Exo-aza spiro inhibitors of menin-MLL interaction
Inventors
Dai, Xuedong • Querolle, Olivier Alexis Georges • KROSKY, Daniel Jason • Cai, Wei • Fu, Liqiang • Kong, Linglong • LIU, Yingtao • Wan, Zhao-Kui • Morschhäuser Geb. Herkert, Barbara • Pande, Vineet • Edwards, James Patrick • PATRICK, Aaron Nathaniel • Angibaud, Patrick René • Poncelet, Virginie Sophie
Assignees
Janssen Pharmaceutica NV • Johnson and Johnson China Investment Ltd • Janssen Cilag SAS • Janssen Research and Development LLC
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Publication Number
US-11396517-B1
Publication Date
2022-07-26
Expiration Date
Abstract
Provided are compounds of Formula (I), pharmaceutical compositions comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.
Core Innovation
The invention relates to compounds of Formula (I), including tautomeric and stereoisomeric forms thereof, and pharmaceutically acceptable salts or solvates. The compounds are defined by selectable structural variables including R1, Y1, R2, Y2, A, Q, and a linker group L-R3 selected from alternative structural families (a) through (f), with additional definitions for Het1, Het2, Het3, Het4, Ring B, and index variables n1, n2, m1, and m2.
R1 is selected from CH3, CH2F, CHF2, and CF3, and Y1 is N or CRy, with R2 selected according to whether Y1 is N or CRy. Y2 is CH2 or O, A is a covalent bond or -CR15aR15b-, and R15a and R15b are each independently hydrogen or C1-4 alkyl. Q is hydrogen or C1-4 alkyl optionally substituted with phenyl.
The linkage group L-R3 is defined by multiple alternatives that include N-containing linker classes, carbonyl- or sulfonyl-containing motifs, carbon-linked N(RD) forms, and a radical form with Ar and Het1/Het2 patterns. The structural scope also includes R3 as Ar, Het1, Het2, Het3, R17, or a 7- to 10-membered saturated spirocarbobicyclic system, with Het3 selected from formulas (b-1) and (b-2) and Ring B set to phenyl.
Claims Coverage
The consolidated claim coverage centers on one independent compound claim for Formula (I), defined by extensive substituent selections and six alternative L-R3 linkage families. The coverage is primarily controlled by R1, Y1/Y2, A, Q, and the permitted Ar/Het/spirocarbobicyclic and heterocycle patterns within L-R3, with tautomeric/stereoisomeric forms and salts/solvates included.
Compound of formula (I)
A compound of Formula (I) or a tautomer or a stereoisomeric form thereof, wherein R1 is selected from CH3, CH2F, CHF2 and CF3; Y1 is N or CRy; R2 is selected according to Y1; Ry is selected from hydrogen, cyano, and C1-4 alkyl optionally substituted with hydroxy, -O-C1-4 alkyl, or -O-C3-6 cycloalkyl; Y2 is CH2 or O; A is a covalent bond or -CR15aR15b-; R15a and R15b are each independently hydrogen or C1-4 alkyl; and Q is hydrogen or C1-4 alkyl optionally substituted with phenyl.
Alternative L-R3 linkage families
L-R3 is selected from (a), (b), (c), (d), (e), or (f), including N-containing linker forms, carbonyl- or sulfonyl-containing motifs, N(RD)-containing multi-carbon linker forms, an E-defined substituted form, and a radical form with Ar and Het1/Het2 patterns.
Het3 and Ring B constraints
Het3 is selected from formulas (b-1) and (b-2) with Ring B set to phenyl, atom-type variables X1 through X5, and additional constraints for Het4, R17, and index variables n1, n2, m1, and m2.
Pharmaceutically acceptable salt or solvate
The compound includes a pharmaceutically acceptable salt or a solvate thereof.
The claim scope is a broad Formula (I) genus defined by coordinated substituent choices and by six distinct L-R3 linkage families, with additional heteroaryl, heterocyclyl, and ring-B constraints, and with salts, solvates, tautomeric forms, and stereoisomeric forms included.
Stated Advantages
Not explicitly described in patent.
Documented Applications
A method for slowing, interrupting, or arresting the progression of disorders characterized by chromosomal translocations in MLL by administering a therapeutically effective amount of a compound as claimed in claim 1.
Cancer selected from leukemias, myeloma or a solid tumor cancer.
Experimental characterization and pharmacology of the claimed compounds, including analytical chiral separation, optical rotation and NMR spectroscopy, Menin/MLL binding assessment, and anti-proliferative testing in MLL-translocation leukemia cell lines.
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