Compounds, compositions and methods
Inventors
Craig, II, Robert A. • de Vicente Fidalgo, Javier • Estrada, Anthony A. • Feng, Jianwen A. • Lexa, Katrina W. • Osipov, Maksim • Sweeney, Zachary K.
Assignees
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Publication Number
US-12139478-B2
Publication Date
2024-11-12
Expiration Date
Abstract
The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and methods of making and using thereof.
Core Innovation
The invention relates to compounds of Formula I, including pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, and prodrugs thereof. The compounds are defined by a scaffold in which L is heterocyclyl optionally substituted with one or more R13 or heteroaryl optionally substituted with one or more R13, z is 0 or 1, and X1 is O, NR9, or a bond, with explicit provisos depending on z and X1.
The Formula I definition further controls substituent space through R14, R15, R16, and R17, which are independently hydrogen, halo, cyano, —NR6R7, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkyl, with ring-forming combinations also permitted. R18 and R19 are independently hydrogen or C1-6 alkyl, or together form a C1-3 alkylene bridge optionally substituted with one to six R10, and additional constraints define R1 through R5 and R6 through R13 with optional substitution and ring-forming relationships.
The disclosure also specifies provisos that restrict certain substitution patterns depending on whether X1 is a bond or NR9 and depending on whether z is 0, and it excludes a specified compound. In addition, the document describes example chemical structures and specific embodiments, including substituted quinoline-2-carboxamide derivatives and related oxadiazole/tetrahydropyran derivatives, as well as a table of example compounds with defined substituent patterns.
Claims Coverage
The claim coverage centers on a broad Formula I compound family with multiple independently variable substituent positions, stereochemical/prodrug/salt variants, and conditional constraints on z and X1. Across the provided items, the claim set also includes selected compound embodiments and pharmaceutical composition claims.
Formula I compound with conditional X1 and z constraints
A compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein z is 0 or 1 and X1 is O, NR9, or a bond, with the condition that when z is 0, X1 is not O.
L as heterocyclyl or heteroaryl optionally substituted with R13
L is heterocyclyl optionally substituted with one or more R13 or heteroaryl optionally substituted with one or more R13.
Substitution framework for R14 through R17
R14, R15, R16, and R17 are independently hydrogen, halo, cyano, —NR6R7, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkyl, with ring-forming options that allow C3-6 cycloalkyl or C(O)-containing ring combinations with the attached atoms.
R18 and R19 define bridge or alkyl options
R18 and R19 are independently hydrogen or C1-6 alkyl, or together form a C1-3 alkylene bridge optionally substituted with one to six R10.
R1 through R5 and R6 through R13 substitution rules
R1 through R5 and R6 through R13 are defined with broad but specific allowed classes, optional substitution patterns, and ring-forming combinations, including heterocyclyl, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, carbonyl-related, sulfonyl-related, halo, cyano, nitro, oxo, and related substituent types.
Conditional provisos and excluded compound
The claim set includes provisos that restrict allowed structures when X1 is a bond or NR9 and when z is 0, and it excludes a specified named compound.
Specific compound embodiments and selected compounds
The claims include selected compound embodiments and specific structural compound claims, including a second eluting isomer, as well as a pharmaceutical composition comprising a claimed compound with a pharmaceutically acceptable carrier.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound of Formula I, or a specific claimed compound, together with a pharmaceutically acceptable carrier.
Across the independent and dependent claims provided, coverage is centered on a Formula I chemical scaffold with defined L, z, and X1 variables, extensive substituent and ring-formation constraints, explicit provisos restricting certain substitution patterns, and an exclusion of one specific compound. The claim set also extends to selected compound embodiments and pharmaceutical compositions containing a pharmaceutically acceptable carrier.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating eIF2B-mediated diseases, including neurodegenerative disorders and cancer.
Treating or preventing cellular proliferative disorders and cancer.
Treating or preventing lung injury and lung inflammation.
Treating or preventing neurodegenerative diseases.
Treating or preventing ocular diseases including neovascular age-related macular degeneration.
Treating or preventing viral infections including HIV.
Treating or preventing disorders involving unwanted protein synthesis and/or accumulation.
ATF4 nano-luciferase integrated stress response assay for evaluating compound activity categories and IC50 classification.
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