A class of quinazoline compounds with anti-inflammatory activity or its pharmaceutically acceptable salt, pharmaceutical composition and application thereof

Abstract

The application relates to the technical field of medicinal chemistry and pharmacotherapy, in particular to a quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and application thereof. The quinazoline compound or the pharmaceutically acceptable salt thereof has a good inhibitory effect on cell programmed necrosis in an in-vitro experiment, can inhibit TNF-induced cell programmed necrosis in a concentration-dependent manner, and provides a new potential therapeutic drug for treating inflammatory bowel disease.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry and pharmacotherapy, in particular to a quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and application thereof. BACKGROUND

[0002] Necroptosis is a form of programmed cell death that resembles necrosis. Unlike apoptosis, necroptosis has its unique morphological features: cell swelling, plasma membrane rupture, and release of cell contents. This process leads to the infiltration of damage associated molecular patterns (DAMPs) into the surrounding tissue, which in turn causes a large number of inflammatory cell infiltration, and finally triggers the inflammatory response of the surrounding tissue.

[0003] Necroptosis is involved in a variety of pathophysiological processes, and plays an important role in inflammatory diseases, including inflammatory bowel disease, psoriasis, acute kidney injury, acute and chronic kidney disease, rheumatoid arthritis, etc. How to treat the inflammatory diseases related to necroptosis through drug therapy has become a problem to be solved.

[0004] In view of the above defects, the present inventors have finally obtained the present application after long-term research and practice. SUMMARY

[0005] The present application aims to solve the problem of how to treat the inflammatory diseases related to necroptosis through drug therapy, and provides a quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and application thereof.

[0006] In order to achieve the above-mentioned purpose, the present application discloses a quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof, the structure of which is as follows:

[0007]

[0008] wherein R 1 is independently selected from 2-methyl, 3-methyl, 4-methyl, 2-fluoro, 3-fluoro or 4-fluoro;

[0009] X is selected from N or O;

[0010] R 2 is selected from H, methyl or piperidin-4-yl.

[0011] is selected from any one of the following compounds:

[0012]

[0013] The application also discloses a quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof, and a structure general formula is as shown in the following.

[0014] Ar is independently selected from the following aromatic ring or aromatic ring system: 1 is selected from

[0015] Ar is independently selected from the following aromatic ring or aromatic ring system: 2

[0016]

[0017] is selected from any one of the following compounds:

[0018]

[0019]

[0020] The application also discloses a quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof, and a structure general formula is as shown in the following.

[0021]

[0022] Ar is independently selected from the following aromatic ring or aromatic ring system:

[0023] X is selected from O or NCH3.

[0024] is selected from any one of the following compounds:

[0025]

[0026]

[0027]

[0028] The application also discloses a pharmaceutical composition comprising one or more than one therapeutically effective amount of the quinazoline compound with anti-inflammatory activity or the pharmaceutically acceptable salt thereof, and pharmaceutically acceptable adjuvant.

[0029] The application also discloses application of the quinazoline compound with anti-inflammatory activity or the pharmaceutically acceptable salt thereof in preparation of a medicine for preventing and / or treating an inflammatory disease related to cell programmed necrosis.

[0030] ​The inflammatory diseases include inflammatory bowel disease, psoriasis, neuroinflammation, acute and chronic liver inflammation, joint inflammation, acute kidney injury, acute kidney failure, chronic kidney disease, chronic obstructive pulmonary disease, pathogen pneumonia.

[0031] The beneficial effects of the present application compared with the prior art are that the quinazoline compound or the pharmaceutically acceptable salt thereof in the present application has a better inhibitory effect on cell programmed necrosis in in vitro experiments, can inhibit TNF-induced cell programmed necrosis in a concentration-dependent manner, the compound N-(2-fluorophenyl)-7-(6-morphopyridin-3-yl)quinazoline-4-amine prepared in the present application shows a positive therapeutic effect in a dextran sulfate sodium (DSS)-induced acute colitis model of mice, and it can effectively relieve the symptoms of colitis in mice, thereby providing a new potential therapeutic drug for treating inflammatory bowel disease. The compound N-(2,6-difluorophenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazoline-4-amine prepared in the present application also shows a positive therapeutic effect in a psoriasis model of mice, and can significantly improve the symptoms of the psoriasis model mice. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 The pictures of the intestinal tracts of normal group (NC), disease model group (DSS), example 23 treatment group and positive control group (GSK872, WEHI-345) mice are shown in the figure, and it can be seen from the figure that the intestinal tract of the disease model group (DSS) mice is significantly shortened, and the dose-dependent shortening of the intestinal tract is prevented in the example 23 treatment group;

[0033] Figure 2 The length measurement histogram of the intestinal tracts of normal group (NC), disease model group (DSS), example 23 treatment group and positive control group (GSK872, WEHI-345) mice is shown in the figure;

[0034] Figure 3 The weight statistical diagram of normal group (NC), disease model group (DSS), example 23 treatment group and positive control group (GSK872, WEHI-345) mice is shown in the figure, and it can be seen that the body weight of the disease model group (DSS) mice is significantly reduced, and the body weight reduction of the mice is dose-dependently alleviated in the example 23 treatment group;

[0035] Figure 4 The H&E color staining diagram of the intestinal tract tissue sections of normal group (NC), disease model group (DSS), example 23 treatment group and positive control group (GSK872, WEHI-345) mice is shown in the figure, and it can be seen that the inflammation and necrosis of the intestinal tract tissue are dose-dependently improved in the example 23 treatment group;

[0036] Figure 5The skin pictures of normal group (NC), disease model group (IMQ), Example 70 treatment group, and positive control group (methotrexate) mice were taken. As can be seen from the pictures, the skin of the disease model group (IMQ) mice showed psoriasis-like skin diseases such as erythema, dandruff, and keratin thickening. The psoriasis-like symptoms of the skin of the mice of the Example 70 treatment group were reduced in a dose-dependent manner.

[0037] Figure 6 The length statistics chart of the measurement of the skin thickness of normal group (NC), disease model group (IMQ), Example 70 treatment group, and positive control group (methotrexate) mice was taken. As can be seen from the chart, the skin of the disease model group (IMQ) mice was significantly thickened. The skin thickening of the mice of the Example 70 treatment group was alleviated in a dose-dependent manner.

[0038] Figure 7 The H&E color staining chart of the skin tissue sections of normal group (NC), disease model group (IMQ), Example 70 treatment group, and positive control group (methotrexate) mice was taken. As can be seen from the chart, the inflammatory infiltration, tissue damage, and keratin thickening of the skin tissue of the mice of the Example 23 treatment group were reduced in a dose-dependent manner. DETAILED DESCRIPTION

[0039] The above and other technical features and advantages of the present application will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings.

[0040] Example 1

[0041] The reaction formula for synthesizing 7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4-(o-tolyloxy)quinazoline (Compound 1) is as follows:

[0042]

[0043] To a mixture of 1.5 g of 7-bromoquinazolin-4(3H)-one (reactant H1) and 15 mL of SOCl2, 1 drop of N,N'-dimethylformamide (DMF) was added. The mixture was stirred at 110°C for 12 h. After TLC detection showed that the reaction was complete, unreacted SOCl2 was removed by distillation under reduced pressure. CH2Cl2 was added to the distillation residue, and dry white solid 7-bromo-4-chloroquinazoline (intermediate H2) was obtained by suction filtration. The reaction yield was 90%.

[0044] Dissolve 1.4 g of intermediate H2 and 0.85 g of o-toluenol in 40 mL of isopropyl alcohol, add 1.60 g of K2CO3, stir at 60°C for 12 h, after TLC detection of the reaction completion, adjust the pH of the reaction solution to 7-9 using saturated NaHCO3 aqueous solution, extract the reaction solution with ethyl acetate for 3 times, wash the ethyl acetate extract with saturated NaCl solution for 2 times, add anhydrous Na2SO4 for drying, remove the solvent by distillation under reduced pressure, purify the distillation residue by silica gel column chromatography (PE:EA=4:1) to obtain white solid 7-bromo-4-(o-tolyloxy)quinazoline (intermediate H3) with a yield of 85%.

[0045] Dissolve 1.2 g of intermediate H3 and 1.80 g of 4-(4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester in 25 mL of 1,4-dioxane-water mixed solution (V:V=4:1), add 1.05 g of K2CO3 and 0.26 g of bis(triphenylphosphine)palladium(II) dichloride to the reaction solution, stir at 85°C for 12 h under nitrogen protection, after TLC detection of the reaction completion, extract the reaction solution with ethyl acetate for 3 times, wash the extract with saturated NaCl solution for 2 times, add anhydrous Na2SO4 for drying, remove the solvent by distillation under reduced pressure, purify the distillation residue by silica gel column chromatography (PE:EA=1:1) to obtain yellow oil 4-(4-(m-tolyloxy)quinazolin-7-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate H4) with a yield of 66%.

[0046] Dissolve 1.3 g of intermediate H4 in 20 mL of anhydrous CH2Cl2, add 3 mL of trifluoroacetic acid, stir at 25°C for 4 h, after TLC detection of the reaction completion, adjust the pH of the reaction solution to 7-9 using NaHCO3, extract the reaction solution with ethyl acetate for 3 times, wash with saturated NaCl solution for 2 times, add anhydrous Na2SO4 for drying, remove the solvent by distillation under reduced pressure, purify the distillation residue by silica gel column chromatography (PE:EA=4:1) to obtain white solid 7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4-(m-tolyloxy)quinazoline with a yield of 91%.

[0047] 1H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 10.0 Hz, 2H), 8.39 (s, 1H), 8.37 (s, 1H), 8.26 (d, J = 19.5 Hz, 2H), 8.10 - 8.06 (m, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.61 - 4.56 (m, 1H), 3.46 (d, J = 12.9 Hz, 4H), 2.34 - 2.19 (m, 4H), 2.19 (s, 1H), 2.12 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 166.15, 154.93, 152.53, 151.24, 139.27, 137.85, 131.68, 130.63, 127.89, 127.72, 126.49, 126.33, 124.44, 122.88, 122.14, 120.98, 118.90, 113.80, 55.93, 42.58, 29.15, 16.29. HRMS (ESI): m / z [M+H] + calcd for C 23 H 24 N5O: 386.1975. found, 386.1973.

[0048] Example 2

[0049] Synthesis of 7-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-4-(m-tolyloxy)quinazoline (Compound 2):

[0050] The m-cresol was selected as the starting material, and other embodiments were the same as Example 1. The prepared compound was a white solid.

[0051] 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 10.0 Hz, 2H), 8.39 (s, 1H), 8.37 (s, 1H), 8.26 (d, J = 19.5 Hz, 2H), 8.10 - 8.06 (m, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.61 - 4.56 (m, 1H), 3.46 (d, J = 12.9 Hz, 4H), 2.34 - 2.19 (m, 4H), 2.19 (s, 1H), 2.12 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 158.94, 158.77, 156.86, 134.59, 131.33, 130.30, 120.66, 120.60, 118.86, 116.73, 115.33, 115.16, 111.55, 67.21, 30.49, 18.49, 13.47. HRMS (ESI): m / z [M+H] calcd for C + H 23 H 24 N5O: 386.1975; found, 386.1977.

[0052] Example 3

[0053] Synthesis of 7-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)-4-(p-tolyloxy)quinazoline (Compound 3):

[0054] p-Toluenol was selected as the starting material, and other embodiments were the same as Example 1. The prepared compound was a white solid.

