Substituted benzamide analogs as mGluR5 negative allosteric modulators and methods of making and using the same

A compound, or a pharmaceutically acceptable salt thereof, having a structure represented by a formula:

• wherein A is CR2 or N;
• wherein L is O or NR7,
• wherein R1 is a five-membered or six-membered monocyclic heteroaromatic ring substituted with 0-3 of R9;
• wherein R2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, hydroxyl, alkylamino, dialkylamino, NO2, CN, SO2R8, or COR8;
• wherein R3 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN;
• wherein R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, CN, SO2R8, and COR8, with the proviso that when A is N, then R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO2R8, and COR8;
• wherein R5 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO2R8, and COR8;
• wherein R6 is selected from hydrogen, halogen, CN, C1-C6 alkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl and C1-C6 haloalkyl;
• wherein each of R6a, R6b, and R6c is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy;
• wherein R7 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• wherein R8 is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino;
• and
• wherein each R9, when present, is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO2, CN, SO2R8, or COR8;
• wherein the compound exhibits partial or total inhibition of mGluR5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.