Use of azatetraloop-linked pyrazolopyridines for the preparation of a medicament for the treatment of pulmonary arterial hypertension

Abstract

The application belongs to the technical field of medicines, and particularly discloses application of azetidine four-membered ring connected pyrazolopyridine compounds in preparation of medicines for treating pulmonary arterial hypertension. Compared with the prior art, the azetidine four-membered ring connected pyrazolopyridine PDE10A inhibitor can inhibit the enzyme activity of PDE10A, and then plays a potential role in resisting pulmonary arterial hypertension, so that the application further provides a new use of the compound, i.e. application of the azetidine four-membered ring connected pyrazolopyridine PDE10A inhibitor in preparation of medicines for treating pulmonary arterial hypertension.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, in particular the preparation of azatetra-cyclic linked pyrazolopyridine compounds and their use as drug molecules for the treatment of pulmonary arterial hypertension. BACKGROUND

[0002] Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease with high morbidity and mortality. The pathological state is that the pulmonary arterial pressure is too high to exceed a certain limit. The clinical symptoms are dyspnea, fatigue, exercise intolerance, syncope, and chest pain. The pathogenesis of PAH is very complex. Currently, many drugs are used to regulate and intervene the levels of cAMP and cGMP in cells to achieve therapeutic effects. For example, phosphodiesterase PDE5A inhibitors (sildenafil, tadalafil) and soluble guanylate cyclase sGC stimulants (riociguat) regulate the intracellular NO / sGC / cGMP signaling pathway to achieve therapeutic effects. Prostacyclin PGI2 analogues (epoprostenol) or prostacyclin PGI2 receptor agonists (selexipag) regulate the intracellular PGI2 / cAMP signaling pathway to achieve therapeutic effects. In theory, inhibiting the enzyme activity of PDE10A can regulate the content of cAMP and cGMP to a certain extent, thereby playing a potential role in the treatment of PAH.

[0003] Currently, there are very few reports on the use of small molecule selective inhibitors targeting PDE10A for the treatment of PAH, and most of them are focused on the treatment of central nervous system diseases. This requires PDE10A inhibitors to have good blood-brain barrier (BBB) permeability to accumulate in the brain and maintain a certain drug concentration. However, the use of these reported PDE10A inhibitors for the treatment of peripheral tissue (such as PAH) diseases can lead to accumulation in the brain due to their good BBB permeability, and strong inhibition of PDE10A highly expressed in brain tissue, thereby significantly increasing the probability of clinical adverse events. On the other hand, the selective PDE5A inhibitor sildenafil, which is widely used in clinical practice, has a fast in vivo metabolism and poor selectivity for PDE6 (~ 16-fold), which can easily cause visual impairment. Another PDE5A selective inhibitor tadalafil also has poor selectivity for PDE11 (~ 25-fold), which can easily cause muscle pain and other adverse reactions. High-selectivity PDE10A inhibitors have more advantages in terms of PDEs family selectivity, usually more than 100-fold. Therefore, developing PDE10A inhibitors with low BBB permeability, high selectivity, and high activity for the treatment of pulmonary arterial hypertension has more clinical development value and is more innovative. Since PAH patients need to take medication for life, developing oral PDE10A high-selectivity inhibitors with good drug properties is another big challenge. SUMMARY

[0004] In order to solve the above technical problems, the application provides application of aza-tetra-cyclic connected pyrazolo pyridine compounds in preparation of a drug for treating pulmonary arterial hypertension.

[0005] In order to achieve the above object, the application is implemented according to the following technical scheme:

[0006] One of the objects of the application is to provide application of aza-tetra-cyclic connected pyrazolo pyridine compounds in preparation of a drug for treating pulmonary arterial hypertension, the aza-tetra-cyclic connected pyrazolo pyridine compounds having a structure shown in formula (I):

[0007]

[0008] wherein R1, R2, R3 are each independently H, halogen or 18 F, C 1-3 alkyl, C 1-3 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethyl, trifluoromethoxy, acetyl, cyano;

[0009] quinoline substituted quinoline and R6, R 10 substituted quinoline ; one of

[0010] R4 is ; one of

[0011] R5 is H, C 1-5 alkyl, isopropyl, -C (1-3) CH2OH, -C (1-3) CH2OCH3, -C(=O)CH3, -SO2CH3, -C(=O)OCH3; one of

[0012] R6 is independently a single-substituted or double-substituted F atom, 18 F atom, Cl atom, hydroxyl, methyl, trifluoromethyl, methoxy, cyano; one of

[0013] R7 is independently hydroxyl, methyl, trifluoromethyl, C 1-3 alkoxy, R4, -C(=O)-R4, R8, -CH2-R9, -C(=O)CH2-R9, -NHC(=O)-CH2-R9; one of

[0014] R8 is: ; one of

[0015] R9is one of R9and R10;

[0016] R 10 independently methyl, ethyl, isopropyl, C 1-3 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, cyano, R8, one of R9and R10.

[0017] A second object of the present application is to provide a drug for treating pulmonary arterial hypertension, comprising the azatetra-cyclic linked pyrazolo pyridine compound.

[0018] Compared with the prior art, the azatetra-cyclic linked pyrazolo pyridine PDE10A inhibitor of the present application can inhibit the enzyme activity of PDE10A, thereby playing a potential role in resisting pulmonary arterial hypertension, and therefore the present application further provides a new use of the compound, i.e. the application of the azatetra-cyclic linked pyrazolo pyridine PDE10A inhibitor in the preparation of a drug for treating pulmonary arterial hypertension. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 (A) and the measured value of the right ventricular systolic pressure of the rats (B) in Example 2.

[0020] Figure 2 (A) and the measured value of the right ventricular systolic pressure of the rats (B) in Example 2.

[0021] (A) and the measured value of the right ventricular systolic pressure of the rats (B) in Example 2.

[0022] Figure 3 (A) and the measured value of the right ventricular systolic pressure of the rats (B) in Example 2.

[0023] Figure 4 Statistics of the body weight of the mice in Example 3.

[0024] Figure 5 (A) and the measured value of the right ventricular systolic pressure of the rats (B) in Example 2.

[0025] Figure 6 (A) and the measured value of the right ventricular systolic pressure of the rats (B) in Example 2.

[0026] Figure 7For the lung arteriole pathology sections of mice in Example 3, the upper representative right ventricular cross-section WGA staining chart, the lower representative hematoxylin and eosin (H&E) staining chart.

[0027] Figure 8 For the synthesis route chart of compounds A1-A12.

[0028] Figure 9 For the synthesis route chart of compounds M5-M11.

[0029] Figure 10 For the synthesis route chart of compounds A13-A20.

[0030] Figure 11 For the synthesis route chart of compounds B1-B6.

[0031] Figure 12 For the synthesis route chart of compounds B7-B22.

[0032] Figure 13 For the synthesis route chart of compound B23.

[0033] Figure 14 For the synthesis route chart of compounds B24-B26.

[0034] Figure 15 For the synthesis route chart of compound B27.

[0035] Figure 16 For the synthesis route chart of compounds C1-C2.

[0036] Figure 17 For the synthesis route chart of compound C3.

[0037] Figure 18 For the synthesis route chart of compounds C4-C8.

[0038] Figure 19 For the synthesis route chart of compounds C9-C10. DETAILED DESCRIPTION

[0039] In order to make the objectives, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the embodiments. The specific embodiments described herein are only used to explain the present application and do not limit the present application.

[0040] Example 1

[0041] This embodiment exemplarily shows some representative azatetraloc-linked pyrazolopyridine PDE10A inhibitors, the structures of which are specifically as follows:

[0042] This embodiment exemplarily shows some representative azatetraloc-linked pyrazolopyridine PDE10A inhibitors, the structures of which are specifically as follows:

[0043]

[0044]

[0045] In this embodiment, the synthetic route of compounds A1-A12 (see Figure 8 ) is as follows:

[0046] The synthesis process of intermediate M1 is as follows: in a 250 mL gourd-shaped bottle, compound 1-Boc-azetidine-3-carboxylic acid (10 g, 49.7 mmol), isopropylidene malonate (10.74 g, 74.5 mmol) and 4-dimethylaminopyridine (9.10 g, 1.5 mmol) were dissolved in dichloromethane (100 mL). Under argon protection, N,N'-carbonyldiimidazole (9.67 g, 59.6 mmol) in dichloromethane (60 mL) was slowly added dropwise to the above system at 0°C, the reaction mixture was naturally raised to room temperature and stirred overnight, and the reaction was monitored by TLC. After the reaction was completed, saturated aqueous citric acid was slowly added to the reaction system to adjust the pH to 5-6, saturated brine (60 mL) was added, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, the filtrate was filtered and concentrated under reduced pressure, and a yellow oil compound was obtained. The compound was dissolved in anhydrous ethanol (60 mL), heated to 80°C and stirred overnight, and the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a yellow oil compound, intermediate compound M1 (10.28 g, yield 76%). 1 H NMR (400 MHz, CDCl3) δ 4.20 (q, J = 7.2 Hz, 2H), 4.13-4.01 (m, 4H), 3.67-3.56 (m, 1H), 3.47 (s, 2H), 1.43 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H).

[0047] The synthesis process of intermediate M2a is as follows: in a 125 mL gourd-shaped bottle, intermediate M1 (3.02 g, 11.13 mmol) was dissolved in acetonitrile (60 mL), 2-aminopyridine (3.15 g, 33.39 mmol) and carbon tetrabromide (7.38 g, 22.26 mmol) were added. The reaction mixture was stirred at 80°C overnight, and the reaction was monitored by TLC. After the reaction was completed, the crude product was concentrated under reduced pressure, saturated aqueous citric acid (30 mL) was added, and ethyl acetate was extracted twice (30 mL x 2). The organic phase was collected, washed with saturated brine, and purified by silica gel column chromatography after being distilled under reduced pressure to obtain a yellow oil intermediate compound M2a (2.58 g, yield 61%). 1H NMR (400 MHz, CDC13) δ 9.33 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 6.8 Hz, 1H), 7.03 (t, J = 6.8 Hz, 1H), 4.50 - 4.27 (m, 7H), 1.46 (s, 9H), 1.44 (t, J = 6.8 Hz, 3H).

[0048] The synthesis of intermediate M3a was carried out by dissolving intermediate M2a (2.58 g, 7.47 mmol) in dichloromethane (40 mL) and adding trifluoroacetic acid (4 mL) in a 125 mL jar. The reaction mixture was stirred at room temperature overnight and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get yellow oil of intermediate compound M3a (1.76 g, yield 96%). 1 H NMR (400 MHz, CDC13) δ 9.33 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 6.8 Hz, 1H), 7.03 (t, J = 6.8 Hz, 1H), 4.50 - 4.27 (m, 7H), 1.46 (s, 9H), 1.44 (t, J = 6.8 Hz, 3H).

[0049] The synthesis of compound A1 was carried out by dissolving intermediate M3a (100 mg, 0.41 mmol) and 2-chloroquinoline (80 mg, 0.49 mmol) in dry DMF (10 mL) and adding cesium carbonate (267 mg, 0.82 mmol) in a 50 mL jar. The reaction mixture was heated at 110 °C overnight and the reaction was monitored by TLC. After completion of the reaction, the cesium carbonate was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to get compound A1 (72 mg, yield 62%) as a white solid. 1H NMR (500 MHz, CDC13) δ 9.34 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.0 Hz, 1H), 6.66 (d, J = 9.0 Hz, 1H), 4.69 (dd, J = 14.5, 7.0 Hz, 1H), 4.63 (t, J = 7.5 Hz, 4H), 4.45 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H), HRMS (ESI-TOF) m / z [M+H] + calcd for C 22 H 20 N4O2 393.1659, found 373.1668.

[0050] In this example, the synthetic route of intermediates M5-M11 (see Figure 9 ) is as follows:

[0051] The synthesis process of intermediate M5 is as follows: in a 125 mL flask, add compound 2-quinolinone-4-carboxylic acid (9.45 g, 50.0 mmol), carefully add phosphorus oxychloride (30 mL) thereto. The reaction mixture is heated to 110 °C and stirred overnight, and the reaction is monitored by TLC. After the reaction is completed, the phosphorus oxychloride is removed by distillation under reduced pressure to obtain yellow oily intermediate compound M5 (yield 100%).

[0052] The synthesis process of intermediate M6 is as follows: at 0 °C, slowly drop dry methanol (40 mL) into the cooled intermediate M5 (50.0 mmol), then the reaction mixture is stirred at room temperature for 2 hours, and the reaction is monitored by TLC. After the reaction is completed, saturated sodium bicarbonate solution is added to the reaction mixture at 0 °C, the pH of the system is adjusted to 9-10, the aqueous phase is extracted with ethyl acetate twice, the organic phase is dried over anhydrous sodium sulfate, the filtrate is filtered and concentrated by distillation under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain white solid intermediate compound M6 (5.87 g, 53% yield for two steps). 1 H NMR (400 MHz, CDC13) δ 8.73 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.79 (td, J = 6.8, 1.2 Hz, 1H), 7.66 (td, J = 6.8, 1.2 Hz, 1H), 4.05 (s, 3H).

[0053] The synthesis of intermediate 2-chloro-N-methylquinoline-4-carboxamide M7 was carried out by dissolving intermediate M5 (50.0 mmol) in dry dichloromethane (40 mL) and adding methylamine hydrochloride (4.05 g, 60.0 mmol) and triethylamine (15.2 g, 150.0 mmol). The reaction mixture was stirred at room temperature for 3 h and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution at 0 °C to adjust the pH to 9-10 and extracted with dichloromethane twice. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain intermediate compound M7 (8.62 g, 78% yield over 2 steps) as a white solid. 1 H NMR (500 MHz, DMSO-d6 δ 8.84 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.88 (td, J = 7.0, 1.0 Hz, 1H), 7.71 (td, J = 7.0, 1.0 Hz, 1H), 7.65 (s, 1H), 2.87 (d, J = 4.5 Hz, 3H).

[0054] The synthesis of intermediate M8 was carried out by using intermediate M5 (1.0 mmol) and 2,2-difluoroethylamine (97.2 mg, 1.2 mmol) as starting materials, following the procedure for the synthesis of intermediate M7 to obtain intermediate compound M8 (60 mg, 48% yield) as an off-white solid.

