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

A method of treating a patient suffering from a mood disorder comprising administering to a patient in need thereof therapeutically effective amount of a compound of Formula (I)

• or a stereoisomeric form thereof,
• wherein
• R1 is phenyl or 2-pyridinyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, —O—C1-4alkyl, —C1-4alkyl-O—C1-4alkyl, monohaloC1-4alkyloxy, polyhaloC1-4alkyloxy, —C1-4alkyl-OH, C1-4alkylthio, monohaloC1-4alkylthio, polyhaloC1-4alkylthio, cyano, C3-7cycloalkyl optionally substituted with trifluoromethyl, and —SF5;
• or
• R1 is
• R2 is
• R3 is selected from the group consisting of hydrogen and C1-4alkyl;
• R4 is selected from the group consisting of hydrogen, C1-4alkyl, mono polyhaloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl, and —C1-4alkyl-OH;
• R5 and R6 are each independently selected from the group consisting of hydrogen, halo, cyano, C1-4alkyl, —C1-4alkyl-OH, C3-7cycloalkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl, —O—C1-4alkyl, monohaloC1-4alkyloxy, polyhaloC1-4alkyloxy, 1-acetylazetidin-3-yl, and NR′R″;
• and
• R′ and R″ are each independently selected from the group consisting of hydrogen and —C1-4alkyl;
• or
• R′ and R″ together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, and 4-morpholinyl;
• wherein 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, and 4-morpholinyl are optionally substituted with a substituent selected from the group consisting of halo, hydroxy, —C1-4alkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, and —(CO)C1-4alkyl;
• or a N-oxide or a pharmaceutically acceptable salt thereof.

A method of treating a patient suffering from a mood disorder comprising administering to a patient in need thereof therapeutically effective amount of a compound of Formula (V)

• wherein
• R2a is halo,
• R3 is selected from the group consisting of hydrogen and C1-4alkyl;
• and
• R4 is selected from the group consisting of hydrogen, —C1-4alkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl and —C1-4alkyl-OH.

A method of treating a patient suffering from a mood disorder comprising administering to a patient in need thereof therapeutically effective amount of a compound of Formula (II)

• wherein:
• R2 is
• R3 is selected from the group consisting of hydrogen and —C1-4alkyl;
• R4 is selected from the group consisting of hydrogen, C1-4alkyl, mon haloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl and —C1-4alkyl-OH;
• R5 and R6 are each independently selected from the group consisting of hydrogen, halo, cyano, —C1-4alkyl, —C1-4alkyl-OH, C3-7cycloalkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl, —O—C1-4alkyl, monohaloC1-4alkyloxy, polyhaloC1-4alkyloxy, 1-acetylazetidin-3-yl and NR′R″;
• and
• R′ and R″ are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• or
• R′ and R″, together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl and 4-morpholinyl;
• wherein 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl and 4-morpholinyl are optionally substituted with a substituent selected from the group consisting of halo, hydroxy, C1-4alkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl and —(CO)C1-4alkyl.

A method of treating a patient suffering from dementia comprising administering to a patient in need thereof therapeutically effective amount of a compound of Formula (I)

• or a stereoisomeric form thereof,
• wherein
• R1 is phenyl or 2-pyridinyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, —O—C1-4alkyl, —C1-4alkyl-O—C1-4alkyl, monohaloC1-4alkyloxy, polyhaloC1-4alkyloxy, —C1-4alkyl-OH, C1-4alkylthio, monohaloC1-4alkylthio, polyhaloC1-4alkylthio, cyano, C3-7cycloalkyl optionally substituted with trifluoromethyl, and —SF5;
• or
• R1 is
• R2 is
• R3 is selected from the group consisting of hydrogen and C1-4alkyl;
• R4 is selected from the group consisting of hydrogen, C1-4alkyl, mono polyhaloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl, and —C1-4alkyl-OH;
• R5 and R6 are each independently selected from the group consisting of hydrogen, halo, cyano, C1-4alkyl, —C1-4alkyl-OH, C3-7cycloalkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl, —O—C1-4alkyl, monohaloC1-4alkyloxy, polyhaloC1-4alkyloxy, 1-acetylazetidin-3-yl, and NR′R″;
• and
• R′ and R″ are each independently selected from the group consisting of hydrogen and —C1-4alkyl;
• or
• R′ and R″ together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, and 4-morpholinyl;
• wherein 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, and 4-morpholinyl are optionally substituted with a substituent selected from the group consisting of halo, hydroxy, —C1-4alkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, and —(CO)C1-4alkyl;
• or a N-oxide or a pharmaceutically acceptable salt thereof.

A method of treating a patient suffering from a mood disorder comprising administering to a patient in need thereof therapeutically effective amount of a compound of Formula (V)

• wherein
• R2a is halo,
• R3 is selected from the group consisting of hydrogen and C1-4alkyl;
• and
• R4 is selected from the group consisting of hydrogen, —C1-4alkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl and —C1-4alkyl-OH.

A method of treating a patient suffering from dementia comprising administering to a patient in need thereof therapeutically effective amount of a compound of Formula (II)

• wherein:
• R2 is
• R3 is selected from the group consisting of hydrogen and —C1-4alkyl;
• R4 is selected from the group consisting of hydrogen, C1-4alkyl, mon haloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl and —C1-4alkyl-OH;
• R5 and R6 are each independently selected from the group consisting of hydrogen, halo, cyano, —C1-4alkyl, —C1-4alkyl-OH, C3-7cycloalkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl, —C1-4alkyl-O—C1-4alkyl, —O—C1-4alkyl, monohaloC1-4alkyloxy, polyhaloC1-4alkyloxy, 1-acetylazetidin-3-yl and NR′R″;
• and
• R′ and R″ are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• or
• R′ and R″, together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl and 4-morpholinyl;
• wherein 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl and 4-morpholinyl are optionally substituted with a substituent selected from the group consisting of halo, hydroxy, C1-4alkyl, monohaloC1-4alkyl, polyhaloC1-4alkyl and —(CO)C1-4alkyl.