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

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-4-yl)pyridin-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-(6-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;

4-[trans-2-(5-Cyclopentylpyridin-2-yl)cyclopropyl]benzenesulfonamide;

4-{2-[6-(Propan-2-yl)pyridin-3-yl]-3-(trimethylsilyl)cyclopropyl}benzenesulfonamide;

4-{trans-2-[6-(Propan-2-yl)pyridazin-3-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[6-(Propan-2-yl)pyrazin-2-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[5-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[5-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[4-(Propan-2-yl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;

4-{(1R,3R)-2,2-Difluoro-3-[4-(3-fluorophenyl)pyrimidin-2-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[2-(Dimethylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[2-(Cyclopentylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[2-(Benzylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;

tert-Butyl 4-{4-[trans-2-(4-sulfamoylphenyl)cyclopropyl]pyrimidin-2-yl}piperazine-1-carboxylate;

4-(trans-2-{2-[(2,2-Dimethylpropyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;

4-(trans-2-{2-[Methyl(phenyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;

4-{trans-2-[2-(Pyrrolidin-1-yl)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;

4-(trans-2-[2-[(4-Fluorophenyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;

4-[trans-2-(2-Phenylpyrimidin-4-yl)cyclopropyl]benzenesulfonamide;

4-(trans-2-{2-[(2-Phenylethyl)amino]pyrimidin-4-yl}cyclopropyl)benzenesulfonamide;

4-{trans-2-[2-(Phenylamino)pyrimidin-4-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[2-(Propan-2-yl)pyridin-4-yl]cyclopropyl}benzenesulfonamide;

4-[trans-2-(2-Cyclobutylpyridin-4-yl)cyclopropyl]benzenesulfonamide;

4-{trans-2-[6-(Propan-2-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[5-(Pyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[6-(1H-Pyrazol-1-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;

4-{trans-2-[6-(Propan-2-yloxy)pyridin-3-yl]cyclopropyl}benzenesulfonamide; and

4-{trans-2-[6-(2-Cyanopropan-2-yl)pyridin-3-yl]cyclopropyl}benzenesulfonamide;

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) a compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 11 , further comprising a second therapeutic agent selected from the group consisting of acetylcholinesterase inhibitors; NMDA receptor antagonists; antipsychotics; MAO-B inhibitors; and levodopa.

13. A method of treating a patient with cognitive impairments associated with Alzheimer's disease, Parkinson's disease, and schizophrenia, the method comprising administering to the patient the compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to treat the patient.

14. A method for modulating α7 nAChR activity in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.