[0055] 1H NMR (500 MHz, DMSO-d6) δ 8.65 (dd, J = 5.7, 2.9 Hz, 2H), 8.37 (d, J = 8.5 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.08 (t, J = 10.2 Hz, 1H), 7.42 - 7.31 (m, 1H), 7.30 - 7.19 (m, 3H), 4.57 (s, 1H), 3.53 - 3.31 (m, 4H), 2.38 - 2.09 (m, 7H), 1.56 - 1.34 (m, 1H).13C NMR (126 MHz, DMSO-d6) δ 166.74, 166.14, 154.91, 152.53, 151.24, 150.48, 137.78, 135.44, 131.68, 130.52, 127.81, 124.41, 122.88, 122.30, 120.94, 113.77, 56.11, 42.37, 29.10, 26.80. HRMS (ESI): m / z [M+H]+calcd for C 23 H 24 N5O: 386.1975; found, 386.1973.

[0056] Example 4

[0057] Synthesis of 4-(2-fluorophenoxy)-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazoline (Compound 4):

[0058] 2-Fluorophenol was chosen as the starting material, and other embodiments were the same as Example 1. The prepared compound was a white solid.

[0059] 1 H NMR (500 MHz, DMSO-d6) δ 9.48 (d, J = 86.4 Hz, 1H), 8.66 (d, J = 23.6 Hz, 1H), 8.59 (dd, J = 6.9, 5.1 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.21 (t, J = 9.0 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.00 (ddd, J = 48.5, 20.6, 15.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 1H), 7.55 - 7.21 (m, 2H), 4.63 - 4.49 (m, 1H), 4.39 (d, J = 11.9 Hz, 1H), 3.16 - 2.64 (m, 2H), 2.22 (s, 4H), 1.92 (s, 1H), 1.16 (dd, J = 60.0, 52.9 Hz, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 165.71, 163.88, 155.33, 154.66, 154.16, 153.36, 152.63, 139.73, 137.49, 127.60, 126.58, 125.82, 124.95, 124.32, 122.02, 120.92, 117.325, 114.23, 113.25, 55.98, 42.24. HRMS (ESI): m / z [M+H] + calcd for C 22 H 21 FN5O: 390.1725. found, 390.1733.

[0060] Example 5

[0061] Synthesis of 4-(3-fluorophenoxy)-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazoline (Compound 5):

[0062] 3-Fluorophenol was chosen as the starting material, and other embodiments were the same as Example 1. The prepared compound was a white solid.

[0063] 1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J = 18.5 Hz, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 13.7 Hz, 2H), 8.19 - 7.98 (m, 2H), 7.55 (dd, J = 15.2, 8.2 Hz, 1H), 7.36 (dd, J = 9.9, 2.1 Hz, 1H), 7.30 - 7.15 (m, 2H), 4.50 (dt, J = 14.6, 5.1 Hz, 1H), 3.41 (d, J = 6.2 Hz, 4H), 2.22 (dd, J = 17.8, 8.2 Hz, 4H), 1.94 (d, J = 45.9 Hz, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 166.35, 164.02, 163.86, 161.92, 154.70, 152.60, 139.45, 137.69, 131.40, 127.74, 126.40, 124.38, 121.99, 120.83, 118.98, 113.88, 113.325, 110.75, 56.82, 42.91, 29.94. HRMS (ESI): m / z [M+H]+calcd for C 22 H 21 FN5O: 390.1725 found, 390.1732.

[0064] Example 6

[0065] Synthesis of 4-(4-fluorophenoxy)-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazoline (Compound 6):

[0066] 4-Fluorophenol was selected as the starting material, and other embodiments were the same as Example 1. The prepared compound was a white solid.

[0067] 1 H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J = 18.5 Hz, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 13.7 Hz, 2H), 8.19 - 7.98 (m, 2H), 7.55 (dd, J = 15.2, 8.2 Hz, 1H), 7.36 (dd, J = 9.9, 2.1 Hz, 1H), 7.30 - 7.15 (m, 2H), 4.50 (dt, J = 14.6, 5.1 Hz, 1H), 3.41 (d, J = 6.2 Hz, 4H), 2.22 (dd, J = 17.8, 8.2 Hz, 4H), 1.94 (d, J = 45.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 166.64, 161.08, 159.16, 154.76, 152.52, 148.73, 139.31, 137.79, 127.82, 126.30, 124.53, 124.45, 122.03, 120.90, 116.78, 113.96, 56.37, 42.76, 29.61. HRMS (ESI): m / z [M+H] 390.1718 found, 390.1718. + calcd for C 22 H 21 FN5O: 390.1725. found, 390.1718.

[0068] Example 7

[0069] Synthesis of N-(2-fluorophenyl)-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4- amine (Compound 7):

[0070] 2-Fluoroaniline was selected as the starting material, and other embodiments were the same as Example 1. The prepared compound was a white solid.

[0071] 1 H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.33 (dd, J = 8.1, 3.9 Hz, 2H), 7.30 - 7.25 (m, 1H), 4.24 (dd, J = 17.9, 9.0 Hz, 1H), 3.08 (d, J = 12.2 Hz, 2H), 2.63 (t, J = 11.8 Hz, 2H), 2.02 (t, J = 11.6 Hz, 2H), 1.86 (qd, J = 12.0, 3.8 Hz, 2H), 1.27 - 1.03 (m, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 158.85, 158.39, 156.42, 155.48, 150.89, 138.10, 136.98, 128.96, 127.73, 126.75, 124.88, 124.53, 124.17, 122.25, 120.86, 116.51, 116.35, 59.82, 45.44, 33.82. HRMS (ESI): m / z [M+H] 390.1718 found, 390.1718. + calcd for C 22 H 21FN6: 389.1884. found, 389.1885.

[0072] Example 8

[0073] Synthesis of N-(3-fluorophenyl)-7-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)quinazolin-4- amine (Compound 8):

[0074] 3-Fluoroaniline was chosen as the starting material, and other embodiments were the same as Example 1. The prepared compound was a white solid.

[0075] 1 H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.72 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 25.7 Hz, 2H), 8.21 (s, 1H), 7.97 (dd, J = 34.9, 8.0 Hz, 3H), 7.78 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 15.4, 8.0 Hz, 1H), 6.92 (td, J = 8.4, 1.9 Hz, 1H), 4.57 (dd, J = 9.4, 4.5 Hz, 1H), 3.19 (ddd, J = 67.0, 23.3, 8.9 Hz, 5H), 2.38 - 2.17 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 163.36, 161.44, 157.85, 155.06, 150.87, 141.72, 137.76, 137.57, 130.30, 127.51, 124.60, 122.41, 121.04, 118.10, 113.74, 110.16, 109.11, 55.89, 42.36, 28.96. HRMS (ESI): m / z [M+H] + calcd for C 22 H 21 FN6: 389.1884. found, 389.1880.

[0076] Example 9

[0077] Synthesis of N-(4-fluorophenyl)-7-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)quinazolin-4- amine (Compound 9):

[0078] 4-Fluoroaniline was chosen as the starting material, and other embodiments were the same as Example 1. The prepared compound was a white solid.

[0079] 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.55 (d, J = 12.5 Hz, 2H), 8.19 (s, 1H), 8.03 - 7.89 (m, 4H), 7.22 (t, J = 8.8 Hz, 2H), 4.51 - 4.45 (m, 1H), 3.29 - 2.93 (m, 4H), 2.14 (dt, J = 81.0, 42.3 Hz, 5H). 13 C NMR (126 MHz, DMSO-d6) δ 159.78, 158.03, 157.87, 155.28, 150.91, 137.65, 137.39, 136.11, 127.24, 124.84, 124.44, 122.39, 121.04, 115.38, 113.63, 56.92, 43.08, 30.20. HRMS (ESI): m / z [M+H] + calcd for C 22 H 21 FN6: 389.1884. found, 389.1876.

[0080] Example 10

[0081] Synthesis of N-(2-fluorophenyl)-7-(lH-pyrazol-4-yl)quinazolin-4-amine (Compound 10) reaction formula as follows:

[0082]

[0083] Intermediate H2 (7-bromo-4-chloroquinazoline) (1.4 g, 5.79 mmol) and o- fluorophenylamine (0.83 g, 7.52 mmol) were dissolved in IPA (40 mL), K2CO3 (1.60 g, 11.58 mmol) was added, stirred at 60 °C for 12 h, the reaction was detected by TLC, after the reaction was completed, the PH value was adjusted to 7-9 using NaHCO3, and the solution was stirred with ethyl acetate, extracted 2-3 times, washed with saturated NaCl solution, dried over anhydrous Na2SO4, then separated and purified by column chromatography (PE:EA = 4:1), and concentrated to obtain white solid H6 (7-bromo-N-(2-fluorophenyl)quinazolin-4-amine) (1.2 g, 3.79 mmol).

[0084] H5 (7-bromo-N-(2-fluorophenyl)quinazolin-4-amine) (1.2 g, 3.79 mmol) and H9 (4-pyrazole boronic acid pinacol ester) (0.97 g, 4.97 mmol) were dissolved in 1,4-dioxne (20 mL) and H2O (5 mL), K2CO3 (1.05 g, 7.58 mmol) and bis(triphenylphosphine)palladium(II) chloride (PdCl2(PPh3)2) (0.27 g, 0.38 mmol) were added, 2-3 times of nitrogen replacement, 85 °C stirring, 12 h of reaction under the condition of nitrogen protection, after the reaction was completed, it was cooled to room temperature, TLC detection, the reaction solution was added with ethyl acetate, fully stirred, extracted 2-3 times, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and then separated and purified by a chromatographic column (PE:EA = 1:1), to obtain yellow oil 10 (N-(2-fluorophenyl)-7-(1H-pyrazol-4-yl)quinazolin-4-amine) (1.2 g, 3.93 mmol).

[0085] 1 H NMR (500 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.77 (s, 1H), 8.52 (s, 1H), 8.45 (d, J = 8.3 Hz, 2H), 8.21 (s, 1H), 8.04 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.31 - 7.23 (m, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 158.87, 158.42, 156.46, 155.49, 150.94, 138.20, 137.51, 129.06, 127.80, 126.82, 124.88, 124.80, 124.08, 122.49, 120.69, 116.42, 113.24. HRMS (ESI): m / z [M+H] + calcd for C 17 H 13 FN5:306.115.found,306.1147.

[0086] Example 11

[0087] Synthesis of N-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-amine (Compound 11):

[0088] 1-methylpyrazole-4-boronic acid pinacol ester was selected as the raw material, and other embodiments were the same as in Example 10, and the prepared compound was a white solid.

[0089] 1 H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.46 (s, 1H), 8.44 (d, J = 5.5 Hz, 2H), 8.14 (s, 1H), 7.97 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.33 (dd, J = 8.4, 3.6 Hz, 2H), 7.30 - 7.24 (m, 1H), 3.92 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 158.87, 158.40, 155.54, 150.92, 137.84, 137.40, 129.65, 128.99, 127.80, 126.80, 124.86, 124.50, 124.18, 122.33, 121.35, 116.42, 113.29, 40.53.. HRMS (ESI): m / z [M+H] + calcd for C 18 H 15 FN5: 320.1306. found, 320.1313.

[0090] Example 12

[0091] Synthesis of N-(2-fluorophenyl)-7-(1H-pyrazol-3-yl)quinazolin-4-amine (Compound 12):

[0092] Pyrazole-3-boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0093] 1 H NMR (500 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.83 (s, 1H), 8.51 (d, J = 9.9 Hz, 2H), 8.21 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.31 - 7.24 (m, 1H), 7.02 (s, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 158.97, 158.42, 156.45, 155.54, 150.73, 149.52, 138.72, 130.82, 128.98, 127.83, 126.80, 124.88, 124.10, 123.34, 116.45, 114.28, 103.45. HRMS (ESI): m / z [M+H] +C 17 H 13 FN5: 306.115. found, 306.1152.

