Substituted (e)-n'-(1-phenylethylidene) benzohydrazide analogs as histone demethylase inhibitors

Abstract

Substituted (E)-N-(1-phenylethylidene)benzohydrazide analogs or (3-(5-chloro-2-hydroxyphenyl)-4-METHYL-1 H-pyrazol-1-YL)(3- (morpholinosulfonyl)phenyl)methanone, derivatives thereof, and related compounds are useful as inhibitors of lysine-specific histone demethylase, including LSD1. Synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds and compositions to treat disorders associated with dysfunction of the LSD1 (lysine-specific demethylase). A pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and one or more of: (a) at least one agent known to increase histone demethylase activity; (b) at least one agent known to decrease histone demethylase activity; (c) at least one agent known to treat a disorder of uncontrolled cellular proliferation; (d) at least one agent known to treat a neurodegenerative disorder; (e) instructions for treating a neurodegenerative disorder; or (f) instructions for treating a disorder associated with uncontrolled cellular proliferation.

Description

Background technique [0001] In the last decade, it has become evident that epigenetic changes, which alter the activity of genes without altering the DNA sequence, together with genetic errors, contribute to the development and progression of cancer (Tsai, H.C. and Baylin, S.B. CellRes 2011, 21(3), 502-17; and Fullgrabe, J., Kavanagh, E., and Joseph, B. Oncogene 2011). The regulation of modifications to DNA and DNA-associated proteins has become an area of ​​intense interest, and enzymes involved in these processes have been suggested as a new class of protein targets for drug development. The major proteins associated with DNA are histones. The tails of histones host various post-translational modifications, such as phosphorylation, acetylation, methylation, and ubiquitination, and these modifications, especially acetylation and methylation of lysine residues, are important in the regulation of gene expression. plays a major role in and is often dysregulated in cancer (Full...

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Further, there is a scarcity of compounds that are therapeutically effective in th...

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