2, 4-diarylaminopyrimidine analogue as well as preparation method and application thereof

Abstract

The invention relates to a series of 2, 4-diarylaminopyrimidine analogues and a preparation method and application thereof, belongs to the technical field of medicines, and relates to a series of 2, 4-diarylaminopyrimidine analogues and preparation and application thereof, the series of 2, 4-diarylaminopyrimidine analogues have a structure as shown in a formula I, and R1-R7 are as shown in the specification. The invention also comprises pharmaceutically acceptable salts of the 2, 4-diarylaminopyrimidine analogue, and a pharmaceutical composition containing the 2, 4-diarylaminopyrimidine analogue or the pharmaceutically acceptable salts of the 2, 4-diarylaminopyrimidine analogue as an active ingredient. The 2, 4-diarylaminopyrimidine analogue or the medicinal salt thereof disclosed by the invention has better anticancer activity, and the preparation method is simple, feasible and easy to operate. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a series of new 2,4-diarylaminopyrimidine analogs and medicines with the compounds as active ingredients, which are used for preparing medicines for treating cancer and inflammatory diseases. Background Art

[0002] Epidermal growth factor receptor (EGFR) is one of the carcinogenic driving factors, which is closely related to the occurrence of lung cancer and is an important drug target for the treatment of lung cancer. EGFR can transmit and regulate signals for normal cell growth. If it is overexpressed, it will lead to uncontrolled cell growth and the appearance of tumors. EGFR inhibitors can block the transmission of its signals and achieve the purpose of inhibiting cell growth. EGFR inhibitors have become a hot topic in the development and research of anti-tumor drugs (Yang Yaqiong, Li Zonghai. Research progress of tumor molecular targeted drugs targeting EGFR [J]. Chinese Journal of Biotechnology, 2012, 32 (5): 91-96.). EGFR inhibitors osimertinib, WZ4002 and CO-1686 all have 2-arylaminopyrimidine structures, occupy the ATP binding pocket in a "U"-shaped conformation, and form a hydrogen bond interaction with residue Met793. Among them, osimertinib is the first FDA-approved drug that interacts with EGFR. T790M The third-generation EGFR inhibitor that irreversibly binds to mutant receptors can be used to produce EGFR after gefitinib treatment. T790M Osimertinib significantly enhanced the inhibitory effect on EGFR double mutants, and had a weaker inhibitory effect on wild-type EGFR. However, after a period of medication, some patients developed a new drug resistance problem, C797S mutation, which weakened the therapeutic effect (Wang Huiyi, Kang Xiaohong. Research progress on the resistance mechanism of osimertinib in the treatment of non-small cell lung cancer patients [J]. China Medical Herald, 2020, 17 (28): 32-35.). In addition, osimertinib interacts with non-targets, leading to the generation of toxic side effects. Therefore, it is urgent to develop new highly selective EGFR inhibitors that can inhibit mutant EGFR receptors. Summary of the invention

[0003] The present invention uses osimertinib, a third-generation EGFR small molecule tyrosine kinase inhibitor, as a lead compound, retains the 2-arylaminopyrimidine mother nucleus, structurally modifies the phenylamino groups at the C4, C5, C6 and C2 positions of pyrimidine, and designs a series of new 2,4-diarylaminopyrimidine compounds. Pharmacological experiments have shown that these compounds can inhibit the proliferation of various tumor cells, and their main effect is anti-tumor.

[0004] The 2,4-diarylaminopyrimidine compound provided by the present invention has the following structure:

[0005]

[0006] Wherein, R1, NR2R3, and NHCOR4 independently represent none or 1-3 substituents on the benzene ring, and the substituent R1 is selected from C1-C6 alkoxy, C1-C6 alkyl, C1-C6 substituted amino, C1-C6 amide, and halogen.

[0007] NR2R3 is a substituted or unsubstituted 5-6 membered heterocyclic group, a C1-C8 alkylamino group, a C3-C7 cycloalkylamino group, or a C1-C8 alkylamino group, wherein the substituent is selected from: C1-C 12 Alkyl, phenyl, C1-C6 alkoxyphenyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 alkyl containing hydroxyl, C1-C8 alkyl substituted with 1-3 nitrogen atoms, C1-C8 alkyl containing phenyl; the heterocyclic group contains 1-3 heteroatoms of N, O or S. R4 represents C1-C 10 Alkyl or C1-C 10 The alkenyl group.

[0008] R5 and R6 independently represent none or 1-2 substituents on the pyrimidine ring, and the substituents are independently selected from C1-C8 alkyl, C1-C8 alkanoyl, C1-C8 alkoxy, hydroxyl, and halogen.

[0009] NHR7 represents no substituent or one substituent on the benzene ring, and R7 is selected from C1-C8 sulfonamide, C1-C8 amide, and C1-C8 alkyl.

[0010] Preferably, R1, NR2R3, and NHCOR4 independently represent none or 1-3 substituents on the benzene ring, and the substituent R1 is selected from C1-C4 alkoxy, C1-C4 alkyl, C1-C4 substituted amino, C1-C4 amide, and halogen.

[0011] NR2R3 is a substituted or unsubstituted 5-6 membered heterocyclic group, C1-C6 alkylamino group, or C3-C7 cycloalkylamino group, wherein the substituent is selected from the group consisting of C1-C9 alkyl group, phenyl group, C1-C4 alkoxyphenyl group, C2-C5 alkenyl group, C2-C6 alkynyl group, C1-C6 alkyl group containing a hydroxyl group, C1-C6 alkyl group containing a phenyl group, and C1-C6 alkyl group substituted with 1-2 nitrogen atoms; the heterocyclic group contains 1-3 heteroatoms of N, O or S. R4 represents a C1-C8 alkyl group or a C1-C8 alkenyl group.

[0012] R5 and R6 independently represent none or 1-2 substituents on the pyrimidine ring, and the substituents are independently selected from C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxy, and halogen.

