Quinoline amide M1 receptor positive allosteric modulators

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

X 1 is N;

X 2 -X 3 is selected from the group consisting of

(1) —O—CH 2 —, and

(2) —CH 2 —O—,

X 4 , X 5 , X 6 and X 7 are each selected from the group consisting of

(1) N,

(2) N→O, and

(3) CH,

wherein one of X 4 , X 5 , X 6 and X 7 is N or N→O and the others are each CH (or C substituted with R 4 );

R 1 is selected from the group consisting of

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —C 2-6 alkynyl,

(4) phenyl,

(5) ═O,

(6) ═CH 2 , and

(7) hydroxyl,

wherein the R 1 alkyl, alkynyl or phenyl group is optionally substituted with one or more

(a) hydroxyl, or

(b) halogen;

R 2A and R 2B are independently selected from the group consisting of

(1) hydrogen,

(2) hydroxyl, and

(3) halogen,

or R 2A and R 2B together form ═O;

R 3 is optionally present at one or more of the ring carbon atoms, and is independently selected from the group consisting of

(1) halogen,

(2) —O—C 1-6 alkyl, and

(3) —S—C 1-6 alkyl,

R 4 is optionally present at one or more of the ring atoms, and is selected from the group consisting of

(1) hydroxyl,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —O—C 1-6 alkyl,

(5) —S—C 1-6 alkyl,

(6) —C 3-8 cycloalkyl,

(7) —C 6-10 aryl, and

(8) —CN,

and the alkyl, cycloalkyl, or aryl R 4 group is optionally substituted with one or more

(a) halogen,

(b) hydroxyl,

(c) —O—C 1-6 alkyl,

(d) —C 1-6 alkyl, and

(e) —S—C 1-6 alkyl.

2. The compound according to claim 1 represented by structural formula (II) or (III);

wherein

R 3A and R 3B are independently selected from the group consisting of

(1) hydrogen

(2) halogen,

(3) —O—C 1-6 alkyl, and

(4) —S—C 1-6 alkyl

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein X 2 -X 3 is —O—CH 2 —.

4. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein X 2 -X 3 is —CH 2 —O—.

5. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydroxyl, or halogen.

6. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydroxyl.

7. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B are each hydrogen, or R 2A is hydrogen and R 2B is halogen.

8. A compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B are each hydrogen.

9. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B are each hydrogen, one of R 3A and R 3B is halogen and the other is hydrogen.

10. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein one of R 3A and R 3B is halogen and the other is hydrogen.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3A is halogen and R 3B is hydrogen.

12. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each of R 2A , R 2B , R 3A , and R 3B are hydrogen.

13. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of

(1) halogen,

(2) —C 1-6 alkyl,

(3) —O—C 1-6 alkyl, and

wherein said alkyl R 4 group is optionally substituted with one or more

(a) halogen,

(b) hydroxy,

(c) —O—C 1-6 alkyl,

(d) —C 1-6 alkyl, optionally substituted with halogen, and

(e) —S—C 1-6 alkyl.

14. A compound which is:

4-[(6-Chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide;

N-[(1S,2S)-2-Hydroxycyclohexyl]-4-[(6-methylpyridin-3-yl)methyl]quinoline-2-carboxamide;

4-[(6-Chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide 1-oxide;

4-[(6-Cyclopropylpyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide;

N-[(1S,2S)-2-Hydroxycyclohexyl]-4-(pyridine-3-ylmethyl)quinoline-2-carboxamide;

N-[(1S,2S)-2-Hydroxycyclohexyl]-4-{[6-(methylsulfanyl)pyridin-3-yl]methyl}quinoline-2-carboxamide;

N-[(3R,4S)-3-Hydroxycyclohexyl-2H-pyridin-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide;

4-[(6-Ethoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-4-[( 2 -methoxypyridin-4-yl)methyl]quinoline-2-carboxamide;

4-[Fluoro(6-methoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide hydrate;

4-[(6-Chloropyridin-3-yl)methyl]-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-{[6-Difluoromethyl)pyridin-3-yl]methyl}-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[Fluoro(6-methoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-8-methoxyquinoline-2-carboxamide;

8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide;

8-Fluoro-4-[(6-hydroxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxy-1-oxidopyridin-3-yl)methyl]quinoline-2-carboxamide;

8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxamide;

8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxy-1-oxidopyridin-4-yl)methyl]quinoline-2-carboxamide;

5,8-Difluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide;

4-[(6-chloropyridin-3-yl)methyl]-N-(tetrahydro-2H-pyran-3-yl)quinoline-2-carboxamide;

4-[(6-chloropyridin-3-yl)methyl]-N-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide;

1,5-anhydro-3-[({4-[(6-chloropyridin-3-yl)methyl]quinolin-2-yl}carbonyl)amino]-2,3-dideoxy-L-threo-pentitol;

