Antagonists of the muscarinic acetylcholine receptor M4

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is a five- or six-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from N, O and S;

Q is selected from NR a and O;

m is 0, 1, or 2;

R 1 is selected from heteroaryl, aryl, heterocyclyl, cycloalkyl, halo, —OR c ,—NR d R e , and —NHCOR f ;

each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy;

R 3 is selected from hydrogen and C 1 -C 4 alkyl;

R 4 is selected from —(CR h R i ) p -Y′, hydrogen, C 1 -C 8 alkyl, and C 2 -C 8 alkenyl;

n is 1 or 2;

each R 5 is independently selected from hydrogen, C 1 -C 4 alkyl, halo, and —OR g ;

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

Y′ is selected from cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl;

each R a , R c , R d , R e , R f , and R g is independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and aryl;

each R h is independently selected from hydrogen and C 1 -C 4 alkyl;

each R i is independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and aryl; and

wherein each aryl, heteroaryl, arylene, heteroarylene, cycloalkyl, cycloalkenyl, and heterocycle is independently unsubstituted or substituted with 1, 2, or 3 substituents.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each aryl, heteroaryl, heteroarylene, cycloalkyl, cycloalkenyl, and heterocycle is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, hydroxy, cyano, —NHCOR f , and benzyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

A is selected from:

wherein:

T is selected from O, S and NH;

U, V, W, X, Y and Z are independently selected from N and CR 10 , wherein at least one of W, X, Y, and Z is N, and at least one of U and V is N; and

each R 10 is independently selected from hydrogen, C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and hydroxy.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein A is selected from:

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

Q is NR a ; and

R a is hydrogen.

6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

Q is O.

7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from phenyl and a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; and

the phenyl or heteroaryl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and —NHCOR f .

8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

R 3 is hydrogen.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein

R 4 is C 4 -C 6 alkyl.

10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein

R 4 is —(CR h R i ) p -Y′;

R h is hydrogen;

R i is hydrogen;

p is 0, 1, 2, or 3; and

Y′ is selected from: C 3 -C 10 cycloalkyl; C 3 -C 8 cycloalkenyl; aryl; a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; and a 5-, 6-, or 7-membered heterocycle having 1, 2, or 3 heteroatoms independently selected from N, O, and S;

wherein Y′ is unsubstituted or substituted with one or two substituents independently selected from halo and C 1 -C 4 alkyl.

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

or a pharmaceutically acceptable salt thereof.

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

7-(3,3-dimethylbutyl)-N-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-amine;

7-(3,3-dimethylbutyl)-N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-amine;

7-(5-bicyclo[2.2.1]hept-2-enylmethyl)-N-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-amine;

N-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]-7-(2,3,3-trimethylbutyl)-7-azaspiro[3.5]nonan-2-amine;

N-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]-7-(tetrahydropyran-4-ylmethyl)-7-azaspiro[3.5]nonan-2-amine;

N-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]-7-(tetrahydrothiopyran-4-ylmethyl)-7-azaspiro[3.5]nonan-2-amine;

N-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]-7-[(3-methyl-2-pyridyl)methyl]-7-azaspiro[3.5]nonan-2-amine;

7-(5-bicyclo[2.2.1]hept-2-enylmethyl)-N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-amine;

N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-7-(2,3,3-trimethylbutyl)-7-azaspiro[3.5]nonan-2-amine;

N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-7-(tetrahydropyran-4-ylmethyl)-7-azaspiro[3.5]nonan-2-amine;

N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-7-(tetrahydrothiopyran-4-ylmethyl)-7-azaspiro[3.5]nonan-2-amine;

N-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-7-[(3-methyl-2-pyridyl)methyl]-7-azaspiro[3.5]nonan-2-amine;

7-(3,3-dimethylbutyl)-2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

7-(3,3-dimethylbutyl)-2-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-(3,3-dimethylbutyl)-7-azaspiro[3.5]nonane;

7-(5-bicyclo[2.2.1]hept-2-enylmethyl)-2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-(2,3,3-trimethylbutyl)-7-azaspiro[3.5]nonane;

2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-(cyclohexylmethyl)-7-azaspiro[3.5]nonane;

2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-(tetrahydropyran-4-ylmethyl)-7-azaspiro[3.5]nonane;

2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-(tetrahydropyran-3-ylmethyl)-7-azaspiro[3.5]nonane;

2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-(tetrahydrothiopyran-4-ylmethyl)-7-azaspiro[3.5]nonane;

7-benzyl-2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxy-7-[(3-methyl-2-pyridyl)methyl]-7-azaspiro[3.5]nonane;

7-(5-bicyclo[2.2.1]hept-2-enylmethyl)-2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-(2,3,3-trimethylbutyl)-7-azaspiro[3.5]nonane;

7-(cyclohexylmethyl)-2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-(tetrahydropyran-4-ylmethyl)-7-azaspiro[3.5]nonane;

