Benzyl-substituted quinolone M1 receptor positive allosteric modulators

1. A compound of formula (I):

and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein

R 1 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-6 alkyl, and

wherein said R 1 alkyl moiety is optionally substituted with one or more

(a) halogen,

(b) cyano, and

(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo;

R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) halogen,

wherein said R 2 , R 3 , R 4 and R 5 alkyl is optionally substituted with one or more

(a) halogen,

(b) hydroxy, and

(c) —O—C 1-6 alkyl;

provided that when R 2 is hydrogen and R 3 is fluorine then R 4 cannot be chlorine;

R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of

(1) hydrogen, and

(2) halogen;

HET is selected from the group consisting of

wherein X 1 , X 2 , X 3 , X 4 and X 5 together form a 5- or 6-membered aromatic ring, wherein each of X 1 , X 2 , X 3 , X 4 and X 5 is independently selected from the group consisting of

(1) CR 12 ,

(2) N,

(3) NR 13 ,

(4) O, and

(5) S,

provided that X 4 may alternatively be a bond,

and further provided that two R 12 groups, or one R 12 group and one R 13 group, when positioned at neighboring X atoms on the ring, may be linked together to form a group selected from

(1) —O—CH 2 —CH 2 —O—,

(2) —CR 14 ═CR 14 —CR 14 ═CR 14 —, and

(3) —NR 15 —CR 14 ═CR 14 —, or

wherein X 6 is selected from the group consisting of

(1) CR 14 R 14′ ,

(2) NR 15 , and

(3) O;

provided that when p is O, X 6 is CR 14 R 14′ ;

R 12 are selected from the group consisting of

(1) hydrogen,

(2) C 1-6 alkyl,

(3) —O—C 1-6 alkyl,

(4) cyano,

(5) halogen, and

(6) —(CH 2 ) m -aryl,

wherein said R 12 alkyl or aryl moiety is optionally substituted with one or more

(a) halogen,

(b) cyano,

(c) —C 1-6 alkyl, and

(d) —O—C 1-6 alkyl,

wherein said alkyl moiety is optionally substituted with one or more halo;

R 13 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-6 alkyl,

wherein said alkyl and cycloalkyl R 13 moiety is optionally substituted with one or more

(a) halogen,

(b) cyano, or

(c) hydroxy;

R 14 and R 14′ are independently selected from the same group as R 12 and R 12′ ;

R 15 is selected from the same group as R 13 ;

m is 1, 2, 3 or 4; and

p is 0, 1 or 2.

2. A compound of claim 1 , and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein R 1 is hydrogen.

3. A compound of claim 1 , and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen and halogen.

4. A compound of claim 3 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof wherein R 6 , R 7 , R 8 and R 9 are hydrogen.

5. A compound of claim 3 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein R 8 is halogen, and R 6 , R 7 , and R 9 are hydrogen.

6. A compound of claim 1 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein HET is

7. A compound of claim 6 w and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein each of X 1 , X 2 , X 3 , X 4 and X 5 is CR 12 , wherein R 12 is selected from the group consisting of hydrogen, halogen, cyano, —O—C 1-6 alkyl or optionally substituted —C 1-6 alkyl.

8. A compound of claim 6 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein one of X 1 , X 2 , X 3 , X 4 and X 5 is N and the others are each CR 12 , wherein R 12 is selected from the group consisting of hydrogen, halogen, cyano or optionally substituted C 1-6 alkyl.

9. A compound of claim 6 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein two of X 1 , X 2 , X 3 , X 4 and X 5 are N and the others are each CR 12 , wherein R 12 is selected from the group consisting of hydrogen, halogen, cyano or optionally substituted C 1-6 alkyl.

10. A compound of claim 6 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein the X 1 , X 2 , X 3 , X 4 , X 5 group is selected from the group consisting of

11. A compound of claim 6 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein X 4 is a bond, and one of X 1 , X 2 , X 3 and X 5 is N, one is NR 13 , and the others are each CR 12 , wherein R 12 is selected from the group consisting of hydrogen, halogen, cyano or optionally substituted C 1-6 alkyl.