[0013] NHR7 represents no substituent or one substituent on the benzene ring, and R7 is selected from C1-C6 sulfonamide, C1-C6 amide, and C1-C6 alkyl.

[0014] More preferably, R1, NR2R3, and NHCOR4 independently represent 1 to 3 substituents on the benzene ring, and the substituent R1 is selected from C1-C3 alkoxy, C1-C3 alkyl, C1-C3 substituted amino, C1-C3 amide, and halogen.

[0015] NR2R3 is a substituted or unsubstituted 5-6 membered heterocyclic group, C1-C4 alkylamino group, or C3-C5 cycloalkylamino group, wherein the substituent is selected from the group consisting of C1-C8 alkyl group, phenyl group, C1-C3 alkoxyphenyl group, C2-C4 alkenyl group, C1-C4 alkyl group containing a hydroxyl group, C1-C4 alkyl group containing a phenyl group, and C1-C4 alkyl group substituted with 1-2 nitrogen atoms; the heterocyclic group contains 1-3 heteroatoms of N, O or S. R4 represents a C1-C5 alkyl group or a C1-C5 alkenyl group.

[0016] R5 and R6 independently represent none or 1-2 substituents on the pyrimidine ring, and the substituents are independently selected from C1-C4 alkyl, C1-C4 alkanoyl, C1-C4 alkoxy, and halogen.

[0017] NHR7 represents no substituent or one substituent on the benzene ring, and R7 is selected from C1-C5 sulfonamide, C1-C5 amide, and C1-C5 alkyl.

[0018] Furthermore, the compound of the present invention is any one of the following compounds:

[0019]

[0020]

[0021] The present invention also provides a method for preparing the 2,4-diarylaminopyrimidine analogs A1-D7, which is selected from any one of the following methods:

[0022]

[0023] During the above preparation process:

[0024] The solvent used is a conventional reaction solvent and there is no special requirement.

[0025] The present invention provides a pharmaceutical salt containing the 2,4-diarylaminopyrimidine analog, which is a salt of the 2,4-diarylaminopyrimidine analog and a non-toxic organic acid or inorganic acid. The acid used includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, tartaric acid, salicylic acid, methanesulfonic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and maleic acid.

[0026] The present invention also provides a pharmaceutical composition, which is composed of the 2,4-diarylaminopyrimidine analog or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0027] The present invention also provides the use of the 2,4-diarylaminopyrimidine analog or its pharmaceutically acceptable salt or its composition in the preparation of anti-tumor drugs. The tumor is cervical cancer, liver cancer, fibrosarcoma, colon cancer, melanoma, breast cancer, lung cancer, lymphoma, chronic myeloid leukemia or myeloid leukemia.

[0028] Beneficial effects of the present invention:

[0029] The 2,4-diarylaminopyrimidine analogs of the present invention are used to develop novel highly selective EGFR tyrosine kinase inhibitors capable of inhibiting mutant EGFR receptors. These derivatives have stronger physiological activity and stability.

[0030] The 2,4-diarylaminopyrimidine analogs and pharmaceutically acceptable salts thereof of the present invention have good anticancer activity, and the preparation method thereof is simple, feasible and easy to operate. DETAILED DESCRIPTION

[0031] The feasibility of the present invention is illustrated below by using embodiments. Those skilled in the art should understand that according to the teachings of the prior art, modifications or replacements of corresponding technical features still fall within the scope of protection claimed by the present invention.

[0032] Example 1

[0033] Preparation of tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate

[0034]

[0035] Add 3.00g (16.12mmol) 4-fluoro-2-methoxy-5-nitroaniline, 0.20g (1.61mmol) 4-dimethylaminopyridine and dichloromethane solution (30mL) to a 100mL eggplant-shaped bottle, and add 4.22g (19.34mmol) di-tert-butyl dicarbonate in dichloromethane solution (10mL) dropwise under an ice-water bath. After the addition is complete, react at room temperature for 20h. Evaporate dichloromethane under reduced pressure to obtain 3.74g of yellow powder, with a yield of 81.1%. MS (ESI) m / z: 309.1 [M+Na] + .

[0036] Example 2

[0037] Preparation of tert-butyl [2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]carbamate

[0038]

[0039] Add 3.00g (10.48mmol) (4-fluoro-2-methoxy-5-nitrophenyl) carbamic acid tert-butyl ester, 1.57g (15.72mmol) N-methylpiperazine and N,N-dimethylacetamide solution (20mL) to a 50mL eggplant-shaped bottle, stir magnetically to fully dissolve, then add 2.71g (20.96mmol) N,N-diisopropylethylamine, heat to 85℃ and react for 4h. Add 100mL water, orange solid precipitates, filter and dry to obtain 3.58g orange solid, yield 93.2%. MS (ESI) m / z: 367.2 [M+H] + .

[0040] Example 3

[0041] Preparation of tert-butyl [2-methoxy-4-(4-methylpiperazine-1-yl)-5-aminophenyl]carbamate

[0042]

[0043] Add 2.00g (5.46mmol) tert-butyl [2-methoxy-4-(4-methylpiperazine-1-yl)-5-nitrophenyl]carbamate and anhydrous ethanol (20mL) to a 50mL eggplant-shaped bottle and stir evenly. Add 1.75g ​​(32.76mmol) saturated NH4Cl solution and 2.14g (32.76mmol) zinc powder to the above solution in sequence, heat to 80℃ and react for 2h, pad diatomaceous earth and filter the reaction solution while hot to remove zinc powder, wash the filter cake with anhydrous ethanol (5mL×2), evaporate the filtrate under reduced pressure, add 20mL water to the eggplant-shaped bottle, adjust the pH to 1 with hydrochloric acid, wash the water layer with dichloromethane (10mL×1), and adjust the pH to 8 with 40% sodium hydroxide. The aqueous layer was extracted with ethyl acetate (10 mL × 3), the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was evaporated under reduced pressure to obtain 1.20 g of a yellow solid with a yield of 65.2%. MS (ESI) m / z: 337.2 [M+H] + .

