Reaction Steps
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg, 0.22 mmol) in DMF (10 mL) was added HATU (123 mg, 0.32 mmol), DIEA (83 mg, 0.64 mmol), and ethyl 3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride (200 mg). The resulting solution was stirred at room temperature overnight. Water (50 mL) was added. The resulting mixture was extracted with DCM (×3) and the organic layers combined. The combined organic layers were washed brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (82 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min); Detector, 254/220. 20.3 mg product was obtained. This resulted in 20.3 mg (13%) of the formic acid salt of ethyl 3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]methyl)amino]propanoate as an off-white solid. LCMS (Method 28) [M+H]+=659.2, RT=0.90 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.2 Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.03 (t, 1H, J=73.2 Hz), 5.36-5.15 (m, 2H), 4.48-4.33 (m, 1H), 4.02 (q, 2H, J=7.2 Hz), 4.00-3.96 (m, 1H), 3.18-3.00 (m, 1H), 2.89-2.80 (m, 3H), 2.68-2.54 (m, 3H), 2.31 (s, 3H), 1.85-1.76 (m, 2H), 1.61-1.25 (m, 2H), 1.19 (t, 3H, J=6.9 Hz).