[0055] 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.46 (s, 1H), 6.41 (br s, 1H), 6.07 (tt, J = 55.6, 3.6 Hz, 1H), 4.01 - 3.86 (m, 2H).

[0056] The synthesis of intermediate M9 was carried out by using intermediate M5 (1.0 mmol) and N-methylpiperazine (120 mg, 1.2 mmol) as starting materials, following the procedure for the synthesis of intermediate M7 to obtain intermediate compound M9 (60 mg, 48% yield) as a light yellow solid. 1HNMR (400 MHz, CDC13) δ 8.06 (d, J = 8.4 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.31 (s, 1H), 4.04 - 3.84 (m, 2H), 3.77 - 3.66 (m, 1H), 3.29 - 3.11 (m, 3H), 2.64 - 2.51 (m, 2H), 2.33 (s, 3H).

[0057] The synthesis process of intermediate M10 is as follows: taking intermediate M5 (1.0 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (254 mg, 1.2 mmol) as raw materials, referring to the synthesis method of intermediate M7, intermediate compound M10 (290 mg, yield 72%) was obtained as a light yellow solid. 1 H NMR (400 MHz, CDC13) δ 8.06 (d, J = 8.4 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.31 (s, 1H), 4.04 - 3.84 (m, 2H), 3.77 - 3.66 (m, 1H), 3.29 - 3.11 (m, 3H), 2.64 - 2.51 (m, 2H), 2.33 (s, 3H).

[0058] The synthesis process of intermediate M11 is as follows: taking intermediate M5 (1.0 mmol) and N,N-diethylethylene-diamine (139 mg, 1.2 mmol) as raw materials, referring to the synthesis method of intermediate M7, intermediate compound M11 (250 mg, yield 82%) was obtained as a light yellow solid. 1 H NMR (400 MHz, CDC13) δ 8.06 (d, J = 8.4 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.31 (s, 1H), 4.04 - 3.84 (m, 2H), 3.77 - 3.66 (m, 1H), 3.29 - 3.11 (m, 3H), 2.64 - 2.51 (m, 2H), 2.33 (s, 3H).

[0059] The synthesis process of compound A2 is as follows: taking intermediate M3a (100 mg, 0.41 mmol) and intermediate M6 (108 mg, 0.49 mmol) as raw materials, referring to the synthesis method of compound A1, compound A2 (121 mg, yield 69%) was obtained as a white solid.1 HNMR (400 MHz, CDC13) δ 9.34 (d, J = 6.8 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.02 (t, J = 6.8 Hz, 1H), 4.79 - 4.60 (m, 5H), 4.47 (q, J = 7.2 Hz, 2H), 4.01 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 24 H 22 N4O4 431.1714, found 431.1715.

[0060] The synthesis process of compound A3 is as follows: taking intermediate M3a (1.76 g, 7.18 mmol) and intermediate M7 (1.58 g, 7.18 mmol) as raw materials, the synthesis method of compound Al is referred to, to obtain yellow solid compound A3 (1.97 g, yield 64%). 1 HNMR (400 MHz, CDC13) δ 9.34 (d, J = 6.8 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.02 (t, J = 6.8 Hz, 1H), 4.79 - 4.60 (m, 5H), 4.47 (q, J = 7.2 Hz, 2H), 4.01 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 24 H 23 N5O3430.1874, found 430.1888.

[0061] The synthesis process of intermediate M4 is as follows: in a 125 mL of ajar, intermediate A3a (1.97 g, 4.59 mmol) was dissolved in methanol / water (30 mL / 10 mL), sodium hydroxide (550 mg, 13.76 mmol) was added, the reaction mixture was heated to 65 °C and stirred for 3 hours, and the reaction was monitored by TLC. After the reaction was completed, the methanol was removed by distillation under reduced pressure to obtain a crude aqueous solution, the pH of the system was adjusted to 4-5 with 5M hydrochloric acid, a solid was precipitated, and the filter cake was washed with water, and dried in air to obtain white solid intermediate compound M4 (1.51 g, yield 82%). 1 H NMR (400 MHz, CH3OD) δ 9.33 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.46 - 7.39 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 6.8 Hz, 1H), 6.58 (s, 1H), 4.63 - 4.61 (m, 1H), 4.56 - 4.51 (m, 4H), 3.13 (d, J = 4.8 Hz, 3H).

[0062] The synthesis process of compound A4 is as follows: in a 50 mL of ajar, intermediate M4 (100 mg, 0.25 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), compound 2,2-difluoroethanol (41 mg, 0.50 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol) and 4-dimethylaminopyridine (61 mg, 0.50 mmol) were added in sequence, the reaction mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. After the reaction was completed, saturated brine was added, and the organic phase was extracted with ethyl acetate, and the crude product was obtained by distillation under reduced pressure, and purified by silica gel column chromatography to obtain yellowish solid compound A4 (87 mg, yield 75%). 1 H NMR (500 MHz, DMSO-d6) δ 9.23 (d, J = 6.5 Hz, 1H), 8.64 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.56 (d, J = 6.5 Hz, 1H), 7.33 - 7.19 (m, 2H), 6.82 (s, 1H), 6.53 (t, J = 54.5 Hz, 1H), 4.74 - 4.62 (m, 3H), 4.56 (s, 2H), 4.48 (s, 2H), 2.84 (s, 3H). HRMS (ESI-TOF) m / z: [M+H] +C 24 H 21 F2N5O3466.1685, found466.1690.

[0063] The synthesis process of compound A5 is as follows: taking intermediate M4 (100 mg, 0.25 mmol) and isopropanol (30 mg, 0.5 mmol) as raw materials, referring to the synthesis method of compound A4, light yellow compound A5 (66 mg, yield 60%) is obtained. 1 H NMR (500 MHz, CDC13) δ 9.34 (d, J = 7.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.0 Hz, 1H), 6.39 (s, 1H), 5.41 - 5.30 (m, 1H), 4.64 - 4.55 (m, 1H), 4.53 - 4.40 (m, 4H), 3.11 (d, J = 4.5 Hz, 3H), 1.46 (d, J = 6.0 Hz, 6H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 25 H 25 N5O3 444.2030, found 444.2032.

[0064] The synthesis process of compound A6 is as follows: taking intermediate M4 (100 mg, 0.25 mmol) and oxetan-3-ol (37 mg, 0.5 mmol) as raw materials, referring to the synthesis method of compound A4, light yellow compound A6 (77 mg, yield 68%) is obtained. 1HNMR (400 MHz, CDC13) δ 9.28 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 - 7.40 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 6.8 Hz, 1H), 6.78 (q, J = 4.0 Hz, 1H), 6.49 (s, 1H), 5.81 - 5.69 (m, 1H), 5.06 (t, J = 7.2 Hz, 2H), 4.84 (t, J = 7.2 Hz, 2H), 4.72 - 4.61 (m, 1H), 4.59 - 4.48 (m, 4H), 3.10 (d, J = 4.8 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H]+calcd for C + calcd for C 25 H 23 N5O4 458.1823, found 458.1826.

[0065] The synthesis process of compound A7 is as follows: taking intermediate M4 (100 mg, 0.25 mmol) and tetrahydro-2H-pyran-4-ol (51 mg, 0.5 mmol) as raw materials, the synthesis method of compound A4 is referred to, to obtain light yellow compound A7 (83 mg, yield 69%).

[0066] 1 H NMR (500 MHz, CDC13) δ 9.32 (d, J = 6.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.77 - 7.61 (m, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 6.5 Hz, 1H), 7.06 (t, J = 6.0 Hz, 1H), 6.44 (s, 1H), 5.28 (s, 1H), 4.66 - 4.58 (m, 1H), 4.57 - 4.41 (m, 4H), 4.13 - 4.01 (m, 2H), 3.64 (t, J = 10.0 Hz, 2H), 3.11 (d, J = 3.0 Hz, 3H), 2.18 - 2.06 (m, 2H), 1.98 - 1.81 (m, 2H). HRMS (ESI-TOF) m / z: [M + H]+calcd for C 27 H 27 N5O4 486.2136, found 486.2135.

[0067] The synthetic process of compound A8 was: taking intermediate M3a (100 mg, 0.41 mmol) and intermediate M8 (133 mg, 0.49 mmol) as raw materials, referring to the synthetic method of compound A1, light yellow solid compound A8 (98 mg, yield 50%) was obtained. 1 HNMR (400 MHz, CDC13) δ 9.34 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 6.0 Hz, 1H), 7.03 (td, J = 6.8, 0.8 Hz, 1H), 6.49 (s, 1H), 6.10 (tt, J = 56.0, 4.0 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.56 - 4.50 (m, 4H), 4.46 (q, J = 7.2 Hz, 2H), 4.01 - 3.86 (m, 2H), 1.48 (t, J = 7.2 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 25 H 23 F2N5O3480.1842, found 480.1845.

[0068] The synthetic process of compound A9 was: taking intermediate M3a (100 mg, 0.41 mmol) and intermediate M9 (142 mg, 0.49 mmol) as raw materials, referring to the synthetic method of compound A2, light yellow solid compound A9 (134 mg, yield 66%) was obtained. 1HNMR (500 MHz, CDC13) δ 9.33 (d, J = 7.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.41 (td, J = 7.0, 1.0 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.02 (td, J = 7.0, 1.0 Hz, 1H), 6.57 (s, 1H), 4.74 - 4.62 (m, 3H), 4.62 - 4.55 (m, 2H), 4.45 (q, J = 7.0 Hz, 2H), 4.04 - 3.97 (m, 1H), 3.90 - 3.80 (m, 1H), 3.22 (t, J = 5.0 Hz, 2H), 2.62 - 2.49 (m, 2H), 2.31 (s, 3H), 2.27 - 2.21 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 28 H 30 N6O3499.2452, found 499.2447.

[0069] The synthetic process of compound A10 is as follows: taking intermediate M3a (100 mg, 0.41 mmol) and intermediate M10 (196 mg, 0.49 mmol) as raw materials, referring to the synthetic method of compound A2, and then removing the protecting group by trifluoroacetic acid to obtain compound A10 (135 mg, 2-step yield 65%) in light yellow solid. 1 H NMR (500 MHz, CDC13) δ 9.35 (d, J = 7.0 Hz, 1H), 7.75 (dd, J = 11.5, 9.0 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.03 (t, J = 7.0 Hz, 1H), 6.58 (d, J = 18.5 Hz, 1H), 4.79 - 4.56 (m, 5H), 4.47 (q, J = 7.0 Hz, 2H), 4.01 - 3.61 (m, 2H), 3.23 - 3.14 (m, 1H), 3.12 - 2.98 (m, 2H), 2.80 (t, J = 4.5 Hz, 1H), 1.49 (td, J = 7.5, 1.5 Hz, 3H), 0.92 - 0.69 (m, 2H), 0.60 - 0.48 (m, 1H), 0.33 - 0.10 (m, 1H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 29 H30 N6O3 511.2452, found 511.2477.

[0070] The synthesis process of compound A11 is as follows: in a 50 mL tomato flask, intermediate M11 (305 mg, 1.0 mmol) and intermediate M3a (245 mg, 1.0 mmol) are dissolved in anhydrous DMF (20 mL), and cesium carbonate (652 mg, 2.0 mmol) is added. The reaction mixture is heated at 110°C overnight, and the reaction is monitored by TLC. After the reaction is completed, the cesium carbonate is filtered off, and the obtained filtrate is concentrated by distillation under reduced pressure. The obtained crude product is purified by silica gel column chromatography to obtain yellow solid compound A11 (272 mg, yield 53%). 1 H NMR (400 MHz, CDC13) δ 9.35 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.54 (td, J = 7.2, 1.2 Hz, 1H), 7.42 (td, J = 7.2, 1.2 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.03 (td, J = 6.8, 1.2 Hz, 1H), 6.84 - 6.77 (m, 1H), 6.76 (s, 1H), 4.75 - 4.67 (m, 1H), 4.65 - 4.59 (m, 4H), 4.46 (q, J = 7.2 Hz, 2H), 3.64 - 3.55 (m, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.58 (q, J = 7.2 Hz, 4H), 1.48 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 6H).

[0071] The synthesis process of compound A12 is as follows: referring to the synthesis method of compound A1, 2-chloroquinoline is reacted with intermediate M3b to obtain yellow solid compound A12 (142 mg, yield 43%), 1 H NMR (400 MHz, CDC13) δ 9.22 (d, J = 6.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H), 6.94 (t, J = 6.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.77 - 4.59 (m, 5H), 4.47 (q, J = 7.2 Hz, 2H), 2.65 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H).

[0072] In this embodiment, the synthetic route of compounds A13-A20 (see Figure 10 ) is as follows:

[0073] The synthesis of compound A13 was carried out by dissolving intermediate M4 (100 mg, 0.25 mmol) in dry N,N-dimethylformamide (10 mL) in a 50 mL vial, followed by the addition of methylamine hydrochloride (20 mg, 0.30 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.30 mmol) and diisopropylethylamine (97 mg, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure, and the crude obtained was purified by column chromatography on silica gel to give compound A13 (54 mg, 52% yield) as a white solid. 1 H NMR (500 MHz, CD3OD) δ 8.85 (d, J = 7.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.42 (td, J = 7.0, 1.5 Hz, 1H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 7.01 (td, J = 7.0, 1.0 Hz, 1H), 6.77 (s, 1H), 4.62 (t, J = 8.0 Hz, 2H), 4.58 - 4.50 (m, 1H), 4.43 (t, J = 8.0 Hz, 2H), 3.00 (s, 3H), 2.98 (s, 3H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 23 H 22 N6O2 415.1877, found 415.1875.

[0074] The synthesis of compound A14 was carried out by using intermediate M4 (100 mg, 0.25 mmol) and 2-methoxyethylamine (23 mg, 0.30 mmol) as starting materials, following the synthetic procedure of compound A13 to give compound A14 (54 mg, 47% yield) as a light yellow solid. 1H NMR (500 MHz, CD3OD) δ 8.83 (d, J = 7.0 Hz, 1H), 7.89 (dd, J = 8.5, 1.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.43 (td, J = 7.0, 1.0 Hz, 1H), 7.25 (td, J = 7.0, 1.0 Hz, 1H), 7.02 (td, J = 7.0, 1.0 Hz, 1H), 6.78 (s, 1H), 4.67 - 4.61 (m, 2H), 4.62 - 4.56 (m, 1H), 4.49 - 4.42 (m, 2H), 3.65 - 3.63 (m, 4H), 3.44 (s, 3H), 2.98 (s, 3H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 25 H 26 N6O3 459.2139, found 459.2139.

