A pyrimidine compound containing a nitrogen-containing methoxy benzamide and a preparation method and application thereof

Abstract

The present application relates to the technical field of chemical medicines, in particular to a pyrimidine compound containing nitrogen methoxy benzamide and a preparation method and application thereof.The present application provides a brand-new pyrimidine compound containing nitrogen methoxy benzamide, which is a brand-new compound newly synthesized.The pyrimidine compound containing nitrogen methoxy benzamide is novel in structure, has good water solubility, has a strong inhibitory effect on tumor cells, and has a good application prospect in the preparation of antitumor drugs.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, specifically to a pyrimidine compound containing nitrogen-containing methoxybenzamide, its preparation method, and its application. Background Technology

[0002] Lung cancer can be pathologically classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for approximately 80%–90% of all lung cancers. Currently, lung cancer treatment primarily involves comprehensive therapy, mainly surgery. However, unfortunately, about 80% of lung cancer patients are diagnosed at an advanced stage, losing the opportunity for surgery and only able to rely on medical treatment. Despite medical treatments such as chemotherapy and radiotherapy, the prognosis for patients with advanced NSCLC remains poor, with a 5-year survival rate of only 15%. In recent years, the advantages of small molecule targeted drugs, such as their targeting and safety, have gradually attracted attention, leading to continuous research in this field and providing new treatment options for patients with advanced NSCLC, which is beneficial for personalized treatment. Various targeted kinase inhibitors have appeared on the market, such as gefitinib, crizotinib, and erlotinib. However, after prolonged use, these small molecule drugs all develop drug resistance issues.

[0003] Therefore, it is necessary to continuously develop small molecule inhibitors that can overcome drug resistance, which is of great significance for the treatment of NSCLC. Summary of the Invention

[0004] In order to solve the above-mentioned technical problems in the prior art, the present invention provides a pyrimidine compound containing nitrogen methoxybenzamide, its preparation method and application.

[0005] A pyrimidine compound containing nitrogen-containing methoxybenzamide has the following structural formula (Ⅰ):

[0006]

[0007] Furthermore, R1 is any one of CF3, Br, and Cl.

[0008] Furthermore, R2 can be any of the following structures:

[0009]

[0010] That is, the specific structure of the nitrogen-containing methoxybenzamide pyrimidine compound is as follows:

[0011]

[0012]

[0013]

[0014] The method for preparing the nitrogen-containing methoxybenzamide pyrimidine compound includes the following steps:

[0015] 2,4-Dichloro-5-substituted pyrimidine was subjected to a nucleophilic substitution reaction with 2-amino-N-methoxybenzamide to obtain a compound with the structure shown in formula (II). The compound with the structure shown in formula (II) was then subjected to a nucleophilic substitution reaction with a compound with the structure shown in formula (III) under an acidic environment to obtain a pyrimidine compound containing nitrogen-containing methoxybenzamide.

[0016]

[0017]

[0018] Furthermore, R1 is any one of CF3, Br, and Cl.

[0019] Furthermore, R2 can be any of the following structures:

[0020]

[0021] The specific steps are as follows:

[0022] Nucleophilic addition of indomethacin anhydride to O-methoxyamine hydrochloride yields 2-amino-N-methoxybenzamide. Nucleophilic substitution of 2,4-dichloro-5-substituted pyrimidine with 2-amino-N-methoxybenzamide yields a compound with the structure shown in formula (II). Substituting the compound with the structure shown in formula (III) under acidic conditions yields a pyrimidine derivative containing nitrogen-containing methoxybenzamide.

[0023] In this reaction, indorubicin anhydride and O-methoxyamine hydrochloride undergo a nucleophilic addition reaction. The solvent is selected from DCM, methanol, or water, preferably water. The reaction temperature is 0–25°C, preferably 25°C. The reaction time is 2–6 h, preferably 4 h. The molar ratio of indorubicin anhydride, O-methoxyamine hydrochloride, and NaOH is 1:(1–4):(1–3), preferably 1:3:3. After the reaction is complete, 2-amino-N-methoxybenzoyl is preferably obtained by slurrying with DCM.

[0024] The nucleophilic substitution reaction of 2,4-dichloro-5-substituted pyrimidine with 2-amino-N-methoxybenzoyl is preferably carried out under nitrogen and / or inert gas protection in a solvent environment. The solvent is selected from DMF, acetonitrile, methanol, or ethanol, preferably DMF. The reaction system for the nucleophilic substitution reaction also includes a base selected from sodium hydride, sodium carbonate, potassium carbonate, or potassium bicarbonate, preferably sodium hydride. The temperature of the nucleophilic substitution reaction is 0–25°C, preferably 25°C. The reaction time is 2–6 h, preferably 4 h. The molar ratio of 2,4-dichloro-5-substituted pyrimidine to 2-amino-N-methylbenzamide and sodium hydride is 2:(1–2):(1–5), preferably 2:1:5. After the nucleophilic substitution reaction, the compound with the structure shown in formula (II) is preferably obtained by silica gel column chromatography.

[0025] In the substitution reaction between the compound of formula (II) and the compound of formula (III) under acidic conditions, the substitution reaction is carried out in an organic solvent under the protection of nitrogen and / or an inert gas. The organic solvent is selected from DMF, trifluoroethanol, THF, or n-butanol, preferably THF. The reaction system of the substitution reaction also includes an acid, selected from HCl, HOAc, or trifluoroacetic acid, preferably trifluoroacetic acid. The temperature of the substitution reaction is 60℃ to 100℃, preferably 80℃. The time of the nucleophilic substitution reaction is 6h to 24h, preferably 10h. The molar ratio of the compound of formula (II), the compound of formula (III), and trifluoroacetic acid is 1:(1-2):(1-4), preferably 1:1.2:3. After the substitution reaction, the pyrimidine derivative containing nitrogen-containing methoxybenzamide is preferably obtained by silica gel column chromatography.

