Compounds and methods useful for stabilizing phenylalanine hydroxylase mutations
Inventors
De Pascalis, Lucrezia • Finlay, Heather Jane • King, Sandra • Konteatis, Zenon D. • SHOOK, Brian C.
Assignees
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Publication Number
US-11919915-B2
Publication Date
2024-03-05
Expiration Date
Abstract
The disclosure relates to compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein, m, R1-R5, R5A, and L are defined herein.These compounds are useful in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.
Core Innovation
The invention relates to compounds of Formula I-B-1, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. The compounds are characterized by variable substituent parameters including x being 0 to 5, R1 selected from halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy, R2 being H or D, and R6 being optionally substituted heteroaryl.
The disclosed structures share fused bicyclic heteroaromatic scaffolds including pyrazolo[1,5-a]pyridine and imidazo[4,5-c]pyridine or dihydro-1H-imidazo[4,5-c]pyridine cores, with methanone, amide, or oxadiazole-linked heteroaryl substituents. The examples include stereochemically defined (R)- and (S)-enantiomers, together with tautomers and pharmaceutically acceptable salts.
The disclosed compound space includes selected compounds from depicted chemical structures and related formula-defined embodiments. Structural variation includes fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, methyl, cyclopropyl, cyclobutyl, tert-butyl, pyridinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxazole, oxadiazole, triazole, and thiadiazole groups, with dependent claims further narrowing stereochemistry and pharmaceutical composition embodiments.
Claims Coverage
The consolidated claim coverage includes two main independent claim approaches: a Formula I-B-1 compound definition and a selection claim to compounds chosen from depicted chemical structures. Across the combined materials, the independent claims cover compound, tautomer, and pharmaceutically acceptable salt forms, with multiple inventive features centered on scaffold selection, stereochemistry, and defined heteroaryl substitution.
Formula I-B-1 compound scaffold with defined substituents
A compound of Formula I-B-1, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, wherein x is 0 to 5; each R1 independently is halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; R2 is H or D; and R6 is optionally substituted heteroaryl.
Selected compounds from depicted chemical structures
A compound, or tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound is selected from a set of depicted chemical structures.
Stereochemical restriction to an S-enantiomer
A compound within the Formula I-B-1 scope, including its tautomer or a pharmaceutically acceptable salt thereof, is specifically limited to the S-enantiomer in dependent claim coverage.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising a claimed compound or tautomer, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Overall, the claim coverage centers on Formula I-B-1 compounds defined by constrained substituent classes and on a separate claim family covering compounds selected from depicted structures, with coverage including tautomers and pharmaceutically acceptable salts. Dependent claims add stereochemical restriction and a pharmaceutical composition embodiment.
Stated Advantages
Stabilizes mutant phenylalanine hydroxylase (PAH).
Reduces blood phenylalanine levels in phenylketonuria (PKU).
Documented Applications
Stated use as agents for stabilizing mutant PAH protein and reducing phenylalanine levels in subjects.
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