1-(2,6-diazaspiro[3.3]heptan-6-yl)-5,6-dihydro-4h-benzo[f][1,2,4]triazolo[4,3-A][1,4]diazepine derivatives and related compounds as vasopressin antagonists for the treatment of neuro-psychological disorders
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Publication Number
US-12247037-B2
Publication Date
2025-03-11
Expiration Date
Abstract
The present invention relates to 1-(2,6-diazaspiro[3.3]heptan-6-yl)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine derivatives and related compounds of Formula (I): wherein A, B, G, R1, R1b, RiC, R2 and X are as defined herein. The present compounds are vasopressin receptor antagonists (in particular of the Via receptor) for the treatment of neuro-psychological disorders, such as e.g. autism, anxiety, stress-related disorders, depression, schizophrenia or bipolar disorder. The present description discloses the synthesis of exemplary compounds, as well as pharmacological data thereof (e.g. pages 71 to 246; examples 1 to 49; tables 1 to 5). An exemplary compound is e.g. 8-chloro-1-(2-(5-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (example 1, compound no. 1).
Core Innovation
The invention provides compounds having the structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. The structure includes an optional double bond, with A and B independently nitrogen or oxygen with the proviso that A and B are not both oxygen, and G as nitrogen or carbon. X is selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, or cyano, and the scaffold defines variable substituents R1, R1b, R1c, R2, R3, Q, R4, R5, R6, and n.
Within Formula (I), R1 is selected from hydrogen, lower alkyl-R6, haloalkyl, lower alkoxyalkyl, cycloalkyl-R6, aryl-R6, heterocyclyl-R6, lower haloalkyl, and carbonyl-containing substituent options. R1b and R1c are independently hydrogen, lower alkyl, or spiroalkyl, and R1b and R1 or R1b and R3 together with the atoms to which they are attached form a ring. R2 is -Q-(R4)n, -S(=O)2R5, or -C(=O)R5, R3 is lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkyl-R6, O-cycloalkyl-R6, O-heterocyclyl-R6, NHR5, or NR5R5, Q is aryl or heteroaryl, and n is 0, 1, or 2.
The provided content also includes specific compound structure depictions corresponding to substituted heteroaromatic and polycyclic scaffolds with varying halogen and functional-group substituents. The examples are presented with compound numbers and associated image or chemical file attachments, and the disclosed structural space is also reflected through specific formula variants including Formula (II) and Formula (III).
Claims Coverage
The consolidated claim coverage centers on one independent Formula (I) compound claim with pharmaceutically acceptable forms and a defined substituent framework, supported by dependent coverage for Formula (II) and Formula (III), a pharmaceutical composition, and a V1a receptor antagonism use claim. Overall, the inventive features are the Formula (I) scaffold definition, the optional double bond and A/B heteroatom constraint, the substituent and ring-forming relationships, and the target-directed use and composition claims.
Formula (I) compound scaffold with optional double bond and heteroatom constraint
A compound having the structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein an optional double bond is present, A and B are independently nitrogen or oxygen with the proviso that A and B are not both oxygen, and G is nitrogen or carbon.
Variable substituent architecture for X, R1, R1b, R1c, R2, R3, Q, R4, R5, R6, and n
X is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or cyano; R1 is selected from hydrogen, lower alkyl-R6, haloalkyl, lower alkoxyalkyl, cycloalkyl-R6, aryl-R6, heterocyclyl-R6, lower haloalkyl, and carbonyl-containing substituent options; R1b and R1c are independently hydrogen, lower alkyl, or spiroalkyl; R2 is -Q-(R4)n, -S(=O)2R5, or -C(=O)R5; R3 is lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkyl-R6, O-cycloalkyl-R6, O-heterocyclyl-R6, NHR5, or NR5R5; Q is aryl or heteroaryl; and n is 0, 1, or 2.
Ring-forming relationships involving R1b
R1b and R1 or R1b and R3, together with the atoms to which they are attached, form a ring.
Formula (II) and Formula (III) variants
Dependent formula claims specify Formula (II) and Formula (III) variants within the same structural family, with the corresponding substituent and optional bond definitions.
Pharmaceutical composition including a Formula (I) compound
A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable form thereof, together with a pharmaceutically acceptable carrier, diluent, or excipient.
V1a receptor antagonism by contacting with an effective amount
A method for antagonizing the V1a receptor by contacting it with an effective amount of a compound of claim 1, or an allowed chemical form or composition thereof.
Enumerated compounds by depicted structures
A compound of claim 1 specified by reference to one of a series of depicted chemical structures, including pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof.
The claims coverage is centered on a Formula (I) compound family with an optional double bond, an A/B nitrogen-or-oxygen constraint, and a broad but defined substituent framework, including ring-forming relationships through R1b. Dependent coverage further includes Formula (II) and Formula (III) variants, pharmaceutical compositions, V1a receptor antagonism, and compounds identified by depicted chemical structures.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Antagonizing the V1a receptor by contacting it with an effective amount of a compound of claim 1, or an allowed chemical form or composition thereof.
A pharmaceutical composition including a compound of claim 1, or a pharmaceutically acceptable form thereof, together with a pharmaceutically acceptable carrier, diluent, or excipient.
Treatment or prevention of vasopressin-dependent conditions including neuropsychiatric and psychiatric disorders.
Imaging/diagnostic use including PET imaging.
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