Quinazoline compound with anti-inflammatory activity or pharmaceutically acceptable salt, pharmaceutical composition and application thereof

Abstract

The invention relates to the technical field of medicinal chemistry and pharmacotherapeutics, in particular to a quinazoline compound with anti-inflammatory activity or pharmaceutically acceptable salt of the quinazoline compound, a pharmaceutical composition and application of the quinazoline compound or the pharmaceutically acceptable salt of the quinazoline compound. The compound has a good inhibition effect on programmed necrosis of cells in an in-vitro experiment, can inhibit the programmed necrosis of cells induced by TNF (Tumor Necrosis Factor) in a concentration-dependent manner, and provides a new potential therapeutic drug for treating inflammatory bowel diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry and pharmacotherapy, and in particular to a class of quinazoline compounds with anti-inflammatory activity or pharmaceutically acceptable salts thereof, a pharmaceutical composition and application thereof. Background Art

[0002] Necroptosis is a form of programmed cell death that resembles necrosis. Unlike apoptosis, necrosis has its own unique morphological characteristics: cell swelling, plasma membrane rupture, and release of cell contents. This process causes damage associated molecular patterns (DAMPs) to infiltrate surrounding tissues, which in turn causes a large number of inflammatory cell infiltrations, ultimately triggering an inflammatory response in surrounding tissues.

[0003] Programmed necrosis involves a variety of pathophysiological processes, especially playing 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 inflammatory diseases related to programmed necrosis with drugs has become an urgent problem to be solved.

[0004] In view of the above-mentioned defects, the inventors of the present invention finally obtained the present invention after a long period of research and practice. Summary of the invention

[0005] The purpose of the present invention is to solve the problem of how to treat inflammatory diseases related to programmed necrosis by drugs, and provides a class of quinazoline compounds or pharmaceutically acceptable salts thereof with anti-inflammatory activity, a pharmaceutical composition and use thereof.

[0006] In order to achieve the above object, the present invention discloses a class of quinazoline compounds or pharmaceutically acceptable salts thereof having anti-inflammatory activity, the general structural formula of which is as follows:

[0007]

[0008] Among them, R 1 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 Selected from H, methyl or piperidin-4-yl.

[0011] Select any one of the following compounds:

[0012]

[0013] The present invention also discloses a class of quinazoline compounds or pharmaceutically acceptable salts thereof having anti-inflammatory activity, the general structural formula of which is as follows:

[0014] Among them, Ar 1 Selected from

[0015] Ar 2 Independently selected from the following aromatic rings or aromatic ring systems:

[0016]

[0017] Select any one of the following compounds:

[0018]

[0019]

[0020] The present invention also discloses a class of quinazoline compounds or pharmaceutically acceptable salts thereof having anti-inflammatory activity, the general structural formula of which is as follows:

[0021]

[0022] Wherein, Ar is independently selected from the following aromatic rings or aromatic ring systems:

[0023] X is selected from O or NCH 3 .

[0024] Select any one of the following compounds:

[0025]

[0026]

[0027]

[0028] The present invention also discloses a pharmaceutical composition, comprising one or more therapeutically effective amounts of the above-mentioned quinazoline compounds with anti-inflammatory activity or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable adjuvants.

[0029] The present invention also discloses the use of the above quinazoline compounds with anti-inflammatory activity or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing and / or treating inflammatory diseases associated with programmed cell necrosis.

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

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows: the quinazoline compound or its pharmaceutically acceptable salt in the present invention has a good inhibitory effect on programmed cell necrosis in in vitro experiments, and can inhibit TNF-induced programmed cell necrosis in a concentration-dependent manner. The compound N-(2-fluorophenyl)-7-(6-morpholinopyridin-3-yl)quinazoline-4-amine prepared by the present invention shows a positive therapeutic effect in the acute colitis model of mice induced by sodium dextran sulfate (DSS), and it can effectively alleviate the symptoms of colitis in mice, providing a new potential therapeutic drug for the treatment of inflammatory bowel disease. The compound N-(2,6-difluorophenyl)-7-(6-(4-methylpiperazine-1-yl)pyridin-3-yl)quinazoline-4-amine prepared by the present invention also shows a positive therapeutic effect in the mouse psoriasis model, and can significantly improve the symptoms of the psoriasis model mice. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The images are of the intestinal tract of mice in the normal group (NC), the disease model group (DSS), the treatment group of Example 23, and the positive control group (GSK872, WEHI-345). It can be seen from the figure that the intestinal tract of mice in the disease model group (DSS) was significantly shortened, and the shortening of the intestinal tract in the treatment group of Example 23 was prevented in a dose-dependent manner;

[0033] Figure 2 It is a statistical graph of the measured length of the intestine of mice in the normal group (NC), disease model group (DSS), Example 23 treatment group, and positive control group (GSK872, WEHI-345);

[0034] Figure 3 The figure is a statistical graph of the weight of mice in the normal group (NC), the disease model group (DSS), the treatment group of Example 23, and the positive control group (GSK872, WEHI-345). It can be seen that the weight of mice in the disease model group (DSS) was significantly reduced, and the weight loss of mice in the treatment group of Example 23 was alleviated in a dose-dependent manner;

[0035] Figure 4 H&E staining of intestinal tissue sections of mice in the normal group (NC), disease model group (DSS), Example 23 treatment group, and positive control group (GSK872, WEHI-345). It can be seen that the Example 23 treatment group dose-dependently improved intestinal tissue inflammation and necrosis;

[0036] Figure 5These are pictures of mouse skin in the normal group (NC), the disease model group (IMQ), the group treated with Example 70, and the positive control group (methotrexate). It can be seen from the pictures that the mice in the disease model group (IMQ) had psoriasis-like skin diseases such as erythema, dandruff, and thickened keratin on their skin, and the group treated with Example 70 reduced the psoriasis-like symptoms of the mice's skin in a dose-dependent manner;

[0037] Figure 6 The graph is a statistical diagram of the measured length of the skin thickness of mice in the normal group (NC), the disease model group (IMQ), the group treated with Example 70, and the positive control group (methotrexate). It can be seen that the skin of mice in the disease model group (IMQ) was significantly thickened, and the skin thickening of mice in the group treated with Example 70 was alleviated in a dose-dependent manner;

[0038] Figure 7 These are H&E staining images of mouse skin tissue sections from the normal group (NC), disease model group (IMQ), Example 70 treatment group, and positive control group (methotrexate). It can be seen that the Example 23 treatment group dose-dependently reduced skin tissue inflammatory infiltration, tissue damage, and keratin thickening. DETAILED DESCRIPTION

[0039] The above and other technical features and advantages of the present invention are described in more detail below 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] In 1.5 g 7-bromoquinazolin-4(3H)-one (reactant H1), 15 mL SOCl 2 Add 1 drop of N,N'-dimethylformamide (DMF) to the mixture, stir at 110℃ for 12h, and after TLC detection, remove unreacted SOCl by distillation under reduced pressure. 2 , add CH 2 Cl 2 , and filtered to obtain a dry white solid 7-bromo-4-chloroquinazoline (intermediate H2) with a reaction yield of 90%.

[0044] Dissolve 1.4 g of intermediate H2 and 0.85 g of o-cresol in 40 mL of isopropanol and add 1.60 g of K 2 CO 3 , stirred at 60 °C for 12 h, and after the reaction was complete by TLC, saturated NaHCO 3The pH of the reaction solution was adjusted to 7-9 with aqueous solution, the reaction solution was extracted 3 times with ethyl acetate, the ethyl acetate extract was washed 2 times with saturated NaCl solution, anhydrous Na 2 SO 4 After drying, the solvent was removed by distillation under reduced pressure, and the distillation residue was purified by silica gel column chromatography (PE:EA=4:1) to obtain 7-bromo-4-(o-tolyloxy)quinazoline (intermediate H3) as a white solid in a yield of 85%.

[0045] 1.2 g of intermediate H3 and 1.80 g of tert-butyl 4-(4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate were dissolved in 25 mL of a 1,4-dioxane-water mixed solution (V:V = 4:1). 1.05 g of K 2 CO 3 and 0.26 g of bistriphenylphosphine palladium dichloride, under nitrogen protection, stirred at 85 ° C for 12 h. After the reaction was complete, the reaction solution was extracted 3 times with ethyl acetate, and the extract was washed twice with saturated NaCl solution. Anhydrous Na 2 SO 4 After drying, the solvent was removed by distillation under reduced pressure, and the distillation residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain yellow oily product tert-butyl 4-(4-(m-tolyloxy)quinazolin-7-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate H4) in a yield of 66%.

[0046] Dissolve 1.3 g of intermediate H4 in 20 mL of anhydrous CH 2 Cl 2 , add 3 mL of trifluoroacetic acid, stir at 25 °C for 4 h, and after the reaction is complete by TLC, use NaHCO 3 The pH of the reaction solution was adjusted to 7-9, the reaction solution was extracted 3 times with ethyl acetate, washed 2 times with saturated NaCl solution, and anhydrous Na 2 SO 4 After drying, the solvent was removed by distillation under reduced pressure, and the distillation residue was purified by silica gel column chromatography (PE:EA=4:1) to obtain a white solid 7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4-(m-tolyloxy)quinazoline with a yield of 91%.

[0047] 1H NMR (500MHz, DMSO-d6) δ8.65(d,J=10.0Hz,2H),8.39(s,1H),8.37(s,1H),8.26(d,J=19.5Hz,2H),8.10–8.06(m,1H),7.38(d,J=7.4Hz,1H),7.3 2(t,J=7.3Hz,1H),7.27(s,1H),7.25(d,J=8.1Hz,1H),4.61–4.56(m,1H ),3.46(d,J=12.9Hz,4H),2.34–2.19(m,4H),2.19(s,1H),2.12(s,3H). 13 C NMR (126MHz, DMSO-d6) δ166.15,154.93,152.53,151.24,139.27,137.85,131.68,130.63,127.89,127.72,126. 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] + calcdfor C 23 H 24 N 5 O:386.1975.found,386.1973.

[0048] Example 2

[0049] Synthesis of 7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4-(m-tolyloxy)quinazoline (Compound 2):

[0050] Selecting m-cresol as the raw material, other implementation methods are the same as those in Example 1, and the prepared compound is a white solid.

[0051] 1 H NMR (500 MHz, DMSO-d 6 )δ11.13(s,1H),9.14(s,1H),7.53(dd,J=8.9,4.9Hz,2H),7.41(t,J=7.7Hz,3H),7.17(t,J=8.8Hz,2H),7 .07(d,J=7.4Hz,1H),4.05(t,J=6.5Hz,2H),1.76–1.68(m,2H),1.50–1.41(m,2H),0.94(t,J=7.4Hz,3H). 13 C NMR (126 MHz, DMSO-d 6)δ158.94,158.77,156.86,134.59,131.33,130.30,120.66,120.60,118.86,11 6.73,115.33,115.16,111.55,67.21,30.49,18.49,13.47.HRMS(ESI):m / z[M+H] + calcdfor C 23 H 24 N 5 O:386.1975; found,386.1977.