[0026] The detailed synthesis process diagram is as follows:

[0027]

[0028] R1 and R2 are as described above.

[0029] The pyrimidine compounds containing nitrogen-containing methoxybenzamide of this invention have novel structures, good water solubility, and strong inhibitory effects on tumor cells. They have great application prospects in the preparation of anti-tumor drugs, especially in the treatment of lung cancer.

[0030] Compared with the prior art, the technical effects of this invention are reflected in:

[0031] This invention provides a novel pyrimidine compound containing nitrogen-containing methoxybenzamide, the structural formula of which is shown in Formula (I). This compound is a newly synthesized novel compound. This nitrogen-containing methoxybenzamide pyrimidine compound has a novel structure, good water solubility, and strong inhibitory effect on tumor cells, showing great promise for application in the preparation of antitumor drugs. Detailed Implementation

[0032] The technical solution of the present invention will be further defined below with reference to specific embodiments, but the scope of protection is not limited to the description made.

[0033] Example 1: Synthesis of 2-amino-N-methoxybenzoyl

[0034]

[0035] NaOH (620 mg, 15.5 mmol) was dissolved in 8.1 mL of water to obtain a 2 mol / L NaOH solution. O-methoxyamine hydrochloride (1336.62 mg, 16 mmol) was dissolved in 4 mL of water to prepare a 25% solution. At 5 °C, the 2 mol / L NaOH solution was added dropwise to the O-methoxyamine hydrochloride solution. Indomethacin anhydride (815.65 mg, 5 mmol) was added to the above mixed solution in batches. The resulting suspension was stirred at 5 °C for 30 min, then heated to room temperature and reacted for 3 h. After the reaction was completed, the product was filtered through a vacuum funnel, the filter cake was dried, and the solid was slurried with DCM to obtain 0.54 g of product, a white solid with a melting point of 97.4-98.3 °C and a yield of 65%.

[0036] The NMR data for compound 1 are as follows:

[0037] 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),7.27(d,J=7.6Hz,1H),7.25–7.19(m,1H),6.68(d,J=8.0Hz,1H),6.65–6.59(m,1H),5.45(s,2H),3.86(s,3H); 13 CNMR (100MHz, CDCl3) δ168.7,148.9,133.0,127.1,117.3,116.6,112.8,64.6; ESI-HRMS C8H 10 N₂O₂([M+H)) + ):calcd 189.0625, found 189.0634.

[0038] Example 2 Synthesis of 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methoxybenzamide 2a

[0039]

[0040] A mixture of 2,4-dichloro-5-trifluoromethylpyrimidine (1645 mg, 7.61 mmol) and compound 1 (783.29 mg, 3.61 mmol) was stirred in DMF (10 mL) at room temperature. Then, sodium hydride (866 mg, 36.1 mmol) was added at 0 °C, and the reaction proceeded overnight under argon protection for nucleophilic substitution. After the reaction was complete as monitored by TLC, H₂O (30 mL) was added, and the reaction mixture was extracted with EtOAc (3 × 30 mL). The organic phase was dried over MgSO₄, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give the corresponding product 2a (272 mg), a pale white solid with a melting point of 191.8–192.7 °C, in 20% yield.

[0041] The NMR data for compound 2a are as follows:

[0042] 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),11.12(s,1H),8.69(s,1H),8.24(d,J=8.4Hz,1H),7.62(t,J=7.8Hz,2H),7.28(t,J=7.6Hz,1H),3.70(s,3H); 13 CNMR(100MHz,DMSO-d6)δ165.8,162.7,157.4,137.6,132.4,128.5,124.9,123.9,122.2,107.7,107.3,63.7; ESI-HRMS C 13 H 10 ClF3N4O2([M+H) + ):calcd 369.0335, found 369.0337.

[0043] Example 3 Synthesis of 2-((5-bromo-2-chloropyrimidin-4-yl)amino)-N-methoxybenzamide 2b

[0044]

[0045] A mixture of 2,4-dichloro-5-bromopyrimidine (1645 mg, 7.22 mmol) and compound 1 (822.5 mg, 3.61 mmol) was stirred in DMF (10 mL) at room temperature. Then, sodium hydride (866 mg, 36.1 mmol) was added at 0 °C, and the reaction proceeded overnight under argon protection for nucleophilic substitution. After the reaction was complete as monitored by TLC, H₂O (30 mL) was added, and the reaction mixture was extracted with EtOAc (3 × 30 mL). The organic phase was dried over MgSO₄, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give the corresponding product 2b (380 mg), a yellow solid with a melting point of 175.2–176.1 °C, in 15% yield.

[0046] The NMR data for compound 2b are as follows:

[0047] 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),11.19(s,1H),8.57(s,1H),8.40(d,J= 8.4Hz,1H),7.63(dd,J=12.0,7.6Hz,2H),7.24(t,J=7.6Hz,1H),3.73(s,3H); 13 C NMR (100MHz, DMSO-d6) δ166.0,158.9,157.9,138.4,132.6,128.4,124.1,122.3,120.8,105.3,63.9; ESI-HRMS C 12 H 10 BrClN4O2([M+H] + ):calcd378.9562, found 378.9568.

[0048] Example 4: Synthesis of 2-((2,5-dichloropyrimidin-4-yl)amino)-N-methoxybenzamide 2c

[0049]

[0050] A mixture of 2,4,5-trichloropyrimidine (664.7 mg, 4 mmol) and compound 1 (366.84 mg, 2 mmol) was stirred in DMF (10 mL) at room temperature. Then, sodium hydride (600 mg, 25 mmol) was added at 0 °C, and the mixture was allowed to react overnight under argon protection for nucleophilic substitution. After the reaction was complete as monitored by TLC, H₂O (30 mL) was added, and the reaction mixture was extracted with EtOAc (3 × 30 mL). The organic phase was dried over MgSO₄, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to give the corresponding product 2c (350 mg), a yellow solid with a melting point of 200.1–200.5 °C, in 55% yield.

