Cereblon ligands and bifunctional compounds comprising the same

Patent metadata

Field	Value
Publication number	US-12441708-B2
Application number	US-202218079790-A
Country	US
Kind code	B2
Filing date	Dec 12, 2022
Priority date	Jan 31, 2017
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, 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 disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 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. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

First claim

What is claimed is:

1. A compound having the chemical structure:
CLM-L-PTM,
or a pharmaceutically acceptable salt thereof,
wherein the L is a chemical linking moiety covalently linking the CLM and the PTM, and wherein:
the PTM is

wherein R designates the site of attachment to L; and
the CLM is selected from the group consisting of:

wherein
R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;
R 4 is H or C 1 -C 3 alkyl;
R 5 is H or C 1 -C 3 alkyl;
Q 1 , Q 2 , Q 3 , and Q 4 are each independently a carbon substituted with a R′;
R′ is H, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl; and
Q 5 is N; wherein the CLM is covalently joined to L via R 3 , R 4 , R 5 , R′, Q 1 , Q 2 , Q 3 , or Q 4 .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker (L) is:
-(A L )q-
wherein:
q is an integer greater than or equal to 1;
each A L is independently selected from the group consisting of a bond, CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, C 3-11 cycloalkyl substituted with 0-6 R L1 groups, C 3-11 heterocyclyl substituted with 0-6 R L1 groups, aryl substituted with 0-6 R L1 groups, and heteroaryl substituted with 0-6 R L1 groups; and

R L1 , R L2 , R L3 , and R L4 are, independently, selected from H, halogen, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, N (C 1-8 alkyl) 2 , OH, NH 2 , CO 2 H, CN, CF 3 , CHF 2 , and CH 2 F.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker (L) is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units.

4. A compound, wherein the compound is

PROTAC

#
Chemical Structure
Name

PROTAC- 89

rac-3-(4-(4-(4-((1-(4- ((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4- tetrahydronaphthalen-1- yl)phenyl)piperidin-4- yl)methyl)piperazin-1- yl)phenyl)-2-oxo-2,5- yl)piperidine-2,6-dione

PROTAC- 90

rac-N-(2,6-dioxopiperidin-3- yl)-4-(4-(5-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)pentyl)piperazin- 1-yl)-N-methylbenzamide

PROTAC- 91

rac-N-(2,6-dioxopiperidin-3- yl)-5-(4-(5-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)pentyl)piperazin- 1-yl)picolinamide

PROTAC- 92

rac-N-(2,6-dioxopiperidin-3- yl)-N-ethyl-4-(4-(5-(4- ((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)pentyl)piperazin- 1-yl)-2-methoxybenzamide

PROTAC- 93

rac-3-(4-((6-(((R)-1-(2-(4- ((1R,2S)-2-(4-fluorophenyl)- 6-hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)ethyl)pyrrolidin- 3-yl)oxy)pyridin-3-yl)oxy)- 6-oxopyridazin-1(6H)- yl)piperidine-2,6-dione

PROTAC- 94

rac-3-(4-((6-(((R)-1-(2-(4- ((1S,2R)-2-(4-fluorophenyl)- 6-hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)ethyl)pyrrolidin- 3-yl)oxy)pyridin-3-yl)oxy)- 6-oxopyridazin-1(6H)- yl)piperidine-2,6-dione

PROTAC- 95

rac-3-(4-((6-(4-(2-(4- ((1R,2S)-2-(4-fluorophenyl)- 6-hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)ethyl)piperazin- 1-yl)pyridin-3-yl)oxy)-6- oxopyridazin-1(6H)- yl)piperidine-2,6-dione

PROTAC- 96

rac-3-(4-((6-(4-(2-(4- ((1R,2S)-2-(4-fluorophenyl)- 6-hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)ethyl)piperazin- 1-yl)pyridin-3-yl)oxy)-6- oxopyridazin-1(6H)- yl)piperidine-2,6-dione

PROTAC- 97

rac-3-(4-((6-(((R)-1-(2-(4- ((1S,2R)-2-(4-fluorophenyl)- 6-hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)ethyl)pyrrolidin- 3-yl)oxy)pyridin-3-yl)oxy)- 6-oxopyridazin-1(6H)- yl)piperidine-2,6-dione

PROTAC- 98

rac-3-(4-((6-(4-(4-((1R,2S)- 2-(4-fluorophenyl)-6- hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenoxy)butyl)pyridin-3- yl)oxy)-6-oxopyridazin- 1(6H)-yl)piperidine-2,6- dione

PROTAC- 99

rac-3-(4-((6-(5-(4-((1R,2S)- 2-(4-fluorophenyl)-6- hydroxy-1,2,3,4- tetrahydronaphtha

Assignees

• Arvinas Operations Inc

Inventors

• Crew Andrew P
• Berlin Michael
• Hornberger Keith R
• Snyder Lawrence B
• Wang Jing
• Qian Yimin
• Dong Hanqing
• Zimmermann Kurt

Classifications

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D495/14

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title