[0044] Example 4

[0045] Preparation of tert-butyl [2-methoxy-4-(4-methylpiperazine-1-yl)-5-acrylamidophenyl]carbamate

[0046]

[0047] Add 2.00g (5.95mmol) tert-butyl [2-methoxy-4-(4-methylpiperazine-1-yl)-5-aminophenyl]carbamate, 1.64g (11.90mmol) potassium carbonate and dry dichloromethane solution (10mL) to a 25mL eggplant-shaped bottle, and cool to 0°C in an ice-water bath. Under nitrogen protection, add 0.56g (6.15mmol) dichloromethane solution (2mL) of acryloyl chloride dropwise, and react at room temperature for 1h. Add saturated sodium bicarbonate aqueous solution, extract the water layer with dichloromethane (10mL×3), combine the organic phases, wash with saturated brine (10mL×2), dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain 2.11g of yellow solid, with a yield of 91.0%. MS (ESI) m / z: 391.1 [M+H] + .

[0048] Example 5

[0049] Preparation of N-[5-amino-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl]acrylamide

[0050]

[0051] Add 1.00g (2.56mmol) of [2-methoxy-4-(4-methylpiperazine-1-yl)-5-acrylamidophenyl]carbamic acid tert-butyl ester and hydrogen chloride-ethanol solution (5mL) to a 25mL eggplant-shaped bottle, and stir at room temperature for 12h. Remove ethanol under reduced pressure, add 20mL of water, adjust the pH to 8 with saturated sodium bicarbonate aqueous solution under stirring, extract the aqueous layer with dichloromethane (10mL×3), wash the organic phase with saturated brine (10mL×2), dry over anhydrous sodium sulfate, remove the desiccant by suction, and concentrate under reduced pressure to obtain 0.61g of yellow solid, with a yield of 82.4%. MS (ESI) m / z: 291.1 [M+H] + .

[0052] Example 6

[0053] N 1 Preparation of -(2-chloropyrimidin-4-yl)phenyl-1,2-diamine

[0054]

[0055] Add 0.50g (4.63mmol) o-phenylenediamine, 0.69g (4.63mmol) 2,4-dichloropyrimidine and isopropanol solution (5mL) to a 25mL eggplant-shaped bottle, and finally add 1.19g (9.26mmol) N,N-diisopropylethylamine. After addition, reflux at 85°C for 2h, solid precipitates, and 0.91g of white solid is obtained by suction filtration, with a yield of 89.2%. MS (ESI) m / z: 220.9 [M+H] + .

[0056] Example 7

[0057] Preparation of N-{2-[(2-chloropyrimidin-4-yl)amino]phenyl}acetamide

[0058]

[0059] 0.37 g (1.68 mmol) N 1 -(2-chloropyrimidin-4-yl)phenyl-1,2-diamine, 0.40g (5.04mmol) pyridine and dry dichloromethane solution (3mL), cooled to 0°C in an ice-water bath. Under nitrogen protection, 0.16g (2.02mmol) acetyl chloride was added dropwise and reacted at room temperature for 2h. Dichloromethane was evaporated under reduced pressure, 20mL water was added to the eggplant-shaped flask, a large amount of white solid precipitated, and 0.40g of white solid was obtained by suction filtration, with a yield of 90.9%. MS (ESI) m / z: 263.0 [M+H] + .

[0060] Example 8

[0061] Synthesis of Compound A1

[0062]

[0063] Add 0.20g (0.69mmol) N-[5-amino-4-methoxy-2-(4-methylpiperazine-1-yl)phenyl]acrylamide, 0.15g (0.58mmol) N-{2-[(2-chloropyrimidin-4-yl)amino]phenyl}acetamide and acetonitrile solution (5mL) to a 25mL eggplant-shaped bottle, and finally add 0.11g (0.58mmol) p-toluenesulfonic acid monohydrate, and heat to 85℃ for 12h. Remove the solvent under reduced pressure, add 20mL water, extract the aqueous phase with dichloromethane (5mL×3), combine the organic phases, wash with saturated brine (10mL×2), dry over anhydrous sodium sulfate, remove the desiccant by suction, and concentrate the filtrate to obtain 0.11g of light yellow solid, with a yield of 36.7%, and a melting point of 108-110℃. MS (ESI) m / z: 517.3 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ9.51(s,1H,NH),8.98(s,1H,NH),8.49(s,1H,NH),8.38(s,1H,NH),7.95(d,J=5.7Hz,1H,Pyrimidinyl-6-H),7.62(d,J =7.9Hz,1H,Ar-H),7.60(s,1H,Ar-H),7.47(d,J=7.8Hz,1H,Ar-H),7.12-7.04(m,2H,Ar-H),6.79(s,1H,Ar-H),6.61(dd,J=17.0,10.2Hz,1H,CO CH =CH2),6.19(dd,J=17.0,2.0Hz,1H,COCH= CH2 ),6.15(d,J=5.7Hz,1H,Pyrimidinyl-5-H),5.72(dd,J=10.2,1.9Hz,1H,COCH= CH2 ),3.80(s,3H,-OCH3),2.84(t,J=4.8Hz,4H,N- CH2 CH2×2),2.65-2.55(m,4H,N-CH2 CH2 ×2),2.29(s,3H,N-CH3),2.02(s,3H,COCH3).

[0064] Example 9

[0065] Prepare the compound according to the method of Example 6-7 White solid, yield 92.0%. MS (ESI) m / z: 296.9 [M+H] + .

[0066] Example 10

[0067] Prepare the compound according to the method of Example 8 Yellow solid, yield 78.1%. MS (ESI) m / z: 446.9 [M+H] + .