[0052] Example 3

[0053] Synthesis of 7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4-(p-tolyloxy)quinazoline (Compound 3):

[0054] Select p-cresol as the raw material, and other implementation methods are the same as those in Example 1. The prepared compound is a white solid.

[0055] 1H NMR (500MHz, DMSO-d6) δ8.65(dd,J=5.7,2.9Hz,2H),8.37(d,J=8.5Hz,1H),8.32(d,J=8.5Hz,1H),8.27(d,J=2.6Hz,1H),8.23(d,J=8.1Hz,1 H),8.08(t,J=10.2Hz,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 (126MHz, DMSO-d6) δ166.74,166.14,154.91,152.53,151.24,150.48,137.78,135.44,131.68,130.52, 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 N 5 O: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] Select 2-fluorophenol as the raw material, and other implementation methods are the same as Example 1. The prepared compound is a white solid.

[0059] 1 H NMR(500MHz,DMSO-d6)δ9.48(d,J=86.4Hz,1H),8.66(d,J=23.6Hz,1H),8.59(dd,J=6.9,5.1 Hz,1H),8.29(d,J=8.6Hz,1H),8.21(t,J=9.0Hz,1H),8.12(d,J=8.3Hz,1H),8.00(ddd,J=48 .5,20.6,15.5Hz,2H),7.79(d,J=8.5Hz,1H),7.55–7.21(m,2H),4.63–4.49(m,1H),4.39(d, J=11.9Hz,1H),3.16–2.64(m,2H),2.22(s,4H),1.92(s,1H),1.16(dd,J=60.0,52.9Hz,1H). 13 C NMR(126MHz,DMSO-d6)δ165.71,163.88,155.33,154.66,154.16,153.36,152.63,139.73,137.49,127.60,12 6.58,125.82,124.95,124.32,122.02,120.92,117.325,114.23,113.25,55.98,42.24.HRMS(ESI):m / z[M+H] + Calculate for C 22 H 21 FN 5 O: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 selected as the raw material, and other implementation methods were the same as those in Example 1. The prepared compound was a white solid.

[0063] 1H NMR (500MHz, DMSO-d6) δ8.72(d,J=18.5Hz,1H),8.65(d,J=5.6Hz,1H),8.32(d,J =8.6Hz,1H),8.25(d,J=13.7Hz,2H),8.19–7.98(m,2H),7.55(dd,J=15.2,8.2Hz ,1H),7.36(dd,J=9.9,2.1Hz,1H),7.30–7.15(m,2H),4.50(dt,J=14.6,5.1Hz,1 H), 3.41 (d, J = 6.2Hz, 4H), 2.22 (dd, J = 17.8, 8.2Hz, 4H), 1.94 (d, J = 45.9Hz, 1H). 13 C NMR (126MHz, DMSO-d6) δ166.35,164.02,163.86,161.92,154.70,152.60,139.45,137.69,131.40,127.74,126. 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 FN 5 O:390.1725found,390.1732.

[0064] Example 6

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

[0066] Select 4-fluorophenol as the raw material, and other implementation methods are the same as Example 1. The prepared compound is a white solid.

[0067] 1 H NMR (500MHz, DMSO-d6) δ8.69(s,1H),8.64(s,1H),8.34(d,J=8.6Hz,1H),8.28(s,1H),8.24(s,1H),8.09(d,J=1.2Hz,1H),8.08(d,J=1.3Hz, 1H),7.46–7.38(m,2H),7.34(t,J=8.8Hz,2H),4.60–4.45(m,1H),3.09(dd,J=38.1,25.9Hz,4H),2.23(dd,J=41.3,11.3Hz,4H),1.99(s,1H). 13C NMR(126MHz,DMSO-d6)δ166.64,161.08,159.16,154.76,152.52,148.73,139.31,137.79,127.82,1 26.30,124.53,124.45,122.03,120.90,116.78,113.96,56.37,42.76,29.61.HRMS(ESI):m / z[M+H] + Calculate for C 22 H 21 FN 5 O: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] Select 2-fluoroaniline as the raw material, and other implementation methods are the same as Example 1. The prepared compound is a white solid.

[0071] 1 H NMR(500MHz,DMSO-d6)δ9.80(s,1H),8.54(s,1H),8.47(s,1H),8.45(s,1H),8.16(s,1 H),8.00(s,1H),7.93(d,J=8.4Hz,1H),7.58(d,J=7.7Hz,1H),7.33(dd,J=8.1,3.9Hz,2 H),7.30–7.25(m,1H),4.24(dd,J=17.9,9.0Hz,1H),3.08(d,J=12.2Hz,2H),2.63(t,J =11.8Hz,2H),2.02(t,J=11.6Hz,2H),1.86(qd,J=12.0,3.8Hz,2H),1.27–1.03(m,1H). 13 C NMR (126MHz, DMSO-d6) δ158.85,158.39,156.42,155.48,150.89,138.10,136.98,128.96,127.73,126. 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] + Calculate for C 22 H 21FN 6 :389.1884.found,389.1885.

[0072] Example 8

[0073] Synthesis of N-(3-fluorophenyl)-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4-amine (Compound 8):

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

[0075] 1 H NMR (500MHz, DMSO-d6) δ10.10(s,1H),8.72(d,J=8.7Hz,1H),8.60(d,J=25.7Hz,2H),8.21(s,1H),7.97(dd,J=34.9,8.0Hz,3H),7.78(d,J=8.2Hz,1 H),7.40(dd,J=15.4,8.0Hz,1H),6.92(td,J=8.4,1.9Hz,1H),4.57(dd,J=9.4,4.5Hz,1H),3.19(ddd,J=67.0,23.3,8.9Hz,5H),2.38–2.17(m,4H). 13 C NMR (126MHz, DMSO-d6) δ163.36,161.44,157.85,155.06,150.87,141.72,137.76,137.57,130.30,127. 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] + Calculate for C 22 H 21 FN 6 :389.1884.found,389.1880.

[0076] Example 9

[0077] Synthesis of N-(4-fluorophenyl)-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4-amine (Compound 9):

[0078] Select 4-fluoroaniline as the raw material, and other implementation methods are the same as Example 1. The prepared compound is a white solid.

[0079] 1H NMR(500MHz,DMSO-d6)δ10.04(s,1H),8.71(d,J=8.5Hz,1H),8.55(d,J=12.5Hz,2H),8.19(s,1H),8.03– 7.89(m,4H),7.22(t,J=8.8Hz,2H),4.51–4.45(m,1H),3.29–2.93(m,4H),2.14(dt,J=81.0,42.3Hz,5H). 13 C NMR (126MHz, DMSO-d6) δ159.78,158.03,157.87,155.28,150.91,137.65,137.39,136.11,127. 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] + Calculate for C 22 H 21 FN 6 :389.1884.found,389.1876.

[0080] Example 10

[0081] The reaction formula for synthesizing N-(2-fluorophenyl)-7-(1H-pyrazol-4-yl)quinazolin-4-amine (Compound 10) is as follows:

[0082]

[0083] Intermediate H2 (7-bromo-4-chloroquinazoline) (1.4 g, 5.79 mmol) and o-fluoroaniline (0.83 g, 7.52 mmol) were dissolved in IPA (40 mL) and K 2 CO 3 (1.60 g, 11.58 mmol), stirred at 60 °C for 12 h, the reaction solution was detected by TLC, and after the reaction was complete, NaHCO 3 Adjust the pH value to 7-9, add ethyl acetate and stir thoroughly, extract 2-3 times, wash with saturated NaCl solution, and add anhydrous Na 2 SO 4 After drying, separation and purification by chromatography column (PE:EA=4:1) and concentration, a white solid H6 (7-bromo-N-(2-fluorophenyl)quinazolin-4-amine) (1.2 g, 3.79 mmol) was obtained.

[0084] H5 (7-bromo-N-(2-fluorophenyl)quinazolin-4-amine) (1.2 g, 3.79 mmol) and H9 (4-pyrazoleboronic acid pinacol ester) (0.97 g, 4.97 mmol) were dissolved in 1,4-dioxne (20 mL) and H 2 O (5 mL), K 2 CO 3 (1.05 g, 7.58 mmol) and bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 )(0.27 g, 0.38 mmol), replaced with nitrogen 2-3 times, stirred at 85 ° C, reacted for 12 h under nitrogen protection, cooled to room temperature after the reaction was complete, detected by TLC, the reaction solution was added with ethyl acetate and stirred thoroughly, extracted 2-3 times, washed with saturated NaCl solution, anhydrous Na 2 SO 4 After drying, separation and purification by chromatography column (PE:EA=1:1) and concentration, a yellow oily substance 10(N-(2-fluorophenyl)-7-(1H-pyrazol-4-yl)quinazolin-4-amine) (1.2 g, 3.93 mmol) was obtained.

[0085] 1 H NMR(500MHz,DMSO-d6)δ13.16(s,1H),9.77(s,1H),8.52(s,1H),8.45(d,J=8.3Hz,2H),8.21(s,1H ),8.04(s,1H),7.96(d,J=8.6Hz,1H),7.58(t,J=7.8Hz,1H),7.38–7.32(m,2H),7.31–7.23(m,1H). 13 C NMR(126MHz,DMSO-d6)δ158.87,158.42,156.46,155.49,150.94,138.20,137.51,129.06,12 7.80,126.82,124.88,124.80,124.08,122.49,120.69,116.42,113.24.HRMS(ESI):m / z[M+H] + Calculate for C 17 H 13 FN 5 :306.115.found,306.1147.

[0086] Embodiment 11

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

[0088] 1-Methylpyrazole-4-boric acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0089] 1 H NMR(500MHz,DMSO-d6)δ9.77(s,1H),8.46(s,1H),8.44(d,J=5.5Hz,2H),8.14(s,1H),7.97(s,1H),7.9 0(d,J=8.5Hz,1H),7.58(t,J=7.7Hz,1H),7.33(dd,J=8.4,3.6Hz,2H),7.30–7.24(m,1H),3.92(s,3H). 13 C NMR(126MHz,DMSO-d6)δ158.87,158.40,155.54,150.92,137.84,137.40,129.65,128.99,127.80 ,126.80,124.86,124.50,124.18,122.33,121.35,116.42,113.29,40.53..HRMS(ESI):m / z[M+H] + Calculate for C 18 H 15 FN 5 :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 selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0093] 1 H NMR (500MHz, DMSO-d6) δ13.16(s,1H),9.83(s,1H),8.51(d,J=9.9Hz,2H),8.21(s,1H),8.16(d,J= 8.4Hz,1H),7.90(s,1H),7.59(t,J=7.8Hz,1H),7.37–7.31(m,2H),7.31–7.24(m,1H),7.02(s,1H). 13C NMR(126MHz,DMSO-d6)δ158.97,158.42,156.45,155.54,150.73,149.52,138.72,130.82,12 8.98,127.83,126.80,124.88,124.10,123.34,116.45,114.28,103.45.HRMS(ESI):m / z[M+H] + Calculate for C 17 H 13 FN 5 :306.115.found,306.1152.

