COMPOUNDS FOR TREATING DISORDERS MEDIATED BY METABOTROPIC GLUTAMATE RECEPTOR 5, AND METHODS OF USE THEREOF

摘要

Provided herein are compounds and methods of synthesis thereof. The compounds set forth herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders, neurodegenerative disorders, neuropsychiatric disorders, disorders of cognition, learning or memory, gastrointestinal disorders, lower urinary tract disorder, and cancer. Compounds set forth herein modulate the activity of metabotropic glutamate receptor 5 (mGluR5) in the central nervous system or the periphery. Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.

主权项

1. A compound of formula I:wherein.
R1 is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl or heteroaryl, each of which is optionally substituted; R2 is hydrogen, lower alkyl, lower alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl, heteroaryl, —C(O)OR12, or —CO—NR12, each of which is optionally substituted; R3 is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl or heteroaryl, each of which is optionally substituted; or R2 and R3 are optionally joined, together with the atoms to which they are attached, to form a mono or bicyclic ring that is carbocyclic or heterocyclic, each of which is optionally substituted; G is CHR2 or NR2 when b and c are both single bonds, or G is CR2 or N when one of b and c is a double bond; Q is NH or CH2 when d and e are single bonds, or N or CH when one of d or e is a double bond, or; X is CH or N when f is a single bond, or C when f is a double bond; Z is CH2, C═O, C═S or a bond when b is a single bond, or CH or N when b is a double bond; b, c, d, e, and f are each independently a single bond or a double bond, provided that when b is a double bond, c is a single bond; when c is a double bond, b and d are single bonds; when d is a double bond, c and e are single bonds; when e is a double bond, d and f are single bonds; and when f is a double bond, e is a single bond; Y1, Y2 and Y3 are each independently CH, C-halogen, C-lower alkyl, or N, provided that no more than one of Y2 and Y3 is N; L1 is —C≡C—, —HC═CH—, -(lower alkyl)C═C(lower alkyl)-, —CH2—CH2—, —CO—CH2—, —CH(OH)—CH2, —CH2—CO—, —C0-6alkyl-O—C0-6alkyl-, —NR12SO—, —SONR12—, —NR12SO2—, —SO2NR12—, —NR12—CO—, —CO—NR12—, R12 is hydrogen or lower alkyl; W1 and W2 are each independently N or CH; W3 is O, S or NR4; and R4 is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof; provided that at least one of c and d is a double bond.