I. Studies on the Synthesis of Pyrazolo[1,5-α] [1,3,5]triazine Class CRHR1 Antagonists II. Synthetic Studies Toward CRHR1 Antagonists Through C-H Activation of 2,7-Dimethylpyrazolo[1,5-α] [1,3,5]triazin-4(3H)-one

Abstract

Part I. Studies on the Synthesis of Pyrazolo[1,5-α][1,3,5]triazine class CRHR1 antagonists The study of corticotrophin-releasing hormone is of great interest in mental health. Compounds that have a pyrazolo[1,5-α][1,3,5]triazine skeleton such as BMK-I-152 and MJL1-109-2 have been revealed as high-affinity potential CRHR1 Positron Emission Tomography (PET) ligands. It has become obvious that fluorinated compounds have an extraordinary property in medicinal chemistry and will play an important role in therapeutic applications. Since BMK-I-152 had shown extremely high binding affinities but less desirable in vivo PK behavior, we were curious about the outcome on the change of the methoxy group of BMK-I-152 to a trifluoromethyl group. Part I describes the study on the synthesis of such trifluoromethyl-containing pyrazolo[1,5-α][1,3,5]triazine class CRHR1 antagonists. Key words: CRHR1 antagonists, fluoro compound, pyrazolo[1,5-α]-1,3,5-triazine

Part II. Synthetic Studies Toward CRHR1 Antagonists Through C-H Activation of 2,7-Dimethylpyrazolo[1,5-α][1,3,5]triazin-4(3H)-one Synthesis of CRHR1 antagonists in a linear fashion requires lengthy steps. Therefore, a convergent synthesis using an intermolecular coupling reaction as a key step will be a very attractive alternative. Herein, we report an efficient intermolecular reaction of two fragments based on the C-H activation of 2,7-dimethylpyrazolo[1,5-α][1,3,5]triazin-4(3H)-one using palladium catalyst. This protocol can be utilized as a novel approach for the efficient synthesis of pyrazolo[1,5-α][1,3,5]triazine class CRHR1 antagonists. Key words: C-H activation, pyrazole, CRHR1 antagonists, palladium catalysis