6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
AssigneeJanssen Pharmaceutica NV
InventorsSusana Conde-Ceide, Michiel Luc, Maria Van Gool, María Luz Martín-Martín
Life of this patent
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Abstract
The present invention relates to novel 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives as negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 2 (“mGluR2”). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which the mGluR2 subtype of metabotropic receptors is involved.
Claims30
-15. (canceled)
A method of treating a central nervous system disorder or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I)
- or a stereoisomeric form thereof, wherein
- R1 is phenyl or 2-pyridinyl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyl, monohalo-C1-4alkyl, polyhalo-C1-4alkyl, —C1-4alkyl-OH, —CN, —C1-4alkyl-O—C1-4alkyl, C3-7cycloalkyl, —O—C1-4alkyl, monohalo-C1-4alkyloxy, polyhalo-C1-4alkyloxy, SF5, C1-4alkylthio, monohalo-C1-4alkylthio, polyhalo-C1-4alkylthio;
- R2 is selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkyl-OH, C3-7cycloalkyl, monohalo-C1-4alkyl, polyhalo-C1-4alkyl, —C1-4alkyl-O—C1-4alkyl, NR5aR5b, Aryl, and Het;
- wherein
- Aryl is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyl, —C1-4alkyl-OH, monohalo-C1-4alkyl, polyhalo-C1-4alkyl, —CN, —O—C1-4alkyl, —OH, —C1-4alkyl-O—C1-4alkyl, —NR6aR6b, —NHC(O)C1-4alkyl, —C(O)NR6aR6b, —C(O)NH[C(O)C1-4alkyl], —S(O)2NR6aR6b, —S(O)2NH[C(O)C1-4alkyl], and —SO2—C1-4alkyl;
- Het is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyl, —C1-4alkyl-OH, monohalo-C1-4alkyl, polyhalo-C1-4alkyl, —CN, —O—C1-4alkyl, —OH, —C1-4alkyl-O—C1-4alkyl, —NR6aR6b, —NHC(O)C1-4alkyl, —C(O)NR6aR6b, —C(O)NH[C(O)C1-4alkyl], —S(O)2NR6aR6b, —S(O)2NH[C(O)C1-4alkyl], and —SO2—C1-4alkyl;
- R5a, R5b, R6a and R6b are each independently selected from the group consisting of hydrogen and C1-4alkyl;
- R3 is selected from the group consisting hydrogen and C1-4alkyl;
- R4 is selected from the group consisting of hydrogen, C1-4alkyl, monohalo-C1-4alkyl, polyhalo-C1-4alkyl, —C1-4alkyl-O—C1-4alkyl, and —C1-4alkyl-OH;
- or a N-oxide, or a pharmaceutically acceptable salt thereof.
The method of claim 1 wherein
- R1 is phenyl substituted with one or two substituents each independently selected from the group consisting of halo, and poly-haloC1-4alkyl;
- R2 is selected from the group consisting of methyl, pyridinyl, pyridinyl substituted with NH2 and pyrazinyl;
- or a N-oxide, or a pharmaceutically acceptable salt thereof.
The method of claim 1, wherein R3 is hydrogen and R4 is a substituent different from hydrogen having a configuration as depicted in the Formula (I′)
- wherein the 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one core, R1 and R2 are in the plane of the drawing and R4 is projected above the plane of the drawing;
- or a N-oxide, or a pharmaceutically acceptable salt thereof.
The method of claim 1 wherein the formula is:
- or a stereoisomeric form, a N-oxide, or a pharmaceutically acceptable salt thereof.
The method of claim 1 wherein the formula is:
- or a stereoisomeric form, a N-oxide, or a pharmaceutically acceptable salt thereof.
The method of claim 1 wherein the formula is:
- or a stereoisomeric form, a N-oxide, or a pharmaceutically acceptable salt thereof.
The method of claim 1 wherein the formula is:
- or a stereoisomeric form, a N-oxide, or a pharmaceutically acceptable salt thereof.
The method of claim 1 wherein the central nervous system disorder or condition is a mood disorder.
The method of claim 1 wherein the central nervous system disorder or condition is a psychotic disorder.
The method of claim 1 wherein the central nervous system disorder is dementia.
Dependencies are inferred from the claim text.