Substituted 4-(1H-pyrazol-4-yl)benzyl analogues as positive allosteric modulators of mAChR M
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 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 R 1 is selected from hydrogen and C1-C6 alkyl;
wherein each of R 2a and R 2b is independently selected from hydrogen, 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 Q 1 is selected from N and CR 3a ; wherein Q 2 is selected from N and CR 3b ; wherein Q 3 is selected from N and CR 3c ; wherein Q 4 is selected from N and CR 3d ; and wherein 0, 1, or 2 of Q 1 , Q 2 , Q 3 , and Q 4 are N;
wherein each of R 3a , R 3b , R 3c , and R 3d , when present, is independently selected from hydrogen, halogen, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, and C1-C6 alkyl;
wherein each of R 4a and R 4b 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 Q 5 is selected from N and CR 5a ; wherein Q 6 is selected from N and CR 5b ; wherein Q 7 is selected from N and CR 5c ; wherein Q 8 is selected from N and CR 5d ; and wherein 0, 1, or 2 of Q 5 , Q 6 , Q 7 , and Q 8 are N;
wherein each of R 5a , R 5b , R 5c , and R 5d , 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 R 6 , when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein each of R 7a , R 7b , R 7c , and R 7d , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, and —CO 2 R 10 , provided that 0-1 of R 7a , R 7b , R 7c , and R 7d , when present, is —CO 2 R 10 ;
wherein R 10 , when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R 8 is selected from hydrogen and C1-C6 alkyl;
wherein each of R 9a and R 9b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, —(C═O)OR 11 , —(C═O)NHR 11 , and —SO 2 R 11 , provided that R 9a and R 9b are not simultaneously —(C═O)OR 11 , —(C═O)NR 11 , or —SO 2 R 11 ; and
wherein R 11 , 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 thereof.
2. The compound of claim 1 , wherein Z is selected from a structure represented by a formula:
3. The compound of claim 1 , wherein Z is selected from a structure represented by a formula:
4. The compound of claim 1 , wherein each of Q 1 , Q 2 , Q 3 , and Q 4 is not N.
5. The compound of claim 1 , wherein each of Q 5 , Q 6 , Q 3 , and Q 8 is not N.
6. The compound of claim 1 , wherein R 1 is methyl; wherein each of R 2a and R 2b is hydrogen; and wherein each of R 4a and R 4b is hydrogen.
7. The compound of claim 1 , wherein Z has a structure represented by a formula:
wherein R 1 is methyl; wherein each of R 2a and R 2b is hydrogen; wherein R 3a is —F; wherein each of R 3b , R 3c , and R 3d is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 polyhaloalkyl; wherein each of R 4a and R 4b is hydrogen, wherein each of R 5a and R 5c is independently selected from hydrogen and —F; wherein each of R 5b and R 5d is hydrogen; wherein R 9a is selected from —(C═O)OR 11 , —(C═O)NR 11 , or —SO 2 R 11 ; and wherein R 9b is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, and C1-C3 alkoxy.
8. The compound of claim 1 , wherein Z has a structure represented by a formula:
wherein R 1 is methyl; wherein each of R 2a and R 2b is hydrogen; wherein R 3a is —F; wherein each of R 3b , R 3c , and R 3d is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 polyhaloalkyl; wherein each of R 4a and R 4b is hydrogen, wherein each of R 5a and R 5c is independently selected from hydrogen and —F; wherein each of R 5b and R 5d is hydrogen; wherein R 9a is selected from —(C═O)OR 11 , —(C═O)NR 11 , or —SO 2 R 11 ; and wherein R 9b is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, and C1-C3 alkoxy.