[0094] Example 13

[0095] Synthesis of N-(2-fluorophenyl)-7-(l-methyl-lH-pyrazol-3-yl)quinazolin-4- amine (Compound 13):

[0096] 1 -methylpyrazole-3 -boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0097] 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.53 (d, J = 9.2 Hz, 2H), 8.19 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.36 (dd, J = 8.1, 3.7 Hz, 2H), 7.33 - 7.27 (m, 1H), 7.02 (d, J = 1.6 Hz, 1H), 3.99 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 158.96, 155.57, 149.29, 146.12, 138.30, 133.30, 132.05, 128.95, 127.82, 126.80, 124.88, 124.03, 123.15, 116.42, 114.28, 104.28, 102.76, 38.91. HRMS (ESI): m / z [M+H] + calcd for C 18 H 15 FN5: 320.1306. found, 320.1312.

[0098] Example 14

[0099] Synthesis of N-(2-fluorophenyl)-7-(pyridin-3-yl)quinazolin-4-amine (Compound 14):

[0100] 3-pyridine boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0101] 1H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.13 (s, 1H), 8.68 (d, J = 4.5 Hz, 1H), 8.62 (d, J = 8.6 Hz, 1H), 8.55 (s, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.58 (dd, J = 7.7, 4.6 Hz, 1H), 7.38 - 7.34 (m, 2H), 7.29 (dd, J = 10.4, 6.0 Hz, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 159.08, 158.42, 156.46, 155.79, 150.60, 149.91, 148.61, 142.00, 135.22, 134.76, 129.02, 128.00, 126.65, 125.70, 124.91, 124.61, 124.48, 116.50, 114.71. HRMS (ESI): m / z [M+H] + calcd for C 19 H 13 FN4 317.1197.found,317.1202.

[0102] Example 15

[0103] Synthesis of N-(2-fluorophenyl)-7-(pyridin-4-yl)quinazolin-4-amine (Compound 15):

[0104] Example 15 was prepared using 4-pyridineboronic acid pinacol ester as starting material, following the procedure of Example 10. The compound was obtained as a white solid.

[0105] 1 H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.76 (d, J = 5.9 Hz, 2H), 8.66 (d, J = 8.6 Hz, 1H), 8.59 (s, 1H), 8.25 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 5.7 Hz, 2H), 7.62 (t, J = 7.7 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.34 - 7.28 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 159.07, 158.42, 155.89, 150.91, 150.55, 146.16, 142.01, 129.06, 128.04, 126.60, 126.15, 125.30, 124.93, 124.72, 122.18, 116.50, 115.40. HRMS (ESI): m / z [M+H] calcd for C + calcd for C 19 H 13 FN4 317.1197.found,317.1198.

[0106] Example 16

[0107] Synthesis of N-(2-fluorophenyl)-7-(6-fluoropyridin-3-yl)quinazolin-4-amine (Compound 16):

[0108] 2-Fluoropyridine-5-boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0109] 1 H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.80 (s, 1H), 8.61 (d, J = 8.6 Hz, 1H), 8.57 - 8.49 (m, 2H), 8.16 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.35 (s, 1H), 7.32 - 7.27 (m, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 164.52, 162.63, 159.06, 155.81, 150.55, 146.68, 141.42, 140.74, 133.36, 129.02, 128.00, 126.60, 125.62, 124.93, 124.90, 124.61, 116.50, 114.70, 110.30. HRMS (ESI): m / z [M+H] calcd for C + calcd for C 19 H 13 F2N 4: 335.1103found,335.1101.

[0110] Example 17

[0111] Synthesis of N-(2-fluorophenyl)-7-(4-methylpyridin-3-yl)quinazolin-4-amine (Compound 17):

[0112] Using 2-methylpyridine-5-boronic acid pinacol ester as the starting material, other embodiments are the same as in Example 10, the prepared compound is a white solid.

[0113] 1 H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.59 (d, J = 8.5 Hz, 1H), 8.55 (s, 1H), 8.52 (d, J = 5.7 Hz, 2H), 7.81 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 4.9 Hz, 1H), 7.36 (dd, J = 12.7, 4.8 Hz, 2H), 7.30 (dd, J = 10.5, 6.0 Hz, 1H), 2.35 (s, 3H). 13 CNMR (126 MHz, DMSO-d6) δ 159.14, 158.47, 156.50, 155.73, 150.15, 149.80, 149.32, 144.76, 142.76, 136.56, 129.05, 128.22, 128.01, 126.68, 125.89, 124.92, 123.83, 116.50, 114.45, 19.87. HRMS (ESI): m / z [M+H]+calcd for C 20 H 16 FN4: 331.1354. found, 331.1352.

[0114] Example 18

[0115] Synthesis of N-(2-fluorophenyl)-7-(5-methylpyridin-3-yl)quinazolin-4- amine (Compound 18):

[0116] Using 3-methylpyridine-5-boronic acid pinacol ester as the starting material, other embodiments are the same as in Example 10, the prepared compound is a white solid.

[0117] 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.84 (s, 1H), 8.53 (d, J = 8.6 Hz, 1H), 8.47 (s, 1H), 8.44 (s, 1H), 8.07 (d, J = 4.1 Hz, 2H), 7.98 (d, J = 8.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.28 (dd, J = 12.6, 4.9 Hz, 2H), 7.24 - 7.17 (m, 1H), 2.35 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 159.07, 158.42, 156.45, 155.78, 150.59, 150.26, 145.77, 142.07, 135.57, 134.25, 133.80, 129.01, 128.00, 126.66, 125.66, 124.91, 124.55, 116.49, 114.67, 18.34. HRMS (ESI): m / z [M+H] 331.1354. found, 331.1357. + calcd for C 20 H 16 FN4: 331.1354. found, 331.1357.

[0118] Example 19

[0119] Synthesis of N-(2-fluorophenyl)-7-(6-methylpyridin-3-yl)quinazolin-4-amine (Compound 19):

[0120] 4-methylpyridine-5-boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0121] 1 H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.98 (d, J = 1.5 Hz, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.53 (s, 1H), 8.20 (dd, J = 8.0, 2.1 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.38 - 7.33 (m, 2H), 7.31 - 7.25 (m, 1H), 2.56 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 159.07, 158.42, 156.45, 155.78, 150.59, 150.26, 145.77, 142.07, 135.57, 134.25, 133.80, 129.01, 128.00, 126.66, 125.66, 124.91, 124.55, 116.49, 114.67, 18.34. HRMS (ESI): m / z [M+H] 331.1354. found, 331.1357. + calcd for C 20 H 16 FN4: 331.1354. found, 331.1357.

[0122] Example 20

[0123] Synthesis of N-(2-fluorophenyl)-7-(4-morpholinophenyl)quinazolin-4- amine (Compound 20):

[0124] 4-(4-morpholinophenyl)boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0125] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.54 - 8.46 (m, 2H), 7.99 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 8.2, 3.8 Hz, 2H), 7.28 (td, J = 8.9, 4.7 Hz, 1H), 7.09 (s, 1H), 7.07 (s, 1H), 3.81 - 3.73 (m, 4H), 3.23 - 3.18 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 158.96, 158.39, 156.43, 155.54, 151.70, 150.81, 144.76, 129.17, 128.96, 128.28, 127.80, 126.84, 125.08, 124.86, 124.16, 123.63, 116.42, 115.61, 66.50, 48.36. HRMS (ESI): m / z [M+H] + calcd for C 24 H 21 FN4O: 400.1932. found, 400.1933.

[0126] Example 21

[0127] Synthesis of N-(2-fluorophenyl)-7-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin- 4-amine (Compound 21):

[0128] 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0129] 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.58 - 8.41 (m, 2H), 8.04 - 7.89 (m, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.40 - 7.23 (m, 3H), 7.07 (d, J = 8.6 Hz, 2H), 3.24 (s, 4H), 2.47 (s, 4H), 2.23 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 158.95, 158.40, 155.53, 151.60, 150.82, 144.81, 129.13, 128.80, 128.25, 127.79, 126.85, 125.04, 124.87, 124.15, 123.51, 116.42, 115.79, 113.56, 54.96, 47.99, 46.25. HRMS (ESI): m / z [M+H] + calcd for C 25 H 25 FN5: 414.2089. found, 414.2087.

[0130] Example 22

[0131] Synthesis of N-(2-fluorophenyl)-7-(4-(piperazin-l-yl)phenyl)quinazolin-4- amine (Compound 22):

[0132] Pinacol 4-(4-piperazinyl)phenylboronate was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0133] 1 H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.61 (d, J = 8.6 Hz, 1H), 8.46 (s, 1H), 7.95 (s, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 4.3 Hz, 2H), 7.30 (d, J = 5.4 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.06 (d, J = 8.8 Hz, 2H), 3.17 - 3.12 (m, 4H), 2.90 - 2.82 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 158.91, 158.41, 156.45, 155.46, 152.21, 150.72, 144.77, 128.93, 128.54, 128.20, 127.61, 124.90, 124.82, 124.54, 123.30, 116.47, 116.31, 115.68, 49.29, 46.02. HRMS (ESI): m / z [M+H] + calcd for C 24 H 22 FN5: 400.1932. found, 400.1933.

[0134] Example 23

[0135] Synthesis of N-(2-fluorophenyl)-7-(6-morpholinopyridin-3-yl)quinazolin-4- amine (Compound 23):

[0136] Example 23 was synthesized according to the procedure described in Example 10 using 6-(4-morpholinyl)pyridine-3-boronic acid pinacol ester as starting material. The compound was obtained as a white solid.

[0137] 1 H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.50 (d, J = 6.9 Hz, 2H), 8.05 (dd, J = 8.9, 1.8 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.82 (dd, J = 8.9, 5.1 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 6.90 (d, J = 8.9 Hz, 1H), 3.68 - 3.64 (m, 4H), 3.50 - 3.45 (m, 4H). 13 CNMR (126 MHz, DMSO-d6) δ 159.85, 159.35, 158.03, 157.94, 155.34, 150.76, 146.76, 142.35, 136.63, 135.98, 124.80, 124.71, 124.19, 123.97, 123.55, 115.61, 115.44, 113.99, 107.43, 66.41, 45.46. HRMS (ESI): m / z [M+H] + calcd for C 23 H 20 FN5O: 402.1725. found, 402.1729.

[0138] Example 24

[0139] Synthesis of N-(2-fluorophenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4- amine (Compound 24):

[0140] (6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid as starting material, other embodiments are the same as Example 10, the prepared compound is a white solid.

[0141] 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.58 - 8.45 (m, 2H), 8.09 (dd, J = 8.9, 2.4 Hz, 1H), 8.03 - 7.93 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.31 (ddd, J = 28.7, 7.8, 3.9 Hz, 3H), 6.96 (d, J = 9.0 Hz, 1H), 3.68 - 3.54 (m, 4H), 2.44 - 2.36 (m, 4H), 2.23 (s, 3H). 13 CNMR (126 MHz, DMSO-d6) δ 167.42, 159.20, 158.95, 156.42, 155.56, 150.79, 146.79, 142.54, 136.54, 131.96, 129.08, 124.88, 124.85, 124.69, 124.34, 123.42, 116.42, 113.73, 107.42, 54.84, 46.29, 44.98. HRMS (ESI): m / z [M+H] + calcd for C 24 H 24 FN6: 415.2041. found, 415.2047.

