Methods and compounds for treating disorders
The present invention relates to methods and compositions for the treatment of BAF-related disorders such as cancers and viral infections.
1. A method of treating synovial sarcoma in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the structure of Formula I:
A-L-B Formula I
wherein
L is a linker;
B is a degradation moiety, which has the structure of Formula A-1:
wherein
Y 1 is
each of R 3 and R 4 is, independently, H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;
q is 0, 1, 2, 3, or 4; and
each R 2 is, independently, halogen, 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, hydroxyl, —SH, or optionally substituted amino;
A has the structure of Formula E-a:
where
R 22 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;
R 23 is H, halogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 6 -C 10 aryl;
s′ is 0, 1, or 2;
each R 24 is, independently, halogen, 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, hydroxyl, —SH, or optionally substituted amino, or two R 24 combine with the carbon atoms to which they are attached to form an optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 9 heteroaryl;
s is 0, 1, 2, 3, or 4; and
each R 25 is, independently, halogen, 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, hydroxyl, —SH, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.
2. The compound method of claim 1 , wherein the linker has the structure of Formula II:
A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D)-(B 3 ) i -(C 2 ) j -(B 4 ) k -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 B 1 , B 2 , B 3 , and B 4 is, independently, optionally substituted C 1 -C 2 alkyl, optionally substituted C 1 -C 3 heteroalkyl, O, S, S(O) 2 , or NR N ;
R N is 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;
each of C 1 and C 2 is, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl;
f, g, h, l, j, and k are each, independently, 0 or 1; and
D is optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 6-12 aryl, optionally substituted C 2 -C 10 polyethylene glycol, or optionally substituted C 1-10 heteroalkyl, or a chemical bond linking A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - to -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 .
3. The method of claim 1 , wherein the compound has the structure of any of compounds:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein Formula E-a has the structure of Formula E-2a:
where
R 22 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;
R 23 is H, halogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 6 -C 10 aryl;
s is 0, 1, 2, 3, or 4;
each R 25 is, independently, halogen, 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, hydroxyl, —SH, or optionally substituted amino;
X 1 is N or CR 24a ;
X 2 is N or CR 24b ;
X 3 is N or CR 24c ;
X 4 is N or CR 24d ; and
each of R 24a , R 24b , R 24c , and R 24d is, independently, H, halogen, hydroxyl, 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, hydroxyl, —SH, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.