Compounds and uses thereof
The present invention relates to compositions and methods for the treatment of BAF-related disorders, such as cancers and viral infections.
1. A compound having the structure of Formula I:
A-L-B Formula I,
wherein
A is:
wherein
A 1 is a bond between A and L;
R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 carbocyclyl;
R 5 is H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl;
R 6a is H, halogen, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino;
R 6b is H, halogen, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or R 6a and R 6b , together with the carbon atoms to which each is attached, combine to form optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 9 heteroaryl;
B is:
wherein
A 2 is a bond between B and L; and
R A5 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;
L is:
A 1 -(E 1 )-(F 1 )—(F 2 )—(F 3 )-(E 2 ) p -A 2 , Formula II
wherein
A 1 is a bond between the linker and A;
A 2 is a bond between B and the linker;
each of E 1 and E 2 is, independently, O, S, NR N , optionally substituted C 1-10 alkylene, optionally substituted C 2-10 alkenylene, optionally substituted C 2-10 alkynylene, optionally substituted C 2 -C 10 polyethylene glycol, or optionally substituted C 1-10 heteroalkylene;
each R N is, independently, H, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 6-12 aryl, or optionally substituted C 1-7 heteroalkyl; and
each of F 1 , F 2 , and F 3 is, independently, optionally substituted C 3 -C 10 carbocyclylene, optionally substituted C 2-10 heterocyclylene, optionally substituted C 6 -C 10 arylene, or optionally substituted C 2 -C 9 heteroarylene,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein E 1 is —CH 2 —.
3. The compound of claim 1 , wherein E 2 is O, NR w ,
wherein
c is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
d is 0, 1, 2, or 3;
e is 0, 1, 2, 3, 4, 5, or 6;
f is 0, 1, 2, 3, or 4;
R d is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl;
R e is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl;
R f is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl;
R g is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl; and
W is O or NR w , wherein R w is H or optionally substituted C 1 -C 6 alkyl.
4. The compound of claim 3 , wherein E 2 is —NR N —.
5. The compound of claim 4 , wherein E 2 is —NH—.
6. The compound of claim 1 , wherein F 1 is
7. The compound of claim 1 , wherein F 2 is
8. The compound of claim 1 , wherein F 3 is optionally substituted C 6 -C 10 arylene.
9. The compound of claim 1 , wherein R A5 is H.
10. The compound of claim 1 , wherein R 4 is —CH 3 .
11. The compound of claim 1 , wherein R 5 is H or —CH 3 .
12. The compound of claim 1 , wherein R 6a is H, F, cyano,
13. The compound of claim 1 , wherein R 6b is H, F, cyano,
14. The compound of claim 1 , wherein:
E 1 is —CH 2 —;
E 2 is O, NR N ,
wherein
c is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
d is 0, 1, 2, or 3;
e is 0, 1, 2, 3, 4, 5, or 6;
f is 0, 1, 2, 3, or 4;
R d is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl;
R e is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl;
R f is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl;
R g is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl; and
W is O or NR w , wherein R w is H or optionally substituted C 1 -C 6 alkyl;
F 1 is
F 2 is
F 3 is optionally substituted C 6 -C 10 arylene;
R A5 is H;
R 4 is —CH 3 ;
R 5 is H or —CH 3 ;
R 6a is H, F, cyano,
and
R 6b is H, F, cyano,
15. The compound of claim 14 , wherein:
E 2 is —NR N —;
F 1 is
F 2 is
R 5 is H;
R 6a is —CH 3 ; and
R 6b is —CH 3 .