Thyroid hormone receptor beta agonist compounds
Inventors
Kirschberg, Thorsten A. • HALCOMB, Randall • XU, Yingzi • Romero, F. Anthony
Assignees
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Publication Number
US-11203587-B2
Publication Date
2021-12-21
Expiration Date
Abstract
Provided herein are compounds, preferably thyroid hormone receptor beta (THR beta) agonist compounds, compositions thereof, methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by THR beta.
Core Innovation
The invention relates to compounds of formula (I), including pharmaceutically acceptable salts thereof, defined by variable substituents R1 through R11, a linkage group L, and ring-forming groups M1 through M3. The structural definitions specify substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, halo, carbonyl-containing groups, heterocycloalkyl options, and ring formation when M3 is taken together with M2 and the carbon atoms to which they are attached to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S.
The disclosed compounds are characterized as selective THRβ agonists over THRα, with selectivity assessed by TR-FRET. The scope further includes stereochemical forms, tautomers, N-oxides, solvates, prodrugs, isotopomers, and crystalline and non-crystalline forms, and the document presents example embodiments, representative compounds, and analytical characterization.
The invention further addresses pharmaceutical compositions and therapeutic use. Therapeutic methods are described for treating THR beta-mediated disorders, with explicit disorders including NASH, NAFLD, dyslipidemia, metabolic syndrome, hypertriglyceridemia, and hypercholesterolemia.
Claims Coverage
The consolidated claim coverage centers on the broad formula (I) scaffold with defined substituent ranges, linkage group L, and ring-forming groups M1-M3, including pharmaceutically acceptable salts. Across the provided materials, the main inventive features are the compound scaffold and therapeutic use for THRβ-mediated disorders, with one item also mentioning a selected compound from an enumerated group.
Formula (i) compound scaffold with variable substituents and salts
A compound of formula (I), including pharmaceutically acceptable salt thereof, defined by R1 through R11 with the stated allowed alkyl, cycloalkyl, halo, carbonyl, and heterocycloalkyl options, together with linkage group L.
Ring-forming groups M1 through M3
M1 and M2 are independently halo or substituted or unsubstituted C1-C6 alkyl; M3 is H, halo, or substituted or unsubstituted C1-C6 alkyl, or M3 is taken together with M2 and the carbon atoms to form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S.
Therapeutic treatment of THRβ-mediated disorders by administering an effective amount
A method for treating a THRβ-mediated disorder in a patient by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, wherein the disorder is NASH, NAFLD, dyslipidemia, metabolic syndrome, hypertriglyceridemia, or hypercholesterolemia.
Selected compound from an enumerated group
A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of enumerated alternatives.
Overall, the claim coverage is anchored by the broad formula (I) scaffold with explicit variable substituent and ring-forming definitions, and by therapeutic administration for THRβ-mediated disorders including NASH, NAFLD, and metabolic/dyslipidemic conditions.
Stated Advantages
Selective THRβ agonism over THRα.
Treatment and/or delay of liver and metabolic disorders, including NAFLD, NASH, metabolic syndrome, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia.
Selectivity over THRα, with selectivity assessed via TR-FRET.
Documented Applications
Therapeutic treatment of THRβ-mediated disorders in a patient by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt.
Methods for treating NASH, NAFLD, dyslipidemia, metabolic syndrome, hypertriglyceridemia, or hypercholesterolemia.
Use in assays including biochemical assay and TR-FRET.
Pharmaceutical compositions and formulations for administration by multiple routes.
Kits and articles of manufacture concepts.
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