DOT1L degraders and uses thereof

A compound of Formula (I′) or (I):

• or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
• R8 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
• R9 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
• R10 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
• R10′ is hydrogen, optionally substituted alkyl, or —N(R10A)2;
• each instance of R10A is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
• R11 is halogen or optionally substituted alkyl;
• each instance of R12 is independently hydrogen or an oxygen protecting group;
• R13 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
• each instance of R14 is independently hydrogen, or optionally substituted alkyl;
• or, optionally wherein one instance of R14 and one instance of R10′ are taken together with their intervening atoms to form a substituted or unsubstituted 3-10 membered heterocyclic or substituted or unsubstituted 5-10 membered heteroaryl ring, wherein the heterocyclic or heteroaryl comprises 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or, optionally wherein one instance of R14 and one instance of R10A are taken together with their intervening atoms to form a substituted or unsubstituted 3-10 membered heterocyclic or substituted or unsubstituted 5-10 membered heteroaryl ring, wherein the heterocyclic or heteroaryl comprises 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or, optionally wherein the moiety
• W is optionally substituted —CH2— or —N(RW)—, wherein RW is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
• Z is -(optionally substituted carbocyclyl)- or optionally substituted —CH2—;
• L is a linker, which has any one of structures:
• wherein
• lR indicates the point of attachment to D1, and lA indicates the point of attachment to the moiety
• n1 is 1, 2, 3, 4, 5, or 6;
• n2 is 1, 2, 3, 4, 5, or 6;
• n3 is 1, 2, 3, 4, 5, or 6;
• n4′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;
• n5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
• and
• g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
• and
• D1 is an E3 ubiquitin ligase binding moiety and is of formula IA or IB:
• wherein:
• XA is C(O) or C(R3A)2;
• —X1—X2— is C(R3A)═N or C(R3A)2—C(R3A)2;
• each R1A is independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy;
• each R3A is independently H or C1-C3 alkyl;
• each R3′ is independently C1-C3 alkyl;
• each R4A is independently H or C1-C3 alkyl;
• or two R4A, together with the carbon atom to which they are attached, form a C(O), C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
• R5A is H, C1-C3 alkyl, or halogen;
• m is 0, 1, 2 or 3;
• n is 0, 1, or 2;
• and
• a1 is 0 or 1,
• wherein the alkyl, heterocyclic, heteroaryl, carbocyclyl, is optionally substituted with halogen, —NO2, —N3, —SO2H, —SO3H, —C(═O)C1-10 alkyl, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, 5-14 membered heteroaryl, branched C1-10 alkyl, —OH, —O(C1-10 alkyl), —O(C2-10 alkenyl), —O(C2-10 alkynyl), —COOH, —COO(C1-10 alkyl), —NH2, —NH(C1-10 alkyl), —N(C1-10 alkyl)2, —C(═O)N(C1-10 alkyl), urea, imide, —CN, or carbamate, wherein the heterocyclyl or heteroaryl comprises 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.