.32, 129.32, 128.25,127.88, 126.64, 126.08, 124.78, 117.69,117.57, 37.44, 28.85, 26.74, 14.35. ESI-MS:mass calcd for [M+H] + (C 29 H 25 N5O)460.21; found m / z, 460.22.

[0213] Synthesis of target compound 8e(4-(1-(4-(2-cyanopropan-2-yl)phenyl)-2-methyl-1H-imidazo[4,5-c]quinoline-8-yl)benzyl nitrile)

[0214] It was prepared by general synthesis method N4 from compound 5c and 4-cyanobenzonic acid. Yield 51.77%, gray solid. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.77(dd, J = 19.6, 8.1 Hz, 3H), 7.55 (dd, J = 16.9, 8.3 Hz, 4H), 7.33 (d, J = 8.2Hz, 2H), 7.13 (d, J = 1.3 Hz, 1H), 2.50 (s, 3H), 1.82 (s, 6H). 13 C NMR (101MHz, CDCl3) δ152.61, 145.05, 144.62, 144.51, 144.21, 136.50, 136.43, 136.26,135.39, 132.67,131.27, 128.70, 127.61, 127.41, 126.00, 123.64, 118.60,118.19, 117.41, 111.43, 37.24,29.11, 14.24. ESI-MS: mass calcd for [M+H] + (C28 H 21 N5) 428.18; found m / z,428.19.

[0215] Synthesis of target compound 8f (2-methyl-2-(4-(2-methyl-8-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propionitrile)

[0216] It was prepared by general synthetic method N4 from compound 5c and 4-trifluoromethylphenylboronic acid. Yield 53.29%, grayish-brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.84 (ddd, J = 10.9, 7.7, 2.0 Hz, 3H), 7.62 – 7.58 (m, 4H), 7.41 (d, J = 8.1Hz, 2H), 7.19 (d, J = 1.9 Hz, 1H), 2.56 (s, 3H), 1.87 (s, 6H). 13 C NMR (101MHz, CDCl3) δ152.18, 145.01, 144.46, 144.35, 143.77, 136.74, 136.59, 135.23,131.30, 128.73,127.49, 127.14, 126.00, 125.80, 125.76, 123.64, 118.11,117.42, 37.28, 29.11, 14.19.ESI-MS: mass calcd for [M+H] + (C 28 H 21 F3N 4) 471.17;found m / z, 471.18.

[0217] Synthesis of 8g of the target compound (2-methyl-2-(4-(2-methyl-8-(p-tolyl)-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propionitrile)

[0218] It was prepared by general synthetic method N4 from compound 5c and 4-methylphenylboronic acid. Yield 57.26%, light brown solid. 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.83(d, J = 8.4 Hz, 3H), 7.55 (d, J = 8.3 Hz, 2H), 7.19 (dd, J = 7.9, 4.9 Hz, 3H), 7.14(d, J = 8.1 Hz, 2H), 2.54 (s, 3H), 2.36 (s, 3H), 1.88 (s, 6H). 13 CNMR (101 MHz, CDCl3)δ 152.04, 144.25, 144.11, 143.73, 138.19, 137.74, 137.08,136.60, 136.24, 135.26,130.70, 129.61, 128.73, 127.40, 126.64, 126.28,123.71, 117.41, 117.05, 37.35, 29.24,21.09, 14.17. ESI-MS: mass calcd for [M+H] + (C 28 H 24 N4) 417.20; found m / z,417.21.

[0219] Synthesis of the target compound 8h (methyl 4-(1-(4-(2-cyanopropan-2-yl)phenyl)-2-methyl-1H-imidazo[4,5-c]quinoline-8-yl)benzoate)

[0220] It was prepared by general synthetic method N4 from compound 5c and 4-methoxycarbonylphenylboronic acid. Yield 45.17%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.88 – 7.84 (m, 3H), 7.61 – 7.57 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.24 (d, J= 1.9 Hz, 1H), 3.94 (s, 3H), 2.55 (s, 3H), 1.89 (s, 6H). 13 C NMR (101MHz, CDCl3) δ 166.70, 152.10, 145.02, 144.54, 144.44,144.43, 136.93, 136.62,135.21, 131.29, 130.10, 129.30, 128.72, 127.44,126.72, 126.05, 123.62, 118.00,117.43, 52.22, 37.35, 29.26, 14.22. ESI-MS:mass calcd for [M+H] + (C 29 H 24 N4O2)461.19; found m / z, 461.19.

[0221] Synthesis of target compound 8i (2-(4-(8-(4-hydroxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0222] It was prepared by general synthesis method N4 from compound 5c and 4-hydroxyphenylboronic acid. Yield 48.25%, light gray solid. 1 H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 9.17 (s, 1H), 8.12 (d, J =8.8Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.89 – 7.82 (m, 3H), 7.18 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 1.7 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 2.47 (s, 3H), 1.87 (s, 6H). 13C NMR(101 MHz, DMSO) δ 158.01, 152.48, 144.33, 143.92, 143.42,137.48, 136.61, 134.98,131.01, 130.19, 129.33, 127.94, 127.88, 125.62,124.84, 117.64, 116.32, 116.06, 37.41,28.80, 14.34. ESI-MS: mass calcd for [M+H] + (C 27 H 22 N4O) 419.18; found m / z,419.19.

[0223] Synthesis of target compound 8j (2-(4-(8-(4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0224] It was prepared by general synthetic method N4 from compound 5c and 4-methoxyphenylboronic acid. Yield 54.37%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.23 ​​(d, J = 8.8 Hz, 1H), 7.87–7.79 (m, 3H), 7.57 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 1.8 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 2.54 (s, 3H), 1.89 (s, 6H). 13 C NMR (101MHz, CDCl3) δ 159.50, 151.81, 144.24, 144.18, 143.79, 137.83,136.78, 136.50,135.15, 132.57, 130.93, 128.78, 127.87, 127.38, 125.96,123.73, 117.48, 116.68,114.35, 55.36, 37.29, 29.22, 14.23. ESI-MS: mass calcdfor [M+H] + (C28 H 24 N4O)433.20; found m / z, 433.21.

[0225] Synthesis of the target compound 8k(2-(4-(8-(3-(hydroxymethyl)-4-methoxyphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0226] It was prepared according to general synthetic method N4, from compound 5c and (3-hydroxymethyl-4-methoxyphenyl)boronic acid. Yield 50.11%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.17 (d, J =8.7 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.86 (dd, J = 14.7, 4.9 Hz, 3H), 7.52(s, 1H),7.18 (s, 1H), 7.13 – 7.07 (m, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.52 (s, 2H), 3.79 (s, 3H), 2.46 (s, 3H), 1.85 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ156.44, 152.56, 144.31,144.07, 143.53, 137.93, 136.65, 136.54, 134.94,131.79, 131.44, 131.10, 129.24,127.88, 126.03, 125.93, 124.92, 117.69,116.75, 111.12, 58.32, 55.80, 37.28, 28.64,14.37. ESI-MS: mass calcd for [M+H] + (C 29 H 26 N4O2) 463.21; found m / z, 463.22.

