Substituted (1-(methylsulfonyl)azetidin-3-yl)(heterocycloalkyl)methanone analogs as antagonists of muscarinic acetylcholine M
In one aspect, the invention relates to substituted (1-(methylsulfonyl)azetidin-3-yl)(heterocycloalkyl)methanone analogs, derivatives thereof, and related compounds, which are useful as antagonists of the muscarinic acetylcholine receptor M 1 (mAChR M 1 ); 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.
1. A compound having a structure represented by a formula:
wherein Q is selected from a structure represented by a formula:
wherein L is N or CR 6 ;
wherein R 1 is selected from C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 polyhaloalkyl, C3-C8 cycloalkyl, C3-C9 heterocycloalkyl, aryl and heteroaryl; and wherein R 1 is substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
wherein each of R 2a , R 2b , R 2c , and R 2d is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R 3 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein each occurrence of R 4 is independently selected from hydrogen, halogen, cyano, hydroxyl, —NH 2 , 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 each occurrence of R 5 is independently selected from hydrogen, halogen, cyano, hydroxyl, —NH 2 , 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 R 6 , when present, is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R 7 is selected from Ar 1 and Ar 2 ;
wherein Ar 1 is selected from phenyl, indenyl, and napthalenyl; and wherein Ar 1 is substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
wherein Ar 2 is a heteroaryl substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
2. The compound of claim 1 , wherein L is N.
3. The compound of claim 1 , wherein Q has a structure represented by a formula:
4. The compound of claim 1 , wherein Q has a structure represented by a formula:
5. The compound of claim 1 , wherein R 1 is selected from aryl and heteroaryl; and wherein R 1 is substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino
6. The compound of claim 1 , having a structure represented by a formula:
7. The compound of claim 1 , having a structure represented by a formula:
8. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by a formula:
wherein Q is selected from a structure represented by a formula:
wherein L is N or CR 6 ;
wherein R 1 is selected from C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 polyhaloalkyl, C3-C8 cycloalkyl, C3-C9 heterocycloalkyl, aryl and heteroaryl; and wherein R 1 is substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
wherein each of R 2a , R 2b , R 2c , and R 2d is independently selected from hydrogen, C-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R 3 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein each occurrence of R 4 is independently selected from hydrogen, halogen, cyano, hydroxyl, —NH 2 , 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 each occurrence of R 5 is independently selected from hydrogen, halogen, cyano, hydroxyl, —NH 2 , 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 R 6 , when present, is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R 7 is selected from Ar 1 and Ar 2 ;
wherein Ar 1 is selected from phenyl, indenyl, and napthalenyl; and wherein Ar 1 is substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
wherein Ar 2 is a heteroaryl substituted with 0-3 groups selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino;
or pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.