IP Library › Granted Patent US 12,528,814
Granted Patent B2
US 12,528,814 · App. 17/904,592 · Granted Jan 20, 2026

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

Inventors: Wylie Solang Palmer (San Francisco, CA); Jeffrey Wu (San Francisco, CA); Sheila Zipfel (Foster City, CA); Kerem Ozboya (San Francisco, CA); Dahlia Weiss (San Francisco, CA)
Assignees: Nurix Therapeutics, Inc.; Gilead Sciences, Inc.
C07D487/04C07D519/00
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Quick Facts
Patent No.
US 12,528,814
App. No.
17/904,592
Granted
Jan 20, 2026
Kind
B2
Abstract

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

Claims (217)

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 —.

10 . The compound of claim 9 , wherein Formula (IIA2) has the following structure:

wherein, 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.

11 . The compound of claim 10 wherein Formula (IIA2′) has the following structures:

12 . The compound of claim 3 , wherein

W is —CH—;

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 )—, —O—C(O)—N(R g )—; and

B ring is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, each being optionally substituted with 1 to 3 R j ;

R g is hydrogen or C 1-6 alkyl;

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.

13 . The compound of claim 12 wherein Formula (IIA) has one of the following structures:

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

wherein,

W is —C(R g )— or —N—;

D ring is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, each being optionally substituted with 1 to 3 R j ;

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 ;

R g is hydrogen or C 1-6 alkyl;

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.

15 . The compound of claim 14 , wherein Formula (IIB) has the following structure:

wherein

Z 5 is —C(O)—, —C(S)—, —C(NR g )—, —N(R g )—, —N═, or —C(R g ) 2 —;

Z 6 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 7 is —C(O)—, —C(S)—, —C(NR g )—, —N(R g )—, —O—, —S—, —N═, or —C(R g ) 2 —; and

R g is hydrogen or C 1-6 alkyl.

16 . The compound of claim 15 wherein Formula (IIB1) has the following structure:

17 . The compound of claim 16 wherein Formula (IB1′) has the following structure:

wherein,

q is 0, 1 or 2; and

R 2 is C 1-6 alkyl, halo, halo C 1-6 alkyl, —N(R c ) 2 , CN, nitro, hydroxyl, or —O—C 1-4 alkyl.

18 . The compound of claim 1 wherein LHM targets Von Hippel-Lindau (VHL) ligase and has one of the following structures:

wherein,

V 1 is —C(O)—, —C(O)O—, —C(O)O—C(R e ) 2 —, —C(O)—N(R e )—, —C(O)—C(R e ) 2 —, or —C(O)—N(R e )—C(R e ) 2 —;

V 2 is —C(O)—C(R e ) 2 —;

G ring is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each being optionally substituted with 1 to 3 R j ;

J ring is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, each being optionally substituted with 1 to 3 R j ;

each R e is independently hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl;

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 ,

each R g is independently hydrogen or C 1-6 alkyl;

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;

R 3 is hydrogen or hydroxyl; and

R 4 is —C(O)R f , wherein R f is C 1-6 alkyl or C 3-8 cycloalkyl, each being optionally substituted with halo or —CN.

19 . The compound of claim 18 wherein Formulae (IIIA), (IIIB), (IIIC) and (IIID) have the structures represented by Formulae (IIIA1), (IIIB1), (IIIC1), (IIID1), (IIIE1), respectively:

wherein,

p is 0 or 1;

R j is 5-6 member heteroaryl optionally substituted with 1 to 3 R k ;

each R k is independently halo, oxo, —CN, —OH, C 1-6 alkyl, C 3-8 cycloalkyl, or —O—C 1-6 alkyl;

each R e is independently hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl;

each R g is independently hydrogen or C 1-6 alkyl;

R 3 is hydrogen or hydroxyl; and

R 4 is —C(O)R f , wherein R f is C 1-6 alkyl or C 3-8 cycloalkyl, each being optionally substituted with halo or —CN.

20 . The compound of claim 19 wherein p is 1 and R j is thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, each being optionally substituted with C 1-6 alkyl, C 3-8 cycloalkyl, halo, CN, haloalkyl, or hydroxyalkyl.

21 . The compound of claim 20 having one of the following structures:

22 . The compound of claim 19 wherein p is 0 and Formula (IIIA), (IIIB) or (IIIC), (IIID) has any one of the following structures:

23 . The compound of claim 1 wherein LHM targets inhibitor of apoptosis proteins (IAP) ligase and has one of the following structures:

wherein,

each R 5 is independently hydrogen or C 1-6 alkyl;

each R 6 is independently hydrogen, or C 1-6 alkyl;

each R 7 is independently hydrogen, C 1-6 alkyl, or C 3-8 cycloalkyl;

each R 8 is independently aryl, 5-12 membered cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocyclyl, each being optionally substituted with 1 to 3 R j ;

each R 9 is independently hydrogen, halo, or C 1-6 alkyl;

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 ;

each R g is independently hydrogen or C 1-6 alkyl;

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;

U 1 is direct bond or —C(O)—;

Z is —CH— or —N—; and

K ring is phenyl or naphthyl.