[0227] Synthesis of target compound 8l (2-(4-(8-(3,5-bis(trifluoromethyl)phenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0228] It was prepared by general synthetic method N4 from compound 5c and 3,5-bis(trifluoromethyl)phenylboronic acid. Yield 41.71%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.5, 1.8 Hz, 3H), 7.78 (s, 2H),7.63 – 7.58(m, 2H), 7.42 (d, J = 1.9 Hz, 1H), 2.51 (s, 3H), 1.83 (s, 6H). 13 CNMR (101 MHz, CDCl3) δ 152.71, 145.55, 144.62, 144.58, 142.74, 136.79, 136.42,135.60, 134.85,132.41, 132.08, 131.89, 128.49, 127.45, 127.12, 126.00,124.57, 123.53, 121.86,121.25, 118.23, 117.66, 37.25, 28.97, 14.36. ESI-MS:mass calcd for [M+H] + (C 29 H 20 F6N4) 539.16; found m / z, 539.17.

[0229] Synthesis of the target compound 8m(2-methyl-2-(4-(2-methyl-8-(3,4,5-trifluorophenyl)-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propionitrile)

[0230] It was prepared by general synthetic method N4 from compound 5c and 3,4,5-trifluorophenylboronic acid. Yield 47.12%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 0.4 Hz, 1H), 8.27 (d, J =8.8Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.72 (dd, J= 8.8, 1.3 Hz, 1H), 7.62 –7.56 (m, 2H),7.15 (d, J = 1.7 Hz, 1H), 6.90 (dd, J = 8.1, 6.8 Hz, 2H), 2.55(s, 3H), 1.90 (s, 6H). 13CNMR (101 MHz, CDCl3) δ 152.37, 145.18, 144.71,144.34, 136.65, 136.49, 135.06,131.49, 128.66, 127.51, 125.33, 123.55,117.58, 117.41, 110.79, 110.73, 110.63,110.57, 37.41, 29.13, 14.20. ESI-MS: mass calcd for [M+H] + (C 27 H 19 F3N4) 457.16;found m / z, 457.17.

[0231] Synthesis of target compound 8n(2-(4-(8-(3,5-dimethylphenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0232] It was prepared by general synthetic method N4 from compound 5c and 3,5-dimethylphenylboronic acid. Yield 52.87%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.82 (dd, J = 8.6, 3.5 Hz, 3H), 7.58 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 1.7Hz, 1H), 6.96(s, 3H), 2.51 (s, 3H), 2.33 (s, 6H), 1.84 (s, 6H). 13C NMR (101MHz, CDCl3) δ 151.99,144.47, 144.13, 144.08, 140.49, 138.84, 138.33, 136.76,136.52, 135.05, 130.95,129.28, 128.69, 127.22, 126.77, 125.04, 123.62,117.48, 117.43, 37.35, 29.31, 21.51,14.33. ESI-MS: mass calcd for [M+H] + (C 29 H 26 N4) 431.22; found m / z, 431.23.

[0233] Synthesis of target compound 8o(2-(4-(8-(4-aminophenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0234] It was prepared by general synthetic method N4 from compound 5c and 4-aminophenylboronic acid. Yield 46.15%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.85–7.75 (m, 3H), 7.55 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.2 Hz, 3H), 6.63 (d, J = 8.4 Hz, 2H), 2.53 (s, 3H), 1.88 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 151.76,146.42, 144.07,143.88, 143.59, 138.14, 136.76, 136.40, 135.10, 130.75,129.99, 128.75, 127.70,127.33, 125.78, 123.78, 117.51, 115.91, 115.32, 37.28,29.22, 14.21. ESI-MS: masscalcd for [M+H] + (C 27 H 23N5) 418.20; found m / z,418.20.

[0235] Synthesis of the target compound 8p(2-(4-(8-(2-aminopyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-c]quinoline-1-yl)phenyl)-2-methylpropionitrile)

[0236] It was prepared by general synthetic method N4 from compound 5c and pinacol ester of 2-aminopyrimidine-5-boronic acid. Yield 51.16%, grayish-brown solid. 1 H NMR (400 MHz, DMSO) δ 9.19 (s, 1H), 8.22 (s, 2H), 8.15(d, J = 8.8 Hz, 1H), 7.93 (dd, J = 13.7, 8.7 Hz, 3H), 7.83 (d, J = 8.3 Hz, 2H), 7.00 (s, 1H), 6.86 (s, 2H), 2.48 (s, 3H), 1.86 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 163.46,156.14, 152.66, 144.51, 144.17, 143.52, 136.68, 136.49,134.89, 132.83, 131.34,129.42, 127.75, 124.77, 121.46, 117.67, 114.98, 99.99,37.61, 29.05, 14.32. ESI-MS:mass calcd for [M+H] + (C 25 H 21 N7) 420.19; found m / z,420.20.

[0237] Synthesis of target compound 8q (2-(4-(8-(6-aminopyridin-3-yl)-2-methyl-1H-imidazo[4,5-c]quinoline-1-yl)phenyl)-2-methylpropionitrile)

[0238] It was prepared by general synthetic method N4 from compound 5c and pinacol ester of 2-aminopyridine-5-boronic acid. Yield 46.34%, brown solid. 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 8.11 (d, J=8.7 Hz,1H), 8.01 (s, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.85 (dd, J = 14.4, 9.0 Hz, 3H), 7.27 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.45 (d, J = 8.5 Hz, 1H), 6.18 (s,2H), 2.47 (s,3H), 1.88 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 159.85, 152.52,146.21, 144.39,143.78, 143.31, 136.64, 136.58, 135.54, 135.17, 134.90,131.09, 129.36, 127.80,125.00, 124.78, 123.06, 117.71, 115.04, 108.53, 37.51,28.93, 14.33. ESI-MS: masscalcd for [M+H] + (C 26 H 22 N6) 419.19; found m / z,419.20.

[0239] Synthesis of the target compound 8r(2-(4-(8-(6-methoxypyridin-3-yl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0240] It was prepared by general synthetic method N4 from compound 5c and 2-methoxy-5-pyridineboronic acid. Yield 42.91%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.26 (d, J = 8.7Hz, 1H), 8.06 (d, J = 2.3 Hz, 1H), 7.88 – 7.84 (m, 2H), 7.76 (dd, J = 8.7, 2.0Hz, 1H),7.60 – 7.57 (m, 2H), 7.52 (dd, J = 8.6, 2.6 Hz, 1H), 7.07 (d, J= 1.9Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 3.94 (s, 3H), 2.56 (s, 3H), 1.93 – 1.88 (m,6H). 13 C NMR (101 MHz, CDCl3) δ 163.75, 152.00, 144.90, 144.53, 144.50, 143.87,136.77, 136.62, 136.51,135.13, 134.98, 131.19, 128.96, 128.77, 128.39,128.27, 127.47, 125.45, 123.70,117.48, 116.82, 110.90, 53.53, 37.40, 29.23,14.17. ESI-MS: mass calcd for [M+H] + (C 27 H 23 N5O) 434.19; found m / z, 434.20.

