Methods and compounds for treating disorders

Patent metadata

Field	Value
Publication number	US-11773085-B2
Application number	US-202016942021-A
Country	US
Kind code	B2
Filing date	Jul 29, 2020
Priority date	Jan 30, 2018
Publication date	Oct 3, 2023
Grant date	Oct 3, 2023

Abstract

The present invention relates to methods and compositions for the treatment of BAF-related disorders such as cancers and viral infections.

First claim

What is claimed is:

1. A method of treating synovial sarcoma in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the structure of Formula I:
A-L-B   Formula I

wherein
L is a linker;
B is a degradation moiety, which has the structure of Formula A-1:

wherein
Y 1 is

each of R 3 and R 4 is, independently, H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;
q is 0, 1, 2, 3, or 4; and
each R 2 is, independently, 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, hydroxyl, —SH, or optionally substituted amino;
A has the structure of Formula E-a:

where
R 22 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;
R 23 is H, halogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 6 -C 10 aryl;
s′ is 0, 1, or 2;
each R 24 is, independently, 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, hydroxyl, —SH, or optionally substituted amino, or two R 24 combine with the carbon atoms to which they are attached to form an optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 9 heteroaryl;
s is 0, 1, 2, 3, or 4; and
each R 25 is, independently, 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, hydroxyl, —SH, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

2. The compound method of claim 1 , wherein the linker has the structure of Formula II:
A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2    Formula II

wherein
A 1 is a bond between the linker and A;
A 2 is a bond between B and the linker;
each of B 1 , B 2 , B 3 , and B 4 is, independently, optionally substituted C 1 -C 2 alkyl, optionally substituted C 1 -C 3 heteroalkyl, O, S, S(O) 2 , or NR N ;
R N is H, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 6-12 aryl, or optionally substituted C 1-7 heteroalkyl;
each of C 1 and C 2 is, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl;
f, g, h, l, j, and k are each, independently, 0 or 1; and
D is optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 6-12 aryl, optionally substituted C 2 -C 10 polyethylene glycol, or optionally substituted C 1-10 heteroalkyl, or a chemical bond linking A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - to -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 .

3. The method of claim 1 , wherein the compound has the structure of any of compounds:

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein Formula E-a has the structure of Formula E-2a:

where
R 22 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;
R 23 is H, halogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 6 -C 10 aryl;
s is 0, 1, 2, 3, or 4;
each R 25 is, independently, 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, hydroxyl, —SH, or optionally substituted amino;
X 1 is N or CR 24a ;
X 2 is N or CR 24b ;
X 3 is N or CR 24c ;
X 4 is N or CR 24d ; and
each of R 24a , R 24b , R 24c , and R 24d is, 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, hydroxyl, —SH, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

Assignees

• Foghorn Therapeutics Inc

Inventors

• Zhou Qianhe
• Bocker Michael
• Millan David Simon
• Chan Ho Man
• Soares Luis
• Netherton Matthew Russell
• Ruppel Sabine K
• Yang Zhaoxia
• Lowe Jason T
• Brucelle Francois

Classifications

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61K9/1605

  Excipients; Inactive ingredients · CPC title

• A61K45/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/55 Primary

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title