SUBSTITUTED 4-(1H-PYRAZOL-4-YL)BENZYL ANALOGUES AS POSITIVE ALLOSTERIC MODULATORS OF MACHR M1 RECEPTORS

摘要

In one aspect, the invention relates to substituted 4-(1H-pyrazol-4-yl)benzyl analogs compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M1 (mAChR M1); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. 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.

主权项

1. A compound having a structure represented by a formula: wherein R1 is selected from hydrogen and C1-C6 alkyl; wherein each of R2a and R2b is independently selected from hydrogen, halogen, hydroxyl, cyano, —NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein Q1 is selected from N and CR3a; wherein Q2 is selected from N and CR3b; wherein Q3 is selected from N and CR3c; wherein Q4 is selected from N and CR3d; and wherein 0, 1, or 2 of Q1, Q2, Q3, and Q4 are N;
wherein each of R3a, R3b, R3c, and R3d, when present, is independently selected from hydrogen, halogen, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, and C1-C6 alkyl; wherein each of R4a and R4b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl; wherein Z is selected from a structure represented by a formula: wherein n is 0, 1, or 2; wherein Q5 is selected from N and CR5a; wherein Q6 is selected from N and CR5b; wherein Q7 is selected from N and CR5c; wherein Q8 is selected from N and CR5d; and wherein 0, 1, or 2 of Q5, Q6, Q7, and Q8 are N;
wherein each of R5a, R5b, R5c, and R5d, when present, is independently 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 R6, when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; wherein each of R7a, R7b, R7c, and R7d, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, and —CO2R10, provided that 0-1 of R7a, R7b, R7c, and R7d, when present, is —CO2R10;
wherein R10, when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; wherein R8 is selected from hydrogen and C1-C6 alkyl; wherein each of R9a and R9b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, —(C═O)OR11, —(C═O)NHR11, and —SO2R11, provided that R9a and R9b are not simultaneously —(C═O)OR11, —(C═O)NR11, or —SO2R11; and
wherein R11, when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, heterocyclyl, aryl, heteroaryl, —(C1-C6 alkyl)-NH(C═O)-heterocyclyl, —(C1-C6 alkyl)-NH(C═O)-heteroaryl, and —(C1-C6 alkyl)-NH(C═O)-aryl; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.