MENIN-MLL INHIBITORS AND METHODS OF USE THEREOF

摘要

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.

主权项

1. A composition comprising a compound having the structure of formula I: wherein Y is independently selected from OH, OR7, NH2, NHR7, or NR7aR7b; wherein R7 selected from C1-6-alkyl, monohalo-C1-6-alkyl, polyhalo-C1-6-alkyl, (C1-4-alkyloxy)-C1-6-alkyl, (C1-4-dialkylamino)-C1-6-alkyl, C1-4—(C3-6-cycloalkyl), C1-4—(C5-6-heteroaryl), C1-4—(C5-6-aryl), C1-4—OH, C1-4—NH2, and C1-4—CN; wherein R7a and R7b are selected from C1-6-alkyl, monohalo-C1-6-alkyl, polyhalo-C1-6-alkyl, (C1-4-alkyloxy)-C1-6-alkyl, (C1-4-dialkylamino)-C1-6-alkyl, C1-4—(C3-6-cycloalkyl), C1-4—(C5-6-heteroaryl), C1-4—(C5-6-aryl), C1-4—OH, C1-4—NH2, and C1-4—CN, or may form a ring between R7a and R7b with C3-7 carbons; wherein R1 is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, C1-3-alkyl, C1-3-alkyloxy, monohalo-C1-3-alkyl, polyhalo-C1-3-alkyl, and sulfonyl-C1-3-alkyl; wherein R2 is selected from heteroaryl, heterocycle, carbocycle containing a C3-8 ring size, or acyclic C1-6-alkyl; wherein R2 is substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, C1-3-alkyl, C1-3-alkyloxy, monohalo-C1-3-alkyl, polyhalo-C1-3-alkyl, and sulfonyl-C1-3-alkyl; wherein A is a 1,4-disubstituted aryl or heteroaryl ring substituted with X and R3 and may contain a third group R6 independently selected from cyano, halo, hydroxyl, C1-3-alkyl, C1-3 alkyloxy, monohalo-C1-3-alkyl, polyhalo-C1-3-alkyl, sulfonyl-C1-3-alkyl and sulfonamide; wherein X is O, NH, or NR8; wherein when X is NR8, R8 may be independently selected from C1-3-alkyl, C1-3-alkyloxy, monohalo-C1-3-alkyl, polyhalo-C1-3-alkyl, and sulfonyl-C1-3-alkyl wherein R3 is CN, SO2NH2, SO2NR9aR9b, CONR9aR9b, SO2CH3, OCF3, CF3, Cl, CH3, CH2CN, CH2NH2, CH2NHC(O)R10, CH2NHSO2R10, NO2, 4-pyridyl, 3-pyridyl, C(O)R, 1,2,3-triazole, OCH3; wherein R9a and R9b may be independently selected from hydrogen, C1-3-alkyl, or polyhalo-C1-3-alkyl, or may form a ring between R9a and R9b with C3-7 carbons; wherein R10 is C1-3-alkyl; or polyhalo-C1-3-alkyl; wherein R4 is hydrogen, or C1-3-alkyl; and wherein R5 is hydrogen, OH, or C1-3-alkyl.