[0068] Embodiment 11

[0069] Prepare the compound according to the method of Example 5 Orange solid, yield 90.9%. MS (ESI) m / z: 527.2 [M+H] + .

[0070] Example 12

[0071] Prepare the compound according to the method of Example 3 Yellow solid, yield 62.7%. MS (ESI) m / z: 497.2 [M+H] + .

[0072] Embodiment 13

[0073] Synthesis of compound C1

[0074]

[0075] Compound C1 was prepared by referring to the method of Example 4: light yellow solid, yield 41.2%, melting point 148-149°C. MS (ESI) m / z: 565.3 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ10.07(s,1H,NH),8.77(s,1H,NH),8.47(s,1H,NH),8.22(s,1H,NH),8.13(s,1H,Pyrimidinyl-6-H),7.95(s,1H,Ar -H),7.79(d,J=8.1Hz,1H,Ar-H),7.27(d,J=7.7Hz,1H,Ar-H),7.14-7.06(m,2H,Ar-H),6.83(s,1H,Ar-H),6.79(dd,J=14.9,7.1Hz,1H,COCH= CH ),6.36(d,J=15.2Hz,1H,CO CH =CH),3.82(s,3H,-OCH3),2.91(t,J=4.8Hz,4H,N- CH2 CH2×2),2.72-2.62(m,4H,N-CH2 CH2 ×2),2.39(s,3H,N-CH3),2.14(s,3H,COCH3),1.94(d,J=6.8Hz,3H,-CH3).

[0076] Embodiment 14

[0077] Compounds A2-A5, B1-B3 were synthesized according to the methods of Examples 1-8 above.

[0078] A2: light yellow solid, yield 40.6%, melting point 137-138°C. MS (ESI) m / z: 551.3 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ10.02(s,1H,NH),8.95(s,1H,NH),8.42(s,1H,NH),8.13(s,1H,NH),8.08(s,1H,Pyrimidinyl-6-H),7.89(s,1H,A r-H),7.72(d,J=7.9Hz,1H,Ar-H),7.22(d,J=7.7Hz,1H,Ar-H),7.12-7.03(m,2H,Ar-H),6.77(s,1H,Ar-H),6.62(dd,J=17.0,10.2Hz,1H,CO CH =CH2),6.19(dd,J=16.9,1.9Hz,1H,COCH= CH2 ),5.73(d,J=10.2,1.9Hz,1H,COCH= CH2 ),3.77(s,3H,-OCH3),2.85(t,J=4.8Hz,4H,N- CH2 CH2×2),2.67-2.49(m,4H,N-CH2 CH2 ×2),2.32(s,3H,N-CH3),2.09(s,3H,COCH3).

[0079] A3: light yellow solid, yield 38.7%, melting point 119-122°C. MS (ESI) m / z: 531.3 [M+H] + . 11H NMR (600 MHz, DMSO-d6), δ 9.93 (s, 1H, NH), 8.96 (s, 1H, NH), 8.35 (s, 1H, NH), 8.00 (s, 1H, NH), 7.85 (s, 1H, Pyrimidinyl-6-H), 7.74 (d, J = 8.0 Hz, 1H, Ar-H), 7.35 (s, 1H, Ar-H), 7.28 (d, J = 7.8 Hz, 1H, Ar-H), 7.13 - 7.05 (m, 2H, Ar-H), 6.76 (s, 1H, Ar-H), 6.61 (dd, J = 17.0, 10.3 Hz, 1H, CO CH =CH2), 6.19 (dd, J = 17.1, 2.0 Hz, 1H, COCH= CH2 ), 5.72 (dd, J = 10.2, 2.0 Hz, 1H, COCH= CH2 ), 3.79 (s, 3H, -OCH3), 2.82 (t, J = 4.8 Hz, 4H, N- CH2 CH2×2), 2.58 - 2.48 (m, 4H, N-CH2 CH2 ×2), 2.28 (s, 3H, N-CH3), 2.08 (s, 3H, Pyrimidinyl-5-CH3), 2.02 (s, 3H, COCH3).

[0080] A4: Pale yellow solid, yield 35.5%, melting point 127 - 129 °C. MS (ESI) m / z: 531.3 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), δ 9.50 (s, 1H, NH), 8.95 (s, 1H, NH), 8.44 (s, 1H, NH), 8.34 (s, 1H, NH), 7.62 (d, J = 8.1 Hz, 1H, Ar-H), 7.55 (s, 1H, Pyrimidinyl-5-H), 7.44 (d, J = 8.0 Hz, 1H, Ar-H), 7.13 - 7.04 (m, 2H, Ar-H), 6.78 (s, 1H, Ar-H), 6.60 (dd, J = 17.3, 10.3 Hz, 1H, CO CH =CH2), 6.18 (d, J = 16.9 Hz, 1H, COCH= CH2 ), 6.01 (s, 1H, Ar-H), 5.71 (d, J = 10.2 Hz, 1H, COCH= CH2 ), 3.80 (s, 3H, -OCH3), 2.82 (t, J = 5.2 Hz, 4H, N- CH2 CH2×2),2.58-2.48(m,4H,N-CH2 CH2 ×2),2.25(s,3H,N-CH3),2.17(s,3H,Pyrimidinyl-6-CH3),2.01(s,3H,COCH3).

[0081] A5: light yellow solid, yield 38.2%, melting point 142-143°C. MS (ESI) m / z: 595.2 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ10.03(s,1H,NH),8.95(s,1H,NH),8.22(s,1H,NH),8.16(s,1H,NH),8.10(s,1H,Pyrimidinyl-6-H),7.94(s,1H,A r-H),7.76(d,J=8.0Hz,1H,Ar-H),7.18(d,J=7.7Hz,1H,Ar-H),7.12-7.05(m,2H,Ar-H),6.79(s,1H,Ar-H),6.62(dd,J=17.0,10.2Hz,1H,CO CH =CH2),6.20(d,J=17.0Hz,1H,COCH= CH2 ),5.73(dd,J=10.1,1.9Hz,1H,COCH= CH2 ),3.78(s,1H,-OCH3),2.83(t,J=4.7Hz,4H,N- CH2 CH2×2),2.59-2.49(m,4H,N-CH2 CH2 ×2),2.26(s,3H,N-CH3),2.10(s,3H,COCH3).