[0241] Synthesis of the target compound 8S(2-(4-(8-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline-1-yl)phenyl)-2-methylpropionitrile)

[0242] It was prepared according to general synthetic method N4 from compound 5c and 3,5-dimethylisoxazole-4-boronic acid. Yield 47.81%, grayish-brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.28 (d, J =8.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.50 (dd, J = 8.7, 1.9 Hz, 1H), 7.01 (d, J = 1.5 Hz, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.07 (s, 3H), 1.87 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 165.26, 158.06, 152.39, 144.90,144.24, 143.66, 136.71,136.62, 134.70, 131.17, 128.47, 128.05, 127.67,127.62, 123.50, 119.54, 117.44,116.01, 37.28, 29.15, 14.27, 11.71, 10.88.ESI-MS: mass calcd for [M+H] + (C 26 H 23 N5O) 422.19; found m / z, 422.20.

[0243] Synthesis of target compound 8t (2-methyl-2-(4-(2-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-c]quinoline-1-yl)phenyl)propionitrile)

[0244] It was prepared by general synthetic method N4 from compound 5c and 1-methyl-1H-pyrazole-4-boronic acid. Yield 53.13%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.17 (d, J = 8.6Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 19.2 Hz, 2H), 7.05 (s, 1H), 3.89 (s, 3H), 2.53 (s, 3H), 1.93(s, 6H). 13CNMR (101 MHz, CDCl3) δ 151.89, 144.21, 143.83, 143.46, 136.72,136.44, 136.32,134.80, 130.98, 130.11, 128.81, 127.40, 126.91, 125.12,123.80, 122.52, 117.58,114.88, 39.11, 37.20, 29.13, 14.19. ESI-MS: mass calcdfor [M+H] + (C25 H 22 N6) 407.19; found m / z, 407.19.

[0245] Synthesis of the target compound 8u(2-methyl-2-(4-(2-methyl-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinolin-yl)phenyl)propionitrile)

[0246] It was prepared by general synthetic method N4 from compound 5c and quinoline-3-boronic acid. Yield 52.37%, brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.11 – 8.06 (m, 2H), 7.94 (dd, J = 8.7, 2.0 Hz, 1H), 7.85 (dd, J = 16.0,8.2 Hz, 3H), 7.75 – 7.69 (m, 1H), 7.59 (dd, J = 15.8, 7.8 Hz, 3H), 7.30 (d, J = 1.9 Hz,1H), 2.57 (s, 3H), 1.86 (s, 6H). 13 C NMR (101 MHz, CDCl3)δ 152.31, 149.29, 147.42,144.93, 144.69, 144.12, 136.65, 136.52, 135.22,135.16, 133.12, 132.95, 131.46,129.72, 129.27, 128.72, 127.94, 127.77,127.49, 127.27, 126.16, 123.72, 118.18,117.58, 37.45, 29.30, 14.25. ESI-MS: mass calcd for [M+H] + (C 30 H 23 N5) 454.20;found m / z, 454.21.

[0247] Synthesis of target compound 8v (2-methyl-2-(4-(2-methyl-8-(naphth-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propionitrile)

[0248] It was prepared by general synthesis method N4 from compound 5c and 2-naphthoboric acid. Yield 50.97%, light brown solid. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.31 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.8, 1.9 Hz, 1H), 7.81 (dt, J = 12.0, 8.6 Hz, 6H), 7.58 (d, J = 8.4 Hz,2H), 7.52– 7.46 (m, 2H), 7.36 (dd, J = 8.5, 1.6 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 2.54 (s, 3H), 1.83 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 152.01, 144.56,144.30, 144.12, 138.24,137.47, 136.69, 136.53, 135.19, 133.53, 132.67,131.10, 128.76, 128.58, 128.17,127.65, 127.36, 126.57, 126.52, 126.34,125.99, 124.83, 123.71, 117.86, 117.53, 37.38,29.27, 14.25. ESI-MS: masscalcd for [M+H] + (C 31 H 24 N4) 453.20; found m / z,453.21.

[0249] Synthesis of target compound 8w (2-methyl-2-(4-(2-methyl-8-(2-morpholinidin-5-yl)-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propionitrile)

[0250] It was prepared by general synthetic method N4 from compound 5c and 2-morpholinylpyrimidine-5-ylboronic acid. Yield 51.88%, brown solid.1 H NMR (400 MHz, CDCl3) δ 9.29 (d, J = 4.6 Hz, 1H), 8.24 (dd, J = 8.1, 4.1 Hz, 3H), 7.87 (dd, J = 8.5, 1.9 Hz, 2H), 7.72 (ddd, J = 8.6, 4.3,1.9 Hz,1H), 7.62 – 7.55 (m, 2H), 7.02 – 6.96 (m, 1H), 3.85 – 3.72 (m, 8H),2.56 (d, J = 2.7Hz, 3H), 1.93 (d, J = 1.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ160.98, 155.50,151.96, 144.60, 144.53, 143.81, 136.65, 136.57 135.00, 132.59,131.42, 128.81,127.46, 124.28, 123.65, 122.04, 117.59, 115.63, 66.75, 44.28,37.50, 29.30, 14.16.ESI-MS: mass calcd for [M+H] + (C 29 H 27 N7O) 490.23; found m / z, 490.24.

[0251] Synthesis of target compound 8x (2-methyl-2-(4-(2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline-1-yl)phenyl)propionitrile)

[0252] It was prepared by general synthetic method N4 from compound 5c and pinacol ester of 7-azaindole-5-boronic acid. Yield 55.71%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.22 (s,1H), 8.20 (d, J = 8.7 Hz, 2H), 8.01 (dd, J = 8.8, 1.7 Hz, 1H), 7.96 (d, J= 8.4Hz, 2H), 7.89 (dd, J = 15.4, 5.1 Hz, 3H), 7.52 (d, J = 3.0 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 6.47(d, J = 3.2 Hz, 1H), 2.49 (s, 3H), 1.84 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ152.62, 148.63, 144.46, 144.22, 143.59, 141.66, 136.68,136.63, 136.54, 134.99,131.26, 129.39, 127.78, 127.61, 126.38, 126.19,124.76, 120.16, 117.71, 117.13,100.55, 37.57, 28.98, 14.35. ESI-MS: masscalcd for [M+H] + (C 28 H 22 N6) 443.19;found m / z, 443.20.

[0253] Synthesis of the target compound 8y (2-(4-(8-(1H-indol-5-yl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0254] It was prepared according to general synthetic method N4 from compound 5c and 5-indoleboric acid. Yield 48.12%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.18 (s, 1H), 8.16 (d, J =8.8Hz, 1H), 8.03 – 7.91 (m, 3H), 7.86 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 7.39(t, J =5.6 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1H), 7.07 (dd, J= 8.5, 1.5 Hz, 1H), 6.46 (s, 1H), 2.47 (s, 3H), 1.84 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 152.46,144.31, 143.82, 143.42,139.34, 136.64, 136.63, 136.10, 134.97, 130.98,130.73, 129.33, 128.73, 127.80,126.83, 126.49, 124.84, 120.39, 118.60,117.72, 116.82, 112.41, 101.99, 37.48, 28.88,14.37. ESI-MS: mass cald for [M+H] + (C 29 H 23 N5) 442.20; found m / z, 442.21.

