Novel tyrosine kinase inhibitor 1,4-disubstituted-1,2,3-triazole compound and preparation and applications thereof
A compound, di-substitution technology, applied in its preparation, 1, can solve problems such as ineffective treatment of CML
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[0086] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.
[0087] The invention also relates to novel intermediates and / or starting materials. Particular preference is given to reaction conditions and novel intermediates which are the same or similar to those mentioned in the examples.
[0088] Both intermediates and final products can be worked up and / or purified according to conventional methods, including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.
[0089] In addition, the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.
[0090] The following examples are only used to illustrate the present invention and do not limit the present invention in any way.
Embodiment 1
[0091] Example 1 (2-methyl-5-{1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[1,2,3]triazole-4- Preparation of base}-phenyl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine
[0092]
[0093] Step 1.1: Preparation of N-methoxy-N-methyl-4-methyl-2-[(4-pyridin-3-yl-pyrimidin-2-yl)-amino]benzamide
[0094] Take a 50ml three-neck round bottom flask, add solvent CH 2 Cl 2 (20ml), at 0°C, add 4-methyl-2-[(4-pyridin-3-yl-pyrimidin-2-yl)-amino]benzoic acid (1.00g, 3.26mmol), HOBt ( 0.49g, 3.63mmol), EDCI (0.69g, 3.60mmol), 4-methylmorpholine (0.99g, 9.79mmol), the reaction system was kept at 0°C, and stirred for 20min. Then N,O-dimethylhydroxylamine hydrochloride (0.47g, 4.82mmol) was added, and the reaction was continued for 3h while keeping the temperature constant. During the reaction, the progress of the reaction was monitored by TLC. After the reaction was completed, the reaction solution was added to 30ml saturated NaHCO 3 solution, extracted with dichloromethane (3x100ml), combined...
Embodiment 2
[0111] Example 2N-(2-methyl-5-{1-{4-[(4-methylpiperazin-1-yl) methyl]-3-(trifluoromethyl)phenyl}-1H-[ Preparation of 1,2,3]-triazol-4-yl}phenyl)-4-(pyridin-3-yl)pyrimidin-2-amine
[0112]
[0113] Replace 4-(4-methyl-piperazinyl-1-ylmethyl in Example 1 with 3-trifluoromethyl-4-[(4-methylpiperazin-1-yl)methyl]aniline ) aniline, the compound was prepared by the same method as in Example 1, and the final yield of the target product was 55.02%.
[0114] MS of the compound: [M+H]+586.21; 1 H NMR (400MHz, DMSO-D6): δppm9.43(s, 1H), 9.29(d, J=2.0HZ 1H), 9.08(s, 1H), 8.68(dd, J=1.6, 4.8HZ, 1H) , 8.55(d, J=5.2HZ, 1H), 8.48(d, J=8.0HZ, 1H), 8.27(d, J=9.2HZ, 3H), 7.98(d, J=8.4HZ, 1H), 7.66 (dd, J=1.6, 6.0HZ, 1H), 7.52(dd, J=4.8, 2.8HZ, 1H), 7.47(d, J=5.2HZ, 1H), 7.39(d, J=8.0HZ, 1H) , 3.69(s, 2H), 2.56-2.50(m, 8H), 2.32(s, 6H); 13 C-NMR (400MHz, DMSO-D6): δppm 162.0, 161.6, 160.0, 151.9, 148.6, 148.1, 138.9, 138.0, 136.0, 134.8, 132.9, 132.6, 131.4, 129.2, 128.9, 128.4, 125.6, 12...
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