Substituted benzylspiroindolin-2-one analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M1
In one aspect, the invention relates to substituted benzylspiroindolin-2-one analogs compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators 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 m is 0 or 1; wherein n is 1, 2, or 3; wherein q is 0, 1, or 2;
wherein Q 1 is CR 1a ; Q 2 is CR 1b ; Q 3 is CR 1c ; and Q 4 is CR 1d ;
wherein each of R 1a , R 1b , R 1c and R 1d is hydrogen;
wherein Q 5 , when present, is O;
wherein Q 6 is selected from O or NR 3 ;
wherein R 3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyl-(C1-C3 alkyl), aryl, heteroaryl, aryl-(C1-C3 alkyl), —(C═O)—C3-C6 alkyl, —(C═O)—C3-C6 cycloalkyl, —(C═O)-aryl, —(SO 2 )—C1-C3 alky; and wherein R 3 is substituted with 0-2 groups independently selected from fluoro and C1-C3 alkyl;
wherein each of R 4a and R 4b is hydrogen;
wherein each of R 5a and R 5b , when present, is hydrogen;
wherein each of R 6a and R 6b is hydrogen;
wherein Q 7 is CR 7a ; Q 8 is CR 7b ; Q 9 is CR 7c ; and Q 10 is CR 7d ;
wherein each of R 7a , R 7b , R 7c , and R 7d , when present, is independently selected from hydrogen and —F;
wherein R 8 is a pyrazolyl or indazolyl substituted with 0-2 groups selected from methyl, ethyl, propyl, and isopropyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Q 6 is NR 3 , and wherein R 3 is selected from cyclopentyl and cyclohexyl.
3. The compound of claim 1 , wherein R 8 is 1H-pyrazol-4-yl; and wherein R 8 is monosubstituted with methyl.
4. The compound of claim 1 , wherein m is 0, n is 2, and q is 2.
5. The compound of claim 1 , wherein m is 0, n is 2, and q is 1.
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:
wherein each of R 9a and R 9b is independently selected from hydrogen and methyl; and wherein R 19 is methyl.
8. The compound of claim 1 , having a structure represented by a formula:
wherein each of R 9a and R 9b is independently selected from hydrogen and methyl; and wherein R 10 is methyl.
9. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by a formula:
wherein m is 0 or 1; wherein n is 1, 2, or 3; wherein q is 0, 1, or 2;
wherein Q 1 is CR 1a ; Q 2 is CR 1b ; Q 3 is CR 1c ; and Q 4 is CR 1d ;
wherein each of R 1a , R 1b , R 1c and R 1d is hydrogen;
wherein Q 5 , when present, is O;
wherein Q 6 is selected from O or NR 3 ;
wherein R 3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyl-(C1-C3 alkyl), aryl, heteroaryl, aryl-(C1-C3 alkyl), —(C═O)—C3-C6 alkyl, —(C═O)—C3-C6 cycloalkyl, —(C═O)-aryl, —(SO 2 )—C1-C3 alkyl; and wherein R 3 is substituted with 0-2 groups independently selected from fluoro and C1-C3 alkyl;
wherein each of R 4a and R 4b is hydrogen;
wherein each of R 5a and R 5b , when present, is hydrogen;
wherein each of R 6a and R 6b is hydrogen;
wherein Q 7 is CR 7a ; Q 8 is CR 7b ; Q 9 is CR 7c ; and Q 10 is CR 7d ;
wherein each of R 7a , R 7b , R 7c , and R 7d , when present, is independently selected from hydrogen and —F;
wherein R 8 is a pyrazolyl or indazolyl substituted with 0 or 1 groups selected from methyl, ethyl, propyl, and isopropyl;
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. The compound of claim 1 , wherein Q 6 is NR 3 ; and wherein R 3 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, —(SO 2 )—C1-C3 alkyl; and wherein R 3 is substituted with 0-2 groups independently selected from fluoro and C1-C3 alkyl.