2-aminooxy-2-methylpropan-1-ol;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (0.11 g, 0.35 mmol), EDCI (0.081 g, 0.42 mmol), HOBt (0.057 g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (0.055 g, 0.39 mmol) in DMF (1.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 ml). The organic layer was washed with water (5 mL), followed by brine (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 40%, ethyl actetate in DCM) to give a yellow solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (11 mg, 8%). LCMS (method A): RT=7.57 min, [M+H]+=399. 1H NMR (DMSO-d6): 10.37 (1H, s), 8.28 (1H, s), 7.79 (1H, dd, J=7.35, 0.95 Hz), 7.14 (1H, s), 7.02-6.93 (1H, m), 6.91 (1H, d, J=8.28 Hz), 6.82 (1H, s), 6.27 (1H, s), 1.99-1.90 (1H, m), 1.15 (6H, s), 0.99-0.92 (2H, m), 0.73-0.67 (2H, m). The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 ml) The organic layer was washed with water (5 mL) dried (MgSO4) filtered concentrated in vacuo to give a yellow solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (12.0 mg, 89%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (8.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.94 (d, 1H), 8.18 (d, 1H), 7.94 (d, 1H), 7.83 (s, 1H), 7.46 (dd, 1H), 6.17 (s, 2H), 3.75 (d, 2H), 2.36 (s, 3H), 1.95 (1, 1H), 1.41 (s, 6H). LCMS (method A): [MH]+=410, tR=5.39 min. as described in the synthesis of example 15

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (12.0 mg, 89%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (8.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.94 (d, 1H), 8.18 (d, 1H), 7.94 (d, 1H), 7.83 (s, 1H), 7.46 (dd, 1H), 6.17 (s, 2H), 3.75 (d, 2H), 2.36 (s, 3H), 1.95 (1, 1H), 1.41 (s, 6H). LCMS (method A): [MH]+=410, tR=5.39 min. as described in the synthesis of example 15

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(2-fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (737 mg, 1.4 mmol), HOBt (231 mg, 1.7 mmol), and EDCI (327 mg, 1.7 mmol) in DMF (15 mL) was added a solution of 2-aminooxy-2-methyl-propan-1-ol hydrochloride (280 mg, 2.0 mmol), and DIPEA (603 μL, 3.6 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 3 days then diluted with water (30 mL) and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic fractions were filtered through a hydrophobic frit and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (420 mg, 49%). LCMS (Method B): RT=3.47 min, [M+H]+=606. the aqueous layer extracted with dichloromethane (3×20 mL) The combined organic fractions were filtered through a hydrophobic frit concentrated in vacuo