Novel 3-Aminopyrrolidine and Piperidine Macrocyclic Orexin Receptor Agonists for Treating Sleep Disorders

Important Compound Classes

Title

3-Aminopyrrolidine and Piperidine Macrocyclic Orexin Receptor Agonists

Patent Publication Number

WO 2022/109117 A1

URL: https://patents.google.com/patent/WO2022109117A1/en

Publication Date

May 27, 2022

Priority Applications

US 63/117,031 and US 63/279,900

Priority Dates

November 23, 2020, and November 16, 2021

Inventors

Bogen, S. L.; Chen, P.; Clausen, D. J.; Liu, J.; Rudd, M. T.; Xiao, L.; Yang, D.; Lin, S.

Assignee Company

Merck Sharp & Dohme Corp., USA

Disease Area

Sleep disorders

Biological Target

Orexin

Summary

The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: orexin A (OX-A) (a 33 amino acid peptide) and orexin B (OX-B) (a 28 amino acid peptide). Orexins regulate states of sleep and wakefulness, potentially opening novel therapeutic approaches for narcolepsy, idiopathic hypersomnia, excessive daytime sleepiness, shift work disorder, obstructive sleep apnea, and insomnia. Orexins are found to stimulate food consumption in rats, suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior. Orexins have also been indicated as playing roles in arousal, emotion, energy homeostasis, reward, learning, and memory. Two orexin receptors have been cloned and characterized in mammals. They belong to the superfamily of G-protein-coupled receptors: the orexin-1 receptor (OX or OX1R) is partially selective for OX-A, and the orexin-2 receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B with similar affinity. The physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of the OX1 receptor and OX2 receptor as the two subtypes of orexin receptors.

The present application describes a series of novel 3-aminopyrrolidine and piperidine macrocycles as orexin receptor agonists for the treatment or prevention of neurological and psychiatric disorders and diseases, particularly sleep disorders. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

--- = absent or present as a double bond;

X = -O- or -NR- or X may be a direct bond to Y;

Y = C_1–6alkyl or C_2–6alkenyl;

Z = -O- or -NR- or Z may be a direct bond to Y;

R_1a, R_1b, and R_1c = H, halogen, OH, C_1-6alkyl, which is unsubstituted or substituted with 1–3 substituents selected from OH, F, and phenyl, -O-C_1-6alkyl, which is unsubstituted or substituted with 1–3 substituents selected from F and phenyl, C_3-6cycloalkyl, C_2-6alkynyl, -NH₂, -NH(C_1-6alkyl), -N(C_1-6alkyl)₂, -(CO)-O-C_1-6alkyl, keto, phenyl, pyridyl, and -CN;

R₃ = C_1-6alkyl, where the alkyl is unsubstituted or substituted with 1–3 F, C_3-6cycloalkyl, -NH₂, -NH(C_1-6alkyl), -N(C_1-6alkyl)₂, and phenyl;

R₅ and R₆ = H, C_1-6alkyl, where the alkyl is unsubstituted or substituted with OR, NR₂, -C(O)NR₂, or 1–3 F, and C_3-6cycloalkyl;

m = 1 or 2; and n = 1 or 2.

Key Structures

Biological Assay

The human orexin-2 receptor IP assay was performed. The compounds described in this application were tested for their orexin-2 receptor agonists activity. The hOX2R-IP IC₅₀ (nM) are shown in the table below.

Biological Data

The following table shows representative compounds tested for human orexin-2 receptor agonists activity and the biological data obtained from testing representative examples.

Claims

Total claims: 16

Compound claims: 13

Pharmaceutical composition claims: 1

Method of treatment claims: 2

The author declares no competing financial interest.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters virtual special issue “New Drug Modalities in Medicinal Chemistry, Pharmacology, and Translational Science”.