1-Pyrazolyl-5,6-Disubstituted Indazole Derivatives as LRRK2 Inhibitors for Treating Parkinson’s Disease

Important Compound Classes

Title

1-Pyrazolyl-5,6-Disubstituted Indazole Derivatives as LRRK2 Inhibitors, Pharmaceutical Compositions and Uses thereof.

Patent Publication Number

WO 2020/247298 A2

Publication Date

December 10, 2020

Priority Application

US 62/858,137

Priority Date

June 6, 2019

Inventors

Zhou, H.; Acton, J. J., III; Ardolino, M. J.; Chen, Y.; Fuller, P. H.; Gulati, A.; Johnson, R. E.; Kaplan, W. P.; Kattar, S. D.; Keylor, M. H.; Li, D.; Logan, K. M.; Lu, M.; Morriello, G. J.; Neelamkavil, S. F.; Pio, B.; Sciammetta, N.; Simov, V.; Su, J.; Torres, L.; Yan, X.

Assignee Company

Merck Sharp & Dohme Corp., 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 midbrain dopaminergic neurons leading to abnormal motor symptoms such as bradykinesia, rigidity, and resting tremor. Many PD patents show a variety of nonmotor symptoms including cognitive dysfunction, emotional changes, and sleep disruption. The combined motor and nonmotor 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-dependent 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 1-pyrazolyl-5,6-disubstituted indazole derivatives as LRRK2 inhibitors for the treatment of Parkinson’s disease. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = CH or N;

R₁ = Cl, Br, F, CH₃, CN, and CHF₂;

R₂ = -(C₁–C₃)alkyl, -(C₁–C₃)haloalkyl, optionally substituted cycloalkyl, mono, di, or trisubstituted heteroaryl, mono, di, or trisubstituted heterocycloalkyl, wherein substituent selected from oxo, CN, -(O)_0–1(C₁–C₃)alkyl, -(C₃–C₆)-cycloalkyl, -(O)_0–1(C₁–C₃)haloalkyl, NR_2AR_2B, CH₂NHC(O) (C₁–C₃)alkyl, −C(O)OH, −C(O)O(C₁–C₃)alkyl;

R_2A = H and -(C₁–C₃)alkyl;

R_2B = H and -(C₁–C₃)alkyl; and

Key Structures

Biological Assay

The LRRK2 Km ATP LanthaScreen assay was performed using a GST-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 IC₅₀ (μM) values are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for LRRK2 inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 16

Compound claims: 12

Pharmaceutical composition claims: 1

Method of treatment claims: 2

Use of compound claims: 1

Recent Review Articles

• 1.Pischedda F.; Piccoli G.. J. Neurochem. 2021, in press.
• 2.Cogo S.; Manzoni C.; Lewis P. A.; Greggio E.. J. Neurochem. 2020, 152, 273.
• 3.Balestrino R.; Shapira A. H. V.. Eur. J. Neurol. 2020, 27, 27.
• 4.Taylor M.; Alessi D. R.. Curr. Opin. Cell Biol. 2020, 63, 102.
• 5.Poewe W.; Seppi K.; Marini K.; Mahlknecht P.. Neuropharmacology 2020, 171, 108085.
• 6.Schwab A. D.; Thurston M. J.; Machhi J.; Olson K. E.; Namminga K. L.; Gendelman H. E.; Mosley R. L.. Neurobiol. Dis. 2020, 137, 104760.

The author declares no competing financial interest.