Selective modulators of mutant LRRK2 proteolysis and associated methods of use

Patent metadata

Field	Value
Publication number	US-12473294-B2
Application number	US-202318511018-A
Country	US
Kind code	B2
Filing date	Nov 16, 2023
Priority date	Mar 21, 2020
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

Bifunctional compounds, which find utility as modulators of non-receptor Leucine-rich repeat kinase 2 (LRRK2), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds LRRK2, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

First claim

What is claimed is:

1 . A method of treating a disease or a disorder associated with LRRK2, comprising administering an effective amount of a compound having the chemical structure:
PTM-L-CLM, or a pharmaceutically acceptable salt thereof,
wherein:
(a) the CLM is:

wherein:
W is selected from CH 2 , O, CHR, C═O, SO 2 , NH, N, optionally substituted cyclopropyl group, optionally substituted cyclobutyl group, and N-alkyl;
W 3 is C or N;
each X is independently selected from absent, O, S, and CH 2 ;
Y is selected from CH 2 , —C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
Z is selected from absent, O, S, and CH 2 ;
G and G′ are independently selected from H, unsubstituted or substituted linear or branched alkyl, OH, R′OCOOR, R′OCONRR″, CH 2 -heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;
Q 1 , Q 2 , Q 3 , and Q 4 represent C or N independently substituted with H, R, N, or N-oxide;
A is independently selected from H, unsubstituted or substituted linear or branched alkyl, cycloalkyl, —Cl, and —F;
m′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R is a bond, H, —CONR′R″, —C(═O)R′, —OR′, —NR′R″, —SR′, —SO 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, (—CR′O) n′ R″, optionally substituted heterocyclyl, aryl, optionally substituted alkyl-aryl, heteroaryl, unsubstituted or substituted linear or branched alkyl, optionally substituted alkoxyl group, optionally substituted heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF 3 , —CN, —NR′SO 2 NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO 2 )NR′R″, —SO 2 NR′COR″, —NO 2 , —CO 2 R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF 5 and —OCF 3 , wherein at least one R or W is modified to be covalently joined to the PTM, L, or the CLM;
R′ and R″ are independently selected from a bond, H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and optionally substituted heterocyclyl;
n′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

represents a single bond or a double bond; and

represents a bond that may be stereospecific or non-stereospecific;

(b) the PTM is selected from:

and
wherein

of the PTM indicates the site of attachment with a chemical linking group; and
(c) the L is a bond or is a chemical linking group that covalently couples the CLM to the PTM and is selected from:

wherein:
N* is a nitrogen atom that is covalently linked to the CLM or the PTM, or that is shared with the CLM or the PTM;
each m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

and the chemical linker group is optionally substituted with 1, 2, 3, or 4 substitutions independently selected from halogen and C1-4 alkyl and wherein the disease or the disorder associated with LRRK2 is a neurodegenerative disease selected from the group consisting of Parkinson's disease, Parkinson disease with dementia, Parkinson's disease at risk syndrome, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Shy-Drager syndrome.

2 . The method of claim 1 , where LRRK2 is characterized by a G2019S mutation.

3 . The method of claim 1 , wherein the neurodegenerative disease is Parkinson's disease.

4 . The method of claim 1 , wherein the PTM is:

wherein

indicates a site of attachment of the L or the CLM, and wherein each PTM is coupled to at least one L or to the CLM.

5 . The method of claim 1 , wherein the CLM is:

6 . The method of claim 4 , wherein the CLM is:

Assignees

• Arvinas Operations Inc

Inventors

• Araujo Erika Marina Vieira
• Berlin Michael
• Sparks Steven M
• Wang Jing
• Zhang Wei

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title