Spiro bicyclic inhibitors of menin-MLL interaction
Inventors
Angibaud, Patrick Rene • Pande, Vineet • HERKERT, Barbara • KROSKY, Daniel Jason • Querolle, Olivier Alexis Georges • PATRICK, Aaron Nathaniel • Pilatte, Isabelle Noelle Constance
Assignees
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Publication Number
US-11220517-B2
Publication Date
2022-01-11
Expiration Date
Abstract
The present invention relates to compounds of formula (I): wherein the variables have the meaning defined in the Specification. The compounds according to the present invention are useful for therapy and/or prophylaxis in a mammal, and in particular to spiro bicyclic 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), including a tautomer or a stereoisomeric form thereof, and pharmaceutically acceptable salts or solvates. The compounds are defined by selected values for R1 and R2, an L1 group that is N-linked to a thienopyrimidinyl heterocycle with linkage position a, and a terminal portion -L2-R3 selected from defined structural options.
The structural scope includes option (b) and option (f), together with further substituent constraints and ring-containing options. For option (b), L2 is selected from >CR4cR4d and —CHR4cCHR5a—, where R4c, R4d, and R5a are each independently selected from hydrogen and C1-4 alkyl, and R3 includes selections such as C1-6 alkyl optionally substituted with OH or NH2, or —OC1-6 alkyl.
For option (f), R18 is selected from hydrogen, C1-4 alkyl optionally substituted with fluoro or —CN, and C2-4 alkyl substituted with —OR19 or —NR20aR20b, with further defined substituent constraints and ring-forming options. The document also presents the compounds as menin/MLL interaction inhibitors and as compounds for therapeutic use in cancer, including MDS, and other therapeutic contexts including diabetes.
Claims Coverage
The independent claim coverage centers on one compound of Formula (I) with multiple inventive structural features. In total, the claims emphasize four main feature groups: R1/R2 selection, the N-linked thienopyrimidinyl L1 linkage at position a, and the terminal -L2-R3 options (b) or (f) with defined substituent constraints.
Formula (I) compound with selected R1 and R2
A compound of Formula (I), or a tautomer or a stereoisomeric form thereof, wherein R1 is selected from CH3, CH2F, CHF2, and CF3, and R2 is selected from hydrogen and CH3, and wherein the compound is a pharmaceutically acceptable salt or a solvate thereof.
N-linked thienopyrimidinyl heterocycle with linkage position a
L1 is N-linked to the thienopyrimidinyl heterocycle and a represents the position of linkage to the thienopyrimidinyl heterocycle.
Terminal -L2-R3 option (b) with constrained substituent sets
The terminal portion -L2-R3 is selected from option (b), wherein L2 is selected from >CR4cR4d and —CHR4c—CHR5a—, with R4c, R4d, and R5a each independently selected from hydrogen and C1-4 alkyl, and wherein R3 includes C1-6 alkyl optionally substituted with OH or NH2, or —OC1-6 alkyl.
Terminal -L2-R3 option (f) with defined R18 substituent pattern
The terminal portion -L2-R3 is selected from option (f), wherein R18 is selected from hydrogen, C1-4 alkyl optionally substituted with fluoro or —CN, and C2-4 alkyl substituted with —OR19 or —NR20aR20b, with further defined selections for R19, R20a, and R20b and additional ring-containing substituent options.
Across the claims, the inventive scope is defined by a Formula (I) core with specific R1/R2 selections, an N-linked thienopyrimidinyl heterocycle at L1 with linkage position a, and terminal -L2-R3 structural options (b) and (f) with detailed substituent constraints, including pharmaceutically acceptable salts and solvates.
Stated Advantages
Inhibition of menin/MLL interaction.
Treating and/or preventing cancer, including leukemias and solid tumors.
Treating and/or preventing myelodysplastic syndrome (MDS).
Treating and/or preventing diabetes.
Documented Applications
Therapeutic use in cancer, including leukemias and solid tumors such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma.
Therapeutic use in myelodysplastic syndrome (MDS).
Therapeutic use in diabetes.
Use as menin/MLL interaction inhibitors and for menin/MLL protein inhibition in a subject.
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