[0094] Embodiment 13

[0095] Synthesis of N-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (Compound 13):

[0096] 1-Methylpyrazole-3-boric acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0097] 1 H NMR (500MHz, DMSO-d6) δ9.87(s,1H),8.53(d,J=9.2Hz,2H),8.19(s,1H),8.14(d,J=8.6Hz,1H),7.86(d,J=1.7Hz ,1H),7.61(t,J=7.6Hz,1H),7.36(dd,J=8.1,3.7Hz,2H),7.33–7.27(m,1H),7.02(d,J=1.6Hz,1H),3.99(s,3H). 13 C NMR(126MHz,DMSO-d6)δ158.96,155.57,149.29,146.12,138.30,133.30,132.05,128.95,127.8 2,126.80,124.88,124.03,123.15,116.42,114.28,104.28,102.76,38.91.HRMS(ESI):m / z[M+H] + calcd fo rC 18 H 15 FN 5 :320.1306.found,320.1312.

[0098] Embodiment 14

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

[0100] 3-Pyridineboronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0101] 1 H NMR (500MHz, DMSO-d6) δ9.96(s,1H),9.13(s,1H),8.68(d,J=4.5Hz,1H),8.62(d,J=8.6Hz,1H),8.55(s,1H),8.32(d,J=7.9Hz,1H),8. 16(s,1H),8.07(d,J=8.5Hz,1H),7.61(d,J=7.7Hz,1H),7.58(dd,J=7.7,4.6Hz,1H),7.38–7.34(m,2H),7.29(dd,J=10.4,6.0Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ159.08,158.42,156.46,155.79,150.60,149.91,148.61,142.00,135.22,13 4.76,129.02,128.00,126.65,125.70,124.91,124.61,124.48,116.50,114.71.HRMS(ESI):m / z[M+H] + Calculate for C 19 H 13 FN 4 317.1197.found,317.1202.

[0102] Embodiment 15

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

[0104] 4-Pyridineboronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0105] 1H NMR (500MHz, DMSO-d6) δ10.01(s,1H),8.76(d,J=5.9Hz,2H),8.66(d,J=8.6Hz,1H),8.59(s,1H),8.25(s,1H ),8.13(d,J=8.5Hz,1H),7.96(d,J=5.7Hz,2H),7.62(t,J=7.7Hz,1H),7.43–7.36(m,2H),7.34–7.28(m,1H). 13 C NMR(126MHz,DMSO-d6)δ159.07,158.42,155.89,150.91,150.55,146.16,142.01,129.06,12 8.04,126.60,126.15,125.30,124.93,124.72,122.18,116.50,115.40.HRMS(ESI):m / z[M+H] + Calculate for C 19 H 13 FN 4 317.1197.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-boric acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0109] 1 H NMR(500MHz,DMSO-d6)δ9.95(s,1H),8.80(s,1H),8.61(d,J=8.6Hz,1H),8.57–8.49(m,2H),8.16(s, 1H),8.05(d,J=8.4Hz,1H),7.60(t,J=7.7Hz,1H),7.39–7.35(m,2H),7.35(s,1H),7.32–7.27(m,1H). 13C NMR(126MHz,DMSO-d6)δ164.52,162.63,159.06,155.81,150.55,146.68,141.42,140.74,133.36,12 9.02,128.00,126.60,125.62,124.93,124.90,124.61,116.50,114.70,110.30.HRMS(ESI):m / z[M+H] + Calculate for C 19 H 13 F 2 N 4: 335.1103 found, 335.1101.

[0110] Embodiment 17

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

[0112] 2-Methylpyridine-5-boric acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0113] 1 H NMR (500MHz, DMSO-d6) δ9.97(s,1H),8.59(d,J=8.5Hz,1H),8.55(s,1H),8.52(d,J=5.7Hz,2H),7.81(s,1H),7.72(d,J=8.3H z,1H),7.60(t,J=7.7Hz,1H),7.41(d,J=4.9Hz,1H),7.36(dd,J=12.7,4.8Hz,2H),7.30(dd,J=10.5,6.0Hz,1H),2.35(s,3H). 13 CNMR(126MHz,DMSO-d6)δ159.14,158.47,156.50,155.73,150.15,149.80,149.32,144.76,142.76,136.56,1 29.05,128.22,128.01,126.68,125.89,124.92,123.83,116.50,114.45,19.87.HRMS(ESI):m / z[M+H]+calcd for C 20 H 16 FN 4 :331.1354.found,331.1352.

[0114] Embodiment 18

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

[0116] 3-Methylpyridine-5-boric acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0117] 1 H NMR (500MHz, DMSO-d6) δ9.87(s,1H),8.84(s,1H),8.53(d,J=8.6Hz,1H),8.47(s,1H),8.44(s,1H),8.07(d,J=4.1H z,2H),7.98(d,J=8.5Hz,1H),7.52(t,J=7.8Hz,1H),7.28(dd,J=12.6,4.9Hz,2H),7.24–7.17(m,1H),2.35(s,3H). 13 C NMR (126MHz, DMSO-d6) δ159.07,158.42,156.45,155.78,150.59,150.26,145.77,142.07,135.57,134.2 5,133.80,129.01,128.00,126.66,125.66,124.91,124.55,116.49,114.67,18.34.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 16 FN 4 :331.1354.found,331.1357.

[0118] Embodiment 19

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

[0120] 4-Methylpyridine-5-boric acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0121] 1H NMR(500MHz,DMSO-d6)δ9.92(s,1H),8.98(d,J=1.5Hz,1H),8.59(d,J=8.7Hz,1H),8.53(s,1H),8.20(dd,J=8.0,2.1Hz,1H),8.1 1(s,1H),8.03(d,J=8.6Hz,1H),7.59(t,J=7.8Hz,1H),7.42(d,J=8.1Hz,1H),7.38–7.33(m,2H),7.31–7.25(m,1H),2.56(s,3H). 13 CNMR(126MHz,DMSO-d6)δ159.06,158.52,158.42,156.63,156.46,156.27,150.63,142.10,135.39,131.8 7,129.03,127.98,126.68,125.48,124.91,124.53,123.78,116.50,114.51,24.27.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 16 FN 4 :331.1354.found,331.1353.

[0122] Embodiment 20

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

[0124] 4-(4-morpholinyl)phenylboronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0125] 1 H NMR (500MHz, DMSO-d6) δ9.83(s,1H),8.54–8.46(m,2H),7.99(s,1H),7.97(d,J=8.7Hz,1H),7.80(d,J=8.7Hz,2H),7.59(t,J=7.8 Hz,1H),7.34(dd,J=8.2,3.8Hz,2H),7.28(td,J=8.9,4.7Hz,1H),7.09(s,1H),7.07(s,1H),3.81–3.73(m,4H),3.23–3.18(m,4H). 13C NMR (126MHz, DMSO-d6) δ158.96,158.39,156.43,155.54,151.70,150.81,144.76,129.17,128.96,128.2 8,127.80,126.84,125.08,124.86,124.16,123.63,116.42,115.61,66.50,48.36.HRMS(ESI):m / z[M+H] + Calculate for C 24 H 21 FN 4 O:400.1932.found,400.1933.

[0126] Embodiment 21

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

[0128] 4-(4-methylpiperazine-1-yl)phenylboronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0129] 1 H NMR(500MHz,DMSO-d6)δ9.82(s,1H),8.58–8.41(m,2H),8.04–7.89(m,2H),7.77(d,J=8.5Hz,2H),7. 58(t,J=7.7Hz,1H),7.40–7.23(m,3H),7.07(d,J=8.6Hz,2H),3.24(s,4H),2.47(s,4H),2.23(s,3H). 13 C NMR(126MHz,DMSO-d6)δ158.95,158.40,155.53,151.60,150.82,144.81,129.13,128.80,128.25,127.79,1 26.85,125.04,124.87,124.15,123.51,116.42,115.79,113.56,54.96,47.99,46.25.HRMS(ESI):m / z[M+H] + Calculate for C 25 H 25 FN 5 :414.2089.found,414.2087.

[0130] Embodiment 22

[0131] Synthesis of N-(2-fluorophenyl)-7-(4-(piperazin-1-yl)phenyl)quinazolin-4-amine (Compound 22):

[0132] 4-(4-piperazinyl)phenylboronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0133] 1 H NMR (500MHz, DMSO-d6) δ10.06(s,1H),8.61(d,J=8.6Hz,1H),8.46(s,1H),7.95(s,1H),7.93(d,J=8.7Hz,1H),7.76(d,J=8.7Hz,2H),7.57(t ,J=7.7Hz,1H),7.33(d,J=4.3Hz,2H),7.30(d,J=5.4Hz,1H),7.29–7.24(m,1H),7.06(d,J=8.8Hz,2H),3.17–3.12(m,4H),2.90–2.82(m,4H). 13 C NMR (126MHz, DMSO-d6) δ158.91,158.41,156.45,155.46,152.21,150.72,144.77,128.93,128.54,128.2 0,127.61,124.90,124.82,124.54,123.30,116.47,116.31,115.68,49.29,46.02.HRMS(ESI):m / z[M+H] + Calculate for C 24 H 22 FN 5 :400.1932.found,400.1933.

[0134] Embodiment 23

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

[0136] 6-(4-morpholinyl)pyridine-3-boronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0137] 1H NMR(500MHz,DMSO-d6)δ9.76(s,1H),8.64(d,J=2.2Hz,1H),8.50(d,J=6.9Hz,2H),8.05(dd,J=8.9,1.8Hz,1H),7.96–7.8 9(m,2H),7.82(dd,J=8.9,5.1Hz,2H),7.17(t,J=8.8Hz,2H),6.90(d,J=8.9Hz,1H),3.68–3.64(m,4H),3.50–3.45(m,4H). 13 CNMR(126MHz,DMSO-d6)δ159.85,159.35,158.03,157.94,155.34,150.76,146.76,142.35,136.63,135.98,1 24.80,124.71,124.19,123.97,123.55,115.61,115.44,113.99,107.43,66.41,45.46.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 20 FN 5 O:402.1725.found,402.1729.

[0138] Embodiment 24

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

[0140] Select (6-(4-methylpiperazine-1-yl)pyridin-3-yl)boric acid as the raw material, and other implementation methods are the same as Example 10. The prepared compound is a white solid.