4-(4-chlorobenzyl)-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(6-chloropyridin-3-yl)methyl]-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-(4-chlorobenzyl)-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(6-chloropyridin-3-yl)methyl]-5,8-difluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-(4-chlorobenzyl)-5,8-difluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(6-chloropyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-8-(methylsulfanyl)quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide;

4-(4-chlorobenzyl)-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide 1-oxide;

4-(4-chlorobenzyl)-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[fluoro(6-methoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-8-methoxyquinoline-2-carboxamide;

8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-{[6-trifluoromethyl)pyridin-3-yl]methyl}quinoline-2-carboxamide;

4-[4-chlorophenyl)(fluoro)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[fluoro(6-methoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

8-chloro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide;

N-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide;

4-[(6-chloropyridin-3-yl)methyl]-8-fluoro-N-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]quinoline-2-carboxamide;

8-chloro-4-[(2-chloropyridin-4-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(2-chloropyridin-4-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(2-chloropyridin-4-yl)carbonyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(2-chloropyridin-4-yl)methyl]-N-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]quinoline-2-carboxamide;

8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methylpyridin-3-yl)methyl]quinoline-2-carboxamide;

4-[(6-chloropyridin-3-yl)methyl]-N-cyclohexylquinoline-2-carboxamide;

4-[(2-chloropyridin-4-yl)methyl]-N-[(1S,2S)-2-hydroxycylohexyl]quinoline-2-carboxamide;

5,8-difluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3yl)methyl]quinoline-2-carboxamide;

5,8-difluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-{[(6-(trifluoromethyl)pyridin-3-yl]methyl}quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-(pyrazin-2-ylmethyl)quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxamide;

4-{[6-(difluoromethyl)pyridin-3-yl]methyl}-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxy-1-oxidopyridin-3-yl)methyl]quinoline-2-carboxamide;

4-[(2-chloropyridin-4-yl)methyl]-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methylpyridin-4-yl)methyl]quinoline-2-carboxamide;

4-[(6-chloropyridin-3-yl)methyl]-N-[(1S)-2-oxocyclohexyl]quinoline-2-carboxamide;

8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxamide;

8-fluoro-4-[(6-hydroxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(6-hydroxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(2-hydroxypyridin-4-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxy-1-oxidopyridin-4-yl)methyl]quinoline-2-carboxamide;

8-fluoro-4-[(2-hydroxypyridin-4-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

5,8-difluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxamide;

4-[(6-ethoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-{[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]methyl}quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxy-1-oxidopyridin-3-yl)methyl]quinoline-2-carboxamide;

4-[(2-ethoxypyridin-4-yl)methyl]-N-[(3R,4S)-3-hydroxytetrhydro-2H-pyran-4-yl]quinoline-2-carboxamide;

8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}quinoline-2-carboxamide;

4-[(6-fluoropyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-{[6-(methylsulfanyl)pyridin-3-yl]methyl}quinoline-2-carboxamide;

4-[(2-ethoxypyridin-4-yl)methyl]-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

4-[(6-ethoxypyridin-3-yl)methyl]-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide;

N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-{[2-(methylsulfanyl)pyridin-4-yl]methyl}quinoline-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. The composition according to claim 15 wherein the compound is selected from

N-[(3R,4S)-3-Hydroxytetrahydro-2H-pryran-4-yl]-4-[(6-methoxypryridin-3-yl)methyl]quinoline-2-carboxamide,

4-[Fluoro(6-methoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide hydrate,

4-[(6-Chloropyridin-3-yl)methyl]-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide,

8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide, and

8-Fluoro-N[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxamide, or a pharmaceutically acceptable salt thereof.

17. A compound which is represented by structural formula:

or a pharmaceutical acceptable salt thereof.

18. The compound of claim 17 which is N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide.

19. The pharmaceutically acceptable salt of N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide in accordance with claim 17 .

20. A compound which is represented by structural formula:

or a pharmaceutically acceptable salt thereof.

21. A compound of claim 20 which is 4-[Fluoro(6-methoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide hydrate.

22. The pharmaceutically acceptable salt of 4-[Fluoro(6-methoxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide hydrate in accordance to claim 20 .

23. A compound represented by structural formula:

or a pharmacetically acceptable salt thereof.

24. The compound of claim 23 which is 4 1 -[(6-Chloropyridin-3-yl)methyl]-8-fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide.

25. The pharmaceutically acceptable salt of 4-[(6-Chloropyridin-3-yl)methyl]-8-fluoro-N-[3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide in accordance with claim 23 .

26. A compound represented by structural formula:

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 26 which is 8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide.

28. The pharmaceutically acceptable salt of 8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide in accordance with claim 26 .

29. A compound represented by structural formula:

or a pharmaceutically acceptable salt therof.

30. The compound of claim 29 which is 8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxamide.

31. The pharmaceutically acceptable salt of 8-Fluoro-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxamide in accordance with claim 29 .

32. 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 claims 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.