Brd9 bifunctional degraders and their methods of use

Patent metadata

Field	Value
Publication number	US-2022315578-A1
Application number	US-202017020114-A
Country	US
Kind code	A1
Filing date	Sep 14, 2020
Priority date	Sep 16, 2019
Publication date	Oct 6, 2022
Grant date	—

Abstract

The disclosure provides BRD9 bifunctional compounds of Formula (A), (BF-I), (BF-II), (BF-III), (BF-IIIa), (BF-IIIb), (BF-IV), (BF-IVa), (BF-IVb), (BF-I′), (BF-II′), (BF-III′), (BF-IV′), or (BF-V′), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to their preparation, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases and disorders mediated by a bromodomain-containing protein, such as bromodomain-containing protein 9 (BRD9).

First claim

We claim:

1 . A compound of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:

the Targeting Ligand is a group that is capable of binding to a bromodomain-containing protein, e.g., BRD9;
the Linker is a group that covalently links the Targeting Ligand to the Targeting Ligase Binder;
the Targeting Ligase Binder is a group that is capable of binding to a ligase (e.g., Cereblon E3 Ubiquitin ligase).

2 . The compound of claim 1 , wherein the Targeting Ligand is a compound of Formula (TL-I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen and C 1-6 alkyl; or R 1 and R 2 together with the atoms to which they are attached form an aryl or heteroaryl;
R 3 are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxyl, and halogen;
R 5 is selected from the group consisting of hydrogen and C 1-6 alkyl;
n is 0, 1, or 2.

3 . The compound of any one of the preceding claims or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the Targeting Ligand is a compound of Formula (TL-II):

4 . The compound of claim 1 , wherein the Targeting Ligand is a compound of Formula (TL-I′):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen and C 1-6 alkyl; or R 1 and R 2 together with the atoms to which they are attached form an aryl or heteroaryl;
R 3 are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxyl, and halogen;
R 4′ is selected from the group consisting of hydrogen and C 1-6 alkyl; and
n is 0, 1, or 2.

5 . The compound of claim 1 or 4 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the Targeting Ligand is a compound of Formula (TL-II′):

6 . The compound of any one of the preceding claims or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the Targeting Ligand is selected from the group consisting of:

7 . The compound of any one of the preceding claims, wherein the Targeting Ligase Binder is a compound of Formula (TLB-I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
R 4 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxyl, and halogen; and
m is 0, 1, or 2.

8 . The compound of any one of claims 1 - 6 , wherein the Targeting Ligase Binder is a compound of Formula (TLB-I′):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R d1 and R d2 are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 haloalkyl, and C 1-6 heteroalkyl; R d3 is H; R d4 is selected from the group consisting of H, C 1-6 alkyl, halo, C 1-6 haloalkyl, and C 1-6 heteroalkyl; and R d5 is selected from the group consisting of H, C 1-6 alkyl, halo, C 1-6 haloalkyl, and C 1-6 heteroalkyl.

9 . The compound of any one of the preceding claims, wherein the Linker is a compound of Formula (L-I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
L 1 is selected from the group consisting of a bond, O, NR′, C(O), C 1-6 alkylene, C 1-6 heteroalkylene, *C(O)—C 1-6 alkylene, C(O)—C 1-6 alkenylene*, C 1-6 alkenylene, and *C(O)—C 1-6 heteroalkylene, wherein * denotes the point of attachment of L 1 to the Targeting Ligand;
X 1 and X 2 are each independently selected from the group consisting of a bond, carbocyclyl, and heterocyclyl, wherein the carbocyclyl and heterocyclyl are substituted with 0-4 occurrences of R a , wherein each R a is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxyl, and halogen;
L 2 is selected from the group consisting of a bond, O, NR′, C 1-6 alkylene, and C 1-6 heteroalkylene; or
X 1 -L 2 -X 2 form a spiroheterocyclyl; and
L 3 is selected from the group consisting of a bond, O, C(O), C 1-6 alkylene, C 1-6 heteroalkylene, *C(O)—C 1-6 alkylene, *C(O)—C 1-6 heteroalkylene, and *C(O)—C 1-6 alkylene-O , wherein * denotes the point of attachment of L 3 to X 2 in Formula (L-I); wherein no more than 2 of L 1 , X 1 , X 2 , L 2 , and L 3 can simultaneously be a bond.

10 . The compound of any one of the preceding claims, wherein X 1 -L 2 -X 2 is selected from the group consisting of:

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein * denotes the point of attachment to L 1 .

11 . The compound of any one of the preceding claims, wherein the Linker is selected from the group consisting of:

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein * denotes the point of attachment to the Targeting Ligase Binder.

12 . The compound of any one of the preceding claims, wherein the compound is a compound of Formula (BF-I) or (BF-I′):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen and C 1-6 alkyl; or R 1 and R 2 together with the atoms to which they are attached form an aryl or heteroaryl;

Assignees

• Novartis Ag

Inventors

• Chen Xin
• Goude Marie-Line
• Harrington Edmund Martin
• Hollingworth Gregory John
• Lorber Julien
• Sendzik Martin
• Vulpetti Anna
• Zoller Thomas

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K47/55

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