Reaction Steps
(R)-5-(3-Aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, HCl salt, 350 mg, 1.28 mmol) was dissolved in 10 mL DMF. To it were added imidazo[1,2-a]pyridine-6-carboxylic acid (310 mg, 1.92 mmol), DIEA (890 μL, 5.12 mmol) and then PyBOP (1.00 g, 1.92 mmol). The mixture was stirred at RT for 1 hour, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to silica flash column using 0 to 7% MeOH in DCM to isolate (R)—N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (473). Compound 473 (75 mg, 0.20 mmol) was mixed with 4-(tetrahydro-2H-pyran-4-yl)aniline (106 mg, 0.60 mmol), fine-powder cesium carbonate (326 mg, 1.00 mmol), palladium acetate (22 mg, 0.10 mmol), BINAP (62 mg, 0.10 mmol) in 15 mL dioxane. The mixture was degassed using nitrogen stream for 3 min, and stirred in nitrogen atmosphere at 115° C. for 1 hour. It was cooled to RT, diluted with 50 mL EtOAc, stirred and filtered. The filtrate was concentrated and subjected to silica flash column using 0 to 11% MeOH in DCM to isolate (R)—N-(1-(5-cyano-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (474). It was dissolved in 10 mL MeOH and 3 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and 1 mL 30% H2O2. The mixture was stirred at RT for 1.5 hour, quenched with 5 mL MeCN, stirred, concentrated, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate the title compound, (R)—N—O-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (475) (24 mg) as HCl salt, and also the by-product, (R)—N—O-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)-5-hydroxyimidazo[1,2-a]pyridine-6-carboxamide (476) (15 mg) as HCl salt. For compound 475, LC-MS (ESI): m/z (M+1) 541.3. UV: λ=304, 336, 373 nm. Proton NMR (CD3OD): δ 9.26 (1H, s), 8.30 (2H, m), 8.14 (1H, d, J=2.0 Hz), 7.99 (1H, d, J=9.5 Hz), 7.66 (1H, s), 7.51 (2H, d, J=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 4.41 (1H, m), 4.21 (1H, m), 4.10 (1H, m), 3.92 (2H, m), 3.44 (4H, m), 2.66 (1H, m), 2.16 (1H, m), 1.97 (1H, m), 1.84 (1H, m), 1.76 (1H, m), 1.62 (3H, m), 1.56 (1H, m) ppm.