[0075] The synthetic process of compound A15 is as follows: taking intermediate M4 (100 mg, 0.25 mmol) and 2,2-difluoroethanamine (24 mg, 0.30 mmol) as raw materials, referring to the synthetic method of compound A13, compound A15 (66 mg, yield 57%) was obtained as a light yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J = 7.0 Hz, 1H), 8.65 (q, J = 4.5 Hz, 1H), 8.51 (t, J = 5.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.0 Hz, 1H), 6.81 (s, 1H), 6.25 (tt, J = 56.0, 3.5 Hz, 1H), 4.63 - 4.51 (m, 3H), 4.38 (t, J = 6.5 Hz, 2H), 3.84 - 3.73 (m, 2H), 2.84 (d, J = 4.5 Hz, 3H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 24 H 22 F2N6O2465.1845, found 465.1842.

[0076] The synthetic process of compound A16 was carried out by using intermediate M4 (100 mg, 0.25 mmol) and cyclopropylamine (17 mg, 0.30 mmol) as raw materials, referring to the synthetic method of compound A13, to give compound A16 (66 mg, yield 60%) in light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 6.8 Hz, 1H), 8.62 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 3.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.55 (td, J = 6.8, 1.2 Hz, 1H), 7.39 (td, J = 6.8, 1.2 Hz, 1H), 7.24 (td, J = 7.2, 0.8 Hz, 1H), 7.03 (td, J = 6.8, 0.8 Hz, 1H), 6.81 (s, 1H), 4.55 - 4.45 (m, 3H), 4.40 - 4.30 (m, 2H), 2.96 - 2.87 (m, 1H), 2.84 (d, J = 4.4 Hz, 3H), 0.82 - 0.74 (m, 2H), 0.71 - 0.63 (m, 2H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 25 H 24 N6O2441.2034, found 441.2036.

[0077] The synthetic process of compound A17 was carried out by using intermediate M4 (100 mg, 0.25 mmol) and N,N-diethylethylenediamine (35 mg, 0.30 mmol) as raw materials, referring to the synthetic method of compound A13, to give compound A17 (82 mg, yield 66%) in light yellow solid. 1 H NMR (500 MHz, CD3OD) δ 8.92 (d, J = 7.0 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.0 Hz, 1H), 6.79 (s, 1H), 4.68 - 4.59 (m, 3H), 4.47 (t, J = 5.5 Hz, 2H), 3.61 (t, J = 7.0 Hz, 2H), 2.98 (s, 3H), 2.87 (t, J = 7.0 Hz, 2H), 2.77 (q, J = 7.0 Hz, 4H), 1.15 (t, J = 7.0 Hz, 6H). HRMS (ESI-TOF) m / z: [M+H]+ calcd for C 28 H 33 N7O2 500.2768, found 500.2769.

[0078] The synthetic process of compound A18 was as follows: taking intermediate M4 (100 mg, 0.25 mmol) and N,N-diethyl-N'-methylethylenediamine (39 mg, 0.30 mmol) as raw materials, the synthetic method of compound A13 was referred to, and light yellow solid compound A18 (83 mg, yield 65%) was obtained. 1 H NMR (500 MHz, CDC13) δ 8.38 (d, J = 6.5 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 8.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.95 (q, J = 4.0 Hz, 1H), 6.86 (t, J = 6.5 Hz, 1H), 6.56 (s, 1H), 4.54 - 4.40 (m, 4H), 4.24 - 4.14 (m, 1H), 3.86 - 3.39 (m, 2H), 3.09 (s, 3H), 3.06 (d, J = 4.5 Hz, 3H), 2.77 - 2.57 (m, 2H), 2.45 (q, J = 7.0 Hz, 4H), 0.91 (t, J = 7.0 Hz, 6H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 29 H 35 N7O2 514.2925, found 514.2922.

[0079] The synthetic process of intermediate M13 was as follows: in a 125 mL flask, A11 (272 mg, 0.53 mmol) was dissolved in methanol / water (20 mL / 5 mL), sodium hydroxide (64 mg, 1.59 mmol) was added, the reaction mixture was heated to 65 °C and stirred for 3 hours, and the reaction was monitored by TLC. After the reaction was completed, methanol was removed by distillation under reduced pressure to obtain a crude aqueous solution, the pH of the system was adjusted to 4-5 with 5M hydrochloric acid, a solid was precipitated, and the filter cake was washed with water, and dried in air to obtain light yellow solid M12 (236 mg, yield 92%).

[0080] The synthetic process of compound A19 was carried out by using intermediate M12 (100 mg, 0.21 mmol) and dimethylamine hydrochloride (20 mg, 0.25 mmol) as starting materials, referring to the synthetic method of compound A13, to give compound A19 (98 mg, yield 77%) as a light yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ = 8.61 (t, J = 5.5 Hz, 1H), 8.40 (d, J = 7.0 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.0 Hz, 1H), 6.78 (s, 1H), 4.55 (t, J = 8.0 Hz, 2H), 4.38 (t, J = 8.0 Hz, 2H), 4.25 - 4.16 (m, 1H), 3.40 - 3.34 (m, 2H), 3.05 (s, 6H), 2.61 (t, J = 6.5 Hz, 2H), 2.54 (q, J = 7.0 Hz, 4H), 0.99 (t, J = 7.0 Hz, 6H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 29 H 35 N7O2514.2925, found 514.2944.

[0081] The synthetic process of compound A20 was carried out by using intermediate M12 (100 mg, 0.21 mmol) and methoxymethylamine (18 mg, 0.30 mmol) as starting materials, referring to the synthetic method of compound A13, to give compound A20 (95 mg, yield 72%) as a light yellow solid. 1H NMR (400 MHz, CDC13) δ 8.63 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.90 (t, J = 6.8 Hz, 1H), 6.73 (s, 1H), 4.66 - 4.48 (m, 4H), 4.40 - 4.30 (m, 1H), 3.62 - 3.55 (m, 2H), 3.52 (s, 3H), 3.45 (s, 3H), 2.70 (t, J = 6.0 Hz, 2H), 2.57 (q, J = 7.2 Hz, 4H), 1.03 (t, J = 7.2 Hz, 6H). HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 29 H 35 N7O3552.2694, found 552.2693.

[0082] In this example, the synthesis routes of compounds B1-B6 (see Figure 11 ) are as follows:

[0083] The synthesis process of intermediates M14a-f is as follows: in a 125 mL tomato flask, intermediate M1 (1.08 mg, 4.0 mmol) is dissolved in acetonitrile (20 mL), and various R3 or R4 substituted 2-aminopyridine P-2-A derivatives (6.0 mmol) and carbon tetrabromide (1.99 g, 6.0 mmol) are added respectively. The reaction mixture is stirred at 80°C overnight, and the reaction is monitored by TLC. After the reaction is completed, the crude product is concentrated by distillation under reduced pressure, and purified by silica gel column chromatography to obtain yellow oily intermediate compounds M14a-f, respectively.

[0084] Intermediate M14a, yield 67%. 1 H NMR (400 MHz, CDC13) δ 9.33 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 4.50 - 4.27 (m, 7H), 1.46 (s, 9H), 1.44 (d, J = 6.8 Hz, 3H).

[0085] Intermediate M14b, yield 50%. 1H NMR (500 MHz, CDC13) δ 9.18 (d, J = 7.0 Hz, 1H), 7.47 (s, 1H), 6.86 (dd, J = 7.0, 1.5 Hz, 1H), 4.44 - 4.37 (m, 4H), 4.36 - 4.28 (m, 2H), 4.09 - 4.03 (m, 1H), 2.46 (s, 3H), 1.45 (s, 9H), 1.43 (t, J = 7.5 Hz, 3H).

[0086] Intermediate M14c, yield 19%. 1 H NMR (500 MHz, CDC13) δ 9.34 (dd, J = 7.5, 5.5 Hz, 1H), 7.34 (dd, J = 9.0, 2.5 Hz, 1H), 6.89 (td, J = 7.5, 2.5 Hz, 1H), 4.46 - 4.37 (m, 4H), 4.36 - 4.28 (m, 3H), 1.46 (s, 9H), 1.44 (t, J = 7.5 Hz, 3H).

[0087] Intermediate M14d, yield 41%. 1 H NMR (500 MHz, CDC13) δ 9.15 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.28 (dd, J = 9.0, 1.5 Hz, 1H), 4.45 - 4.37 (m, 4H), 4.35 - 4.28 (m, 3H), 4.09 - 4.02 (m, 1H), 2.40 (s, 3H), 1.45 (s, 9H), 1.44 (t, J = 7.5 Hz, 3H).

[0088] Intermediate M14e, yield 22%. 1 H NMR (400 MHz, CDC13) δ 9.32 (dd, J = 4.8, 2.4 Hz, 1H), 7.69 (dd, J = 10.0, 5.2 Hz, 1H), 7.35 (td, J = 7.6, 2.4 Hz, 1H), 4.49 - 4.37 (m, 4H), 4.37 - 4.27 (m, 3H), 1.46 (s, 9H), 1.45 (t, J = 7.2 Hz, 3H).

[0089] Intermediate M14f, yield 35%. 1H NMR (400 MHz, CDC13) δ 8.98 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 10.0 Hz, 1H), 7.21 (dd, J = 9.6, 2.4 Hz, 1H), 4.50 - 4.36 (m, 4H), 4.35 - 4.26 (m, 3H), 3.89 (s, 3H), 1.45 (s, 9H), 1.44 (t, J = 7.2 Hz, 3H).

[0090] The synthesis process of intermediate M15a-f is as follows: in a 50 mL gourd-shaped bottle, intermediate 14a-f (1.0 mmol) is dissolved in methanol (10 mL) and water (2 mL), and sodium hydroxide (120 mg, 3.0 mmol) is added. The reaction mixture is stirred at 60°C overnight, and the reaction is monitored by TLC. After the reaction is completed, the crude product is distilled under reduced pressure to obtain an aqueous solution, a saturated citric acid solution is added to adjust pH = 3-4, and dichloromethane is used for extraction. The organic phase is dried over anhydrous sodium sulfate, and concentrated to obtain white solid or light yellow solid intermediate compound M15a-f (yield 76-88%), which is used directly in the next step without purification.

[0091] The synthesis process of intermediate M16a-f is as follows: in a 50 mL gourd-shaped bottle, intermediate compound M15a-f (0.5 mmol) is dissolved in anhydrous N,N-dimethylformamide (10 mL), and dimethylamine hydrochloride (DMA-HCl) (1.0 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg, 0.6 mmol) and diisopropyl ethylamine (194 mg, 1.5 mmol) are sequentially added. The reaction mixture is stirred at room temperature overnight, and the reaction is monitored by TLC. After the reaction is completed, the crude product is concentrated under reduced pressure, saturated brine (30 mL) is added, and ethyl acetate is used for extraction twice. The organic phase is dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography to obtain light yellow or white solid intermediate compound M16a-f.

[0092] Intermediate M16a, white solid, yield 92%. 1 H NMR (400 MHz, CDC13) δ 9.33 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 4.45 - 4.26 (m, 4H), 3.97 - 3.84 (m, 1H), 3.09 (s, 6H), 1.46 (s, 9H).

[0093] Intermediate M16b, white solid, yield 84%. 1H NMR (400 MHz, CDC13) δ 8.27 (d, J = 6.8 Hz, 1H), 7.40 (s, 1H), 6.71 (dd, J = 6.8, 1.6 Hz, 1H), 4.40 - 4.21 (m, 4H), 3.96 - 3.86 (m, 1H), 3.09 (s, 6H), 2.42 (s, 3H), 1.45 (s, 9H).

[0094] Intermediate M16c, light yellow solid, yield 89%. 1 H NMR (400 MHz, CDC13) δ 8.42 (dd, J = 7.6, 5.6 Hz, 1H), 7.29 (dd, J = 9.6, 2.4 Hz, 1H), 6.76 (td, J = 7.2, 2.4 Hz, 1H), 4.39 - 4.19 (m, 4H), 3.94 - 3.84 (m, 1H), 3.10 (s, 6H), 1.46 (s, 9H).

[0095] Intermediate M16d, white solid, yield 98%. 1 H NMR (400 MHz, CDC13) δ 8.19 (s, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.14 (dd, J = 9.2, 1.6 Hz, 1H), 4.38 - 4.20 (m, 4H), 3.98 - 3.85 (m, 1H), 3.10 (s, 6H), 2.33 (s, 3H), 1.45 (s, 9H).

[0096] Intermediate M16e, light yellow solid, yield 91%. 1 H NMR (400 MHz, CDC13) δ 8.38 (dd, J = 4.4, 2.4 Hz, 1H), 7.62 (dd, J = 10.0, 5.2 Hz, 1H), 7.23 (td, J = 8.0, 2.4 Hz, 1H), 4.37 - 4.21 (m, 4H), 3.98 - 3.85 (m, 1H), 3.10 (s, 6H), 1.46 (s, 9H).

[0097] Intermediate M16f, white solid, yield 88%. 1 H NMR (400 MHz, CDC13) δ 7.98 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 10.0 Hz, 1H), 7.08 (dd, J = 9.6, 2.4 Hz, 1H), 4.34 - 4.23 (m, 4H), 3.95 - 3.84 (m, 1H), 3.82 (s, 3H), 3.11 (s, 6H), 1.45 (s, 9H).

[0098] The synthesis of intermediates M17a-f was carried out by dissolving compound M16a-f (0.5 mmol) in methanol (5 mL) in a 50 mL jar, adding concentrated hydrochloric acid (0.5 mL), stirring the reaction mixture at room temperature overnight, monitoring the reaction by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the intermediate compounds M17a-f as pale yellow solids.