[0051] The NMR data for compound 2c are as follows:

[0052] 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),11.36(s,1H),8.49(s,1H),8.41(d,J=8.4Hz,1H),7.76–7.57(m,2H),7.26–7.17(m,1H),3.73(s,3H); 13 C NMR (100MHz, CDCl3) δ167.8,157.6,156.6,155.0,139.1,133.4,126.7,123.3,122.0,118.3,115.5,65.0; ESI-HRMS C 12 H 10 Cl2N4O2([M+H) + ):calcd 335.0067,found335.0073.

[0053] Example 5 Synthesis of N-methoxy-2-((2-((4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide 3a

[0054]

[0055] Compound 2a (250 mg, 0.72 mmol), 4-(4-morpholino)aniline (161 mg, 0.86 mmol), DMF (5 mL), and trifluoroacetic acid (246 mg, 2.16 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product 3a, a yellow solid (107 mg), with a melting point of 198.7–199.3 °C and a yield of 35%.

[0056] The NMR data for compound 3a are as follows:

[0057] 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),10.61(s,1H),9.65(s,1H),8.40(s,1H),7.58(d,J=7.6Hz,1H),7.47( s,4H),7.17(t,J=7.6Hz,1H),6.87(d,J=8.4Hz,2H),3.81–3.73(m,4H),3.72(s,3H),3.06(t,J=4.8Hz,4H); 13 C NMR(100MHz,DMSO-d6)δ170.8,167.5,166.3,161.4,156.4,147.7,145.6,132.1,1 31.8,128.1,126.6,123.9,123.2,122.6,115.8,111.2,66.6,63.8,49.5;ESI-HRMS C 23 H 23 F3N6O3([M+H) + ):calcd 489.1851,found489.1856.

[0058] Example 6 Synthesis of 2-((2-((3,4-dimethoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methoxybenzamide 3b

[0059]

[0060] Compound 2a (250 mg, 0.72 mmol), 3,4-dimethoxyaniline (132 mg, 0.86 mmol), DMF (5 mL), and trifluoroacetic acid (246 mg, 2.16 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 3b, a yellow solid (117 mg), with a melting point of 196.1–197.6 °C and a yield of 35%.

[0061] The NMR data for compound 3b are as follows:

[0062] 1H NMR (400MHz, DMSO-d6) δ11.99(s,1H),10.68(s,1H),9.65(s,1H),8.42(s,1H),7.58(d,J=7.6Hz,1 13C NMR(100MHz,DMSO-d6)δ168.4,164.8,162.2,156.5,153.6,149.0,145.2,142.9,1 42.2,137.9,132.3,128.4,122.8,119.4,115.8,112.4,63.8,56.3,55.8;ESI-HRMS C 21 H 20 F3N5O4([M+H) + ):calcd464.1536, found 464.1540.

[0063] Example 7 Synthesis of N-methoxy-2-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)

[0064] -5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide 3c

[0065]

[0066] Compound 2a (250 mg, 0.72 mmol), 4-(4-methylpiperazin-1-yl)aniline (165 mg, 0.86 mmol), DMF (5 mL), and trifluoroacetic acid (246 mg, 2.16 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 3c, a yellow solid (137 mg), with a melting point of 131.5-132.1 °C and a yield of 38%.

[0067] The NMR data for compound 3c are as follows:

[0068] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),10.61(s,1H),9.63(s,1H),8.39(d,J=3.2Hz,1H),7.58(d,J=8.0Hz,1H),7.51–7.34(m,3H),7 .22–7.10(m,1H),6.86(d,J=8.4Hz,2H),3.71(d,J=3.2Hz,3H),3.08(d,J=5.6Hz,4H),2.46(d,J=5.6Hz,5H),2.22(d,J=3.6Hz,3H); . 13 C NMR (100MHz, DMSO-d6) δ166.1,160.7,156.4,147.7,144.7,138.7,135.3,132.1,131. 1,130.0,128.1,126.7,123.2,122.7,120.0,116.0,63.7,55.1,49.1,46.2;ESI-HRMS C 24 H 26 F3N7O2([M+H) + ):calcd502.2164, found 502.2172.

[0069] Example 8 Synthesis of N-methoxy-2-((5-(trifluoromethyl)-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)benzamide 3d

[0070]

[0071] Compound 2a (250 mg, 0.72 mmol), 3,4,5-trimethoxyaniline (158 mg, 0.86 mmol), DMF (5 mL), and trifluoroacetic acid (246 mg, 2.16 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product 3d, a yellow solid (93 mg), with a melting point of 176.4–176.9 °C and a yield of 26%.

[0072] The NMR data for compound 3d are as follows:

[0073] 1H NMR (400MHz, DMSO-d6) δ12.03(s,1H),10.75(s,1H),9.71(s,1H),8.47(s,2H),7.59(d,J=7 .6Hz,1H),7.40(s,2H),7.16(t,J=7.6Hz,1H),7.09–6.88(m,2H),3.72(s,3H),3.63(s,9H); 13 C NMR (100MHz, DMSO-d6) δ170.9,166.3,164.6,159.9,156.4,153.1,148.7,139. 1,137.6,137.4,134.8,128.2,123.1.120.3,99.5,63.8,60.6,56.2;ESI-HRMSC 22 H 22 F3N5O5([M+H) + ):calcd 494.1643,found494.1645.

