Azepane inhibitors of menin-MLL interaction
Inventors
Angibaud, Patrick René • Pande, Vineet • HERKERT, Barbara • KROSKY, Daniel Jason • Querolle, Olivier Alexis Georges • PATRICK, Aaron Nathaniel • Pilatte, Isabelle Noëlle Constance
Assignees
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Publication Number
US-10745409-B2
Publication Date
2020-08-18
Expiration Date
Abstract
The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to azepane compounds, pharmaceutical composition 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), or a tautomer or a stereoisomeric form thereof, and to pharmaceutically acceptable salts or solvates of such compounds. The compound is defined by extensive, explicitly enumerated groups for R1, R2, Y1, Y2 and Y3, together with additional substituent variables including R1Y, R2Y, R2YY, R3Y, R4Y and R4YY. The definition also includes a linking moiety -L-R3 selected from structural options (a), (b), (c), (d), (e) or (f), with defined selections for Ar, Het1, Het2 and a 7- to 10-membered saturated spirocarbobicyclic system.
R1 is selected from CH3, CH2F, CHF2 and CF3, while R2 is selected from hydrogen and CH3. Y1 is selected from hydrogen, C1-6 alkyl, and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom, with optional substitution patterns. Y2 and Y3 are independently selected from hydrogen, OH, NH2, -C(=O)NR1yR2y, C1-6 alkyl, and C1-4 alkyl substituted with defined functional groups, with a proviso governing cases where Y2 and Y3 are both substituents at the same carbon atom.
The core definition further constrains substitution patterns through selections from hydrogen, C1-4 alkyl, fluoro, cyano, alkoxy and amino patterns, including non-aromatic heterocyclyl options. Each -L-R3 variant imposes defined linkage patterns and substituent restrictions on Ar, Het1 and Het2, and the supplied description also discusses named compounds, including HCl salts, and enantiomeric separations for specific compound examples. The document also covers pharmaceutical compositions comprising the compound together with a pharmaceutically acceptable carrier or diluent.
Claims Coverage
The consolidated claim coverage centers on one independent Formula (I) compound claim with extensive enumerated substituent selections and defined -L-R3 variants (a) through (f), plus pharmaceutical composition and composition preparation claims. In total, three inventive features are represented across the supplied claim content.
Formula (I) compound with enumerated substituent and linker options
A compound of Formula (I), including a tautomer or stereoisomeric form thereof, wherein R1, R2, Y1, Y2 and Y3 are selected from the enumerated groups, and -L-R3 is selected from (a), (b), (c), (d), (e) or (f) with further stated constraints on Ar, Het1, Het2 and the allowed substituent patterns.
Pharmaceutical composition comprising the Formula (I) compound with carrier or diluent
A pharmaceutical composition comprising a compound as claimed together with a pharmaceutically acceptable carrier or diluent.
Process for preparing a pharmaceutical composition by mixing
A process for preparing a pharmaceutical composition by mixing a pharmaceutically acceptable carrier or diluent with a therapeutically effective amount of the compound.
Overall, the claims are directed to a Formula (I) compound defined through extensive enumerated substituent and linkage selections, including specific branching for -L-R3 variants (a) through (f), and extend to pharmaceutical compositions and a mixing-based preparation process.
Stated Advantages
Not explicitly described in patent.
Documented Applications
A pharmaceutical composition containing the compound together with a pharmaceutically acceptable carrier or diluent.
A process for preparing a pharmaceutical composition by mixing a pharmaceutically acceptable carrier or diluent with a therapeutically effective amount of the compound.
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