[0099] Intermediate M17a, yield 95%. 1 H NMR (400 MHz, CD3OD) δ 8.56 (d, J = 6.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H), 4.75 - 4.53 (m, 1H), 4.45 - 4.33 (m, 4H), 3.11 (s, 6H).

[0100] Intermediate M17b, yield 91%. 1 H NMR (400 MHz, CD3OD) δ 8.57 (d, J = 6.8 Hz, 1H), 7.85 (s, 1H), 7.46 (dd, J = 6.8, 1.2 Hz, 1H), 4.74 - 4.64 (m, 1H), 4.63 - 4.41 (m, 4H), 3.14 (s, 6H), 2.64 (s, 3H).

[0101] Intermediate M17c, yield 96%. 1 H NMR (400 MHz, CD3OD) δ 8.82 (dd, J = 7.6, 5.2 Hz, 1H), 7.94 (dd, J = 8.0, 2.4 Hz, 1H), 7.58 (td, J = 7.6, 2.4 Hz, 1H), 4.78 - 4.66 (m, 1H), 4.65 - 4.45 (m, 4H), 3.18 (s, 6H).

[0102] Intermediate M17d, yield 90%. 1 H NMR (500 MHz, CD3OD) δ 8.15 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.36 (dd, J = 9.0, 1.5 Hz, 1H), 4.47 - 4.34 (m, 5H), 3.09 (s, 6H), 2.37 (s, 3H).

[0103] Intermediate M17e, yield 96%. 1H NMR (400 MHz, CD3OD) δ 8.78 (dd, J = 7.6, 4.8 Hz, 1H), 7.76 (dd, J = 7.6, 2.4 Hz, 1H), 7.58 (td, J = 7.6, 2.4 Hz, 1H), 4.72 - 4.63 (m, 1H), 4.67 - 4.44 (m, 4H), 3.15 (s, 6H).

[0104] Intermediate M17f, yield 94%. 1 H NMR (400 MHz, CD3OD) δ 8.19 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 10.0 Hz, 1H), 7.84 (dd, J = 10.0, 2.4 Hz, 1H), 4.72 - 4.62 (m, 1H), 4.61 - 4.41 (m, 4H), 3.97 (s, 3H), 3.16 (s, 6H).

[0105] In this example, the synthesis process of compounds B1-B6 is as follows: in a 50 mL tomato flask, intermediate M17a-f (0.25 mmol) and M7 (66 mg, 0.30 mmol) are dissolved in anhydrous DMF (10 mL), and cesium carbonate (244 mg, 0.75 mmol) is added. The reaction mixture is heated at 110°C overnight, and the reaction is monitored by TLC. After the reaction is completed, the cesium carbonate is removed by filtration, and the filtrate is distilled under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain compounds B1-B6 as pale yellow or white solids, respectively.

[0106] Compound B1, 75 mg, pale yellow solid, yield 77%. 1 H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.48 (t, J = 7.0 Hz, 1H), 7.32 (s, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 7.0 Hz, 1H), 6.86 (t, J = 6.0 Hz, 1H), 6.46 (s, 1H), 4.49 - 4.33 (m, 4H), 4.10 - 4.01 (m, 1H), 3.11 (s, 6H), 3.05 (s, 3H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 24 H 24 N6O2 429.2034, found 429.2033.

[0107] Compound B2, 38 mg, white solid, yield 69%.1 H NMR (500 MHz, CDC13) δ 8.27 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.50 (td, J = 7.0, 1.0 Hz, 1H), 7.33 (s, 1H), 7.18 (td, J = 7.0, 1.0 Hz, 1H), 6.91 (q, J = 4.5 Hz, 1H), 6.70 (dd, J = 7.0, 1.5 Hz, 1H), 6.53 (s, 1H), 4.50 - 4.37 (m, 4H), 4.13 - 4.04 (m, 1H), 3.11 (s, 6H), 3.07 (d, J = 5.0 Hz, 3H), 2.39 (s, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 25 H 26 N6O2 443.2190, found 443.2189.

[0108] Compound B3, 50 mg, yellowish solid, yield 72%. 1 H NMR (500 MHz, CDC13) δ 8.27 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.50 (td, J = 7.0, 1.0 Hz, 1H), 7.33 (s, 1H), 7.18 (td, J = 7.0, 1.0 Hz, 1H), 6.91 (q, J = 4.5 Hz, 1H), 6.70 (dd, J = 7.0, 1.5 Hz, 1H), 6.53 (s, 1H), 4.50 - 4.37 (m, 4H), 4.13 - 4.04 (m, 1H), 3.11 (s, 6H), 3.07 (d, J = 5.0 Hz, 3H), 2.39 (s, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 24 H 23 N6O2F 447.1939, found 447.1933.

[0109] Compound B4, 49 mg, white solid, yield 75%. 1H NMR (500 MHz, CDC13) δ 8.19 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.17 (td, J = 7.5, 1.0 Hz, 1H), 7.12 (dd, J = 9.5, 1.5 Hz, 1H), 6.98 (q, J = 4.5 Hz, 1H), 6.51 (s, 1H), 4.49 - 4.35 (m, 4H), 3.12 (s, 6H), 3.06 (d, J = 5.0 Hz, 3H), 2.32 (s, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 25 H 26 N6O2 443.2190, found 443.2193.

[0110] Compound B5, 52 mg, yellowish solid, yield 66%. 1 H NMR (400 MHz, DMSO) δ 8.66 (q, J = 4.4 Hz, 1H), 8.51 (dd, J = 4.4, 2.4 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 10.0, 5.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.56 (td, J = 7.2, 0.8 Hz, 1H), 7.48 (td, J = 8.0, 2.4 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H), 6.82 (s, 1H), 4.55 (t, J = 8.0 Hz, 2H), 4.37 (t, J = 7.2 Hz, 2H), 4.26 - 4.15 (m, 1H), 3.05 (s, 6H), 2.85 (d, J = 4.4 Hz, 3H). HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 24 H 23 N6O2F 469.1759, found 469.1770.

[0111] Compound B6, 82 mg, white solid, yield 80%. 1H NMR (500 MHz, CDC13) δ 7.99 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.0 Hz, 1H), 7.48 (d, J = 9.5 Hz, 1H), 7.22 (t, J = 7.0 Hz, 1H), 7.06 (dd, J = 9.5, 2.5 Hz, 1H), 6.60 (s, 1H), 6.54 (q, J = 4.5 Hz, 1H), 4.56 - 4.42 (m, 4H), 4.16 - 4.06 (m, 1H), 3.82 (s, 3H), 3.15 (s, 6H), 3.08 (d, J = 5.0 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 25 H 26 N6O3 459.2139, found 459.2142.

[0112] In this example, the synthetic route of compounds B7-B22 (see Figure 12 ) is as follows:

[0113] The synthesis process of intermediate M18 is as follows: in a 125 mL of ajar, intermediate M17e (2.0 g, 7.62 mmol) and M6 (2.03 g, 9.15 mmol) were dissolved in anhydrous DMF (30 mL), and cesium carbonate (4.96 g, 15.24 mmol) was added. The reaction mixture was heated at 110 °C overnight, and the reaction was monitored by TLC. After the reaction was completed, the cesium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain white solid compound M18 (1.64 g, yield 48%). 1 H NMR (500 MHz, CDC13) δ 7.99 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.0 Hz, 1H), 7.48 (d, J = 9.5 Hz, 1H), 7.22 (t, J = 7.0 Hz, 1H), 7.06 (dd, J = 9.5, 2.5 Hz, 1H), 6.60 (s, 1H), 6.54 (q, J = 4.5 Hz, 1H), 4.56 - 4.42 (m, 4H), 4.16 - 4.06 (m, 1H), 3.82 (s, 3H), 3.15 (s, 6H), 3.08 (d, J = 5.0 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H] 13CNMR (126 MHz, CDC13) δ 166.89, 162.69, 157.81, 153.40 (d, J = 237.8 Hz), 149.01, 148.20 (d, J = 2.1 Hz), 144.08, 136.40, 129.88, 126.94, 125.49, 123.38, 119.92, 118.41 (d, J = 25.4 Hz), 117.54 (d, J = 8.9 Hz), 116.65 (d, J = 2.0 Hz), 113.78, 113.45, 110.99, 56.26, 52.58, 28.55.

[0114] The synthesis process of intermediate M19 is as follows: in a 125 mL of ajar, intermediate M18 (1.64 g, 3.66 mmol) was dissolved in methanol (30 mL) and water (6 mL), sodium hydroxide (440 mg, 11.0 mmol) was added. The reaction mixture was stirred at 60 °C overnight, and the reaction was monitored by TLC. After the reaction was completed, the crude product was distilled under reduced pressure to obtain an aqueous solution, a saturated citric acid solution was added to adjust pH = 3-4, and a solid was precipitated. The filter cake was suction filtered, washed with water, and dried in air to obtain white solid compound M19 (1.46 g, yield 92%).

[0115] The synthesis process of compounds B7, B8, B10, B11 and B15 is as follows: in a 50 mL of ajar, compound M19 (100 mg, 0.23 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and the corresponding amine compound (0.28 mmol) was sequentially added, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (105 mg, 0.28 mmol) and diisopropylethylamine (89 mg, 0.69 mmol) were added, and the reaction mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. After the reaction was completed, the crude product was concentrated by distillation under reduced pressure, saturated brine (30 mL) was added, and the product was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain yellowish or white solid compounds B7, B8, B10, B11 and B15, respectively.

[0116] Compound B7, 72 mg, yellowish solid, yield 56%. 1H NMR (400 MHz, DMSO) δ 8.61 (t, J = 5.6 Hz, 1H), 8.51 (dd, J = 4.4, 2.4 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 9.6, 5.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.56 (td, J = 7.2, 1.2 Hz, 1H), 7.48 (td, J = 8.0, 2.4 Hz, 1H), 7.25 (td, J = 7.2, 1.2 Hz, 1H), 6.78 (s, 1H), 4.55 (t, J = 8.0 Hz, 2H), 4.36 (t, J = 7.2 Hz, 2H), 4.26 - 4.15 (m, 1H), 3.48 - 3.38 (m, 2H), 3.05 (s, 6H), 2.61 (t, J = 6.8 Hz, 2H), 2.54 (dd, J = 14.4, 7.2 Hz, 4H), 0.99 (t, J = 7.2 Hz, 6H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 29 H 34 N7O2F 532.2831, found 532.2860.

[0117] Compound B8, 62 mg, yellowish solid, yield 57%. 1 H NMR (400 MHz, DMSO) δ 8.65 (t, J = 5.6 Hz, 1H), 8.50 (dd, J = 4.8, 2.4 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.70 (dd, J = 10.0, 5.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.56 (td, J = 6.8, 1.2 Hz, 1H), 7.48 (td, J = 8.0, 2.0 Hz, 1H), 7.26 (t, J = 8.0, 1.2 Hz, 1H), 6.79 (s, 1H), 4.55 (t, J = 8.0 Hz, 2H), 4.37 (t, J = 8.0 Hz, 2H), 4.26 - 4.14 (m, 1H), 3.52 - 3.41 (m, 2H), 3.05 (s, 6H), 2.46 (t, J = 6.8 Hz, 2H), 2.22 (s, 6H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 27 H 30 N7O2F 504.2518, found 504.2544.

[0118] Compound B10, 51 mg, yellowish solid, yield 48%. 1H NMR (500 MHz, DMSO-d6) δ 9.79 (br s, 1H), 9.28 (br s, 1H), 9.11 (t, J = 6.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 10.0, 5.0 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 6.5 Hz, 1H), 7.48 (dt, J = 8.0, 2.0 Hz, 1H), 7.28 (t, J = 7.0 Hz, 1H), 7.09 (s, 1H), 4.66 - 4.53 (m, 2H), 4.47 - 4.35 (m, 2H), 4.27 - 4.21 (m, 1H), 4.20 (d, J = 6.0 Hz, 2H), 3.05 (s, 6H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 25 H 24 N7O2FS 506.1769, found 506.1770.

[0119] Compound B11, 52 mg, yellowish solid, yield 49%. 1 H NMR (400 MHz, CDCl3) δ 8.37 (ddd, J = 4.4, 2.4, 0.4 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.55 (ddd, J = 9.6, 5.2, 0.4 Hz, 1H), 7.50 (td, J = 6.8, 1.2 Hz, 1H), 7.24 - 7.15 (m, 2H), 6.59 (s, 1H), 4.75 (d, J = 6.0 Hz, 2H), 4.52 - 4.39 (m, 4H), 4.13 - 4.04 (m, 1H), 3.12 (s, 6H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 26 H 22 N7O3FS2 564.1282, found 564.1307.

[0120] Compound B15, yellowish solid, yield 56%. 1H NMR (400 MHz, CDC13) δ 8.40 (dd, J = 4.0, 2.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.62 - 7.50 (m, 2H), 7.30 - 7.17 (m, 2H), 6.68 (s, 1H), 6.41 (d, J = 7.2 Hz, 1H), 4.58 (t, J = 8.0 Hz, 2H), 4.52 (t, J = 8.0 Hz, 2H), 4.31 - 4.21 (m, 1H), 4.20 - 4.10 (m, 1H), 3.47 (dd, J = 14.4, 9.6 Hz, 1H), 3.14 (s, 6H), 2.93 - 2.77 (m, 4H), 2.63 (dd, J = 14.4, 4.0 Hz, 1H), 2.13 (dd, J = 5.6, 2.8 Hz, 1H), 1.81 - 1.66 (m, 3H), 1.62 - 1.49 (m, 1H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 30 H 32 N7O2F 542.2674, found 542.2680.

[0121] In a 50 mL vial, compound M19 (100 mg, 0.23 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), the corresponding amine compound (0.28 mmol) was added, followed by 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (105 mg, 0.28 mmol) and diisopropylethylamine (89 mg, 0.69 mmol). The reaction mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. After the reaction was completed, the system was concentrated under reduced pressure to obtain a crude product. Saturated brine (30 mL) was added to the crude product, which was extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a light yellow or white solid compound. The compound was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. After the reaction was completed, the crude product was concentrated under reduced pressure. The pH was adjusted to 9-10 by adding a saturated sodium bicarbonate solution, and ethyl acetate (10 mL) was added to extract twice. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain a light yellow solid B9, B12-B14, B16, and B18.

