Novel C-Linked Isoquinoline Amides as LRRK2 Inhibitors for Treating Parkinson’s Disease

Abstract

Provided herein are novel C-linked isoquinoline amides as LRRK2 inhibitors, their pharmaceutical compositions, the use of such compounds in treating Parkinson’s disease, and processes for preparing such compounds.

Important Compound Classes

Title

C-Linked Isoquinoline Amides as LRRK2 Inhibitors, Pharmaceutical Compositions, and Uses Thereof

Patent Publication Number

WO 2023/055679 A1

URL:https://patents.google.com/patent/WO2023055679A1/en

Publication Date

April 6, 2023

Priority Application

US 63/251,193

Priority Date

October 1, 2021

Inventors

Fuller, P. H.; Gulati, A.; Kattar, S. D.; Keylor, M. H.; Margrey, K. A.; Torres, L.; Yan, X.

Assignee Company

Merck Sharp & Dohme LLC, USA

Disease Area

Parkinson’s disease

Biological Target

Leucine-rich repeat kinase 2 (LRRK2)

Summary

Parkinson’s disease (PD) is a common neurodegenerative disease caused by progressive loss of mid-brain dopaminergic neurons leading to abnormal motor symptoms such as bradykinesia, rigidity, and resting tremor. Many PD patients show a variety of non-motor symptoms including cognitive dysfunction, emotional changes, and sleep disruption. The combined motor and non-motor symptoms of PD severely impact patient quality of life.

While most PD cases are idiopathic, there are several genetic determinants such as mutations in SNCA, Parkin, PINK1, DJ-1, and LRRK2. Linkage analysis studies have demonstrated that multiple missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene lead to an autosomal late onset form of PD. LRRK2 is a 286 kDa cytoplasmic protein containing kinase and GTPase domains as well as multiple protein–protein interaction domains.

In vitro biochemical studies have demonstrated that LRRK2 proteins harboring the PD-associated proteins generally confer increased kinase activity and decreased GTP hydrolysis compared to the wild-type protein, thereby suggesting that small molecule LRRK2 kinase inhibitors may be able to block aberrant LRRK2-depedent signaling in PD. LRRK2 expression is highest in the same brain regions that are affected by PD. LRRK2 is found in Lewy bodies, a pathological hallmark of PD as well as other neurodegenerative diseases such as Lewy body dementia.

The present application describes a series of novel C-linked isoquinoline amides as LRRK2 inhibitors for the treatment of PD. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

R₁ = C_1–6 alkyl, -(R)-phenyl, monocyclic, spirocyclic or bicyclic -(R)-C_3–8 cycloalkyl, -(R)-C_3–10 heterocyclyl, and -(R)-C_5–10 heteroaryl, said alkyl, phenyl, cycloalkyl, heterocyclyl and heteroaryl optionally substituted with 1 to 4 groups selected from R_a;

R₂ = H, C_1–6 alkyl, and halogen; and

R₃ = C_1–6 alkyl, spiropentanyl, cyclopropyl, cyclobutyl, cyclohexyl, and C-linked tetrahydropyranyl, C-linked piperidinyl, and C-linked oxabicycloheptanyl, said alkyl, spiropentanyl, cyclopropyl, cyclobutyl, cyclohexyl, tetrahydropyranyl, piperidinyl, and oxabicycloheptanyl are unsubstituted or substituted with 1 to 3 groups selected from R_c.

Key Structures

Biological Assay

The LRRK2 Km ATP LanthaScreen assay was performed using a GST20-tagged truncated human mutant G2019S LRRK2 in the presence of the fluorescein-labeled peptide substrate LRRKtide. The compounds described in this application were tested for their ability to inhibit LRRK2. The LRRK2 pIC₅₀ values (nM) are shown in the table below.

Biological Data

The following table shows representative compounds tested for LRRK2 inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 24

Compound claims: 20

Pharmaceutical composition claims: 1

Method of treatment claims: 2

Use of compound claims: 1

Recent Review Articles

See refs (1−6).

The authors declare no competing financial interest.