[0141] 1 H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.69(d,J=2.2Hz,1H),8.58–8.45(m,2H),8.09(dd,J=8.9,2.4Hz,1H),8.03–7.93(m,2H),7. 58(d,J=7.6Hz,1H),7.31(ddd,J=28.7,7.8,3.9Hz,3H),6.96(d,J=9.0Hz,1H),3.68–3.54(m,4H),2.44–2.36(m,4H),2.23(s,3H). 13CNMR(126MHz,DMSO-d6)δ167.42,159.20,158.95,156.42,155.56,150.79,146.79,142.54,136.54,131.96,129. 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] + Calculate for C 24 H 24 FN 6 :415.2041.found,415.2047.

[0142] Embodiment 25

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

[0144] Select (6-(piperazine-1-yl)pyridin-3-yl)boric acid as the raw material, and other implementation methods are the same as Example 10. The prepared compound is a white solid.

[0145] 1 H NMR(500MHz,DMSO-d6)δ10.03(s,1H),8.73(d,J=2.1Hz,1H),8.61(d,J=8.6Hz ,1H),8.48(s,1H),8.17(dd,J=8.9,2.2Hz,1H),8.05–7.96(m,2H),7.57(t,J= 7.7Hz,1H),7.33(dd,J=12.7,4.9Hz,2H),7.27(dd,J=10.5,5.9Hz,1H),7.07( d,J=8.9Hz,1H),3.87–3.83(m,4H),3.17–3.13(m,4H),1.95(d,J=38.0Hz,1H). 13 C NMR(126MHz,DMSO-d6)δ158.98,158.49,156.48,155.62,150.73,146.74,142.23,136.95,129.03,127.85,1 26.80,124.87,124.75,124.61,124.51,123.60,116.42,113.87,107.95,42.96,42.44.HRMS(ESI):m / z[M+H] + Calculate for C 23 H22 FN 6 :401.1884.found,401.1888.

[0146] Embodiment 26

[0147] Synthesis of N-(2-fluorophenyl)-7-(6-(piperidin-1-yl)pyridin-3-yl)quinazolin-4-amine (Compound 26):

[0148] 2-(Piperidinyl)pyridine-5-boronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0149] 1 H NMR(500MHz,DMSO-d6)δ9.83(s,1H),8.68(d,J=1.9Hz,1H),8.51(d,J=8.7Hz,1H) ,8.49(s,1H),8.06(dd,J=8.9,2.2Hz,1H),7.99(s,1H),7.97(d,J=8.7Hz,1H),7. 58(t,J=7.8Hz,1H),7.35(d,J=4.3Hz,1H),7.33(s,1H),7.30–7.25(m,1H),6.95( d,J=9.0Hz,1H),3.64–3.60(m,4H),1.64(d,J=4.7Hz,2H),1.57(d,J=4.1Hz,4H). 13 C NMR (126MHz, DMSO-d6) δ159.07,158.95,155.55,150.81,146.89,142.67,136.47,128.99,127.83,126.80,124. 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] + Calculate for C 24 H 23 FN 5 :400.1932.found,400.1922.

[0150] Embodiment 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)pyridine-3-boronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0153] 1 H NMR (500MHz, DMSO-d6) δ9.82(s,1H),8.66(s,1H),8.51(s,1H),8.48(s,1H),8.05(dd,J=8.8,2.2Hz,1H),7.97(d,J=2.9Hz,1H),7.95(s, 1H),7.59(t,J=7.7Hz,1H),7.35(d,J=4.2Hz,1H),7.33(s,1H),7.30–7.26(m,1H),6.57(d,J=8.8Hz,1H),3.46(s,4H),2.09–1.89(m,4H). 13 C NMR(126MHz,DMSO-d6)δ158.61,158.07,156.90,156.11,155.21,150.50,146.88,142.69,135.62,128.66,127.4 9,126.49,124.54,124.21,123.90,122.51,121.48,116.12,113.11,106.67,46.64,25.15.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 21 FN 5 :386.1776.found,386.1784.

[0154] Embodiment 28

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

[0156] 6-(4-morpholinyl)pyridine-3-boronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as those in Example 10. The prepared compound was a white solid.

[0157] 1H NMR(500MHz,DMSO-d6)δ9.87(s,1H)paid,8.53(dd,J=20.4,11.7Hz,3H),8.38(s,1H),8.33(d,J=8.4Hz,1H),8.11(t,J=8.5 Hz,1H),7.58(t,J=7.5Hz,1H),7.50–7.43(m,1H),7.34(d,J=7.8Hz,2H),7.31–7.24(m,1H),3.79(d,J=4.3Hz,4H),3.30(s,4H). 13 C NMR(126MHz,DMSO-d6)δ159.00,158.38,156.39,155.49,150.59,146.85,144.99,143.44,137.46,136.71,1 28.92,124.90,124.39,123.97,123.78,122.32,121.61,116.45,114.51,66.31,47.72.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 21 FN 5 O:403.1735.found,403.1730.

[0158] Embodiment 29

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

[0160] 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester was selected as the raw material, and other embodiments were the same as those in Example 10. The prepared compound was a white solid.

[0161] 1 H NMR (500MHz, DMSO-d6) δ9.78(s,1H),8.90(s,2H),8.46(d,J=8.7Hz,1H),8.43(s,1H),8.01(s,1H),7.92(d,J=8.6Hz ,1H),7.50(d,J=7.9Hz,1H),7.26(dd,J=12.4,4.7Hz,2H),7.23–7.17(m,1H),3.78–3.69(m,4H),3.66–3.60(m,4H). 13C NMR(126MHz,DMSO-d6)δ161.35,158.98,156.88,155.65,150.72,139.91,131.96,129.20,127.90,1 26.70,124.87,124.45,124.37,123.44,121.25,116.42,114.00,66.46,44.52.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 21 FN 5 O:403.1735.found,403.1734.

[0162] Embodiment 30

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

[0164] Select 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl)morpholine as the raw material, and other embodiments are the same as those in Example 10. The prepared compound is a white solid.

[0165] 1 H NMR(500MHz,DMSO-d6)δ9.96(s,1H),8.69(s,1H),8.63(s,1H),8.59(d,J=8.8Hz,1H),8.55(s,1H),8.43(d,J=8.6Hz,1H) ,7.61(s,1H),7.58(d,J=7.8Hz,1H),7.39–7.34(m,2H),7.31–7.26(m,1H),3.78(d,J=4.8Hz,4H),3.73(d,J=4.6Hz,4H). 13 C NMR (126MHz, DMSO-d6) δ163.02,160.84,159.04,158.63,158.43,156.46,155.73,150.41,142.01,129.0 1,128.00,126.63,126.43,124.94,123.98,116.50,116.09,100.14,66.36,44.47.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 21 FN 5 O:403.1735.found,403.1732.

[0166] Embodiment 31

[0167] The reaction formula for the synthesis of N-(7-(1H-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) 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) and K 2 CO 3 (1.60 g, 11.58 mmol), stirred at 60 °C for 12 h, the reaction solution was detected by TLC, and after the reaction was complete, NaHCO 3 Adjust the pH value to 7-9, add ethyl acetate and stir thoroughly, extract 2-3 times, wash with saturated NaCl solution, and add anhydrous Na 2 SO 4 The residue was dried, separated and purified by chromatography (PE:EA=4:1), and concentrated to give a 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-pyrazoleboronic acid pinacol ester (0.97 g, 4.97 mmol) were dissolved in 1,4-dioxne (20 mL) and H 2 O (5 mL), K 2 CO 3 (1.05 g, 7.58 mmol) and bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 )(0.27 g, 0.38 mmol), replaced with nitrogen 2-3 times, stirred at 85 ° C, reacted for 12 h under nitrogen protection, cooled to room temperature after the reaction was complete, detected by TLC, the reaction solution was added with ethyl acetate and stirred thoroughly, extracted 2-3 times, washed with saturated NaCl solution, anhydrous Na 2 SO 4 After drying, separation and purification by chromatography column (PE:EA=1:1) and concentration, a yellow oil 10 (N-(7-(1H-pyrazol-4-yl)quinazolin-4-yl)benzo[d]thiazol-5-amine) (0.8 g, 2.33 mmol) was obtained.

[0171] 1 H NMR (500 MHz, DMSO-d 6 )δ13.14–13.03(m,1H),9.88(s,1H),9.35(s,1H),8.69(d,J=1.8Hz,1H),8.56(s,1H),8.51(d,J=8.7Hz,1H),8.4 9–8.40(m,1H),8.18–8.10(m,1H),8.09(d,J=8.7Hz,1H),7.98(d,J=1.3Hz,1H),7.90(s,1H),7.90–7.88(m,1H). 13 C NMR (126 MHz, DMSO-d 6 )δ158.03,157.34,155.23,154.03,150.96,138.40,138.20,137.55,128.77,127.47,1 24.75,124.03,122.58,122.40,121.49,120.64,116.41,113.62.HRMS(ESI):m / z[M+H] + Calculate for C 18 H 13 N 6 S:345.0911.found,345.0917.

[0172] Embodiment 32

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

[0174] 4-Pyridineboronic acid pinacol ester was selected as the raw material, and the other implementation methods were the same as Example 31. The prepared compound was a white solid.

[0175] 1 H NMR (500 MHz, DMSO-d 6 )δ10.06(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=8.7Hz,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-d 6)δ158.20,157.45,155.65,154.02,150.93,150.61,146.10,141.95,138.17,129.07,1 26.23,125.30,124.70,122.48,122.21,121.52,116.58,115.86.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 14 N 5 S:356.0959.found,356.0964.

[0176] Embodiment 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 selected as the raw material, and the other implementation methods were the same as those in Example 31. The prepared compound was a white solid.

[0179] 1 H NMR (500 MHz, DMSO-d 6 )δ10.06(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=8.7Hz,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-d 6 )δ158.20,157.45,155.65,154.02,150.93,150.61,146.10,141.95,138.17,129.07,1 26.23,125.30,124.70,122.48,122.21,121.52,116.58,115.86.HRMS(ESI):m / z[M+H] + Calculate for C 18 H 13 N 6 S:345.0911.found,345.0917.

[0180] Embodiment 34

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

[0182] 3-Pyridineboronic acid pinacol ester was selected as the raw material, and other implementation methods were the same as Example 31. The prepared compound was a white solid.

[0183] 1 H NMR (500 MHz, DMSO-d 6 )δ10.06(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=8.7Hz,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-d 6 )δ158.20,157.45,155.65,154.02,150.93,150.61,146.10,141.95,138.17,129.07,1 26.23,125.30,124.70,122.48,122.21,121.52,116.58,115.86.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 14 N 5 S:356.0959.found,356.0964.

[0184] Embodiment 35

[0185] Synthesis of N-(7-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl)benzo[d]thiazol-5-amine (Compound 35):

[0186] 1-Methylpyrazole-3-boric acid pinacol ester was selected as the raw material, and the other implementation methods were the same as those in Example 31. The prepared compound was a white solid.

