POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M1

• US 20200131180A1
• Filed: 10/24/2019
• Published: 04/30/2020
• Est. Priority Date: 10/24/2018
• Status: Abandoned Application

• Current Assignee: Vanderbilt University
• Original Assignee: Vanderbilt University
• Inventors: Lindsley, Craig W., Conn, P. Jeffrey, Engers, Darren W., Engers, Julie L., Long, Madeline, Bender, Aaron M.
• Application Number:
  US16/662,919
• Publication Number:
  US 20200131180A1
• Time in Patent Office: Days
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Described are positive allosteric modulators of muscarinic acetylcholine receptor M₁ (mAChR M₁), pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for treating neurological disorders, psychiatric disorders, or a combination thereof.

Claims

1. A compound of formula (I),

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

A¹ is Cyc²-Cyc³, wherein Cyc² and Cyc³ are each independently optionally substituted as defined in claim 1.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

A¹ is Cyc²-Cyc³;

Cyc² is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl, and

Cyc³ is a 5- to 12-membered heteroaryl, wherein Cyc² and Cyc³ are optionally substituted as defined in claim 1.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

A¹ is Cyc²-Cyc³;

Cyc² is

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2;

and R⁶ is halogen.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

A² is L¹-G¹;

G¹ is a C_3-12cycloalkyl or a 4- to 12-membered heterocycle containing one oxygen atom, wherein G¹ is optionally substituted as defined in claim 1; and

L¹ is a bond.

24. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein

G¹ is a monocyclic C_3-8cycloalkyl, a monocyclic 4- to 8-membered heterocycle containing one oxygen atom, or a 7- to 12-membered spirocyclic heterocycle containing one oxygen atom, wherein G¹ is optionally substituted with 1-2 substituents selected from OH and C_1-4alkyl.

25. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein

G¹ is

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

6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-tetrahydropyran-4-yl-imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1R,2R)-2-hydroxycyclohexyl]-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-(2-oxaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1R,2R)-2-hydroxycyclopentyl]-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-tetrahydropyran-4-yl-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-(2-oxaspiro[3.3]heptan-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1R,2R)-2-hydroxycyclobutyl]-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclopentyl]-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]-N-tetrahydropyran-4-yl-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]-N-(2-oxaspiro[3.3]heptan-6-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1R,2R)-2-hydroxycyclobutyl]-6-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclopentyl]-6-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-7-[(4-pyrazol-1-ylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[(4-pyrazol-1-ylphenyl)methyl]-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-7-[(4-pyrazol-1-ylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-2-methyl-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[(4-pyrazol-1-ylphenyl)methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[(4-pyrazol-1-ylphenyl)methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclopentyl]-6-[(4-pyrazol-1-ylphenyl)methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[[6-(1-methylpyrazol-3-yl)-3-pyridyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[[6-(1-methylpyrazol-3-yl)-3-pyridyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[[6-(1-methylpyrazol-3-yl)-3-pyridyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[[4-(2-methyloxazol-4-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[(4-pyrazol-1-ylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[[4-(2-methyloxazol-4-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[(4-pyrazol-1-ylphenyl)methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-tetrahydropyran-4-yl-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[4-(2-methyloxazol-4-yl)phenyl]methyl]-N-tetrahydropyran-4-yl-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[(4-pyrazol-1-ylphenyl)methyl]-N-tetrahydropyran-4-yl-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[[6-(1-methylpyrazol-3-yl)-3-pyridyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[2,6-difluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2,6-difluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2,6-difluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2,6-difluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[2,6-difluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[2,6-difluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[2,6-difluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide; and

6-[[2,6-difluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclopentyl]imidazo[1,2-a]pyridine-8-carboxamide;

6-[[2-fluoro-4-(1-methylpyrazol-3-yl)phenyl]methyl]-N-[(1S,2S)-2-hydroxycyclopentyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-pyrazol-1-yl-3-pyridyl)methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycycloheptyl]-6-[(6-pyrazol-1-yl-3-pyridyl)methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[(6-pyrazol-1-yl-3-pyridyl)methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-6-[[6-(trifluoromethyl)-3-pyridyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-6-[[6-(trifluoromethyl)-3-pyridyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide; and

7-(4-(1H-pyrazol-1-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising the compound of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

37. A method of treating a neurological disorder or psychiatric disorder, or a combination thereof comprising administering a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.

2. (canceled)

6-8. -8. (canceled)

11-13. -13. (canceled)

16. (canceled)

18-21. -21. (canceled)

23. (canceled)

26-29. -29. (canceled)

32-36. -36. (canceled)

38-42. -42. (canceled)

43. A compound of formula (I),

44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein

A² is L¹-G¹;

G¹ is a monocyclic C_3-8cycloalkyl, a monocyclic 4- to 8-membered heterocycle containing one oxygen atom, or a 7- to 12-membered spirocyclic heterocycle containing one oxygen atom, wherein G¹ is optionally substituted with 1-2 substituents selected from OH and C_1-4alkyl; and

L¹ is a bond.

45. The compound of claim 43, selected from the group consisting of

N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-5-methyl-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide;

N-[(1S,2S)-2-hydroxycyclohexyl]-5-methyl-6-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]imidazo[1,2-a]pyridine-8-carboxamide; and

6-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-5-methyl-imidazo[1,2-a]pyridine-8-carboxamide;

or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising the compound of claim 43, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

47. A method of treating a neurological disorder or psychiatric disorder, or a combination thereof comprising administering a therapeutically effective amount of the compound of claim 43, or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.