Therapeutic thiophene-, furan-, and pyridine-fused azolopyrimidin-5-(6h)-ones
Inventors
Branstetter, Bryan • Breitenbucher, James • Dyck, Brian • Gomez, Laurent • Hudson, Andrew Richard • Marrone, Tami Jo • Peters, Marco • VICKERS, Troy • Weinhouse, Michael
Assignees
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Publication Number
US-9533996-B2
Publication Date
2017-01-03
Expiration Date
Abstract
Described herein are compounds of Formula I and Formula II, methods of their synthesis, compositions comprising the compounds, and use of the compounds and compositions in treating numerous diseases and disorders, including cognitive deficits associated with CNS diseases and disorders.
Core Innovation
The disclosure relates to compounds of Formula I and Formula II, including pharmaceutically acceptable salts, with structural variables A, X, M, D, and substituent positions R1 through R13 defining thiophene-fused, furan-fused, pyridine-fused, and azolopyrimidin-5-(6H)-one or related fused heterocycle scaffolds. A is oxygen or sulfur, X is CH or nitrogen, and M is 1 or 2, while multiple substituent positions accept broad groups including halo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, heterocycle, cyano, nitro, sulfonyl, sulfonamide, amide, ester, carbonate, and carboxylate variants.
The definitions further provide for optional formation of an optionally substituted 5-6 member saturated or unsaturated monocyclic ring system, including ring systems comprising one or more oxygen, sulfur, or nitrogen atoms. R3 and R4 may also be taken together to form a monocyclic ring system defined by D, m, and n, where D is O, S, —SO—, —SO2—, or —N—R9— and the sum of m and n is constrained when D is selected from those groups. Related substituent sets for R5 through R8 and R10 through R11, and for R9, R12, and R13, further define the scaffold.
The document also discloses specific example compounds and characterization data, including 1H NMR and LC-MS information, with numbered examples and named embodiments across substituted thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one and pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one scaffolds. The examples and structural figures identify compounds by molecular formulas and substitution patterns, and the disclosure includes pharmaceutical composition embodiments comprising a claimed compound and a pharmaceutically acceptable carrier.
Claims Coverage
The consolidated claim coverage includes broad Formula I compound claims, an example-selection claim, and a pharmaceutical composition context. Across the independent claims, the inventive features center on the Formula I scaffold with A, X, M, optional ring formation for R1/R2 and R3/R4, defined D/m/n constraints, and, in one claim, a selection limited to specified numbered Examples.
Formula I compound with A, X, and M constraints
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is O or S, X is CH or N, and M is 1 or 2.
R1 and R2 substituent selection with optional monocyclic ring formation
Each occurrence of R1 and R2 is independently selected from specified substituent sets, including halo, aryl, heteroaryl, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, sulfonyl, sulfonamide, amide, ester, carbonate, and related groups, or R1 and R2 are on adjacent carbons and taken together form an optionally substituted 5-6 member saturated or unsaturated monocyclic ring system comprising one or more oxygen, sulfur, or nitrogen atoms.
R3 and R4 substituent selection with defined ring-forming structure
R3 and R4 are independently selected from specified substituent sets, or R3 and R4 taken together with the carbons to which they are attached form a monocyclic ring system having D as O, S, —SO—, —SO2—, or —N—R9— and m and n constrained as recited.
Defined substituents for R5 through R8 and R10 through R11
R5, R6, R7, R8, R10, and R11 are independently selected from H, F, C1-C6 alkyl, C1-C6 haloalkyl, OH, C1-C6 alkoxy, C1-C6 haloalkoxy, SO2C1-C6 alkyl, SO2N(C1-C6 alkyl)2, CO2(C1-C6 alkyl), CONH(C1-C6 alkyl), and CON(C1-C6 alkyl)2.
Defined substituents for R9, R12, and R13 with heterocycle option
R9, R12, and R13 are independently selected from H, C1-C6 alkyl, aryl, heteroaryl, and sulfone/carbonyl-type substituent options, and R12 and R13 taken together with the nitrogen form an optionally substituted heterocycle.
Example-based compound selection
A compound selected from the group consisting of Examples 31, 33, 34, 35, 36, 38, 39, 44, 51, 55, 61, 62, 63, 69, 105, 109, 135 and 141, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition including a pharmaceutically acceptable carrier
A pharmaceutical composition includes the compound and a pharmaceutically acceptable carrier.
The consolidated claim coverage centers on broad Formula I scaffold definitions with extensive variable substituent sets, optional monocyclic ring formation, and defined D/m/n structural conditions, together with an example-selection claim and a pharmaceutical composition embodiment.
Stated Advantages
Enhancement of long-term contextual and trace memory in mice.
Enhancement of neurite outgrowth and neurogenic phenotypes in NS1 cells.
Improvement of memory in object recognition and contextual/trace fear conditioning assays.
PDE1B inhibitory activity is reported using an IMAP TR-FRET assay, with IC50/pIC50 grouping.
Selectivity toward PDE1B versus other PDE isoforms is assessed, including PDE1A and PDE1C.
Blood pressure lowering in cardiovascular function models.
Occasional QTc prolongation is reported in the cardiovascular evaluation.
Documented Applications
Therapeutic use as PDE1 inhibitors, especially PDE1B, for CNS disorders.
Therapeutic use for cognitive disorders.
Therapeutic use for cardiovascular/vascular disorders.
Therapeutic use for renal disorders.
Use in cardiovascular, renal, hematological, GI/liver, cancer, and neurodegenerative/injury conditions.
Evaluation of pde1b inhibition and Formula I/II compounds in novel object recognition and contextual and trace fear conditioning assays.
Evaluation in cardiovascular function models reporting effects on blood pressure and QTc interval.
Downstream therapeutic indication context centered on PDE1B inhibition and CREB and cAMP/cGMP signaling.
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