AR101394A1 - COMPOSITE OF 6,7-DIHYDROPIRAZOLO [1,5-A] PIRAZIN-4 (5H) -ONA AND ITS USE AS NEGATIVE ALOSTERIC MODULATORS OF mGluR2 RECEPTORS - Google Patents

Abstract

The present application relates to 6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one derivatives as negative allosteric modulators (NAMs) of subtype 2 metabotropic glutamate receptor (mGluR2). It is also directed to pharmaceutical compositions comprising said compounds, to processes for preparing said compounds and compositions and to the use of said compounds and compositions to prevent or treat disorders in which the mGluR2 subtype of metabotropic receptors is involved. Claim 1: A compound of formula (1) or a stereoisomeric form thereof, wherein R¹ is phenyl or 2-pyridinyl, each optionally substituted by one or more substituents each independently selected from the group consisting of halo, C₁₋ alkyl ₄, monohalo-C₁₋₄ alkyl, polyhalo-C₁₋₄ alkyl, -C₁₋₄-alkyl, -CN, -C₁₋₄-O-C₁₋₄ alkyl, C₁₋₄ cycloalkyl, -O-C₁ alkyl ₋₄, monohalo-C₁₋₄oxy alkyl, polyhalo-C₁₋₄oxy alkyl, SF₅, C₁₋₄tio alkyl, monohalo-C₁₋₄tio alkyl and polyhalo-C₁₋₄tio alkyl; R² is selected from the group consisting of C₁₋₄ alkyl; C₃₋₇ cycloalkyl; Het¹; aryl; Het²; and C₁₋₄ alkyl substituted by one more substituents each independently selected from the group consisting of halo, C₃₋₇ cycloalkyl, aryl, Het¹ and Het²; wherein aryl is phenyl optionally substituted by one or more substituents each independently selected from the group consisting of halo, C₁₋₄ alkyl, -C₁₋₄-alkyl, monohalo-C₁₋₄ alkyl, polyhalo-C₁₋₄ alkyl, -CN, -O-C₁₋₄ alkyl, -OH, -C₁₋₄ alkyl-O-C₁₋₄ alkyl, -NRR, -NHC (O) C₁₋₄ alkyl, -C (O) NRR, -C ( O) NH [C (O) C₁₋₄ alkyl], -S (O) ₂NRR, -S (O) ₂NH [C (O) C₁₋₄ alkyl] and -SO₂-C₁₋₄ alkyl; Het¹ is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl; Het² is (a) a 6-membered aromatic heterocyclyl substituent that is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each of which may optionally be substituted by one or more substituents each independently selected from the group consisting of halo, C₁₋₄ alkyl, -C₁₋₄-alkyl; monohalo-C₁₋₄ alkyl, polyhalo-C₁₋₄ alkyl, -CN, -O-C₁₋₄ alkyl, -OH, -C₁₋₄ alkyl-O-C₁₋₄ alkyl, -NRR, -NHC (O) alkyl C₁₋₄, -C (O) NRR, -C (O) NH [C (O) C₁₋₄ alkyl], -S (O) ₂NRR, -S (O) ₂NH [C (O) C₁₋₄ alkyl ] and -SO₂-C₁₋₄ alkyl; or (b) a 5-membered aromatic heterocyclyl that is selected from the group consisting of thiazolyl, oxazolyl, 1H-pyrazolyl and 1H-imidazolyl, each of which may be optionally substituted by one or more substituents each independently selected from the group that consists of halo, C₁₋₄ alkyl, -C₁₋₄-alkyl, monohalo-C₁₋₄ alkyl, polyhalo-C₁₋₄ alkyl, -CN, -O-C₁₋₄ alkyl, -OH, -C₁₋₄ alkyl -O-C₁₋₄ alkyl, -NRR, -NHC (O) C₁₋₄ alkyl, -C (O) NRR, -C (O) NH [C (O) C₁₋₄ alkyl], -S (O) ₂NRR, -S (O) ₂NH [C (O) C₁₋₄ alkyl] and -SO₂-C₁₋₄ alkyl; each R and R is independently selected from the group consisting of hydrogen, C₁₋₄ alkyl and -C₂₋₄-alkyl; and R³ is selected from hydrogen and C₁₋₄ alkyl; R⁴ is selected from the group consisting of hydrogen, C₁₋₄ alkyl, monohalo-C₁₋₄ alkyl, polyhalo-C₁₋₄ alkyl, C₁₋₄-O-C₁₋₄ alkyl and -C₁₋₄-OH alkyl; or an N-oxide, or a pharmaceutically acceptable salt or a solvate thereof.