Novel Heterocyclic Compounds for Treating Huntington’s Disease

Abstract

Provided herein are novel heterocyclic compounds, pharmaceutical compositions, use of such compounds in treating Huntington’s disease, and processes for preparing such compounds.

Important Compound Classes

Title

Heterocyclic Compounds for Treating Huntington’s Disease

Patent Publication Number

WO 2023/225244 A1

URL: https://patents.google.com/patent/WO2023225244A1/en

Publication Date

November 23, 2023

Priority Application

US 63/344,494

Priority Date

May 20, 2022

Inventors

Huff, S. E.; Mustafa, D. N.; Antoszewski, A.; Mondal, D.; Pfaffenbach, M.; Harvey, J.; Smith, D. R.; Bolduc, P.; Bansal, N.; Xu, C.; Peterson, E.

Assignee Company

Biogen Ma Inc., USA

Disease Area

Huntington’s disease

Biological Target

Huntington protein

Summary

Huntington’s disease (HD) is an autosomal dominant progressive neurodegenerative disorder, which has a prevalence of between three and seven individuals per 100,000 worldwide. HD is caused by cytosine–adenine–guanine (CAG) repeat expansions in the Huntington (HTT) gene resulting in the production of a ubiquitously expressed pathogenic mutant HTT (mHTT) protein. Mutant Huntington contains an abnormally long polyglutamine (polyQ) sequence that corresponds to the CAG genetic expansion; the protein exhibits toxic properties that cause dysfunction and death of neurons. The disease is characterized by motor, cognitive, psychiatric, and functional capacity decline. Currently, a small-molecule compound platform, which modulates RNA expression, i.e., splicing, is under development.

The present application describes a series of novel heterocyclic compounds for treating Huntington’s disease. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

--- = single or double bond, provided the ring containing X₁, X₂, X₃, and X₄ is a bicyclic heteroaryl ring comprising at least one N atom;

X₁ = C or N; X₂ = O, N, or CR₂; X₃ = N or C;

X₄ = N, O, NR₄, or CR₄, provided when X₁ is C, at least two of X₂, X₃, and X₄ are O, N, or NR₄;

R₅ = H, halo, OH, C_1–6alkyl, C_1–6haloalkyl, C_1–6alkoxyl, or C_1–6haloalkoxyl; and

R₆ = A, N(R_6a)-A, C(=O)A, N(R_6a)C(=O)-A, or C(=O)N(R_6a)-A; and

R₇ = B; additionally R₆ is B and R₇ is A when X₁ is N.

Key Structures

Biological Assay

The in vitro mutant and total Huntington (HTT) protein cellular assay in humans was performed. The compounds described in this application were tested, and their IC₅₀ values (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested and the biological data obtained from testing representative examples.For IC₅₀, A means <100 nM.

Claims

Total claims: 61

Compound claims: 59

Pharmaceutical composition claims: 1

Method of treatment claims: 1

Recent Review Articles

See refs (1−6).

The authors declare no competing financial interest.