IRAK degraders and uses thereof

Patent metadata

Field	Value
Publication number	US-12551564-B2
Application number	US-202017784401-A
Country	US
Kind code	B2
Filing date	Dec 9, 2020
Priority date	Dec 10, 2019
Publication date	Feb 17, 2026
Grant date	Feb 17, 2026

Abstract

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

First claim

We claim:

1 . A compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,

Ring B is phenyl,

Ring C is phenyl

L 2 and L 3 are covalent bonds;
each R 1 is independently R 5 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O) (NR)R, —P(O) (OR) 2 , —P(O)(NR 2 ) 2 , —CFR 2 , —CF 2 (R), —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O) OR, or —C(O)NR 2 ;
each R is independently hydrogen, or an optionally substituted 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;
each R 2 is independently R 5 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O) (NR)R, —P(O)(OR) 2 , —P(O)(NR 2 ) 2 , —CFR 2 , —CF 2 (R), —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O) OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;
R 4 is selected from hydrogen,

Ring D is phenyl or

each R 3 is independently R 5 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O) (NR)R, —P(O)(OR) 2 , —P(O)(NR 2 ) 2 , —CFR 2 , —CF 2 (R), —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O) OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;
each R 5 is independently an optionally substituted group selected from C 1-5 aliphatic and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
n is 0, 1, or 2;
m is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
L is a covalent bond or a bivalent straight or branched C 1-50 saturated hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by —Cy—, —O—, —N(R)—, —Si(R) 2 —, —Si(OH) (R)—,—Si (OH) 2 —, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR 2 )—, —S—, —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—,

each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated 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, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
LBM is;
(i)

wherein:
R* is H or Me; or
(ii)

wherein:

Ring M is
X 4 is

q is 0;
L 1 is a covalent bond;
Ring N is phenyl or a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R 3a is independently R 5 , halogen, —CN, or —OR; and
s is 0, 1, 2, or 3.

2 . The compound of claim 1 , wherein said compound is any one of the following formulae:

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein said compound is any one of the following formulae:

or pharmaceutically acceptable salt thereof.

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

or pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 , wherein said compound is any one of the following formulae:

or pharmaceutically acceptable salt thereof, wherein:
R* is H or Me.

6 . The compound of claim 1 , wherein said compound is any one of the following formulae:

or pharmaceutically acceptable salt thereof.

7 . The compound of claim 1 , wherein L is a covalent bond or 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)—, —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—.

8 . The compound of claim 1 , wherein said compound is:

or a pharmaceutically acceptable salt thereof.

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

10 . A method of degrading and/or inhibiting an IRAK4 protein kinase in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound of claim 1 , or a pharmaceutical composition thereof.

11 . A method of treating an IRAK4-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of claim 1 ,

Assignees

• Kymera Therapeutics Inc

Inventors

• Zhang Yi
• Zheng Xiaozhang
• Zhu Xiao

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K47/545 Primary

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

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title