Cereblon modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-11771689-B2
Application number	US-202016950697-A
Country	US
Kind code	B2
Filing date	Nov 17, 2020
Priority date	Dec 28, 2018
Publication date	Oct 3, 2023
Grant date	Oct 3, 2023

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 having a structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

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 —;
R 2 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 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 12 )S(═O) 2 R 12 , substituted or unsubstituted C1-C6 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′ 2 ) 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 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 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 C2-C9heterocycloalkyl;
each R 12 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, 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 C2-C9heterocycloalkyl;
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;
q is 0, 1, 2, 3, 4, 5 or 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 R 8 is H, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6aminoalkyl.

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

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

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

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

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

11. The small molecule adduct of claim 10 , wherein Y is:
H, —OR 6 , halogen, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C 1 -C 6 haloalkyl.

12. The small molecule adduct of claim 1 , wherein R 13 is

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

13. The small molecule adduct of claim 1 , wherein F is C(R 5 ).

14. The small molecule adduct of claim 1 , wherein X is absent or —O—.

15. The small molecule adduct of claim 1 , wherein one or more of 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 C1-C4alkyl.

16. The small molecule adduct of claim 1 , wherein m is 0 or 1 and p is 0, 1, or 2.

17. The small molecule adduct of claim 1 , wherein A is CR 2 , and B, D, and F are each CH.

18. The small molecule adduct of claim 17 , wherein R 2 is CN.

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

20. The small molecule adduct of claim 1 , selected from:

or a pharmaceutically acceptable salt or solvate thereof.

Assignees

• Vividion Therapeutics Inc
• Scripps Research Inst

Inventors

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

Classifications

• A61K31/445 Primary

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

• A61K31/397

  having four-membered rings, e.g. azetidine · 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

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title