azetidine-3-carbonitrile

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

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

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

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

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

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

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

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

Procedure: To a solution of 6-bromo-N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (142) (200 mg, 0.47 mmol) and DIEA (0.25 mL, 1.41 mmol) in dichloromethane (5 mL) was added MsCl (108.1 mg, 0.94 mmol). The mixture was stirred at room temperature for 10 minutes and then diluted with dichloromethane (10 mL) and washed with water. The organic layers were dried over Na2SO4, filtered and concentrated to give a residue which was dissolved in DMF (2 mL). Then azetidine-3-carbonitrile (116 mg, 1.41 mmol) was added and the reaction mixture was heated at 80° C. for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated to give the crude product which was purified by silica chromatography to yield 6-bromo-N-(5-(5-((3-cyanoazetidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (143). 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 9.62 (dd, J=0.8, 2.0 Hz, 1H), 8.60 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.79 (dd, J=0.8, 9.6 Hz, 1H), 7.68 (dd, J=2.0, 9.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.06 (s, 2H), 3.67 (m, 2H), 3.51-3.60 (m, 3H), 2.37 (s, 3H). MS m/z 492.0, 494.0 (M+1)+. washed with water The organic layers were dried over Na2SO4 filtered concentrated to give a residue which the reaction mixture was heated at 80° C. for 1 hour extracted with EtOAc The organic layers were dried over Na2SO4 filtered concentrated to give the crude product which was purified by silica chromatography

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

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

Procedure: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and azetidine-3-carbonitrile

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

Procedure: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and azetidine-3-carbonitrile

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

Procedure: To a solution of 6-bromo-N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (142) (200 mg, 0.47 mmol) and DIEA (0.25 mL, 1.41 mmol) in dichloromethane (5 mL) was added MsCl (108.1 mg, 0.94 mmol). The mixture was stirred at room temperature for 10 minutes and then diluted with dichloromethane (10 mL) and washed with water. The organic layers were dried over Na2SO4, filtered and concentrated to give a residue which was dissolved in DMF (2 mL). Then azetidine-3-carbonitrile (116 mg, 1.41 mmol) was added and the reaction mixture was heated at 80° C. for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated to give the crude product which was purified by silica chromatography to yield 6-bromo-N-(5-(5-((3-cyanoazetidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (143). 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 9.62 (dd, J=0.8, 2.0 Hz, 1H), 8.60 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.79 (dd, J=0.8, 9.6 Hz, 1H), 7.68 (dd, J=2.0, 9.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.06 (s, 2H), 3.67 (m, 2H), 3.51-3.60 (m, 3H), 2.37 (s, 3H). MS m/z 492.0, 494.0 (M+1)+. washed with water The organic layers were dried over Na2SO4 filtered concentrated to give a residue which the reaction mixture was heated at 80° C. for 1 hour extracted with EtOAc The organic layers were dried over Na2SO4 filtered concentrated to give the crude product which was purified by silica chromatography