2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-(tetrahydropyran-3-ylmethyl)-7-azaspiro[3.5]nonane;

2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-(tetrahydrothiopyran-4-ylmethyl)-7-azaspiro[3.5]nonane;

7-benzyl-2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-yl]oxy-7-[(3-methyl-2-pyridyl)methyl]-7-azaspiro[3.5]nonane;

7-(5-bicyclo[2.2.1]hept-2-enylmethyl)-2-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]oxy-7-(2,3,3-trimethylbutyl)-7-azaspiro[3.5]nonane;

7-(cyclohexylmethyl)-2-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]oxy-7-(tetrahydropyran-4-ylmethyl)-7-azaspiro[3.5]nonane;

2-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]oxy-7-(tetrahydrothiopyran-4-ylmethyl)-7-azaspiro[3.5]nonane;

7-benzyl-2-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]oxy-7-azaspiro[3.5]nonane;

2-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]oxy-7-[(3-methyl-2-pyridyl)methyl]-7-azaspiro[3.5]nonane;

N-[[7-(3,3-dimethylbutyl)-7-azaspiro[3.5]nonan-2-yl]methyl]-6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-amine;

N-[[7-(5-bicyclo[2.2.1]hept-2-enylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]-6-(2-chloro-5-fluoro-phenyl)pyridazin-3-amine;

6-(2-chloro-5-fluoro-phenyl)-N-[[7-(3,3-dimethylbutyl)-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

6-(2-chloro-5-fluoro-phenyl)-N-[[7-(cyclohexylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

6-(2-chloro-5-fluoro-phenyl)-N-[[7-(tetrahydropyran-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

6-(2-chloro-5-fluoro-phenyl)-N-[[7-(tetrahydropyran-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

N-[(7-benzyl-7-azaspiro[3.5]nonan-2-yl)methyl]-6-(2-chloro-5-fluoro-phenyl)pyridazin-3-amine;

6-(2-chloro-5-fluoro-phenyl)-N-[[7-[(2-fluorophenyl)methyl]-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

6-(2-chloro-5-fluoro-phenyl)-N-[[7-(2-pyridylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

6-(2-chloro-5-fluoro-phenyl)-N-[[7-[(6-methoxy-2-pyridyl)methyl]-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

N-[[7-(1,3-benzodioxol-5-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]-6-(2-chloro-5-fluoro-phenyl)pyridazin-3-amine;

N-[[7-(cyclohexylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]-6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-amine;

6-(1,3-dimethylpyrazol-4-yl)-N-[[7-(tetrahydropyran-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

6-(1,3-dimethylpyrazol-4-yl)-N-[[7-(tetrahydropyran-4-ylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

N-[(7-benzyl-7-azaspiro[3.5]nonan-2-yl)methyl]-6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-amine;

6-(1,3-dimethylpyrazol-4-yl)-N-[[7-[(2-fluorophenyl)methyl]-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

6-(1,3-dimethylpyrazol-4-yl)-N-[[7-(2-pyridylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

6-(1,3-dimethylpyrazol-4-yl)-N-[[7-[(3-methyl-2-pyridyl)methyl]-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

N-[[7-(1-adamantylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]-6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-amine;

6-(1,3-dimethylpyrazol-4-yl)-N-[[7-[(4-fluorophenyl)methyl]-7-azaspiro[3.5]nonan-2-yl]methyl]pyridazin-3-amine;

N-[[7-(5-bicyclo[2.2.1]hept-2-enylmethyl)-7-azaspiro[3.5]nonan-2-yl]methyl]-6-(1,3-dimethylpyrazol-4-yl)pyridazin-3-amine;

2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-7-(3,3-dimethylbutyl)-7-azaspiro[3.5]nonane;

7-(5-bicyclo[2.2.1]hept-2-enylmethyl)-2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-7-azaspiro[3.5]nonane;

2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-7-(cyclohexylmethyl)-7-azaspiro[3.5]nonane;

2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-7-(tetrahydropyran-3-ylmethyl)-7-azaspiro[3.5]nonane;

2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-7-(tetrahydropyran-4-ylmethyl)-7-azaspiro[3.5]nonane;

7-benzyl-2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-7-azaspiro[3.5]nonane; and

2-[[6-(2-chloro-5-fluoro-phenyl)pyridazin-3-yl]oxymethyl]-7-(2-pyridylmethyl)-7-azaspiro[3.5]nonane,

or a pharmaceutically acceptable salt thereof.

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

14. A method for antagonizing mAChR M 4 in a subject, comprising a step of administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

15. A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M 4 , comprising a step of administering to the mammal a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein the disorder is a neurodegenerative disorder, a movement disorder, or a brain disorder.

17. The method of claim 16 , wherein the disorder is a movement disorder.

18. The method of claim 15 , wherein the disorder is selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.

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

20. The method of claim 19 , wherein the subject has a disorder selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.