[0255] Synthesis of target compound 8z (2-(4-(8-(1H-benzo[d]imidazol-5-yl)-2-methyl-1H-imidazol[4,5-c]quinoline-1-yl)phenyl)-2-methylpropionitrile)

[0256] It was prepared by general synthetic method N4 from compound 5c and 1H-benzimidazole-5-boronic acid pinacol ester. Yield 45.39%, brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 9.24 (s,1H), 8.22 (d, J = 8.7 Hz, 1H), 8.10 (s, 1H), 8.01 (dd, J = 8.8, 1.8 Hz, 1H), 7.96– 7.92(m, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.64 (s,1H), 7.28 (d, J =1.9 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 2.48 (s, 3H), 1.82 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 152.69, 144.46, 144.41, 143.88, 141.04,138.18, 137.75, 136.71, 136.52,135.07, 133.82, 131.24, 129.33, 127.86,126.58, 124.86, 122.71, 121.54, 119.79,118.09, 117.60, 108.66, 37.37, 28.74,14.36. ESI-MS: mass calcd for [M+H] + (C 28 H 22 N6) 443.19; found m / z, 443.20.

[0257] Synthesis of target compound 14a (2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinoline)-2-methylpropionitrile)

[0258] It was prepared by general synthetic method N4 from compound 13a and pinacol 7-azaindole-5-boronic acid. Yield: 48.25%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.23 (s,1H), 8.27 (d, J = 2.1 Hz, 1H), 8.22 (dd, J = 8.6, 1.9 Hz, 3H), 8.09 (d, J = 8.2Hz, 2H), 8.03 (dd, J = 8.8, 1.9 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.55 – 7.51(m, 1H), 7.16 (d, J = 1.7 Hz, 1H), 6.41 (dd, J = 3.2, 1.6 Hz, 1H), 2.50 (s,3H). 13C NMR (101 MHz, DMSO-d6) δ 152.48, 148.65, 144.26, 143.63, 141.63,140.82, 136.78, 136.69, 134.82,131.32, 130.19, 128.12, 128.08, 127.85,127.45, 126.35, 126.10, 122.97, 120.24,117.58, 117.08, 100.38, 14.36. ESI-MS:mass calcd for [M+H] + (C 25 H 16 F3N5)444.14; found m / z, 444.15.

[0259] Synthesis of target compound 14b (1,2-dimethyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0260] It was prepared by general synthetic method N4 from compound 13b and pinacol 7-azaindole-5-boronic acid. Yield: 42.33%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.09 (s,1H), 8.76 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.22(d, J = 8.7 Hz, 1H), 8.04 (dd, J = 8.7, 1.8 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 6.57 (d, J= 3.3 Hz, 1H), 4.28 (s, 3H), 2.66 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 153.09,148.68, 144.08, 143.35, 142.52, 137.18, 136.66, 134.42,131.06, 128.38, 127.63,127.24, 126.47, 120.28, 118.67, 118.51, 100.77, 34.02,14.20. ESI-MS: mass calcd for[M+H] + (C 19 H 15 N5) 314.13; found m / z, 314.14.

[0261] Synthesis of target compound 14c (1-cyclopropyl-2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0262] It was prepared by general synthetic method N4 from compound 13c and pinacol 7-azaindole-5-boronic acid. Yield 45.17%, brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.08 (d, J =3.6Hz, 2H), 8.73 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 1.9 Hz, 1H), 8.22 (d, J =8.7 Hz, 1H), 8.06 (dd, J = 8.7, 1.7 Hz, 1H), 7.56 (s, 1H), 6.58 (d, J = 2.2Hz, 1H), 4.01 – 3.93 (m,1H), 2.73 (s, 3H), 1.51 (d, J = 5.8 Hz, 2H), 1.25 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 154.62, 148.67, 144.10, 143.62, 142.33,136.79, 136.50, 135.31, 130.96, 128.49,127.65, 127.04, 126.42, 120.37,120.12, 118.49, 100.87, 27.79, 15.95, 10.80. ESI-MS:mass calcd for [M+H] + (C 21 H 17 N5) 340.15; found m / z, 340.16.

[0263] Synthesis of target compound 14d ((S)-2-methyl-1-(1-phenylethyl)-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0264] It was prepared by general synthetic method N4 from compound 13d and pinacol 7-azaindole-5-boronic acid. Yield: 46.29%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.20 (s,1H), 8.16 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 3.0 Hz, 3H), 7.45(d, J = 7.0 Hz, 3H), 7.31 (d, J = 7.0 Hz, 2H), 6.55 (d, J = 3.3 Hz, 1H), 6.41 (s, 1H), 2.76 (s, 3H), 2.00 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 153.85,148.60, 144.56, 143.68, 142.02, 140.78, 137.85, 136.73, 133.37,131.17, 129.82,128.10, 127.83, 127.66, 126.77, 126.07, 120.16, 117.82,100.63, 54.71, 18.99, 15.46.ESI-MS: mass calcd for [M+H] + (C 26 H 21 N5) 404.18;found m / z, 404.19.

[0265] Synthesis of target compound 14e ((R)-2-methyl-1-(1-phenylethyl)-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0266] It was prepared according to general synthetic method N4 from compound 13e and pinacol 7-azaindole-5-boronic acid. Yield 45.11%, brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.21 (s,1H), 8.18 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 8.6 Hz, 1H), 7.84 – 7.51 (m, 3H), 7.47(d, J= 7.0 Hz, 3H), 7.33 (d, J = 7.0 Hz, 2H), 6.57 (d, J = 2.1 Hz, 1H), 6.42(s, 1H), 2.77 (s,3H), 2.02 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ153.82, 148.61,144.58, 143.70, 142.04, 140.81, 137.87, 136.72, 133.35,131.18, 129.82, 128.10,127.85, 127.63, 126.76, 126.10, 126.02, 120.14,117.83, 100.63, 54.70, 19.00, 15.46.ESI-MS: mass calcd for [M+H] + (C 26 H 21 N5)404.18; found m / z, 404.18.

[0267] Synthesis of target compound 14f (4-(2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinolin-1-yl)benzyl nitrile)

[0268] It was prepared by general synthetic method N4 from compound 13f and pinacol ester of 7-azaindole-5-boronic acid. Yield: 47.21%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.23 (s,1H), 8.35 (d, J = 8.4 Hz, 2H), 8.25 (d, J = 2.1 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.09(d, J = 8.4 Hz, 2H), 8.02 (dd, J = 8.8, 2.0 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.56 (d, J= 2.3 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 6.50 (d, J= 3.3 Hz,1H), 2.49 (s, 3H). 13CNMR (101 MHz, DMSO-d6) δ 152.38, 148.64, 144.23,143.62, 141.57, 141.27, 136.80,136.77, 135.07, 134.75, 131.30, 130.38,127.89, 127.55, 126.42, 126.34, 120.27,118.41, 117.49, 117.22, 113.60,100.60, 14.37. ESI-MS: mass cald for [M+H] + (C 25 H 16 N6) 401.14; found m / z,401.15.

