Irak degraders and uses thereof

Patent metadata

Field	Value
Publication number	US-2025375526-A1
Application number	US-202519056013-A
Country	US
Kind code	A1
Filing date	Feb 18, 2025
Priority date	Dec 9, 2020
Publication date	Dec 11, 2025
Grant date	—

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

First claim

1 - 17 . (canceled)

18 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R x is selected from C 1-6 aliphatic and —OC 1-6 aliphatic;
x is 0 or 1;
L is —(C 1-10 aliphatic)-NR—(C 1-10 aliphatic)-, -Cy-NR—(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-NR—(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-Cy-NR—(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic)-NR—(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-Cy-NR—(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-NR-Cy-(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-O—(C 1-10 aliphatic)-, -Cy-O—(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-O—(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-Cy-O—(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic)-O—(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-Cy-O—(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-O-Cy-(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic)-, or —(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic)-, wherein:
each -Cy- is independently a bivalent ring selected from a 4-7 membered saturated carbocyclylenyl, a 7-11 membered saturated spiro carbocyclylenyl, a 4-7 membered saturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic saturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each -Cy- is optionally substituted with 1-2 fluoro or methyl; and
IRAK is an IRAK4 binding moiety of the following structure:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is cyclobutyl or cyclohexyl;
Ring B is phenyl,

Ring C is phenyl or a 5-10 membered mono- or bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of L 2 and L 3 is a covalent bond;
R 1 is hydrogen, C 1-6 alkyl, fluoro, chloro, —CN, —OR, —CFR 2 , —CF 2 (R), —CF 3 , —CR 2 (OR), —C(O)OR, or —C(O)NR 2 ;
each R 2 is independently hydrogen, C 1-6 alkyl, fluoro, chloro, —CN, —OR, —NR 2 , —CFR 2 , —CF 2 (R), or —CF 3 ;
each R is independently selected from hydrogen, or a group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 4 is selected from hydrogen or a 5-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spiro heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
n is 0 or 1; and
m is 0, 1, or 2.

19 . The compound of claim 18 , wherein said compound is one of the following formulae:

or a pharmaceutically acceptable salt thereof.

20 . The compound of claim 18 , wherein Ring B is

21 . The compound of claim 18 , wherein said compound is one of the following formulae:

or a pharmaceutically acceptable salt thereof.

22 . The compound of claim 18 , wherein Ring C is phenyl,

23 . The compound of claim 18 , wherein R 1 is methyl or —OMe.

24 . The compound of claim 18 , wherein R 2 is C 1-6 alkyl, fluoro, chloro, —CN, —OR, —CFR 2 , —CF 2 (R), or —CF 3 .

25 . The compound of claim 18 , wherein R 4 is a 5-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spiro heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

26 . The compound of claim 18 , wherein L is —(C 1-10 aliphatic)-NR—(C 1-10 aliphatic)-, -Cy-NR—(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-NR—(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-Cy-NR—(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-O—(C 1-10 aliphatic)-, -Cy-O—(C 1-10 aliphatic)-, —(C 1-10 aliphatic)-Cy-O—(C 1-10 aliphatic)-, -Cy-(C 1-10 aliphatic)-, or —(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic)-.

27 . The compound of claim 18 , wherein said compound is one of the following formulae:

or a pharmaceutically acceptable salt thereof.

28 . The compound of claim 18 , wherein the IRAK4 binding moiety is

29 . The compound of claim 18 , wherein said compound is selected from:

or a pharmaceutically acceptable salt thereof.

30 . A pharmaceutical composition comprising a compound of claim 18 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

31 . The pharmaceutical composition of claim 30 , further comprising an additional therapeutic agent.

Assignees

• Kymera Therapeutics Inc

Inventors

• Zheng Xiaozhang
• Zhu Xiao

Classifications

• A61K47/55

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/513

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

• C07D401/14

  containing three or more hetero rings · CPC title