Positive modulators of the muscarinic acetylcholine receptor M4
Inventors
Lindsley, Craig W. • Engers, Darren W. • Temple, Kayla J. • Gregro, Alison R. • Richardson, Alexa E. • Long, Madeline F.
Assignees
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Publication Number
US-12552790-B2
Publication Date
2026-02-17
Expiration Date
Abstract
Deuterium-labeled 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidines substituted with pyrrolo[3,4-b]pyridin-5-one, furo[3,4-b]pyridin-5(7H)-one, or [1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one are positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4) and may have use in treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.
Core Innovation
The invention relates to positive allosteric modulators of muscarinic acetylcholine receptor M4 and to deuterium-labeled compounds of Formula (I) with a specified heterocyclic core and variable substituents. The disclosure includes pharmaceutically acceptable salts, pharmaceutical compositions, and deuterated variants identified as Formula (Ia)-(Ie) and (Ia-1)-(Ie-1).
The invention also relates to a method of preparing a product having the structure of Compound 3, 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. The method forms an ether-linked piperidine substituent from tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate and 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol with a quaternary ammonium salt and a base, then converts the intermediate to an acid addition salt.
Compound 3 is then formed by contacting the acid addition salt of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine with 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one and a base. The document includes deuterated intermediates, an enumerated list of concrete deuterated compounds, and an assay figure assessing Compound 3 activity in an amphetamine-induced hyperlocomotion setting.
Claims Coverage
The provided claim set includes one independent claim directed to a method of preparing Compound 3, with dependent claims refining the sequence and reagent selections. The inventive features cover ether formation with a deuterated 2,3-dihydrobenzo[b][1,4]dioxin-6-ol precursor, conversion to an acid addition salt, and final coupling to form Compound 3, with additional claims specifying heating, tetrabutylammonium, trifluoroacetic acid, and an alkylamine base.
Tert-butyl protected ether formation to build the d4-dioxin-oxy piperidine intermediate
Contacting tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate with 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol, a quaternary ammonium salt, and a base to form tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-carboxylate.
Acid addition salt conversion of the deprotected piperidine
Contacting the tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine-1-carboxylate with acid to form an acid addition salt of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine.
Coupling of the acid addition salt with a 2-chloro pyrrolo[3,4-b]pyridinone to form Compound 3
Contacting the acid addition salt of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine with 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one and a base to form Compound 3.
Heating refinement for ether formation and pyrrolo coupling
Heating tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate with 2,3-dihydrobenzo[b][1,4]dioxin-2,2,3,3-d4-6-ol, a quaternary ammonium salt, and base; and heating an acid addition salt of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)piperidine with 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one in the presence of a base.
Specific reagent selections for quaternary ammonium salt, acid, and base class
Using a tetrabutylammonium salt as the quaternary ammonium salt; using trifluoroacetic acid as the acid for forming the acid addition salt; and using an alkylamine base in the coupling step.
Claim coverage centers on producing Compound 3 through three linked transformations: forming a tert-butyl-protected ether with a deuterated 2,3-dihydrobenzo[b][1,4]dioxin-6-ol derivative using a quaternary ammonium salt and base, converting that intermediate to an acid addition salt, and coupling that salt with 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one using a base, with dependent claims refining heating and specifying tetrabutylammonium, trifluoroacetic acid, and an alkylamine base.
Stated Advantages
Deuterium-label metabolic stability/pharmacokinetic advantages.
Optional PET isotopic labeling using 11C, 13N, 15O, 18F.
Documented Applications
Treating neurological/psychiatric disorders associated with muscarinic acetylcholine receptor (mAChR) dysfunction, notably mAChR M4.
Use of labeled compounds for mAChR M4 activity assessment.
Use in pharmaceutical compositions containing compounds of formula (I).
Pharmaceutical formulations and administration options, including oral administration, parenteral administration, liposomes, and nanoparticulate compositions.
Kits for treating cholinergic/mAChR M4-related disorders using combinations of disclosed compounds and agents that increase or decrease mAChR M4 activity.
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