[0269] Synthesis of target compound 14g (2-(4-(2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)acetonitrile)

[0270] It was prepared by general synthetic method N4 from compound 13 g and pinacol 7-azaindole-5-boronic acid. Yield 43.69%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.22 (s,1H), 8.30 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 8.8, 2.0Hz, 1H),7.86 – 7.78 (m, 5H), 7.53 (d, J = 1.5 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 6.55 (d, J = 3.1Hz, 1H), 4.31 (s, 2H), 2.46 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 152.72, 148.62,144.23, 143.59, 141.71, 136.68, 136.66, 136.55,134.87, 134.28, 131.22, 130.60,129.39, 127.78, 127.57, 126.38, 126.14,120.31, 119.33, 117.76, 117.17, 100.77, 22.70,14.35. ESI-MS: mass calcd for[M+H] + (C 26 H 18 N6) 415.16; found m / z, 415.17.

[0271] Synthesis of target compound 14h (2-methyl-2-(5-(2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline-1-yl)pyridin-2-yl)propionitrile)

[0272] It was prepared by general synthetic method N4 from compound 13h and pinacol 7-azaindole-5-boronic acid. Yield 52.17%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.24 (s,1H), 9.10 (d, J = 2.1 Hz, 1H), 8.44 (dd, J = 8.4, 2.3 Hz, 1H), 8.28 – 8.18 (m,2H), 8.05(dd, J = 19.4, 8.6 Hz, 2H), 7.92 (s, 1H), 7.54 (s, 1H), 7.15 (s,1H), 6.48 (d, J = 2.7 Hz,1H), 2.51 (s, 3H), 1.87 (d, J = 7.3 Hz, 6H). 13C NMR(101 MHz, DMSO-d6) δ 161.97,152.92, 149.12, 148.66, 144.24, 143.66, 141.66,138.46, 136.86, 136.84, 135.09,133.38, 131.41, 127.84, 127.62, 126.60,126.24, 124.21, 121.55, 120.18, 117.61,117.00, 100.59, 28.07, 27.63, 14.39.ESI-MS: mass calcd for [M+H] + (C 27 H 21 N7)444.19; found m / z, 444.20.

[0273] Synthesis of target compound 14i (2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-c]quinoline)

[0274] It was prepared by general synthetic method N4 from compound 13i and pinacol ester of 7-azaindole-5-boronic acid. Yield 51.13%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.13 (s,1H), 8.70 (d, J = 1.7 Hz, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 4.63 (d, J = 6.7Hz, 2H), 3.87 (d, J = 10.9 Hz, 2H), 3.26 (dd, J = 17.4,7.0 Hz, 2H), 2.70 (s, 3H), 2.35(s, 1H), 1.63 – 1.44 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 153.36, 148.67, 144.34,143.50, 142.34, 137.47, 137.07, 133.59,131.35, 128.49, 127.74, 127.16, 126.48,120.32, 118.76, 118.21, 100.72, 66.88,51.01, 36.25, 30.47, 14.67. ESI-MS: mass calcd for [M+H] + (C 24 H 23 N5O) 398.19; found m / z, 398.20.

[0275] Synthesis of target compound 14j (2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-c]quinoline)

[0276] It was prepared by general synthetic method N4 from compound 13j and pinacol 7-azaindole-5-boronic acid. Yield 50.98%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.12 (s,1H), 8.76 (d, J = 1.9 Hz, 1H), 8.59 (s, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.24 (d, J = 8.7Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.57 (s, 1H), 6.57 (d, J = 3.0 Hz, 1H), 4.72 (qd, J =15.5, 7.9 Hz, 2H), 3.98 (dd, J = 13.9, 8.0 Hz, 1H), 3.76 –3.67 (m, 1H), 3.61 (d, J =4.6 Hz, 2H), 2.99 (s, 1H), 2.71 (s, 3H), 2.04 (td, J = 13.5, 8.0 Hz, 1H), 1.83 (dt, J=12.5, 7.3 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 153.10, 148.67, 144.32, 143.53,142.47, 137.46, 136.97, 133.66, 131.39,128.36, 127.65, 127.23, 126.50, 120.32,118.55, 118.25, 100.78, 69.83, 67.13,47.66, 29.38, 14.47. ESI-MS: mass calcd for [M+ H]+ (C 23 H 21 N5O) 384.17; foundm / z, 384.18.

[0277] Synthesis of target compound 14k (2-methyl-1-phenyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0278] It was prepared by general synthetic method N4 from compound 13k and pinacol ester of 7-azaindole-5-boronic acid. Yield 53.13%, brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.22 (s,1H), 8.19 (dd, J = 10.1, 5.4 Hz, 2H), 7.99 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 1.8Hz, 1H),7.79 (s, 5H), 7.53 (d, J = 3.4 Hz, 1H), 7.27 (d, J = 1.5 Hz, 1H), 6.49 (d, J = 3.4 Hz, 1H), 2.46 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 152.68,148.51, 144.23, 143.56,141.55, 137.18, 136.67, 136.62, 134.95, 131.18,130.98, 130.77, 128.78, 127.77,127.69, 126.42, 126.38, 120.18, 117.76,117.30, 100.65, 14.32. ESI-MS: mass calcdfor [M+H] + (C 24 H 17 N5) 376.15; found m / z, 376.17.

[0279] Synthesis of target compound 14l ((R)-1-(1-(4-fluorophenyl)ethyl)-2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0280] It was prepared by general synthetic method N4 from compound 13l and pinacol 7-azaindole-5-boronic acid. Yield: 48.37%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.21 (s,1H), 8.19 (d, J = 8.7 Hz, 2H), 7.94 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 3.4Hz, 1H), 7.41 – 7.36 (m, 2H), 7.29 (t, J = 8.8 Hz, 2H), 6.55 (d, J = 3.4Hz, 1H), 6.42(s, 1H), 2.76 (s, 3H), 2.02 (d, J = 6.9 Hz, 3H). 13C NMR (101MHz, DMSO-d6) δ163.24, 160.81, 153.81, 148.62, 144.61, 143.74, 141.99,137.89, 137.06, 137.03,136.80, 133.30, 131.27, 128.43, 128.35, 127.90,127.74, 126.69, 126.11, 120.14,117.79, 116.61, 116.39, 100.53, 54.33, 19.27,15.50. ESI-MS: mass calcd for [M+H] + (C 26 H 20 FN5) 422.17; found m / z, 422.18.

