Pyrazolopyridine kinase inhibitors
A compound and an independent technology, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve the problems of inability to eliminate Listeria monocytogenes and incompensation
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Embodiment 1
[0213] Example 1 Compound 1
[0214] 4-(tert-Butyldimethylsilyl)-2,3,5-trifluoropyridine
[0215]
[0216] A solution of diisopropylamine (98.85 g, 136.9 mL, 976.9 mmol) in THF (1.350 L) was cooled to -65 °C. n-BuLi (2.5M in hexane) (375.8 mL, 2.5M, 939.4 mmol) was added dropwise via cannula over 1 h at a rate to maintain the reaction temperature below -60 °C. Once the addition was complete, the cooling bath was removed and the reaction mixture was warmed to 0 °C. The reaction mixture was stirred at 0 °C for 15 min, then recooled to -78 °C. 2,3,5-Trifluoropyridine (100 g, 751.5 mmol) was added dropwise via cannula over 20 min at a rate to maintain the reaction temperature below -69°C. The reaction mixture was stirred at -78°C for 45 min, during which time the solution turned orange-brown. A solution of tert-butyl-chloro-dimethyl-silane (147.2 g, 976.9 mmol) in THF (150 mL) was then added via cannula over 30 min. The reaction mixture was stirred at -78°C for 90 minutes,...
Embodiment 2
[0239] Example 2: Compound 11
[0240] (R)-4-(6-Chloro-5-cyano-3-fluoropyridin-2-yl)-2-isobutylpiperazine-1-carboxylic acid tert-butyl ester
[0241]
[0242] (2R)-2-Isobutylpiperazine-1-carboxylic acid tert-butyl ester (515 mg, 2.13 mmol), 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (405.9 mg, 2.13 mmol) and A mixture of DIPEA (274.6 mg, 370.1 μL, 2.13 mmol) in NMP was heated at 130° C. under microwave conditions for 20 minutes. After this time, the reaction mixture was cooled to ambient temperature, diluted with EtOAc and water. The organic layer was separated, washed with brine, and dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. By column chromatography (ISCOCompanion TM , 120 g column, eluting with EtOAc / petroleum ether) to obtain the subtitle compound (629.9 mg, 75% yield). 1 H NMR (400MHz, CDCl 3 )δ7.37(d, J12.6Hz, 1H), 4.55-4.23(m, 3H), 4.11(q, J=7.2Hz, 1H), 3.23(dd, J=13.4, 3.6Hz, 1H), 3.08 (d, J=9.4Hz, 2H), 1.64-1.52(m, 1H), 1.50-1.28(m, 11H), 0...
Embodiment 3
[0258] PKCθ
[0259] Prepared by 100mM HEPES (pH 7.5), 10mM MgCl 2 , 25mM NaCl, 0.1mM EDTA and 0.01% Brij assay buffer solution. Prepare in assay buffer solution containing a final assay concentration of 0.00001% Triton X-100, 200 μg / mL phosphatidylserine, 20 μg / mL diacylglycerol, 360 μM NADH, 3 mM phosphoenolpyruvate, 70 μg / mL pyruvate kinase, 24 μg / mL lactate dehydrogenase, 2 mM DTT, 100 μM substrate peptide (ERMRPRKRQGSVRRRV SEQ ID NO. 1) and 18 nM PKC theta kinase reagent enzyme buffer. Add 2 µL of the DMSO stock solution of VRT to 60 µL of this enzyme buffer in a 384-well culture plate. The mixture was equilibrated at 30°C for 10 mins. Enzyme reactions were initiated by adding 5 μL of ATP stock solution prepared with assay buffer to a final assay concentration of 240 μM. Initial rate data were determined from the rate of change of absorbance at 340 nM (equivalent to stoichiometric consumption of NADH) using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) ...
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