[0082] B1: light yellow solid, yield 35.1%, melting point 126-129°C. MS (ESI) m / z: 631.2 [M+H] + . 11H NMR (600 MHz, DMSO-d6), δ 9.52 (s, 1H, NH), 8.99 (s, 1H, NH), 8.38 (s, 1H, NH), 8.20 (s, 1H, NH), 8.19 (s, 1H, Pyrimidinyl-6-H), 8.09 (s, 1H, Ar-H), 8.04 (d, J = 8.1 Hz, 1H, Ar-H), 7.31 (d, J = 9.4 Hz, 1H, Ar-H), 7.16 - 7.05 (m, 2H, Ar-H), 6.81 (s, 1H, Ar-H), 6.63 (dd, J = 17.0, 10.3 Hz, 1H, CO CH =CH2), 6.19 (d, J = 17.0 Hz, 1H, COCH= CH2 ), 5.72 (dd, J = 10.2, 1.9 Hz, 1H, COCH= CH2 ), 3.77 (s, 1H, -OCH3), 2.98 (s, 3H, -CH3), 2.95 - 2.87 (m, 4H, N- CH2 CH2×2), 2.78 - 2.71 (m, 4H, N-CH2 CH2 ×2), 2.41 (s, 3H, N-CH3).

[0083] B2: Pale yellow solid, yield 37.8%, melting point 121 - 123 °C. MS (ESI) m / z: 645.1 [M + H] + . 1 1H NMR (600 MHz, DMSO-d6), δ 9.36 (s, 1H, NH), 8.96 (s, 1H, NH), 8.42 (s, 1H, NH), 8.18 (s, 1H, NH), 8.15 (s, 1H, Pyrimidinyl-6-H), 8.06 (s, 1H, Ar-H), 7.98 (d, J = 8.0 Hz, 1H, Ar-H), 7.26 (d, J = 7.8 Hz, 1H, Ar-H), 7.14 - 7.03 (m, 2H, Ar-H), 6.80 (s, 1H, Ar-H), 6.61 (dd, J = 17.0, 10.3 Hz, 1H, CO CH =CH2), 6.18 (d, J = 16.0 Hz, 1H, COCH= CH2 ), 5.71 (d, J = 11.2 Hz, 1H, COCH= CH2 ), 3.77 (s, 3H, -OCH3), 3.04 (q, J = 7.3 Hz, 2H, - CH2 CH3), 2.91 - 2.81 (m, 4H, N- CH2 CH2×2),2.65-2.58(m,4H,N-CH2 CH2 ×2),2.27(s,3H,N-CH3),1.22(t,J=7.5Hz,3H,-CH3).

[0084] B3: light yellow solid, yield 34.2%, melting point 130-133°C. MS (ESI) m / z: 657.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ9.42(s,1H,NH),8.98(s,1H,NH),8.39(s,1H,NH),8.21(s,1H,NH),8.19(s,1H,Pyrimidinyl-6-H),8. 10-7.95(m,2H,Ar-H),7.33(d,J=7.9Hz,1H,Ar-H),7.16-7.04(m,2H,Ar-H),6.81(s,1H,Ar-H),6.62(dd,J=17.0,10.3Hz,1H,CO CH =CH2),6.18(dd,J=17.1,1.9Hz,1H,COCH= CH2 ),5.71(dd,J=10.2,1.9Hz,1H,COCH= CH2 ),3.77(s,3H,-OCH3),2.87(t,J=4.8Hz,4H,N- CH2 CH2×2),2.63-2.55(m,5H,N-CH2 CH2 ×2and-CH),2.30(s,3H,N-CH3),0.99-0.89(m,2H,-CH2),0.87-0.82(m,2H,-CH2).

[0085] Embodiment 15

[0086] Compounds C2-C5, D1-D7 were synthesized according to the methods of Examples 9-13 above.

[0087] C2: light yellow solid, yield 35.3%, melting point 166-168°C. MS (ESI) m / z: 565.3 [M+H] + . 1H NMR(600MHz,DMSO-d6),δ10.02(s,1H,NH),8.94(s,1H,NH),8.43(s,1H,NH),8.37 (s,1H,NH),8.09(s,1H,Pyrimidinyl-6-H),7.96(s,1H,Ar-H),7.76(d,J=7.6Hz,1 H,Ar-H),7.22(d,J=7.7Hz,1H,Ar-H),7.13-7.06(m,2H,Ar-H),6.90(s,1H,Ar-H), 5.87(s,1H,=CH2),5.54(s,1H,=CH2),3.77(s,3H,-OCH3),2.85(t,J=4.7Hz,4H,N- CH2 CH2×2),2.68-2.50(m,4H,N-CH2 CH2 ×2),2.25(s,3H,N-CH3),2.10(s,3H,COCH3),2.03(s,3H,-CH3).

[0088] C3: light yellow solid, yield 38.2%, melting point 162-164°C. MS (ESI) m / z: 579.3 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ10.03(s,1H,NH),8.55(s,1H,NH),8.41(s,1H,NH),8.17(s,1H,NH),8.07(s,1H,Pyrimidinyl-6-H),7.92(s,1H,Ar-H),7.75(d,J =7.5Hz,1H,Ar-H),7.21(d,J=7.7Hz,1H,Ar-H),7.11-7.05(m,2H,Ar-H),6.77 (s,1H,Ar-H),6.01(s,1H,-CH=),3.75(s,3H,-OCH3),2.84(t,J=4.8Hz,4H,N- CH2 CH2×2),2.68-2.59(m,4H,N-CH2 CH2 ×2),2.33(s,3H,N-CH3),2.12(s,3H,-CH3),2.09(s,3H,COCH3),1.88(s,3H,-CH3).