[0281] Synthesis of target compound 14m ((S)-1-(1-(4-fluorophenyl)ethyl)-2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0282] It was prepared by general synthetic method N4 from compound 13m and pinacol 7-azaindole-5-boronic acid. Yield 46.18%, brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.20 (s,1H), 8.18 (d, J = 8.7 Hz, 2H), 7.94 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 41.0 Hz, 2H), 7.57(d, J = 3.4 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.28 (t, J = 8.8 Hz, 2H), 6.54 (d, J = 3.4 Hz,1H), 6.41 (s, 1H), 2.75 (s, 3H), 2.02 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.24, 160.81, 153.81, 148.61, 144.61,143.74, 141.98, 137.86, 137.07, 137.04,136.80, 131.27, 128.44, 128.35,127.89, 127.74, 126.69, 126.11, 120.14, 117.79,116.61, 116.40, 100.53, 54.34,19.29, 15.46. ESI-MS: mass cald [M+H] + (C 26 H 20 FN5) 422.17; found m / z,422.18.

[0283] Synthesis of target compound 14n (1-(5-fluoropyridin-2-yl)-2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0284] It was prepared by general synthetic method N4 from compound 13n and pinacol ester of 7-azaindole-5-boronic acid. Yield: 46.18%, as a brownish-yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.25 (s,1H), 8.96 (d, J = 3.0 Hz, 1H), 8.33 (td, J = 8.4, 3.1 Hz, 1H), 8.25 (dd, J = 9.9, 5.4 Hz, 2H), 8.18 (dd, J = 8.7, 4.0 Hz, 1H), 8.02 (td, J = 4.2, 2.0 Hz, 2H), 7.55 (d, J = 3.4 Hz, 1H), 7.08 (d, J = 1.7 Hz, 1H), 6.51 (d, J = 3.4 Hz, 1H), 2.52 (s, 3H). 13C NMR (101MHz, DMSO-d6) δ 161.56, 159.00, 152.43, 148.59,146.18, 146.15, 144.28, 143.66,141.61, 139.24, 138.98, 137.00, 136.64,134.70, 131.31, 127.85, 127.81, 127.67,126.80, 126.60, 125.88, 125.82,120.27, 117.70, 117.40, 100.66, 14.36. ESI-MS: mass calcd for [M+H] + (C 23 H 15 FN6) 395.13; found m / z, 395.14.

[0285] Synthesis of target compound 14o (1-benzyl-2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline)

[0286] It was prepared by general synthetic method N4 from compound 13o and pinacol 7-azaindole-5-boronic acid. Yield: 51.39%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.19 (s,1H), 8.39 (d, J = 1.9 Hz, 1H), 8.24 – 8.17 (m, 2H), 7.96 (d, J = 7.1 Hz, 2H), 7.56(d, J= 3.4 Hz, 1H), 7.40 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.18(d, J = 7.4 Hz, 2H), 6.55 (d, J = 3.4 Hz, 1H), 6.05 (s, 2H), 3.35 (s, 2H), 2.73 (s, 3H). 13C NMR (101MHz, DMSO-d6) δ 153.61, 148.59, 144.30, 143.46,142.19, 137.11, 137.03, 134.03,131.02, 129.65, 128.14, 128.02, 127.65,126.94, 126.37, 126.10, 120.19, 118.84,117.93, 100.68, 49.04, 14.12. ESI-MS:mass calcd for [M+H] + (C 25 H 19 N5) 390.16;found m / z, 390.17.

[0287] Synthesis of target compound 14p (2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazo[4,5-c]quinoline)

[0288] It was prepared by general synthetic method N4 from compound 13p and pinacol ester of 7-azaindole-5-boronic acid. Yield 46.17%, brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.35 –9.21 (m,2H), 8.70 (dd, J = 8.2, 2.0 Hz, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.26 (dd, J =14.5, 5.4 Hz, 2H), 8.05 (dd, J = 8.8, 1.9 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.54 (d, J =3.2 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 6.42 (d, J = 3.3 Hz, 1H), 2.53 (s, 3H). 13C NMR(101 MHz, DMSO-d6) δ 152.83, 150.59, 148.69, 144.28,143.72, 141.66, 139.47,137.01, 136.95, 134.95, 131.47, 127.90, 127.49,126.62, 126.18, 122.94, 120.24,117.49, 117.07, 100.39, 14.42. ESI-MS: masscalcd for [M+H] + (C 24 H 15 F3N6) 445.13; found m / z, 445.14.

[0289] Synthesis of target compound 14q (4-(4-(2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinoline-1-yl)phenyl)morpholine)

[0290] It was prepared by general synthetic method N4 from compound 13q and pinacol 7-azaindole-5-boronic acid. Yield: 48.28%, brownish-red solid. 1 H NMR (400 MHz, DMSO) δ 13.16 (s, 1H), 9.20 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.12 (s, 1H), 7.99 (dd, J = 8.8, 1.6 Hz, 1H), 7.75(d, J =8.4 Hz, 1H), 7.64 (s, 1H), 7.57 (dd, J = 8.8, 3.5 Hz, 2H), 7.41 (d, J = 1.5 Hz, 1H), 7.26(dd, J = 8.9, 3.3 Hz, 2H), 7.07 (d, J = 8.4 Hz, 1H), 3.83– 3.77 (m, 4H), 3.29 (d, J =3.9 Hz, 4H), 2.46 (s, 3H). 13C NMR (101 MHz, DMSO)δ 153.12, 152.63, 144.41,143.82, 140.97, 137.98, 137.92, 136.58, 135.42,133.98, 131.05, 129.17, 127.44,126.38, 122.75, 121.43, 120.10, 118.38,117.80, 116.31, 108.55, 66.50, 48.50, 14.23. ESI-MS: mass calcd for [M+H] + (C 28 H 24 N6O) 461.20; found m / z, 461.21.

[0291] Synthesis of target compound 14r(2-(4-(7-fluoro-2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropionitrile)

[0292] It was prepared by general synthetic method N4 from compound 13r and pinacol 7-azaindole-5-boronic acid. Yield: 47.27%, light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.25 (s,1H),8.13 (s, 1H), 7.99 (d, J = 12.4 Hz, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5Hz, 3H), 7.55 (d, J = 3.3 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.49 (d, J = 3.4 Hz, 1H), 2.48 (s, 3H), 1.76 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 159.60,157.14, 152.64,148.43, 145.43, 144.62, 144.50, 142.85, 142.81, 142.16,136.32, 136.27, 135.06,129.33, 128.33, 128.31, 127.78, 127.31, 127.14,126.75, 124.67, 122.87, 121.80,121.75, 119.84, 115.24, 115.03, 114.79,100.63, 37.50, 28.88, 14.30. ESI-MS: mass calcd for [M+H] + (C 28 H 21 FN6) 461.18;found m / z, 461.19.

[0293] Example 2: Inhibitory activity of the target compound against tumor cells

[0294] The tumor cell lines used in this experiment were colon cancer cells HT29, HCT15, and SW620, lung cancer cell line H3122, and cervical cancer cell line HeLa. All these cell lines were purchased from ATCC (American Society for Cancer Research). Cell culture conditions followed ATCC guidelines. The culture medium was RPMI 1640, L-15, and DMEM provided by Gibco; 37 ℃, 5% CO2, 1% penicillin / streptomycin (V / V), and 10% Gibco fetal bovine serum.

