[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][C:12]1[N:16]2[N:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1.[H-].[Na+].I[CH3:30].O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:30])=[CH:4][C:3]=1[CH2:11][C:12]1[N:16]2[N:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:19]=[CH:20][C:15]2=[N:14][CH:13]=13-(6-Fluoro-1H-indazol-5-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 167, 18.6 mg, 0.054 mmol) was dissolved in DMF (0.310 mL) and cooled down to 0° C. NaH (1.9 mg, 0.080 mmol) was added and the RM was stirred for 30 min. Then iodomethane (4.02 μL) was introduced and it was allowed to warm up to rt. After 2.5 h of stirring, water was added and it was extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 1.0 min (conditions 2), MH+=362).
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