9. The compound of claim 1 , having a structure represented by a formula:
10. 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 a compound having a structure represented by a formula:
wherein R 1 is selected from hydrogen and C1-C6 alkyl;
wherein each of R 2a and R 2b is independently selected from hydrogen, 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 Q 1 is selected from N and CR 3a ; wherein Q 2 is selected from N and CR 3b ; wherein Q 3 is selected from N and CR 3a ; wherein Q 4 is selected from N and CR 3d ; and wherein 0, 1, or 2 of Q 1 , Q 1 , Q 3 , and Q 4 are N;
wherein each of R 3a , R 3b , R 3c , and R 3d , when present, is independently selected from hydrogen, halogen, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, and C1-C6 alkyl;
wherein each of R 4a and R 4b 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 Q 5 is selected from N and CR 5a ; wherein Q 6 is selected from N and CR 5b ; wherein Q 7 is selected from N and CR 5c ; wherein Q 8 is selected from N and CR 5d ; and wherein 0, 1, or 2 of Q 5 , Q 6 , Q 7 , and Q 8 are N;
wherein each of R 5a , R 5b , R 5c , and R 5d , 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 R 6 , when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein each of R 7a , R 7b , R 7c , and R 7d , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, and —CO 2 R 10 , provided that 0-1 of R 7a , R 7b , R 7c , and R 7d , when present, is —CO 2 R 10 ;
wherein R 10 , when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R 8 is selected from hydrogen and C1-C6 alkyl;
wherein each of R 9a and R 9b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, —(C═O)OR 11 , —(C═O)NHR 11 , and —SO 2 R 11 , provided that R 9a and R 9b are not simultaneously —(C═O)OR 11 , —(C═O)NR 11 , or —SO 2 R 11 ; and
wherein R 11 , 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 thereof;
wherein the neurological and/or psychiatric disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorder, severe major depressive disorder, mood disorder associated with aa psychotic disorder, acute mania, depression associated with a bipolar disorder, mood disorder associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder, movement disorders, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders.
11. The method of claim 10 , wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.
12. The method of claim 10 , further comprising the step of identifying a mammal in need of treatment of the disorder.
13. The method of claim 12 , wherein the disorder is associated with a mAChR M 1 dysfunction.
14. The method of claim 10 , wherein the disorder is a neurological and/or psychiatric disorder associated with mAChR M 1 dysfunction.
15. The method of claim 10 , wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder and a cognitive disorder.
16. The method of claim 15 , wherein the disorder is Alzheimer's disease.
17. A kit comprising at least one compound having a structure represented by a formula:
wherein R 1 is selected from hydrogen and C1-C6 alkyl;
wherein each of R 2a and R 2b is independently selected from hydrogen, 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 Q 1 is selected from N and CR 3a ; wherein Q 2 is selected from N and CR 3b ; wherein Q 3 is selected from N and CR 3c ; wherein Q 4 is selected from N and CR 3d ; and wherein 0, 1, or 2 of Q 1 , Q 2 , Q 3 , and Q 4 are N;
wherein each of R 3a , R 3b , R 3c , and R 3d , when present, is independently selected from hydrogen, halogen, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, and C1-C6 alkyl;
wherein each of R 4a and R 4b 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 Q 5 is selected from N and CR 5a ; wherein Q 6 is selected from N and CR 5b ; wherein Q 7 is selected from N and CR 5c ; wherein Q 8 is selected from N and CR 5d ; and wherein 0, 1, or 2 of Q 5 , Q 6 , Q 7 , and Q 8 are N;
wherein each of R 5a , R 5b , R 5c , and R 5d , 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 R 6 , when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein each of R 7a , R 7b , R 7c , and R 7d , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, and —CO 2 R 10 , provided that 0-1 of R 7a , R 7b , R 7c , and R 7d , when present, is —CO 2 R 10 ;
wherein R 10 , when present, is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
wherein R 8 is selected from hydrogen and C1-C6 alkyl;
wherein each of R 9a and R 9b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, —(C═O)OR 11 , —(C═O)NHR 11 , and —SO 2 R 11 , provided that R 9a and R 9b are not simultaneously —(C═O)OR 11 , —(C═O)NR 11 , or —SO 2 R 11 ; and
wherein R 11 , 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 thereof; and one or more of:
(a) at least one agent known to increase mAChR M 1 activity;
(b) at least one agent known to decrease mAChR M 1 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 M 1 receptor activity; or
(f) instructions for administering the compound in connection with cognitive or behavioral therapy.
18. The kit of claim 17 , wherein the at least one compound and the at least one agent are co-formulated.
19. The kit of claim 17 , wherein the at least one compound and the at least one agent are co-packaged.