[0295] The MTT assay was used to assess tumor cell inhibitory activity. The main component of MTT is 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide, which can interact with succinate dehydrogenase produced in the mitochondria of viable cells to generate water-insoluble formazan. This phenomenon was used to assess the effect on cell viability. Cells were inoculated at 2–4 × 10⁻⁶ cells / year. 3Cells were seeded at a density of 0.1 mL / well in 96-well plates. After 24 h of culture, the compound was added, and after 72 hours of treatment, 20 μL of MTT solution (5 mg / mL) was added to each well, and the plates were incubated at 37 °C for another 2–4 h. The supernatant was discarded, and 150 μL of DMSO was added to each well, and the plates were shaken thoroughly for 10–15 min to dissolve. The absorbance (OD) of the 96-well plates was measured at 570 nm using a Spectra MAXM5 microplate spectrophotometer (Molecular Devices, CA, USA) to calculate the relative inhibition rate of tumor cell proliferation for each target compound. The IC50 value was then calculated using software. The results are shown in Table 1. The IC50 value of each compound was set in three wells, representing the average of three repeated independent experiments. The relative cell proliferation inhibition rate (%) was calculated using the formula: (solvent blank control group A570 - experimental group A570) / solvent blank control group A570 × 100%, and the corresponding IC50 value (in μmol / L) was calculated using GraphPad Prism5 software.

[0296] Table 1

[0297]

[0298]

[0299] The experimental results show that, firstly, we fixed the R3 group and discussed the effect of the R1 substituent on the activity. We found that when the R1 substituent is a benzene ring structure with hydrogen bond donors and acceptors, the antitumor activity is significantly improved. We found compounds 6p and 6x with better activity. Then, we further modified the compounds and found compounds 8p and 8x with even better activity. The experimental results show that the antitumor activity of 8x is significantly better than that of other molecules. We fixed the R1 group as 7-azaindolyl and studied different substituents in the R3 group. We found that changes in the R3 group altered the antitumor activity. When the R3 group was fluorinated, the compound's antitumor activity was significantly reduced. We found that when the R3 group was substituted with 2-(5-aminopyridin-2-yl)-2-methylpropionitrile, we obtained the molecule 14h with the best activity. Its IC50 values ​​for antitumor activity in HT29, HCT15, H3122, HeLa, and SW620 tumor cells were 0.25 μM, 0.17 μM, 0.29 μM, 0.09 μM, and 0.16 μM, respectively. The antitumor activity of compound 14h was significantly superior to the positive control drugs PI-103 and BEZ235. Therefore, we hypothesize that compound 14h modulates its mechanism of action through the PI3K / m-TOR protein pathway, thereby enhancing its antitumor activity.

[0300] The structural formulas of the positive control drugs PI-103 and BEZ235 are as follows:

[0301]

[0302] Example 3: Assay of the inhibitory activity of the target compound against PI3K / m-TOR kinase

[0303] The inhibitory activities of the target compounds against m-TOR and PI3K were determined using the Kinase-Glo Plus Luminescent assay and the Lance Ultra assay, respectively. The kinases tested in the broad-spectrum screening of the compounds were PI3Kα, PI3Kδ, and m-TOR. PI-103 and BEZ235 were used as positive controls. The inhibitory rates of the compounds against the kinases at a concentration of 50 nM were tested, and the results are shown in Table 2.

[0304] Table 2

[0305]

[0306] -: Not tested.

[0307] The test results show that compound 14h exhibits significantly better inhibition rates against PI3Kα, PI3Kδ, and m-TOR than other molecules, and compounds 8q and 8x also show superior inhibition rates compared to the positive control. Analysis of the experimental results reveals that the activity is significantly enhanced when the R1 substituent is an aryl benzene ring with both hydrogen bond donor and acceptor; the activity is significantly enhanced when the R3 group is an aryl hydrophobic conjugated group; and the activity decreases when the R2 substituent is replaced with F. We further screened the compounds and found that the activity is significantly enhanced when the R1 substituent is 7-azaindolyl, R2 is H-substituted, and R3 is 2-(5-aminopyridin-2-yl)-2-methylpropionitrile.

[0308] IC50 of compound 14h in m-TOR and PI3K I kinases 50 The test was conducted, and the results are shown in Table 3.

[0309] Table 3

[0310]

[0311] All experimental results represent three independent replicate experiments.

[0312] The test results show that compound 14h is significantly superior to the positive controls PI-103 and BEZ235, with IC50 values ​​of 3.5 nM, 4.6 nM, and 21.3 nM for PI3Kα, PI3Kδ, and m-TOR kinases, respectively. It has obvious selective inhibitory effects on the m-TOR and PI3K I pathways, indirectly proving that compound 14h has good in vitro antitumor activity.

[0313] Example 4: Molecular docking of target compound molecules over 14 hours

[0314] To predict the binding mode of compound 14h with the PI3Kα / m-TOR protein, we performed molecular docking analysis using GOLD5.0 (GOLD5.0, laxoSmithKline, CCDC, UK). The crystal structures of the PI3Kα protein (PDB code: 4JPS) and m-TOR protein (PDB code: 4JT6) were provided from the RCSB protein database. During molecular docking, water molecules were removed from the protein crystals and hydrogen atoms were added. The docking site value was 20 Å, and the remaining parameters were set to system defaults. The docking results are shown below. Figure 1 As shown.

[0315] The figure shows a simulated diagram of the interaction between compound molecule 14h and the target PI3Kα / m-TOR protein. Compound 14h interacts with key groups of the PI3Kα / m-TOR protein, and docking results show that it binds tightly to the protein's ATP pocket. Molecular docking results showed that in the PI3Kα protein docking, the NH atom on the azaindole ring had a key hydrogen bond with Asp933 and with lLE932; the quinoline core had π-π stacking interactions with Cys838 and Met922, and a key hydrogen bond with Val850; and the methyl group on the imidazole ring had a hydrophobic interaction with Trp780. These key interacting groups may be closely related to the compound's 14-hour inhibition of PI3Kα kinase activity, consistent with in vitro kinase assay results. In the m-TOR protein docking, π-π stacking interactions were observed between the quinoline benzene ring and trp2239; a key hydrogen bond between the nitrogen atom on the quinoline ring and val2240; and a key hydrogen bond between the N atom on the azaindole isoquinoline ring and glu2190. These may be key factors in enhancing the inhibition of m-TOR activity. These results indicate that the introduction of N into the quinoline ring... The heteroindole ring and the 2-(5-aminopyridin-2-yl)-2-methylpropionitrile structure can play a key role in the target protein, and the molecular docking results are consistent with the SAR results of kinase assay and MTT assay.

[0316] Example 5: Study on the 14-hour cytotoxicity of the target compound to normal cells.

[0317] To determine the toxicity of the target compound molecule to normal cells after 14 hours, we selected normal human hepatocytes (LO2) for the study. PI-103 and BEZ235 were selected as positive control groups. The IC50 value of the compound in LO2 was determined using the same method as in Example 2. The results are shown in Table 4.

[0318] Table 4

[0319]

[0320] Experimental results showed that the target compound 14h was significantly less toxic to cells than the positive control drug, demonstrating that compound 14h has a certain selectivity for tumor cells and good biosafety in in vitro antitumor activity experiments.

