Substituted 1-benzylindolin-2-one analogs as positive allosteric modulators of muscarinic acetylcholine m1 receptors

A method for the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal comprising the step of administering to the mammal an effective amount of least one compound having a structure represented by a formula:

• wherein n is 0 or 1;
• wherein L is selected from O, (C═O), and NR3;
• wherein Q1 is selected from N and CR1a;
• wherein Q2 is selected from N and CR1b;
• wherein Q3 is selected from N and CR1c;
• wherein Q4 is selected from N and CR1d;
• and wherein 0, 1, or 2 of Q1, Q2, Q3, and Q4 are N;
• wherein each of R1a, R1b, R1c, and R1d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino;
• wherein R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
• wherein R3 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
• wherein R4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
• wherein each of R5a and R5b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
• wherein Q5 is selected from N and CR6a;
• wherein Q6 is selected from N and CR6b;
• wherein Q7 is selected from N and CR6c;
• wherein Q8 is selected from N and CR6d;
• and wherein 0, 1, or 2 of Q5, Q6, Q7, and Q8 are N;
• wherein each of R6a, R6b, R6c, and R6d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
• wherein R7 is a heterocyclyl substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
• or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

A kit comprising at least one compound having a structure represented by a formula:

• wherein n is 0 or 1;
• wherein L is selected from O, (C═O), and NR3;
• wherein Q1 is selected from N and CR1a;
• wherein Q2 is selected from N and CR1b;
• wherein Q3 is selected from N and CR1c;
• wherein Q4 is selected from N and CR1d;
• and wherein 0, 1, or 2 of Q1, Q2, Q3, and Q4 are N;
• wherein each of R1a, R1b, R1c, and R1d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino;
• wherein R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
• wherein R3 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
• wherein R4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl;
• wherein each of R5a and R5b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
• wherein Q5 is selected from N and CR6a;
• wherein Q6 is selected from N and CR6b;
• wherein Q7 is selected from N and CR6C;
• wherein Q8 is selected from N and CR6d;
• and wherein 0, 1, or 2 of Q5, Q6, Q7, and Q8 are N;
• wherein each of R6a, R6b, R6c, and R6d, when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
• wherein R7 is a heterocyclyl substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
• or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof;
• and one or more of:
• (a) at least one agent known to increase mAChR M1 activity;
• (b) at least one agent known to decrease mAChR M1 activity;
• (c) at least one agent known to treat a disorder associated with cholinergic activity;
• (d) instructions for treating a disorder associated with cholinergic activity;
• (e) instructions for treating a disorder associated with mAChR M1 receptor activity;
• or
• (f) instructions for administering the compound in connection with cognitive or behavioral therapy.