Substituted 6-membered aryl or heteroaryl allosteric modulators of nicotinic acetylcholine receptors

Patent metadata

Field	Value
Publication number	US-11026958-B2
Application number	US-201716345997-A
Country	US
Kind code	B2
Filing date	Oct 30, 2017
Priority date	Nov 1, 2016
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

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 6-membered heteroaryl ring which is substituted with 1 to 4 R groups each independently selected from OH, oxo, amino, amido, carboxyl, keto, cyano, alkoxy, S(O) m -alkyl, halogen, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, alkynyl, aryl, heteroaryl, and heterocyclyl, wherein said amino, amido, carboxyl, keto, alkoxy, S(O) m -alkyl, aminoalkyl, hydroxyalkyl, alkyl, cycloalkyl, alkynyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, OH, oxo, CF 3 , OCF 3 , CN, (C 1 -C 6 )alkyl, O(C 1 -C 4 )alkyl, S(O) m —(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, Si(CH 3 ) 3 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 and R 8 are independently selected from H, (C 1 -C 6 )alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, OH, CF 3 , (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, cycloalkyl, CN, aryl, heteroaryl, and heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, OH, CF 3 , (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, CN;
R a is H or (C 1 -C 4 )alkyl;
R b is H or (C 1 -C 4 )alkyl; and
m is 0, 1, or 2.

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 pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyridinone, pyrimidinone, pyrazinone, and pyridazinone each substituted with 1 to 2 R groups independently selected from halogen, CN, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, NR 7 R 8 , (C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said alkyl, NR 7 R 8 , (C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, CN, (C 1 -C 4 )alkyl, (C═O)O(C 1 -C 4 )alkyl and phenyl, wherein said alkyl is optionally substituted with one or more halogen.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R a and R b 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, Si(CH 3 ) 3 or methyl.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are independently selected from H, (C 1 -C 6 )alkyl, cyclopentyl and phenyl wherein said alkyl and phenyl are optionally substituted with halogen or phenyl.

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

or a pharmaceutically acceptable salt thereof, wherein;
A is selected from pyridine, pyrimidine, pyridazine and pyrazine each substituted with 1 R group selected from (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, NR 7 R 8 , (C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each are optionally substituted with one or more substituents independently selected from halogen, CF 3 , CN, (C 1 -C 4 )alkyl, (C═O)O(C 1 -C 4 )alkyl and phenyl;
R 3 is H or Si(CH 3 ) 3 ;
R 4 is H; and
R 7 and R 8 are independently selected from H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen and phenyl.

9. The compound of claim 8 having the formula Ia, or a pharmaceutically acceptable salt thereof, wherein;
A is selected from pyridine, pyrimidine, pyridazine and pyrazine each substituted with 1 R group selected from (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, NR 7 R 8 , cyclobutyl, cyclopentyl, phenyl, pyridinyl, morpholinyl, imidazolyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, triazolyl and tetrahydropyranyl wherein each are optionally substituted with one or more substituents independently selected from halogen, CF 3 , CN, (C 1 -C 4 )alkyl, (C═O)O(C 1 -C 4 )alkyl and phenyl;
R 3 is H or Si(CH 3 ) 3 ;
R 4 is H; and
R 7 and R 8 are independently selected from H, (C 1 -C 6 )alkyl, cyclopentyl and phenyl, wherein each alkyl, cyclopentyl, and phenyl are optionally substituted with one or more substituents independently selected from halogen and phenyl.

10. The compound of claim 1 which is selected from the group consisting of
4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Morpholin-4-yl)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;
4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-[trans-2-(5-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-{trans-2-[4-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(Pyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;
4-[(1R,3R)-2,2-Dimethyl-3-{4-[5-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl]benzenesulfonamide;
4-{trans-2-[4-(3-Fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;
4-(trans-2-{4-[5-(Trifluoromethyl)pyridin-3-yl]pyrimidin-2-yl}cyclopropyl)benzenesulfonamide;
4-{trans-2-[6-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[4-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-[trans-2-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;
4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[5-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[3-(Propan-2-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(1H-Pyrazol-1-yl)pyridin-2-yl]cyclopropyl}benzenesulfonamide;
4-{trans-2-[6-(Tetrahydro-2H-pyran-

Assignees

• Merck Sharp & Dohme

Inventors

• Crowley Brendan M
• Bell Ian M
• Harvey Andrew John
• Campbell Brian T
• Greshock Thomas J
• Rada Vanessa L

Classifications

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07F7/0812

  comprising a heterocyclic ring · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• C07D271/06

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title