Novel Heteroaryl Compounds for Treating Huntington’s Disease

Important Compound Classes

Title

Heteroaryl Compounds for Treating Huntington’s Disease

Patent Publication Number

WO 2020/005882 A1

Publication Date

January 2, 2020

Priority Application

US 62/690,605

Priority Date

June 27, 2018

Inventors

Chen, G.; Bhattacharyya, A.; Jiang, Y.; Karp, G. M.; Narasimhan, J.; Turpoff, A.; Zhang, N.

Assignee Company

PTC Therapeutics, Inc., USA

Disease Area

Huntington’s disease

Biological Target

Huntington protein

Summary

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13–15 years after the onset of symptoms. The prevalence of HD is between three to seven individuals per 100 000 in populations of western European descent. In North America, an estimated 30 000 people have HD, while an additional 200 000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the “mutant” huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded polyglutamine (polyQ) stretch, also known as a “CAG repeat” sequence. There are no current small molecule therapies targeting the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or ameliorating HD.

The present application describes a series of novel bicyclic heteroaryl compounds of Formula (I), Formula (II), Formula (III), or Formula (IV), useful for treating or ameliorating Huntington’s disease. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = N-R_b, O, and a bond;

R_b = H and C_1–6alkyl;

R₁ = heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated 3–7 membered monocyclic, 6–10 membered bicyclic, or 13–16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, and wherein each heterocyclyl is optionally substituted by valences with one, two, three, or four R₃ substituents;

R₃ = CN, halogen, OH, C_1–6alkyl, deutero-C_1–6alkyl, halo-C_1–6alkyl, C_1–6alkoxy, halo-C_1–6alkoxy, C_1–6alkoxy-C_1–6alkyl, amino, C_1–6alkyl-amino, (C_1–6alkyl)₂-amino, amino-C_1–6alkyl, hydroxy-C_1–6alkyl, and C_3–10cycloalkyl;

R₂ = phenyl and heteroaryl, wherein heteroaryl is 3–7 membered monocyclic, 6–10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, and wherein each phenyl or heteroaryl is optionally substituted by valences with one, two, or three R₄ substituents and optionally, with one additional R₅ substituent;

R₄ = CN, halogen, OH, C_1–6alkyl, deutero-C_1–6alkyl, halo-C_1–6alkyl, C_1–6alkoxy, halo-C_1–6alkoxy, C_1–6alkoxy-C_1–6alkyl, amino, C_1–6alkyl-amino, (C_1–6alkyl)₂-amino, amino-C_1–6alkyl, and hydroxy-C_1–6alkyl;

R₅ = heteroaryl, wherein heteroaryl is 3–7 membered monocyclic, 6–10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O or S, and wherein each heteroaryl is optionally substituted by valences with one, two, or three R₆ substituents; and

R₆ = CN, halogen, OH, C_1–6alkyl, deutero-C_1–6alkyl, halo-C_1–6alkyl, C_1–6alkoxy, halo-C_1–6alkoxy, C_1–6alkoxy-C_1–6alkyl, amino, C_1–6alkyl-amino, (C_1–6alkyl)₂-amino, amino-C_1–8alkyl, and hydroxy-C_1–6alkyl.

Key Structures

Biological Assay

The endogenous Huntington protein assay was performed. The compounds described in this application were tested, and their IC₅₀ (μM) values are shown in the following Table.

Biological Data

The Table below shows representative compounds that were tested. The biological data obtained from testing representative examples are listed in the following Table. For IC₅₀: (*) means between >3.0 μM and ≤9.0 μM; (**) means between >1.0 μM and ≤3.0 μM; (***) means between >0.5 μM and ≤1.0 μM; (****) means between >0.1 μM and ≤0.5 μM; and (*****) means ≤0.1 μM.

Claims

Total claims: 16

Compound claims: 6

Pharmaceutical composition claims: 2

Use of compound claims: 6

Method of treatment claims: 2

Recent Review Articles

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• 3.Karagas N. E.; Rocha N. P.; Stimming E. F.. J. Huntington’s Dis. 2020, 9, 107. 10.3233/JHD-200397.
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• 6.Gubert C.; Renoir T.; Hannan A. J.. Neurobiol. Dis. 2020, 142, 104958. 10.1016/j.nbd.2020.104958.

The author declares no competing financial interest.