SUBSTITUTED 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZINES AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS

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.

1 .- 15 . (canceled) 
     
     
         16 . A method of treating a neurocognitive disorder comprising administering a compound of Formula (I) to a patient in need thereof 
       
         
           
           
               
               
           
         
         or a stereoisomeric form thereof, wherein 
         R 1  is phenyl or 2-pyridinyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyl, monohalo-C 1-4 alkyl, polyhalo-C 1-4 alkyl, —C 1-4 alkyl-OH, —CN, —C 1-4 alkyl-O—C 1-4 alkyl, C 3-7 cycloalkyl, —O—C 1-4 alkyl, monohalo-C 1-4 alkyloxy, polyhalo-C 1-4 alkyloxy, SF 5 , C 1-4 alkylthio, monohalo-C 1-4 alkylthio and polyhalo-C 1-4 alkylthio; 
         R 2  is selected from the group consisting of hydrogen; C 1-4 alkyl; C 3-7 cycloalkyl; Het 1 ; Aryl; —C(O)R 5 ; —C(O)Het 2 ; Het 2 ; and C 1-4 alkyl substituted with one or more substituents each independently selected from the group consisting of halo, C 3-7 cycloalkyl, Aryl, Het 1  and Het 2 ; 
         R 5  is selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-7 cycloalkyl; 
         Aryl is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyl, —C 1-4 alkyl-OH, monohalo-C 1-4 alkyl, polyhalo-C 1-4 alkyl, —CN, —O—C 1-4 alkyl, —OH, —C 1-4 alkyl-O—C 1-4 alkyl, —NR′R″, —NHC(O)C 1-4 alkyl, —C(O)NR′R″, —C(O)NH[C(O)C 1-4 alkyl], —S(O) 2 NR′R″, —S(O) 2 NH[C(O)C 1-4 alkyl] and —S(O) 2 —C 1-4 alkyl; 
         Het 1  is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl; 
         Het 2  is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyl, —C 1-4 alkyl-OH, monohalo-C 1-4 alkyl, polyhalo-C 1-4 alkyl, —CN, —O—C 1-4 alkyl, —OH, —C 1-4 alkyl-O—C 1-4 alkyl, —NR′R″, —NHC(O)C 1-4 alkyl, —C(O)NR′R″, —C(O)NH[C(O)C 1-4 alkyl], —S(O) 2 NR′R″, —S(O) 2 NH[C(O)C 1-4 alkyl] and —S(O) 2 —C 1-4 alkyl; or (b) a 5-membered aromatic heterocyclyl selected from the group consisting of thiazolyl, oxazolyl, 1H-pyrazolyl and 1H-imidazolyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1-4 alkyl, —C 1-4 alkyl-OH, monohalo-C 1-4 alkyl, polyhalo-C 1-4 alkyl, —CN, —O—C 1-4 alkyl, —OH, —C 1-4 alkyl-O—C 1-4 alkyl, —NR′R″, —NHC(O)C 1-4 alkyl, —C(O)NR′R″, —C(O)NH[C(O)C 1-4 alkyl], —S(O) 2 NR′R″, —S(O) 2 NH[C(O)C 1-4 alkyl] and —S(O) 2 —C 1-4 alkyl; 
         R′ and R″ are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; 
         R 3  is selected from the group consisting of hydrogen and C 1-4 alkyl; and 
         R 4  is selected from the group consisting of hydrogen, C 1-4 alkyl, monohalo-C 1-4 alkyl, polyhalo-C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl and —C 1-4 alkyl-OH; 
         or a N-oxide, or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The method of  claim 16 , wherein
 R 1  is phenyl or 2-pyridinyl, each optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1-4 alkyl, monohalo-C 1-4 alkyl, polyhalo-C 1-4 alkyl, —CN, —C 1-4 alkyl-O—C 1-4 alkyl, —O—C 1-4 alkyl, monohalo-C 1-4 alkyloxy and polyhalo-C 1-4 alkyloxy;   R 2  is selected from the group consisting of hydrogen; C 1-4 alkyl; C 3-7 cycloalkyl; Het 1 ; Aryl; —C(O)R 5 ; —C(O)Het 2 ; Het 2 ; and C 1-4 alkyl substituted with one or more substituents each independently selected from the group consisting of C 3-7 cycloalkyl, Aryl, Het 1  and Het 2 ;   Aryl is phenyl optionally substituted with a substituent selected from the group consisting of halo, C 1-4 alkyl, —O—C 1-4 alkyl and —S(O) 2 —C 1-4 alkyl;   Het 2  is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of pyridinyl, pyrimidinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1-4 alkyl, —O—C 1-4 alkyl and —NR′R″; or (b) a 5-membered aromatic heterocyclyl selected from the group consisting of thiazolyl, oxazolyl and 1H-imidazolyl, each of which may be optionally substituted with a C 1-4 alkyl substituent;   R′ and R″ are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;   R 3  is hydrogen; and   R 4  is selected from the group consisting of hydrogen, C 1-4 alkyl and —C 1-4 alkyl-O—C 1-4 alkyl; or a N-oxide, or a pharmaceutically acceptable salt or a solvate thereof.   
     
