2-piperidin-1-ylethyl methanesulfonate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The 1-piperidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.

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

Procedure: The 1-piperidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The 1-piperidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-(4-(2-morpholinoethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (40 mg, 80%). 1H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.05-7.90 (m, 4 h), 7.57 (s, 1H), 7.42 (t, 1H, J=8.0 Hz), 7.04-7.01 (m, 2H), 6.22 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.30-4.19 (m, 3H), 3.80-3.77 (m, 4 h), 3.70-3.64 (m, 1H), 3.51-3.48 (m, 1H), 2.87 (t, 2H, J=5.7 Hz), 2.65-2.62 (m, 4 h), 2.17-2.05 (m, 3H), 1.78 (brs, 1H), 1.26 (d, 3H, J=6.3 Hz). LC/MS: 500 [M+H]+, tR=1.11 min. HPLC: 99.73% at 214 nm, 99.60% at 254 nm, tR=99.73% min. After cooling extracted with EtOAc (3×10 mL) The combined organic layers were washed with brine dried over MgSO4 filtered concentrated in vacuo The residue was purified by chromatography (silica, EtOAc)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.01-7.90 (m, 4 h), 7.57 (s, 1H), 7.42 (t, 1H, J=7.8 Hz), 7.05-7.01 (m, 2H), 6.21 (d, 1H, J=7.8 Hz), 6.04 (d, 1H, J=8.7 Hz), 4.30-4.20 (m, 3H), 3.70-3.64 (m, 1H), 3.53-3.45 (m, 1H), 2.84 (t, 2H, J=6.2 Hz), 2.56 (brs, 4 h), 2.20-2.03 (m, 3H), 1.78 (brs, 1H), 1.67-1.62 (m, 4 h), 1.50-1.48 (m, 2H), 1.27 (d, 3H, J=6.3 Hz). LC/MS: 498 [M+H]+, tR=1.13 min. HPLC: 99.24% at 214 nm, 99.34% at 254 nm, tR=5.70 min. After cooling extracted with EtOAc (3×10 mL) The combined organic layers were washed with brine then dried over MgSO4 After filtration and concentration the residue was purified by chromatography (silica, EtOAc)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-morpholinoethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.65 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.59-7.54 (m, 3H), 7.45-7.40 (m, 2H), 7.04-7.02 (m, 2H), 6.22 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=7.8 Hz), 4.25-4.20 (m, 3H), 3.79-3.76 (m, 4 h), 3.68 (brs, 1H), 3.51-3.48 (m, 1H), 2.87 (t, 2H, J=5.7 Hz), 2.64 (brs, 4 h), 2.14-2.06 (m, 3H), 1.78 (brs, 1H), 1.67-1.62 (m, 4 h), 1.50-1.48 (m, 2H), 1.25 (d, 3H, J=6.3 Hz). LC/MS: 500 [M+H]+, tR=1.13 min. HPLC: 95.85% at 214 nm, 95.41% at 254 nm, tR=5.12 min. After cooling extracted with EtOAc (10 mL×3) The combined organic layers were washed with brine dried over MgSO4 After filtration and concentration the residue was purified by chromatography (silica, EtOAc)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (8 mL 3). The combined organic layers were washed with brine, then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica gel, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-(piperidin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.67 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.60-7.53 (m, 3H), 7.45-7.37 (m, 2H), 7.05-7.01 (m, 1H), 6.23 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.31-4.21 (m, 3H), 3.71-3.65 (m, 1H), 3.54-3.48 (m, 1H), 2.85 (t, 2H, J=6.0 Hz), 2.57 (brs, 4 h), 2.17-2.04 (m, 3H), 1.76-1.62 (m, 5H), 1.48 (brs, 2H), 1.26 (d, 3H, J=6.6 Hz). LC/MS: 498 [M+H]+, tR=1.15 min. HPLC: 99.14% at 214 nm, 99.51% at 254 nm, tR=3.97 min. After cooling extracted with EtOAc (8 mL 3) The combined organic layers were washed with brine dried over MgSO4 After filtration and concentration the residue was purified by chromatography (silica gel, EtOAc)

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

Procedure: The 1-piperidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.

Conditions: temp:0.00; pressure:0.00; stir: