Selective ROCK2 kinase inhibitors
A selected and optional technology, applied in directions such as organic active ingredients, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as side effects and insufficient selectivity
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Embodiment 1
[0157] Example 1: Compound 1 (2-(3-(4-(2-(1H-indazol-4-yl)vinyl)quinazolin-2-yl)phenoxy)-N-isopropylethyl amide)
[0158]
[0159] 1) Under nitrogen protection, 2,4-dichloroquinazoline (1.0g, 5.03mmol) was dissolved in dioxane / water solvent, and trimethylcyclotriboroxane (1.3g, 5.03mmol) was added successively. ), potassium acetate (1.5 g, 15.09 mmol) and PdCl 2 (dppf) (183 mg, 0.25 mmol), the reaction system was stirred at 80°C overnight. The reaction solution was directly filtered, concentrated under reduced pressure, and purified by reverse-phase column to obtain 2-chloro-4-methylquinazoline (650 mg, yellow solid), yield: 73%. 1 H NMR (400MHz, CDCl 3 ): δ=8.11-8.09 (m, 1H), 7.98-7.89 (m, 2H), 7.67-7.63 (m, 1H), 2.97 (s, 3H).
[0160]2) Under nitrogen protection, 2-chloro-4-methylquinazoline (500mg, 2.81mmol) was dissolved in dioxane / water solvent, followed by adding (3-(2-(isopropylamino) -2-Oxyethoxy)phenyl)boronic acid (665 mg, 2.81 mmol), potassium acetate (1.2 g...
Embodiment 2
[0162] Example 2: Compound 9 (((E)-2-(4-(3-(1H-pyrazol-4-yl)styryl)pyrimidin-2-yl)-5-methoxyisoindoline )
[0163]
[0164] 1) 3-Bromobenzaldehyde (1.0g, 5.42mmol), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (1.26g, 5.98mmol) and potassium carbonate (1.49g, 10.84 mmol) was dissolved in 1,4-dioxane / water solvent, and Pd(dppf)Cl was added under nitrogen protection 2 (198 mg, 0.271 mmol) and the reaction was stirred for 16 hours. Spin-dried through a normal phase column to obtain 3-(1H-pyrazol-4-yl)benzaldehyde (310 mg, white solid), yield: 30.2%.
[0165] 2) 2,6-dichloropyrimidine (4.0g, 26.6mmol) was added to tetrahydrofuran, ferric oxide (60mg, 0.26mmol) was added, methylmagnesium bromide (4.75g, 39.9mmol) was added under nitrogen protection at 0°C ) and the reaction was stirred at 25°C for 2 hours. Water was added to the reaction system, ethyl acetate was added for extraction, and the mixture was spin-dried through a silica gel column to obtain 2-chloro-6-me...
Embodiment 3
[0168] Example 3: Compound 19 ((E)-(6-(4-(3-(1H-pyrazol-4-yl)styryl)pyrimidin-2-yl)-1-methyl-1H-indole -2-yl)(3,3-difluoroazetidin-1-yl)methanone)
[0169]
[0170] 1) Dissolve ethyl 6-bromo-1H-indole-2-carboxylate (400mg, 1.49mmol) in N,N-dimethylformamide, add sodium hydride (105mg, 1.64mmol) at 0°C The reaction was stirred for 30 minutes. Then add iodomethane (231mg, 1.64mmol), the reaction is stirred at 25 ° C for 2 hours, water is added to the reaction solution, extracted with ethyl acetate, and spin-dried through a normal phase column to obtain 6-bromo-1-methyl-1H-indium Ethyl dole-2-carboxylate (250 mg, transparent oil), yield: 59.5%.
[0171] 2) Add 6-bromo-1-methyl-1H-indole-2-carboxylic acid ethyl ester (200 mg, 0.71 mmol) to 1,4-dioxane / water solvent, add pinacol biboronate (206 mg, 0.781 mmol) and potassium acetate (139 mg, 1.42 mmol) were added Pd(dppf)Cl under nitrogen 2 (22 mg, 0.03 mmol) and the reaction was stirred at 90°C for 2 hours. Water was added ...
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