[0187] 1 H NMR (500 MHz, DMSO-d 6)δ9.95(s,1H),9.42(s,1H),8.77(s,1H),8.64(s,1H),8.58(d,J=8.7Hz,1H),8.44(s,1H),8.16(s,1H), 8.15(d,J=2.4Hz,1H),7.99(d,J=1.3Hz,1H),7.96(d,J=1.5Hz,1H),7.92(d,J=8.6Hz,1H),3.92(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ158.01,157.31,155.27,154.03,150.93,138.41,137.82,137.42,129.68,128.76,124. 48,124.12,122.42,122.38,121.45,121.30,116.38,113.67,39.82.HRMS(ESI):m / z[M+H] + Calculate for C 19 H 15 N 6 S:359.1068.found,359.1073

[0188] Embodiment 36

[0189] Synthesis of N-(7-phenylquinazolin-4-yl)benzo[d]thiazol-5-amine (Compound 36):

[0190] Phenylboric acid was selected as the raw material, and other implementation methods were the same as Example 31. The prepared compound was a white solid.

[0191] 1 H NMR (500 MHz, DMSO-d 6 )δ10.07(s,1H),9.43(s,1H),8.80(d,J=1.6Hz,1H),8.72(d,J=8.7Hz,1H),8.70(s,1H),8.17(d,J=8.7Hz,1H),8.08(d,J=1.2H z,1H),8.04(d,J=8.6Hz,1H),8.00(dd,J=8.7,1.6Hz,1H),7.91(d,J=7.5Hz,2H),7.56(t,J=7.6Hz,2H),7.49(d,J=7.4Hz,1H). 13 C NMR (126 MHz, DMSO-d 6)δ158.17,157.37,155.41,154.04,150.70,144.94,139.17,138.33,129.64,129.03,128. 89,127.75,125.71,125.39,124.32,122.43,121.45,116.44,114.77.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 15 N 4 S:355.1006.found,355.1012.

[0192] Embodiment 37

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

[0194] 2-Methoxyphenylboronic acid was selected as the raw material, and other implementation methods were the same as Example 31. The prepared compound was a white solid.

[0195] 1 H NMR (500 MHz, DMSO-d 6 )δ10.04(s,1H),9.43(s,1H),8.81(d,J=1.6Hz,1H),8.69(s,1H),8.64(d,J=8.7Hz,1H),8.17(d,J=8.7Hz,1H),8.00(dd,J=8.7,1.7Hz,1 H),7.90(d,J=1.2Hz,1H),7.81(dd,J=8.6,1.4Hz,1H),7.51–7.48(m,1H),7.45(s,1H),7.20(d,J=8.3Hz,1H),7.12(s,1H),3.84(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ158.13,157.36,156.74,155.15,154.05,150.16,143.38,138.41,131.11,130.35,128.88,128.83, 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] + Calculate for C 22 H 17 N 4OS:385.1112.found,385.1118.

[0196] Embodiment 38

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

[0198] Select 4-methoxyphenylboronic acid as the raw material, and other implementation methods are the same as Example 31. The prepared compound is a white solid.

[0199] 1 H NMR (500 MHz, DMSO-d 6 )δ10.03(s,1H),9.43(s,1H),8.80(d,J=1.8Hz,1H),8.67(d,J=9.4Hz,2H),8.17(d,J=8.7Hz,1H),8 .02(s,1H),8.00(dd,J=8.7,1.5Hz,2H),7.87(d,J=8.5Hz,2H),7.11(d,J=8.6Hz,2H),3.85(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.25,158.12,157.34,155.33,154.04,150.78,144.55,138.39,131.34,128.95,128.81, 125.34,124.39,124.18,122.40,121.42,116.38,115.06,114.25,55.75.HRMS(ESI):m / z[M+H] + Calculate for C 22 H 17 N 4 OS:385.1112.found,385.1118.

[0200] Embodiment 39

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

[0202] 2-Fluorophenylboric acid was selected as the raw material, and other implementation methods were the same as Example 31. The prepared compound was a white solid.

[0203] 1 H NMR (500 MHz, DMSO-d 6)δ10.11(s,1H),9.44(s,1H),8.80(d,J=1.5Hz,1H),8.73(s,1H),8.72(s,1H),8.18(d,J=8.7Hz,1H),8.02–7 .99(m,1H),7.98(s,1H),7.88(d,J=8.6Hz,1H),7.75(s,1H),7.53(s,1H),7.42(d,J=10.1Hz,1H),7.40(s,1H) 13 C NMR (126 MHz, DMSO-d 6 )δ159.71,158.17,157.39,155.48,154.03,150.27,140.08,138.26,131.56,131.09,128.98,128. 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] + Calculate for C 21 H 14 FN 4 S:373.0912.found,373.0918.

[0204] Embodiment 40

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

[0206] 3-Fluorophenylboric acid was selected as the raw material, and other implementation methods were the same as Example 31. The prepared compound was a white solid.

[0207] 1 H NMR (500 MHz, DMSO-d 6 )δ10.08(s,1H),9.43(s,1H),8.80(d,J=1.6Hz,1H),8.73(d,J=8.9Hz,1H),8.71(s,1H),8.17(d,J=8.7Hz,1H),8.13(s ,1H),8.06(d,J=8.5Hz,1H),8.00(dd,J=8.7,1.6Hz,1H),7.80(s,1H),7.77(s,1H),7.60(d,J=6.5Hz,1H),7.31(s,1H). 13 C NMR (126 MHz, DMSO-d 6)δ163.25,158.15,157.38,155.49,154.03,150.64,143.44,141.57,138.28,131.56,128.94,125. 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] + Calculate for C 21 H 14 FN 4 S:373.0912.found,373.0918.

[0208] Embodiment 41

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

[0210] 4-Fluorophenylboric acid was selected as the raw material, and other implementation methods were the same as Example 31. The prepared compound was a white solid.

[0211] 1 H NMR (500 MHz, DMSO-d 6 )δ10.06(s,1H),9.43(s,1H),8.80(d,J=1.7Hz,1H),8.72(s,1H),8.70(s,1H),8.17(d,J=8.7Hz,1H),8.06( d,J=1.4Hz,1H),8.01(t,J=9.3Hz,2H),7.98(d,J=6.2Hz,1H),7.96(d,J=5.5Hz,1H),7.38(t,J=8.8Hz,2H). 13 C NMR (126 MHz, DMSO-d 6 )δ163.00,158.15,157.37,155.45,154.03,150.68,143.83,138.31,135.62,135.60,129. 90,128.90,125.47,124.34,122.42,121.44,116.54,116.41,114.71.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 14 FN 4 S:373.0912.found,373.0918.

[0212] Embodiment 42

[0213] Synthesis of N-(7-(4-(piperazin-1-yl)phenyl)quinazolin-4-yl)benzothiazol-5-amine (Compound 42):

[0214] Select (4-(piperazine-1-yl)phenyl)boric acid as the raw material, and other implementation methods are the same as Example 31. The prepared compound is a white solid.

[0215] 1 H NMR (500 MHz, DMSO-d 6 )δ10.05(s,1H),9.42(s,1H),8.80(s,1H),8.66(t,J=4.0Hz,2H),8.16(d,J=8.7Hz,1H),7.99(s,2H ),7.97(s,1H),7.80(d,J=8.7Hz,2H),7.09(d,J=8.7Hz,2H),3.40(s,1H),3.27(s,4H),3.01(s,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ158.10,157.33,155.27,154.04,151.66,150.85,144.68,138.45,128.95,128.74,128.31,125 .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] + Calculate for C 25 H 23 N 6 S:439.1694.found,439.1699.

[0216] Embodiment 43

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

[0218] Select (4-(4-methylpiperazine-1-yl)phenyl)boric acid as the raw material, and other implementation methods are the same as Example 31. The prepared compound is a white solid.

[0219] 1 H NMR (500 MHz, DMSO-d 6)δ10.04(s,1H),9.42(s,1H),8.92(s,1H),8.79(s,1H),8.66(s,1H),8.16(d,J=8.7Hz,1H),7.99(d,J=8.2Hz,2H),7. 81(s,1H),7.13(d,J=8.5Hz,2H),6.81(d,J=8.7Hz,1H),6.67(d,J=8.7Hz,1H),3.12(s,4H),2.88(s,4H),2.59(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ158.11,157.36,155.29,154.04,151.91,150.84,144.64,138.42,128.38,125.07,124.18,123.74,12 2.41,121.44,118.62,116.37,116.14,116.00,114.05,53.81,48.64,46.83.HRMS(ESI):m / z[M+H]+calcd for C 26 H 25 N 6 S:453.185.found,453.1856.

[0220] Embodiment 44

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

[0222] (4-Morpholinophenyl)boronic acid was selected as the raw material, and other implementation methods were the same as Example 31. The prepared compound was a white solid.

[0223] 1 H NMR (500 MHz, DMSO-d 6 )δ10.23–10.09(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=8.7Hz,2H),7.10(d,J=8.7Hz,2H),3.79–3.76(m,4H),3.24–3.21(m,4H). 13 C NMR (126 MHz, DMSO-d 6)δ158.29,157.46,154.91,154.01,151.81,145.02,129.12,128.87,128.34,128.25,127.25,127 .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] + Calculate for C 25 H 22 N 5 OS:440.1534.found,440.154.

[0224] Embodiment 45

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

[0226] Select (6-(piperazine-1-yl)pyridin-3-yl)boric acid as the raw material, and other implementation methods are the same as Example 31. The prepared compound is a white solid.

[0227] 1 H NMR (600 MHz, DMSO-d 6 )δ10.05(s,2H),9.38(d,J=4.7Hz,1H),8.74(s,1H),8.66(s,1H),8.64–8.62(m,1H),8.62(d,J=4.1Hz,1H) ,8.13(dd,J=8.4,4.8Hz,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-d 6 )δ159.53,157.31,155.69,155.34,154.04,152.39,150.84,146.81,138.55,124.63,1 24.33,122.38,121.54,120.21,118.95,116.41,116.08,107.27.HRMS(ESI):m / z[M+H] + Calculate for C 25 H 23 N 6 S:439.1637.found,439.1640.

[0228] Embodiment 46

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

[0230] Select (6-(4-methylpiperazine-1-yl)pyridin-3-yl)boric acid as the raw material, and other implementation methods are the same as Example 31. The prepared compound is a white solid.

[0231] 1 H NMR (500 MHz, DMSO-d 6 )δ10.00(s,1H),9.42(s,1H),8.79(d,J=1.8Hz,1H),8.70(d,J=2.4Hz,1H),8.67(s,1H),8.64(s,1H),8.16(d,J=8.7Hz,1H) ,8.10(dd,J=8.9,2.5Hz,1H),8.04–7.97(m,3H),6.97(d,J=9.0Hz,1H),3.62–3.56(m,4H),2.44–2.39(m,4H),2.23(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.20,158.08,157.34,155.31,154.03,150.84,146.82,142.49,138.39,136.57,128.79,124.69,124 .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] + Calculate for C 25 H 24 N 7 S:454.1803.found,454.1808.

