POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4

• US 20190330231A1
• Filed: 11/07/2017
• Published: 10/31/2019
• Est. Priority Date: 11/07/2016
• Status: Active Grant

• Current Assignee: Vanderbilt University
• Original Assignee: Vanderbilt University
• Inventors: Lindsley, Craig W., Conn, P. Jeffrey, Engers, Darren W., Gregro, Alison R., Temple, Kayla, Spearing, Paul K., Long, Madeline F., Engers, Julie L.
• Granted Patent: US 10,927,126 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 495/14 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Disclosed herein are thieno[2,3-b:5,4-c′]dipyridin-8-amine and pyrido[4′,3′:4,5]thieno[2,3-c]pyridazin-8-amine compounds, which may be useful as positive allosteric modulators of the muscarinic acetylcholine receptor M₄ (mAChR M₄). 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.

Claims

1. A compound of formula (I),

2. The compound of claim 1, wherein

X is N.

3. The compound of claim 1, wherein

X is CR¹.

4. The compound of claim 3, wherein

R¹ is C₁-C₄ alkyl.

5. The compound of claim 4, wherein

R¹ is methyl.

6. The compound of any one of claims 1-5, wherein

R² is hydrogen.

7. The compound of any one of claims 1-5, wherein

R² is C₁-C₄ alkyl.

8. The compound of claim 7, wherein

R² is methyl.

9. The compound of any one of claims 1-8, wherein

R³ is hydrogen.

10. The compound of any one of claims 1-8, wherein

R³ is halo.

11. The compound of any one of claims 1-8, wherein

R³ is chloro.

12. The compound of any one of claims 1-11, wherein

R⁴ is hydrogen.

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

14. The compound of claim 1, wherein the compound is a compound of formula (Ib):

15. The compound of claim 1, wherein the compound is a compound of formula (Ic):

16. The compound of claim 1, wherein the compound is a compound of formula (Id):

17. The compound of claim 1, wherein the compound is a compound of formula (Ie):

18. The compound of claim 1, wherein the compound is a compound of formula (If):

19. The compound of claim 1, wherein the compound is a compound of formula (Ig):

20. The compound of any one of claims 1-19, wherein

R⁵ is hydrogen or alkyl;

and

R⁶ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, and —

(CR^bR^c)_n—

Y, each of which may be optionally substituted.

21. The compound of claim 20, wherein

R⁵ is selected from hydrogen and methyl;

R⁶ is selected from the group consisting of C₁-C₄ alkyl, C₃-C₆ cycloalkyl, a 3- to 6-membered heterocycle having one heteroatom selected from N and O, and —

(CR^bR^c)_n—

Y;

n is 1, 2 or 3;

R^b and R^c are each hydrogen;

Y is selected from the group consisting of —

OR, aryl, C₃-C₆ cycloalkyl, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S; and

R is C₁-C₄ alkyl;

wherein each aryl, cycloalkyl, heteroaryl and heterocycle is independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, halo, hydroxy, aryl, C₃-C₆ cycloalkyl, a 3- to 6-membered heterocycle having one heteroatom selected from N and O, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S.

22. The compound of claim 20, wherein

R⁵ is hydrogen;

R⁶ is —

(CR^bR^c)_n—

Y;

n is 1;

R^b and R^c are each hydrogen; and

Y is phenyl, which is unsubstituted or substituted with 1 or 2 substituents independently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, halo, hydroxy, —

OR, and —

COR; and

each R is independently selected from C₃-C₆-cycloalkyl-C₁-C₄-alkyl, and a 3- to 6-membered heterocycle having one or two heteroatoms selected from O, N, and S.

23. The compound of any one of claims 1-19, wherein

R⁵ and R⁶ are taken together with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl group, which may be optionally 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^bR^c)_p—

Y, wherein p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

24. The compound of claim 1, selected from the group consisting of:

N-cyclopentyl-2,4-dimethylthieno[2,3-b;

5,4-c]dipyridin-8-amine;

2,4-dimethyl-8-(pyrrolidin-1-yl)thieno[2,3-b;

5,4-c′

]dipyridine;

N-cyclobutyl-2,4-dimethylthieno[2,3-b;

5,4-c′

]dipyridin-8-amine;

N,N,2,4-tetramethylthieno[2,3-b;

5,4-c′

]dipyridin-8-amine;

N-cyclopentyl-3,4-dimethyl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

3,4-dimethyl-8-pyrrolidin-1-yl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazine;

N-cyclobutyl-3,4-dimethyl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

N-cyclopropyl-3,4-dimethyl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

N-[(4-methoxyphenyl)methyl]-3,4-dimethyl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