[0142] Example 25

[0143] Synthesis of N-(2-fluorophenyl)-7-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-4-amine (Compound 25):

[0144] (6-(piperazin-1-yl)pyridin-3-yl)boronic acid as starting material, other embodiments are the same as Example 10, the prepared compound is a white solid.

[0145] 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 8.6 Hz, 1H), 8.48 (s, 1H), 8.17 (dd, J = 8.9, 2.2 Hz, 1H), 8.05 - 7.96 (m, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.33 (dd, J = 12.7, 4.9 Hz, 2H), 7.27 (dd, J = 10.5, 5.9 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 3.87 - 3.83 (m, 4H), 3.17 - 3.13 (m, 4H), 1.95 (d, J = 38.0 Hz, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 158.98, 158.49, 156.48, 155.62, 150.73, 146.74, 142.23, 136.95, 129.03, 127.85, 126.80, 124.87, 124.75, 124.61, 124.51, 123.60, 116.42, 113.87, 107.95, 42.96, 42.44. HRMS (ESI): m / z [M+H] + calcd for C 23 H 22 FN6: 401.1884. found, 401.1888.

[0146] Example 26

[0147] Synthesis of N-(2-fluorophenyl)-7-(6-(piperidin-l-yl)pyridin-3-yl)quinazolin-4- amine (Compound 26):

[0148] 2-(piperidinyl)pyridine-5-boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0149] 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 8.7 Hz, 1H), 8.49 (s, 1H), 8.06 (dd, J = 8.9, 2.2 Hz, 1H), 7.99 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 4.3 Hz, 1H), 7.33 (s, 1H), 7.30 - 7.25 (m, 1H), 6.95 (d, J = 9.0 Hz, 1H), 3.64 - 3.60 (m, 4H), 1.64 (d, J = 4.7 Hz, 2H), 1.57 (d, J = 4.1 Hz, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.07, 158.95, 155.55, 150.81, 146.89, 142.67, 136.47, 128.99, 127.83, 126.80, 124.87, 124.62, 124.25, 123.12, 122.64, 116.53, 116.37, 113.58, 107.19, 45.98, 25.52, 24.81. HRMS (ESI): m / z [M+H] + calcd for C 24 H 23 FN5: 400.1932. found, 400.1922.

[0150] Example 27

[0151] Synthesis of N-(2-fluorophenyl)-7-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinazolin-4- amine (Compound 27):

[0152] 6-(Pyrrolidin-1-yl)pyridin-3-boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0153] 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.05 (dd, J = 8.8, 2.2 Hz, 1H), 7.97 (d, J = 2.9 Hz, 1H), 7.95 (s, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 4.2 Hz, 1H), 7.33 (s, 1H), 7.30 - 7.26 (m, 1H), 6.57 (d, J = 8.8 Hz, 1H), 3.46 (s, 4H), 2.09 - 1.89 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 158.61, 158.07, 156.90, 156.11, 155.21, 150.50, 146.88, 142.69, 135.62, 128.66, 127.49, 126.49, 124.54, 124.21, 123.90, 122.51, 121.48, 116.12, 113.11, 106.67, 46.64, 25.15. HRMS (ESI): m / z [M+H] + calcd for C 23 H 21 FN5: 386.1776. found, 386.1784.

[0154] Example 28

[0155] Synthesis of N-(2-fluorophenyl)-7-(5-morpholinopyridin-2-yl)quinazolin-4- amine (Compound 28):

[0156] Select 6-(4-morpholinyl)pyridine-3-boronic acid pinacol ester as raw material, other embodiments are the same as Example 10, and the prepared compound is a white solid.

[0157] 1 H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.05 (dd, J = 8.8, 2.2 Hz, 1H), 7.97 (d, J = 2.9 Hz, 1H), 7.95 (s, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 4.2 Hz, 1H), 7.33 (s, 1H), 7.30 - 7.26 (m, 1H), 6.57 (d, J = 8.8 Hz, 1H), 3.46 (s, 4H), 2.09 - 1.89 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 159.00, 158.38, 156.39, 155.49, 150.59, 146.85, 144.99, 143.44, 137.46, 136.71, 128.92, 124.90, 124.39, 123.97, 123.78, 122.32, 121.61, 116.45, 114.51, 66.31, 47.72. HRMS (ESI): m / z [M+H] 403.1735. found, 403.1730. + calcd for C 23 H 21 FN5O:403.1735.found,403.1730.

[0158] Example 29

[0159] Synthesis of N-(2-fluorophenyl)-7-(5-morpholinopyrimidin-2-yl)quinazolin-4- amine (Compound 29):

[0160] 2-(4-Morpholinopyrimidin-5-yl)boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as Example 10. The prepared compound was a white solid.

[0161] 1 H NMR (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.90 (s, 2H), 8.46 (d, J = 8.7 Hz, 1H), 8.43 (s, 1H), 8.01 (s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.26 (dd, J = 12.4, 4.7 Hz, 2H), 7.23 - 7.17 (m, 1H), 3.78 - 3.69 (m, 4H), 3.66 - 3.60 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 161.35, 158.98, 156.88, 155.65, 150.72, 139.91, 131.96, 129.20, 127.90, 126.70, 124.87, 124.45, 124.37, 123.44, 121.25, 116.42, 114.00, 66.46, 44.52. HRMS (ESI): m / z [M+H] 403.1735. found, 403.1734. + calcd for C 23 H 21 FN5O:403.1735.found,403.1734.

[0162] Example 30

[0163] Synthesis of N-(2-fluorophenyl)-7-(6-morpholinopyrimidin-4-yl)quinazolin-4- amine (Compound 30):

[0164] The compound was prepared according to the procedures described in Example 10, using 4-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-4-yl)morpholine as the starting material. The compound was obtained as a white solid.

[0165] 1 H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.69 (s, 1H), 8.63 (s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.55 (s, 1H), 8.43 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.31 - 7.26 (m, 1H), 3.78 (d, J = 4.8 Hz, 4H), 3.73 (d, J = 4.6 Hz, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 163.02, 160.84, 159.04, 158.63, 158.43, 156.46, 155.73, 150.41, 142.01, 129.01, 128.00, 126.63, 126.43, 124.94, 123.98, 116.50, 116.09, 100.14, 66.36, 44.47. HRMS (ESI): m / z [M+H] + calcd for C 23 H 21 FN5O: 403.1735. found, 403.1732.

[0166] Example 31

[0167] Synthesis of N-(7-(lH-pyrazol-4-yl)quinazolin-4-yl)benzo[d]thiazol-5-amine N-(7-(pyridin-3-yl)quinazolin-4-yl)benzo[d]thiazol-5-amine (Compound 31) The reaction scheme is as follows:

[0168]

[0169] Intermediate H2 (7-bromo-4-chloroquinazoline) (1.4 g, 5.79 mmol) and benzothiazol-5-amine (1.13 g, 7.52 mmol) were dissolved in IPA (40 mL), K2CO3 (1.60 g, 11.58 mmol) was added, stirred at 60 °C for 12 h, the reaction was monitored by TLC, after completion of the reaction, the pH was adjusted using NaHCO3 to make the pH of the solution 7-9, ethyl acetate was added and stirred well, extracted 2-3 times, washed with saturated NaCl solution, dried over anhydrous Na2SO4, then purified by column chromatography (PE:EA = 4:1), concentrated to get white solid H6 N-(7-bromoquinazolin-4-yl)benzo[d]thiazol-5-amine (1.3 g, 3.79 mmol).

[0170] H6 (N-(7-bromoquinazolin-4-yl)benzo[d]thiazol-5-amine) (1.3 g, 3.79 mmol) and 4- pyrazole boronic acid pinacol ester (0.97 g, 4.97 mmol) were dissolved in 1,4-dioxne (20 mL) and H2O (5 mL), K2CO3 (1.05 g, 7.58 mmol) and dichlorobis(triphenylphosphine)palladium (PdCl2(PPh3)2) (0.27 g, 0.38 mmol) were added, purged with nitrogen for 2-3 times, stirred at 85 °C, reaction was carried out for 12 h under nitrogen atmosphere, after completion of the reaction, cooled to room temperature, the reaction was monitored by TLC, ethyl acetate was added to the reaction solution and stirred well, extracted 2-3 times, washed with saturated NaCl solution, dried over anhydrous Na2SO4, then purified by column chromatography (PE:EA = 1:1), concentrated to get yellow oil 10 (N-(7-(1H-pyrazol-4-yl)quinazolin-4-yl)benzo[d]thiazol-5-amine) (0.8 g, 2.33 mmol).

[0171] 1 H NMR (500 MHz, DMSO-d6) δ 13.14 - 13.03 (m, 1H), 9.88 (s, 1H), 9.35 (s, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.56 (s, 1H), 8.51 (d, J = 8.7 Hz, 1H), 8.49 - 8.40 (m, 1H), 8.18 - 8.10 (m, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.90 (s, 1H), 7.90 - 7.88 (m, 1H). 13C NMR (126 MHz, DMSO-d6) 5 158.03, 157.34, 155.23, 154.03, 150.96, 138.40, 138.20, 137.55, 128.77, 127.47, 124.75, 124.03, 122.58, 122.40, 121.49, 120.64, 116.41, 113.62. HRMS (ESI): m / z [M+H] Calcd for C + calcd for C 18 H 13 N6S:345.0911.found,345.0917.

[0172] Example 32

[0173] Synthesis of N-(7-(pyridin-4-yl)quinazolin-4-yl)benzo[d]thiazol-5-amine (Compound 31):

[0174] 4-Pyridine boronic acid pinacol ester was selected as the starting material, and other embodiments were the same as Example 31. The prepared compound was a white solid.

[0175] 1 H NMR (500 MHz, DMSO-d6) 5 10.06 (s, 1H), 9.36 (s, 1H), 8.71 (s, 1H), 8.69 (s, 1H), 8.68 (s, 1H), 8.67 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.08 - 8.05 (m, 1H), 7.93 - 7.90 (m, 1H), 7.89 (s, 1H), 7.88 (s, 1H). 13 C NMR (126 MHz, DMSO-d6) 5 158.20, 157.45, 155.65, 154.02, 150.93, 150.61, 146.10, 141.95, 138.17, 129.07, 126.23, 125.30, 124.70, 122.48, 122.21, 121.52, 116.58, 115.86. HRMS (ESI): m / z [M+H] Calcd for C + calcd for C 20 H 14 N5S:356.0959.found,356.0964.

[0176] Example 33

[0177] Synthesis of N-(7-(1H-pyrazol-3-yl)quinazolin-4-yl)benzo[d]thiazol-5-amine (Compound 33):

[0178] Pyrazole-3-boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as example 31. The prepared compound was a white solid.

[0179] 1 H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.36 (s, 1H), 8.71 (s, 1H), 8.69 (s, 1H), 8.68 (s, 1H), 8.67 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.08 - 8.05 (m, 1H), 7.93 - 7.90 (m, 1H), 7.89 (s, 1H), 7.88 (s, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 158.20, 157.45, 155.65, 154.02, 150.93, 150.61, 146.10, 141.95, 138.17, 129.07, 126.23, 125.30, 124.70, 122.48, 122.21, 121.52, 116.58, 115.86. HRMS (ESI): m / z [M+H] + calcd for C 18 H 13 N6S: 345.0911. found, 345.0917.

[0180] Example 34

[0181] Synthesis of N-(7-(pyridin-3-yl)quinazolin-4-yl)benzo[d]thiazol-5-amine (Compound 34):

[0182] Pyrazole-3-boronic acid pinacol ester was chosen as the starting material, and other embodiments were the same as example 31. The prepared compound was a white solid.

