Substituted imidazopyrimidin-5(6H)-ones as allosteric modulators of MGLUR5 receptors
In one aspect, the invention relates to imidazopyrimidin-5(6H)-one analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. A compound having a structure represented by a formula:
wherein ----- is an optional covalent bond, wherein valence is satisfied;
wherein Ar 1 is phenyl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar 1 is monocyclic heteroaryl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
wherein when ----- is present and A 1 and A 2 are joined by a covalent double bond, A 1 is CR 1a , and A 2 is CR 2a ;
wherein R 1a is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
wherein R 2a is selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
wherein when ----- is not present and A 1 and A 2 are joined by a covalent single bond, A 1 is CR 1b R 1c , and A 2 is CR 2b R 2c ;
wherein each of R 1b and R 1c are independently selected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
wherein each of R 2b and R 2c are independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
wherein R 3 , when ----- is present, is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar 2 ;
wherein Ar 2 is phenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH 2 , —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar 2 is monocyclic heteroaryl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH 2 , —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl); and,
wherein R 3 , when ----- is not present, is Ar 2 ;
wherein R 4 is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, and C1-C4 alkoxy;
wherein each of R 5a and R 5b is independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1 , having a structure represented by a formula:
3. The compound of claim 1 , having a structure represented by a formula:
4. The compound of claim 1 , having a structure represented by a formula:
wherein R 7 and R 8 are independently selected from hydrogen and C1-C4 alkyl.
5. The compound of claim 1 , having a structure represented by a formula:
wherein R 6 is C1-C4 alkyl.
6. The compound of claim 1 , having a structure represented by a formula:
7. The compound of claim 1 , having a structure represented by a formula:
8. The compound of claim 1 , having a structure represented by a formula:
9. The compound of claim 1 , having a structure represented by a formula:
10. The compound of claim 1 , having a structure represented by a formula:
wherein R 7 and R 8 are independently selected from hydrogen and C1-C4 alkyl.
11. The compound of claim 1 , having a structure represented by a formula:
wherein R 6 is C1-C4 alkyl.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.