N-linked quinolineamide M1 receptor positive allosteric modulators

1. A compound of formula (I):

and pharmaceutically acceptable salts thereof, wherein

X═Y═CH 2 , X═O and Y═CH 2 , or X═CH 2 and Y═O;

each R is selected from the group consisting of

(1) hydrogen,

(2) C 6-10 aryl,

(3) C 5-10 heterocycle, optionally substituted with 1 to 3 groups of R a ,

(4) —C 1-6 alkyl, optionally substituted with 1 to 3 groups of R a ,

(5) —C 2-6 alkenyl, optionally substituted with 1 to 3 groups of R a ,

(6) —S(═O) n —R 1 ,

(7) —OH,

(8) or R and R can be linked together with the nitrogen to which they are both attached to form a 3-6membered saturated heterocyclic ring, wherein one or two of the ring carbon atoms are optionally replaced by a nitrogen, oxygen or sulfur; wherein said saturated 25 heterocyclic ring is optionally susbstituted with 1 to 3 groups of R a ,

R a and R a1 are independently selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) C 1-6 alkyl,

(4) C 6-10 aryl, which is unsubstituted or substituted with 1 to 3 groups of R b ,

(5) (CH 2 ) n heterocyclyl, which is unsubstituted or substituted with 1 to 3 groups of R b , and

(6) —CN,

R b is selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) C 1-6 alkyl, and

(4) C 1-4 haloalkyl,

R 1 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 2-6 alkenyl, and

(4) —N(R 1 ) 2

n is 0-4.

2. The compound according to claim 1 of formula (I) wherein X═O and Y═CH 2 .

3. The compound according to claim 1 of formula (I) wherein X═Y═CH 2 .

4. The compound according to claim 1 of formula (I) wherein R and R are linked together with the nitrogen to which they are both attached to form a 3-6 membered saturated heterocyclic ring, wherein one or two of the ring carbon atoms is optionally replaced by a nitrogen, oxygen or sulfur; and wherein said saturated heterocyclic ring is optionally susbstituted with 1 to 3 groups of R a .

5. The compound according to claim 4 of formula (I) wherein the heterocyclic ring formed by linking R and R is optionally substituted piperidinyl or piperazinyl.

6. The compound according to claim 1 of formula (I) whereinR a is selected from the group consisting of halogen, CN, and optionally substituted phenyl, pyridyl, pyrazolyl, pyrazinyl, pyrimidinyl and pyradazinyl.

7. The compound according to claim 1 of formula (I) represented by structural formula Ia:

or a pharmceutically acceptable salt thereof.

8. The compound according to claim 7 represented by structural formula Ib:

or a pharmaceutically acceptable salt thereof wherein X, Y and R a are as originally described and—represents a bond that is present or absent.

9. The compound according to claim 8 wherein X═Y═CH 2 or X═O and Y═CH 2 , —is absent, and R a is selected from the group consisting of CN, halo, and optionally substituted phenyl, pyridyl, pyrazolyl, pyrazinyl, pyrimidinyl and pyradazinyl.

10. The compound according to claim 7 represented by the structural formula Ic:

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 wherein X═Y═CH 2 or X═O and Y═CH 2 , and R a is selected from the group consisting of CN, halo, and optionally substituted phenyl, pyridyl, pyrazolyl, pyrazinyl, pyrimidinyl and pyradazinyl.

12. A compound which is

4 -[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

N-[(1S,2S)- 2 -hydroxycyclohexyl]-4-{[4-(1-methyl-1H-pyrazole-4-yl)piperzin-1-yl]methyl}quinoline-2-,

4-{[4-cyano-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

4-[(4-cyano-4-phenylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carbozamide,

4-{[4-cyano-4-(2-fluorophenyl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

4-{[4-(2-chlorophenyl)-4-cyanopiperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

4-{[4-cyano-4-(2-methylphenyl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

1,5-anhydro-3-{[(4-{[4-cyano-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}quinoline-2-yl)carbonyl]amino}-2,3-dideoxy-L-threo-penitol,

4-[(4-cyano-4-pyridin-3-ylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

4-[(4-cyano-4-pyridin-4-ylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

8-fluoro-4-[(4-fluoro-[(4-phenylpiperidin-1-yl)methyl]-N-(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

1,5-anhydro-2,3-dideoxy-3-[({8-fluoro-4-[(4-fluoro-4-phenylpiperidin-1-yl)methyl]quinoline-2-yl}carbonyl)amino]-L-threo-penitol,

8-fluro-N-[(1S,2S)- 2 -hydroxycyclohexyl]-4-{[4-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]methyl}quinoline-2-carboxamide,

4-[(4-cyano-4-pyrazin-2-ylpiperidin-1-yl)methyl]8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

4-[(4-cyano-4-pyrimidin-4-ylpiperidin-1-yl)methyl]8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

8-fluoro-4-[(4-fluoro-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinline-2-carboxamide,

4-[(4-cyano-4-pyridazin-4-ylpiperidin-1-yl)methyl]-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

4-(3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-ylmethyl)-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-({5-[4-(trifluoromethyl)phenyl]piperidin-1-yl}methyl)quinoline-2-carboxamide,

8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-pyridin-4-ylpiperidin-1-yl)methyl]quinoline-2-carboxamide,

8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-phenylpiperidin-1-yl)methyl]quinoline-2-carboxamide,

4-[(4-cyano-4-ylpiperidin-1-yl)methyl]-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-pyridin-3-ylpiperidin-1-yl)methyl]quinoline-2-carboxamide,

4-[(4-cyano-3-ylpiperidin-1-yl)methyl]-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]-4-[(4-pyridin-2-ylpiperidin-1-yl)methyl]quinoline-2-carboxamide,

4-[(4-cyano-4-fluoropiperidin-1-yl)methyl]-8-fluoro-N-[(1S,2S)- 2 -hydroxycyclohexyl]quinoline-2-carboxamide,

4-[(4-cyano-4-fluoropiperidin-1-yl)methyl]-5,8-difluoro-N-[(1S,2S)- 2 -hydroxycyclohexyl]quinoline-2-carboxamide,

4-{[4-cyano-4-(4-methylpyridin-2-yl]methyl}-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

4-{[4-cyano-4-(4-methylpyridin-2-yl]methyl}-5,8-difluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

4-{[4-(4-chloropyridin-2-yl)-4-fluoropiperidin-1-yl]methyl}-8-fluoro-N-[(1S,2S)- 2 -hydroxycyclohexyl]quinoline-2-carboxamide,

8-fluoro-4-{[4-fluoro-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide,

and pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition for the treatment of a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain or sleep disorders, comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A method of treating a disease or disorder mediated by the muscarinic M1 receptor, wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain or sleep disorders in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.