[0122] Compound B9, 32 mg, white solid, yield 42%. 1H NMR (500 MHz, CD3OD_SPE) δ 8.44 (dd, J = 4.0, 2.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.42 (td, J = 8.0, 2.5 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 6.88 (s, 1H), 4.64 (t, J = 8.0 Hz, 2H), 4.46 (t, J = 8.0 Hz, 2H), 4.32 - 4.23 (m, 1H), 3.49 - 3.37 (m, 2H), 3.22 (dd, J = 12.5, 6.5 Hz, 1H), 3.14 (s, 6H), 1.20 (d, J = 6.5 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 26 H 28 N7O2F 490.2361, found 490.2356.

[0123] Compound B12, 57 mg, yellowish solid, yield 38%. 1 H NMR (500 MHz, CD3OD) δ 8.47 - 8.45 (m, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.63 (dd, J = 10.0, 5.0 Hz, 1H), 7.45 (dt, J = 8.0, 2.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 4.75 (t, J = 8.5 Hz, 2H), 4.72 - 4.66 (m, 1H), 4.58 - 4.52 (m, 2H), 4.37 - 4.29 (m, 1H), 3.68 (dd, J = 12.0, 7.0 Hz, 1H), 3.57 - 3.50 (m, 1H), 3.49 - 3.39 (m, 2H), 3.14 (s, 6H), 2.51 - 2.41 (m, 1H), 2.25 - 2.16 (m, 1H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 27 H 28 N7O2F 502.2361, found 502.2358.

[0124] Compound B13, 52 mg, yellowish solid, yield 38%. 1H NMR (500 MHz, DMSO) δ 8.79 (d, J = 7.5 Hz, 1H), 8.51 (dd, J = 4.5, 2.5 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 10.0, 5.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (td, J = 7.0, 1.0 Hz, 1H), 7.48 (td, J = 7.0, 2.5 Hz, 1H), 7.26 (td, J = 8.0, 1.0 Hz, 1H), 6.78 (s, 1H), 4.56 (t, J = 8.0 Hz, 2H), 4.37 (t, J = 8.0 Hz, 2H), 4.24 - 4.17 (m, 1H), 4.11 - 3.99 (m, 1H), 3.25 - 3.14 (m, 2H), 3.05 (s, 6H), 2.93 - 2.82 (m, 2H), 2.04 - 1.93 (m, 2H), 1.66 - 1.54 (m, 2H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 28 H 30 N7O2F 516.2518, found 516.2514.

[0125] Compound B14, 54 mg, yellowish solid, yield 44%. 1 H NMR (500 MHz, CD3OD) δ 8.48 (dd, J = 4.0, 2.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.66 (dd, J = 9.5, 5.0 Hz, 1H), 7.54 (dt, J = 6.0, 2.5 Hz, 1H), 7.49 (dt, J = 8.0, 2.5 Hz, 1H), 7.15 (s, 1H), 4.97 (t, J = 9.5 Hz, 2H), 4.73 (dd, J = 9.5, 6.0 Hz, 2H), 4.47 - 4.39 (m, 1H), 4.39 - 4.31 (m, 1H), 3.65 (dd, J = 12.5, 4.0 Hz, 1H), 3.35 (dt, J = 12.5, 4.0 Hz, 1H), 3.13 (s, 6H), 3.07 - 2.98 (m, 2H), 2.23 - 2.15 (m, 1H), 2.13 - 2.05 (m, 1H), 1.94 - 1.83 (m, 1H), 1.79 - 1.69 (m, 1H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 28 H 30 N7O2F 516.2518, found 516.2514.

[0126] Compound B16, 50 mg, yellowish solid, yield 53%. 1 H NMR (400 MHz, CDC13) δ 8.43 - 8.38 (m, 1H), 7.75 (t, J = 9.2 Hz, 1H), 7.58 (m, 3H), 7.31 - 7.18 (m, 3H), 6.56 (d, J = 14.0 Hz, 1H), 4.70 - 4.59 (m, 1H), 4.59 - 4.49 (m, 3H), 4.22 - 4.11 (m, 1H), 4.04 - 3.59 (m, 2H), 3.19 (dd, J = 9.6, 4.8 Hz, 1H), 3.15 (d, J = 1.6 Hz, 6H), 3.11 - 2.98 (m, 2H), 2.84 - 2.77 (m, 1H), 0.85 - 0.67 (m, 2H), 0.54 (t, J = 6.9 Hz, 1H), 0.35 - 0.08 (m, 1H). HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 29 H 30 N7O2F 550.2337, found 550.2358.

[0127] Compound B18, 45 mg, yellowish solid, yield 47%. 1 H NMR (500 MHz, CD3OD) δ 8.47 - 8.41 (m, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.69 - 7.51 (m, 3H), 7.43 (td, J = 8.0, 2.5 Hz, 1H), 7.31 (q, J = 8.0 Hz, 1H), 6.87 - 6.73 (m, 1H), 4.79 - 4.70 (t, 1H), 4.69 - 4.58 (m, 2H), 4.46 (t, J = 7.0 Hz, 2H), 4.33 - 4.23 (m, 1H), 3.47 (t, J = 14.0 Hz, 1H), 3.40 - 3.31 (m, 1H), 3.28 - 3.16 (m, 2H), 3.14 (s, 6H), 3.10 - 2.77 (m, 2H), 1.38 - 0.98 (m, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 28 H 30 N7O2F 516.2518, found 516.2505.

[0128] The synthesis process of compound B17 is as follows: compound B16 (100 mg, 0.19 mmol) is dissolved in methanol (6 mL) in a 50 mL flask, and an aqueous formaldehyde solution (0.2 mL, 37%) and sodium cyanoborohydride (36 mg, 0.57 mmol) are added, and the reaction mixture is stirred at room temperature overnight, and the reaction is monitored by TLC. After the reaction is completed, the crude product is concentrated by distillation under reduced pressure, saturated brine (10 mL) is added to it, and ethyl acetate is extracted twice, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated by distillation under reduced pressure. The obtained crude product is purified by silica gel column chromatography to obtain compound B17 (82 mg, yield 80%) as a light yellow solid. 1 H NMR (500 MHz, CD3OD) δ 8.47-8.42 (m, 1H), 7.73 (dd, J = 11.5, 8.5 Hz, 1H), 7.66-7.57 (m, 3H), 7.43 (td, J = 8.0, 2.0 Hz, 1H), 7.31 (dd, J = 14.0, 6.5 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 4.72-4.57 (m, 2H), 4.50-4.41 (m, 2H), 4.34-4.23 (m, 1H), 4.11-3.83 (m, 1H), 3.82-3.67 (m, 1H), 3.47-3.37 (m, 1H), 3.14 (s, 6H), 3.10-3.01 (m, 1H), 2.80 (t, J = 5.0 Hz, 1H), 2.46 (d, J = 3.5 Hz, 3H), 0.84-0.71 (m, 2H), 0.68-0.57 (m, 1H), 0.41-0.08 (m, 1H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 30 H 32 N7O2F 542.2674, found 542.2669.

[0129] The synthesis process of compound B19 is as follows: compound B12 (80 mg, 0.16 mmol) is used as the raw material, and the synthesis method of compound B17 is referred to, to obtain compound B19 (48 mg, yield 59%) as a light yellow solid. 1H NMR (400 MHz, CDC13) δ 8.40 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.62 - 7.50 (m, 2H), 7.27 - 7.16 (m, 2H), 7.07 (d, J = 6.8 Hz, 1H), 6.71 (s, 1H), 4.82 - 4.70 (m, 1H), 4.57 (t, J = 8.0 Hz, 2H), 4.51 (t, J = 6.8 Hz, 2H), 4.20 - 4.08 (m, 1H), 3.14 (s, 6H), 3.05 - 2.97 (m, 1H), 2.87 (d, J = 10.0 Hz, 1H), 2.67 - 2.63 (m, 1H), 2.50 - 2.44 (m, 1H), 2.40 (s, 3H), 2.33 - 2.27 (m, 1H), 1.96 - 1.77 (m, 1H).

[0130] The synthetic process of compound B20 is as follows: compound B18 (100 mg, 0.19 mmol) as the raw material, referring to the synthetic method of compound B17, compound B20 (74 mg, yield 72%) of light yellow solid is obtained. 1 H NMR (400 MHz, CDC13) δ 8.40 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.62 - 7.50 (m, 2H), 7.27 - 7.16 (m, 2H), 7.07 (d, J = 6.8 Hz, 1H), 6.71 (s, 1H), 4.82 - 4.70 (m, 1H), 4.57 (t, J = 8.0 Hz, 2H), 4.51 (t, J = 6.8 Hz, 2H), 4.20 - 4.08 (m, 1H), 3.14 (s, 6H), 3.05 - 2.97 (m, 1H), 2.87 (d, J = 10.0 Hz, 1H), 2.67 - 2.63 (m, 1H), 2.50 - 2.44 (m, 1H), 2.40 (s, 3H), 2.33 - 2.27 (m, 1H), 1.96 - 1.77 (m, 1H).

[0131] The synthetic process of compound B21 is as follows: compound B13 (120 mg, 0.23 mmol) as the raw material, referring to the synthetic method of compound B17, compound B21 (92 mg, yield 75%) of light yellow solid is obtained. 1H NMR (400 MHz, CDC13) δ 8.38 (dd, J = 4.0, 2.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.60 - 7.47 (m, 2H), 7.25 - 7.15 (m, 2H), 6.66 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 4.59 - 4.40 (m, 4H), 4.15 - 3.99 (m, 2H), 3.12 (s, 6H), 2.91 - 2.78 (m, 2H), 2.64 - 2.57 (m, 2H), 2.29 (s, 3H), 2.17 - 2.11 (m, 2H), 1.75 - 1.59 (m, 2H).

[0132] The synthetic process of compound B22 is as follows: compound B14 (120 mg, 0.23 mmol) as a raw material, according to the synthetic method of compound B17, compound B22 (96 mg, yield 78%) of light yellow solid was obtained. 1 H NMR (400 MHz, CDC13) δ 8.38 (dd, J = 4.0, 2.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.60 - 7.47 (m, 2H), 7.25 - 7.15 (m, 2H), 6.66 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 4.59 - 4.40 (m, 4H), 4.15 - 3.99 (m, 2H), 3.12 (s, 6H), 2.91 - 2.78 (m, 2H), 2.64 - 2.57 (m, 2H), 2.29 (s, 3H), 2.17 - 2.11 (m, 2H), 1.75 - 1.59 (m, 2H).

[0133] In this example, the synthetic route of compound B23 (see Figure 13 ) is as follows:

[0134] The synthesis of intermediate M20 was carried out by dissolving compound 2-(1-tert-butoxycarbonyl)azetidin-3-yl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (3.35 g, 10.0 mmol), N,O-dimethylhydroxylamine (1.46 g, 15.0 mmol), N,N-diisopropylethylamine (3.88 g, 30.0 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.18 g, 11.0 mmol) in N,N-dimethylformamide (30 mL) in a 125 mL flask. The reaction mixture was stirred at room temperature overnight, the reaction was monitored by TLC. After completion of the reaction, the filtrate was concentrated under reduced pressure and the crude obtained was purified by silica gel column chromatography to yield intermediate compound M20 (2.27 g, 60% yield) as a yellow solid. 1 H NMR (400 MHz, CDC13) δ 8.61 (dd, J = 4.6, 2.4 Hz, 1H), 7.64 (dd, J = 9.8, 5.0 Hz, 1H), 7.25 (ddd, J = 10.0, 7.4, 2.0 Hz, 1H), 4.28 (d, J = 8.4 Hz, 4H), 4.09 (q, J = 7.6 Hz, 1H), 3.47 (s, 3H), 3.42 (s, 3H), 1.45 (s, 9H).

[0135] The synthesis of intermediate M21 was carried out by dissolving M20 (1.82 g, 4.82 mmol) and methyl magnesium bromide (5 mL, 14.44 mmol) in tetrahydrofuran (40 mL) at 0 °C in a 125 mL flask. The reaction mixture was then stirred at room temperature overnight, the reaction was monitored by TLC. After completion of the reaction, saturated ammonium chloride solution was added to the reaction mixture at 0 °C and the aqueous phase was extracted with ethyl acetate twice, the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure and the crude obtained was purified by silica gel column chromatography to yield intermediate compound M21 (1.01 g, 63% yield) as a white solid. 1 H NMR (400 MHz, CDC13) δ 8.61 (dd, J = 4.6, 2.4 Hz, 1H), 7.64 (dd, J = 9.8, 5.0 Hz, 1H), 7.25 (ddd, J = 10.0, 7.4, 2.0 Hz, 1H), 4.28 (d, J = 8.4 Hz, 4H), 4.09 (q, J = 7.6 Hz, 1H), 3.47 (s, 3H), 3.42 (s, 3H), 1.45 (s, 9H).

[0136] The synthesis process of intermediate M22 is as follows: in a 50 mL gourd-shaped bottle, compound M21 (200 mg, 0.6 mmol) is dissolved in methanol (10 mL), concentrated hydrochloric acid (1.0 mL) is added, the reaction mixture is stirred at room temperature overnight, and the reaction is monitored by TLC. After the reaction is completed, it is concentrated by distillation under reduced pressure to obtain white solid intermediate compound M22 (140 mg, yield 100%). 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (dd, J = 5.4, 2.4 Hz, 1H), 7.88 (dd, J = 9.8, 5.4 Hz, 1H), 7.77 - 7.69 (m, 1H), 4.52 (p, J = 8.0 Hz, 1H), 4.03 (t, J = 7.4 Hz, 2H), 3.77 (t, J = 7.8 Hz, 2H), 2.52 (s, 3H).

[0137] The synthesis process of compound B23 is as follows: in a 50 mL gourd-shaped bottle, intermediate M22 (100 mg, 0.43 mmol) and M7 (95 mg, 0.43 mmol) are dissolved in anhydrous DMF (10 mL), and cesium carbonate (420 mg, 1.29 mmol) is added. The reaction mixture is heated to 110°C and reacted overnight, and the reaction is monitored by TLC. After the reaction is completed, the cesium carbonate is removed by filtration, and the filtrate is distilled under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain white solid compound B23 (86 mg, yield 48%). 1 H NMR (400 MHz, CDCl3) δ 9.78 (dd, J = 5.2, 2.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 10.0, 5.2 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.43 - 7.38 (m, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.64 (s, 1H), 6.35 (q, J = 4.8 Hz, 1H), 4.68 - 4.55 (m, 5H), 3.10 (d, J = 4.8 Hz, 3H), 2.62 (s, 3H).

