Quinolizidinone carboxamide M1 receptor positive allosteric modulators

1. A compound of formula (I):

wherein R 1 is selected from the group consisting of

(1) hydrogen, or

(2) —C 1-6 alkyl,

R 2 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 2-6 alkenyl,

(4) —OC 1-6 alkyl,

(5) —C 3-8 cycloalkyl,

(6) —C 5-8 cycloalkenyl,

(7) a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S,

(8) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S, or

(9) —C 6-10 aryl,

wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl or aryl R2 moiety is optionally substituted by one or more

(a) halogen,

(b) hydroxyl,

(c) —C 1-6 alkyl,

(d) —O—C 1-6 alkyl,

(e) —C 3-8 cycloalkyl,

(f) —C 6-10 aryl,

(g) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S, or

(h) —(C═O)—C 1-6 alkyl,

(i) —NR A R B , wherein R A and R B are selected from the group consisting of

(i) hydrogen, or

(ii) —C 1-6 alkyl,

or R A and R B are linked together with the nitrogen to which they are attached to form a 4-6 membered carbocyclic ring, wherein one or two of the ring carbon atoms is optionally replaced by a nitrogen, oxygen or sulfur, and the ring is optionally substituted with one or more

(i) halogen,

(ii) hydroxyl,

(iii) C 1-6 alkyl,

(iv) —O—C 1-6 alkyl,

(v) —C(═O)—(O) n —C 1-6 alkyl,

or R 1 and R 2 are linked together with the nitrogen to which they are both attached to form a 4-8 membered saturated or unsaturated carbocyclic ring, wherein one or two of the ring carbon atoms is replaced by a nitrogen, oxygen or sulfur, and the carbocyclic is optionally substituted with one or more

(a) halogen,

(b) hydroxyl,

(c) —C 1-6 alkyl,

(d) —O—C 1-6 alkyl,

(e) —C 3-8 cycloalkyl,

(f) —C 6-10 aryl,

(g) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S, or

(h) —(C═O)—C 1-6 alkyl;

R 3 is optionally present at one or more of the phenyl moiety C atoms, and is selected from the group consisting of

(1) —C 1-6 alkyl,

(2) —OC 1-6 alkyl, or

(3) halogen;

R 4 is selected from the group consisting of

(1) a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S,

(2) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,

(3) —C 3-8 cycloalkyl,

(4) —C 5-8 cycloalkenyl, or

(5) —C 6-10 aryl,

wherein the heterocyclic, heteroaryl or aryl moiety is optionally substituted with one or more

(a) halogen,

(b) hydroxyl,

(c) —C 1-6 alkyl,

(d) —O—C 1-6 alkyl,

(e) —C 3-8 cycloalkyl,

(f) —C 6-10 aryl,

(g) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S, or wherein the alkyl, cycloalkyl, aryl or heteroaryl moiety is optionally substituted with one or more

(i) halogen,

(ii) hydroxyl,

(iii) —C 1-6 alkyl, or

(iv) —O—C 1-6 alkyl,

or a pharmaceutically acceptable salt thereof, provided when R 2 is a heterocyclic or heteroaryl group that is tetrazole then R 4 is not an aryl that is phenyl.

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

3. A compound of claim 1 , wherein R 2 is —C 3-8 cycloalkyl, or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 , wherein R 2 is a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S, or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 , wherein R 2 is heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S, or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 , wherein or R 1 and R 2 are linked together with the nitrogen to which they are both attached to form a 4-8 membered carbocyclic ring, wherein one or two of the ring carbon atoms is replaced by a nitrogen, oxygen or sulfur, or a pharmaceutically acceptable salt thereof.

7. A compound of claims 1 wherein R 3 is absent or is methyl at the following position:

or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 wherein R 4 is a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S, or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 wherein R 4 is heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S, or a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 wherein R 4 is —C 6-10 aryl, or a pharmaceutically acceptable salt thereof.

11. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are as defined in claim 1 .

12. A compound of claim 11 , wherein R 4 is a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S, or a pharmaceutically acceptable salt thereof.

13. A compound of claim 11 , wherein R 4 is heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S, or a pharmaceutically acceptable salt thereof.

14. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III)

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R 3 are defined in claim 1 , and R 6 is selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) —C 1-6 alkyl,

(4) —O—C 1-6 alkyl,

(5) —C 3-8 cycloalkyl,

(6) —C 6-10 aryl,

(7) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,

wherein the alkyl, cycloalkyl, aryl or heteroaryl moiety is optionally substituted with one or more

(a) halogen,

(b) hydroxyl,

(c) —C 1-6 alkyl,

(d) —O—C 1-6 alkyl.

