Numerous small molecule CRF receptor antagonists have

Numerous small molecule CRF receptor antagonists have been reported in the literature. Some representative examples are shown in . In preclinical studies (DMP696), , was found to be efficacious in preclinical behavioral models for anxiety and depression. In an open label clinical trial with (R121919), it was reported that depressed patients showed reductions in depression symptoms, as rated by both patients and clinicians., However, when (CP-316,311) was tested in patients in a 6-week randomized, placebo-controlled trial for the treatment of major depression, it failed to show efficacy. Likewise, when pexacerfont () was tested in a randomized, double-blind, active comparator and placebo-controlled clinical trial for generalized anxiety disorder, it also failed to show efficacy in patients. Although the outcomes of these trials were mixed, there remains an urgent need for novel treatment approaches with a rapid onset of action for those suffering from anxiety and depression disorders. Efforts to discover additional small-molecule CRF receptor antagonists suitable for testing in clinical trials, thus potentially offering a novel approach for the treatment of diseases such as anxiety and depression, have been the focus of a number of research groups. Common features shared by most of the reported small molecule CRF receptor antagonists include a monocyclic or bicyclic heterocyclic aromatic scaffold containing a required sp-hybridized basic nitrogen, which serves as a key hydrogen bond acceptor (). This core heterocyclic ring system generally bears three substituents: a small substituent at R (e.g., methyl, halo, cyano, etc.), which is believed to fit into a small lipophilic pocket; a larger group at R, which appears to fit into a large lipophilic pocket that can accommodate a wider variety of substituents, thus providing the potential opportunity to optimize binding affinity and physical properties; and an orthogonally oriented aryl or heteroaryl group attached to the core heterocycle by a carbon, nitrogen or oxygen omecamtiv (B, ). Various small molecule CRF receptor antagonists have been reported with heterocyclic R groups included to modulate potency and polarity. Examples in include the pyrazole (emicerfont; pIC=7.2), which also contains a hydrogen bond donor group, the oxadiazole (p=8.2) and the phenyl-substituted 1,2,3,6-tetrahydropyridine (IC=20nM). 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 compound 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 ().