[0183] 1 H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.36 (s, 1H), 8.71 (s, 1H), 8.69 (s, 1H), 8.68 (s, 1H), 8.67 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.08 - 8.05 (m, 1H), 7.93 - 7.90 (m, 1H), 7.89 (s, 1H), 7.88 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 158.20, 157.45, 155.65, 154.02, 150.93, 150.61, 146.10, 141.95, 138.17, 129.07, 126.23, 125.30, 124.70, 122.48, 122.21, 121.52, 116.58, 115.86. HRMS (ESI): m / z [M+H] Calcd for C + calcd for C 20 H 14 N5S:356.0959.found,356.0964.

[0184] Example 35

[0185] Synthesis of N-(7-(l-methyl-lH-pyrazol-3-yl)quinazolin-4-yl)benzo[d]thiazol-5- amine (Compound 35):

[0186] Example 35 was prepared by using l-methylpyrazole-3-boronic acid pinacol ester as starting material, following the procedure of Example 31. The compound was obtained as a white solid.

[0187] 1 H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.42 (s, 1H), 8.77 (s, 1H), 8.64 (s, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 3.92 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 158.20, 157.45, 155.65, 154.02, 150.93, 150.61, 146.10, 141.95, 138.17, 129.07, 126.23, 125.30, 124.70, 122.48, 122.21, 121.52, 116.58, 115.86. HRMS (ESI): m / z [M+H] Calcd for C + calcd for C 19 H 15 N6S:359.1068.found,359.1073

[0188] Example 36

[0189] Synthesis of N-(7-(2-methoxyphenyl)quinazolin-4-yl)benzo[d]thiazol-5- amine (Compound 37):

[0190] Benzene boronic acid was chosen as the starting material, and other embodiments were the same as in Example 31. The prepared compound was a white solid.

[0191] 1 H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.43 (s, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 8.7 Hz, 1H), 8.70 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 1.2 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 8.00 (dd, J = 8.7, 1.6 Hz, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.6 Hz, 2H), 7.49 (d, J = 7.4 Hz, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 158.17, 157.37, 155.41, 154.04, 150.70, 144.94, 139.17, 138.33, 129.64, 129.03, 128.89, 127.75, 125.71, 125.39, 124.32, 122.43, 121.45, 116.44, 114.77. HRMS (ESI): m / z [M+H] + calcd for C 21 H 15 N4S: 355.1006. found, 355.1012.

[0192] Example 37

[0193] Synthesis of N-(7-(2-methoxyphenyl)quinazolin-4-yl)benzo[d]thiazol-5- amine (Compound 37):

[0194] Benzene boronic acid was chosen as the starting material, and other embodiments were the same as in Example 31. The prepared compound was a white solid.

[0195] 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.43 (s, 1H), 8.81 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.64 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.7, 1.7 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.81 (dd, J = 8.6, 1.4 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.45 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.12 (s, 1H), 3.84 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 158.13, 157.36, 156.74, 155.15, 154.05, 150.16, 143.38, 138.41, 131.11, 130.35, 128.88, 128.83, 128.46, 128.14, 123.01, 122.43, 121.47, 121.42, 116.37, 114.36, 112.44, 56.11. HRMS (ESI): m / z [M+H] + calcd for C 22 H 17 N4OS: 385.1112. found, 385.1118.

[0196] Example 38

[0197] Synthesis of N-(7-(4-methoxyphenyl)quinazolin-4-yl)benzo[d]thiazol-5-amine (Compound 38):

[0198] 4-methoxyphenylboronic acid was selected as the starting material, and other embodiments were the same as Example 31. The prepared compound was a white solid.

[0199] 1 H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.43 (s, 1H), 8.81 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.64 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.7, 1.7 Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.81 (dd, J = 8.6, 1.4 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.45 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.12 (s, 1H), 3.84 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 160.25, 158.12, 157.34, 155.33, 154.04, 150.78, 144.55, 138.39, 131.34, 128.95, 128.81, 125.34, 124.39, 124.18, 122.40, 121.42, 116.38, 115.06, 114.25, 55.75. HRMS (ESI): m / z [M+H] + C 22 H 17 N4OS: 385.1112. found, 385.1118.

[0200] Example 39

[0201] Synthesis of N-(7-(2-fluorophenyl)quinazolin-4-yl)benzo[d]thiazol-5-amine (Compound 39):

[0202] 2-Fluorophenylboronic acid was selected as the starting material, and other embodiments were the same as Example 31. The prepared compound was a white solid.

[0203] 1 H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.44 (s, 1H), 8.80 (d, J = 1.5 Hz, 1H), 8.73 (s, 1H), 8.72 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.02 - 7.99 (m, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.42 (d, J = 10.1 Hz, 1H), 7.40 (s, 1H) 13 C NMR (126 MHz, DMSO-d6) δ 159.71, 158.17, 157.39, 155.48, 154.03, 150.27, 140.08, 138.26, 131.56, 131.09, 128.98, 128.03, 127.48, 127.47, 125.67, 123.92, 122.44, 121.48, 116.81, 116.50, 114.95. HRMS (ESI): m / z [M+H] + C 21 H 14 FN4S: 373.0912. found, 373.0918.

[0204] Example 40

[0205] Synthesis of N-(7-(3-fluorophenyl)quinazolin-4-yl)benzo[d]thiazol-5- amine (Compound 40):

[0206] 3-Fluorophenylboronic acid was chosen as the starting material, and other embodiments were the same as Example 31. The prepared compound was a white solid.

[0207] 1 H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.43 (s, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.73 (d, J = 8.9 Hz, 1H), 8.71 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.13 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 8.00 (dd, J = 8.7, 1.6 Hz, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.60 (d, J = 6.5 Hz, 1H), 7.31 (s, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 163.25, 158.15, 157.38, 155.49, 154.03, 150.64, 143.44, 141.57, 138.28, 131.56, 128.94, 125.77, 125.65, 124.41, 123.86, 122.43, 121.45, 116.47, 115.75, 115.12, 114.55. HRMS (ESI): m / z [M+H] + calcd for C 21 H 14 FN4S: 373.0912. found, 373.0918.

[0208] Example 41

[0209] Synthesis of N-(7-(4-fluorophenyl)quinazolin-4-yl)benzo[d]thiazol-5- amine (Compound 41):

[0210] 4-Fluorophenylboronic acid was chosen as the starting material, and other embodiments were the same as Example 31. The prepared compound was a white solid.

[0211] 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.43 (s, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.72 (s, 1H), 8.70 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 8.01 (t, J = 9.3 Hz, 2H), 7.98 (d, J = 6.2 Hz, 1H), 7.96 (d, J = 5.5 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 163.00, 158.15, 157.37, 155.45, 154.03, 150.68, 143.83, 138.31, 135.62, 135.60, 129.90, 128.90, 125.47, 124.34, 122.42, 121.44, 116.54, 116.41, 114.71. HRMS (ESI): m / z [M+H] + calcd for C 21 H 14 FN4S: 373.0912. found, 373.0918.

[0212] Example 42

[0213] Synthesis of N-(7-(4-(piperazin-l-yl)phenyl)quinazolin-4-yl)benzothiazole-5- amine (Compound 42):

[0214] (4-(piperazin-l-yl)phenyl)boronic acid as starting material, other procedures were the same as Example 31. The compound was prepared as a white solid.

[0215] 1 H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.43 (s, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.72 (s, 1H), 8.70 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 8.01 (t, J = 9.3 Hz, 2H), 7.98 (d, J = 6.2 Hz, 1H), 7.96 (d, J = 5.5 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 158.10, 157.33, 155.27, 154.04, 151.66, 150.85, 144.68, 138.45, 128.95, 128.74, 128.31, 125.03, 124.15, 123.66, 122.39, 121.40, 116.33, 115.97, 114.02, 47.91, 44.94. HRMS (ESI): m / z [M+H]+ calcd for C + C 25 H 23 N6S: 439.1694. found, 439.1699.

[0216] Example 43

[0217] Synthesis of N-(7-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4-yl)benzothiazole-5- amine (Compound 43):

[0218] (4-(4-methylpiperazin-1-yl)phenyl)boronic acid as starting material, other procedures were the same as Example 31. The compound was prepared as a white solid.

[0219] 1 H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.42 (s, 1H), 8.92 (s, 1H), 8.79 (s, 1H), 8.66 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.81 (s, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 3.12 (s, 4H), 2.88 (s, 4H), 2.59 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 158.11, 157.36, 155.29, 154.04, 151.91, 150.84, 144.64, 138.42, 128.38, 125.07, 124.18, 123.74, 122.41, 121.44, 118.62, 116.37, 116.14, 116.00, 114.05, 53.81, 48.64, 46.83. HRMS (ESI): m / z [M+H]+ calcd for C 26 H 25 N6S: 453.185. found, 453.1856.

[0220] Example 44

[0221] Synthesis of N-(7-(4-morpholinophenyl)quinazolin-4-yl)benzo[d]thiazol-5- amine (Compound 44):

[0222] (4-morpholinophenyl)boronic acid as the starting material, and other embodiments are the same as Example 31. The prepared compound is a white solid.

[0223] 1 H NMR (500 MHz, DMSO-d6) δ 10.23 - 10.09 (m, 1H), 9.42 (s, 1H), 8.78 - 8.73 (m, 1H), 8.69 (s, 1H), 8.67 - 8.65 (m, 1H), 8.19 - 8.16 (m, 1H), 8.05 - 8.00 (m, 1H), 8.00 - 7.98 (m, 1H), 7.98 - 7.95 (m, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 3.79 - 3.76 (m, 4H), 3.24 - 3.21 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 158.29, 157.46, 154.91, 154.01, 151.81, 145.02, 129.12, 128.87, 128.34, 128.25, 127.25, 127.01, 125.29, 124.28, 122.48, 121.59, 116.66, 115.60, 113.80, 66.49, 49.07. HRMS (ESI): m / z [M+H] + calcd for C 25 H 22 N5OS: 440.1534. found, 440.154.

[0224] Example 44

[0225] Synthesis of N-(7-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-4-yl)benzo[d]thiazol-5- amine (Compound 45):

[0226] (6-(piperazin-1-yl)pyridin-3-yl)boronic acid as the starting material, and other embodiments are the same as Example 31. The prepared compound is a white solid.

[0227] 1H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 2H), 9.38 (d, J = 4.7 Hz, 1H), 8.74 (s, 1H), 8.66 (s, 1H), 8.64 - 8.62 (m, 1H), 8.62 (d, J = 4.1 Hz, 1H), 8.13 (dd, J = 8.4, 4.8 Hz, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.97 - 7.95 (m, 1H), 7.95 - 7.93 (m, 1H), 6.92 (s, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 159.53, 157.31, 155.69, 155.34, 154.04, 152.39, 150.84, 146.81, 138.55, 124.63, 124.33, 122.38, 121.54, 120.21, 118.95, 116.41, 116.08, 107.27. HRMS (ESI): m / z [M+H] + calcd for C 25 H 23 N6S: 439.1637. found, 439.1640.

[0228] Example 46

[0229] Synthesis of N-(7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4- yl)benzothiazole-5-amine (Compound 46):

[0230] (6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid was selected as the starting material, and other embodiments were the same as Example 31. The prepared compound was a white solid.

[0231] 1 H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.42 (s, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.10 (dd, J = 8.9, 2.5 Hz, 1H), 8.04 - 7.97 (m, 3H), 6.97 (d, J = 9.0 Hz, 1H), 3.62 - 3.56 (m, 4H), 2.44 - 2.39 (m, 4H), 2.23 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 159.20, 158.08, 157.34, 155.31, 154.03, 150.84, 146.82, 142.49, 138.39, 136.57, 128.79, 124.69, 124.23, 123.44, 123.40, 122.40, 121.41, 116.36, 114.09, 107.43, 54.84, 46.30, 44.95. HRMS (ESI): m / z [M+H] Calcd for C + C 25 H 24 N7S: 454.1803. Found, 454.1808.

