Cereblon modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-10869860-B2
Application number	US-201916503415-A
Country	US
Kind code	B2
Filing date	Jul 3, 2019
Priority date	Dec 28, 2018
Publication date	Dec 22, 2020
Grant date	Dec 22, 2020

Abstract

Disclosed herein are compositions and methods for modulating cereblon neosubstrates. A small molecule modulator of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof can be used to modulate cereblon neosubstrates.

First claim

What is claimed is:

1. A small molecule adduct of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof:

wherein,
A is N or C(R 2 )
B is N or C(R 3 );
D is N or C(R 4 );
E is H or

F is N or C(R 5 );
X is absent, —O—, —NR 6 —, or —S—;
Y is H, halogen, —OR 6 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 haloalkyl;
L is —C(═O)—, —S(═O)—, or —S(═O) 2 —;
Z 1 is —C(R) 2 —CR 8 R 9 — or —CR 7 ═CR 8 —;
R 2 is H, halogen, —CN, —N(R 12 ) 2 , —OR 6 , —CH(OR 6 )R 12 , —C(═O)R 2 , —C(═O)N(R 12 ) 2 , —S(═O) 2 R 12 , —S(═O) 2 N(R 12 ) 2 , —N(R 12 )C(═O)R 12 , —N(R 12 )S(═O) 2 R 12 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is H, halogen, —CN, —N(R 12 ) 2 , —OR 6 , —CH(OR 6 )R 12 , —C(═O)R 12 , —C(═O)N(R 12 ) 2 , —S(═O) 2 R 12 , —S(═O) 2 N(R 12 ) 2 , —N(R 12 )C(═O)R 12 , —N(R 2 )S(═O) 2 R 12 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is H, halogen, —CN, —N(R 12 ) 2 , —C(═O)R 12 , —C(═O)N(R 12 ) 2 , —S(═O) 2 R 12 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is H, halogen, —CN, —N(R 12 ) 2 , —OR 6 , —C(═O)R 12 , —C(═O)N(R 12 ) 2 , —N(R 12 )C(═O)R 12 , —S(═O) 2 R 12 , —N(R 12 )S(═O) 2 R 12 , —S(═O) 2 N(R 12 ) 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R 6 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, or substituted or unsubstituted C 1 -C 10 heteroalkyl;
R 7 is H, —CN, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
R 8 is H, —NR 10 R 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 aminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1-6 alkylene-C 6-10 aryl, or substituted or unsubstituted C 2 -C 6 heterocycloalkyl;
R 9 is H or substituted or unsubstituted C 1 -C 6 alkyl;
R 10 and R 11 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 8 heteroalkyl; or
R 10 and R 11 are taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl;
each R 12 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, or substituted or unsubstituted aryl; or
two R 12 on the same nitrogen are taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl;
each R 13 is independently halogen, —CN, —OR 6 , —C(═O)N(R 12 ) 2 , —N(R 12 )C(═O)R 12 , —N(R 12 )S(═O) 2 R 12 , —N(S(═O) 2 R 12 ) 2 , —S(═O) 2 R 12 , —S(═O) 2 N(R 12 ) 2 , —(CH 2 ) p —(OCH 2 CH 2 ) q -substituted C 1-4 alkyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, or substituted or unsubstituted C 1 -C 20 heteroalkyl;
R 14 is H or substituted or unsubstituted C 1 -C 6 alkyl;
each R 15 , R 16 , R 17 , and R 18 is independently selected from the group consisting of H, F, —OR 6 , and substituted or unsubstituted C 1 -C 6 alkyl;
m is 0, 1, or 2;
n is 0 or 1;
each p is independently 0, 1, 2, or 3;
p is 1-6;
S represents the sulfur atom of a cysteine residue C287 as set forth in SEQ ID NO: 1, or cysteine residue C286 as set forth in SEQ ID NO: 2 or 3; and
CP represents the cereblon polypeptide set forth in SEQ ID NO: 1, 2, or 3.

2. The small molecule adduct of claim 1 , wherein the S is the cysteine residue C287 as set forth in SEQ ID NO: 1.

3. The small molecule adduct of claim 1 , wherein S is the cysteine residue C286 as set forth in SEQ ID NO: 2.

4. The small molecule adduct of claim 1 , wherein S is the cysteine residue C286 as set forth in SEQ ID NO: 3.

5. The small molecule adduct of claim 1 , wherein the compound of Formula (I*) has a structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

6. The small molecule adduct of claim 1 , wherein the compound of Formula (I*) has a structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:

7. The small molecule adduct of claim 1 , wherein R 8 is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 aminoalkyl.

8. The small molecule adduct of claim 1 , wherein R 8 is H, unsubstituted C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted with one or more substituents selected from C 6-10 aryl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, halogen, and amine; C 1-6 alkylene-C 6-10 aryl substituted with one or more substituents selected from C 1-6 alkyl, alkoxyl, halogen, and amine; and substituted or unsubstituted C 1 -C 6 aminoalkyl.

9. The small molecule adduct of claim 1 , wherein A is C(R 2 ).

10. The small molecule of claim 9 , wherein R 2 is H, halogen, —CN, —N(R 12 ) 2 , —OR 6 , —C(═O)N(R 12 ) 2 , —S(═O) 2 R 12 , or —S(═O) 2 N(R 12 ) 2 .

11. The small molecule adduct of claim 1 , wherein B is C(R 3 ).

12. The small molecule adduct of claim 11 , wherein R 3 is H.

13. The small molecule adduct of claim 1 , wherein D is C(R 4 ).

14. The small molecule adduct of claim 13 , wherein R 4 is H.

15. The small molecule adduct of claim 1 , wherein E is H.

16. The small molecule adduct of claim 1 , wherein E is

17. The small molecule adduct of claim 16 , wherein Y is:
H, —OR 6 , halogen, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 haloalkyl; or
H, —OH, —OCH 3 , —OCH 2 CH 3 , —OCF 3 , F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CH 3 , or —CH 2 CF 3 .

18. The small molecule adduct of claim 1 , wherein R 1 is

and q is 1, 2, 3, 4, 5, or 6.

19. The small molecule adduct of claim 1 , wherein F is C(RS).

20. The small molecule adduct of claim 19 , wherein R 5 is H.

21. The small molecule adduct of claim 1 , wherein X i

Assignees

• Vividion Therapeutics Inc
• Scripps Research Inst

Inventors

• Cravatt Benjamin F
• Patricelli Matthew
• Stamos Dean
• Simon Gabe
• Horning Benjamin
• Weinstein David
• Vinogradova Ekaterina

Classifications

• C07D403/12

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

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/445 Primary

  Non condensed piperidines, e.g. piperocaine · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• C07D211/46 Primary

  having a hydrogen atom as the second substituent in position 4 · CPC title