Substituted pyrazolo[1,5-a]pyrazines as negative allosteric modulators of group II metabotropic glutamate receptor

A compound of Formula (1):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• Ring A is a saturated 4- to 10-membered heterocyclyl, C6-10 aromatic carbocyclyl, or 5- to 10-membered aromatic heterocyclyl;
• X is CRe or N;
• R1 is H, halogen, CN, C1-4 alkyl, or a saturated C3-6 carbocyclyl;
• wherein the C1-4 alkyl or saturated C3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• R2 is H, halogen, CN, C1-4 alkyl, or a saturated C3-6 carbocyclyl;
• wherein the C1-4 alkyl or saturated C3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• or
• R1 and R2, taken together with the carbon atom to which they are attached, form a saturated C3-4 carbocyclyl;
• wherein the saturated C3-4 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• R3 is H, halogen, CN, C1-6 alkyl, C2-4 alkenyl, OH, C1-4 alkoxy, C1-4 alkylthio, a saturated C3-6 carbocyclyl, C3-6 cycloalkoxy, a saturated 4- to 6-membered heterocyclyl, or a 5- or 6-membered aromatic heterocyclyl;
• wherein the C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, saturated 4- to 6-membered heterocyclyl, or 5- or 6-membered aromatic heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;
• and
• wherein the saturated C3-6 carbocyclyl or C3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and C1-4 alkyl;
• R4 is H, halogen, CN, C1-6 alkyl, C2-4 alkenyl, OH, C1-4 alkoxy, C1-4 alkylthio, a saturated C3-6 carbocyclyl, C3-6 cycloalkoxy, a saturated 4- to 6-membered heterocyclyl, or a 5- or 6-membered aromatic heterocyclyl;
• wherein the C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, saturated 4- to 6-membered heterocyclyl, or 5- or 6-membered aromatic heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;
• and
• wherein the saturated C3-6 carbocyclyl or C3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and C1-4 alkyl;
• R5 is H, halogen, CN, CH2C(O)NRaRb, C1-6 alkyl, C(O)Rd, C(O)NRaRb, C(O)ORd, NRaRb, NRdC(O)Rc, NRdC(O)NRaRb, NRdC(O)ORc, NRdS(O)2Rc, OH, C1-6 alkoxy, C1-6 alkylthio, a saturated C3-6 carbocyclyl, C3-6 cycloalkoxy, or a saturated 4- to 6-membered heterocyclyl;
• wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, or saturated 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• wherein the C3-6 cycloalkoxy or saturated C3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy;
• and
• wherein each C1-4 alkoxy substituent of the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, saturated C3-6 carbocyclyl, C3-6 cycloalkoxy, or saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;
• R6 is H, halogen, CN, CH2C(O)NRaRb, C1-6 alkyl, C(O)Rd, C(O)NRaRb, C(O)ORd, NRaRb, NRdC(O)Rc, NRdC(O)NRaRb, NRdC(O)ORc, NRdS(O)2Rc, OH, C1-6 alkoxy, C1-6 alkylthio, a saturated C3-6 carbocyclyl, C3-6 cycloalkoxy, or a saturated 4- to 6-membered heterocyclyl;
• wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, or saturated 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• wherein the C3-6 cycloalkoxy or saturated C3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy;
• and
• wherein each C1-4 alkoxy substituent of the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, saturated C3-6 carbocyclyl, C3-6 cycloalkoxy, or saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;
• each Ra is independently H, C1-4 alkyl, a saturated C3-6 carbocyclyl, or a saturated 4- to 6-membered heterocyclyl;
• wherein each C1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• and
• wherein each saturated C3-6 carbocyclyl and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy;
• each Rb is independently H, C1-4 alkyl, a saturated C3-6 carbocyclyl, or a saturated 4- to 6-membered heterocyclyl;
• wherein each C1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• and
• wherein each saturated C3-6 carbocyclyl and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy;
• or
• each Ra and Rb, taken together with the nitrogen atom to which they are attached, independently forms a saturated 4- to 6-membered heterocyclyl;
• wherein each saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy;
• each Rc is independently C1-4 alkyl, a saturated C3-6 carbocyclyl, or a saturated 4- to 6-membered heterocyclyl;
• wherein each C1-4 alkyl, saturated C3-6 carbocyclyl, and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• each Rd is independently H, C1-4 alkyl, a saturated C3-6 carbocyclyl, or a saturated 4- to 6-membered heterocyclyl;
• wherein each C1-4 alkyl, saturated C3-6 carbocyclyl, and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy;
• and
• Re is H, halogen, CN, C1-6 alkyl, or C1-6 alkoxy;
• wherein the C1-6 alkyl or C1-6 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.