[0089] C4: light yellow solid, yield 35.3%, melting point 171-172°C. MS (ESI) m / z: 579.3 [M+H] + . 11H NMR (600 MHz, DMSO-d6), δ 10.03 (s, 1H, NH), 8.74 (s, 1H, NH), 8.42 (s, 1H, NH), 8.15 (s, 1H, NH), 8.07 (s, 1H, Pyrimidinyl-6-H), 7.90 (s, 1H, Ar-H), 7.73 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (d, J = 7.8 Hz, 1H, Ar-H), 7.13 - 7.06 (m, 2H, Ar-H), 6.80 - 6.75 (m, 2H, Ar-H and COCH= CH ), 6.28 (d, J = 15.0 Hz, 1H, CO CH =CH), 3.76 (s, 3H, -OCH3), 2.85 (t, J = 4.9 Hz, 4H, N- CH2 CH2×2), 2.68 - 2.60 (m, 4H, N-CH2 CH2 ×2), 2.34 (s, 3H, N-CH3), 2.28 - 2.21 (m, 2H, - CH2 CH3), 2.09 (s, 3H, COCH3), 1.06 (t, J = 7.1 Hz, 3H, -CH2 CH3 ).

[0090] C5: Pale yellow solid, yield 38.9%, melting point 178 - 180 °C. MS (ESI) m / z: 593.3 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), δ 10.03 (s, 1H, NH), 8.75 (s, 1H, NH), 8.42 (s, 1H, NH), 8.16 (s, 1H, NH), 8.08 (s, 1H, Pyrimidinyl-6-H), 7.90 (s, 1H, Ar-H), 7.73 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (d, J = 7.8 Hz, 1H, Ar-H), 7.12 - 7.04 (m, 2H, Ar-H), 6.77 (s, 1H, Ar-H), 6.72 (dt, J = 14.7, 7.0 Hz, 1H, COCH= CH ), 6.30 (d, J = 15.3 Hz, 1H, CO CH =CH), 3.76 (s, 3H, -OCH3), 2.85 (t, J = 4.9 Hz, 4H, N- CH2 CH2×2), 2.69 - 2.59 (m, 4H, N-CH2 CH2 ×2), 2.34 (s, 3H, N-CH3), 2.23 - 2.17 (m, 2H, - CH2 CH2CH3),2.09(s,3H,COCH3),1.51-1.46(m,2H,-CH2 CH2 CH3),0.93(t,J=7.4Hz,3H,-CH2CH2 CH3 ).

[0091] D1: light yellow solid, yield 38.9%, melting point 140-141°C. MS (ESI) m / z: 582.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ10.03(s,1H,NH),9.05(s,1H,NH),8.23(s,1H,NH),8.15(s,1H,NH),8.14(s,1H,Pyrimidinyl-6-H),7.95(s,1H,A r-H),7.75(d,J=7.9Hz,1H,Ar-H),7.17(d,J=7.7Hz,1H,Ar-H),7.12-7.04(m,2H,Ar-H),6.81(s,1H,Ar-H),6.65(dd,J=17.0,10.2Hz,1H,CO CH =CH2),6.20(dd,J=17.0,2.0Hz,1H,COCH= CH2 ),5.73(dd,J=10.2,1.9Hz,1H,COCH= CH2 ),3.83-3.75(m,7H,-OCH3 and OCH2×2),2.82(t,J=4.5Hz,4H,N-CH2×2),2.09(s,3H,COCH3).

[0092] D2: light yellow solid, yield 33.3%, melting point 153-156°C. MS (ESI) m / z: 625.3 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ10.03(s,1H,NH),8.95(s,1H,NH),8.21(s,1H,NH),8.14(s,1H,NH),8.10(s,1H,Pyrimidinyl-6-H),7.94(s,1H,A r-H),7.75(d,J=8.0Hz,1H,Ar-H),7.17(d,J=7.8Hz,1H,Ar-H),7.13-7.04(m,2H,Ar-H),6.79(s,1H,Ar-H),6.62(dd,J=17.0,10.2Hz,1H,CO CH =CH2),6.19(dd,J=17.0,1.9Hz,1H,COCH= CH2 ),5.72(dd,J=10.2,1.9Hz,1H,COCH= CH2 ),4.44(s,1H,-OH),3.76(s,3H,-OCH3),3.58-3.51(m,2H,N-CH2 CH2 OH), 2.83(t, J=4.8Hz, 4H, N- CH2 CH2×2),2.69-2.60(m,4H,N-CH2 CH2 ×2),2.48(s,2H,N- CH2 CH2OH), 2.09(s,3H,COCH3).

[0093] D3: light yellow solid, yield 34.9%, melting point 121-122°C. MS (ESI) m / z: 597.2 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ10.09(s,1H,NH),10.06(s,1H,NH),8.41(s,1H,NH),8.23(s,1H,NH),8.15(s,1H,Pyrimidinyl-6-H),8.02(s,1H,A r-H),7.76(d,J=9.4Hz,1H,Ar-H),7.16(d,J=9.2Hz,1H,Ar-H),7.08-7.02(m,2H,Ar-H),6.93(s,1H,Ar-H),6.42(dd,J=16.9,10.3Hz,1H,CO CH =CH2),6.22(dd,J=16.9,2.0Hz,1H,COCH= CH2 ),5.75(dd,J=10.1,2.0Hz,1H,COCH= CH2 ),3.74(s,3H,-OCH3),2.86(t,J=5.6Hz,2H,N- CH2 CH2),2.68(s,3H,N-CH3),2.36-2.21(m,2HN-CH2 CH2 ),2.23(s,6H,N-CH3×2),2.09(s,3H,COCH3).

