The circadian clock links our daily cycles of sleep and activity to the external environment. Deregulation of the clock is implicated in a number of human disorders, including depression, seasonal affective disorder, and metabolic disorders. Circadian rhythms are controlled in mammals by the master clock located in the suprachiasmatic nucleus of the hypothalamus (Antle and Silver, Trends Neurosci 28: 145-151). At the cellular level, the molecular events behind clock cycling are described by the regular increase and decrease in mRNAs and proteins that define feedback loops, resulting in approximately 24 hour cycles. The suprachiasmatic nucleus is primarily regulated, or entrained, directly by light via the retinohypothalamic tract. The cycling outputs of the suprachiasmatic nucleus, not fully identified, regulate multiple downstream rhythms, such as those in sleep and awakening, body temperature, and hormone secretion (Ko and Takahashi, Hum Mol Gen 15: R271-R277.). Furthermore, diseases such as depression, seasonal affective disorder, and metabolic disorders, may have a circadian origin (Barnard and Nolan, PLoS Genet. 2008 May; 4(5): e1000040).
Phosphorylation of circadian clock proteins is an essential element in controlling the cyclical rhythm of the clock. CK1ε and CK1δ are closely related Ser-Thr protein kinases that serve as key clock regulators as demonstrated by mammalian mutations in each that dramatically alter the circadian period. (Lowrey et al., Science 288: 483-492). Therefore, inhibitors of CK1δ/ε have utility in treating circadian disorders. Thus it is an object of this invention to provide compounds of Formula I that are inhibitors of CK1δ or CK1ε. This object and other objects of this invention become apparent from the detailed discussion of the invention that follows.