Compounds, salts thereof and methods for treatment of diseases
Inventors
Burstein, Ethan S. • Olsson, Roger • JANSSON, Karl Erik • SKÖLD, Niklas Patrik • WAHLSTRÖM, Larisa Yudina • BORGSTRÖM, Björn Gustav • Von Wachenfeldt, Henrik • BERGNER, Magnus Gustav Wilhelm
Assignees
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Publication Number
US-11440884-B2
Publication Date
2022-09-13
Expiration Date
Abstract
The present disclosure relates to compounds according to Formulae (I), (II) and (VIII), useful for treating diseases.
Core Innovation
The invention relates to compounds according to Formula (1), Formula (II), Formula (VIII), and related embodiments, including pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, and deuterated analogue forms. The compounds are defined by substituent parameters m, n, p, and q, with constrained groups in which R1 and R1d are fluoro, R1a, R1b, and R1c are hydrogen, A is —O—, and X is O or S.
The structural scope further includes substituent variables R2, R2a, R2b, R2c, and R2d, with defined sets that include hydrogen, deuterium, halogen, cyano, hydroxyl, -OD, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkoxy, cycloalkyl, heteroalicyclyl, aryl, and heteroaryl. At least one of these substituents is not hydrogen, or selected substituent pairs taken together with the atoms to which they are attached form a ring system.
R3 is selected from allowed substituent sets or is defined by a ring-forming condition in which the nitrogen to which R3 is attached and a carbon atom adjacent to that nitrogen together with R6 or R7 form a heteroalicyclic ring system. Additional constraints are provided for R4a, R4b, R5a, R5b, R6, R7, R6a, and R8 as hydrogen, deuterium, unsubstituted or substituted C1-6 alkyl, halogen, hydroxyl, oxo, -OD, cyano, C1-4 alkyl, C1-4 alkoxy, aryl, absent, or selected groups.
The disclosure also includes a specific compound selection recited as substituted carbamates, formamides, enamides, and related amide structures, including [4-(propan-2-yloxy)phenyl]methyl N-[(2,4-difluorophenyl)methyl]-N-(piperidin-4-yl)carbamate and related piperidinyl variants. The exemplified compounds correspond to compounds of Formula (I), Formula (II), and Formula (17), and the disclosed content includes 5-HT2A receptor activity evaluation by R-SAT assay methodology.
Claims Coverage
The claim set includes one broad independent claim to a Formula (1) compound family and one independent claim to selected specific substituted carbamates, formamides, and amides. In total, the claims present two inventive feature groups: a generalized Formula (1) scaffold with extensive substituent and ring-forming constraints, and an explicit group of individual compounds with defined arylalkoxy and piperidinyl substitutions.
Formula (1) compound framework with constrained substituents and ring-forming conditions
A compound according to Formula (1), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, or deuterated analogue thereof, wherein m and n are independently 0-3, p and q are independently 0-4, R1 and R1d are fluoro, R1a, R1b, and R1c are hydrogen, A is —O—, X is O or S, and R2/R2a/R2b/R2c/R2d, R3, R4a/R4b/R5a/R5b, R6, R7, R6a, and R8 are defined by enumerated substituent sets and ring-system formation conditions.
Selected substituted carbamates, formamides, enamides, and amides
A compound, pharmaceutically acceptable salt, polymorph, or stereoisomer selected from explicitly listed substituted carbamate, formamide, enamide, and amide structures, including difluorophenylmethyl-piperidinyl carbamates, substituted arylalkoxy variants, and sulfanyl formamide and acetamide members.
The claims center on a broad Formula (1) structural class with specific fluorine and hydrogen constraints, an —O— linkage, X as O or S, and enumerated substituent and ring-system options, together with a separate list of explicitly identified substituted carbamates, formamides, enamides, and amides.
Stated Advantages
hERG inhibition thresholds are stated for the disclosed compounds, including <65% and in some cases <50%.
Documented Applications
A method of treating a disease by administering compounds of Formulas (I)-(II) is stated, and Alzheimer’s disease is mentioned.
Use of the R-SAT assay methodology to determine 5-HT2A receptor activity and characterize exemplified compounds is described.
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