Cereblon modulators and uses thereof
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.
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.