[0094] D4: light yellow solid, yield 35.8%, melting point 133-135°C. MS (ESI) m / z: 609.2 [M+H] + . 11H NMR (600 MHz, DMSO-d6), δ 9.96 (s, 1H, NH), 8.89 (s, 1H, NH), 8.15 (s, 1H, NH), 8.08 (s, 1H, NH), 8.03 (s, 1H, Pyrimidinyl-6-H), 7.87 (s, 1H, Ar-H), 7.68 (d, J = 8.0 Hz, 1H, Ar-H), 7.10 (d, J = 7.8 Hz, 1H, Ar-H), 7.08 - 7.00 (m, 2H, Ar-H), 6.72 (s, 1H, Ar-H), 6.55 (dd, J = 17.0, 10.2 Hz, 1H, CO CH =CH2), 6.12 (d, J = 16.9, 1.9 Hz, 1H, COCH= CH2 ), 5.65 (d, J = 10.1, 1.9 Hz, 1H, COCH= CH2 ), 3.69 (s, 3H, -OCH3), 2.77 (t, J = 4.8 Hz, 4H, N- CH2 CH2×2), 2.59 - 2.49 (m, 4H, N-CH2 CH2 ×2), 2.36 (q, J = 7.1 Hz, 2H, N- CH2 CH3), 2.02 (s, 3H, COCH3), 0.97 (t, J = 7.1 Hz, 3H, N-CH2 CH3 ).

[0095] D5: Pale yellow solid, yield 38.5%, melting point 138 - 139 °C. MS (ESI) m / z: 594.2 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), δ 10.03 (s, 1H, NH), 8.92 (s, 1H, NH), 8.22 (s, 1H, NH), 8.14 (s, 1H, NH), 8.11 (s, 1H, Pyrimidinyl-6-H), 7.95 (s, 1H, Ar-H), 7.75 (d, J = 7.9 Hz, 1H, Ar-H), 7.17 (d, J = 7.7 Hz, 1H, Ar-H), 7.12 - 7.04 (m, 2H, Ar-H), 6.76 (s, 1H, Ar-H), 6.65 (dd, J = 17.0, 10.2 Hz, 1H, CO CH =CH2), 6.19 (d, J = 16.0 Hz, 1H, COCH= CH2 ), 5.72 (d, J = 10.3 Hz, 1H, COCH= CH2 ), 3.75 (s, 3H, -OCH3), 2.94 (t, J = 10.9 Hz, 2H, N- CH2 CH2), 2.62(t, J=10.7Hz, 2H, N- CH2 CH2),2.09(s,3H,COCH3),1.70-1.65(m,2H,N-CH2 CH2 ),1.45-1.39(m,3H,N-CH2 CH2 and-CH),0.97(d,J=6.1Hz,3H,-CH3).

[0096] D6: light yellow solid, yield 40.9%, melting point 131-133°C. MS (ESI) m / z: 598.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6),δ10.04(s,1H,NH),8.95(s,1H,NH),8.24(s,1H,NH),8.16(s,1H,NH),8.15(s,1H,Pyrimidinyl-6-H),7.96(s,1H,A r-H),7.74(d,J=7.8Hz,1H,Ar-H),7.17(d,J=7.7Hz,1H,Ar-H),7.09-7.00(m,2H,Ar-H),6.80(s,1H,Ar-H),6.70(dd,J=17.0,10.2Hz,1H,CO CH =CH2),6.21(dd,J=16.9,2.0Hz,1H,COCH= CH2 ),5.74(dd,J=10.1,1.9Hz,1H,COCH= CH2 ),3.77(s,3H,-OCH3),3.08-2.99(m,4H,N-CH2×2),2.85-2.77(m,4H,SCH2×2),2.09(s,3H,COCH3).

[0097] D7: light yellow solid, yield 37.1%, melting point 124-126°C. MS (ESI) m / z: 568.2 [M+H] + . 1H NMR(600MHz,DMSO-d6),δ10.04(s,1H,NH),9.08(s,1H,NH),8.35(s,1H,NH),8.21(s,1H,NH),8.15(s,1H,Pyrimidinyl-6-H),8.07(s,1H,A r-H),7.76(d,J=9.0Hz,1H,Ar-H),7.14(d,J=9.0Hz,1H,Ar-H),7.08-7.00(m,2H,Ar-H),6.86(s,1H,Ar-H),6.68(dd,J=16.9,10.2Hz,1H,CO CH =CH2),6.18(d,J=16.8Hz,1H,COCH= CH2 ),5.71(dd,J=10.2,1.9Hz,1H,COCH= CH2 ),3.74(s,3H,-OCH3),2.93(q,J=6.9Hz,4H,N- CH2 CH3×2),2.09(s,3H,COCH3),0.90(t,J=7.1Hz,6H,N-CH2 CH3 ×2).

[0098] Example 16

[0099] The MTT method was used to determine the proliferation inhibitory effects of compounds (A1-A5, B1-B3, C1-C5, D1-D7) on human non-small cell lung cancer cells A549, human brain neuroblastoma cells LN229 and human glioma cells U251 as test cell lines.

[0100] Adherent tumor cells in the logarithmic growth phase were selected and digested with trypsin. A549, LN229, and U251 cells were cultured with 10% fetal bovine serum to make a 5×10 4 / ml (subsequent drug treatment for 48h), inoculated into 96-well culture plates, 100ml per well, 37℃, 5% CO2 for 24h. The experimental group replaced with new culture medium containing different concentrations of the tested samples, and the control group replaced with culture medium containing an equal volume of solvent. Each group had 3 parallel wells, and cultured for 48h at 37℃, 5% CO2. Discard the supernatant, wash carefully twice with PBS, add 100ml of freshly prepared culture medium containing 0.5mg / ml MTT to each well, and continue to culture at 37℃ for 4h. Carefully discard the supernatant, add 150ml DMSO, mix with a micro-oscillator for 10min, and measure the optical density (OD) at 492nm with an enzyme marker.

