Positive allosteric modulators of the muscarinic acetylcholine receptor M4
Disclosed herein are pyrido[3′,2′:4,5]thieno[2,3-d]pyridazin-8-amine and thieno[2,3-c:4,5-d′]dipyridazin-8-amine compounds, which may be useful as positive allosteric modulators of the muscarinic acetylcholine receptor M 4 (mAChR M 4 ). Also disclosed herein are methods of 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.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is N or CR 1 ;
Z is O or S;
R 1 is selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, halo, and —OR a ;
R 2 is selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, halo, and —OR b ;
R 3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, and —(CR c R d ) n —Y, any of which may be optionally substituted;
or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring;
R 5 is selected from hydrogen and C 1 -C 4 -alkyl;
Y is selected from halo, —OR, —SR, —C(O)R, —C(O)OR, —S(O)R, —SO 2 R, —NR 2 , —C(O)NR 2 , —S(O) 2 NR 2 , aryl, heteroaryl, cycloalkyl, and heterocycle, any of which may be optionally substituted;
n is 1, 2, 3, 4, 5, 6, 7, or 8;
R a and R b are each independently selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycle;
R c and R d are each independently selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and halo; and
each R is independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, and heteroalkyl, any of which may be optionally substituted.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Z is S.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
X is CR 1 .
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from hydrogen and C 1 -C 4 -alkyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 4 -alkyl.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
X is N.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is selected from hydrogen, C 1 -C 4 -alkyl, halo, and —OR b ; and
R b is C 1 -C 4 -alkyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is halo.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chloro.
11. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 4 -alkyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is hydrogen or alkyl; and
R 4 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, and —(CR c R d ) n —Y, any of which may be optionally substituted.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl or 3-azabicyclo[3.1.0]hexan-3-yl ring, each of which is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, oxo, and —(CR c R d ) p —Y, wherein p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is hydrogen and R 4 is selected from the group consisting of C 3 -C 8 cycloalkyl, —(CR c R d ) n —O—C 1 -C 4 -alkyl, —(CR c R d ) n —C 3 -C 6 cycloalkyl, and —(CR c R d ) n -phenyl, wherein the cycloalkyl and phenyl groups are unsubstituted or substituted with 1-3 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkoxy, and a 5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, N and S; and n is 1, 2, 3, or 4; or
R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered monocyclic or 6- to 10-membered fused bicyclic heterocycle, the monocyclic or bicyclic heterocycle containing 0-2 additional heteroatoms independently selected from N, O, and S, and optionally substituted with —OR and/or 1-4 substituents independently selected from C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, oxo, hydroxy, and C 1 -C 4 alkoxy, wherein R is a 5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, N and S.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is hydrogen.
16. The compound of claim 1 , selected from the group consisting of:
3-chloro-N-cyclobutyl-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazin-8-amine;
3-chloro-2,4-dimethyl-8-(pyrrolidin-1-yl)pyrido[3′,2′:4,5]thieno[2,3-d]pyridazine;
8-(3-azabicyclo[3.1.0]hexan-3-yl)-3-chloro-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazine;
3-chloro-N-(4-(difluoromethoxy)benzyl)-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazin-8-amine;
3-chloro-N-(3-fluoro-4-methoxybenzyl)-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazin-8-amine;
3-chloro-2,4-dimethyl-8-(piperidin-1-yl)pyrido[3′,2′:4,5]thieno[2,3-d]pyridazine;
3-chloro-N-(3-methoxypropyl)-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazin-8-amine;
8-(azetidin-1-yl)-3-chloro-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazine
3-chloro-N-(cyclobutylmethyl)-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazin-8-amine;
3-chloro-N-(3,3-difluorocyclobutyl)-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazin-8-amine;
3-chloro-N-cyclopropyl-2,4-dimethylpyrido[3′,2′:4,5]thieno[2,3-d]pyridazin-8-amine;
3,4-dimethyl-8-(pyrrolidin-1-yl)thieno[2,3-c:4,5-d]dipyridazine;
3-chloro-2,4,5-trimethyl-8-(pyrrolidin-1-yl)pyrido[3′,2′:4,5]thieno[2,3-d]pyridazine;
2-(4-(((3,4-dimethylthieno[2,3-c:4,5-d]dipyridazin-8-yl)amino)methyl)phenyl)propan-2-ol;
2-(4-(((3,4-dimethylthieno[2,3-c:4,5-d]dipyridazin-8-yl)amino)methyl-d 2 )phenyl)propan-2-ol;
2-(4-(((3,4-dimethylthieno[2,3-c:4,5-d]dipyridazin-8-yl)amino)methyl)phenyl)propan-1,1,1,3,3,3-d 6 -2-ol;
2-(4-(((3,4-dimethylthieno[2,3-c:4,5-d]dipyridazin-8-yl)amino)methyl)-3-fluorophenyl)-2-methylpropan-1-ol;
N-(3-fluoro-4-methoxybenzyl)-3,4-dimethylthieno[2,3-c:4,5-d]dipyridazin-8-amine;
N-(4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethylthieno[2,3-c:4,5-d]dipyridazin-8-amine;
3,4-dimethyl-8-(3-(pyridin-3-yloxy)azetidin-1-yl)thieno[2,3-c:4,5-d]dipyridazine; and
(S)-3,4-dimethyl-8-(3-(pyridin-3-yloxy)pyrrolidin-1-yl)thieno[2,3-c:4,5-d-]dipyridazine,
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A method for treating a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, comprising a step of administering to the mammal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 , wherein the disorder is a neurological and/or psychiatric disorder associated with mAChR M 4 dysfunction.
20. The method of claim 18 , wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder, and a cognitive disorder.