[0232] Example 47

[0233] Synthesis of N-(7-(6-morpholino-pyridin-3-yl)quinazolin-4-yl)benzo[d]thiazol-5- amine (Compound 47):

[0234] (6-morpholino-pyridin-3-yl)boronic acid as starting material, other procedures as in Example 31. The compound was prepared as a white solid.

[0235] 1 H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.42 (s, 1H), 8.79 (s, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.71 - 8.63 (m, 2H), 8.19 - 8.11 (m, 2H), 8.04 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 3.76 - 3.71 (m, 4H), 3.58 - 3.54 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.20, 158.08, 157.34, 155.31, 154.03, 150.84, 146.82, 142.49, 138.39, 136.57, 128.79, 124.69, 124.23, 123.44, 123.40, 122.40, 121.41, 116.36, 114.09, 107.43, 54.84, 46.30, 44.95. HRMS (ESI): m / z [M+H] + C 24 H 21 N6OS: 441.1492. Found, 441.1487.

[0236] Example 48

[0237] Synthesis of N-(lH-indol-5-yl)-7-(6-morpholinopyridin-3-yl)quinazoline-4- amine (Compound 48):

[0238] The reaction is as follows:

[0239]

[0240] Intermediate H2 (7-bromo-4-chloroquinazoline) (1.4 g, 5.79 mmol) and lH-indol-5-amine (0.99 g, 7.52 mmol) were dissolved in IPA (40 mL), K2CO3 (1.60 g, 11.58 mmol) was added, stirred at 60 °C for 12 h, the reaction was monitored by TLC, after the reaction was completed, the PH value was adjusted using NaHCO3 to make the solution PH at 7-9, ethyl acetate was added and stirred well, extracted 2-3 times, washed with saturated NaCl solution, dried over anhydrous Na2SO4, then separated and purified by column chromatography (PE:EA = 4:1), concentrated to obtain white solid H7 (7-bromo-N-(lH-indol-5-yl)quinazoline-4-amine) (1.29 g, 3.79 mmol).

[0241] H7 (7-bromo-N-(lH-indol-5-yl)quinazoline-4-amine) (1.29 g, 3.79 mmol) and 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (1.49 g, 4.97 mmol) were dissolved in 1,4-dioxne (20 mL) and H2O (5 mL), K2CO3 (1.05 g, 7.58 mmol) and bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2) (0.27 g, 0.38 mmol) were added, replaced with nitrogen for 2-3 times, stirred at 85 °C, reacted for 12 h under the protection of nitrogen, after the reaction was completed, cooled to room temperature, TLC detection, the reaction solution was added with ethyl acetate and stirred well, extracted 2-3 times, washed with saturated NaCl solution, dried over anhydrous Na2SO4, then separated and purified by column chromatography (PE:EA = 1:1), concentrated to obtain yellow oil 48 (N-(lH-indol-5-yl)-7-(6-morpholinopyridin-3-yl)quinazoline-4-amine) (0.9 g, 2.13 mmol).

[0242] 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.77 (s, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.61 (d, J = 8.7 Hz, 1H), 8.51 (s, 1H), 8.11 (dd, J = 8.9, 2.2 Hz, 1H), 8.01 - 7.88 (m, 3H), 7.38 (dd, J = 16.1, 13.5 Hz, 3H), 6.97 (d, J = 8.9 Hz, 1H), 6.47 (s, 1H), 3.79 - 3.69 (m, 4H), 3.61 - 3.52 (m, 4H). 13 CNMR (126 MHz, DMSO-d6) δ 159.31, 158.57, 155.78, 150.68, 146.68, 142.02, 136.60, 133.82, 131.07, 127.97, 126.43, 124.30, 124.23, 124.17, 123.50, 118.88, 115.37, 114.16, 111.49, 107.44, 101.68, 66.42, 45.49. HRMS (ESI): m / z [M+H] + calcd for C 25 H 23 N6O:423.1928. found,423.1928.

[0243] Example 49

[0244] Synthesis of N-(2-chlorophenyl)-7-(6-morpholinopyridin-3-yl)quinazolin-4- amine (Compound 49):

[0245] 2-chloroaniline was selected as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0246] 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.77 (s, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.61 (d, J = 8.7 Hz, 1H), 8.51 (s, 1H), 8.11 (dd, J = 8.9, 2.2 Hz, 1H), 8.01 - 7.88 (m, 3H), 7.38 (dd, J = 16.1, 13.5 Hz, 3H), 6.97 (d, J = 8.9 Hz, 1H), 6.47 (s, 1H), 3.79 - 3.69 (m, 4H), 3.61 - 3.52 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 159.35, 157.80, 155.13, 150.82, 146.80, 142.51, 141.38, 136.62, 133.23, 130.55, 124.83, 124.19, 123.85, 123.57, 123.48, 121.70, 120.64, 114.06, 107.40, 66.41, 45.45. HRMS (ESI): HRMS (ESI): m / z [M+H] Calcd for C + C 23 H 21 ClN5O: 418.1424. Found, 418.1429.

[0247] Example 50

[0248] Synthesis of N-(3-chlorophenyl)-7-(6-morpholinopyridin-3-yl)quinazolin-4- amine (Compound 50):

[0249] 3-chloroaniline was selected as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0250] 1 H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.67 (s, 1H), 8.60 (d, J = 8.7 Hz, 1H), 8.16 (s, 1H), 8.14 - 8.09 (m, 1H), 8.04 - 7.96 (m, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 3.86 - 3.68 (m, 4H), 3.64 - 3.49 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.35, 157.80, 155.13, 150.82, 146.80, 142.51, 141.38, 136.62, 133.23, 130.55, 124.83, 124.19, 123.85, 123.57, 123.48, 121.70, 120.64, 114.06, 107.40, 66.41, 45.45. HRMS (ESI): HRMS (ESI): m / z [M+H] Calcd for C + C 23 H 21 ClN5O: 418.1424. Found, 418.1429.

[0251] Example 51

[0252] Synthesis of N-(4-chlorophenyl)-7-(6-morpholino-pyridin-3-yl)-quinazolin-4- amine (Compound 51):

[0253] 4-Chloroaniline was chosen as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0254] 1 H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.66 - 8.58 (m, 2H), 8.14 (dd, J = 8.9, 2.2 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.97 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.9 Hz, 1H), 3.81 - 3.68 (m, 4H), 3.63 - 3.50 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.38, 157.87, 155.22, 150.82, 146.81, 142.47, 138.77, 136.67, 128.83, 124.79, 124.24, 124.09, 123.91, 123.69, 123.57, 114.08, 107.46, 66.42, 45.47. HRMS (ESI): m / z [M+H] + C 23 H 21 ClN5O: 418.1424. found, 418.1429.

[0255] Example 52

[0256] Synthesis of 7-(6-morpholino-pyridin-3-yl)-N-(o-tolyl)-quinazolin-4-amine (Compound 52):

[0257] 2-Methylaniline was chosen as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0258] 1H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 8.7 Hz, 1H), 8.34 (s, 1H), 8.04 (dd, J = 8.9, 2.5 Hz, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.87 (dd, J = 8.7, 1.6 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.23 - 7.13 (m, 2H), 6.91 (d, J = 8.9 Hz, 1H), 3.69 - 3.64 (m, 4H), 3.51 - 3.45 (m, 4H), 2.14 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 159.33, 159.18, 155.82, 150.70, 146.71, 142.27, 137.61, 136.64, 135.46, 130.92, 128.28, 126.88, 126.72, 124.52, 124.26, 124.17, 123.53, 113.75, 107.46, 66.42, 45.49, 18.45. HRMS (ESI): m / z [M+H] + calcd for C 24 H 24 N5O: 398.197. found, 398.1975.

[0259] Example 53

[0260] Synthesis of 7-(6-morpholinopyridin-3-yl)-N-(m-tolyl)quinazolin-4-amine (Compound 53):

[0261] 3-methylaniline was selected as the starting material, and other embodiments were the same as those in Example 48. The prepared compound was a white solid.

[0262] 1 H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 6.7 Hz, 2H), 8.11 (dd, J = 8.8, 2.0 Hz, 1H), 8.07 - 7.90 (m, 2H), 7.71 (d, J = 10.5 Hz, 2H), 7.29 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 3.81 - 3.69 (m, 4H), 3.62 - 3.53 (m, 4H), 2.36 (s, 3H). 13CNMR (126 MHz, DMSO-d6) δ 159.33, 158.07, 155.42, 150.76, 146.74, 142.28, 139.60, 138.09, 136.61, 128.78, 124.88, 124.59, 124.23, 124.00, 123.53, 123.30, 120.04, 114.12, 107.42, 66.41, 45.46, 21.69. HRMS (ESI): m / z [M+H]+calcd for C + calcd for C 24 H 24 N5O:398.197.found,398.1975.

[0263] Example 54

[0264] Synthesis of 7-(6-morpholinopyridin-3-yl)-N-(p-tolyl)quinazolin-4-amine (Compound 54):

[0265] 4-methylaniline was selected as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0266] 1 H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.62 - 8.54 (m, 2H), 8.11 (dd, J = 8.9, 2.4 Hz, 1H), 8.02 - 7.90 (m, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.9 Hz, 1H), 3.77 - 3.71 (m, 4H), 3.61 - 3.49 (m, 4H), 2.32 (s, 3H). 13 CNMR (126 MHz, DMSO-d6) δ 159.34, 158.07, 155.46, 150.76, 146.74, 142.22, 137.10, 136.62, 133.20, 129.36, 124.52, 124.23, 124.03, 123.54, 122.93, 114.10, 107.43, 66.42, 45.47, 21.03. HRMS (ESI): m / z [M+H]+calcd for C 24 H 24 N5O:398.197.found,398.1975.

[0267] Example 55

[0268] Synthesis of N-(2-methoxyphenyl)-7-(6-morpholino-pyridin-3-yl)- quinazolin-4-amine (Compound 55):

[0269] 2-methoxyaniline was chosen as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0270] 1 H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.49 (d, J = 8.7 Hz, 1H), 8.45 (s, 1H), 8.11 (dd, J = 8.9, 2.5 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.97 - 7.91 (m, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.06 - 6.97 (m, 2H), 3.80 (s, 3H), 3.77 - 3.71 (m, 4H), 3.58 - 3.52 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.34, 159.01, 155.71, 153.92, 150.68, 146.72, 142.22, 136.65, 127.69, 127.61, 127.07, 124.53, 124.14, 124.13, 123.53, 120.71, 113.92, 112.27, 107.48, 66.42, 56.09, 45.50. HRMS (ESI): m / z [M+H] + calcd for C 24 H 24 N5O2: 414.1919. found, 414.1925.

[0271] Example 56

[0272] Synthesis of N-(3-methoxyphenyl)-7-(6-morpholino-pyridin-3-yl)- quinazolin-4-amine (Compound 56):

[0273] 3-methoxyaniline was chosen as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0274] 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.71 (d, J = 1.5 Hz, 1H), 8.68 - 8.59 (m, 2H), 8.12 (d, J = 8.8 Hz, 1H), 8.06 - 7.95 (m, 2H), 7.61 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.73 (dd, J = 8.0, 1.7 Hz, 1H), 3.80 (s, 3H), 3.77 - 3.68 (m, 4H), 3.56 (d, J = 4.3 Hz, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.85, 159.34, 157.98, 155.32, 150.80, 146.77, 142.33, 140.95, 136.62, 129.65, 124.64, 124.22, 123.96, 123.57, 114.86, 114.15, 109.35, 108.47, 107.41, 66.42, 55.55, 45.46. HRMS (ESI): m / z [M+H] + calcd for C 24 H 24 N5O2: 414.1919. found, 414.1925.

