Tau-protein targeting compounds and associated methods of use

Patent metadata

Field	Value
Publication number	US-12559486-B2
Application number	US-202318486668-A
Country	US
Kind code	B2
Filing date	Oct 13, 2023
Priority date	Jul 17, 2019
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.

First claim

What is claimed is:

1 . A compound having the chemical structure:
PTM-L-ULM, or a pharmaceutically acceptable salt thereof, wherein: the PTM is:

wherein:
X PTM7 and X PTM8 are independently nitrogen or carbon;
each R 7 is independently H or halogen;
each R 9 is independently halogen, H, or C 1-3 fluoroalkyl when R 9 is bonded to a carbon atom;
or each R 9 is independently absent when R 9 is bonded to a nitrogen atom; and

is the point of attachment of the L;
the ULM is:

wherein:
Q 1 is N or CR′;
W is CH 2 or C═O;
A is H or C 1-3 alkyl;
n is 1, 2, 3, or 4;
G is H or C 1-3 alkyl;
each R is independently selected from H, OH, NH 2 , —Cl, —F, —Br, C 1-3 alkyl, C 1-3 fluoroalkyl, or C 1-3 alkoxy, wherein one R is modified to be covalently joined to the L;
R′ is H, halogen, C 1-3 alkyl, or C 1-3 alkoxy; and
represents a bond that is stereospecific or non-stereospecific; and

the L is selected from:

wherein each * is a site of attachment of the PTM or the ULM.

2 . The compound according to claim 1 , wherein the PTM is selected from:

wherein is the point of attachment of the L.

3 . The compound of claim 1 , wherein the ULM is:

4 . The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

5 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6 . The compound of claim 1 , wherein the PTM is:

7 . The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

8 . A pharmaceutical composition comprising the compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9 . A pharmaceutical composition comprising the compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10 . A method of treating a disease state or condition associated with Tau aggregation and accumulation in a patient comprising administering to said patient an effective amount of the compound according to claim 4 .

11 . The method of claim 10 , wherein the disease is Alzheimer's disease.

12 . A method of treating a disease state or condition associated with Tau aggregation and accumulation in a patient comprising administering to said patient an effective amount of the compound according to claim 7 .

13 . The method of claim 12 , wherein the disease is Alzheimer's disease.

Assignees

• Arvinas Operations Inc

Inventors

• Crew Andrew P
• Berlin Michael
• Cacace Angela M
• Chandler Julian T

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K45/06

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

• A61K47/54

  the modifying agent being an organic compound · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title