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A mixture of 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylic acid (500 mg, 1.26 mmol), 5-aminoisoindoline-1,3-dione (250 mg, 1.51 mmol) and pyridine (10 mL) was stirred at 0° C. for 2 h. POCl3 (20 drops) was added and stirred for 10 mins, then water (5 mL) was added and the mixture extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give the product. HCl (1 mL) was added and then the mixture concentrated in vacuo to give 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1,3-dioxoisoindolin-5-yl)piperidine-3-carboxamide hydrochloride (10 mg, 2%). 1H NMR (300 MHz, DMSO): δ 11.23 (s, 1H), 10.65 (s, 1H), 10.21 (s, 1H), 8.15 (s, 2H), 7.98 (s, 1H), 7.86 (d, 1H, J=8.4 Hz), 7.77 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=8.1 Hz), 6.93 (d, 1H, J=8.1 Hz), 4.29 (d, 1H, J=11.7 Hz), 4.14 (d, 1H, J=12.3 Hz), 3.91 (s, 3H), 7.56 (s, 3H), 3.23-3.02 (m, 2H), 2.73 (s, 1H), 2.10-2.06 (s, 1H), 1.82-1.75 (m, 3H). LC-MS: [M+H]+, 543, tR=1.406 min, HPLC: 98.08% at 214 nm, 98.69% at 254 nm, tR=5.25 min.

1. stirringstirred for 10 mins
2. extractionthe mixture extracted with ethyl acetate (10 mL)
3. washThe organic layer was washed with brine (10 mL)
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm
8. waitgradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min
9. custom) to give the product
10. concentrationthe mixture concentrated in vacuo