DOT1L degraders and uses thereof

1. A compound of Formula (I′) or (I):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

R 8 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

R 9 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

R 10 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

R 10′ is hydrogen, optionally substituted alkyl, or —N(R 10A ) 2 ;

each instance of R 10A is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

R 11 is halogen or optionally substituted alkyl;

each instance of R 12 is independently hydrogen or an oxygen protecting group;

R 13 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

each instance of R 14 is independently hydrogen, or optionally substituted alkyl;

or, optionally wherein one instance of R 14 and one instance of R 10′ 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 R 14 and one instance of R 10A 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 —CH 2 — or —N(R W )—, wherein R W is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

Z is -(optionally substituted carbocyclyl)- or optionally substituted —CH 2 —;

L is a linker, which has any one of structures:

wherein

l R indicates the point of attachment to D1, and l A 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:

X A is C(O) or C(R 3A ) 2 ;

—X 1 —X 2 — is C(R 3A )═N or C(R 3A ) 2 —C(R 3A ) 2 ;

each R 1A is independently halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;

each R 3A is independently H or C 1 -C 3 alkyl;

each R 3 ′ is independently C 1 -C 3 alkyl;

each R 4A is independently H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;

R 5A is H, C 1 -C 3 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, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —C(═O)C 1-10 alkyl, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, branched C 1-10 alkyl, —OH, —O(C 1-10 alkyl), —O(C 2-10 alkenyl), —O(C 2-10 alkynyl), —COOH, —COO(C 1-10 alkyl), —NH 2 , —NH(C 1-10 alkyl), —N(C 1-10 alkyl) 2 , —C(═O)N(C 1-10 alkyl), urea, imide, —CN, or carbamate, wherein the heterocyclyl or heteroaryl comprises 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1 , wherein the compound is any one of formulas:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

R 8 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

R 9 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

R 10 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

R 11 is halogen or optionally substituted alkyl;

each instance of R 12 is independently hydrogen or an oxygen protecting group.

3. The compound of claim 1 , wherein a1 is 1.

4. The compound of claim 1 , wherein R 3A is hydrogen.

5. The compound of claim 1 , wherein two R 4A , together with the carbon atom to which they are attached, form a C(O).

6. The compound of claim 1 , wherein X A is C(O) or —CH 2 —.

7. The compound of claim 1 , wherein m is 0.

8. The compound of claim 1 , wherein n is 0.

9. The compound of claim 1 , wherein D1 is of the formula:

10. The compound of claim 1 , wherein one of R 8 , R 9 , R 10 , and R 13 is hydrogen.

11. The compound of claim 1 , wherein R 10′ is N(R 10A ) 2 ; and one instance of R 14 and one instance of R 10A are taken together with their intervening atoms to form a substituted or unsubstituted 6-14 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.

12. The compound of claim 1 , wherein R 11 is optionally substituted C 1-6 alkyl or unsubstituted t-butyl.

13. The compound of claim 1 , wherein both instances of R 12 are hydrogen.

14. The compound of claim 1 , wherein the moiety

15. The compound of claim 1 , wherein W is unsubstituted —CH 2 — or —NH—.

16. The compound of claim 1 , wherein Z is -(optionally substituted cyclobutyl)- or unsubstituted —CH 2 —.

17. The compound of claim 1 , wherein the moiety

W is —NH—; and Z is —CH 2 —.

18. The compound of claim 1 , wherein L is of the formula:

19. The compound of claim 1 , wherein:

n1 is 4 or 6;

n2 is 2, 3, or 12;

n3 is 3;

n4 is 10, 11, or 12;

n4′ is 3, 5, 6, 7, or 9;

n5 is 8; and

g is 3, 5, or 13.

20. The compound of claim 1 , wherein L is of the formula:

21. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

22. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

23. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

24. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof of claim 9 , and optionally a pharmaceutically acceptable excipient.

25. A method of treating a disease in which DOT1L plays a role, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof of claim 9 , wherein the disease is a hematological cancer.

26. The method of claim 25 , wherein the hematological cancer is selected from multiple myeloma, lymphoma, and leukemia.

27. The method of claim 26 , wherein the leukemia is acute myelocytic leukemia, mixed-lineage leukemia (MLL) rearranged acute myelocytic leukemia, acute myelocytic leukemia with a mutation in the nucleophosmin (NPM1) gene, acute myelocytic leukemia with a mutation in the DNMT3A gene, or acute myeloid eosinophilic leukemia.

28. A method of inducing the degradation of DOT1L in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof of claim 9 .