Fluoroalkyl-oxadiazoles and uses thereof
Inventors
Patel, Snahel • Mandegar, Mohammad A. • Ding, Pingyu • Bhatt, Ulhas • HOLAN, Martin • Lee, John • Li, Yihong • Medina, Julio • NERURKAR, Alok • SEIDL, Frederick • Sperandio, David • WIDJAJA, Tien
Assignees
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Publication Number
US-12312345-B2
Publication Date
2025-05-27
Expiration Date
Abstract
Provided herein are compounds identified as inhibitors of HDAC6 activity having the formula: or a pharmaceutically acceptable salt thereof, that can be used to treat various diseases and disorders.
Core Innovation
The invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, defined by variable substituents R1 through R5, a heteroatom X1 selected from S, O, NH, or NR6, Y fixed as N, and n selected from 0, 1, and 2. The structural framework constrains R1, R2, R3, R4, and R5 to specified chemical-group selections, with optional substitution patterns including oxo, halogen, C1-5 alkyl, C1-5 haloalkyl, C1-5 alkoxy, C1-5 haloalkoxy, cyano, amido, ester, and alkylamino.
R1 is selected from H, halo, C1-3 alkyl, cycloalkyl, haloalkyl, and alkoxy. R2 and R3 are independently selected from H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, or together with the atom to which they are attached form a cycloalkyl or heterocyclyl. R4 is selected from alkylenealkoxy, alkyleneheterocyclyl, —S(O)2- and —C(O)-linked alkyl, cycloalkyl, alkylenecycloalkyl, and alkyleneheterocyclyl variants, and R5 is selected from alkyl, haloalkyl, alkylene-aryl, heterocyclyl, cycloalkyl, aryl, or heteroaryl.
The disclosure also includes ring-forming options where R4 and R5 together with the atom to which they are attached form a heterocyclyl, in some materials with defined ring-size and heteroatom constraints. The examples and descriptions repeatedly reference fused heteroaryl, sulfonamide, and carbonyl-containing motifs, including difluoromethyl-substituted 1,3,4-oxadiazole and thiazole-linked scaffolds and related heteroaryl substitution patterns.
Claims Coverage
The independent claim coverage centers on one independent Formula (I) claim family, defined by five inventive structural feature groups: R1, R2/R3, R4, R5, and X1 with Y = N and n = 0, 1, or 2.
Formula (I) compound with constrained variable scaffold
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, defined by R1 through R5, X1 selected from S, O, NH, or NR6, Y fixed as N, and n selected from 0, 1, or 2.
R1, R2, and R3 selection set
R1 is selected from H, halo, C1-3 alkyl, cycloalkyl, haloalkyl, and alkoxy; R2 and R3 are independently selected from H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, or together with the atom to which they are attached form a cycloalkyl or heterocyclyl.
R4 sulfonyl and carbonyl substituent classes
R4 is selected from alkylenealkoxy, alkyleneheterocyclyl, —S(O)2alkyl, —S(O)2cycloalkyl, —S(O)2alkylenecycloalkyl, —S(O)2alkyleneheterocyclyl, —S(O)2N(H)alkyleneheterocyclyl, —C(O)alkyl, —C(O)cycloalkyl, —C(O)alkylenecycloalkyl, —C(O)alkyleneheterocyclyl, or —C(O)N(H)alkyleneheterocyclyl, each optionally substituted with the specified oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cyano, and amido groups.
R5 substituent class and R4/R5 ring formation
R5 is alkyl, haloalkyl, alkylene-aryl, heterocyclyl, cycloalkyl, aryl, or heteroaryl, each optionally substituted with the specified oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, heteroaryl, ester, amido, cyano, cyanoalkyl, and alkylamino groups; or R4 and R5 together with the atom to which they are attached form a heterocyclyl.
X1 heteroatom selection with Y = N and discrete n value
X1 is selected from S, O, NH, or NR6, where R6 is selected from C1-C6 alkyl, alkoxy, haloalkyl, cycloalkyl, and heterocyclyl; Y is N; and n is selected from 0, 1, and 2.
The independent claim coverage is the Formula (I) scaffold with constrained R1 through R5 substituent classes, optional ring formation for R2/R3 and for R4/R5, and X1 selection from S, O, NH, or NR6 with Y fixed as N and n limited to 0, 1, or 2.
Stated Advantages
Reduced toxicity or adverse effects compared to pan-HDAC inhibition, via selective targeting of HDAC6 versus pan-HDAC inhibition.
Documented Applications
Spectroscopic and LCMS characterization of multiple sulfonamide compounds having a shared core containing difluoromethyl-1,3,4-oxadiazole and 1,3-thiazole motifs, with reported 1H NMR signals and LCMS retention times/m/z values.
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