Compounds and uses thereof

A compound, or a pharmaceutically acceptable salt thereof, of Formula I:

• wherein
• m is 0, 1, 2, or 3;
• k is 0, 1, or 2;
• R is absent or optionally substituted C1-C6 alkyl;
• each R1 is, independently, halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C6 alkynyl, optionally substituted amino, or cyano;
• each X is, independently, halo or optionally substituted C1-C6 heteroalkyl;
• L is a linker of Formula II:
• or a pharmaceutically acceptable salt thereof,
• wherein
• A1 is a bond between the linker and the ring system A;
• A2 is a bond between the degradation moiety and the linker;
• each of B1, B2, B3, and B4 is, independently, optionally substituted C1-C4 alkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-12 aryl, O, S, S(O)2, or NRN;
• each RN is, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, or optionally substituted C1-7 heteroalkyl;
• each of C1 and C2 is, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl;
• each of f, g, h, i, j, and k is, independently, 0 or 1;
• and
• D is optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, optionally substituted C6-12 aryl, optionally substituted C2-C10 polyethylene glycol, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-10 heteroalkyl;
• or D is absent, and the linker is A1-(B1)f—(C1)g—(B2)h—(B3)i—(C2)j—(B4)k-A2;
• and
• B is a degradation moiety of Formula A-1:
• wherein
• Y1 is
• RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RA6 is H or optionally substituted C1-C6 alkyl;
• and RA7 is H or optionally substituted C1-C6alkyl;
• or RA6 and RA7, together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl;
• or RA6 and RA7, together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl;
• RA8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• each of RA1, RA2, RA3, and RA4 is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted —O—C3-C6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino;
• or RA1 and RA2, RA2 and RA3, and/or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form
• and is optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is optionally substituted with A2,
• where one of RA1, RA2, RA3, and RA4 is A2, or
• is substituted with A2;
• and
• A2 is a bond between the degradation moiety and the linker;
• or
• a degradation moiety of Formula C:
• wherein
• L4 is —N(RB1)(RB2),
• RB1 is H, A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB3 is A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl;
• RB4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl;
• RB5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• v2 is 0, 1, 2, 3, or 4;
• each RB6 is, independently, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino;
• each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl;
• RB9 is H or optionally substituted C1-C6 alkyl;
• RB10 is H or F;
• and
• A2 is a bond between the degradation moiety and the linker;
• wherein one and only one of RB1, RB3, and RB6 is A2,
• or a pharmaceutically acceptable salt thereof;
• or
• a degradation moiety of Formula D:
• where
• L4 is —N(RB1)(RB2),
• RB1 is H, A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB3 is A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl;
• RB4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl;
• RB5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• v2 is 0, 1, 2, 3, or 4;
• each RB6 is, independently, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, cyano, or optionally substituted amino;
• RB9 is H or optionally substituted C1-C6 alkyl;
• and
• A2 is a bond between the degradation moiety and the linker;
• where one and only one of RB1, RB3, and RB6 is A2,
• or a pharmaceutically acceptable salt thereof;
• or
• a degradation moiety of Formula E:
• where
• L4 is —N(RB1)(RB2),
• RB1 is H, A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB3 is A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl;
• RB4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl;
• RB5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB9 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C2-C10 heterocyclyl;
• B10 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted amino, or cyano, and
• A2 is a bond between the degradation moiety and the linker;
• where one and only one of RB1, RB3, and RB6 is A2,
• or a pharmaceutically acceptable salt thereof;
• or
• a degradation moiety of Formula F:
• where
• L4 is —N(RB1)(RB2),
• RB1 is H, A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB2 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• RB3 is A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl;
• RB4 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1-C6 alkyl C6-C10 aryl;
• RB5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
• A2 is a bond between the degradation moiety and the linker;
• where one and only one of RB1 or RB3 is A2,
• or a pharmaceutically acceptable salt thereof.