Allosteric modulators of nicotinic acetylcholine receptors

Patent metadata

Field	Value
Publication number	US-9840481-B2
Application number	US-201715463336-A
Country	US
Kind code	B2
Filing date	Mar 20, 2017
Priority date	Mar 22, 2016
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

The present disclosure relates to compounds of formula I that are useful as modulators of α7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation

First claim

What is claimed is:

1. A compound having the formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from

Y is 4 substituents, each independently selected from H, (C 1 -C 4 )alkyl, halogen, and OH, wherein said alkyl is optionally substituted with one or more halogen or OH;
A is a 5-membered heteroaryl ring which is substituted with 1 to 3 R groups each independently selected from OH, oxo, NR 7 R 8 , CN, alkoxy, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein said alkoxy, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF 3 , OCF 3 , CN, (C 1 -C 6 )alkyl, O(C 1 -C 4 )alkyl, S(C 1 -C 4 )alkyl, C═O(C 1 -C 4 )alkyl, (C═O)NR 7 R 8 , (C═O)OR 7 , (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 )cycloalkyl, C═O(C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally independently substituted with one or more halogen, CF 3 , OH and oxo;
R 1 is H or (C 1 -C 4 )alkyl;
R 2 is H or (C 1 -C 4 )alkyl;
R 3 is H, halogen or (C 1 -C 4 )alkyl, wherein said alkyl is optionally substituted with one or more halogen;
R 4 is H, halogen or (C 1 -C 4 )alkyl, wherein said alkyl is optionally substituted with one or more halogen;
or, R 3 and R 4 optionally can come to together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring wherein said ring may be optionally substituted with one or more substituents independently selected from OH, halogen, or (C 1 -C 4 )alkyl;
R 5 is H or (C 1 -C 4 )alkyl;
R 6 is H or (C 1 -C 4 )alkyl;
R 7 is H or (C 1 -C 4 )alkyl;
R 8 is H or (C 1 -C 4 )alkyl; and
R a is H or (C 1 -C 4 )alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is

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

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein A is selected from

each substituted with 1 to 3 R groups independently selected from (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF 3 , OCF 3 , CN, (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, S(C 1 -C 4 )alkyl, C═O(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 )cycloalkyl, C═O(C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally independently substituted with one or more F, Cl, CF 3 , OH and oxo.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are independently H or methyl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently H, F or methyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula:

wherein;
A is selected from

each substituted with 1 to 2 R groups independently selected from (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF 3 , OCF 3 , CN, (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, S(C 1 -C 4 )alkyl, C═O(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 )cycloalkyl, C═O(C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally independently substituted with one or more F, Cl, CF 3 , OH and oxo;
R 3 and R 4 are independently H, F or methyl; and
R 5 and R 6 are independently H or methyl.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, having the formula:

wherein;
A is selected from

each substituted with 1 to 2 R groups independently selected from (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl wherein each are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF 3 , OCF 3 , CN, (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, S(C 1 -C 4 )alkyl, C═O(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 )cycloalkyl, C═O(C 3 -C 6 )cycloalkyl, phenyl, O-phenyl, imidazolyl, pyrazinyl, furanyl, oxazolidinyl, pyrrolidinyl, and benzoxazolyl, wherein said alkyl, phenyl, oxazolidinyl, pyrrolidinyl, and benzoxazolyl are optionally independently substituted with one or more F, Cl, CF 3 and oxo; and
R 3 and R 4 are independently H, F or methyl; and
R 5 and R 6 are independently H or methyl.

9. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein;
R is selected from (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, indanyl, piperidinyl, pyridinyl, furanyl, oxazolyl, benzoxazinyl, cyclopentalpyrrolyl, thienopyrrolyl, thiazolyl, imidazolyl, azetidinyl, pyrrolyl, pyrazinyl, quinolinyl and benzothiazolyl wherein each are optionally substituted with one or more substituents independently selected from F, Cl, Br, OH, oxo, CF 3 , OCF 3 , CN, (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, S(C 1 -C 4 )alkyl, C═O(C 1 -C 4 )alkyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, O(C 3 -C 6 )cycloalkyl, C═O(C 3 -C 6 )cycloalkyl, phenyl, O-phenyl, imidazolyl, pyrazinyl, furanyl, oxazolidinyl, pyrrolidinyl, and benzoxazolyl, wherein said alkyl, phenyl, oxazolidinyl, pyrrolidinyl, and benzoxazolyl are optionally independently substituted with one or more F, Cl, CF 3 and oxo;
R 3 and R 4 are independently H, F or methyl; and
R 5 and R 6 are independently H or methyl.

10. The compound of claim 1 which is selected from the group consisting of
4-((1S,3S)-3-(3-(5-Fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)-2,2-dimethylcyclopropyl)-benzenesulfonamide;
4-((1S,3S)-3-(5-(2-Cyclopropylethyl)-1,2,4-oxadiazol-3-yl)-2,2-dimethylcyclopropyl)benzenesulfonamide;
4-((1S,3S)-2,2-Dimethyl-3-(5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazol-3-yl)cyclopropyl) benzenesulfonamide;
4-((1R,2R)-2-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)benzenesulfonamide;
4-{(1R,3R)-3-[5-(2,4-Difluorophenyl)-1,3,4-thiadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide;
4-{(1S,3S)-3-[5-(2,4-Difluorophenyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylcyclopropyl}benzenesulfonamide;
4-{(1S,3S)-2,2-Difluoro-3-[3-(propan-

Assignees

• Merck Sharp & Dohme

Inventors

• Crowley Brendan M
• Campbell Brian T
• Duffy Joseph L
• Greshock Thomas J
• Guiadeen Deodial G
• Harvey Andrew John
• Huff Belinda C
• Leavitt Kenneth J
• Rada Vanessa L
• Sanders John M
• Shipe William D
• Suen Linda M
• Bell Ian M

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  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 title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title