[0138] In this example, the synthesis routes of compounds B24-B26 (see Figure 14 ) are as follows:

[0139] The synthesis of intermediate M23 was carried out by dissolving ethyl 2-(azetidin-3-yl)-6-fluoroimidazo[l,2-a]pyridine-3-carboxylate M14e (400 mg, 1.52 mmol) and 2-chloro-4-methylquinoline in toluene (30 mL) in a 100 mL jar followed by the addition of sodium tert-butoxide (438 mg, 4.56 mmol), x-Phos (145 mg, 0.30 mmol) and Pd2(dba)3(139 mg, 0.15 mmol). The reaction mixture was heated at 100 °C under argon overnight. After completion of the reaction, the mixture was distilled under reduced pressure to obtain the crude product which was purified by silica gel column chromatography to obtain intermediate compound M23 (128 mg, 54% yield) as a light yellow solid. 1 HNMR (400 MHz, CDC13) δ 9.33 (dd, J = 4.4, 2.0 Hz, 1H), 7.81 - 7.72 (m, 2H), 7.65 (dd, J = 9.6, 4.8 Hz, 1H), 7.52 (dt, J = 6.8, 1.2 Hz, 1H), 7.35 - 7.29 (m, 1H), 7.26 - 7.20 (m, 1H), 6.52 (s, 1H), 4.71 - 4.55 (m, 5H), 4.47 (q, J = 7.2 Hz, 2H), 2.59 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H).

[0140] The synthesis of intermediate M24 was carried out by dissolving intermediate M23 (295 mg, 0.73 mmol) in methanol (10 mL) and water (3 mL) in a 50 mL jar followed by the addition of sodium hydroxide (88 mg, 2.19 mmol). The reaction mixture was stirred at 60 °C overnight and the reaction was monitored by TLC. After completion of the reaction, the crude product was obtained as an aqueous solution which was acidified by the addition of 5 M hydrochloric acid solution to adjust the pH to 3-4. The solid was filtered, washed with water and dried under air to obtain intermediate compound M24 (240 mg, 88% yield) as a light yellow solid.

[0141] The synthesis of intermediate M25 was carried out by dissolving intermediate M24 (200 mg, 0.53 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (126 mg, 0.64 mmol), N,N-diisopropylethylamine (205 mg, 1.59 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (242 mg, 0.64 mmol) in N,N-dimethylformamide (10 mL) in a 125 mL jar. The reaction mixture was stirred at room temperature overnight and the reaction was monitored by TLC. After completion of the reaction, the filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography to obtain intermediate compound M25 (280 mg, 94.6% yield) as a white solid.1 H NMR (500 MHz, CDC13) δ 8.17 (s, 1H), 7.76 (dd, J = 8.0, 4.0 Hz, 2H), 7.62 - 7.55 (m, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.21 (ddd, J = 10.0, 8.0, 2.5 Hz, 1H), 6.46 (s, 1H), 4.71 (s, 2H), 4.61 - 4.53 (m, 2H), 4.21 (s, 4H), 3.93 - 3.43 (m, 3H), 2.72 - 2.66 (m, 1H), 2.56 (s, 3H), 1.49 (s, 9H).

[0142] The synthesis process of compound B24 is as follows: in a 50 mL tomato bottle, intermediate M25 (280 mg, 0.5 mmol) is dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) is added carefully. The reaction mixture is stirred at room temperature overnight, and the reaction is monitored by TLC. After the reaction is completed, the mixture is distilled under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain white solid compound B24 (195 mg, yield 85%). 1 H NMR (400 MHz, CDC13) δ 8.27 (dd, J = 3.6, 2.4 Hz, 1H), 7.79 (dd, J = 8.2, 1.2 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 9.8, 5.2 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.25 (dd, J = 8.2, 1.2 Hz, 1H), 7.20 (ddd, J = 10.0, 7.8, 2.4 Hz, 1H), 6.50 (s, 1H), 4.60 (t, J = 8.1 Hz, 2H), 4.56 - 4.48 (m, 2H), 4.23 - 4.15 (m, 1H), 3.94 (s, 2H), 3.81 (s, 4H), 2.81 (d, J = 9.0 Hz, 1H), 2.63 - 2.51 (m, 3H), 1.63 (d, J = 9.4 Hz, 1H).

[0143] The synthesis process of compound B25 is as follows: in a 50 mL tomato bottle, compound B24 (143 mg, 0.31 mmol) is dissolved in methanol (10 mL), and formaldehyde aqueous solution (1 mL, 37%) and sodium cyanoborohydride (59 mg, 0.94 mmol) are added. The reaction mixture is stirred at room temperature overnight, and the reaction is monitored by TLC. After the reaction is completed, the crude product is concentrated by distillation under reduced pressure, saturated brine (10 mL) is added, and ethyl acetate is extracted twice. After drying over anhydrous sodium sulfate, the filtrate is concentrated by distillation under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain white solid compound B25 (66 mg, yield 45%). 1H NMR (400 MHz, CDC13) δ 8.22 (dd, J = 4.2, 2.2 Hz, 1H), 7.85 - 7.71 (m, 2H), 7.59 (dd, J = 9.8, 5.2 Hz, 1H), 7.52 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.27 - 7.12 (m, 2H), 6.50 (d, J = 1.2 Hz, 1H), 4.60 (t, J = 8.2 Hz, 2H), 4.56 - 4.48 (m, 2H), 4.17 (ddd, J = 14.8, 8.4, 6.4 Hz, 1H), 3.92 - 3.53 (m, 5H), 2.96 - 2.63 (m, 3H), 2.59 (s, 3H), 2.30 (s, 3H).

[0144] The process for the synthesis of compound B26 was as follows: in a 50 mL vial, intermediate M24 (200 mg, 0.53 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), N-methylpiperazine (106 mg, 1.06 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (242 mg, 0.64 mmol) and diisopropylethylamine (206 mg, 1.59 mmol) were added sequentially, the reaction mixture was stirred at room temperature overnight, the reaction was monitored by TLC. After completion of the reaction, the crude was concentrated by distillation under reduced pressure, to this saturated brine (30 mL) was added, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, the filtrate was concentrated by distillation under reduced pressure, the crude obtained was purified by silica gel column chromatography to get compound B26 (76 mg, yield 31%) as a light yellow or white solid. 1 H NMR (400 MHz, CDC13) δ 8.22 (dd, J = 4.2, 2.2 Hz, 1H), 7.85 - 7.71 (m, 2H), 7.59 (dd, J = 9.8, 5.2 Hz, 1H), 7.52 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.27 - 7.12 (m, 2H), 6.50 (d, J = 1.2 Hz, 1H), 4.60 (t, J = 8.2 Hz, 2H), 4.56 - 4.48 (m, 2H), 4.17 (ddd, J = 14.8, 8.4, 6.4 Hz, 1H), 3.92 - 3.53 (m, 5H), 2.96 - 2.63 (m, 3H), 2.59 (s, 3H), 2.30 (s, 3H).

[0145] In this example, the synthetic route of compound B27 (see Figure 15 ) was as follows:

[0146] The synthesis process of intermediate M26 is as follows: in a 50 mL of ajar, 2,4-dibromoquinoline (1.0 g, 3.48 mmol) was dissolved in anhydrous 1,4-dioxane (20 mL). The mixture was heated to 90 °C, and 40% HBr (4 mL) was added dropwise. The reaction mixture was continuously heated at 90 °C overnight. After the reaction was completed, the mixture was concentrated by distillation under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain intermediate compound M26 (614 mg, yield 79%) as a gray-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 7.82 (dd, J = 8.0, 1.2 Hz, 1H), 7.61 (dt, J = 7.2, 1.2 Hz, 1H), 7.36 (dd, J = 8.0, 0.8 Hz, 1H), 7.30 (dt, J = 7.2, 1.2 Hz, 1H), 7.03 (s, 1H).

[0147] The synthesis process of intermediate M27 is as follows: in a 100 mL of ajar, intermediate M26 (224 mg, 1.0 mmol) and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (223 mg, 1.0 mmol) were dissolved in 1,4-dioxane (20 mL) and H2O (5 mL), followed by the addition of K2CO3 (977 mg, 3.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium Pd(dppf)Cl2 (73 mg, 0.10 mmol). The reaction mixture was heated at 90 °C overnight under argon protection. After the reaction was completed, the mixture was concentrated by distillation under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain intermediate compound M27 (192 mg, yield 80%) as a light yellow solid. 1 H NMR (400 MHz, CDCl3) δ 12.37 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.53-7.42 (m, 2H), 7.19 (dt, J = 8.0, 0.8 Hz, 1H), 6.55 (s, 1H), 5.84 (s, 1H), 3.25-3.15 (m, 2H), 2.75 (t, J = 5.6 Hz, 2H), 2.58-2.51 (m, 2H), 2.48 (s, 3H).

[0148] The synthesis process of intermediate M28 is as follows: in a 100 mL of ajar, intermediate M27 (575 mg, 2.39 mmol) was dissolved in toluene (20 mL), followed by the addition of phosphorus oxychloride (2 mL). The reaction mixture was heated at 100 °C for 4 hours. After the reaction was completed, the mixture was concentrated by distillation under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain intermediate compound M28 (570 mg, yield 92%) as a light yellow solid. 1H NMR (400 MHz, CDC13) δ 7.96 (s, 1H), 7.94 (s, 1H), 7.64 (dt, J = 7.2, 1.2 Hz, 1H), 7.45 (dt, J = 7.2, 1.2 Hz, 1H), 7.14 (s, 1H), 5.85 - 5.76 (m, 1H), 3.15 (dd, J = 6.0, 2.8 Hz, 2H), 2.70 (t, J = 5.6 Hz, 2H), 2.57 - 2.48 (m, 2H), 2.42 (s, 3H).

[0149] The synthesis process of compound B27 is as follows: in a 100 mL of ajar, intermediate M28 (570 mg, 2.20 mmol) and intermediate M17e (578 mg, 2.20 mmol) are dissolved in toluene (30 mL), followed by adding sodium tert-butoxide (634 mg, 6.60 mmol), x-Phos (210 mg, 0.44 mmol) and Pd2(dba)3(201 mg, 0.22 mmol), and the reaction mixture is heated at 100 °C under argon protection overnight. After the reaction is completed, the mixture is distilled under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain compound B27 (156 mg, yield 15%) in a light yellow solid. 1 H NMR (400 MHz, CDC13) δ 8.36 (dd, J = 4.0, 2.4 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.72 (d, J = 0.8 Hz, 1H), 7.56 - 7.43 (m, 2H), 7.23 - 7.10 (m, 2H), 6.44 (s, 1H), 4.60 - 4.40 (m, 4H), 4.18 - 4.06 (m, 1H), 3.76 - 3.50 (m, 4H), 2.53 (s, 3H), 2.51 - 2.33 (m, 4H), 2.28 (s, 3H).

[0150] In this example, the synthesis route of compounds C1-C2 (see Figure 16 ) is as follows:

[0151] The synthesis process of intermediate M29 is as follows: in a 125 mL of ajar, methyl 2-amino-5-methylbenzoate (1.65 g, 10.0 mmol) is dissolved in acetic acid (10 mL), and a solution of potassium cyanate (973 mg, 12.0 mmol) in water (10 mL) is slowly added dropwise, and the reaction mixture is heated at 60 °C overnight, and the reaction is monitored by TLC. After the reaction is completed, the reaction is reduced to room temperature, water (40 mL) is added to the reaction mixture, and stirred for 10 minutes, and the precipitated solid is filtered, the filter cake is washed with water, and dried in air to obtain white solid intermediate compound M29 (1.68 g, yield 81%). 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.0 Hz, 1H), 6.54 (br s, 2H), 3.86 (s, 3H), 2.26 (s, 3H).

[0152] The synthesis process of intermediate M30 is as follows: in a 125 mL flask, intermediate M29 (1.68 g, 8.1 mmol) was dissolved in absolute ethanol (30 mL), sodium hydroxide (645 mg, 16.2 mmol) was added, the reaction mixture was heated to 80 °C and refluxed overnight, and the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature, and a solid was precipitated. The solid was filtered, washed with water, and dried in air to obtain white solid intermediate compound M30 (1.42 g, yield 100%). 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.0 Hz, 1H), 6.54 (br s, 2H), 3.86 (s, 3H), 2.26 (s, 3H).

[0153] The synthesis process of intermediate M31 is as follows: in a 125 mL flask, intermediate M30 (1.42 g, 8.1 mmol) and phosphorus oxychloride (20 mL) were mixed, the reaction mixture was heated to 110 °C and refluxed overnight, and the reaction was monitored by TLC. After the reaction was completed, the reaction was cooled to room temperature, and the phosphorus oxychloride was removed by distillation under reduced pressure to obtain a crude product. Dichloromethane and triethylamine were slowly added to the cooled crude product until the pH of the system was 8-9. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain white solid intermediate compound M31 (1.33 g, yield 77%). 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.0 Hz, 1H), 6.54 (br s, 2H), 3.86 (s, 3H), 2.26 (s, 3H).

[0154] The synthesis process of intermediate M32a is as follows: in a 125 mL flask, intermediate M31 (891 mg, 4.18 mmol) was dissolved in absolute acetonitrile (40 mL), and 2,4-dimethoxybenzylamine (699 mg, 4.18 mmol) and diisopropylethylamine (1.62 g, 12.54 mmol) were added in sequence. The reaction mixture was heated to 50 °C and stirred overnight, and the reaction was monitored by TLC. After the reaction was completed, the reaction was cooled to room temperature, and a solid was precipitated. The precipitated solid was filtered, washed with water, and dried in air to obtain white solid intermediate compound M32a (1.32 g, yield 92%).1 H NMR (400 MHz, CDC13) δ 7.63 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 8.4, 1.2 Hz, 1H), 7.35 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.54 - 6.45 (m, 2H), 6.25 (t, J = 4.4 Hz, 1H), 4.76 (d, J = 5.2 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.46 (s, 3H).

