Bicyclic oxazole and thiazole compounds and their use as allosteric modulators of mGluR5 receptors
In one aspect, the invention relates to novel bicyclic oxazole and thiazole compounds which are positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (“mGluR5”); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions; and methods for the treatment or prevention of disorders associated with glutamate dysfunction and diseases in which the mGluR5 subtype of receptors is involved. 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 Z is O or S;
wherein each of m and n is independently selected from 1, 2, and 3;
wherein -A 1 -A 2 - is —OCH 2 —;
wherein R 1 is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, trialkylsiloxyl, C 1-4 -alkyl, C 1-4 -alkyloxy, monohalo-C 1-4 -alkyl, and polyhalo-C 1-4 -alkyl;
wherein R 2 is selected from C 1-6 -alkyl, (C 1-6 -alkyloxy)-C 1-6 -alkyl, monohalo-C 1-6 -alkyl, polyhalo-C 1-6 -alkyl, C 3-8 -cycloalkyl, (C 3-8 -cycloalkyl)-C 1-6 -alkyl, and —OR 3 ; and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, —NH 2 , C 1-4 -alkyl, C 1-4 -alkyloxy, monohalo-C 1-4 -alkyl, polyhalo-C 1-4 -alkyl, C 1-4 -alkyloxycarbonylamino, aryloxy-C 1-4 -alkyl, aryloxy-C 1-4 -alkyl, aryl-C 3-8 -cycloalkyl, polyhalo-C 1-4 -alkyloxy, C 1-4 -alkyloxy-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkylheterocyclyl, and heterocyclyl substituted with carbonyl;
or wherein R 2 is selected from Ar 1 , Ar 1 -C 1-6 -alkyl-, Ar 1 -C 3-8 -cycloalkyl-, Ar 1 -oxy-C 1-4 -alkyl; Ar 2 , Ar 2 -C 1-6 -alkyl-, Ar 2 -C 3-8 -cycloalkyl-, Ar 2 -oxy-C 1-4 -alkyl; Ar 3 , Ar 3 -C 1-6 -alkyl-, Ar 1 -oxy-C 1-4 -alkyl; Ar 3 -C 3-8 -cycloalkyl-, and Ar 3 -oxy-C 1-4 -alkyl;
wherein Ar 1 , when present, is phenyl substituted with 0, 1, 2, or 3 groups each independently selected from halo, cyano, —NH 2 , monoalkylamino, dialkylamino, C 1-4 -alkyl, C 1-4 -alkyloxy, C 1-4 -alkyloxy-C 1-4 -alkyl, monohalo-C 1-4 -alkyl, polyhalo-C 1-4 -alkyl, polyhalo-C 1-4 -alkyloxy, and pentafluorosulfanyl;
wherein Ar 2 , when present, is monocyclic heterocyclyl substituted with 0, 1, 2, or 3 groups each independently selected from halo, cyano, —NH 2 , monoalkylamino, dialkylamino, C 1-4 -alkyl, C 1-4 -alkyloxy, and monohalo-C 1-4 -alkyl, polyhalo-C 1-4 -alkyl, and pentafluorosulfanyl;
wherein Ar 3 , when present, is bicyclic heterocyclyl substituted with 0, 1, 2, or 3 groups each independently selected from halo, cyano, amino, monoalkylamino, dialkylamino, C 1-4 -alkyl, C 1-4 -alkyloxy, and monohalo-C 1-4 -alkyl, polyhalo-C 1-4 -alkyl, and pentafluorosulfanyl;
wherein R 3 is selected from Ar 4 and Ar 4 -C 1-6 -alkyl-;
wherein Ar 4 , when present, is phenyl substituted with 0, 1, 2, or 3 groups each independently selected from halo, cyano, C 1-4 -alkyl, C 1-4 -alkyloxy, monohalo-C 1-4 -alkyl, and polyhalo-C 1-4 -alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein, R 1 is six-membered monocyclic aryl or six-membered monocyclic heteroaryl.
3. The compound of claim 2 , wherein, R 1 is selected from phenyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and substituted with 0, 1, 2, or 3 groups each independently selected from halo, C1-4-alkyl, C1-4-alkyloxy, monohalo-C1-4-alkyl, and polyhalo-C1-4-alkyl.
4. The compound of claim 1 , wherein Z is O.
5. The compound of claim 1 , wherein:
R 1 is phenyl substituted with 0, 1, 2, or 3 groups each independently selected from halo, C 1-4 alkyl, C 1-4 alkyloxy, and mono- and poly-haloC 1-4 alkyl;
R 2 is selected from C 1-6 alkyl, (C 1-6 alkyloxy)C 1-6 alkyl, mono- and polyhalo-C 1-6 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-6 alkyl, —OR 3 , Ar 1 , and heteroaryl;
Ar 1 , when present, is phenyl substituted with 0, 1, 2, or 3 groups each independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkyloxy, and mono- and polyhalo-C 1-4 alkyl; and
heteroaryl is pyridinyl; and optionally substituted with 1, 2 or 3 groups each independently selected from halo, C 1-4 alkyl, cyano, C 1-4 alkyloxy and mono- and polyhalo-C 1-4 alkyl.
6. The compound of claim 1 , having a structure represented by a formula:
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.