Compounds and methods for the enhanced degradation of targeted proteins

Patent metadata

Field	Value
Publication number	US-12264157-B2
Application number	US-202217931814-A
Country	US
Kind code	B2
Filing date	Sep 13, 2022
Priority date	Mar 18, 2015
Publication date	Apr 1, 2025
Grant date	Apr 1, 2025

Abstract

The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

First claim

The invention claimed is:

1. A compound according to the following structure:

or a pharmaceutically acceptable salt thereof, wherein:
R is

and
ULM is

wherein:
one of R 5 and R 6 is —OH, and the other is H;
R 7 is H;
E is C═O or C═S;
G is C═J;
J is 0;
M is:

R 9 and R 10 are each independently H or optionally substituted alkyl;
R 11 is optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl;
each R 14 is independently H or alkyl;
R 15 is optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted heterocyclyl;
each R 16 is independently halo, optionally substituted alkyl, CN, or optionally substituted haloalkoxy;
each R 25 is H;
R 23 is H;
o is 0, 1, 2, 3, or 4; and
L is:
—(A) q —,

wherein:
q is an integer from 1 to 20;
each A is independently selected from a bond, CR L1 R L2 , O, S, SO 2 , NR L3 , SO 2 NR L3 CONR L3 , C 0 , CR L 1CR L2 , C═C, C 311 cycloalkyl optionally substituted with 0-6 R L1 , C 3-11 heteocyclyl optionally substituted with 0-6 R L1 , aryl optionally substituted with 0-6 R L1 heteroaryl optionally substituted with 0-6 R L1 , wherein R L1 or R L2 , each independently, can be linked to other groups to form cycloalkyl and/or heterocyclyl; and
R L1 , R L2 , and R L3 are, each independently, selected from H, halo, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OH, NH 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, and CON(C 1-8 alkyl) 2 ;
or L is optionally substituted polyethylene glycol that contains between 2 and 10 ethylene glycol units; and
the chemical linker group (L) is covalently attached to the ULM via R S , R 10 , or R 11 .

2. The compound of claim 1 , wherein:
E is C═O;
G is C═J;
J is O;
R 7 is H;
o is 0;
R 15 is:

and
R 17 is selected from H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, and optionally substituted alkenyl.

3. The compound of claim 1 , wherein R 15 is selected from:

Assignees

• Arvinas Operations Inc
• Univ Yale

Inventors

• Crew Andrew P
• Crews Craig M
• Chen Xin
• Dong Hanqing
• Ferraro Caterina
• Qian Yimin
• Siu Kam
• Wang Jing
• Jin Meizhong
• Berlin Michael
• Zimmermann Kurt
• Snyder Lawrence

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title