[0074] Example 9 Synthesis of 2-((2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methoxybenzamide 3e

[0075]

[0076] Compound 2a (250 mg, 0.72 mmol), 2-(4-(4-aminophenyl)piperazin-1-yl)ethane-1-ol (191 mg, 0.86 mmol), DMF (5 mL), and trifluoroacetic acid (246 mg, 2.16 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 3e, a white solid (250 mg), melting point: 175.2-176.1 °C, yield 65.2%.

[0077] The NMR data for compound 3e are as follows:

[0078] 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),10.70(s,1H),9.71(s,1H),8.62–8.24(m,2H),7.59(t,J=6.4Hz,1H),7.47(s,1 H),7.15(ddt,J=22.4,14.4,7.2Hz,4H),6.64(t,J=6.8Hz,1H),3.72(d,J=5.6Hz,3H),3.70–3.59(m,4H),2.98(s,4H); 13 C NMR(100MHz,DMSO-d6)δ167.6,161.3,156.5,151.9,140.5,132.2,129.3,128.2,1 26.4,123.5,123.2,121.7,119.9,112.4,110.5,107.8,66.6,63.8,48.9;ESI-HRMS C 25 H 28 F3N7O3([M+H) + ):calcd532.2263, found 532.2278.

[0079] Example 10 Synthesis of N-methoxy-2-((2-((3-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide 3f

[0080]

[0081] Compound 2a (250 mg, 0.72 mmol), 3-morpholinoaniline (161 mg, 0.86 mmol), DMF (5 mL), and trifluoroacetic acid (246 mg, 2.16 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product 3f, a yellow solid (72 mg), with a melting point of 193.1–194.4 °C and a yield of 25.5%.

[0082] The NMR data for compound 3f are as follows:

[0083] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),10.70(s,1H),9.70(s,1H),8.46(s,1H),7.59(d,J=8.0Hz,1H),7.47(t,J=8 .0Hz,1H),7.15(dq,J=22.8,8.0,7.2Hz,4H),6.64(d,J=7.6Hz,1H),3.72(s,3H),3.71–3.64(m,4H),2.99(s,4H); 13 CNMR(100MHz,DMSO-d6)δ169.1,166.3,161.3,156.5,151.9,140.5,139.0,132.2,129.3,1 28.2,126.4,123.7,123.5,123.2,120.5,112.3,110.5,107.8,66.6,63.8,48.9;ESI-HRMS C 23 H 23 F3N6O3([M+H) + ):calcd 489.1850, found 489.1856.

[0084] Example 11 Synthesis of 3g of 2-((2-((3-fluoro-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methoxybenzamide

[0085]

[0086] Compound 2a (250 mg, 0.72 mmol), 3-fluoro-4-morpholinoaniline (168.8 mg, 0.86 mmol), DMF (5 mL), and trifluoroacetic acid (246 mg, 2.16 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give 3 g of the corresponding product, a yellow solid (72 mg), with a melting point of 205.4–206.9 °C and a yield of 24%.

[0087] The NMR data for 3g of compound are as follows:

[0088] 1H NMR (400MHz, DMSO-d6) δ11.99(s,1H),10.58(s,1H),10.04–9.68(m,1H),8.46(s,2H),7.75–7.56(m,2H),7.52(t,J=8.0Hz ,1H),7.26(s,1H),7.21(t,J=7.6Hz,1H),6.95(t,J=9.2Hz,1H),3.74(d,J=4.8Hz,3H),3.72(s,4H),2.94(t,J=4.4Hz,4H); 13 C NMR(100MHz,DMSO-d6)δ166.2,161.1,156.5,156.2,153.8,138.3,135.2,135.1,132.2,12 9.0,128.3,126.4,123.6,120.6,119.3,116.7,109.1,108.9,66.7,63.8,51.3;ESI-HRMSC 23 H 22 F4N6O3([M+H) + ):calcd 507.1760,found 507.1762.

[0089] Example 12 Synthesis of N-methoxy-2-((2-(2-methoxy-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide 3h

[0090]

[0091] Compound 2a (210 mg, 0.60 mmol), 2-methoxy-4-morpholinoaniline (150 mg, 0.72 mmol), DMF (5 mL), and trifluoroacetic acid (205 mg, 1.8 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product as a yellow solid (67 mg) with a melting point of 155.3-156.3 °C and a yield of 21.3%.

[0092] The NMR data for compound 3h are as follows:

[0093] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),10.70(s,1H),8.75(s,1H),8.33(s,1H),7.53(d,J=7.6Hz,1H),7.28(s,2H),7.08(t,J =7.6Hz,1H),6.66(d,J=2.4Hz,1H),6.48(dd,J=8.8,2.5Hz,1H),3.79–3.75(m,7H),3.70(s,3H),3.14(dd,J=4.4,2.4Hz,4H); 13 CNMR(100MHz,DMSO-d6)δ166.4,162.6,161.8,156.4,153.9,148.3,139.3,132.1,128.0,127. 3,123.9,122.0,123.66,119.56,111.4,106.9,100.2,94.5,66.6,63.7,55.9,49.4;ESI-HRMS C 24 H 25 F3N6O4([M+H) + ):calcd 519.1955, found 519.1962.

[0094] Example 13 Synthesis of 2-((5-chloro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 4a

[0095]

[0096] Compound 2c (313.14 mg, 1 mmol), 4-(4-morpholino)aniline (199.42 mg, 1.2 mmol), DMF (8 mL), and trifluoroacetic acid (342 mg, 3 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product, a yellow solid (210 mg), melting point: 224.7-225.6 °C, yield 47%.