[0321] Example 6: Plate cloning study of the target compound at 14 hours

[0322] To further test the inhibitory effect of the target compound on tumor cells, we selected the compound with the best cell activity, 14h, as the target compound. Combined with the MTT assay data of this compound in different tumor cell types, its IC50 value is as follows: Figure 2 .

[0323] HeLa and SW620 cell lines, exhibiting the best activity of the target molecule after 14 hours, were selected as experimental groups for plate cloning experiments. HT29 and HCT15 cells (500 cells / well) were seeded in 6-well plates and incubated overnight at 37 °C. Then, the specified dose of the compound (0-1.25 μM) was added for 14 hours, with DMSO as a blank control. Cells were cultured for 15 days in freshly prepared culture medium. Cell culture was terminated when obvious cell colonies were observed. The supernatant was removed, and the cells were washed twice with PBS buffer. Before discarding the solution, the colonies were fixed with 4% paraformaldehyde for 15 minutes and stained with 0.5% crystal violet solution for 15 minutes. The crystal violet solution was then removed, and the staining solution was rinsed with PBS buffer. Experimental results are shown below. Figure 3 All data represent three independent replicate experiments.

[0324] The experimental results show that compound 14h inhibited cell colony formation in SW620 and HeLa cells at different concentrations. At a concentration of 1.25 μM, 14h almost completely inhibited cell colony formation in SW620 cells. In HeLa cells, at a concentration of 0.625 μM, almost no significant cell colony formation was observed. The test results confirm that the inhibitory effect of compound 14h on SW620 and HeLa cells significantly increased with increasing concentration and was concentration-dependent. This also confirms the effective antitumor inhibitory ability of compound 14h in vitro, especially in HeLa cells, where it significantly inhibited cell colony formation at low concentrations. The plate clone experiment results suggest that compound 14h may have good in vivo antitumor proliferation effects.

[0325] Example 7: Study on the antitumor activity of the compound in vivo

[0326] To investigate the antitumor effect at 14 hours in vivo, we considered the in vitro activity data at 14 hours and selected HeLa and SW620, which showed the best in vitro activity, as experimental cell lines for in vivo tumor modeling. Balb / cnude mice were used as the experimental animals.

[0327] Laboratory animal husbandry and requirements: All animal experiments are conducted with the approval of the Laboratory Animal Management Committee of Sichuan University, and the husbandry rules are implemented in accordance with the international standard of the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

[0328] Animal model establishment: HeLa (6×10⁶) and SW620 (8×10⁶) cells in the logarithmic growth phase were collected and subcutaneously injected into 6-7 week old female BALB / c mice. When the average tumor volume of nude mice grew to approximately 100 mm³ after inoculation, each mouse cell model group was randomly divided into five groups (n = 7 per group). The mice were given compound 14h solutions (15 mg / kg, 30 mg / kg, and 60 mg / kg dissolved in 10% DMSO, 1% Tween-80, and 30% PEG300, 60% saline), and the positive control group was BEZ235 (30 mg / kg dissolved in 10% DMSO, 1% Tween-80, and 30% PEG300, 60% saline), administered orally by gavage. Tumor size and body weight were measured every two days. The tumor volume is measured using calipers, and the calculation formula is: 0.5 × shortest diameter² × longest diameter. The formula for the tumor growth inhibition rate is: 100 × {1 - [final tumor volume]} 实验组 - Initial tumor volume 实验组 [Final tumor volume] 空白组 - Initial tumor volume 空白组 The experiment lasted for 30 days. After the experiment, mice were euthanized with chloral hydrate, and tumors, heart, liver, spleen, lungs, kidneys, and other organs were dissected. The tumors were weighed and grouped together with the organs, then stored in 4% paraformaldehyde. The results of the 30-day experiment with compound administration for 14 hours are as follows: Figures 4-7 .

[0329] Experimental Results: During the 30-day administration period, Balb / c nude mice were healthy, active, had normal food intake, glossy fur, normal feces, and no diarrhea occurred. No inflammation was observed at the tumor site. In both the positive control group (BEZ235 group) and the blank control group, mouse weight decreased slightly with increasing administration time, with the weight loss in the positive control group being slightly more significant. Based on in vitro activity test data, we speculate that this is due to the toxicity of the positive control drug. The experimental results show that in the HeLa xenograft model, both the target compound 14h and the positive control drug BEZ235 can inhibit tumor growth to some extent. Figure 4In the 14-hour administration, the tumor growth inhibition rate (TGI) was observed to be 80.22%, 73.50%, and 60.79% in groups with 14-hour administration doses of 60 mg / kg, 30 mg / kg, and 15 mg / kg, respectively. However, the positive control drug BEZ235 showed a TGI of only 53.29% at 30 mg / kg, significantly lower than the equivalent dose of the compound at 14 hours. The tumor growth inhibition rate increased significantly with increasing 14-hour administration dose, indicating a dose-dependent relationship between the 14-hour administration dose and the tumor growth inhibition rate. Similarly, in the SW620 xenograft model, both the target 14-hour administration and BEZ235 could inhibit tumor growth to some extent. At 14-hour administration doses of 60 mg / kg, 30 mg / kg, and 15 mg / kg, the observed TGIs were 81.03%, 70.81%, and 60.58%, respectively, while the positive control drug BEZ235 showed a significantly lower TGI at 30 mg / kg. The tumor growth inhibition rate (TGI) at 14 mg / kg was 51.67%, which was less effective than the equivalent dose at 14h. Furthermore, the dose at 14h also showed a dose-dependent relationship with the tumor growth inhibition rate. We can see that in HeLa and SW620 tumor xenograft models, compound 14h showed superior in vivo antitumor effects compared to the positive control drug at the same dose, and the mice remained tolerable even at higher drug concentrations. Figure 6 It was observed that during the 30-day treatment period, the body weight of mice in the target group (14h administration group) showed no significant change, while the positive control group showed weight loss with increasing treatment time. This indicates that the safety of compound 14h in vivo is superior to that of the positive control drug BEZ235. Furthermore, during the 30-day treatment period, there was no significant difference in body weight among the different doses of 14h administration groups; the mice maintained normal diet and water intake, had smooth skin, and were in good health. Therefore, it can be concluded that compound 14h demonstrated excellent in vivo antitumor efficacy in both HeLa and SW620 mouse xenograft models, and possesses a certain degree of safety.

Claims

1. A compound characterized by: The compound has any one of the following structural formulas: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. Use of the compound of claim 1 in the preparation of PI3K / m-TOR inhibitors.

3. Use of the compound of claim 1 in the preparation of antitumor drugs.

4. Use of the compound according to claim 3 for the preparation of an antitumor medicament, characterized in that: The drug targets the PI3K / m-TOR signaling pathway.

5. Use of the compound according to claim 3 for the preparation of an antitumor medicament, characterized in that: The tumor is colon cancer, lung cancer, or cervical cancer.

6. A pharmaceutical composition, characterized in that: It consists of an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

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