[0155] The synthesis process of intermediate M32b is as follows: taking intermediate M31 (426 mg, 2.0 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (424 mg, 2.0 mmol) as raw materials, referring to the synthesis method of compound M32a, intermediate compound M32b (748 mg, yield 97%) was obtained as a white solid. 1 H NMR (500 MHz, CDC13) δ 7.70 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.54 (dd, J = 8.5, 1.5 Hz, 1H), 4.57 - 4.21 (m, 4H), 3.77 - 3.42 (m, 2H), 2.49 (s, 3H), 2.00 - 1.89 (m, 2H), 1.89 - 1.72 (m, 2H), 1.52 (s, 9H).

[0156] The synthesis process of intermediate M33a is as follows: in a 50 mL tomato flask, intermediate M32a (343 mg, 1.0 mmol) and M7 (262 mg, 1.0 mmol) were dissolved in anhydrous DMF (10 mL), and cesium carbonate (1.62 g, 3.0 mmol) was added. The reaction mixture was heated at 110 °C overnight, and the reaction was monitored by TLC. After the reaction was completed, the cesium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain intermediate compound M33a (158 mg, yield 28%) as a light yellow solid. 1H NMR (400 MHz, CDC13) δ 8.44 - 8.39 (m, 1H), 7.59 (dd, J = 10.0, 4.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.23 - 7.16 (m, 1H), 4.60 - 4.45 (m, 4H), 4.40 - 4.15 (m, 4H), 4.13 - 4.01 (m, 1H), 3.62 - 3.31 (m, 2H), 3.15 (s, 6H), 2.40 (s, 3H), 1.99 - 1.85 (m, 4H), 1.51 (s, 9H).

[0157] The synthesis process of intermediate M33b is as follows: taking intermediate M32b (200 mg, 0.51 mmol) and M7 (135 mg, 0.51 mmol) as raw materials, referring to the synthesis method of compound M33a, intermediate compound M33b (134 mg, yield 42%) of light yellow solid was obtained. 1 H NMR (400 MHz, CDC13) δ 8.44 - 8.39 (m, 1H), 7.59 (dd, J = 10.0, 4.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.23 - 7.16 (m, 1H), 4.60 - 4.45 (m, 4H), 4.40 - 4.15 (m, 4H), 4.13 - 4.01 (m, 1H), 3.62 - 3.31 (m, 2H), 3.15 (s, 6H), 2.40 (s, 3H), 1.99 - 1.85 (m, 4H), 1.51 (s, 9H).

[0158] The synthesis process of compound C1 is as follows: in a 50 mL vial, intermediate M33a (158 mg, 0.28 mmol) was dissolved in methanol (10 mL), and concentrated hydrochloric acid (1 mL) was carefully added. The reaction mixture was heated at 65 °C for 24 hours, and the reaction was monitored by TLC. After the reaction was completed, the mixture was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain compound C1 (91 mg, yield 78%) of light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.49 (dd, J = 5.0, 2.0 Hz, 1H), 7.86 (s, 1H), 7.71 (dd, J = 10.0, 5.5 Hz, 1H), 7.58 (brs, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.43 (t, J = 8.0 Hz, 2H), 4.27 (t, J = 8.0 Hz, 2H), 4.11 - 4.02 (m, 1H), 3.03 (s, 6H), 2.36 (s, 3H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 22 H 22 N7OF 420.1943, found 420.1946.

[0159] The synthesis of compound C2 was carried out by dissolving intermediate M33b (134 mg, 0.22 mmol) in dichloromethane (10 mL) in a 50 mL vial, and trifluoroacetic acid (1 mL) was added carefully. The reaction mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. After completion of the reaction, the mixture was distilled under reduced pressure to get the crude product, which was purified by silica gel column chromatography to get compound C2 (88 mg, yield 79%) as a light yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.59 (dd, J = 9.6, 5.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 4.66 - 4.44 (m, 4H), 4.30 - 4.16 (m, 2H), 4.14 - 4.02 (m, 1H), 3.64 - 3.52 (m, 2H), 3.46 - 3.33 (m, 2H), 3.15 (s, 6H), 2.48 (brs, 1H), 2.40 (s, 3H), 2.22 - 1.88 (m, 2H), 1.85 - 1.72 (m, 2H). HRMS (ESI-TOF) m / z: [M+H] + calcd for C 28 H 31 N8OF 515.2678, found 515.2682.

[0160] The synthesis route of compound C3 in this example (see Figure 17 ) is as follows:

[0161] The synthesis process of intermediate M34 was as follows: intermediate 2,4-dichloroquinazoline (1.0 g, 5.0 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (1.06 g, 5.0 mmol) were used as raw materials, and the synthetic method of compound M32a was referred to give intermediate compound M34 (1.37 g, yield 73%) in light yellow solid. 1 H NMR (400 MHz, CDC13) δ 8.41 (dd, J = 4.4, 2.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.54 - 7.48 (m, 1H), 7.19 (td, J = 7.6, 2.4 Hz, 1H), 7.07 (td, J = 8.0, 1.2 Hz, 1H), 4.57 (t, J = 8.0 Hz, 2H), 4.52 (t, J = 8.0 Hz, 2H), 4.15 - 4.04 (m, 1H), 3.78 - 3.69 (m, 4H), 3.58 (s, 2H), 3.15 (s, 6H), 1.49 (s, 9H), 1.01 (t, J = 6.0 Hz, 2H), 0.79 (t, J = 6.0 Hz, 2H).

[0162] The synthesis process of intermediate M35 was as follows: intermediate M34 (187 mg, 0.50 mmol) and M17e (131 mg, 0.50 mmol) were used as raw materials, and the synthetic method of compound M33a was referred to give intermediate compound M35 (71 mg, yield 57%) in light yellow solid. 1 H NMR (400 MHz, CDC13) δ 8.41 (dd, J = 4.4, 2.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.54 - 7.48 (m, 1H), 7.19 (td, J = 7.6, 2.4 Hz, 1H), 7.07 (td, J = 8.0, 1.2 Hz, 1H), 4.57 (t, J = 8.0 Hz, 2H), 4.52 (t, J = 8.0 Hz, 2H), 4.15 - 4.04 (m, 1H), 3.78 - 3.69 (m, 4H), 3.58 (s, 2H), 3.15 (s, 6H), 1.49 (s, 9H), 1.01 (t, J = 6.0 Hz, 2H), 0.79 (t, J = 6.0 Hz, 2H).

[0163] The synthesis process of compound C3 was as follows: intermediate M32 (130 mg, 0.22 mmol) was used as raw material, and the synthetic method of compound C2 was referred to give compound C3 (93 mg, yield 86%) in light yellow solid. 1H NMR (500 MHz, CDC13) δ 8.42 (dd, J = 4.5, 2.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.20 (td, J = 7.5, 2.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 4.57 (t, J = 8.0 Hz, 2H), 4.52 (t, J = 8.0 Hz, 2H), 4.15 - 4.04 (m, 1H), 3.72 - 3.64 (m, 2H), 3.54 (s, 2H), 3.15 (s, 6H), 3.14 - 3.11 (m, 2H), 0.66 (t, J = 5.5 Hz, 2H), 0.59 (t, J = 5.5 Hz, 2H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 27 H 29 N8OF 501.2521, found 501.2518.

[0164] In this example, the synthetic route of compounds C4-C8 (see Figure 18 ) is as follows:

[0165] The synthetic process of intermediate M36 is as follows: with compound M14e (825 mg, 2.27 mmol) as the raw material, the synthetic method of compound C1 is referred to, and yellow solid compound M36 (526 mg, yield 88%) is obtained. 1 H NMR (400 MHz, DMSO) δ 9.22 (dd, J = 4.8, 2.4 Hz, 1H), 7.88 (dd, J = 9.6, 5.2 Hz, 1H), 7.70 (td, J = 8.0, 2.4 Hz, 1H), 4.58 - 4.47 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.08 (t, J = 8.0 Hz, 2H), 3.92 (t, J = 8.8 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0166] The synthetic process of compound C4 is as follows: with compound 2-chloro-4-methylquinazoline (357 mg, 2.0 mmol) and M36 (526 mg, 2.0 mmol) as the raw materials, the synthetic method of intermediate M33a is referred to, and light yellow solid compound C4 (559 mg, yield 69%) is obtained. 1H NMR (400 MHz, CDC13) δ 9.33 (dd, J = 4.8, 2.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.71 - 7.56 (m, 3H), 7.32 (td, J = 7.6, 2.4 Hz, 1H), 7.24 - 7.15 (m, 1H), 4.75 - 4.60 (m, 5H), 4.46 (q, J = 7.2 Hz, 2H), 2.79 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 22 H 20 N5O2F 406.1674, found 406.1675.

[0167] The synthesis process of intermediate M37 is as follows: in a 125 mL flask, compound C4 (520 mg, 1.28 mmol) was dissolved in methanol (20 mL) and water (5 mL), and sodium hydroxide (154 mg, 3.84 mmol) was added. The reaction mixture was stirred at 60 °C overnight, and the reaction was monitored by TLC. After the reaction was completed, the crude product was distilled under reduced pressure to obtain an aqueous solution, a saturated citric acid solution was added to adjust the pH to 3-4, and a solid was precipitated. The filter cake was filtered, washed with water, and dried in air to obtain white solid intermediate compound M37 (460 mg, yield 95%). 1 H NMR (500 MHz, DMSO) δ 9.82 (dd, J = 5.5, 2.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.55 (dd, J = 10.0, 5.5 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.45 (t, J = 7.0 Hz, 2H), 4.34 (t, J = 7.0 Hz, 2H), 2.75 (s, 3H).

[0168] The synthesis of compound C5 was carried out by dissolving intermediate M37 (100 mg, 0.26 mmol) in dry N,N-dimethylformamide (8 mL) in a 50 mL jar, adding sequentially compound methylamine hydrochloride (24 mg, 0.29 mmol), 2-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (121 mg, 0.32 mmol) and diisopropylethylamine (103 mg, 0.78 mmol), stirring the reaction mixture at room temperature overnight, monitoring the reaction by TLC. After completion of the reaction, the crude was distilled under reduced pressure and purified by silica gel column chromatography to obtain C5 (81 mg, 76% yield) as a yellowish solid. 1 HNMR (400 MHz, CDC13) δ 8.43 (dd, J = 4.0, 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.58 (dd, J = 10.0, 5.2 Hz, 1H), 7.25 - 7.14 (m, 2H), 4.72 - 4.53 (m, 4H), 4.22 - 4.06 (m, 1H), 3.15 (s, 6H), 2.79 (s, 3H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 22 H 21 N6OF 405.1834, found 405.1846.

[0169] The synthesis of intermediate M38a-c was carried out by dissolving intermediate M37 (100 mg, 0.26 mmol) in dry N,N-dimethylformamide (8 mL) in a 50 mL jar, adding sequentially compound various amines (0.29 mmol), 2-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (121 mg, 0.32 mmol) and diisopropylethylamine (103 mg, 0.78 mmol), stirring the reaction mixture at room temperature overnight, monitoring the reaction by TLC. After completion of the reaction, the crude was distilled under reduced pressure and purified by silica gel column chromatography to obtain intermediate compounds M38a-c as yellowish solids, respectively.

[0170] Intermediate M38a, 126 mg, 87% yield. 1H NMR (400 MHz, CDC13) δ 9.32 (s, 1H), 8.02 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.59 (dd, J = 9.6, 5.2 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.26 - 7.22 (m, 1H), 4.83 - 4.59 (m, 5H), 4.41 - 4.30 (m, 1H), 3.83 - 3.75 (m, 1H), 3.58 - 3.50 (m, 2H), 2.81 (s, 3H), 2.38 - 2.27 (m, 1H), 2.10 - 1.90 (m, 2H), 1.46 (s, 9H).

[0171] Intermediate M38b, 135 mg, 91% yield. 1 H NMR (500 MHz, CDC13) δ 8.95 (s, 1H), 7.92 - 7.83 (m, 2H), 7.74 (t, J = 7.5 Hz, 1H), 7.70 (dd, J = 9.5, 5.0 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.29 - 7.14 (m, 2H), 4.99 - 4.83 (m, 2H), 4.79 - 4.62 (m, 3H), 4.22 - 4.08 (m, 3H), 3.01 - 2.88 (m, 2H), 2.85 (s, 3H), 2.07 - 1.98 (m, 2H), 1.70 - 1.57 (m, 2H), 1.46 (s, 9H).

[0172] Intermediate M38c, 230 mg, 95%. 1 H NMR (500 MHz, CDC13) δ 8.43 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.60 (dd, J = 10.0, 5.0 Hz, 1H), 7.25 - 7.19 (m, 2H), 4.63 (t, J = 8.5 Hz, 2H), 4.57 (t, J = 7.5 Hz, 2H), 4.17 - 4.08 (m, 1H), 4.07 - 3.70 (m, 2H), 3.48 (m, 4H), 2.80 (s, 3H), 1.50 (s, 9H), 1.40 - 1.13 (m, 2H), 1.04 - 0.48 (m, 2H).

[0173] Compound C6, 45 mg, 82% yield. 1H NMR (400 MHz, CDC13) δ 9.24 (dd, J = 4.8, 2.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.56 (dd, J = 10.0, 5.2 Hz, 1H), 7.26 - 7.17 (m, 2H), 6.04 (d, J = 8.0 Hz, 1H), 4.77 - 4.59 (m, 4H), 4.48 - 4.35 (m, 1H), 4.24 - 4.10 (m, 1H), 3.30 - 3.17 (m, 2H), 2.91 - 2.80 (m, 2H), 2.78 (s, 3H), 2.20 - 2.08 (m, 2H), 1.72 - 1.55 (m, 2H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 24 H 24 N7OF 446.2099, found 446.2098.

