Bifunctional degraders of interleukin-1 receptor-associated kinases and therapeutic use thereof

Patent metadata

Field	Value
Publication number	US-12528814-B2
Application number	US-202117904592-A
Country	US
Kind code	B2
Filing date	Feb 19, 2021
Priority date	Feb 19, 2020
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

Abstract

The present disclosure provides bifunctional compounds as IRAK4 degraders via ubiquitin proteasome pathway, and method for treating diseases modulated by IRAK4.

First claim

The invention claimed is:

1 . A compound of Formula (I)

or a pharmaceutically acceptable salt or isotopic form thereof, wherein:
R 1 is C 1-10 alkyl optionally substituted with 1-3 R a ; C 3-10 cycloalkyl optionally substituted with 1-3 R a ; or 3-12 membered heterocyclyl optionally substituted with 1-3 R a ;
L is -L 1 -L 2 -L 3 -L 4 -L 5 -, each L 1 , L 2 , L 3 , L 4 and L 5 being independently:
a) C 3-12 cycloalkyl optionally substituted with 1-3 R b ;
b) C 6-12 aryl optionally substituted with 1-3 R b ;
c) 3-12 membered heterocyclyl optionally substituted with 1-3 R b ;
d) 5-12 membered heteroaryl optionally substituted with 1-3 R b ;
e) direct bond;
f) C 1-12 alkylene chain optionally substituted with 1-3 R d ;
g) C 2-12 alkenylene chain optionally substituted with 1-3 R d ;
h) C 2-12 alkynylene chain optionally substituted with 1 to 3 R d ;
i) 1-6 ethylene glycol units;
j) 1-6 propylene glycol units;
k) —C(O)—, —C(O)O—, —O—, —N(R c )—, —S—, —C(S)—, —C(S)—O—, —S(O) 2 —, —S(O)═N—, —S(O) 2 NH—, —C(O)—N(R c )—, —C═N—, —O—C(O)—N(R c )—, or —O—C(O)—O—;

LHM is a ligase harness moiety;
each R a is independently halo, —CN, C 1-3 alkyl optionally substituted with 1 to 3 R d , C 3-6 cycloalkyl optionally substituted with 1 to 3 R d , or —OR c ;
each R b is independently oxo, imino, sulfoximino, halo, nitro, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, —O—R c , —C(O)—R c , —C(O)O—R c , —C(O)—N(R c )(R c ), —N(R c )(R c ), —N(R c )C(O)—R c , —N(R c )C(O)O—R c , —N(R c )C(O)N(R c )(R c ), —N(R c )S(O) 2 (R c ), —NRCS(O) 2 N(R c )(R c ), —N(R c )S(O) 2 O(R c ), —OC(O) R c , —OC(O)—N(R c )(R c ), —Si(R c ) 3 , —S—R c , —S(O) R c , —S(O)(NH)R c , —S(O) 2 R c or —S(O) 2 N(R c )(R c ), wherein each of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl may be optionally substituted with 1 to 3 R d ;
each R c is independently hydrogen or C 1-6 alkyl; and
each R d is independently halo, oxo, —CN, —OH, C 1-6 alkyl optionally substituted with 1 to 3 fluoro, or C 3-8 cycloalkyl, or —O—C 1-6 alkyl optionally substituted with 1 to 3 fluoro.

2 . The compound of claim 1 having the following structure:

3 . The compound of claim 1 , wherein LHM targets cereblon and has the following structure:

wherein,
W is —C(R g )— or —N—;
Y is direct bond, C 1-4 alkylene chain, —C(O)—, —C(O)O—, —O—, —N(R g )—, —S—C(S)—, —C(S)—O—, —O—C(O)O—, —C(O)—N(R g )—, or —O—C(O)—N(R g )—;
B ring is C 6-12 aryl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, each being optionally substituted with 1 to 3 R j ;

each R j is independently oxo, imino, sulfoximino, halo, nitro, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, —O—R g , —C(O)—R g , —C(O)O—R g , —C(O)—N(R g )(R g ), —N(R g )(R g ), —N(R g )C(O)—R g , —N(R g )C(O)O—R g , —N(R g )C(O)N(R g )(R g ), —N(R g )S(O) 2 (R g ), —NR g S(O) 2 N(R g )(R g ), —N(R g )S(O) 2 O(R g ), —OC(O)R g , —OC(O)—N(R g )(R g ), —Si(R g ) 3 , —S—R g , —S(O) R g , —S(O)(NH)R g , —S(O) 2 R g or —S(O) 2 N(R g )(R g ), wherein each of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl may be optionally substituted with 1 to 3 R k ;
R g is hydrogen or C 1-6 alkyl; and
each R k is independently halo, oxo, —CN, —OH, C 1-6 alkyl optionally substituted with 1 to 3 fluoro, C 3-8 cycloalkyl, or —O—C 1-6 alkyl optionally substituted with 1 to 3 fluoro.

