Bicyclic pyridazinones and methods of use thereof
Inventors
McGowan, David Craig • Raboisson, Pierre Jean-Marie Bernard • Vandyck, Koen • Deval, Jerome • Beigelman, Leonid
Assignees
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Publication Number
US-11858913-B2
Publication Date
2024-01-02
Expiration Date
Abstract
Disclosed herein are compounds of Formula I: or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising such compounds, and methods of treating disease by administering or contacting a subject with one or more of the above compounds.
Core Innovation
The invention relates to Formula I compounds, including stereoisomers, tautomers, pharmaceutically acceptable salts thereof, and deuterated analogs. The compounds are defined by substituent variables R1 to R8, Q, and X, together with ring and linker types, and the framework includes ether-linked embodiments with triazine or triazine-dione moieties.
R1 and R2 together with the carbon atoms to which they are attached form a C4-C7 non-aromatic monocyclic ring, a C6 aromatic monocyclic ring, or a non-aromatic polycyclic ring, each optionally substituted within defined substitution classes. R3 and R4 are each independently selected from halogen, CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C2 alkoxy, optionally substituted C2-C3 alkenyl, and cyclopropyl, while R5, R6, R7, and R8 are further defined by additional selectable values. Q is selected from N, CH, and CF, X is 0 or CH2, and 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).
The disclosure further includes selected triazine-3,5(2H,4H)-dione compounds with a 6-amino substituent and a substituted phenyl-oxy connection to a tetrahydro-1-oxo cyclopenta[d]pyridazin-4-yl motif. Representative embodiments include fused, spiro, bridged, bicyclic, and hexahydrophthalazin-like variants, including deuterated and stereoisomeric forms.
The document contemplates pharmaceutical compositions comprising the disclosed THR-beta modulators and methods of treating THR-beta related disorders. Target diseases explicitly listed include NASH, obesity, hyperlipidemia/hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.
Claims Coverage
The consolidated claim coverage includes broad Formula I compounds and specific triazine-3,5(2H,4H)-dione species. Across the independent claims, the inventive features center on the Formula I structural definition, the substituted phenyl-oxy connected triazine-dione scaffold, and explicit stereoisomer, tautomer, salt, and deuterium scope.
Formula I compound with defined R1 and R2 ring formation
A compound of Formula I, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 together with the carbon atoms to which they are attached form a C4-C7 non-aromatic monocyclic ring, a C6 aromatic monocyclic ring, or a non-aromatic polycyclic ring, each optionally substituted.
Defined substituent set for R3 to R8
R3 and R4 are each independently selected from halogen, CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C2 alkoxy, optionally substituted C2-C3 alkenyl, and cyclopropyl; R5, R6, R7, and R8 are selected from the recited option sets, including H and C1-C3 alkyl for R6 and R7, and H, halogen, CN, optionally substituted C1-C3 alkyl, and optionally substituted C1-C2 alkoxy for R8.
Defined linkage variables Q and X with deuterium substitution scope
Q is selected from N, CH, and CF, X is 0 or CH2, and 0 to 10 hydrogen atoms attached to one or more carbon atoms are replaced with deuterium atom(s).
Triazine-3,5(2H,4H)-dione core with 6-amino substitution
A compound selected from the group consisting of embodiments that include 6-amino 1,2,4-triazine-3,5(2H,4H)-dione derivatives and related embodiments that maintain the 6-amino triazine-dione framework.
3,5-dichloro substituted phenyl connected via oxy linkage
A substituted phenyl group with 3,5-dichloro substitution is connected through an oxy group to the heterocycle portion, as expressed in 2-(3,5-dichloro-4-((...)oxy)phenyl) and related phenyl-oxy variants.
Ether-linked tetrahydro-1-oxo cyclopenta[d]pyridazin-4-yl motif and structural variants
An oxy-linked heterocycle defined as 7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl, with related explicitly recited fused, spiro, bridged, bicyclic, and hexahydro cage-like variants, including deuterated and stereoisomeric forms.
The independent claims collectively cover a broad Formula I chemical class defined by R1/R2 ring formation, R3-R8 substituent selection, Q/X variables, and deuterium substitution, together with a group of specifically enumerated triazine/triazine-dione ether-linked compounds that include stereoisomeric and deuterated forms.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Methods of treating THR-beta related disorders, including NASH, obesity, hyperlipidemia/hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.
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