Substituted thiophene- and furan-fused azolopyrimidine-5-(6H)-one compounds
Inventors
Branstetter, Bryan • Breitenbucher, James • Dyck, Brian • Gomez, Laurent • Hudson, Andrew Richard • Marrone, Tami Jo • Peters, Marco • VICKERS, Troy
Assignees
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Publication Number
US-9499562-B2
Publication Date
2016-11-22
Expiration Date
Abstract
Described herein are compounds and chemical entities of Formula (I), methods of their synthesis, compositions comprising them, and their use in treating numerous diseases and disorders, including cognitive deficits associated with CNS diseases and disorders.
Core Innovation
The disclosure concerns chemical entities of Formula I and related thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one derivatives, together with pharmaceutically acceptable salts thereof. The scaffold is defined by X being —CH— or —N—, Y being —O— or —S—, M being 0-5, and variable substituents at R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13, with ring-forming alternatives and quantitative constraints on D, m, and n.
The disclosed compounds include substituted benzyl, chlorobenzyl, methoxybenzyl, biphenylmethyl, and heterocycle-containing substituents on the same core scaffold. Additional examples include fused analogs and related ring systems, including tetrahydropyrido and hexahydro forms, as well as morpholinomethyl, piperazinylmethyl, and azetidinylmethyl side chains, together with salts, prodrugs, metabolites, isotopically labeled compounds, solvates, conformers, polymorphs, co-crystals, and trifluoroacetic acid or hydrochloride salt forms.
The patent further discloses pharmaceutical compositions comprising an effective amount of a chemical entity of Formula (I) with a pharmaceutically acceptable excipient. In the provided content, the biological context is associated with PDE1, notably PDE1b, and with cyclic nucleotide signaling, Ca2+/calmodulin activation, CREB pathway, neurological/CNS disorders, cognitive deficits, and dysregulated PDE1 signaling.
Claims Coverage
The independent claims cover four inventive feature sets: a Formula I chemical entity, a pharmaceutical composition comprising an effective amount of a Formula (I) chemical entity, a compound of Formula I or pharmaceutically acceptable salt, and selected enumerated thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one compounds (including salts). The coverage is driven by the defined scaffold and the allowed substituent and ring-forming patterns, with extensive variable definitions and provisos.
Chemical entity of formula I
X is —CH— or —N—; Y is —O— or —S—; M is 0-5; R1 is each independently selected from H, halo, —CN, —C1-6alkyl, —C1-6haloalkyl, —C1-6thioalkyl, —C1-6alkoxy, —C1-6haloalkoxy, —SO2C1-6alkyl, aryl, heteroaryl, and heterocycloalkyl; R3 and R4 are each independently selected from enumerated groups or taken together to form a saturated or unsaturated monocyclic ring system; D is —O—, —N(R9)—, or a bond with constraints on m and n and a proviso when D is a bond; R5, R6, R7, and R8 are each independently selected from H, F, —C1-6alkyl, —C1-6haloalkyl, —OH, —C1-6alkoxy, and —C1-6haloalkoxy; R9, R10, R11, R12, and R13 are defined by enumerated substituent sets, including ring-forming alternatives for R12 and R13; the chemical entity is selected from compounds of Formula (I) and pharmaceutically acceptable salts.
Pharmaceutical composition comprising an effective amount of formula I chemical entity
A pharmaceutical composition comprising an effective amount of a chemical entity of Formula (I) and a pharmaceutically acceptable excipient, with the same Formula I scaffold definition, variable substituent sets, ring-forming alternatives, constraints on D, m, and n, and inclusion of pharmaceutically acceptable salts.
Compound of formula I or pharmaceutically acceptable salt
A compound of Formula I or a pharmaceutically acceptable salt thereof, with the same X, Y, M, R1, R3, R4, D, m, n, R5-R8, R9, R10, R11, R12, and R13 definitions and ring-forming alternatives as the Formula I claim.
Selected thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one compounds
A compound selected from enumerated thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one derivatives and pharmaceutically acceptable salts thereof, including specific substituted benzyl, chlorobenzyl, methoxybenzyl, biphenylmethyl, morpholinomethyl, piperazinylmethyl, azetidinylmethyl, and fused tetrahydropyrido or hexahydro variants.
The claim coverage centers on a Formula I scaffold with extensive substituent and ring-forming definitions, a pharmaceutical composition containing an effective amount of that scaffold, and a selected-compound claim set for specific thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one derivatives, all including pharmaceutically acceptable salts where stated.
Stated Advantages
Treating neurological/CNS disorders and cognitive deficits by inhibiting PDE1, notably PDE1b.
Addressing dysregulated PDE1 signaling, including neurodegeneration, through PDE1 inhibition.
Documented Applications
Pharmaceutical composition use as a composition comprising an effective amount of a chemical entity of Formula (I) with a pharmaceutically acceptable excipient.
Treating neurological/CNS disorders.
Treating cognitive deficits.
Addressing neurodegeneration associated with dysregulated PDE1 signaling.
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