[0097] The NMR data for compound 4a are as follows:

[0098] 1H NMR (400MHz, DMSO-d6) δ12.05(s,1H),10.92(s,1H),9.24(s,1H),8.70(d,1H),8.18(d,1H),7.62(d,J=9.6H z,34H),7.49(t,J=8.8Hz,2H),7.14(t,J=7.6Hz,1H),6.89(d,J=9.2Hz,2H),3.74(s,7H),3.12–3.01(m,4H); 13 CNMR(100MHz,DMSO-d6)δ158.5,155.4,155.2,147.0,138.2132.9,132.4,128.2,122.5,121.7,118.2,115.9,105.5,66.6,63.8,49.7; ESI-HRMS C 22 H 23 ClN6O3([M+H) + )calcd 455.1592, found 455.1592.

[0099] Example 14 Synthesis of 2-((5-chloro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 4b

[0100]

[0101] Compound 2c (250 mg, 0.80 mmol), 3,4,5-trimethoxyaniline (176 mg, 0.96 mmol), DMF (5 mL), and trifluoroacetic acid (273 mg, 2.4 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product as a yellow solid (58 mg) with a melting point of 181.2–182.3 °C and a yield of 14.7%.

[0102] The NMR data for compound 4b are as follows:

[0103] 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),11.00(s,1H),9.33(s,1H),8.74(d,J=8.4Hz,1H),8.25(s,1H),7.62( d,J=7.6Hz,1H),7.46(t,J=8.0Hz,1H),7.26–7.08(m,2H),3.75(d,J=7.2Hz,3H),3.67(s,6H),3.63(s,3H); 13 C NMR(100MHz,DMSO-d6)δ166.3,158.2,155.3,153.1,139.7,136.7,133.2,1 32.5,128.3,122.5,121.6,119.2,105.5,98.4,63.85,6.61,56.2;ESI-HRMS C 21 H 22 ClN5O5([M+H) + ):calcd 460.1368,found460.1382.

[0104] Example 15 Synthesis of 2-((5-chloro-2-((3,4-dimethoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 4c

[0105]

[0106] Compound 2c (250 mg, 0.80 mmol), 3,4,5-trimethoxyaniline (147 mg, 0.96 mmol), DMF (5 mL), and trifluoroacetic acid (273 mg, 2.4 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product 4c, a yellow solid (108 mg), with a melting point of 169.9–170.8 °C and a yield of 31.5%.

[0107] The NMR data for compound 4c are as follows:

[0108] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),10.95(s,1H),9.26(d,J=3.6Hz,1H),8.72(d,J=8.4Hz,1H),8.20(d,J=6.4Hz,1H),7.62(d,J=7.6H z,1H),7.47(s,1H),7.24(d,J=2.4Hz,1H),7.21–7.18(m,1H),7.17–7.11(m,1H),6.87(d,J=8.8Hz,1H),3.76–3.71(m,6H),3.66(s,3H); 13 C NMR (100MHz, DMSO-d6) δ158.4,155.2,149.1,144.7,139.7,134.2,132.4,128.3,122. 5,121.9,119.2,113.8,112.6,112.3,106.7,106.2,105.0,63.8,56.4,55.9;ESI-HRMS C 20 H 20 ClN5O4([M+H) + ):calcd 430.1268,found430.1277.

[0109] Example 16 Synthesis of 2-((5-chloro-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 4d

[0110]

[0111] Compound 2c (250 mg, 0.80 mmol), 2-(4-(4-aminophenyl)piperazin-1-yl)ethane-1-ol (212.5 mg, 0.96 mmol), DMF (5 mL), and trifluoroacetic acid (273 mg, 2.4 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 4d, a white solid (42 mg), with a melting point of 141.2–142.3 °C and a yield of 10.5%.

[0112] The NMR data for compound 4d are as follows:

[0113] 1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.97(s,1H),9.21(s,1H),8.71(s,1H), 8.17(s,1H),7.62(dd,J=7.6,1.6Hz,1H),7.47(dd,J=15.6,8.2Hz,3H),7.13(t, J=7.6Hz,1H),6.90–6.84(m,2H),4.42(t,J=5.2Hz,1H),3.73(s,3H),3.54(q,J= 5.6Hz,2H),3.07(t,J=4.8Hz,4H),2.56(t,J=5.2Hz,4H),2.44(t,J=6.3Hz,2H); 13 C NMR(100MHz,DMSO-d6)δ157.9,156.4,155.5,155.2,136.1,134.3,132.4,128.3,1 22.8,122.3,119.4,115.8,108.2,108.0,104.9,66.7,63.8,58.5,51.4;ESI-HRMS C 24 H 28 ClN7O3([M+H) + ):calcd498.2006,found498.2015.

[0114] Example 17 Synthesis of 2-((5-chloro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 4e

[0115]

[0116] Compound 2c (250 mg, 0.80 mmol), 4-(4-methylpiperazin-1-yl)aniline (184 mg, 0.96 mmol), DMF (5 mL), and trifluoroacetic acid (273 mg, 2.4 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product 4e, a yellow solid (106 mg), with a melting point of 131.5–132.1 °C and a yield of 28.3%.

[0117] The NMR data for compound 4e are as follows:

[0118] 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),10.91(s,1H),9.22(s,1H),8.88–8.56(m,1H),8.18(s,1H),7.62(dd,J=7.6,1.6Hz,1H),7.50 –7.37(m,3H),7.13(t,J=7.6Hz,1H),6.87(d,J=8.8Hz,2H),3.74(s,3H),3.07(t,J=4.8Hz,4H),2.46(t,J=4.8Hz,5H),2.22(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.9,156.4,155.5,155.2,136.1,134.3,132.4,128.3,1 22.8,122.3,119.4,115.8,108.2,108.0,104.9,66.7,63.8,58.5,51.4;ESI-HRMSC 23 H 26 ClN7O2([M+H) + ):calcd468.1892, found 468.1909.

