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 2020/223136 A1

Publication Date

November 5, 2020

Priority Application

US 62/842,099

Priority Date

May 2, 2019

Inventors

Bell, I. M.; Campbell, B. T.; Crowley, B. M.; Fells, J.; Leavitt, K. J.; Roecker, A. J.; Harvey, A. J.; Huff, B. C.; Paul, D.; Morice, C.; Joseph, C.; Bazzini, P.; Contreras, J.; Garrido, F.; Witzel, A.

Assignee Company

Merck Sharp & Dohme Corp., USA

Disease Area

Central nervous system disorders

Biological Target

α7 nAChR

Summary

In the 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 and is 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 = or ;

R_a = H, (C₁–C₄)alkyl, (C₃–C₇)cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from R₈;

R_b = H, (C₁–C₄)alkyl;

R_c = (C₁–C₄)alkyl or heteroaryl, wherein alkyl is optionally substituted with R₉ and heteroaryl is optionally substituted with one or more R₁₀;

A = aryl or heteroaryl, wherein aryl or heteroaryl is substituted with 0, 1, 2, or 3 R₄ groups;

R₄ = OH, oxo, halogen, cyano, −S(O)_n C_1–6 alkyl, C_1–8 alkyl, (C₁–C₈)haloalkyl, C_1–6 alkoxy, C_1–6 alkoxyC_1–6 alkyl, C_1–6 alkylamino, aminoC_1–6 alkyl, hydroxyC_1–6 alkyl, C_3–8 cycloalkyl, C_3–8 cycloalkylC_1–6 alkoxy, heterocyclyl, aryl, and heteroaryl;

R₅ = H or (C₁–C₄)alkyl;

R₆ = H or (C₁–C₄)alkyl;

z = 0, 1, 2, or 3;

R₃ = H, halogen, cyano, (C₁–C₄)alkyl, OH, (C₁–C₄)haloalkyl;

R₁ and R₂ = H, halogen, (C₁–C₄)alkyl, and (C₁–C₄)haloalkyl;

Y = −C(R_dR_e)–X, −C(R_dR_e)–X–C(R_fR_g), −(C=O)–NR_h, or-C(R_d)=C(R_e);

X = O, NR_h, S(O)_m, or C(R_fR_g);

R₈ = OH, (C₁–C₄)alkyl, −O(C₁–C₄)alkyl, halogen, aryl, heteroaryl or heterocyclyl;

R₉ = halogen, aryl, heteroaryl or heterocyclyl;

R₁₀ = (C₁–C₄)alkyl, −O(C₁–C₄)alkyl, CF₃ or hydroxy;

R₁₁ = (C₁–C₄)alkyl, −O(C₁–C₄)alkyl, (C₁–C₄)haloalkyl, or hydroxy;

m = 0, 1, or 2; and

n = 0, 1, or 2.

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 (μM) are shown in the following table.

Biological Data

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

Potency is defined for EC₅₀: “A” means ≤0.1 μM; “B” means 0.1 to ≤0.5 μM; “C” means 0.5 to ≤5.0 μM and “D” 5.0 to ≤50.0 μM.

Claims

Total claims: 21

Compound claims: 17

Pharmaceutical composition claims: 2

Method of treatment claims: 1

Use of compound claims: 1

Recent Review Articles

• 1.Terry A. V.; Callahan P. M.. Neuropharmacology 2020, 170, 108053.
• 2.Miller C. N.; Kamens H. M.. Brain Res. Bull. 2020, 163, 135.
• 3.Gulsevin A.Neuropharmacology 2020, 177, 108257.
• 4.Nirthanan S.Biochem. Pharmacol. 2020, 181, 114168.
• 5.Papke R. L.; Lindstrom J. M.. Neuropharmacology 2020, 168, 108021.
• 6.Lewis A. S.; Picciotto M. R.. Neuropharmacology 2020, 167, 107929.

The author declares no competing financial interest.