Pyrazolo[1,5- a]pyrimidines, triazolo[1,5- a]pyrimidines and their tricyclic derivatives as corticotropin-releasing factor 1 (CRF 1) receptor antagonists

To identify structurally novel CRF1 receptor antagonists, a series of bicyclic core antagonists, pyrazolo[1,5-a]pyrimidines, triazolo[1,5- a]pyrimidines, imidazo[1,2- a]pyrimidines and pyrazolo[1,5- a][1,3,5]triazines were designed, synthesized and evaluated as CRF1 receptor antagonists. Compounds 2– 27 showed binding affinity (IC 50 = 4.2–418 nM) and antagonist activity (EC 50 = 4.0–889 nM). Compound 5 was found to show oral efficacy in an Elevated Plus Maze test in rats. Further chemical modification of them led us to discovery of the tricyclic core antagonists pyrazolo[1,5- a]pyrrolo[3,2- e]pyrimidines. The discovery process of these compounds is presented, as is the study of the structure–activity relationship.