5-Bromo-4-methyl-2-(methylthio)pyrimidine can be used to prepare pyrazole derivatives having the following structure, which can act as inhibitors of cyclin-dependent kinases. These compounds, their intermediates, and pharmaceutical compositions comprising these compounds can be used to treat diseases related to protein kinase disorders. This invention also reports these compounds or compositions thereof as modulators of Jak1, Jak2, and Jak3, as well as CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, and CDK9. This invention also relates to methods of combination therapy, which apply the compounds or pharmaceutical compositions of this invention or their kits to inhibit protein kinase activity in cells or to treat, prevent, or improve one or more symptoms of cancer, transplant rejection, and autoimmune diseases in patients.
Sodium methanethiol (1.04 g, 11.6 mmol) was added batchwise to a solution of 5-bromo-4-methyl-2-chloropyrimidine (2.0 g, 9.66 mmol) in DMF (20 mL) at 0 C. After addition, the mixture was stirred at room temperature for 16 h, then poured into water (100 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with water (50 mL), brine (50 mL), dried with Na2SO4 and then concentrated in vacuum to give the target compound (2.0 g, 94.5%) as a yellow oil.LC-MS:[MH]+ =218.8.
