IRAK degraders and uses thereof

Patent metadata

Field	Value
Publication number	US-12150995-B2
Application number	US-202117646556-A
Country	US
Kind code	B2
Filing date	Dec 30, 2021
Priority date	Dec 30, 2020
Publication date	Nov 26, 2024
Grant date	Nov 26, 2024

Abstract

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

First claim

We claim:

1. A compound of formula I-d-5:

or a pharmaceutically acceptable salt thereof, wherein:
each R x is independently —OC 1-6 aliphatic or —CR 2 (OR);
each R is independently hydrogen or C 1-6 aliphatic;
each R y is independently R z , fluoro, chloro, —CN, or —OR;
each R z is a C 1-6 aliphatic optionally substituted with one or more fluoro;
Ring T is selected from phenyl or a 5-9 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups;
L x is —C(O)N(H)—, wherein either the carbon or nitrogen atom of —C(O)N(H)— is attached to Ring T;
X is a covalent bond

x is 0 or 1;
y is 0, 1, or 2;
L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-30 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —CRF—, —CF 2 —, —O—, —N(R)—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—, wherein
each -Cy- is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
DIM is a degradation inducing moiety selected from a cereblon E3 ubiquitin ligase binding moiety of formula I-ccc-1:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is —C(O)—;
X 2a is —C(O)—;
X 3a is —CH 2 — or —C(O)—;
R 1 is hydrogen;
each of R 2 is independently fluoro, chloro, C 1-4 aliphatic, or —OC 1-4 aliphatic;
Ring A a is a fused 6-membered aryl containing 0-1 nitrogen atoms; and
m is 0, or 1.

2. The compound of claim 1 , wherein said compound is of formula I-j-4:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein L is a bivalent, saturated or unsaturated, straight or branched C 1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —N(R)—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, or —N(R)C(O)O—.

4. The compound of claim 1 , wherein said compound is selected from any one of the following compounds:

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

6. The compound of claim 1 , wherein the cereblon E3 ubiquitin ligase binding moiety is

7. The compound of claim 1 , wherein R x is

—OMe, —OEt, —OiPr, or

8. The compound of claim 1 , wherein R y is C 1-6 aliphatic optionally substituted with one to three fluoro.

9. The compound of claim 1 , wherein R y is —CN, —CF 3 , fluoro, chloro, —CF 2 Me, —CFMe 2 , -Me, —OMe, or cyclopropyl.

10. The compound of claim 1 , wherein Ring T is a 5-9 membered mono- or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

11. The compound of claim 1 , wherein Ring T is phenyl,

12. The compound of claim 1 , wherein X is

13. The compound of claim 1 , wherein L is —NR—(CH 2 ) 1-10 —, —(CH 2 ) 1-10 —NR—(CH 2 ) 1-10 —, —(CH 2 ) 1-10 —Cy-NR—(CH 2 ) 1-10 —, —Cy-(CH 2 ) 1-10 —NR—, —Cy-(CH 2 ) 1-10 —NR—(CH 2 ) 1-10 —, —(CH 2 ) 1-10 -Cy-NR—(CH 2 ) 1-10 —, —(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —NR—, —(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —NR—(CH 2 ) 1-10 —, —Cy-(CH 2 ) 1-10 -Cy-NR—, —Cy-(CH 2 ) 1-10 —NR-Cy-, —Cy-(CH 2 ) 1-10 -Cy-NR—(CH 2 ) 1-10 —, —Cy-(CH 2 ) 1-10 —NR-Cy-(CH 2 ) 1-10 —, —Cy-(CH 2 ) 1-10 —, —(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —, —(CH 2 ) 1-10 -Cy-(CH 2 CH 2 O) 1-10 CH 2 CH 2 —, —Cy-(CH 2 ) 1-10 -Cy-, —Cy-(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —, —Cy-(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 -Cy-, or —(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —.

14. The compound of claim 1 , wherein -Cy- is

15. The compound of claim 1 , wherein L is

Assignees

• Kymera Therapeutics Inc

Inventors

• Mainolfi Nello
• Ji Nan
• Weiss Matthew M
• Zheng Xiaozhang
• Zhang Yi
• Fleming Paul R
• Zhu Xiao

Classifications

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title