[0232] Embodiment 47

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

[0234] Select (6-morpholinopyridine-3-yl)boric acid as the raw material, and other implementation methods are the same as Example 31. The prepared compound is a white solid.

[0235] 1 H NMR (500 MHz, DMSO-d 6)δ10.02(s,1H),9.42(s,1H),8.79(s,1H),8.73(d,J=2.2Hz,1H),8.71–8.63(m,2H),8.19–8.11(m,2H),8.04(s ,1H),8.02(d,J=8.8Hz,1H),7.99(d,J=8.6Hz,1H),6.98(d,J=8.9Hz,1H),3.76–3.71(m,4H),3.58–3.54(m,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.37,158.10,157.32,155.31,154.04,150.79,146.80,142.43,138.38,136.64,128.82,124.74, 124.27,123.95,123.57,122.40,121.43,116.39,114.16,107.44,66.42,45.48.HRMS(ESI):m / z[M+H] + Calculate for C 24 H 21 N 6 OS:441.1492.found,441.1487.

[0236] Embodiment 48

[0237] Synthesis of N-(1H-indol-5-yl)-7-(6-morpholinylpyridin-3-yl)quinazolin-4-amine (Compound 48):

[0238] The reaction formula is as follows:

[0239]

[0240] Intermediate H2 (7-bromo-4-chloroquinazoline) (1.4 g, 5.79 mmol) and 1H-indole-5-amine (0.99 g, 7.52 mmol) were dissolved in IPA (40 mL) and K 2 CO 3 (1.60 g, 11.58 mmol), stirred at 60 °C for 12 h, the reaction solution was detected by TLC, and after the reaction was complete, NaHCO 3 Adjust the pH value to 7-9, add ethyl acetate and stir thoroughly, extract 2-3 times, wash with saturated NaCl solution, and add anhydrous Na 2 SO 4After drying, separation and purification by chromatography column (PE:EA=4:1) and concentration, a white solid H7 (7-bromo-N-(1H-indol-5-yl)quinazolin-4-amine) (1.29 g, 3.79 mmol) was obtained.

[0241] H7 (7-bromo-N-(1H-indol-5-yl)quinazolin-4-amine) (1.29 g, 3.79 mmol) and 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (1.49 g, 4.97 mmol) were dissolved in 1,4-dioxne (20 mL) and H 2 O (5 mL), add K 2 CO 3 (1.05 g, 7.58 mmol) and bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 )(0.27 g, 0.38 mmol), replaced with nitrogen 2-3 times, stirred at 85 ° C, reacted for 12 h under nitrogen protection, cooled to room temperature after the reaction was complete, detected by TLC, the reaction solution was added with ethyl acetate and stirred thoroughly, extracted 2-3 times, washed with saturated NaCl solution, anhydrous Na 2 SO 4 After drying, separation and purification by chromatography column (PE:EA=1:1) and concentration, a yellow oily substance 48 (N-(1H-indol-5-yl)-7-(6-morpholinopyridin-3-yl)quinazolin-4-amine) (0.9 g, 2.13 mmol) was obtained.

[0242] 1 H NMR (500 MHz, DMSO-d 6 )δ11.10(s,1H),9.77(s,1H),8.71(d,J=2.3Hz,1H),8.61(d,J=8.7Hz,1H),8.51(s,1H),8.11(dd,J=8.9,2.2Hz,1H),8.0 1–7.88(m,3H),7.38(dd,J=16.1,13.5Hz,3H),6.97(d,J=8.9Hz,1H),6.47(s,1H),3.79–3.69(m,4H),3.61–3.52(m,4H). 13 CNMR (126MHz, DMSO-d 6)δ159.31,158.57,155.78,150.68,146.68,142.02,136.60,133.82,131.07,127.97,126.43,124.30,124 .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] + Calculate for C 25 H 23 N 6 O:423.1928.found,423.1928.

[0243] Embodiment 49

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

[0245] Select 2-chloroaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0246] 1 H NMR (500 MHz, DMSO-d 6 )δ9.81(s,1H),8.64(d,J=2.3Hz,1H),8.45(d,J=8.7Hz,1H),8.38(s,1H),8.05(dd,J=8.9,2.4Hz,1H),7.91(dd,J=15.1,6.5Hz,2 H),7.53(d,J=8.0Hz,2H),7.38(d,J=6.8Hz,1H),7.31–7.26(m,1H),6.91(d,J=8.9Hz,1H),3.71–3.62(m,4H),3.55–3.46(m,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.35,159.19,155.59,150.77,146.77,142.49,136.66,136.41,131.56,130.35,130.22,128 .34,128.14,124.78,124.24,124.07,123.53,113.65,107.46,66.42,45.48.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 21 C1N 5O:418.1424.found,418.1429.

[0247] Embodiment 50

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

[0249] 3-Chloroaniline was selected as the raw material, and other implementation methods were the same as Example 48. The prepared compound was a white solid.

[0250] 1 H NMR (500 MHz, DMSO-d 6 )δ9.88(s,1H),8.71(d,J=1.8Hz,1H),8.67(s,1H),8.60(d,J=8.7Hz,1H),8.16(s,1H),8.14–8.09(m,1H),8.04–7.96(m,2H),7 .89(d,J=8.1Hz,1H),7.42(t,J=8.1Hz,1H),7.17(d,J=7.8Hz,1H),6.96(d,J=8.9Hz,1H),3.86–3.68(m,4H),3.64–3.49(m,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.35,157.80,155.13,150.82,146.80,142.51,141.38,136.62,133.23,130.55,124.83,124.19,1 23.85,123.57,123.48,121.70,120.64,114.06,107.40,66.41,45.45.HRMS(ESI):HRMS(ESI):m / z[M+H] + calcdfor C 23 H 21 C1N 5 O:418.1424.found,418.1429.

[0251] Embodiment 51

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

[0253] Select 4-chloroaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0254] 1H NMR (500 MHz, DMSO-d 6 )δ9.89(s,1H),8.72(d,J=1.9Hz,1H),8.66–8.58(m,2H),8.14(dd,J=8.9,2.2Hz,1H),8.05–7.99(m,2H), 7.97(d,J=8.8Hz,2H),7.46(d,J=8.8Hz,2H),6.99(d,J=8.9Hz,1H),3.81–3.68(m,4H),3.63–3.50(m,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.38,157.87,155.22,150.82,146.81,142.47,138.77,136.67,128.83,124.79,124 .24,124.09,123.91,123.69,123.57,114.08,107.46,66.42,45.47.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 21 C1N 5 O:418.1424.found,418.1429.

[0255] Embodiment 52

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

[0257] Select 2-methylaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0258] 1 H NMR (500 MHz, DMSO-d 6 )δ9.62(s,1H),8.63(d,J=2.4Hz,1H),8.45(d,J=8.7Hz,1H),8.34(s,1H),8.04(dd,J=8.9,2.5Hz,1H),7.91(d,J=1.4Hz,1H),7.87(d d,J=8.7,1.6Hz,1H),7.32–7.24(m,2H),7.23–7.13(m,2H),6.91(d,J=8.9Hz,1H),3.69–3.64(m,4H),3.51–3.45(m,4H),2.14(s,3H). 13 C NMR (126 MHz, DMSO-d 6)δ159.33,159.18,155.82,150.70,146.71,142.27,137.61,136.64,135.46,130.92,128.28,126.88 ,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] + calcdfor C 24 H 24 N 5 O:398.197.found,398.1975.

[0259] Embodiment 53

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

[0261] 3-Methylaniline was selected as the raw material, and other implementation methods were the same as Example 48. The prepared compound was a white solid.

[0262] 1 H NMR (500 MHz, DMSO-d 6 )δ9.74(s,1H),8.71(d,J=2.1Hz,1H),8.61(d,J=6.7Hz,2H),8.11(dd,J=8.8,2.0Hz,1H),8.07–7.90(m,2H),7.71( d,J=10.5Hz,2H),7.29(t,J=7.7Hz,1H),6.97(d,J=8.4Hz,2H),3.81–3.69(m,4H),3.62–3.53(m,4H),2.36(s,3H). 13 CNMR (126MHz, DMSO-d 6 )δ159.33,158.07,155.42,150.76,146.74,142.28,139.60,138.09,136.61,128.78,124.88,124.59 ,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] + Calculate for C 24 H 24 N 5 O:398.197.found,398.1975.

[0263] Embodiment 54

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

[0265] Select 4-methylaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0266] 1 H NMR (500 MHz, DMSO-d 6 )δ9.74(s,1H),8.71(d,J=2.2Hz,1H),8.62–8.54(m,2H),8.11(dd,J=8.9,2.4Hz,1H),8.02–7.90(m,2H),7.75(d ,J=8.3Hz,2H),7.21(d,J=8.2Hz,2H),6.97(d,J=8.9Hz,1H),3.77–3.71(m,4H),3.61–3.49(m,4H),2.32(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.34,158.07,155.46,150.76,146.74,142.22,137.10,136.62,133.20,129.36,124.52,12 4.23,124.03,123.54,122.93,114.10,107.43,66.42,45.47,21.03.HRMS(ESI):m / z[M+H]+calcd for C 24 H 24 N 5 O:398.197.found,398.1975.

[0267] Embodiment 55

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

[0269] Select 2-methoxyaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0270] 1 H NMR (500 MHz, DMSO-d 6)δ9.38(s,1H),8.69(d,J=2.3Hz,1H),8.49(d,J=8.7Hz,1H),8.45(s,1H),8.11(dd,J=8.9,2.5Hz,1H),7.98(d,J=1.3Hz,1H),7.97–7.91(m, 1H),7.65(d,J=6.8Hz,1H),7.29–7.24(m,1H),7.14(d,J=8.1Hz,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-d 6 )δ159.34,159.01,155.71,153.92,150.68,146.72,142.22,136.65,127.69,127.61,127.07,124.53 ,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] + Calculate for C 24 H 24 N 5 O 2 :414.1919.found,414.1925.

[0271] Embodiment 56

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

[0273] Select 3-methoxyaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0274] 1 H NMR (500 MHz, DMSO-d 6)δ9.74(s,1H),8.71(d,J=1.5Hz,1H),8.68–8.59(m,2H),8.12(d,J=8.8Hz,1H),8.06–7.95(m,2H),7.61(s,1H),7.55(d,J=8.1Hz,1 H),7.31(t,J=8.1Hz,1H),6.97(d,J=8.8Hz,1H),6.73(dd,J=8.0,1.7Hz,1H),3.80(s,3H),3.77–3.68(m,4H),3.56(d,J=4.3Hz,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.85,159.34,157.98,155.32,150.80,146.77,142.33,140.95,136.62,129.65,124.64,124.22 ,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] + calcdfor C 24 H 24 N 5 O 2 :414.1919.found,414.1925.

