Menin-MLL inhibitors and methods of use thereof
The present invention relates generally to compounds that inhibit the binding of menin and MLL or MLL fusion proteins and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperidine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), for example, for the treatment of leukemia, solid cancers, diabetes, and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, MLL-PTD and/or menin.
1. A composition comprising a compound having the structure of formula I:
wherein Y is independently selected from OH, OR 7 , NH 2 , NHR 7 , or NR 7 aR 7b ;
wherein R 7 selected from C 1-6 -alkyl, monohalo-C 1-6 -alkyl, polyhalo-C 1-6 -alkyl, (C 1-4 -alkyloxy)-C 1-6 -alkyl, (C 1-4 -dialkylamino)-C 1-6 -alkyl, C 1-4 —(C 3-6 -cycloalkyl), C 1-4 —(C 5-6 -heteroaryl), C 1-4 —(C 5-6 -aryl), C 1-4 —OH, C 1-4 —NH 2 , and C 1-4 —CN;
wherein R 7a and R 7b are selected from C 1-6 -alkyl, monohalo-C 1-6 -alkyl, polyhalo-C 1-6 -alkyl, (C 1-4 -alkyloxy)-C 1-6 -alkyl, (C 1-4 -dialkylamino)-C 1-6 -alkyl, C 1-4 —(C 3-6 -cycloalkyl), C 1-4 —(C 5-6 -heteroaryl), C 1-4 —(C 5-6 -aryl), C 1-4 —OH, C 1-4 —NH 2 , and C 1-4 —CN, or may form a ring between R 7a and R 7b with C 3-7 carbons;
wherein R 1 is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, C 1-3 -alkyl, C 1-3 -alkyloxy, monohalo-C 1-3 -alkyl, polyhalo-C 1-3 -alkyl, and sulfonyl-C 1-3 -alkyl;
wherein R 2 is selected from heteroaryl, heterocycle, carbocycle containing a C 3-8 ring size, or acyclic C 1-6 -alkyl;
wherein R 2 is substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, C 1-3 -alkyl, C 1-3 -alkyloxy, monohalo-C 1-3 -alkyl, polyhalo-C 1-3 -alkyl, and sulfonyl-C 1-3 -alkyl;
wherein A is a 1,4-disubstituted aryl or heteroaryl ring substituted with X and R 3 and may contain a third group R 6 independently selected from cyano, halo, hydroxyl, C 1-3 -alkyloxy, monohalo-C 1-3 -alkyl, polyhalo-C 1-3 -alkyl, sulfonyl-C 1-3 -alkyl and sulfonamide;
wherein X is O, NH, or NR 8 ; wherein when X is NR 8 , R 8 may be independently selected from C 1-3 -alkyl, C 1-3 -alkyloxy, monohalo-C 1-3 -alkyl, polyhalo-C 1-3 -alkyl, and sulfonyl-C 1-3 -alkyl
wherein R 3 is CN, SO 2 NH 2 , SO 2 NR 9a R 9b , CONR 9a R 9b , SO 2 CH 3 , OCF 3 , CF 3 , Cl, CH 2 CN, CH 2 NH 2 , CH 2 NHC(O)R 10 , CH 2 NHSO 2 R 10 , NO 2 , 4-pyridyl, 3-pyridyl, 1,2,3-triazole, OCH 3 ; wherein R 9a and R 9b may be independently selected from hydrogen, C 1-3 -alkyl, or polyhalo-C 1-3 -alkyl, or may form a ring between R 9a and R 9b with C 3-7 carbons; wherein R 10 is C 1-3 -alkyl; or polyhalo-C 1-3 -alkyl;
wherein R 4 is hydrogen, or C 1-3 -alkyl; and
wherein R 5 is hydrogen, OH, or C 1-3 -alkyl.
2. The composition of claim 1 , wherein one or both of R 1 and R 2 are phenyl.
3. The composition of claim 1 , wherein R 1 is phenyl or substituted phenyl, and R 2 is a C5 carbocycle.
4. The composition of claim 1 , wherein R 1 is phenyl or substituted phenyl, R 2 is heterocyclic or substituted heterocyclic.
5. The composition of claim 4 , wherein R 2 is 2-heterocyclic or substituted 2-heterocyclic.
6. The composition of claim 1 , wherein Y is NH 2 , NHR 7 , or NR 7a R 7b .
7. The composition of claim 1 , wherein Y is OH or OR 7 .
8. The composition of claim 1 , wherein A is a 1,4-disubstituted phenyl group.
9. The composition of claim 8 , wherein A is a phenyl group connected to the rest of the scaffold at the 1 position and comprising a substituent of 30 or fewer atoms at the 4 position.
10. The composition of claim 9 , wherein said substituent at the 4 position comprises a heteroaryl.
11. The composition of claim 9 , wherein said substituent at the 4 position comprises 5 or fewer atoms.
12. The composition of claim 11 , wherein said substituent at the 4 position selected from the list consisting of CN, Cl, Br, CF 3 , OCF 3 , and SO 2 NH 2 .
13. The composition of claim 11 , wherein R 6 is a halogen.
14. The composition of claim 1 , wherein X is O.
15. The composition of claim 1 , wherein one or both of R 4 and R 5 are H.
16. The composition of claim 15 , wherein R 4 is H.
17. A composition comprising an effective amount of a compound selected from:
18. A method for the treatment of leukemia or other hematological malignancies, or diabetes comprising administering a composition of claim 1 to a subject suffering from said disease.
19. The method of claim 18 , wherein said leukemia comprises AML or ALL.