Cycloalkyl and heterocycloalkyl benzisoxazole sulfonamide derivatives
Inventors
Brodsky, Oleg • GREASLEY, SAMANTHA ELIZABETH • Hoffman, Robert Louis • Kung, Pei-Pei • Richardson, Paul Francis • Stupple, Paul Anthony
Assignees
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Publication Number
US-12545669-B2
Publication Date
2026-02-10
Expiration Date
Abstract
The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Ring A, Y, R1-R8, m, n and p are defined herein. The novel cycloalkyl and heterocycloalkyl benzisoxazole sulfonamide derivatives are useful in the treatment of abnormal cell growth, such as cancer, in patients. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in patients.
Core Innovation
The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. Ring A is absent or is a C3-C9 cycloalkyl or a 4-9 membered heterocycloalkyl, with the constraint that when Ring A is absent, p is 0. Y is O or NR8, with the constraint that when Y is NR8, both of m and n are 0.
The compound of formula (I) defines substituent options for R1 as hydrogen, fluoro, cyano, C1-C3 alkyl, —CH2CN, —CH2F, —CHF2, —CF3, oxo, C1-C3 alkoxy, —CH2OCH3, —C(O)CH3, —C(O)OCH2-phenyl, —S(O)2CH3, or phenyl optionally substituted by fluoro. R2, R3, and R4 are each independently hydrogen, fluoro, or methyl, while R5 is hydrogen, methyl, or methoxy, and each of R6, R7, and R8 is hydrogen or methyl.
The indices m, n, and p are constrained such that m is 0, 1, 2, or 3; n is 0 or 1; and p is 0 or 1. The provided description includes substituted benzoxazole/pyrazole-containing cyclopropane sulfonamides, with variations in cycloalkyl and heterocycle substituents, additional oxygen-containing rings, fluorinated cycloalkyl motifs, and representative synthetic routes to sulfonamide derivatives.
Claims Coverage
The claim coverage centers on a formula (I) compound or pharmaceutically acceptable salt defined by constrained Ring A and Y relationships and specific substituent and index limitations. Independent claims cover one inventive scaffold with five inventive features, and dependent claims further narrow Ring A, R1, and allowed m/n pairs, while also adding a pharmaceutical composition and a method of treating breast cancer.
Formula I compound scaffold with Ring A and Y constraints
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring A is absent or is C3-C9 cycloalkyl or 4-9 membered heterocycloalkyl, provided that when Ring A is absent, p is 0; and Y is O or NR8, provided that when Y is NR8, both of m and n are 0.
Defined R1 substituent set and phenyl optional fluoro substitution
R1 is hydrogen, fluoro, cyano, C1-C3 alkyl, —CH2CN, —CH2F, —CHF2, —CF3, oxo, C1-C3 alkoxy, —CH2OCH3, —C(O)CH3, —C(O)OCH2-phenyl, —S(O)2CH3, or phenyl, wherein the phenyl is optionally substituted by fluoro.
Substituent constraints for R2, R3, R4, R5, and R6-R8
R2, R3, and R4 are each independently selected from hydrogen, fluoro, and methyl; R5 is hydrogen, methyl, or methoxy; each R6, R7, and R8 are hydrogen or methyl.
Index constraints for m, n, and p
m is 0, 1, 2, or 3; n is 0 or 1; and p is 0 or 1.
Specific ring system refinements and index narrowing
Dependent claims refine Ring A to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, specify R1 selections, and restrict allowed m and n value pairs.
Overall, the claims cover a formula (I) compound or salt defined by a constrained Ring A presence/absence framework, a Y = O or NR8 choice with an m/n constraint when Y is NR8, and defined allowed substituents for R1-R5 and R6-R8, with dependent claims further narrowing Ring A and specific m/n and R1 selections.
Stated Advantages
Inhibits Lysine Acetyl Transferase (KAT) in the MYST family (MOF, HBO1, MOZ, MORF, TIP60).
Used for treating abnormal cell growth, including cancer, including breast cancer and ER-positive breast cancer.
Provides pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier or diluent.
Documented Applications
KAT biological assay readouts for KAT6A inhibition, including percent inhibition and IC50/Ki values.
Protein preparation and assay readouts for KAT5/KAT6A/KAT7.
A method of treating breast cancer.
Treating cancer via administration of the compounds to a patient.
Treating ER-positive breast cancer.
Combination context with anti-tumor agents or radiation therapy.
Use as KAT inhibitors of the MYST family (MOF, HBO1, MOZ, MORF, TIP60) in the context of cancer.
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