Novel Spiropiperidine Allosteric Modulators of Nicotinic Acetylcholine Receptors for Treating Central Nervous System Disorders

Important Compound Classes

Title

Spiropiperidine Allosteric Modulators of Nicotinic Acetylcholine Receptors

Patent Publication Number

WO 2021/091751 A1

Publication Date

May 14, 2021

Priority Application

US 62/930,764

Priority Date

November 5, 2019

Inventors

Bell, I. M.; Crowley, B. M.; Nantermet, P.

Assignee Company

Merck Sharp & Dohme Corp., USA

Disease Area

Central nervous system disorders

Biological Target

α7 nAChR

Summary

In human brain, α7 nicotinic acetylcholine receptors (α7 nAChRs) are highly expressed in the cortex and hippocampus, regions associated with cognition. Cognitive impairments are prevalent in many neurological and psychiatric diseases, including Alzheimer’s disease (AD), schizophrenia, and Parkinson’s disease (PD), and dysfunction in cholinergic signaling contributes to the cognitive impairments of these diseases. More specific to the α7 nAChR, it was recently demonstrated that encenicline, a partial agonist of the α7 nAChR, improves cognition in Alzheimer’s disease. Evidence implicating α7 nAChRs in the etiology of schizophrenia comes from studies demonstrating reduced expression of neuronal α7 nAChRs in the brain of schizophrenic patients. Therefore, targeting the α7 nAChR represents a therapeutic strategy for the treatment of cognitive impairments associated with various cognitive disorders. Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive deficits in motor function, such as tremor, bradykinesia, rigidity, and impaired postural reflex. Overall, α7 nAChR is an attractive target for both ameliorating disease progression and managing dyskinesia.

In recent years, α7-selective positive allosteric modulators (PAMs) have been proposed as a therapeutic approach to treating cognitive impairments in AD, PD, schizophrenia, and L-DOPA induced dyskinesia.

The present application describes a series of novel spiropiperidine allosteric modulators of α7 nicotine acetylcholine receptors that are useful for preventing, treating, or ameliorating central nervous system disorders such as cognitive impairments in AD, PD, and schizophrenia. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

W = aryl or 6–14 membered heteroaryl ring, wherein W is substituted with 0, 1, 2, or 3 R₃ substituents each independently selected from OH, oxo, NR₆R₇, CN, O(C₁–C₆)alkyl, halogen, (C₁–C₆)haloalkyl, aminoalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each R₃ is independently substituted with 0, 1, 2, or 3 R₅;

Z = H, (C₁–C₆)alkyl, aryl, or heteroaryl, wherein Z is substituted with 0, 1, 2, or 3 R₄ substituents each independently selected from OH, oxo, NR₆R₇, CN, O(C₁–C₆)alkyl, halogen, (C₁–C₆)haloalkyl, aminoalkyl, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each R₄ is independently substituted with 0, 1, 2, or 3 R₅;

X = S(O)₂ or C(O);

R₁₀ is selected from NR_aR_b and R_c;

R₂ = halogen, (C₁–C₆)alkyl, O(C₁–C₆)alkyl, cycloalkyl, or (C₁–C₆)haloalkyl or two R₂ when both are (C₁–C₄)alkyl and are attached to the same carbon atom and may join to form a cyclopropyl, cyclobutyl or cyclopentyl ring or two R₂ when both are (C₁–C₄)alkyl and are attached to the different carbon atom and may join to form a bridged ring, wherein said cyclopropyl, cyclobutyl, or cyclopentyl ring or bridged ring may be optionally substituted with 0, 1, 2, or 3 substituents independently selected from OH, halogen, or (C₁–C₄)alkyl; and

R₁ = halogen, (C₁–C₆)alkyl, O(C₁–C₆)alkyl, or (C₁–C₆)haloalkyl, or two R₁ when both are (C₁–C₄)alkyl may join to form a cyclopropyl, cyclobutyl or cyclopentyl ring and said ring is substituted with 0, 1, 2, or 3 substituents independently selected from OH, halogen or (C₁–C₄)alkyl.

Key Structures

Biological Assay

The automated patch-clamp electrophysiology functional assay (Assay A) was performed. The compounds described in this application were tested for their ability to modulate α7 nicotinic acetylcholine receptors (α7 nAChRs). The α7 nAChR EC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for α7 nAChR modulation. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 20

Compound claims: 16

Pharmaceutical composition claims: 2

Method of treating claims: 1

Use of compound claims: 1

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The author declares no competing financial interest.