3-methylsulfonylazetidine

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

Procedure: A solution of 3-methanesulfonyl-azetidine (10.95 mg, 0.08 mmol) (Pharmablock Co. Ltd, cat# PBJH0053), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (24 mg, 0.081 mmol) and DIEA (15.50 μL, 0.09 mmol) in 0.5 mL of NMP was heated in a microwave at 125° C. for 30 min. Purification of the crude reaction mixture on a silica gel column (1-6% MeOH in DCM) gave 2-(2-methyl-3-(3-(methylsulfonyl)azetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16 mg, 48% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br.), 7.93 (1H, m, 7.65 (1H, m), 7.44 (1H, m), 7.14 (1H, s), 6.99 (1H, br.), 4.72 (2H, m), 4.60 (2H, m), 4.48 (1H, m), 3.43 (2H, m), 3.15 (3H, s), 2.89 (2H, m), 2.63 (3H, s). m/z (ESI, +ve) 12.1 (M+H)+. Purification of the crude reaction mixture on a silica gel column (1-6% MeOH in DCM)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (0.327 mL, 2.345 mmol) and 3-(methylsulfonyl)azetidine (PharmaBlock, Carrboro, N.C.; 241 mg, 1.786 mmol) were sequentially added to a solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl methanesulfonate (375 mg, 0.558 mmol) in CH2Cl2 (5.5 mL) and the resulting mixture was stirred at 25° C. for 21 h. The reaction mixture was then concentrated in vacuo and chromatographically purified (silica gel, 0 to 100% (10% MeOH-EtOAc)/hexanes) to furnish N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(3-(methylsulfonyl)azetidin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (141.0 mg, 0.198 mmol, 35.5% yield) as a yellow oil. m/z (ESI, +ve) 711.3 (M+H)+. The reaction mixture was then concentrated in vacuo chromatographically purified (silica gel, 0 to 100% (10% MeOH-EtOAc)/hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (0.327 mL, 2.345 mmol) and 3-(methylsulfonyl)azetidine (PharmaBlock, Carrboro, N.C.; 241 mg, 1.786 mmol) were sequentially added to a solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl methanesulfonate (375 mg, 0.558 mmol) in CH2Cl2 (5.5 mL) and the resulting mixture was stirred at 25° C. for 21 h. The reaction mixture was then concentrated in vacuo and chromatographically purified (silica gel, 0 to 100% (10% MeOH-EtOAc)/hexanes) to furnish N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(3-(methylsulfonyl)azetidin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (141.0 mg, 0.198 mmol, 35.5% yield) as a yellow oil. m/z (ESI, +ve) 711.3 (M+H)+. The reaction mixture was then concentrated in vacuo chromatographically purified (silica gel, 0 to 100% (10% MeOH-EtOAc)/hexanes)

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

Procedure: The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.200 g, 0.346 mmol) and 3-(methylsulfonyl)azetidine (PharmaBlock, Carrboro, N.C.) (0.070 g, 0.519 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.81 (s, 1H); 8.88 (br. s., 1H); 8.54 (d, J=2.74 Hz, 1H); 8.38 (d, J=1.76Hz, 1H); 8.13 (dd, J=8.90, 2.64 Hz, 1H); 7.77-7.94 (m, 2H); 6.85 (d, J=8.80 Hz, 1H); 4.09-4.58 (m, 7H); 3.85 (s, 3H); 3.12 (s, 3H); 2.44 (s, 3H). m/z (ESI, +ve ion) 456.8 (M+H)+.

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

Procedure: A solution of 3-methanesulfonyl-azetidine (10.95 mg, 0.08 mmol) (Pharmablock Co. Ltd, cat# PBJH0053), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (24 mg, 0.081 mmol) and DIEA (15.50 μL, 0.09 mmol) in 0.5 mL of NMP was heated in a microwave at 125° C. for 30 min. Purification of the crude reaction mixture on a silica gel column (1-6% MeOH in DCM) gave 2-(2-methyl-3-(3-(methylsulfonyl)azetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16 mg, 48% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br.), 7.93 (1H, m, 7.65 (1H, m), 7.44 (1H, m), 7.14 (1H, s), 6.99 (1H, br.), 4.72 (2H, m), 4.60 (2H, m), 4.48 (1H, m), 3.43 (2H, m), 3.15 (3H, s), 2.89 (2H, m), 2.63 (3H, s). m/z (ESI, +ve) 12.1 (M+H)+. Purification of the crude reaction mixture on a silica gel column (1-6% MeOH in DCM)