     
         18 . The method of  claim 16 , wherein
 R 1  is phenyl or 2-pyridinyl, each optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1-4 alkyl, polyhalo-C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl, —O—C 1-4 alkyl and polyhalo-C 1-4 alkyloxy;   R 2  is selected from the group consisting of Aryl; and Het 2 ;   Aryl is phenyl optionally substituted with a halo substituent;   Het 2  is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of pyridinyl, pyrimidinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1-4 alkyl, —O—C 1-4 alkyl and NR′R″; or (b) a 5-membered aromatic heterocyclyl selected from the group consisting of thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl and 1H-imidazolyl, each of which may be optionally substituted with a C 1-4 alkyl substituent;   R′ and R″ are each independently hydrogen;   R 3  is hydrogen; and   R 4  is selected from the group consisting of hydrogen, C 1-4 alkyl and —C 1-4 alkyl-O—C 1-4 alkyl;   or a N-oxide, or a pharmaceutically acceptable salt thereof.   
     
     
         19 . The method of  claim 16 , wherein
 R 1  is phenyl or 2-pyridinyl, each optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1-4 alkyl, polyhalo-C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl, —O—C 1-4 alkyl and polyhalo-C 1-4 alkyloxy;   R 2  is selected from the group consisting of Aryl; and Het 2 ;   Aryl is phenyl optionally substituted with a halo substituent;   Het 2  is (a) pyridinyl or pyrazinyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C 1-4 alkyl, —O—C 1-4 alkyl and NR′R″; or (b) a thiazolyl;   R′ and R″ are each independently hydrogen; and   R 3  is hydrogen; and   R 4  is selected from the group consisting of CH 3  and CH 2 OCH 3 ; or a N-oxide, or a pharmaceutically acceptable salt thereof.   
     
     
         20 . The method of  claim 16 , wherein the compound is of Formula (I′) 
       
         
           
           
               
               
           
         
         wherein R 4  is selected from the group consisting of C 1-4 alkyl, monohalo-C 1-4 alkyl, polyhalo-C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl and —C 1-4 alkyl-OH 
         or a N-oxide, or a pharmaceutically acceptable salt thereof. 
       
     
     
         21 . The method of  claim 16 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         22 . The method of  claim 16 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         23 . The method of  claim 16 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         24 . The method of  claim 16  wherein the neurocognitive disorder is selected from the group consisting of neurocognitive disorders due to Alzheimer's disease, vascular neurocognitive disorders, neurocognitive disorders due to HIV infection, neurocognitive disorders due to traumatic brain injury, neurocognitive disorders due to Parkinson's disease, neurocognitive disorders due to Huntington's disease, frontotemporal neurocognitive disorders, neurocognitive disorders due to prion disease and sub stance/medication-induced neurocognitive disorders. 
     
     
         25 . The method of  claim 24  wherein the neurocognitive disorder is due to Alzheimer's disease. 
     
     
         26 . The method of  claim 24  wherein the neurocognitive disorder is dementia.