[0275] Example 57

[0276] Synthesis of N-(4-methoxyphenyl)-7-(6-morpholinopyridin-3-yl)quinazolin-4- amine (Compound 57):

[0277] 4-methoxyaniline was chosen as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0278] 1 H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.71 (d, J = 1.5 Hz, 1H), 8.68 - 8.59 (m, 2H), 8.12 (d, J = 8.8 Hz, 1H), 8.06 - 7.95 (m, 2H), 7.61 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.73 (dd, J = 8.0, 1.7 Hz, 1H), 3.80 (s, 3H), 3.77 - 3.68 (m, 4H), 3.56 (d, J = 4.3 Hz, 4H). 13C NMR (126 MHz, DMSO-d6) δ 159.33, 158.15, 156.29, 155.55, 150.70, 146.72, 142.16, 136.61, 132.50, 124.77, 124.44, 124.17, 124.07, 123.52, 114.14, 114.04, 107.43, 66.42, 55.70, 45.47. HRMS (ESI): m / z [M+H] 414.1925. calcd for C25H22FN5O2: 414.1919. + calcd for C 24 H 24 N5O2: 414.1919. found, 414.1925.

[0279] Example 58

[0280] Synthesis of N-(3-fluorophenyl)-7-(6-morpholino-pyridin-3-yl)-quinazoline-4-amine (Compound 58):

[0281] 3-Fluoroaniline was selected as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0282] 1 H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.50 (d, J = 6.9 Hz, 2H), 8.05 (dd, J = 8.9, 1.8 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.82 (dd, J = 8.9, 5.1 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 6.90 (d, J = 8.9 Hz, 1H), 3.70 - 3.63 (m, 4H), 3.50 - 3.45 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.35, 158.05, 157.93, 155.32, 150.76, 146.76, 142.35, 136.63, 135.98, 124.81, 124.74, 124.68, 124.19, 123.97, 123.55, 115.61, 115.41, 113.98, 107.43, 66.42, 45.46. HRMS (ESI): m / z [M+H] 402.1719. calcd for C25H21FN5O: 402.1725. + calcd for C 23 H 20 FN5O: 402.1725;. found, 402.1719.

[0283] Example 59

[0284] Synthesis of N-(4-fluorophenyl)-7-(6-morpholino-pyridin-3-yl)-quinazoline-4- amine (Compound 59):

[0285] 4-Fluoroaniline was chosen as the starting material, and other embodiments were the same as in Example 48. The prepared compound was a white solid.

[0286] 1 H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.71 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 8.0 Hz, 2H), 8.12 (dd, J = 8.9, 2.1 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.89 (dd, J = 8.3, 5.1 Hz, 2H), 7.25 (t, J = 8.8 Hz, 2H), 6.98 (d, J = 8.9 Hz, 1H), 3.77 - 3.70 (m, 4H), 3.58 - 3.52 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.88, 159.35, 158.05, 157.97, 155.33, 150.70, 146.77, 142.38, 136.61, 135.98, 124.82, 124.51, 123.97, 123.51, 115.51, 114.00, 107.42, 66.42, 45.48. HRMS (ESI): m / z [M+H] + calcd for C 23 H 21 FN5O: 402.1725;.found, 402.1719.

[0287] Example 60

[0288] Synthesis of N-(2,6-difluorophenyl)-7-(6-morpholino-pyridin-3-yl)-quinazoline-4- amine (Compound 60):

[0289] 2,6-Difluoroaniline was chosen as the starting material, and other embodiments were the same as in Example 48. The prepared compound was a white solid.

[0290] 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.72 (s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.49 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.45 (s, 1H), 7.26 (t, J = 7.8 Hz, 2H), 6.99 (d, J = 8.9 Hz, 1H), 3.76 - 3.71 (m, 4H), 3.59 - 3.54 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 160.05, 159.38, 159.21, 158.09, 155.56, 150.73, 146.81, 142.70, 136.67, 128.76, 125.02, 124.33, 123.97, 123.54, 116.03, 113.54, 112.59, 112.41, 107.46, 66.42, 45.49. HRMS (ESI): m / z [M+H]+calcd for C 23 H 20 F2N5O: 420.1625; found, 420.1639.

[0291] Example 61

[0292] Synthesis of N-(2,3-difluorophenyl)-7-(6-morpholinopyridin-3-yl)quinazolin-4- amine (Compound 61):

[0293] 2,3-difluoroaniline was chosen as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0294] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.72 (s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.49 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.45 (s, 1H), 7.26 (t, J = 7.8 Hz, 2H), 6.99 (d, J = 8.9 Hz, 1H), 3.76 - 3.71 (m, 4H), 3.59 - 3.54 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 159.38, 158.70, 155.46, 150.83, 146.80, 142.65, 136.66, 128.96, 124.95, 124.34, 123.96, 123.86, 123.52, 114.81, 113.70, 107.46, 66.42, 45.50. HRMS (ESI): m / z [M+H] 420.1634. Calcd for C25H21F2N5O: 420.1625. + calcd for C 23 H 20 F2N5O:420.1625.found,420.1634

[0295] Example 62

[0296] Synthesis of N-(2,4-difluorophenyl)-7-(6-morpholinopyridin-3-yl)quinazolin-4- amine (Compound 62):

[0297] 2,4-difluoroaniline was selected as the starting material, and other embodiments were the same as Example 48. The prepared compound was a white solid.

[0298] 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 9.1 Hz, 2H), 8.12 (dd, J = 8.9, 2.3 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.60 (dd, J = 15.1, 8.7 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.21 - 7.14 (m, 1H), 6.98 (d, J = 8.9 Hz, 1H), 3.79 - 3.68 (m, 4H), 3.64 - 3.48 (m, 4H). 13 CNMR (126 MHz, DMSO-d6) δ 159.36, 159.06, 155.56, 150.72, 146.77, 142.51, 136.65, 130.20, 124.81, 124.25, 123.99, 123.49, 113.63, 111.92, 111.74, 107.45, 105.23, 105.03, 104.82, 66.42, 45.47. HRMS (ESI): m / z [M+H] 420.1634. Calcd for C25H21F2N5O: 420.1625. + calcd for C 23 H 20 F2N5O:420.1625.found,420.163。

[0299] Example 63

[0300] Synthesis of N-(2,5-difluorophenyl)-7-(6-morpholino-pyridin-3-yl)- quinazoline-4-amine (Compound 63):

[0301] 2,5-difluoroaniline was chosen as the starting material, and other embodiments were the same as in Example 48. The prepared compound was a white solid.

[0302] 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.76 (d, J = 1.7 Hz, 1H), 8.60 - 8.46 (m, 2H), 8.17 (dd, J = 8.8, 2.0 Hz, 1H), 8.11 - 8.02 (m, 2H), 7.53 - 7.41 (m, 1H), 7.30 (t, J = 8.1 Hz, 2H), 7.02 (d, J = 8.9 Hz, 1H), 3.78 - 3.74 (m, 4H), 3.62 - 3.57 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 170.81, 160.03, 159.37, 159.20, 158.10, 155.57, 150.74, 146.82, 142.69, 136.67, 128.78, 125.03, 124.26, 123.96, 123.55, 116.01, 113.53, 112.50, 107.44, 66.42, 45.46. HRMS (ESI): m / z [M+H] + calcd for C 23 H 20 F2N5O: 420.1625. Found, 420.163.

[0303] Example 64

[0304] Synthesis of N-(3,4-difluorophenyl)-7-(6-morpholino-pyridin-3-yl)- quinazoline-4-amine (Compound 64):

[0305] 3,4-difluoroaniline was chosen as the starting material, and other embodiments were the same as in Example 48. The prepared compound was a white solid.

[0306] 1 H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.71 (s, 1H), 8.61 (d, J = 28.3 Hz, 2H), 8.13 (s, 2H), 8.01 (s, 2H), 7.67 (s, 1H), 7.47 (s, 1H), 6.99 (s, 1H), 3.74 (s, 4H), 3.56 (s, 4H). 13CNMR (126 MHz, DMSO-d6) δ 159.36, 157.80, 155.16, 150.78, 146.79, 142.44, 137.31, 136.64, 124.73, 124.22, 123.92, 123.51, 118.77, 117.56, 117.42, 114.22, 111.56, 111.39, 107.44, 66.42, 45.46 HRMS (ESI): m / z [M+H] + calcd for C 23 H 20 F2N5O: 420.1625. found, 420.163.

[0307] Example 65

[0308] Synthesis of N-(2-fluoro-4-(trifluoromethyl)phenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4-amine (Compound 65):

[0309] The reaction scheme is as follows:

[0310]

[0311] Intermediate H2 (7-bromo-4-chloroquinazoline) (1.4 g, 5.79 mmol) and 2-fluoro-4- (trifluoromethyl)phenylamine (1.35 g, 7.52 mmol) were dissolved in IPA (40 mL), K2CO3 (1.60 g, 11.58 mmol) was added, stirred at 60 °C for 12 h, the reaction was monitored by TLC, after the reaction was completed, the PH value was adjusted to 7-9 using NaHCO3, ethyl acetate was added and stirred well, extracted 2-3 times, washed with saturated NaCl solution, dried over anhydrous Na2SO4, then separated and purified by column chromatography (PE:EA = 4:1), concentrated to obtain white solid H8 (7-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)quinazolin-4-amine) (1.45 g, 3.79 mmol).

[0312] H8 (7-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)quinazolin-4-amine) (1.45 g, 3.79 mmol) and 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1.49 g, 4.97 mmol) were dissolved in 1,4-dioxane (20 mL) and H2O (5 mL), K2CO3 (1.05 g, 7.58 mmol) and bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2) (0.27 g, 0.38 mmol) were added, 2-3 times of nitrogen replacement, 85 °C stirring, reaction under the condition of nitrogen protection for 12 h, after the reaction was completed, it was cooled to room temperature, TLC detection, the reaction solution was added with ethyl acetate and stirred well, extracted 2-3 times with saturated NaCl solution, dried over anhydrous Na2SO4, and then separated and purified by column chromatography (PE:EA = 1:1) to obtain yellow oil 65 N-(2-fluoro-4-(trifluoromethyl)phenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4-amine (0.9 g, 1.86 mmol).

[0313] 1 H NMR (500 MHz, DMSO-d6) δ 10.12-9.98 (m, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.51 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 8.02 (s, 2H), 7.89 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 3.62-3.58 (m, 4H), 2.44-2.40 (m, 4H), 2.23 (s, 3H). 13 CNMR (126 MHz, DMSO-d6) δ 159.24, 158.42, 157.87, 155.30, 154.20, 146.84, 142.84, 136.58, 128.68, 127.83, 125.00, 124.48, 123.36, 122.04, 120.63, 114.10, 113.93, 110.45, 107.45, 54.84, 46.28, 44.97. HRMS (ESI): m / z [M+H] + calcd for C 25 H 23 F4N6: 483.1852. found, 483.1860.

[0314] Example 66

[0315] Synthesis of N-(2-fluoro-5-(trifluoromethyl)phenyl)-7-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4-amine (Compound 66):

[0316] 2-Fluoro-5-(trifluoromethyl)aniline was chosen as the starting material, and other embodiments were the same as Example 65. The prepared compound was a white solid.

