Previously we reported the structure
Previously, we reported the structure–activity-relationships (SAR) of a series of pyrazinone-based CRF receptor antagonists, , , leading to highly potent and efficacious compounds such as , and ultimately to the discovery of (BMS-764459, ). Detailed SAR studies of the lower phenyl/pyridyl substituent and the small substituent (R), as well as a limited group of substituents at R were described. During the greater course of our investigation, SAR studies that included additional structural diversity at the upper R substituent were also conducted. As part of this investigation, an attempt was made to incorporate a modest degree of polarity into the R substituent to improve the physiochemical properties of these molecules and to further probe this region of the CRF receptor to assess the tolerance for other functionalities. In this Letter, the synthesis and SAR of pyrazinone-based CRF receptor antagonists incorporating either carbamate or aryl ether functional groups within the R substituent are described (). These target molecules could be rapidly prepared from a common alcohol intermediate (). On the basis of previously described SAR for our pyrazinone-based chemotype, the cyclopropyl group at the branching position of R was held constant. The synthesis of a series of pyrazinones bearing ester, carbamate and aryl ether functional groups is illustrated in , . The synthesis of was previously described. We observed that demethylation of the methoxy group in Imiloxan hydrochloride could be effected in high yield by treatment with BBr. The resultant alcohol () was then converted to an ester by treatment with NaH and an acid chloride to afford compounds – in moderate yields. Treatment of alcohol with NaH and various isocyanates at 0°C resulted in the formation of carbamate analogs – and –. For analog , where no commercially available isocyanate was available, a two-step procedure was employed. Alcohol was treated with 4-nitrophenylchloroformate and EtN to afford an activated carbonate intermediate which was subsequently treated with 3-(6-OMe-2-Me)-pyridylamine in the presence of HOBt to form the desired carbamate analog (). Preparation of the 2-pyridyl ether analogs (–) was accomplished by alkylation of alcohol with 2-bromopyridines in the presence of NaH to afford the desired pyridyl ether analogs in low to moderate yield. Preparation of the 3-pyridyl analog was carried out by conversion of alcohol to the tosylate, followed by displacement with 3-hydroxypyridine in the presence of NaH to afford . As previously reported, it was found that there was little difference in the potency of enantiomers at the chiral center in the R substituent in this pyrazinone chemotype; hence, it was decided to synthesize only -enantiomers for this investigation. Preparation of carbamate analogs containing a difluoromethoxypyridyl group in place of the methoxypyridyl group was carried out in a similar fashion whereby methyl ether was treated with BBr followed by alkylation with an isocyanate in the presence of sodium hydride to furnish – ().