24 . The compound of claim 23 wherein Formulae (IVA), (IVB), (IVC) and (IVD) has the following structure, respectively:

25 . The compound of claim 1 , wherein L 1 has any one of the following ring structures:

wherein each ring may be optionally substituted by 1 to 3 R b ,

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 ; and

R d is independently halo, oxo, —CN, —OH, C 1-6 alkyl, C 3-8 cycloalkyl optionally substituted with 1 to 3 fluoro, or —O—C 1-6 alkyl optionally substituted with 1 to 3 fluoro.

26 . The compound of claim 25 , wherein L 1 has any one of the following ring structures:

27 . The compound of claim 25 , wherein -L 2 -L 3 -L 4 -L 5 - is —C(O)—, —NH—C(O)—, —C(O)—(CH 2 ) n —, —C(O)—(CH 2 ) n —C(O)—, —C(O)—(CH 2 ) n —O—, —(CH 2 ) n —, —C(O)—(CH 2 ) n —NH—, —C(O)—(CH 2 CH 2 O) m —, —C(O)—(CH 2 CH 2 O) m —(CH 2 ) n —C(O)—, —C(O)—(CH 2 CH 2 O) m —(CH 2 ) n —NH—, —C(O)—(CH 2 CH 2 O) m —(CH 2 ) n —, —NH—C(O)—(CH 2 CH 2 O) m —(CH 2 ) n —C(O)—, —NH—C(O)—(CH 2 CH 2 O) m —(CH 2 ) n —NH—, —NH—C(O)—(CH 2 ) n —C(O)—, —NH—C(O)—(CH 2 CH 2 O) m —, —NH—C(O)—(CH 2 ) n —O—, —NH—C(O)—(CH 2 ) n —NH— or —NH—C(O)—(CH 2 CH 2 O) m —(CH 2 ) n —, wherein m is an integer of 1 to 6, and n is an integer of 1 to 12, and wherein one or two hydrogens of each of the above linker moieties may be replaced by C 1-3 alkyl.

28 . The compound of claim 27 , wherein L 1 is

and L has the one of the following structures:

wherein, m is 1, 2, 3, 4, 5 or 6 and n is 2, 3, 4, 5, or 6.

29 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein m is 1, 2, 3, 4, 5 or 6 and n is 2, 4, or 6.

30 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein, m is 1, 2, 3, 4, 5 or 6 and n is 2, 4, or 6.

31 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein m is 1, 2, 3, 4, 5 or 6.

32 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.

33 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 2, 3, 4, 5 or 6.

34 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 4, 5, 6, 7 or 8.

35 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein R c is hydrogen or C 1-3 alkyl, n is 1, 2 or 3.

36 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.

37 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein, m is 1, 2, 3, 4, 5 or 6 and n is 2, 4, or 6.

38 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 1, 2, 3, 4, 5, or 6.

39 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

40 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein, m is 1, 2, 3, 4, 5 or 6 and n is 2, 4, or 6.

41 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8 or 9.

42 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein m is 1, 2, 3, 4, 5, 6, 7 or 8.

43 . The compound of claim 27 , wherein L 1 is

and L has one of the following structures:

wherein, n is 1, 2, 3, 4, 5, 6, 7 or 8.

44 . The compound of claim 27 , wherein L 1 is

and L has one of the following structures:

wherein n is 1, 2 or 3.

45 . The compound of claim 27 , wherein L 1 is

and L has one of the following structures:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, or 9.

46 . The compound of claim 27 , wherein L 1 is

and L has one of the following structures:

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, or 9.

47 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 1, 2, or 3.

48 . The compound of claim 27 , wherein L 1 is

and L has the following structure:

wherein n is 1, 2, or 3.

49 . The compound of claim 27 , wherein L 1 is

and -L 2 -L 3 -L 4 -L 5 - is one of the following structures:

50 . The compounds of claim 1 wherein L has one of the following structures:

wherein R c is H or C 1-3 alkyl.

51 . The compounds of claim 1 wherein L or a partial L has one of the following structures:

52 . The compound of claim 1 , wherein R 1 is:

a) C 1-5 alkyl optionally substituted with halo, —OH, or —CN;

b) 4-8 membered heterocyclyl optionally substituted with halo, C 1-5 alkyl, —OH, or —CN;

c) C 3-10 cycloalkyl optionally substituted with halo, C 1-5 alkyl, —OH, or —CN.

53 . The compound of claim 52 wherein R 1 is oxetane, tetrahydrofuran or tetrahydropyran optionally substituted with F, C 1-3 alkyl, —OH, or —CN.

54 . The compound of claim 52 , wherein

the

moiety is:

55 . The compound of claim 52 , wherein the

moiety has one of the following structures:

56 . A compound which is:

or a pharmaceutically acceptable salt thereof.

57 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 19, 2023
From: PALMER, WYLIE SOLANG; WU, JEFFREY; ZIPFEL, SHEILA; OZBOYA, KEREM; WEISS, DAHLIA
To: NURIX THERAPEUTICS, INC.; GILEAD SCIENCES, INC.
Reel/Frame 065279/0544 →
Continuity (2)
Provisional Application 62978635 · Feb 19, 2020
Related Publication 20230142629A1 · May 11, 2023
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