Inhibitors of the menin-MLL interaction
The present disclosure is directed to inhibitors of Formula (0), or a stereoisomer thereof, or pharmaceutically acceptable salt thereof, of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction,
1. A compound of Formula 0,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
W is N or CH;
X is C═O, S(═O)(═NR 5 ), or S(═O) 2 ;
Y is NH, O, or a bond;
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy;
R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy;
R 1 and R 2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C 1 -C 6 alkyl, halo, OH, CN, or C 1 -C 6 alkoxy;
R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(R N ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy or aryl;
R 4 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or N(R N ) 2 ;
each R N is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
each R 5 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
2. The compound of claim 1 , wherein W is N or CH.
3. The compound of claim 2 , wherein X is C═O, or S(═O) 2 .
4. The compound of claim 3 , wherein Y is NH, O, or a bond.
5. The compound of claim 4 , wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy is optionally substituted by one or more halo, OH, OBn, oxo, CN, or C 3 -C 6 cycloalkyl.
6. The compound of claim 5 , wherein R 1 is ethyl substituted by one or more halo.
7. The compound of claim 6 , wherein R 1 is —CH 2 —CHF 2 , or —CH 2 —CF 3 .
8. The compound of claim 5 , wherein R 1 is isopropyl.
9. The compound of claim 4 , wherein R 1 is C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
10. The compound of claim 9 , wherein R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, wherein the alkyl, alkoxy is optionally substituted by one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
11. The compound of claim 10 , wherein R 2 is ethyl.
12. The compound of claim 10 , wherein R 2 is propyl.
13. The compound of claim 10 , wherein R 2 is isopropyl.
14. The compound of claim 10 , wherein R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, NH 2 , NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , wherein the alkyl, alkenyl, alkynyl, alkoxy, is optionally substituted with one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
15. The compound of claim 10 , wherein R 3 is C 1 -C 6 alkyl, NH—C 1 -C 6 alkyl, N—(C 1 -C 6 alkyl) 2 , or 5- to 10-membered heteroaryl, wherein the alkyl or heteroaryl is optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
16. The compound of claim 10 , wherein R 3 is C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
17. The compound of claim 10 , wherein R 3 is C 1 -C 3 alkyl, NH—C 1 -C 3 alkyl, N—(C 1 -C 3 alkyl) 2 , or 5- to 6-membered heteroaryl, wherein the alkyl or heteroaryl is optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy.
18. The compound of claim 14 , R 4 is H or halo.
19. The compound of claim 1 , wherein each R 5 is independently H, or C 1 -C 6 alkyl.
20. The compound of claim 1 , wherein each R 5 is H.
21. A compound selected from:
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 1 , wherein the compound is useful for the treatment of leukemia in a subject in need thereof, wherein the compound minimizes hERG binding, and wherein the treatment comprises administering to the subject a therapeutically effective amount of the compound of claim 1 .
23. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
24. A method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of claim 1 .
25. A method of treating leukemia in a patient comprising administering to the patient a compound of claim 1 .
26. The method of claim 25 , wherein the leukemia is mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with a MLL rearrangement or a rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, childhood leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), therapy related leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, or leukemic meningitis.
27. The method of claim 25 , wherein the leukemia is an abstract nucleophosmin (NPM1)-mutated acute myeloid leukemia.
28. The compound of claim 1 , for use in treating or preventing a disease caused by, or associated with, menin expression, activity, and/or function, wherein the disease is leukemia and wherein the treatment comprises administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 .