Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators

Formation of 10/12/14‐Membered Rings is Favored over 5/6/7‐Membered. An Unexpected Result from Oxazole Chemistry

“…Oxazole is a well‐recognized biologically relevant heterocyclic template which is widespread among natural compounds (such as marine alkaloids) and synthetic drugs , . Fused oxazoles have been widely used in drug discovery, which is confirmed by structures of several marketed drugs and clinical candidates: anti‐insomnia drug suvorexant, nonsteroidal anti‐inflammatory drug flunoxaprofen, α‐adrenergic agonist azepexole, VU0409551/JNJ‐46778212 targeting schizophrenia,, or potential antidepressant and antimanic agent DSR‐98776, (Figure ). Taking into account the importance of such structural motifs, we have aimed at the preparation of the parent oxazole derivatives fused with heteroaliphatic amines ( 1 – 3 ).…”

“…It should be noted that the previous syntheses of the bicyclic systems of type 1 – 3 relied on the construction of the oxazole ring; in all cases, only compounds substituted at the C‐2 position of the heteroaromatic moiety were obtained. In this work, we have considered an alternative retrosynthetic disconnection of the bicyclic systems 1 – 3 , which relied on an intramolecular cyclization of the bifunctional oxazole derivatives 4 (Scheme ).…”