Substituted octahydropyrrolo[3,4-b]pyrroles as antagonists of the muscarinic acetylcholine receptor M4

1. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

Ring A is:

R 1 is hydrogen, halo, NR b R c , OR a , aryl, or heteroaryl;

R 2 is hydrogen, halo, C 1 -C 4 alkyl, or OR d ;

R 3 is hydrogen or C 1 -C 4 alkyl;

R 4 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or (CR e R f ) n Y′;

R a is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or aryl;

R b is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or aryl;

R c is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or aryl;

R d is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or aryl;

each R e is independently hydrogen or C 1 -C 4 alkyl;

each R f is independently hydrogen, C 1 -C 4 alkyl, or aryl;

Y′ is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; and

n is 0, 1, 2, 3, or 4;

wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, benzyl, hydroxy, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, benzyl, hydroxy, OC 1 -C 4 alkyl, and OC 1 -C 4 haloalkyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is phenyl or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the phenyl or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is hydrogen.

5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is hydrogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is C 4 -C 6 alkyl or C 4 -C 6 alkenyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R 4 is (CR e R f )Y′;

each R e is independently hydrogen;

each R f is independently hydrogen, methyl, or phenyl;

Y′ is C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, 5- or 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heterocyclyl and the 5- or 6-membered heteroaryl each contain 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, 5- or 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, and benzyl; and

n is 0, 1, 2, or 3.

8. The compound of claim 1 , wherein the compound is of formula (Ia):

or a pharmaceutically acceptable salt or stereoisomer thereof.

9. The compound of claim 8 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is aryl or heteroaryl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is phenyl or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the phenyl or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl.

11. The compound of claim 8 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R 3 is hydrogen;

R 4 is (CR e R f ) n Y′;

each R e is independently hydrogen;

each R f is independently hydrogen, methyl, or phenyl;

Y′ is C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, 5- or 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heterocyclyl and the 5- or 6-membered heteroaryl each contain 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, 5- or 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, and benzyl; and

n is 0, 1, 2, or 3.

12. The compound of claim 1 , wherein the compound is selected from the group consisting of:

5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(4,4-dimethylpentyl)octahydropyrrolo[3,4-b]pyrrole;

5-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-((3-methylpyridin-2-yl)methyl)octahydropyrrolo[3,4-b]pyrrole;

5-benzyl-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-phenethyloctahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(3-phenylpropyl)octahydropyrrolo[3,4-b]pyrrole;

5-((1-benzylpiperidin-4-yl)methyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(3-phenylbutyl)octahydropyrrolo[3,4-b]pyrrole;

5-(adamantan-2-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(2-phenylpropyl)octahydropyrrolo[3,4-b]pyrrole;

(Z)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(hept-4-en-1-yl)octahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-hexyloctahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(2,2-diphenylethyl)octahydropyrrolo[3,4-b]pyrrole;

5-(adamantan-1-ylmethyl)-1-(6-(4-ethylpyridin-3-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole; and

5-(adamantan-1-ylmethyl)-1-(6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole,

5-(adamantan-1-ylmethyl)-1-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

5-(adamantan-1-ylmethyl)-1-(6-(2-chloro-4-fluorophenyl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

5-(adamantan-1-ylmethyl)-1-(6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(3,3-dimethylbutyl)octahydropyrrolo[3,4-b]pyrrole;

(3aR,6aR)-5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;

1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-((tetrahydro-2H-pyran-4-yl)methyl)octahydropyrrolo[3,4-b]pyrrole; and

(3aS,6aS)-5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole,

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

14. A method for antagonizing muscarinic acetylcholine receptor M 4 in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

15. The method of claim 14 , wherein the subject has a movement disorder.

16. The method of claim 15 , wherein the movement disorder is selected from the group consisting of a cognitive deficit associated with schizophrenia, attention deficit hyperactivity disorder, cerebral palsy, chorea, drug-induced Parkinsonism, a dyskinesia, dystonia, excessive daytime sleepiness, Huntington's disease, Parkinson's disease, progressive supranuclear palsy, schizophrenia, and Tourette's syndrome.

17. A method for treating motor symptoms in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

18. The method of claim 17 , wherein the subject has a disorder selected from the group consisting of a cognitive deficit associated with schizophrenia, attention deficit hyperactivity disorder, cerebral palsy, chorea, drug-induced Parkinsonism, a dyskinesia, dystonia, excessive daytime sleepiness, Huntington's disease, Parkinson's disease, progressive supranuclear palsy, schizophrenia, and Tourette's syndrome.