[0119] Example 18 Synthesis of 2-((5-chloro-2-((3-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 4f

[0120]

[0121] Compound 2c (250 mg, 0.80 mmol), 3-morpholinoaniline (171 mg, 0.96 mmol), DMF (5 mL), and trifluoroacetic acid (273 mg, 2.4 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product 4f, a yellow solid (68 mg), with a melting point of 161.2–162.0 °C and a yield of 18.7%.

[0122] The NMR data for compound 4f are as follows:

[0123] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),10.97(s,1H),9.33(s,1H),8.73(d,J=8.4Hz,1H),8.24(s,1H),7.63(d,J=7.86Hz, 1H),7.50(t,J=8.0Hz,1H),7.32–6.99(m,4H),6.66–6.43(m,1H),3.75(s,3H),3.73–3.64(m,4H),3.02(t,J=4.9Hz,4H); 13 C NMR (100MHz, DMSO-d6) δ158.2,155.3,155.2,151.9,141.4,132.5,129.3,128. 3,122.5,122.0,119.3,111.5,109.6,107.0,105.4,66.6,63.8,49.0;ESI-HRMS C 22 H 23 ClN6O3([M+H) + ):calcd 455.1591,found455.1593.

[0124] Example 19 Synthesis of 4g of 2-((5-chloro-2-((3-fluoro-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide

[0125]

[0126] Compound 2c (250 mg, 0.80 mmol), 3-fluoro-4-morpholinoaniline (188 mg, 0.96 mmol), DMF (5 mL), and trifluoroacetic acid (273 mg, 2.4 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain 4 g of the corresponding product, a yellow solid (71 mg), with a melting point of 203.8–204.3 °C and a yield of 19.5%.

[0127] The NMR data for compound 4g are as follows:

[0128] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),10.89(s,1H),9.52(s,1H),8.65(d,J=8.4Hz,1H),8.25(s,1H),7.72–7.61(m,2H),7.57–7.49 (m,1H),7.27(dd,J=8.8,2.5Hz,1H),7.17(td,J=7.6,1.2Hz,1H),6.99–6.91(m,1H).3.80–3.65(m,7H),2.95(dd,J=4.4,2.4Hz,3H); 13 C NMR (100MHz, DMSO-d6) δ166.4,157.9,156.4,155.5,155.2,154.0,139.4,136.2,134. 4,132.4,128.3,122.8,122.3,119.5,115.8,108.2,105.5,66.7,63.9,51.4;ESI-HRMS C 22 H 22 ClFN6O3([M+H) + ):calcd 473.1493, found 473.1499.

[0129] Example 20 Synthesis of 2-((5-chloro-2-((2-methoxy-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 4h

[0130]

[0131] Compound 2c (313.14 mg, 1 mmol), 2-methoxy-4-morpholinoaniline (249.91 mg, 1.2 mmol), DMF (5 mL), and trifluoroacetic acid (342.06 mg, 3 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product, a yellow solid (42 mg) with a melting point of 190.1-180.8 °C and a yield of 9.8%.

[0132] The NMR data for compound 4h are as follows:

[0133] 1H NMR (400MHz, DMSO-d6) δ11.97 (s, 1H), 10.92 (s, 1H), 8.56 (d, J = 8.4Hz, 1H), 8.18(s,1H),8.12(s,1H),7.58(d,J=7.6Hz,1H),7.43(d,J=8.8Hz,1H),7.3 6(t,J=8.0Hz,1H),7.08(t,J=7.6Hz,1H),6.66(d,J=2.4Hz,1H),6.49(dd,J =8.7,2.6Hz,1H),3.76(d,J=5.6Hz,7H),3.73(s,3H),3.12(t,J=4.8Hz,4H); 13 C NMR(100MHz,DMSO-d6)δ166.6,159.5,155.3,155.3,153.3,149.7,139.9,132.3,128.1,1 25.9,122.2,121.7,120.7,118.8,106.9,104.4,100.3,66.6,63.8,55.9,49.6;ESI-HRMS C 23 H 25 ClN6O4([M+H) + ):calcd485.1686,found 485.1699.

[0134] Example 21 Synthesis of 2-((5-bromo-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 5a

[0135]

[0136] Compound 2b (750 mg, 2.1 mmol), 4-(4-morpholino)aniline (450 mg, 2.52 mmol), DMF (8 mL), and trifluoroacetic acid (718 mg, 6.3 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (80 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 5a, a yellow solid (132 mg), with a yield of 12%.

[0137] The NMR data for compound 5a are as follows:

[0138] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.68(s,1H),9.23(s,1H),8.68(d,J=34.4Hz,1H), 8.23(s,1H),7.53(d,J=44.4Hz,4H),7.13(s,1H),6.87(s,2H),3.73(s,7H),3.04(s,4H); 13 C NMR (100MHz, DMSO-d6) δ158.9,158.1,156.1,147.0,139.6,132.8,132.3,128. 2,122.6,122.4,121.7,115.9,115.7,66.6,66.6,63.9,55.4,49.7;ESI-HRMSC 22 H 23 BrN6O3([M+H] + ):calcd 499.1080, found 499.1088.

[0139] Example 22 Synthesis of 2-((5-bromo-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 5b

[0140]

[0141] Compound 2b (250 mg, 0.7 mmol), 3,4,5-trimethoxyaniline (154 mg, 0.84 mmol), DMF (7 mL), and trifluoroacetic acid (239 mg, 2.1 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (80 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product 5b, a deep yellow solid (57 mg), with a melting point of 197.4–197.8 °C and a yield of 16.2%.

[0142] The NMR data for compound 5b are as follows:

[0143] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),10.79(s,1H),9.32(s,1H),8.68(d,J=8.4Hz,1H),8.31(s,1H),7. 62–7.58(m,1H),7.45(s,1H),7.14(d,J=1.2Hz,1H),7.01(s,2H),3.74(s,3H),3.65(s,6H),3.63(s,3H).13 C NMR (100MHz, DMSO-d6) δ166.4,158.6,158.0,156.1,153.1,139.7,136.7,133.2,132.3,128.3,122.6,121.9,98.5,94.7,63.9,60.60,56.1.ESI-HRMS C 21 H 22 BrN5O5([M+H] + ):calcd 504.0856, found 504.0877.

