Modulators of THR-β and methods of use thereof
Inventors
Vandyck, Koen • Raboisson, Pierre Jean-Marie Bernard • McGowan, David • Deval, Jerome
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12180192-B2
Publication Date
2024-12-31
Expiration Date
Abstract
Disclosed herein are compounds of Formula I: TL-La-CE-HD (I) or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, where i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; ii) CE is a moiety of Formula IV; iii) HD is a moiety of Formula V or VI; where the substituents are as defined herein. Disclosed are also pharmaceutical compositions comprising the above compounds, and methods of treating disease by administering or contact a patient with one or more of the above compounds.
Core Innovation
The invention provides compounds of Formula I27 and Formula I′, including stereoisomers, tautomers, and pharmaceutically acceptable salts, defined by linked TL, CE, and HD moieties. TL is selected from Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId, with Q1, Q2, Q3, Q4, Q5, Q6, Q7, and Q8 independently nitrogen or —CRb—, where each Rb is independently hydrogen, halogen, or lower alkyl. The TL moiety further allows broad substituent scope for R1, R2, R3, R4, and R5, including ring-forming combinations and spirocyclic or spiro-heterocyclic ring systems.
CE is defined as a moiety of Formula IV, with R6 and R7 independently selected from halogen or lower alkyl and R8 selected from hydrogen or lower alkyl, or with ring formation to provide a 4-, 5- or 6-membered non-aromatic carbocyclic ring. HD is defined as a moiety of Formula V, with R9 of the form —(C(Rd)2)n—N(Rd)2 and n equal to 0, and with La as —(C(Ra)2)z—, oxygen, or sulfur, where each Ra is hydrogen and z is 1. The moieties are connected at defined points through the Formula IV linkage.
The disclosure also includes embodiments that fix TL to particular sub-formulas, including Formula IIb and Formula IIIc, and narrows R1 in certain claims. The document frames the compounds as thyroid hormone receptor beta (THR-β) modulators and includes therapeutic-use coverage for administering a therapeutically effective amount of the compound to treat specified disorders or diseases.
Claims Coverage
The claim coverage includes 6 inventive features across the independent structural claim and the activity/use claims: the Formula I27 / Formula I′ scaffold, TL/CE/HD moiety definitions with extensive substituent scope, selected TL sub-formulas and R1 narrowing, and THR-β-related method coverage.
Formula I27 / Formula I′ compound defined by TL, CE, and HD moieties
A compound of Formula I27 or Formula I′, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, wherein TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; CE is a moiety of Formula IV; and HD is a moiety of Formula V, with the specified connection points and variable definitions.
TL moiety substituent scope via Q1 to Q8 and R1 to R5 definitions
TL is defined so that each of Q1, Q2, Q3, Q4, Q5, Q6, Q7, and Q8 is independently nitrogen or —CRb—, where each Rb is independently hydrogen, halogen, or lower alkyl; and R1, R2, R3, R4, and R5 are defined with the allowed substituent classes, including ring-forming and spirocyclic options.
CE and HD moieties with defined ring formation and linkage constraints
CE is a moiety of Formula IV with R6, R7, R8, and Q7 as defined, including the option for a 4-, 5- or 6-membered non-aromatic carbocyclic ring; HD is a moiety of Formula V with R9 as —(C(Rd)2)n—N(Rd)2, n equal to 0, and La as —(C(Ra)2)z—, oxygen, or sulfur, where each Ra is hydrogen and z is 1.
Selected TL sub-formulas and R1 narrowing
Dependent claim coverage includes TL fixed to Formula IIb or Formula IIIc and an R1 definition that permits one to five substituents selected from hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C6-C10 aralkoxy.
Selective THR-beta modulation by contacting the receptor
A method for selectively modulating the activity of thyroid hormone receptor beta (THR-β) by contacting the receptor with the claimed compound, stereoisomer, tautomer, or pharmaceutically acceptable salt.
Treatment of thyroid hormone receptor-related disorders by administration
A method of treating a subject’s disorder or disease by administering a therapeutically effective amount of the claimed compound, with listed disorders including NASH, obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, hypothyroidism, and thyroid cancer.
The claims are directed to structurally defined Formula I27 / Formula I′ compounds built from TL, CE, and HD moieties with explicit substituent and connectivity constraints, and they extend to selected TL sub-formulas, R1 narrowing, selective THR-β modulation, and treatment of specified disorders.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Selective modulation of the activity of thyroid hormone receptor beta (THR-β) by contacting the thyroid hormone receptor with the claimed compound.
Treatment of specified disorders or diseases by administering a therapeutically effective amount of the claimed compound, including non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, hypothyroidism, and thyroid cancer.
Interested in licensing this patent?