Reaction Steps
1-Pyridin-3-yl-ethanone (2 g, 16.52 mmol) was dissolved in a mixture of AcOH (8 mL) and HBr (4 mL). After stirring for 20 minutes, Br2 (1.0 eq) in CHCl3 (3 mL) was added in a period of 5 minutes. When the reaction was completed, the solids were filtered out and washed with water and extracted with EtOAc. The organic phase was dried, evaporated, and used for next step. Compound 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (300 mg, 1.075 mmol) was dissolved in MeOH (7 mL) and 2-Bromo-1-pyridin-3-yl-ethanone (1.2 eq) was added and refluxed at 85° C. for 30 minutes. The reaction mixture was washed with saturated aqueous solution of NaHCO3 and then extracted with EtOAc. The organic phase was dried, evaporated and used for next step without any purification. Compound 4-[4-(4-pyridin-3-yl-thiazol-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid methyl ester (200 mg, 0.52 mmol) was dissolved in MeOH and 1N NaOH was added. After reaction was complete, the mixture was evaporated and acidified slowly with 1N HCl. The formed solid was filtered out and used for next step without purification. Compound 4-[4-(4-Pyridin-3-yl-thiazol-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid HATU (171 mg, 1.1 eq), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (136 mg, 1.1 eq), and DIPEA (0.14 mL, 2.0 eq) were dissolved in DMF and heated at 50° C. overnight. The reaction mixture was washed with water and extracted with EtOAc. The organic phase was dried, evaporated, and re-dissolved in a mixture of DCM and TFA (1:1). After stirring for 1 hour at room temperature the mixture was evaporated and purified by reverse phase chromatography to give Example 22. MS found for C30H26N4O2S2 as (M+H)+ 539.12. 1H NMR (400 MHz, dmso-d6): δ: 9.64 (s, 1H), 9.12 (d, J=1.6 Hz, 1H), 8.49 (dd, J=4.8, 3.2 Hz, 1H), 8.26-8.23 (m, 1H), 8.17 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.43-7.28 (m, 2H), 7.27 (t, J=4.4 Hz, 1H), 7.22 (dd, J=8.4, 6.1 Hz, 1H), 7.16-7.15 (m, 1H), 6.97 (dd, J=5.2, 1.6 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.09 (s, 2H), 3.73-3.70 (m, 2H), 3.63-3.58 (m, 2H), 2.67-2.64 (m, 2H), 2.42-2.36 (m, 2H).
