Reaction Steps
A microwave vial containing a mixture of biphenyl-2-yldicyclohexylphosphine (13 mg, 0.037 mmol), thiomorpholine 1,1 dioxide (30 mg, 0.22 mmol), methyl 7-chloro-5-(4-methoxybenzyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (88 mg, 0.186 mmol), potassium phosphate, tribasic (59 mg, 0.28 mmol), and tris(dibenzylideneacetone)dipalladium(0) (8.5 mg, 9.3 μmol) was flushed with nitrogen. DME (0.4 mL) was added and the vial was sealed and heated at 100° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine and the product was captured on an SCX column, washed with EtOAc and MeOH and then removed with 2N NH3 in MeOH and DCM. The solvent was removed and the crude methyl 7-(1,1-dioxido-4-thiomorpholinyl)-5-(4-methoxybenzyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (74 mg). This was dissolved in TFA (5 mL), anisole (0.142 mL, 1.30 mmol) was added, and the reaction was heated at 75° C. for 4 hr. Solvents were removed and the product was captured on an SCX column, washed with MeOH, and released with 2N NH3 in MeOH to leave crude methyl 7-(1,1-dioxido-4-thiomorpholinyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (61 mg). It was suspended in 7 N NH3 in MeOH (7 mL) and heated at 85° C. for 17 hr in a sealed microwave vial. Preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=100:0 to A:B=40:60 [A=95% H2O:5% MeOH:0.1% TFA; B=5% H2O:95% MeOH:0.1% TFA] over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-(1,1-dioxido-4-thiomorpholinyl)-2-(6-methyl-3-pyridinyl)-5H-pyrido[3,2-b]indole-4-carboxamide (14 mg, 0.031 mmol, 23% yield) as a yellow solid. MS (ESI) m/z 436.10 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (1H, br. s.), 9.31 (1H, d, J=2.01 Hz), 8.54 (1H, s), 8.49(1H, dd, J=8.18, 2.39 Hz), 8.35 (1H, s), 8.10 (1H, d, J=8.81 Hz), 7.87 (1H, s), 7.41 (1H, d, J=8.31 Hz), 7.31 (1H, d, J=2.27 Hz), 7.07 (1H, dd, J=8.81, 2.01 Hz), 3.87 (4H, d, J=4.78 Hz), 3.22 (4H, d, J=4.03 Hz), 2.55 (3H, s).
