Irak degraders and uses thereof

Patent metadata

Field	Value
Publication number	US-2025333417-A1
Application number	US-202519178057-A
Country	US
Kind code	A1
Filing date	Apr 14, 2025
Priority date	Dec 17, 2019
Publication date	Oct 30, 2025
Grant date	—

Abstract

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

First claim

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
IRAK is an IRAK binding moiety capable of binding to IRAK4, said compound of formula I is a compound of formulae I-a-2:

or a pharmaceutically acceptable salt thereof, wherein:
each R is independently hydrogen, C 1-6 alkyl, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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(S)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 , —N(R)S(O) 2 R, —N + (O − )R 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —P(O)R 2 , —SiR 3 , —Si(OR)R 2 , or

each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 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 y is independently hydrogen, C 1-6 alkyl, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —CF 2 R, —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O)OR, —C(O)NR 2 , —C(S)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 , —N(R)S(O) 2 R, —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —SiR 3 , —SF 5 , or

Ring T is selected from phenyl or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen oxygen and sulfur;
X is

x is 0, 1, 2, 3 or 4;
y is 0, 1, 2, 3 or 4;
L is a covalent bond or a bivalent saturated or unsaturated, straight or branched C 1-50 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, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 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 4-7 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, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
DIM is a compound of formula I-aa:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is —C(O)—;
X 2 is a carbon atom;
X 3 is —CR 2 —;
R 1 is hydrogen or C 1-4 aliphatic;
each R 2 is independently hydrogen, C 1-6 alkyl, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)(NR 2 ), —OP(O)(NR 2 ) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —NP(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)(NR 2 ), —N(R)P(O)(NR 2 ) 2 , or —N(R)S(O) 2 R;
Ring A is

Ring B is a fused ring selected from 6-membered aryl or 6-membered heteroaryl containing 1-4 nitrogen;
R 4 is C 1-6 alkyl;
L 1 is a covalent bond; and
m is 0, 1, 2, 3 or 4.

2 - 22 . (canceled)

23 . The compound according to 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)—, —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—;

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

or a pharmaceutically acceptable salt thereof.

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

26 . (canceled)

27 . A method of degrading 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.

28 . A method of treating an autoimmune disease, an inflammatory disorder, or an immunodeficiency disorder in a patient comprising administering to said patient a compound of claim 1 , or a pharmaceutical composition thereof.

29 - 30 . (canceled)

31 . The method of claim 28 , wherein the autoimmune disease, inflammatory disorder, or immunodeficiency disorder is ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, optionally including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyper

Assignees

• Kymera Therapeutics Inc

Inventors

• Weiss Matthew M
• Zheng Xiaozhang
• Zhu Xiao

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

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

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title