3,4-dimethyl-N-[1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl]pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

3,4-dimethyl-N-[[4-(trifluoromethoxy)phenyl]methyl]pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

N-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-3,4-dimethyl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

[4-[[(3,4-dimethylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-morpholino-methanone;

N-[(3-fluoro-4-methoxy-phenyl)methyl]-3,4-dimethylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

2-[4-[[(3,4-dimethylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;

N-[(3,4-difluorophenyl)methyl]-3,4-dimethyl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

N-[[3-fluoro-4-(trifluoromethyl)phenyl]methyl]-3,4-dimethyl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

N-[[4-(cyclopropylmethoxy)-3-fluoro-phenyl]methyl]-3,4-dimethyl-pyrido [4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

N-[1-(3,4-difluorophenyl)azetidin-3-yl]-3,4-dimethyl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

2-[4-[[(3,4-dimethylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-phenyl]propan-2-ol;

2-[4-[[(3,4-dimethylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-3-fluoro-phenyl]propan-2-ol;

6-[3-[(3,4-dimethylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-yl)amino]azetidin-1-yl]pyridine-3-carbonitrile;

5-chloro-3,4-dimethyl-8-pyrrolidin-1-yl-pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazine;

2,4-dimethyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)thieno[2,3-b;

5,4-c ′

]dipyridin-8-amine;

N-(3-fluoro-4-methoxybenzyl)-2,4-dimethylthieno[2,3-b;

5,4-c′

]dipyridin-8-amine;

2-(4-(((2,4-dimethylthieno[2,3-b;

5,4-c]dipyridin-8-yl)amino)methyl)phenyl)propan-2-ol;

2-(4-(((2,4-dimethylthieno[2,3-b;

5,4-c]dipyridin-8-yl)amino)methyl)-3-fluorophenyl)propan-2-ol;

3-chloro-N-(4-methoxybenzyl)-2,4-dimethylthieno[2,3-b;

5,4-c′

]dipyridin-8-amine;

2-(4-(((3-chloro-2,4-dimethylthieno[2,3-b;

5,4-c]dipyridin-8-yl)amino)methyl)phenyl)propan-2-ol;

3-chloro-2,4-dimethyl-8-(pyrrolidin-1-yl)thieno[2,3-b;

5,4-c′

]dipyridine;

2-(4-(((3-chloro-2,4-dimethylthieno[2,3-b;

5,4-c′

]dipyridin-8-yl)amino)methyl)-2-fluorophenyl)propan-2-ol;

3-chloro-N-(4-methoxybenzyl)-4-methylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

3-chloro-4-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

3-chloro-N-cyclobutyl-4-methylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

3-chloro-4-methyl-8-(pyrrolidin-1-yl)pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazine;

3-chloro-N-(3-fluoro-4-methoxybenzyl)-4-methylpyrido[4′

,3;

4,5]thieno[2,3-c]pyridazin-8-amine;

3-Methoxy-N-(4-methoxybenzyl)-4-methylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

3-methoxy-4-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

N-cyclobutyl-3-methoxy-4-methylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-amine;

3-(difluoromethyl)-4-methyl-8-(pyrrolidin-1-yl)pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazine;

6-(3-(difluoromethyl)-4-methylpyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazin-8-yl)-2-oxa-6-azaspiro[3.3]heptane; and

3-(difluoromethyl)-4-methyl-8-(3-(pyridin-4-yl)azetidin-1-yl)pyrido[4′

,3′

;

4,5]thieno[2,3-c]pyridazine,

or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 1-24, wherein the compound is isotopically labeled.

26. The compound of claim 25, wherein R² is deuterium.

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. 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 a compound of any one of claims 1-26, or pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the disorder is associated with a mAChR M₄ dysfunction.

30. The method of claim 28, wherein the disorder is a neurological and/or psychiatric disorder associated with mAChR M₄ dysfunction.

31. The method of claim 28, wherein the disorder is selected from Alzheimer'"'"'s disease, schizophrenia, a sleep disorder, a pain disorder, and a cognitive disorder.

32. The method of claim 31, wherein the disorder is Alzheimer'"'"'s disease.

33. The method of claim 28, wherein the disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder;

mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, 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.

34. A kit comprising a compound of any one of claims 1-26, or pharmaceutically acceptable salt thereof, and one or more of:

(a) at least one agent known to increase mAChR M₄ activity;

(b) at least one agent known to decrease mAChR M₄ 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 M₄ receptor activity; and

(f) instructions for administering the compound in connection with cognitive or behavioral therapy.