Novel Bicyclic Heteroaryl Compounds as γ-Secretase Modulators for Treating Alzheimer’s Disease

Important Compound Classes

Title

7-Phenoxy-N-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1.2.4]triazol-2-amine Derivatives and Related Compounds as Gamma-Secretase Modulators for the Treatment of Alzheimer’s Disease

Patent Publication Number

WO 2020/120521 A1

Publication Date

June 18, 2020

Priority Application

EP 18212199.6

Priority Date

December 13, 2018

Inventors

Frei, B; Ratni, H.

Assignee Company

F. Hoffmann-La Roche AG, Switzerland and Hoffmann-La Roche Inc., USA

Disease Area

Alzheimer’s Disease

Biological Target

γ-Secretase

Summary

Alzheimer’s disease (AD) is the most common cause of dementia in later life. Pathologically, AD is characterized by the deposition of amyloid in extracellular plaques and intracellular neurofibrillary tangles in the brain. The amyloid plaques are mainly composed of amyloid peptides (Aβ peptides) which originate from the β-amyloid precursor protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified of which the most abundant are proteins of 695, 751, and 770 amino acid length. They all arise from a single gene through differential splicing. The Aβ peptides are derived from the same domain of the APP.

Aβ peptides are produced from APP through the sequential action of two proteolytic enzymes termed as β-secretase and γ-secretase. β-secretase cleaves first in the extracellular domain of APP just outside of the trans-membrane domain (TM) to produce a C-terminal fragment of APP (CTFβ) containing the TM- and cytoplasmic domain. CTFβ is the substrate for γ-secretase, which cleaves at several adjacent positions within the TM to produce the Aβ peptides and the cytoplasmic fragment. Various proteolytic cleavages mediated by γ-secretase result in Aβ peptides of different chain lengths, e.g., Aβ38, Aβ40, and Aβ42. The later one is regarded to be the more pathogenic amyloid peptide because of its strong tendency to form neurotoxic aggregates. β-Secretase is a typical aspartyl protease.

γ-Secretase is a high molecular weight complex that consists of four essential subunits: presenilin (PS, including PS1 and PS2), nicastrin, interior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2). The presenilins are bearing the catalytic site and represent a group of a typical aspartyl proteases, which cleave their substrates within the TM and which are themselves polytopic membrane proteins. The other essential components of γ-secretase, nicastrin, and the products of the aph1 and pen2 genes are believed to be responsible for substrate recognition and recruitment.

The γ-secretase activity is absolutely required to produce Aβ peptides. This has been shown both by genetic means, i.e., ablation of the presenilin genes, and by low-molecular weight inhibitory compounds. According to the amyloid cascade hypothesis for AD the production and deposition of Aβ is the ultimate cause for the disease. Therefore, it is believed that selective and potent inhibition of γ-secretase might be useful for the prevention and treatment of AD. An alternative mode of treatment is the modulation of γ-secretase activity, which results in a selective reduction of Aβ42 production. This would lead to an increase of shorter Aβ isoforms, such as Aβ38, Aβ37, or others, which have no or reduced capability for aggregation or plaque formation and are not or less neurotoxic. Therefore, modulating the γ-secretase activity is a promising therapeutic strategy for the treatment or prevention of diseases associated with the deposition of β-amyloid in the brain, such as Alzheimer’s disease.

The present application describes a series of novel bicyclic heteroaryl compounds as γ-secretase modulators and are useful for treatment of Alzheimer’s disease. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy or lower alkoxy substituted by halogen, and

R₁ may be different if n = 2 or 3;

m = 1, 2, or 3;

n = 1, 2, or 3;

Ar = a six membered heteroaryl group, selected from

andwherein

R₂ = hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, or lower alkoxy;

R₃ = hydrogen or halogen.

Key Structures

Biological Assay

The human cellular γ-secretase assay was performed. The compounds described in this application were tested for their ability to inhibit Aβ42 secretion. The Aβ42 IC₅₀ (μM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for Aβ42 secretion inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 21

Compound claims: 15

Use of compound claims: 2

Process for preparing compound claims: 1

Pharmaceutical composition claims: 1

Method of treatment claims: 1

Invention claims: 1

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The author declares no competing financial interest.