Compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-12590079-B2
Application number	US-202017631791-A
Country	US
Kind code	B2
Filing date	Jul 31, 2020
Priority date	Jul 31, 2019
Publication date	Mar 31, 2026
Grant date	Mar 31, 2026

Abstract

The present disclosure features compounds useful for the treatment of BAF complex-related disorders.

First claim

The invention claimed is:

1 . A compound having the structure of Formula I:
A-L-B   Formula I,
wherein B is a degradation moiety, L is a linker, and A has the structure of Formula II:

wherein
the degradation moiety is a ubiquitin ligase binding moiety;
R 1 is, independently, H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 carbocyclyl;
Z 1 is CR 5 or N;
R 2 is, independently, H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted sulfone, or optionally substituted sulfonamide, or R 2 and R 3 together with the atoms to which each is attached, form an optionally substituted C 2 -C 9 heterocyclyl;
R 3 and R 4 are, independently, H, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, thiol, optionally substituted sulfone, or optionally substituted amino, and/or R 2 and R 3 together with the atoms to which each is attached, form an optionally substituted C 2 -C 9 heterocyclyl;
R 5 is H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, or optionally substituted C 2 -C 9 heteroaryl; and
G is

G′ is optionally substituted C 3 -C 10 carbocyclylene, C 2 -C 9 heterocyclylene, optionally substituted C 6 -C 10 arylene, or optionally substituted C 2 -C 9 heteroarylene; and
A 1 is a bond between A and the linker,
or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein Z 1 is CR 5 .

3 . The compound of claim 2 , wherein R 5 is H.

4 . The compound of claim 1 , wherein R 3 and R 4 are both H.

5 . The compound of claim 1 , wherein R 1 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 10 carbocyclyl.

6 . The compound of claim 1 , wherein R 2 is optionally substituted C 1 -C 6 alkyl.

7 . The compound of claim 1 , wherein G′ is optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 9 heteroaryl.

8 . The compound of claim 7 , wherein G′ is optionally substituted C 6 -C 10 aryl.

9 . The compound of claim 8 , wherein G′ is

each of R G1′ , R G2′ , R G3′ , R G4′ , and R G5′ is, independently, H, A 1 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted -O-C 3 -C 6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R G1′ and R G2′ , R G2′ and R G3′ , R G3′ and R G4′ , or R G4′ and R G5′ , together with the carbon atoms to which each is attached, combine to form

and

is optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heteroaryl, or optionally substituted C 2 -C 9 heterocyclyl, any of which is optionally substituted with A 1 ,
wherein one of R G1′ , R G2′ , R G3′ , R G4′ , and R G5′ is A 1 ; or

is substituted with A 1 .

10 . The compound of claim 9 , wherein each of R G1′ , R G2′ , R G3′ , R G4′ , and R G5′ is, independently, H, A 1 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted -O-C 3 -C 6 carbocyclyl; or R G1 and R G2 , R G2 and R G3 , R G3 and R G4 , and/or R G4 and R G5 together with the carbon atoms to which each is attached, combine to form

and

is optionally substituted C 2 -C 9 heteroaryl or optionally substituted C 2 -C 9 heterocyclyl, any of which is optionally substituted with A 1 .

11 . The compound of claim 10 , wherein each of R G1′ , R G2′ , R G3′ , R G4′ , and R G5′ is, independently, H, A 1 , F, Cl,

12 . The compound of claim 9 , wherein A has the structure of Formula IIa:

or a pharmaceutically acceptable salt thereof.

13 . The compound of claim 12 , wherein A has the structure of Formula IIb:

or a pharmaceutically acceptable salt thereof.

14 . The compound of claim 13 , wherein A has the structure of Formula IIc:

or a pharmaceutically acceptable salt thereof.

15 . The compound of claim 1 , wherein the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof.

16 . The compound of claim 1 , wherein the degradation moiety comprises the structure of Formula A:

wherein
Y 1 is

R A5 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;
R A6 is H or optionally substituted C 1 -C 6 alkyl; and R A7 is H or optionally substituted C 1 -C 6 alkyl; or R A6 and R A7 , together with the carbon atom to which each is bound, form an optionally substituted C 3 -C 6 carbocyclyl or optionally substituted C 2 -C 5 heterocyclyl; or R A6 and R A7 , together with the carbon atom to which each is bound, form an optionally substituted C 3 -C 6 carbocyclyl or optionally substituted C 2 -C 5 heterocyclyl;
R A8 is H, optionally substituted C 1 -C 6 alkyl, or optionally substitute

Assignees

• Foghorn Therapeutics Inc

Inventors

• Ruppel Sabine K
• Yang Zhaoxia
• Lowe Jason T

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title