[0144] Example 23 Synthesis of 2-((5-bromo-2-((3,4-dimethoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 5c

[0145]

[0146] Compound 2b (250 mg, 0.7 mmol), 3,4-dimethoxyaniline (154 mg, 0.84 mmol), DMF (7 mL), and trifluoroacetic acid (239 mg, 2.1 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (80 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 5c, a deep yellow solid (57 mg), with a melting point of 198.1–199.3 °C and a yield of 16.2%.

[0147] The NMR data for compound 5c are as follows:

[0148] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.74(s,1H),9.26(s,1H),8.75–8.53(m,1H),8.27(s,1H),7.60(d,J=7.6Hz,1H),7.46(t,J =8.0Hz,1H),7.23(s,1H),7.18(d,J=8.4Hz,0H),7.14(d,J=7.6Hz,1H),6.86(d,J=8.8Hz,1H),3.74(d,J=5.6Hz,6H),3.64(s,3H); 13C NMR(100MHz,DMSO-d6)δ166.8,158.8,158.1,156.1,149.1,144.7,139.8,139.3,13 4.1,132.2,128.2,122.5,122.1,119.5,112.6,106.3,63.8,56.4,55.9;ESI-HRMSC 20 H 20 BrN5O4([M+H] + ):calcd 474.0768, found 474.0771.

[0149] Example 24 Synthesis of 2-((5-bromo-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 5d

[0150]

[0151] Compound 2b (250 mg, 0.7 mmol), 4-(4-methylpiperazin-1-yl)aniline (160.7 mg, 0.84 mmol), DMF (7 mL), and trifluoroacetic acid (239 mg, 2.1 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (80 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 5d, an orange-yellow solid (57 mg), with a melting point of 134.1–135.7 °C and a yield of 16%.

[0152] The NMR data for compound 5d are as follows:

[0153] 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),9.22(s,1H),8.73–8.56(m,1H),8.24(s,1H),7.61(d,J=7.6Hz,1H),7.50(d,J=8.0Hz,1H),7.47 (s,1H),7.44(s,1H),7.13(t,J=7.6Hz,1H),6.90–6.84(m,2H),3.74(s,3H),3.08(t,J=4.8Hz,4H),2.48(d,J=4.4Hz,4H),2.24(s,3H); 13C NMR(100MHz,DMSO-d6)δ165.5,162.4,158.9,158.1,156.1,147.0,139.6,136.8,132.5, 132.2,128.2,122.6,122.4,121.8,119.7,116.2,92.2,63.8,55.1,49.2,46.1; ESI-HRMS C 23 H 26 BrN7O2([M+H] + ):calcd 512.1381, found 512.1404.

[0154] Example 25 Synthesis of 2-((5-bromo-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 5e

[0155]

[0156] Compound 2b (250 mg, 0.7 mmol), 2-(4-(4-aminophenyl)piperazin-1-yl)ethane-1-ol (186 mg, 0.84 mmol), DMF (7 mL), and trifluoroacetic acid (239 mg, 2.1 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (80 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 5e, a light yellow solid (90 mg), with a melting point of 136.1–137.0 °C and a yield of 23.7%.

[0157] The NMR data for compound 5e are as follows:

[0158] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),10.68(s,1H),9.22(s,1H),8.65(s,1H),8.24(s,1H),7.60(d,J=7.6Hz,1H),7.46(t,J =10.0Hz,3H),7.13(t,J=7.6Hz,1H),6.86(d,J=8.4Hz,2H),4.47(s,1H),3.74(s,3H),3.55(s,2H),3.08(s,6H),2.59(s,4H); 13C NMR(100MHz,DMSO-d6)δ158.9,158.0,156.1,147.1,144.4,144.0,139.3,136.6,132 .2,128.2,122.6,121.8,119.6,116.2,92.2,63.8,60.7,58.9,53.6,49.3;ESI-HRMS C 24 H 28 BrN7O3([M+H] + ):calcd 542.1496,found542.1510.

[0159] Example 26 Synthesis of 2-((5-bromo-2-((3-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 5f

[0160]

[0161] Compound 2b (250 mg, 0.7 mmol), 3-morpholinylphenylamine (150 mg, 0.84 mmol), DMF (7 mL), and trifluoroacetic acid (239 mg, 2.1 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (80 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to give the corresponding product 5f, a yellowish-brown solid (86 mg), with a melting point of 196.1–197.8 °C and a yield of 24.6%.

[0162] The NMR data for compound 5f are as follows:

[0163] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),10.75(s,1H),9.32(s,1H),8.66(d,J=8.4Hz,1H),8.30(s,1H),7.60(d,J=7.8Hz,1H),7.4 9(s,1H),7.18(d,J=9.6Hz,2H),7.15–7.08(m,1H),6.58(d,J=8.0Hz,1H),3.74(s,3H),3.71–3.66(m,4H),3.00(t,J=4.8Hz,4H); 13C NMR (100MHz, DMSO-d6) δ166.4,158.7,158.1,156.1,151.9,141.3,139.6,132.4,129. 3,128.2,122.6,122.2,119.6,111.6,109.6,107.0,93.5,66.6,63.9,49.0;ESI-HRMSC 22 H 23 BrN6O3([M+H] + ):calcd499.1075,found 499.1088.