[0275] Embodiment 57

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

[0277] Select 4-methoxyaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0278] 1 H NMR (500 MHz, DMSO-d 6 )δ9.72(s,1H),8.70(d,J=2.1Hz,1H),8.62–8.46(m,2H),8.11(dd,J=8.9,2.4Hz,1H),7.99–7.87(m,2H) ,7.73(d,J=8.9Hz,2H),6.98(dd,J=8.3,6.3Hz,3H),3.78(s,3H),3.75–3.69(m,4H),3.60–3.50(m,4H). 13 C NMR (126 MHz, DMSO-d 6)δ159.33,158.15,156.29,155.55,150.70,146.72,142.16,136.61,132.50,124.77,124.44 ,124.17,124.07,123.52,114.14,114.04,107.43,66.42,55.70,45.47.HRMS(ESI):m / z[M+H] + Calculate for C 24 H 24 N 5 O 2 :414.1919.found,414.1925.

[0279] Embodiment 58

[0280] Synthesis of N-(3-fluorophenyl)-7-(6-morpholinylpyridin-3-yl)quinazolin-4-amine (Compound 58):

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

[0282] 1 H NMR (500 MHz, DMSO-d 6 )δ9.76(s,1H),8.64(d,J=2.2Hz,1H),8.50(d,J=6.9Hz,2H),8.05(dd,J=8.9,1.8Hz,1H),7.96–7.89(m,2H),7 .82(dd,J=8.9,5.1Hz,2H),7.17(t,J=8.8Hz,2H),6.90(d,J=8.9Hz,1H),3.70–3.63(m,4H),3.50–3.45(m,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.35,158.05,157.93,155.32,150.76,146.76,142.35,136.63,135.98,124.81,124.74,124 .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] + Calculate for C 23 H 20 FN 5 O:402.1725;.found,402.1719.

[0283] Embodiment 59

[0284] Synthesis of N-(4-fluorophenyl)-7-(6-morpholinylpyridin-3-yl)quinazolin-4-amine (Compound 59):

[0285] Select 4-fluoroaniline as raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0286] 1 H NMR (500 MHz, DMSO-d 6 )δ9.85(s,1H),8.71(d,J=1.4Hz,1H),8.58(d,J=8.0Hz,2H),8.12(dd,J=8.9,2.1Hz,1H),8.03–7.96(m,2H),7 .89(dd,J=8.3,5.1Hz,2H),7.25(t,J=8.8Hz,2H),6.98(d,J=8.9Hz,1H),3.77–3.70(m,4H),3.58–3.52(m,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.88,159.35,158.05,157.97,155.33,150.70,146.77,142.38,136.61,135.98,124 .82,124.51,123.97,123.51,115.51,114.00,107.42,66.42,45.48.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 21 FN 5 O:402.1725;.found,402.1719.

[0287] Embodiment 60

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

[0289] Select 2,6-difluoroaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0290] 1 H NMR (500 MHz, DMSO-d 6)δ9.83(s,1H),8.72(s,1H),8.53(d,J=8.5Hz,1H),8.49(s,1H),8.13(d,J=7.9Hz,1H),8.07–7.97(m, 2H),7.45(s,1H),7.26(t,J=7.8Hz,2H),6.99(d,J=8.9Hz,1H),3.76–3.71(m,4H),3.59–3.54(m,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.05,159.38,159.21,158.09,155.56,150.73,146.81,142.70,136.67,128.76,125.02,124.33 ,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 F 2 N 5 O:420.1625; found,420.1639.

[0291] Embodiment 61

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

[0293] Select 2,3-difluoroaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0294] 1 H NMR (500 MHz, DMSO-d 6 )δ9.99(s,1H),8.71(d,J=2.3Hz,1H),8.53(s,1H),8.51(d,J=8.7Hz,1H),8.15–8.11(m,1H),8.04(s,1H),8.01(d,J=8.7Hz,1H),7 .40(t,J=7.2Hz,1H),7.38–7.33(m,1H),7.28(dd,J=14.7,7.1Hz,1H),6.99(d,J=8.9Hz,1H),3.75–3.72(m,4H),3.58–3.55(m,4H). 13 C NMR (126 MHz, DMSO-d 6)δ159.38,158.70,155.46,150.83,146.80,142.65,136.66,128.96,124.95,124.34, 123.96,123.86,123.52,114.81,113.70,107.46,66.42,45.50.HRMS(ESI):m / z[M+H] + Calculate for C 23 H 20 F 2 N 5 O:420.1625.found,420.1634

[0295] Embodiment 62

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

[0297] Select 2,4-difluoroaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0298] 1 H NMR (500 MHz, DMSO-d 6 )δ9.83(s,1H),8.71(d,J=2.2Hz,1H),8.49(d,J=9.1Hz,2H),8.12(dd,J=8.9,2.3Hz,1H),8.03–7.96(m,2H),7.60(dd, J=15.1,8.7Hz,1H),7.45–7.35(m,1H),7.21–7.14(m,1H),6.98(d,J=8.9Hz,1H),3.79–3.68(m,4H),3.64–3.48(m,4H). 13 CNMR (126MHz, DMSO-d 6 )δ159.36,159.06,155.56,150.72,146.77,142.51,136.65,130.20,124.81,124.25,123.99,123 .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] + Calculate for C 23 H 20 F 2 N 5 O:420.1625.found,420.163.

[0299] Embodiment 63

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

[0301] Select 2,5-difluoroaniline as the raw material, and other implementation methods are the same as Example 48. The prepared compound is a white solid.

[0302] 1 H NMR (500 MHz, DMSO-d 6 )δ9.87(s,1H),8.76(d,J=1.7Hz,1H),8.60–8.46(m,2H),8.17(dd,J=8.8,2.0Hz,1H),8.11–8.02(m,2H) ,7.53–7.41(m,1H),7.30(t,J=8.1Hz,2H),7.02(d,J=8.9Hz,1H),3.78–3.74(m,4H),3.62–3.57(m,4H). 13 C NMR (126 MHz, DMSO-d 6 )δ170.81,160.03,159.37,159.20,158.10,155.57,150.74,146.82,142.69,136.67,128.78,125 .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] + Calculate for C 23 H 20 F 2 N 5 O:420.1625.found,420.163.

[0303] Embodiment 64

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

[0305] 3,4-Difluoroaniline was selected as the raw material, and other implementation methods were the same as Example 48. The prepared compound was a white solid.

[0306] 1 H NMR (500 MHz, DMSO-d 6)δ9.93(s,1H),8.71(s,1H),8.61(d,J=28.3Hz,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). 13 CNMR (126MHz, DMSO-d 6 )δ159.36,157.80,155.16,150.78,146.79,142.44,137.31,136.64,124.73,124.22,123.92,123 .51,118.77,117.56,117.42,114.22,111.56,111.39,107.44,66.42,45.46HRMS(ESI):m / z[M+H] + Calculate for C 23 H 20 F 2 N 5 O:420.1625.found,420.163.

[0307] Embodiment 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 formula is as follows:

[0310]

[0311] Intermediate H2 (7-bromo-4-chloroquinazoline) (1.4 g, 5.79 mmol) and 2-fluoro-4-(trifluoromethyl)aniline (1.35 g, 7.52 mmol) were dissolved in IPA (40 mL) and K 2 CO 3 (1.60 g, 11.58 mmol), stirred at 60 °C for 12 h, the reaction solution was detected by TLC, and after the reaction was complete, NaHCO 3 Adjust the pH value to 7-9, add ethyl acetate and stir thoroughly, extract 2-3 times, wash with saturated NaCl solution, and add anhydrous Na 2 SO 4 After drying, separation and purification by chromatography column (PE:EA=4:1) and concentration, a white solid H8 (7-bromo-N-(2-fluoro-4-(trifluoromethyl)phenyl)quinazolin-4-amine) (1.45 g, 3.79 mmol) was obtained.

[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-dioxne (20 mL) and H 2 O (5 mL), K 2 CO 3 (1.05 g, 7.58 mmol) and bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 )(0.27 g, 0.38 mmol), replaced with nitrogen 2-3 times, stirred at 85 ° C, reacted for 12 h under nitrogen protection, cooled to room temperature after the reaction was complete, detected by TLC, the reaction solution was added with ethyl acetate and stirred thoroughly, extracted 2-3 times, washed with saturated NaCl solution, anhydrous Na 2 SO 4 After drying, separation and purification by chromatography column (PE:EA=1:1) and concentration, a yellow oily substance 65N-(2-fluoro-4-(trifluoromethyl)phenyl)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4-amine (0.9 g, 1.86 mmol) was obtained.

[0313] 1 H NMR (500 MHz, DMSO-d 6 )δ10.12–9.98(m,1H),8.69(s,1H),8.55(s,1H),8.51(d,J=7.5Hz,1H),8.09(d,J=7.9Hz,1H),8.02(s,2H),7.89(s,1H) ,7.80(d,J=9.4Hz,1H),7.66(d,J=7.5Hz,1H),6.98(d,J=9.0Hz,1H),3.62–3.58(m,4H),2.44–2.40(m,4H),2.23(s,3H). 13 CNMR (126MHz, DMSO-d 6 )δ159.24,158.42,157.87,155.30,154.20,146.84,142.84,136.58,128.68,127.83,125.00,124.48 ,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]+ Calculate for C 25 H 23 F 4 N 6 :483.1852.found,483.1860.

[0314] Embodiment 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 selected as the raw material, and other implementation methods were the same as Example 65. The prepared compound was a white solid.

[0317] 1 H NMR (500 MHz, DMSO-d 6 )δ10.14–9.86(m,1H),8.69(d,J=2.3Hz,1H),8.48(d,J=8.4Hz,2H),8.09(dd,J=8.9,2.3Hz,1H),8.02(s,2H),7.99 (s,1H),7.74–7.68(m,1H),7.59(s,1H),6.98(d,J=9.0Hz,1H),3.61–3.58(m,4H),2.44–2.40(m,4H),2.23(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.15,159.23,158.52,158.12,155.27,146.83,142.79,136.57,128.10,125.95,125.57,124.96,124 .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] + Calculate for C 25 H 23 F 4 N 6 :483.1915.found,483.1923.

[0318] Embodiment 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] Select 4-fluoro-3-(trifluoromethyl)aniline as the raw material, and other implementation methods are the same as Example 65. The prepared compound is a white solid.