[0174] Compound C7, 35 mg, yield 79%. 1 H NMR (400 MHz, CDC13) δ 9.24 (dd, J = 4.8, 2.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.56 (dd, J = 10.0, 5.2 Hz, 1H), 7.26 - 7.17 (m, 2H), 6.04 (d, J = 8.0 Hz, 1H), 4.77 - 4.59 (m, 4H), 4.48 - 4.35 (m, 1H), 4.24 - 4.10 (m, 1H), 3.30 - 3.17 (m, 2H), 2.91 - 2.80 (m, 2H), 2.78 (s, 3H), 2.20 - 2.08 (m, 2H), 1.72 - 1.55 (m, 2H). HRMS (ESI-TOF) m / z: [M + H] + calcd for C 25 H 26 N7OF 446.2099, found 446.2098.

[0175] Compound C8, 48 mg, yield 74%. 1H NMR (400MHz, CDCl3) δ8.42(dd,J=3.6,2.4Hz,1H),7.87(d,J=8.0Hz,1H),7.69–7.61(m,2H),7.58(dd,J=9.6,5.2Hz,1H),7.25–7.16(m ,2H),4.67–4.53(m,4H),4.20–4.08(m,1H),4.04–3.27(m,4H),3.03(s,2H),2.79(s,3H),0.77–0.41(m,4H).HRMS(ESI-TOF)m / z:[M+H] + calcd for C 26 H 26 N7OF 472.2256, found 472.2251.

[0176] In this embodiment, the synthetic routes for compounds C9 to C10 are described (see [link]). Figure 19 )as follows:

[0177] The synthesis of compound C9 was as follows: 2-Chloroquinoxaline (164 mg, 1.0 mmol) and intermediate M3a (245 mg, 1.0 mmol) were dissolved in anhydrous DMF (10 mL) in a 125 mL flask, and cesium carbonate (977 mg, 3.0 mmol) was added. The reaction mixture was heated to 110 °C for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the cesium carbonate was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give a pale yellow solid compound C9 (186 mg, 50% yield). 1 H NMR (400MHz, CDCl3) δ9.35(d,J=6.8Hz,1H),8.27(s,1H),7.89(dd,J=8.0,1.2Hz,1H),7.75–7.68(m,2H),7.57(dt,J=7.2,1.2Hz,1H),7.43(dt ,J=7.2,1.2Hz,1H),7.38(dt,J=7.2,1.2Hz,1H),7.04(td,J=6.8,1.2Hz,1H),4.82–4.67(m,5H),4.47(q,J=7.2Hz,2H),1.49(t,J=7.2Hz,3H).

[0178] The synthesis of compound C10 was carried out as follows: using 2-chloroquinoxaline (100 mg, 0.61 mmol) and intermediate M17e (159 mg, 0.61 mmol) as raw materials, and following the synthesis method of compound C9, a pale yellow solid compound C10 (128 mg, yield 54%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 2.4 Hz, 1H), 8.41 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 10.0, 5.2 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.48 (dt, J = 6.4, 2.0 Hz, 1H), 7.41 (dt, J = 6.4, 2.0 Hz, 1H), 4.65 (t, J = 8.4 Hz, 2H), 4.44 (t, J = 8.4 Hz, 2H), 4.30 - 4.20 (m, 1H), 3.04 (s, 6H).

[0179] The aza-tetra-linked pyrazolopyridines of the various embodiments were tested as follows:

[0180] Activity inhibition test of the aza-tetra-linked pyrazolopyridines on PDE10A (phosphodiesterase type 10A)

[0181] The aza-tetra-linked pyrazolopyridines to be tested were incubated with 1.0 μg / mL of recombinant cloned PDE10A protein, 20 mM Tris-HCl (pH = 7.5), 4.0 mmol / L dithiothreitol, 10 mmol / L MgCl2, 20,000-30,000 cpm of 3 H-cAMP mixture at room temperature for 15 minutes, after which the reaction was stopped with 0.2 mol / L ZnSO4and 0.2 mol / L Ba(OH)2respectively, and then the unreacted 3 H-cAMP in the supernatant was measured using a PerkinElmer 2910 counter. The experiment was repeated at least three times. Through concentration testing and non-linear regression calculation, the IC 50 value of the aza-tetra-linked pyrazolopyridines for the activity inhibition of the recombinant cloned PDE10A (phosphodiesterase type 10A) protein was obtained.

[0182] The results of the activity inhibition test of the aza-tetra-linked pyrazolopyridines of the various embodiments on the recombinant cloned PDE10A protein are shown in Table 1, wherein the positive control (papaverine) under the same conditions should be controlled within the IC 50 = 50-100 nmol / L range to ensure that the IC 50 value data of the tested compounds have a reference uniform standard.

[0183] Table 1 Inhibition activity of aza-tetra-linked pyrazolopyridines on PDE10A protein

[0184] Table 1 Inhibition activity of aza-tetra-linked pyrazolopyridines on PDE10A protein

[0185]

[0186] Example 2, Validation experiment of PDE10A inhibitor treatment of pulmonary arterial hypertension in a monocrotaline-induced PAH animal model

[0187] Experimental content: Take PDE10A inhibitor sample A11 as an example to conduct the experiment, and the experiment is divided into 6 groups (1.25, 2.5, 5.0 mg / kg of A11 each group, positive control Tadalafil 5.0 mg / kg group, model group, normal control group), 12 rats in each group. Except for the normal control group given normal saline, the rest of the rats in each group were given 2% monocrotaline 60 mg / kg by intraperitoneal injection to establish a pulmonary arterial hypertension model. The next day, the drug administration began: (1) The normal control group and the model group were given blank solvent [1.6% DMSO + 98.4% CMC-Na (0.5%)] solvent by gavage every day; (2) A11 test drug group was given 1.25 mg / kg (low dose group), 2.5 mg / kg (medium dose group), and 5.0 mg / kg (high dose group) by oral administration every day; (3) All animals were continuously given drugs for three weeks, and the oral administration volume was 0.5 mL / 100 g, and the intraperitoneal injection volume was 0.1 mL / 100 g. During the experiment, the rats' body weight was measured every three days, and the general state of the rats (respiration, activity, etc.) was observed. One hour after the last administration, the animals were anesthetized with 3% sodium pentobarbital intraperitoneally, and the right heart catheter method was used to determine the pulmonary arterial pressure of the rats.

[0188] Determination of rat pulmonary arterial pressure (mPAP): After the rats were anesthetized intraperitoneally, the rats were fixed supine, a longitudinal incision was made on the right clavicle of the neck, the surrounding tissues were bluntly separated, the right external jugular vein was carefully stripped with a mosquito hemostat, and about 1 cm of the vein was freed, two lines were introduced below it, the distal line was ligated, and the proximal line was tied with a loose knot. The proximal and distal lines were fixed on the rat's chest and neck skin with hemostats, respectively, to fully expose and fill the vein. Adjust the calibration physiological recorder while keeping the sensor parallel to the rat's heart position. A V-shaped incision was made at the proximal end with ophthalmic scissors, the curved end of the right heart catheter was inserted into the vascular incision, and the proximal line was tied with a loose knot to hold the catheter inserted into the blood vessel. Slowly push the catheter in, insert 1-2 cm to reach the superior vena cava, 2-3 cm to reach the right atrium, rotate gently and push forward, about 3.5-4 cm to enter the right ventricle, and the right ventricular systolic pressure (RVSP) can be measured. At this time, stop for a moment, and then gently push the catheter to enter the pulmonary artery. During the catheterization process, the position of the catheter tip should be judged according to the shift change of the pressure curve waveform displayed on the monitor, and the average pulmonary arterial pressure is calculated from the pulmonary arterial systolic pressure and pulmonary arterial diastolic pressure values.

[0189] Right ventricular hypertrophy index (RVHI): After the pulmonary hemodynamic index measurement was completed, the neck and chest skin was cut open to expose the trachea, the thoracic cavity was quickly dissected to expose the heart and lung, the trachea was clamped with a hemostat, and the heart, thymus and lung were cut off and taken out together. The heart was taken out, the blood vessels and atrium were removed, the right ventricle (RV) was isolated, the left ventricle and interventricular septum (LV+S) were left, and the blood was washed with physiological saline and then the water was absorbed with filter paper. The weights of the right ventricle (RV) and the left ventricle plus interventricular septum (LV+S) were weighed, and the RV / (LV+S) ratio was taken as the right ventricular hypertrophy index.

[0190] Compared with the model group, the azetidine quaternary ring connected pyrazolopyridine PDE10A inhibitor A11 of the application can significantly reduce the mean pulmonary arterial pressure and right ventricular systolic pressure of the monocrotaline-induced pulmonary arterial hypertension rats (see Figure 1 ), and can improve the intimal hyperplasia (thickening) of the pulmonary arteriole vessel wall caused by pulmonary arterial hypertension, and can significantly improve the right ventricular hypertrophy caused by pulmonary arterial hypertension (see Figure 2 ). The pulmonary tissue section staining including hematoxylin-eosin H&E, Masson and α-smooth muscle actin α-SMA (see Figure 3 ) further illustrates that the azetidine quaternary ring connected pyrazolopyridine PDE10A inhibitor of the application can improve the pathological remodeling of the pulmonary arteriole vessel, and can play a pharmacodynamic effect on the treatment of pulmonary arterial hypertension.

[0191] Example 3, verification of PDE10A inhibitor treatment of pulmonary arterial hypertension in PAH animal model under hypoxic environment

[0192] 1. Animal experiment and administration route

[0193] Taking PDE10A inhibitor sample A11 as an example, the C57 mice (20 g, 56) were adaptively fed for three days before the experiment. Then, according to the normoxic (20% O2) and hypoxic (10% O2) conditions, the mice were randomly divided into groups: normoxic control group, SU5416 (Sugen, synthetic, purity > 99%) + hypoxic (model group), SU5416 + hypoxic administration group (tadalafil group, low, medium and high dose groups of A11). On the first day, the mice in the model group and each administration group were injected with 20 mg / kg of SU5416 once and then fed in a hypoxic environment (for 21 days), and during this period, the mice were injected with 20 mg / kg of SU5416 again on the 8th day and the 16th day. The normoxic control group was fed for 21 days. All the mice were provided with 12 hours of light and dark environment, as well as food and water, and the weight was measured every three days. The specific administration dose is as follows:

[0194]

[0195]

[0196] 2. On the 22nd day, the right ventricular systolic pressure (RVSP) of the mouse was detected by jugular vein cannulation. 1) Machine preparation: select the mouse tidal volume of the small animal respirator, then connect the BL-420N biological signal acquisition and processing system to the computer, select a single channel, give the pipeline to exhaust bubbles, and calibrate zero; 2) Anesthesia: after the mouse was anesthetized by intraperitoneal injection of 1% sodium pentobarbital solution (20 mg / kg), the mouse was laid flat, the depth of anesthesia was checked, and the mouse was fixed on the animal operation table after confirming that the mouse had no reflex; 3) Disinfection: disinfect the neck and chest of the mouse with medical alcohol; 4) Cannulation: make a 1 cm straight incision at the root of the mouse's neck with a scalpel, separate the subcutaneous tissue, and then the trachea can be seen. After blunt and sharp separation of the soft tissue around the trachea with ophthalmic scissors and forceps, the trachea is isolated. A long about 2 mm "V" type incision is cut with ophthalmic scissors, and the mouse's chest rises and falls in synchronization with the respirator after the trachea is inserted. 5) Pressure measurement: cut the chest skin with scissors, exposing the subcutaneous tissue. When cutting, pay attention to blunt separation to avoid injury. Then use forceps to lift the xiphoid process, use scissors to cut the chest, and use forceps to tear the pericardium to expose the heart. Insert the pipe connected to the syringe into the right ventricle, and the right ventricular pressure waveform is displayed on the computer. Last for 10 s, record the data and save.

[0197] 3. The mouse was followed by thoracotomy perfusion to take the heart and lung tissue. After the right ventricular pressure measurement was completed, physiological saline containing heparin sodium was injected into the heart through the right ventricle to flush the heart and lung tissue, so that the blood was flushed out until the liquid was clear and the lung was white. The fat tissue around the heart was cut off, the superior and inferior vena cava, aorta, pulmonary artery trunk and pulmonary vein were cut off, and the left and right heart tissues were extracted and weighed. The left and right lung tissues were extracted, and the lung tissues were taken in three parts. One part was fixed with paraformaldehyde and sent to the company for sectioning and HE staining, and the other two parts were frozen respectively. Two parts of the right ventricle were taken, one part was fixed with paraformaldehyde and sent to the company for sectioning and hematoxylin-eosin H&E and wheat germ agglutinin (WGA) staining, and the other part was frozen for standby use.

[0198] 4. Results: The animal experiment results show that, compared with the model group, the high-dose group of the nitrogen hetero-tetra-ring connected pyrazolo pyridine PDE10A inhibitor A11 of the application can significantly alleviate the weight loss of the rat after modeling (see Figure 4 ), reduce the right heart systolic pressure RVSP (see Figure 5 A) and the right heart hypertrophy index (see Figure 5 B), improve the intimal hyperplasia of the pulmonary arteriole blood vessel wall caused by pulmonary hypertension (see Figure 6 A), and the drug efficacy is close to that of the same dose of positive control tadalafil. Right ventricular WGA staining shows that the high-dose group of A11 can significantly alleviate the hypertrophy of myocardial cells of the rat after modeling, and the effect is similar to that of tadalafil (see Figure 6B) in the Results section. Lung tissue HE staining showed that the A11 high dose group was able to significantly inhibit the SU5416 + hypoxia-induced thickening of the blood vessel wall (see Figure 7 ) in the Results section.

[0199] In summary, the azatetrahydropyrazolopyridine PDE10A inhibitors of the present application can be used as drug molecules for the treatment of pulmonary arterial hypertension.

[0200] The technical solutions of the present application are not limited to the above specific embodiments, and any technical variations made according to the technical solutions of the present application fall within the scope of protection of the present application.

Claims

1. Use of azatetralocyclic linked pyrazolopyridines for the preparation of a medicament for the treatment of pulmonary arterial hypertension, characterized in that: The azatetra-ring linked pyrazolopyridine compound includes one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. A medicament for treating pulmonary arterial hypertension, characterized by, The azatetra-ring linked pyrazolopyridine compound as claimed in claim 1. The azatetra-ring linked pyrazolopyridine compound as claimed in claim 1.

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