[0101] The inhibition rate (IR%) of the drug on tumor cell growth was calculated as follows:

[0102] =[A492 (negative control) - A492 (drug-added group)] / A492 (negative control) × 100%

[0103] Graphpad Prism 6.02 software was used to calculate the half inhibitory concentration (IC 50 ).

[0104] The results are shown in Table 1.

[0105] Table 1 IC of compounds A1-D7 and osimertinib on tumor cells 50 value

[0106]

[0107] The cells were cultured with various concentrations of different samples for 48h.

[0108] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A 2,4-diarylaminopyrimidine compound or a pharmaceutically acceptable salt thereof as shown in Formula I: in, R1, NR2R3, NHCOR4 independently represent none or 1-3 substituents on the benzene ring, and the substituent R1 is selected from C1-C6 alkoxy, C1-C6 alkyl, C1-C6 substituted amino, C1-C6 amide, and halogen; NR2R3 is a substituted or unsubstituted 5-6 membered heterocyclic group, a C1-C8 alkylamino group, a C3-C7 cycloalkylamino group, or a C1-C8 alkylamino group, wherein the substituent is selected from: C1-C 12 Alkyl, phenyl, C1-C6 alkoxyphenyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 alkyl containing hydroxyl, C1-C8 alkyl substituted with 1-3 nitrogen atoms, C1-C8 alkyl containing phenyl; the heterocyclic group contains 1-3 heteroatoms of N, O or S; R4 represents C1-C 10 Alkyl or C1-C 10 The alkenyl group; R5 and R6 independently represent none or 1-2 substituents on the pyrimidine ring, and the substituents are independently selected from C1-C8 alkyl, C1-C8 alkanoyl, C1-C8 alkoxy, hydroxyl, and halogen; NHR7 represents no substituent or one substituent on the benzene ring, and R7 is selected from C1-C8 sulfonamide, C1-C8 amide, and C1-C8 alkyl.

2. The 2,4-diarylaminopyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the structural formula I, R1, NR2R3, and NHCOR4 independently represent none or 1 to 3 substituents on the benzene ring, and the substituent R1 is selected from C1-C4 alkoxy, C1-C4 alkyl, C1-C4 substituted amino, C1-C4 amide, and halogen; NR2R3 is a substituted or unsubstituted 5-6 membered heterocyclic group, C1-C6 alkylamino group, or C3-C7 cycloalkylamino group, wherein the substituent is selected from the group consisting of C1-C9 alkyl group, phenyl group, C1-C4 alkoxyphenyl group, C2-C5 alkenyl group, C2-C6 alkynyl group, C1-C6 alkyl group containing a hydroxyl group, C1-C6 alkyl group containing a phenyl group, or C1-C6 alkyl group substituted with 1-2 nitrogen atoms; the heterocyclic group contains 1-3 heteroatoms of N, O or S; R4 represents a C1-C8 alkyl group or a C1-C8 alkenyl group; R5 and R6 independently represent none or 1-2 substituents on the pyrimidine ring, and the substituents are independently selected from C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxy, and halogen; NHR7 represents no substituent or one substituent on the benzene ring, and R7 is selected from C1-C6 sulfonamide, C1-C6 amide, and C1-C6 alkyl.

3. The 2,4-diarylaminopyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: In the structural formula I, R1, NR2R3, and NHCOR4 independently represent 1 to 3 substituents on the benzene ring, and the substituent R1 is selected from C1-C3 alkoxy, C1-C3 alkyl, C1-C3 substituted amino, C1-C3 amide, and halogen; NR2R3 is a substituted or unsubstituted 5-6 membered heterocyclic group, C1-C4 alkylamino group, or C3-C5 cycloalkylamino group, wherein the substituent is selected from the group consisting of C1-C8 alkyl group, phenyl group, C1-C3 alkoxyphenyl group, C2-C4 alkenyl group, C1-C4 alkyl group containing a hydroxyl group, C1-C4 alkyl group containing a phenyl group, and C1-C4 alkyl group substituted with 1-2 nitrogen atoms; the heterocyclic group contains 1-3 heteroatoms of N, O or S; R4 represents a C1-C5 alkyl group or a C1-C5 alkenyl group; R5 and R6 independently represent none or 1-2 substituents on the pyrimidine ring, and the substituents are independently selected from C1-C4 alkyl, C1-C4 alkanoyl, C1-C4 alkoxy, and halogen; NHR7 represents no substituent or one substituent on the benzene ring, and R7 is selected from C1-C5 sulfonamide, C1-C5 amide, and C1-C5 alkyl.

4. The 2,4-diarylaminopyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The compound is selected from the following compounds:

5. The 2,4-diarylaminopyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The salt refers to the acid addition salt formed by the 2,4-diarylaminopyrimidine compound and an acid, wherein the acid is an organic acid or an inorganic acid selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, tartaric acid, salicylic acid, methanesulfonic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and maleic acid.

6. A pharmaceutical composition, characterized in that The invention comprises the 2,4-diarylaminopyrimidine analogue or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.

7. The method for preparing the 2,4-diarylaminopyrimidine analog or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: Choose from any of the following methods: wherein R1, NR2R3, NHCOR4, R5, R6, and NHR7 are as described in claim 4.

8. Use of the 2,4-diarylaminopyrimidine analogue or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of antitumor drugs.

9. Use of the pharmaceutical composition according to claim 6 in the preparation of anti-tumor drugs.

10. The use according to claim 8 or 9, characterized in that: The tumor is cervical cancer, liver cancer, fibrosarcoma, colon cancer, melanoma, breast cancer, lung cancer, lymphoma, chronic myeloid leukemia or myeloid leukemia.

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