[0164] Example 27 Synthesis of 5g of 2-((5-bromo-2-((3-fluoro-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide

[0165]

[0166] Compound 2b (250 mg, 0.7 mmol), 3-fluoro-4-morpholinoaniline (164 mg, 0.84 mmol), DMF (7 mL), and trifluoroacetic acid (239 mg, 2.1 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (80 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain 5 g of the corresponding product, a yellowish-brown solid (108 mg), with a melting point of 211.6–211.9 °C and a yield of 30.8%.

[0167] The NMR data for 5g of compound are as follows:

[0168] 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),10.84–10.60(m,1H),9.56(s,1H),8.59(d,J=8.4Hz,1H),8.31(s,1H),7.77–7.60(m,2H),7.59–7 .42(m,1H),7.29(dd,J=8.8,2.4Hz,1H),7.17(td,J=7.6,1.2Hz,1H),7.03–6.89(m,1H),3.74(q,J=4.8,3.5Hz,7H),3.05–2.80(m,4H); 13C NMR (100MHz, DMSO-d6) δ166.1,158.3,158.0,156.4,156.2,153.9,139.4,136.1,136. 0,134.4,132.3,128.4,122.9,122.5,119.4,115.8,108.3,66.7,63.8,51.4;ESI-HRMS C 22 H 22 BrFN6O3([M+H] + ):calcd 517.0972, found 517.0993.

[0169] Example 28 Synthesis of 2-((5-bromo-2-((2-methoxy-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methoxybenzamide 5h

[0170]

[0171] Compound 2b (250 mg, 0.7 mmol), 2-methoxy-4-morpholinoaniline (175 mg, 0.84 mmol), DMF (7 mL), and trifluoroacetic acid (239 mg, 2.1 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the flask was placed in an oil bath at 80 °C for 10 h to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated NaHCO3 (80 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was separated by silica gel column chromatography to obtain the corresponding product 5 h, a yellow solid (27 mg), with a melting point of 116.8-117.7 °C and a yield of 7.5%.

[0172] The NMR data for compound 5h are as follows:

[0173] 1 H NMR (400MHz, DMSO-d6) δ11.96 (s, 1H), 10.71 (s, 1H), 8.50 (d, J = 8.4Hz, 1H), 8.1 7(d,J=2.0Hz,2H),7.55(dd,J=7.8,1.6Hz,1H),7.41(d,J=8.8Hz,1H),7.34(d, J=8.0Hz,1H),7.08(td,J=7.6,1.2Hz,1H),6.65(d,J=2.4Hz,1H),6.48(dd,J=8 .8,2.8Hz,1H),3.77(d,J=4.2Hz,7H),3.73(s,3H),3.12(dd,J=5.6,4.0Hz,4H); 13C NMR(100MHz,DMSO-d6)δ166.4,159.9,158.1,156.1,153.3,149.7,139.8,132.2,128.1, 126.0,122.3,121.9,120.7,118.4,106.9,100.3,93.5,66.6,63.9,55.9,49.6;ESI-HRMS C 23 H 25 BrN6O4([M+H] + ):calcd 529.1179,found529.1193.

[0174] Example 29: NCI-H1975 tumor cells are a type of human non-small cell lung cancer (NSCLC) cell, specifically a gefitinib-resistant lung cancer cell line with T790M and L858R mutations. The inhibitory effect of the compound on NCI-H1975 tumor cells was evaluated using the MTT assay, as reported in the literature. NCI-H1975 cells were seeded at a density of 5000 cells per well (100 μL per well) in 96-well plates and cultured at 37°C and 5% CO2 for 24 h. Cells were exposed to different concentrations of the drug (50, 5, 0.5, 0.05, 0.005 μM) and cultured at 37°C and 5% CO2 for 72 h. Then, 100 μL of MTT (5 mg / mL) solution was added to each well under dark conditions, and the cells were incubated at 37°C and 5% CO2 for 4 h. The original culture medium was then discarded, and 150 μL of LDMSO was added to each well. The absorbance was read at 490 nm using a microplate reader (Tecan i-control infinite 200Pro, Shanghai). IC50 50 The calculations were performed on GraphPadPrism 8. See Table 1 for the specific results.

[0175] Table 1. Activity test results of pyrimidine derivatives of nitrogen-containing methoxybenzamides prepared in Examples 5-28

[0176]

[0177]

[0178]

[0179]

[0180] As can be seen from Table 1, the pyrimidine compounds containing nitrogen-containing methoxybenzamides of this application have a good inhibitory effect on NCI-H1975 tumor cells.

[0181] Finally, it should be noted that the above embodiments are merely representative examples of the present invention. Obviously, the technical solution of the present invention is not limited to the above embodiments, and many variations are possible. All variations that can be directly derived or conceived by those skilled in the art from the content disclosed in this invention should be considered within the scope of protection of this invention.

Claims

1. A pyrimidine compound containing nitrogen-containing methoxybenzamide, characterized in that, Its specific structural formula is shown in equation (Ⅰ): Equation (I); R1 is any one of CF3, Br, and Cl; R2 can be any of the following structures: 、 、 、 、 、 、 、 。 2. The method for preparing the pyrimidine compound containing nitrogen-containing methoxybenzamide according to claim 1, characterized in that, Includes the following steps: 2,4-Dichloro-5-substituted pyrimidine was subjected to a nucleophilic substitution reaction with 2-amino-N-methoxybenzamide to obtain a compound with the structure shown in formula (II). The compound with the structure shown in formula (II) was then subjected to a nucleophilic substitution reaction with a compound with the structure shown in formula (III) under an acidic environment to obtain a pyrimidine compound containing nitrogen-containing methoxybenzamide. Formula (II); Formula (Ⅲ); R1 is any one of CF3, Br, and Cl; R2 can be any of the following structures: 、 、 、 、 、 、 、 。 3. The use of the nitrogen-containing methoxybenzamide pyrimidine compound of claim 1 in the preparation of drugs for drug-resistant lung cancer.

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