Pyrazolyl–benzoxazole derivatives as protein kinase inhibitors. Design and validation of a combinatorial library

Abstract The malfunctioning of protein kinases is a hallmark of numerous diseases, for which a satisfactory therapy is missing. We describe the design and synthesis of a kinase targeted library based on a novel 2-(3-phenyl-1 H -pyrazol-4-yl)-1,3-benzoxazole scaffold. Ethyl 3-(3-nitrophenyl)pyrazole-4-carboxylate and its 4-nitro regioisomer were bound to trityl chloride resin, saponified with NaOH in MeOH, and amidated with a choice of two o -aminophenols. The resulting N -(2-hydroxyphenyl)amides were cyclized by Mitsunobu reaction to form four variants of the pyrazolyl–benzoxazole core template. Straightforward stannous chloride reduction of the nitro group on solid phase allowed subsequent scaffold derivatization via acylation or sulfonylation of the obtained amino function. Cleavage with TFA gave rise to the final compounds (36 examples).