[0317] 1 H NMR (500 MHz, DMSO-d6) δ 10.14 - 9.86 (m, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 8.4 Hz, 2H), 8.09 (dd, J = 8.9, 2.3 Hz, 1H), 8.02 (s, 2H), 7.99 (s, 1H), 7.74 - 7.68 (m, 1H), 7.59 (s, 1H), 6.98 (d, J = 9.0 Hz, 1H), 3.61 - 3.58 (m, 4H), 2.44 - 2.40 (m, 4H), 2.23 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 160.15, 159.23, 158.52, 158.12, 155.27, 146.83, 142.79, 136.57, 128.10, 125.95, 125.57, 124.96, 124.32, 123.38, 123.16, 117.81, 117.64, 113.75, 108.96, 107.44, 54.84, 46.28, 44.97. HRMS (ESI): m / z [M+H] + calcd for C 25 H 23 F4N6: 483.1915. found, 483.1923.

[0318] Example 67

[0319] Synthesis of N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4-amine (Compound 67):

[0320] 4-Fluoro-3-(trifluoromethyl)aniline was chosen as the starting material, and other embodiments were the same as Example 65. The prepared compound was a white solid.

[0321] 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.73 (d, J = 8.8 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.64 (s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 8.39 - 8.34 (m, 1H), 8.08 (dd, J = 8.9, 2.1 Hz, 1H), 8.00 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.54 (t, J = 9.8 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 3.60 - 3.57 (m, 4H), 2.44 - 2.40 (m, 4H), 2.23 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 172.71, 159.18, 157.83, 154.89, 155.01, 150.81, 146.82, 142.62, 136.55, 128.44, 125.78, 124.50, 124.49, 123.33, 122.07, 120.40, 117.63, 116.51, 113.93, 107.41, 54.80, 46.24, 44.90. HRMS (ESI): m / z [M+H] + calcd for C 25 H 23 F4N6: 483.1915. found, 483.1918.

[0322] Example 68

[0323] Synthesis of N-(2,4-difluorophenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4- amine (Compound 68):

[0324] 2,4-difluoroaniline was chosen as the starting material, and other embodiments were the same as Example 65. The prepared compound was a white solid.

[0325] 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.09 (dd, J = 8.9, 2.2 Hz, 1H), 8.01 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.60 (dd, J = 15.1, 8.8 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.17 (t, J = 8.4 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 3.61 - 3.57 (m, 4H), 2.43 - 2.39 (m, 4H), 2.23 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 160.07, 159.20, 159.05, 158.10, 155.54, 150.74, 146.80, 142.58, 136.57, 130.17, 124.74, 124.29, 123.45, 123.42, 123.34, 113.58, 111.79, 107.44, 105.00, 54.83, 46.29, 44.95. HRMS (ESI): m / z [M+H] + calcd for C 24 H 23 F2N6:433.1947found,433.1946.

[0326] Example 69

[0327] Synthesis of N-(2,5-difluorophenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4- amine (Compound 69):

[0328] 2,5-difluoroaniline was chosen as the starting material, and other embodiments were the same as Example 65. The prepared compound was a white solid.

[0329] 1 H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.69 (s, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.54 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.57 (s, 1H), 7.38 (dd, J = 14.2, 9.3 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 3.59 (s, 4H), 2.44 - 2.40 (m, 4H), 2.23 (s, 3H).13 C NMR (126 MHz, DMSO-d6) δ 159.19, 158.62, 158.14, 155.40, 153.46, 150.84, 146.82, 142.66, 136.58, 128.14, 124.82, 124.50, 123.41, 123.31, 117.32, 115.08, 113.72, 113.55, 107.45, 54.79, 46.24, 44.91. HRMS (ESI): m / z [M+H] calcd for C + calcd for C 24 H 23 F2N6: 433.1947, found, 433.1947.

[0330] Example 70

[0331] Synthesis of N-(2,6-difluorophenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4- amine (Compound 70):

[0332] 2,6-difluoroaniline was chosen as the starting material, and other embodiments were the same as Example 65. The prepared compound was a white solid.

[0333] 1 H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.73 (s, 1H), 8.56 (d, J = 8.6 Hz, 1H), 8.53 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.55 - 7.40 (m, 1H), 7.29 (t, J = 8.0 Hz, 2H), 6.99 (d, J = 9.0 Hz, 1H), 3.65 - 3.59 (m, 4H), 2.46 - 2.41 (m, 4H), 2.25 (s, 3H). 13 CNMR (126 MHz, DMSO-d6) δ 160.08, 159.21, 158.10, 155.56, 150.77, 146.85, 142.77, 136.59, 128.76, 124.97, 124.25, 123.42, 116.04, 113.47, 112.60, 112.42, 107.43, 54.82, 46.28, 44.94. HRMS (ESI): m / z [M+H] calcd for C + calcd for C 24 H 23 F2N6: 433.1947, found, 433.1942.

[0334] Example 71

[0335] Synthesis of N-(3,4-difluorophenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3- yl)quinazolin-4-amine (Compound 71):

[0336] 3,4-difluoroaniline was chosen as the starting material, and other embodiments were the same as Example 65. The prepared compound was a white solid.

[0337] 1 H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.64 (d, J = 4.7 Hz, 1H), 8.59 - 8.54 (m, 1H), 8.18 - 8.12 (m, 1H), 8.09 (dd, J = 8.8, 2.6 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.68 (d, J = 4.3 Hz, 1H), 7.46 (d, J = 10.3 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 3.61 - 3.58 (m, 4H), 2.45 - 2.41 (m, 4H), 2.23 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 163.61, 159.24, 157.81, 155.11, 154.22, 150.81, 146.84, 142.66, 136.62, 136.58, 124.82, 124.12, 123.44, 123.34, 119.17, 117.51, 113.90, 111.60, 107.45, 54.84, 46.28, 44.97. HRMS (ESI): m / z [M+H] + calcd for C 24 H 23 F2N6: 433.1947, found, 433.1949.

[0338] Example 72

[0339] Synthesis of N-(2-fluoro-6-methylphenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3- yl)quinazolin-4-amine (Compound 72):

[0340] 2-fluoro-6-methylaniline was chosen as the starting material, and other embodiments were the same as Example 65. The prepared compound was a white solid.

[0341] 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.11 (d, J = 6.3 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 3.54 (s, 4H), 2.40 (s, 4H), 2.19 (s, 3H), 2.18 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 159.86, 159.38, 159.12, 157.90, 155.80, 150.68, 146.76, 142.47, 139.08, 136.61, 128.20, 126.32, 125.62, 124.61, 123.68, 123.37, 113.83, 113.62, 107.51, 54.45, 45.95, 44.72, 18.15. HRMS (ESI): m / z [M+H] + calcd for C 25 H 25 FN6: 429.2197. found, 429.2198.

[0342] The performance of the compounds prepared in Examples 1-72 was detected as follows:

[0343] 1. Inhibitory effect of the compounds prepared in Examples 1-72 on programmed necrosis:

[0344] The mouse fibroblast L929 cells were used in the experiment. After pre-incubation of the L929 cells with the test compounds for 1 hour, programmed necrosis was induced by a combination of TNF and Caspase inhibitor z-vad-Fmk (TZ), and a solvent control group (NC) was set up for reference comparison. The cell viability was observed under a microscope to evaluate the anti-necrosis effect of the compounds. “+++” represents very strong inhibition, “++” represents strong inhibition, “+” represents relatively strong inhibition, and “+ / -” represents weak inhibition.

[0345] Table 1 Inhibition degree of the compounds of Examples 1-72 on programmed necrosis of cells

[0346]

[0347]

[0348] 2. Therapeutic effect of Example 23 on mouse ulcerative colitis model

[0349] The therapeutic effect of Example 23 on dextran sulfate sodium (DSS)-induced mouse ulcerative colitis was investigated. According to the RIPK3 inhibitory activity, physicochemical properties, and in vitro anti-inflammatory activity of Example 23, the in vivo pharmacodynamic dosing concentrations were determined to be 5 mg / kg, 10 mg / kg, and 20 mg / kg. As shown in Figure 1 and Figure 2 , compared with the normal group (NC), the colon length of the DSS group mice was significantly shortened. Example 23 dose-dependently restored the colon length of the mice. As shown in Figure 3 , the body weight of the normal group (NC) mice gradually increased within 7 days. The body weight of the mice in other groups decreased, and the body weight of the mice in the DSS group decreased most obviously. Example 23 dose-dependently restored the decrease in the body weight of the mice. After the experiment, the mice were sacrificed, and the colon tissue sections of the mice were subjected to H&E (hematoxylin-eosin) staining for histological observation Figure 4 . From the staining results, compared with the normal control group (NC), the colon tissue of the mice in the DSS treatment group exhibited significant pathological changes such as inflammation and tissue necrosis. These changes included the destruction of epithelial cells, the infiltration of a large number of inflammatory cells, and the loss of colon crypts, which are typical pathological features of colitis. After treatment with Example 23, the pathological phenotypes of inflammation and necrosis in the colon tissue of the mice were dose-dependently alleviated. The above experimental results show that Example 23 has a therapeutic effect on colitis.

[0350] 3. Therapeutic effect of Example 70 on mouse psoriasis model

[0351] The anti-psoriasis activity of Example 70 in mouse psoriasis-like skin lesions induced by imiquimod (IMQ) was investigated. As shown in Figure 5 , compared with the normal group (NC), IMQ induced typical symptoms of psoriasis, including erythema, scaling, and thickening of the stratum corneum. Example 70 dose-dependently improved the IMQ-induced mouse psoriasis-like skin lesions. Figure 6 The skin thickness of the mice was counted. Compared with the normal group (NC), the skin thickness of the mice in the IMQ treatment group increased, and the treatment group of Example 70 dose-dependently reduced the skin thickening caused by IMQ. The skin tissue sections of the mice were subjected to H&E (hematoxylin-eosin) staining for histological observation. As shown in Figure 7 , compared with the IMQ treatment group, Example 70 reduced the infiltration of inflammatory cells, repaired the damage to the skin tissue, and reduced the thickness of the keratinocytes. The above results show that Example 70 has a therapeutic effect on psoriasis.

[0352] The above descriptions are only the preferable embodiments of the present application, which are only illustrative but not restrictive. It is understood by those skilled in the art that many changes, modifications, even equivalences can be made to the present application within the spirit and scope defined by the claims of the present application, and all of them will fall into the protection scope of the present application.

Claims

1. A class of quinazoline compounds or pharmaceutically acceptable salts thereof with anti-inflammatory activity, characterized in that, The general structural formula is as follows: ； Among them, R 1 It is independently selected from 2-methyl, 3-methyl, 4-methyl, 2-fluoro, 3-fluoro or 4-fluoro; X is selected from NH or O; R 2 It is piperidin-4-yl.

2. The quinazoline compound or its pharmaceutically acceptable salt with anti-inflammatory activity as described in claim 1, characterized in that, Selected from any of the following compounds: 、 、 、 、 、 、 、 、 。 3. A pharmaceutical composition, characterized in that, It includes one or more therapeutically effective amounts of a quinazoline compound or a pharmaceutically acceptable salt thereof that has anti-inflammatory activity as described in any one of claims 1 or 2, and pharmaceutically acceptable excipients.

4. The use of a quinazoline compound with anti-inflammatory activity, as described in any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of inflammatory diseases associated with programmed cell necrosis, characterized in that, The inflammatory diseases mentioned are selected from inflammatory bowel disease, psoriasis, neuroinflammation, acute and chronic liver inflammation, joint inflammation, acute kidney injury, chronic kidney disease, chronic obstructive pulmonary disease, and pathogenic pneumonia.

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