12. A compound of claim 6 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein the X 1 , X 2 , X 3 , X 4 , X 5 group is selected from the group consisting of

13. A compound of claim 6 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein two R 12 groups, or one R 12 group and one R 13 group, when positioned at neighboring X atoms on the ring, are linked together to form a group selected from

(1) —O—CH 2 —CH 2 —O—,

(2) —CR 14 ═CR 14 —CR 14 ═CR 14 —, and

(3) —NR 15 —CR 14 ═CR 14 —.

14. A compound of claim 13 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein the X 1 , X 2 , X 3 , X 4 , X 5 group is selected from the group consisting of

15. A compound of claim 1 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein HET is

16. A compound of claim 15 and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof, wherein p is 2 and X 6 is selected from the group consisting of

(1) CR 14 R 14′ ,

(2) NR 15 , or

(3) O.

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

1-[4-(6-chloropyridin-3-yl)-2-fluorobenzyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-(2-fluoro-4-(1-propyl-1H-pyrazol-4-yl)benzyl)-5-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8-fluoro-1-{4-[6-(dimethylamino)pyridin-3-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-(biphenyl-4-ylmethyl)-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-(biphenyl-4-ylmethyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-(biphenyl-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-(biphenyl-4-ylmethyl)-5-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[(2′-fluorobiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[(3′-fluorobiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[(4′-methoxybiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-4-oxo-1-{[4′-(trifluoromethyl)biphenyl-4-yl]methyl}-1,4-dihydroquinoline-3-carboxylic acid;

1-[4-(5-fluoropyridin-2-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[(3-chlorobiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[(3-fluorobiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[(2′-cyanobiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[(3-fluorobiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[(3-fluorobiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[2-fluoro-4-(6-methoxypyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[2-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluorobenzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[2-fluoro-4-(1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[2-fluoro-4-(2-fluoropyridin-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[2-fluoro-4-(3-fluoropyridin-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[2-fluoro-4-(2-methoxypyrimidin-5-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-fluorobenzyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[4-(1-benzofuran-2-yl)-2-fluorobenzyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[2-fluoro-4-(1H-indol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-{2-fluoro-4-[6-(dimethylamino)pyridin-3-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[2-fluoro-4-(3-fluoropyridin-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[2-fluoro-4-(6-fluoropyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-(2-fluoro-4-pyrimidin-5-ylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[2-fluoro-4-(2-fluoropyridin-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-[2-fluoro-4-(5-methoxypyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-1-(2-fluoro-4-pyridin-3-ylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[(4′-methoxybiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-1-[(4′-methoxybiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-1-[2-fluoro-4-(1-isobutyl-1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-1-[2-fluoro-4-(1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-1-[2-fluoro-4-(1-propyl-1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-1-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[(4′-methoxybiphenyl-4-yl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5,8-difluoro-4-oxo-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;

4-oxo-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-4-oxo-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-4-oxo-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[4-(1-isobutyl-1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-{4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[4-(6-methoxypyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[2-fluoro-4-(1-propyl-1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[2-fluoro-4-(6-methoxypyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-(4-{6-[(2-hydroxyethyl)amino]pyridin-3-yl}benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-4-oxo-1-(4-pyridin-3-ylbenzyl)-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[4-(6-morpholin-4-ylpyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[2-fluoro-4-(1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[4-(1-benzyl-1H-pyrazol-4-yl)-2-fluorobenzyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[4-(6-fluoropyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[4-(6-chloropyridin-3-yl)benzyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-{4-[6-(dimethylamino)pyridin-3-yl]benzyl}-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[4-(6-azetidin-1-ylpyridin-3-yl)benzyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-[4-(6-chloropyridin-3-yl)benzyl]-5-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-{2-fluoro-4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-1-[4-(6-fluoropyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-4-oxo-1-[4-(6-pyrrolidin-1-ylpyridin-3-yl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;

8-fluoro-1-[2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

4-oxo-5-piperazin-1-yl-1-[4-(6-piperazin-1-ylpyridin-3-yl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;

5-morpholin-4-yl-1-[4-(6-morpholin-4-ylpyridin-3-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-(methylamino)-1-{4-[6-(methylamino)pyridin-3-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-1-{4-[6-(methylamino)pyridin-3-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-1-(4-{6-[(2-hydroxyethyl)amino]pyridin-3-yl}benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

5-fluoro-4-oxo-1-(4-pyridin-3-ylbenzyl)-1,4-dihydroquinoline-3-carboxylic acid;

and enantiomers and diastereomers thereof, and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.