Indole compounds as positive allosteric modulators of the muscarinic receptor

A compound having a structure represented by a formula:

• wherein each R1a-R1d is independently selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein n is 1 or 2;
• wherein R2 is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein R3 comprises two substituents independently selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein R4 is selected from hydrogen, a hydrolysable residue, and optionally substituted alkyl;
• wherein A1 is selected from pyridinyl, pyridinylmethyl, pyridazinyl, pyrimidinyl, 5-methylisoxazol-3-yl, benzoxazolyl, benzoisoxazolyl, oxetanyl, and thiazolyl, and A1 is substituted with 0-2 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxyl, and C1-C4 haloalkyl;
• wherein each R5a-R5e is independently selected from hydrogen, fluoro, chloro, bromo, iodo, azido, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• provided that at least one of R5a-R5e is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• or at least two of R5a-R5e are independently selected from fluoro, chloro, bromo, iodo, azido, amino, alkyl, and alkoxy.

A method for the treatment of a disorder associated with cholinergic activity in a mammal comprising administering to the mammal, in a dosage and amount effective to treat the disorder in the mammal, a compound having a structure represented by a formula:

• wherein each R1a-R1d is independently selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein n is 0, 1, or 2;
• wherein R2 is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein R3 comprises two substituents independently selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• wherein R4 is selected from hydrogen, a hydrolysable residue, and optionally substituted alkyl;
• wherein A1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• and
• wherein A1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.