15. A compound of claim 14 , wherein R 6 is selected from the group consisting of

(1) —C 6-10 aryl, or

(2) heteroaryl, which is an aromatic cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N, N→O, C(═O) or S, at least one of which is O, N, N→O or S,

wherein the aryl or heteroaryl moiety is optionally substituted with one or more

(a) halogen,

(b) hydroxyl,

(c) —C 1-6 alkyl,

(d) —O—C 1-6 alkyl,

(e) —CN,

wherein the alkyl moiety is optionally substituted with one or more halogen, or a pharmaceutically acceptable salt thereof.

16. A compound of claim 15 , wherein R 1 is hydrogen, or a pharmaceutically acceptable salt thereof.

17. A compound of claim 15 wherein R 2 is —C 3-8 cycloalkyl, or a pharmaceutically acceptable salt thereof.

18. A compound of claim 15 wherein R 2 is a heterocyclic group having 4 to 8 ring atoms selected from C, O, N, N→O, C(═O), SO 2 or S, at least one of which is O, N, N→O, SO 2 or S, or a pharmaceutically acceptable salt thereof.

19. A compound of claim 15 wherein R 1 and R 2 are linked together with the nitrogen to which they are both attached to form a 4-8 membered carbocyclic ring, wherein one or two of the ring carbon atoms is replaced by a nitrogen, oxygen or sulfur, or a pharmaceutically acceptable salt thereof.

20. A compound of claim 1 , which is selected from the group consisting of

1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-4H—N-(tetrahydro-2H-pyran-4-yl)-4H-quinolizine-3-carboxamide;

1-[(5-Bromopyridin-2-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

N-[(1S,2S)-2-Hydroxycyclohexyl]-1-{[5-(1-methyl-1H-pyrazol-4-yl)pyriding-2-yl]methyl}-4-oxo-4H-quinolizine-3-carboxamide;

N-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-1-{[5-(1H-pyrazol-1-yl)pyridine-2-yl]methyl}-4H-quinolizine-3-carboxamide;

1-({4-[6-(Difluoromethyl)pyridine-3-yl]piperazin-1-yl}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

N-[(1S,2S)-2-Hydroxycyclohexyl]-1-{[4-(1-methyl-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate;

rac-1-[(4-Cyano-4-pyridin-2-ylpiperidin-1yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-4H-quinolizine-3-carboxamide;

rac-1-[(4-Cyano-4-pyridin-2-ylpiperidin-1yl)methyl]-N-[(3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl]-4-oxo-4H-quinolizine-3-carboxamide;

1-[(4-Cyano-4-phenylpiperidin-1-yl)methyl]-N-[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-4H-quinolizine-3-carboxamide;

1-{[4-Cyano-4-(3,5-dibromopyridin-2-yl)piperidin-1-yl]methyl}-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-4H-quinolizine-3-carboxamide;

1-[(4-Cyano-4-phenylpiperidin-1yl)methyl]-N-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-4-oxo-4H-quinolizine-3-carboxamide;

1-{[4-(2-Bromophenyl)-4-cyanopiperidin-1-yl]methyl}-N-(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

rac-N-[(1R,2R)-2-Bromocyclohexyl)-1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-4H-quinolizine-3-carboxamide;

rac-1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(1R,2R)-2-hydroxy-2-methylcyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-N-[(1R)-2-oxocyclohexyl]-4H-quinolizine-3-carboxamide;

rac-1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(1R,2R)-2-(methylthio)cyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

rac-1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-{(1R,2R)-2-[(S)-methylsulfinyl]cyclohexyl}-4-oxo-4H-quinolizine-3-carboxamide;

rac-1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(1R,2R)-2-(methylsulfonyl)cyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-N-piperidin-3-yl-4H-quinolizine-3-carboxamide;

Methyl 4-[({1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-4H-quinolizin-3-yl}carbonyl)amino]piperidine-1-carboxylate;

rac-1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(3R,4S)-3-methyltetrahydro-2H-pyran-4-yl]-4-oxo-4H-quinolizine-3-carboxamide;

1-{[4-Cyano-4-(4-cyanopyridin-2-yl)piperidin-1-yl]methyl}-N-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

1-({4-Cyano-4-[4-(fluoromethyl)pyridine-2-yl]piperidin-1-yl}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

1-({4-Cyano-4-[4-(difluoromethyl)pyridin-2-yl]piperidin-1-yl}methyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide;

1-[(4-Cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-9-methyl-4-oxo-N-(tetrahydro-2H-pyran-4-yl)-4H-quinolizine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

21. A compound of claim 1 , which is a compound of formula (IA)

wherein R A and R B are paired from the group consisting of

R B

R A

or a pharmaceutically acceptable salt thereof.

22. A compound of claim 1 , which is a compound of formula (IB)

wherein R A and R B are paired from the group consisting of

R B

R A

or a pharmaceutically acceptable salt thereof.

23. 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.