Thiazolymethyl and Oxazolylmethyl Heteroaryl Derivatives
OwnerYuelian Xu, Linghong Xieinventors
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Abstract
Compounds of Formula I are provided, as are methods for their preparation. The variables in the above formula are defined herein. Such compounds may be used to modulate ligand binding to GABAA receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agents(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABAA receptors (e.g., receptor localization studies).
Claims30
A compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- X, Y and Z are independently CRC, N or NRC;
- wherein V and W are O or S;
- Each RC is independently chosen from:
- (a) hydrogen, halogen, nitro and cyano;
- (b) groups of the formula:
- (c) groups that are taken together with an adjacent RC to form a fused phenyl or a fused 5- or 6-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, nitro, cyano, and groups of the formula:
- Each L is independently absent, a single covalent bond or C1-C8alkylene;
- Each G is independently a single covalent bond, N(RB) (i.e.
- O, C(═O) (i.e.,
- C(═O)O (i.e.,
- C(═O)N(RB) (i.e.,
- N(RB)C(═O) (i.e.,
- S(O)m (i.e., —
- CH2C(═O), S(O)mN(RB) (e.g.,
- or N(RB)S(O)m (e.g.,
- wherein m is 0, 1 or 2;
- Each RA and RB are independently selected from:
- (i) hydrogen;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C8cycloalkyl)C0-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl, (C6-C10aryl)C0-C2alkyl and (5- to 10-membered heteroaryl)C0-C2alkyl, each of which is optionally substituted, and is preferably substituted with from 0 to 4 substituents independently selected from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, C1-C4alkanoyl, mono- and di-(C1-C4alkyl)amino, C1-C4haloalkyl and C1-C4haloalkoxy;
- R5 is:
- (a) hydrogen, halogen or cyano;
- or
- (b) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C4alkoxy, or mono- or di-(C1-C4alkyl)amino, each of which is optionally substituted, and is preferably substituted with from 0 to 5 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, mono- and di-(C1-C4alkyl)amino, C3-C8cycloalkyl, phenyl, phenylC1-C4alkoxy and 5- or 6-membered heteroaryl;
- such that if X, Y and Z are all CH, then R5 is not hydrogen;
- R6 and R7 are independently hydrogen, methyl, ethyl or halogen;
- R8 is hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, mono- and di(C1-C4alkyl)amino, C3-C7cycloalkyl, C1-C2haloalkyl or C1-C2haloalkoxy;
- and
- Ar represents phenyl, naphthyl or 5- to 10-membered heteroaryl, each of which is optionally substituted, and is preferably substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, aminocarbonyl, C1-C8alkyl, C1-C8alkenyl, C1-C8alkynyl, C1-C8alkoxy, C1-C8alkylthio, (C3-C7cycloalkyl)C0-C4alkyl, (C3-C7cycloalkyl)C1-C4alkoxy, C1-C8alkyl ether, C1-C8alkanone, C1-C8alkanoyl, (3- to 7-membered heterocycle)C0-C4alkyl, C1-C8haloalkyl, C1-C8haloalkoxy, oxo, C1-C8hydroxyalkyl, C1-C8aminoalkyl, and mono- and di-(C1-C8alkyl)aminoC0-C8alkyl.
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Dependencies are inferred from the claim text.