[0321] 1 H NMR (500 MHz, DMSO-d 6 )δ10.26(s,1H),8.73(d,J=8.8Hz,1H),8.68(d,J=2.1Hz,1H),8.64(s,1H),8.44(d,J=5.9Hz,1H),8.39–8.34(m,1H),8.08(dd,J=8.9,2.1H z,1H),8.00(s,1H),7.98(d,J=8.8Hz,1H),7.54(t,J=9.8Hz,1H),6.96(d,J=9.0Hz,1H),3.60–3.57(m,4H),2.44–2.40(m,4H),2.23(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ172.71,159.18,157.83,154.89,155.01,150.81,146.82,142.62,136.55,128.44,125.78,124.50,124 .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] + Calculate for C 25 H 23 F 4 N 6 :483.1915.found,483.1918.

[0322] Embodiment 68

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

[0324] Select 2,4-difluoroaniline as the raw material, and other implementation methods are the same as Example 65. The prepared compound is a white solid.

[0325] 1 H NMR (500 MHz, DMSO-d 6)δ9.86(s,1H),8.69(d,J=2.2Hz,1H),8.51(d,J=8.7Hz,1H),8.48(s,1H),8.09(dd,J=8.9,2.2Hz,1H),8.01(s,1H),7.98(d,J=8.7Hz,1H),7.6 0(dd,J=15.1,8.8Hz,1H),7.42–7.36(m,1H),7.17(t,J=8.4Hz,1H),6.97(d,J=9.0Hz,1H),3.61–3.57(m,4H),2.43–2.39(m,4H),2.23(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ160.07,159.20,159.05,158.10,155.54,150.74,146.80,142.58,136.57,130.17,124.74,124.29 ,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] + Calculate for C 24 H 23 F 2 N 6 :433.1947found,433.1946.

[0326] Embodiment 69

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

[0328] Select 2,5-difluoroaniline as the raw material, and other implementation methods are the same as Example 65. The prepared compound is a white solid.

[0329] 1 H NMR (500 MHz, DMSO-d 6)δ10.03(s,1H),8.69(s,1H),8.58(d,J=8.5Hz,1H),8.54(s,1H),8.09(d,J=7.8Hz,1H),8.02(s,1H),7.98(d,J=8.5Hz,1H),7.57 (s,1H),7.38(dd,J=14.2,9.3Hz,1H),7.17(d,J=7.9Hz,1H),6.97(d,J=9.0Hz,1H),3.59(s,4H),2.44–2.40(m,4H),2.23(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.19,158.62,158.14,155.40,153.46,150.84,146.82,142.66,136.58,128.14,124.82,124.50 ,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] + Calculate for C 24 H 23 F 2 N 6 :433.1947.found,433.1947.

[0330] Embodiment 70

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

[0332] Select 2,6-difluoroaniline as the raw material, and other implementation methods are the same as Example 65. The prepared compound is a white solid.

[0333] 1 H NMR (500 MHz, DMSO-d 6 )δ9.85(s,1H),8.73(s,1H),8.56(d,J=8.6Hz,1H),8.53(s,1H),8.12(s,1H),8.07(s,1H),8.04(d,J=8.6Hz,1H),7 .55–7.40(m,1H),7.29(t,J=8.0Hz,2H),6.99(d,J=9.0Hz,1H),3.65–3.59(m,4H),2.46–2.41(m,4H),2.25(s,3H). 13CNMR (126MHz, DMSO-d 6 )δ160.08,159.21,158.10,155.56,150.77,146.85,142.77,136.59,128.76,124.97,124.25 ,123.42,116.04,113.47,112.60,112.42,107.43,54.82,46.28,44.94.HRMS(ESI):m / z[M+H] + Calculate for C 24 H 23 F 2 N 6 :433.1947,found,433.1942.

[0334] Embodiment 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 selected as the raw material, and other implementation methods were the same as Example 65. The prepared compound was a white solid.

[0337] 1 H NMR (500 MHz, DMSO-d 6 )δ9.91(s,1H),8.69(d,J=2.5Hz,1H),8.64(d,J=4.7Hz,1H),8.59–8.54( m,1H),8.18–8.12(m,1H),8.09(dd,J=8.8,2.6Hz,1H),8.01(d,J=2.2Hz,1 H),7.99(d,J=1.8Hz,1H),7.68(d,J=4.3Hz,1H),7.46(d,J=10.3Hz,1H), 6.97(d,J=8.9Hz,1H),3.61–3.58(m,4H),2.45–2.41(m,4H),2.23(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ163.61,159.24,157.81,155.11,154.22,150.81,146.84,142.66,136.62,136.58,124.82,124.12 ,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]+ Calculate for C 24 H 23 F 2 N 6 :433.1947,found,433.1949.

[0338] Embodiment 72

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

[0340] Select 2-fluoro-6-methylaniline as the raw material, and other implementation methods are the same as Example 65. The prepared compound is a white solid.

[0341] 1 H NMR (500 MHz, DMSO-d 6 )δ9.75(s,1H),8.61(s,1H),8.60(s,1H),8.34(s,1H),8.02(d,J=8.6Hz,1H),7.92(s,1H),7.88(d,J=8.4Hz,1H),7.22(d,J=5.9 Hz,1H),7.11(d,J=6.3Hz,1H),7.08(d,J=8.8Hz,1H),6.91(d,J=8.9Hz,1H),3.54(s,4H),2.40(s,4H),2.19(s,3H),2.18(s,3H). 13 C NMR (126 MHz, DMSO-d 6 )δ159.86,159.38,159.12,157.90,155.80,150.68,146.76,142.47,139.08,136.61,128.20,126.32,12 5.62,124.61,123.68,123.37,113.83,113.62,107.51,54.45,45.95,44.72,18.15.HRMS(ESI):m / z[M+H] + calcdfor C 25 H 25 FN 6 :429.2197.found,429.2198.

[0342] The properties of the compounds prepared in Examples 1 to 72 were tested as follows:

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

[0344] The experiment used mouse fibroblast L929 cells. After L929 cells were pre-incubated with the test compound 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. Cell viability was observed under a microscope to evaluate the anti-necrosis effect of the compound. "+++" indicates a strong inhibitory effect, "++" indicates a strong inhibitory effect, "+" indicates a relatively strong inhibitory effect, and "+ / -" indicates a weak inhibitory effect.

[0345] Table 1 Inhibition degree of programmed cell necrosis by compounds of Examples 1 to 72

[0346]

[0347]

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

[0349] The therapeutic effect of Example 23 on dextran sodium sulfate (DSS)-induced ulcerative colitis in mice was studied. Based on the RIPK3 inhibitory activity, physicochemical properties, and in vitro anti-inflammatory activity of Example 23, the in vivo pharmacodynamic administration concentrations of 5 mg / kg, 10 mg / kg, and 20 mg / kg were determined. Figure 1 and Figure 2 As shown in Figure 2, compared with the normal group (NC), the colon length of the mice in the DSS group was significantly shortened. However, Example 23 was able to restore the colon length of the mice in a dose-dependent manner. Figure 3 As shown in the figure, the weight of mice in the normal group (NC) gradually increased within 7 days. The weight of mice in other groups decreased, and the weight loss of mice in the DSS group was the most obvious. Example 23 was able to restore the weight loss of mice in a dose-dependent manner. After the experiment, the mice were killed, and the colon tissue sections of the mice were stained with H&E (hematoxylin-eosin) for histological observation ( Figure 4 ). From the staining results, it can be seen that compared with the normal control group (NC), the colon tissue of the mice in the DSS-treated group showed significant pathological changes such as inflammation and tissue necrosis. These changes include the destruction of epithelial cells, the infiltration of a large number of inflammatory cells, and the loss of colonic crypts, which are all typical pathological characteristics of colitis. After treatment with Example 23, the pathological phenotypes such as inflammation and necrosis of the mouse colon tissue were alleviated in a dose-dependent manner. 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-psoriatic activity of Example 70 in the minai model (IMQ)-induced psoriasis-like skin lesions in mice was investigated. Figure 5 As shown, compared with the normal group (NC), IMQ induced typical symptoms of psoriasis, including erythema, scaling, and thickening of keratin. Example 70 dose-dependently improved IMQ-induced psoriasis-like skin lesions in mice. Figure 6 The thickness of mouse skin was counted. Compared with the normal group (NC), the thickness of the skin of mice in the IMQ-treated group increased. The skin thickening caused by IMQ was reduced in a dose-dependent manner in the Example 70-treated group. H&E (hematoxylin-eosin) staining was performed on the skin tissue sections of the mice for histological observation. Figure 7 As shown, compared with the IMQ-treated group, Example 70 reduced inflammatory cell infiltration, repaired skin tissue damage, and reduced keratinocyte thickness. The above results indicate that Example 70 has a therapeutic effect on psoriasis.

[0352] The above description is only a preferred embodiment of the present invention, which is only illustrative and not restrictive of the present invention. Those skilled in the art understand that many changes, modifications, and even equivalences may be made to the present invention within the spirit and scope defined by the claims of the present invention, but all of them will fall within the scope of protection of the present invention.

Claims

1. A quinazoline compound or a pharmaceutically acceptable salt thereof having anti-inflammatory activity, characterized in that: The general structural formula is shown below: Among them, R 1 Independently selected from 2-methyl, 3-methyl, 4-methyl, 2-fluoro, 3-fluoro or 4-fluoro; X is selected from N or O; R 2 Selected from H, methyl or piperidin-4-yl.

2. A quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that: Select any one of the following compounds:

3. A quinazoline compound or a pharmaceutically acceptable salt thereof having anti-inflammatory activity, characterized in that: The general structural formula is shown below: Among them, Ar 1 Selected from Ar 2 Independently selected from the following aromatic rings or aromatic ring systems:

4. A quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof as claimed in claim 3, characterized in that: Select any one of the following compounds:

5. A quinazoline compound or a pharmaceutically acceptable salt thereof having anti-inflammatory activity, characterized in that: The general structural formula is shown below: Wherein, Ar is independently selected from the following aromatic rings or aromatic ring systems: X is selected from O or NCH3.

6. The quinazoline compound with anti-inflammatory activity or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that: Select any one of the following compounds:

7. A pharmaceutical composition, characterized in that The invention comprises one or more therapeutically effective amounts of the quinazoline compounds with anti-inflammatory activity as claimed in any one of claims 1 to 6 or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

8. Use of a quinazoline compound having anti-inflammatory activity or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6 in the preparation of a medicament for preventing and / or treating an inflammatory disease associated with programmed cell necrosis.

9. Use of a quinazoline compound having anti-inflammatory activity or a pharmaceutically acceptable salt thereof as claimed in claim 8 in the preparation of a medicament for preventing and / or treating an inflammatory disease associated with programmed cell necrosis, characterized in that: The inflammatory diseases include inflammatory bowel disease, psoriasis, neuroinflammation, acute and chronic liver inflammation, joint inflammation, acute kidney injury, acute renal failure, chronic kidney disease, chronic obstructive pulmonary disease, and pathogen pneumonia.

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