Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as FXR activators
Inventors
Chao, Jianhua • Jain, Rakesh • Hu, Lily • Lewis, Jason Gustaf • Baribault, Helene • Caldwell, Jeremy
Assignees
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Publication Number
US-11091482-B2
Publication Date
2021-08-17
Expiration Date
Abstract
The disclosure relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): wherein L1, L2, A, B, R1, R2, R3, and R4 are described herein.
Core Innovation
The disclosure provides a compound family defined by Formula (I) with broad structural definitions for substituents including L1, L2, A, B, and R1-R4. The compounds include an 8-azabicyclo[3.2.1]octane core or related bicyclic core structures, an oxazole-4-carboxylate or oxazole-4-carboxylic acid motif, and substituted 1,3-benzothiazole or benzothiazole-related heteroaromatic motifs with variable substituent patterns.
The described structural variants incorporate sulfonamide, sulfonyl, carbamoyl, formamido, and sulfonylcarbamoyl motifs, together with carboxylate and carboxylic acid forms and further aromatic substitution. The scaffold is described with linker options including L1 and L2, with L2 as sulfone or sulfonyl and with alkylene linkers, as well as defined stereochemical features and multiple variable regions across the enumerated compounds.
The disclosed compounds are presented as enantiomers, stereoisomers, tautomers, and related forms, and may include pharmaceutically acceptable salts, hydrates, solvates, and prodrugs. The disclosure also relates to stereodefined small-molecule compounds of Formula (I) and related embodiments, including FXR activator compounds and variants such as Ia-Iq.
Claims Coverage
The consolidated independent claim coverage is directed to selected compounds from enumerated groups of stereodefined alternatives. The inventive coverage centers on an 8-azabicyclo[3.2.1]octane/oxazole carbonyloxy framework combined with substituted benzothiazole or related heteroaromatic motifs, with variable functional groups and ring substituents; five inventive features are identified.
Stereodefined bicyclic oxazole-carbonyloxy scaffold
A compound selected from enumerated stereodefined alternatives containing an 8-azabicyclo[3.2.1]octane framework connected to a 1,2-oxazole-4-carbonyloxy, oxazole-4-carboxylate, or oxazole-4-carboxylic acid motif.
Substituted benzothiazole or related heteroaromatic motif
The selected compounds include a substituted 1,3-benzothiazole or benzothiazole-related heteroaromatic ring system with defined substitution patterns such as fluoro, methoxy, methyl, trifluoromethoxy, and trifluoromethyl.
Carboxylate and carboxylic acid functional group variants
The enumerated group includes carboxylate and carboxylic acid forms on the benzothiazole or oxazole-associated portions of the scaffold.
Sulfonamide, sulfonyl, carbamoyl, and formamido-containing substituent variants
The selected compounds further include sulfonamide, sulfonyl, carbamoyl, formamido, and sulfonylcarbamoyl-like substituents, including motifs described as methanesulfonylcarbamoyl and sulfonic-acid/sulfonamide-like variants.
Additional ring and aryl substitution variants
The enumerated compounds include variants with different aryl substituents on the oxazole-associated phenyl portion and additional fused or linked aromatic or bicyclic ring systems, including spiro/bicyclic ring members and other aromatic alternatives.
Claim coverage is directed to selected stereodefined compounds that share an 8-azabicyclo[3.2.1]octane-linked oxazole carbonyloxy scaffold with substituted benzothiazole or related heteroaromatic motifs. The coverage is broadened by enumerated substituent, functional-group, and ring-system variations.
Stated Advantages
Intestinal-selective FXR target gene activation with limited liver effects.
FXR activation with associated anti-inflammatory effects through NFκB repression.
The disclosed compounds are stated to be FXR modulators and/or activators.
Documented Applications
Treating, preventing, and/or modulating FXR-related diseases, including liver disease, intestinal disease, kidney disease, autoimmune disorders, and cancer.
Pharmaceutical compositions in tablets, gelatin capsules, injectables, suppositories, and liposome delivery.
Administration to a patient in need in the context of FXR pathway engagement.
FXR ligand-binding assay and cell-based FXR activation assay characterization is provided, including reported pEC50 and efficacy values.
PK/WD in vivo efficacy and gene-expression findings are provided for Compound I-2, including intestinal versus systemic FXR activation patterns.
Therapeutic-use statements are provided for diseases where FXR is implicated, including liver disease, intestinal disease, kidney disease, autoimmune disorder, and cancer.
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