4 . The compound of claim 3 , wherein Y is direct bond and Formula (IIA) has the following structure:

wherein,
W is —C(R g )— or —N—;
Z 1 is —C(O)—, —C(S)—, —C(NR g )—, —C(R g ) 2 —, —N═, —N(R g )—, —C(R g ) 2 —C(O)—, —C(O)—N(R g )—, —CR g ═CR g —, —C(R g ) 2 —C(S)—, —C(R g )═N—, or —C(R g ) 2 —C(R g ) 2 —;
Z 2 is —C(O)—, —C(S)—, —C(NR g )—, —N(R g )—, —N═, or —C(R g ) 2 —;
R g is hydrogen or C 1-6 alkyl; and
E ring is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each being optionally substituted with 1 to 3 R j .

5 . The compound of claim 4 , wherein Z 2 is —C(O)— and Formula (IIA1) has the following structure:

wherein,
W is —C(R g )— or —N—;
Z 1 is —C(O)—, —C(S)—, —C(NR g )—, —C(R g ) 2 —, —C(R g ) 2 —C(O)—, —C(O)—N(R g )—, —CR g ═CR g —, —C(R g )═N—, —C(R g ) 2 —C(S)—, or —C(R g ) 2 —C(R g ) 2 —;
q is 0, 1 or 2;
R g is hydrogen or C 1-6 alkyl; and
R 2 is C 1-6 alkyl, halo, halo C 1-6 alkyl, —N(R g ) 2 , CN, nitro, hydroxyl, or —O—C 1-4 alkyl.

6 . The compound of claim 5 wherein
W is —CH—; and
Z 1 is —C(O)—, —CH 2 —, —CH 2 —C(O)—, or —CH═CH—.

7 . The compound of claim 6 , wherein Formula (IIA1′) has one of the following structures:

8 . The compound of claim 3 wherein Formula (IIA) has the following structure:

wherein,
W is —C(R g )— or —N—;
Z 3 is —C(O)—, —C(S)—, —C(NR g )—, —C(R g ) 2 —, —N═, —N(R g )—, —C(R g ) 2 —C(O)—, —C(O)—N(R g )—, —CR g ═CR g —, —C(R g ) 2 —C(S)—, —C(R g )═N—, —C(R g ) 2 —C(R g ) 2 —, —C(R g ) 2 —O—, —C(R g ) 2 —S—, —O—, or —S—;
Z 4 is —C(O)—, —C(S)—, —C(NR g )—, —N(R g )—, —N═, —O—, —S—, or —C(R g ) 2 —;
R g is hydrogen or C 1-6 alkyl;
E ring is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each being optionally substituted with 1 to 3 R j ;

each R j is independently oxo, imino, sulfoximino, halo, nitro, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, —O—R g , —C(O)—R g , —C(O)O—R g , —C(O)—N(R g )(R g ), —N(R g )(R g ), —N(R g )C(O)—R g , —N(R g )C(O)O—R g , —N(R g )C(O)N(R g )(R g ), —N(R g )S(O) 2 (R g ), —NR g S(O) 2 N(R g )(R g ), —N(R g )S(O) 2 O(R g ), —OC(O)R g , —OC(O)—N(R g )(R g ), —Si(R g ) 3 , —S—R g , —S(O) R g , —S(O)(NH)R g , —S(O) 2 R g or —S(O) 2 N(R g )(R g ), wherein each of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl may be optionally substituted with 1 to 3 R k ; and
each R k is independently halo, oxo, —CN, —OH, C 1-6 alkyl optionally substituted with 1 to 3 fluoro, C 3-8 cycloalkyl, or —O—C 1-6 alkyl optionally substituted with 1 to 3 fluoro.

9 . The compound of claim 8 wherein
W is —CH—;
Z 3 is —C(R g ) 2 —, —N(R g )—, —C(R g ) 2 —C(O)—, —C(O)—N(R g )—, —CR g ═CR g —, —C(R g ) 2 —C(S)—, —C(R g )═N—, —C(R g ) 2 —C(R g ) 2 —, —C(R g ) 2 —O—, or —C(R g ) 2 —S—; and
Z 4 is —C(O)—, —C(S)—, —C(NR g )—, or —C(R g ) 2 —.

Assignees

• Nurix Therapeutics Inc
• Gilead Sciences Inc

Inventors

• Palmer Wylie Solang
• Wu Jeffrey
• Zipfel Sheila
• Ozboya Kerem
• Weiss Dahlia

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P29/00

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

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title