4-Oxo-1-3-substituted phenyl-1,4-dihydro-1,8-naphthyridine-3-carboxamide phosphodiesterase-4 inhibitors

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Ar is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiadiazolyl, or imidazolyl; or oxides thereof when Ar is a heteroaryl;

Y is —COOH, or —C 1-6 alkyl(C 1-4 alkyl) n —COOH, wherein the —C 1-6 alkyl is optionally substituted with halogen, alkoxy, hydroxy or nitrile, and the (C 1-4 alkyl) substituents are optionally linked to form a C 3-4 cycloalkyl ; wherein n is 0, 1, 2, 3 or 4;

R is H or —C 1-6 alkyl;

R 1 is H, or —C 1-6 alkyl, —C 3-6 cycloalkyl, —C 1-6 alkoxy, —C 2-6 alkenyl, —C 3-6 alkynyl, heteroaryl, or heterocycle group, optionally substituted with 1-3 independent haloC 1-6 alkyl, —C 1-6 alkyl, —C 1-6 alkoxy, OH, amino, —(C 0-6 alkyl)—SO p —(C 1-6 alkyl), nitro, CN, ═N—O—C 1-6 alkyl, —O—N═C 1-6 alkyl, or halogen substituents, wherein p is 0, 1 or 2;

R 2 is H, halogen, —CN, —NO 2 , —C 1-6 alkyl, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, O—C 1-6 alkyl, O—C 3-6 cycloalkyl-C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), —C 1-6 alkoxy, phenyl, heteroaryl, heterocycle, amino, —C(O)—C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, —C 1-6 alkyl(═N—OH), —C(N═NOH)C 1-6 alkyl, —C 0-6 alkyl(oxy)C 1-6 alkyl-phenyl, —SO k NH(C 0-6 alkyl), or —(C 0-6 alkyl)-SO k —(C 1-6 alkyl), wherein the phenyl, heteroaryl or heterocycle is optionally substituted with halogen, —C 1-6 alkyl, —C 1-6 alkoxy, hydroxy, amino, or —C(O)—O—C 1-6 alkyl, and wherein the alkyl or cycloalkyl is optionally substituted with 1-6 independently selected halogens or —OH, and wherein k is 0, 1, or 2;

R 3 is selected from H, halogen, CN, —C 1-6 alkyl, —C 3-6 cycloalkyl, nitro, —C(O)—C 1-6 alkyl, —C(O)—O—C 0-6 alkyl, —SO n′ NH(C 0-6 alkyl), or —(C 0-6 alkyl)-SO n′ —(C 1-6 alkyl), O—C 1-6 alkyl, O—C 3-6 cycloalkyl, wherein n′ is 0, 1, or 2 and wherein the alkyl and cycloalkyl is optionally substituted with 1-6 independently selected halogen or OH.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, wherein

Ar is pyridyl, pyrimidyl, or oxide thereof.

3. The compound according to claim 2 , or a pharmaceutically acceptable salt, wherein

R 1 is —C 1-6 alkyl optionally substituted with 1-3 independent —C 1-6 alkyl, —C 1-6 a 1 koxy, OH, amino, —(C 0-6 alkyl)SO p —(C 1-6 alkyl), nitro, CN, ═N—O—C 1-6 alkyl, —O—N═C 1-6 alkyl, or halogen substituents.

4. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof wherein

R 1 is —C 3-6 cycloalkyl optionally substituted with 1-3 independent —C 1-6 alkyl, —C 1-6 alkoxy, OH, amino, —(C 0-6 alkyl)SO p —(C 1-6 alkyl), nitro, CN, ═N—O—C 1-6 alkyl, —O—N═C 1-6 alkyl, or halogen substituents.

5. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein

R is hydrogen.

6. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is hydrogen or .—C 1-3 alkyl or halogen.

7. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is —C 3-6 cycloalkyl optionally substituted with methyl or halo; and

R is hydrogen.

8. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof wherein

R 1 is cyclopropyl optionally substituted with methyl or halo; and

R and R 2 are hydrogen or halogen;

R 3 hydrogen or halogen.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R and R 3 are hydrogen,;

R 1 is —C 3-6 cycloalkyl optionally substituted with methyl or halo, or —C 1-3 alkyl optionally substituted with 1-3 halo; and Ar is phenyl.

10. The compound which is

2-(trans)-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-3-yl}cyclopropanecarboxylic acid;

2-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-3-yl}-2-methylpropanoic acid;

2-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-bipheny-4-yl}-2-methylpropanoic acid;

3-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-bipheny-4-yl}-3-methylbutanoic acid;

{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}(hydroxy)acetic acid;

1-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(cis)-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

5-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl }-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid;

1-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-3-yl}cyclopropanecarboxylic acid;

1-cyano-3-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1-biphenyl-4-yl}-2,2-dimethylcyclopropanecarboxylic acid;

(cis)-2-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-3-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-bromo-5′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-3-methyl-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-2-methy-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3-chloro-3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4 -carboxylic acid;

2-(trans)-{3′-[3-(morpholin-4-ylcarbonyl)-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-[4-oxo-3-({[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]amino}carbonyl)-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-[3-({[2-(methylthio)ethyl]amino}carbonyl)-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-[3-({[2-(methylsulfonyl)ethyl]amino}carbonyl)-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-(5-{3-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]phenyl}thien-2-yl)cyclopropanecarboxylic acid;

2-(trans)-{3′-[3-{[(cyclopropylmethyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid;

2-(trans)-{3′-[3-{[(1-cyanocyclopropyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H-yl]-1,1′-biphenyl-4-yl}cyclopropanecarboxylic acid; or

3-{3′-[3-[(isopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-1,1′-biphenyl-4-yl}-3-methylbutanoic acid, or a pharmaceutically acceptable salt thereof.

11. A The compound which is

(+)-(trans)-2-{3-fluoro-3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

1-({3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl]-yl}methyl)cyclobutanecarboxylic acid;

(trans)-2-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}-2-methylcyclopropanecarboxylic acid;

(trans)-2-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-2-yl}cyclopropanecarboxylic acid;

3-methyl-3-{3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H) -yl]biphenyl-4-yl}butanoic acid;

(trans)-2-{3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H) -yl]biphenyl-2-yl}cyclopropanecarboxylic acid;

(trans)-2-{3′-[4-oxo-3-{[(2,2,3,3,3-pentafluoropropyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

(trans)-2-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl }-1-fluorocyclopropanecarboxylic acid;

(+)-(trans)-2-{3-chloro-3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H) -yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

(−)-(trans)-2-{3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

(+)-(trans)-ethyl 2-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylate;

(+)-(trans)-isopropyl 2-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylate;

tert-butyl 3-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}-2,2-dimethylpropanoate;

3-{3-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}-2,2-dimethyipropanoic acid;

3-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-3-yl}-2,2-dimethyipropanoic acid;

1-({3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-3-yl}methyl)cyclobutanecarboxylic acid;

3-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-2-yl}-2,2-dimethyipropanoic acid;

1-({3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-2-yl}methyl)cyclobutanecarboxylic acid;

(+)-(trans)-2-{3′-[3-[(tert-butylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

(+)-(trans)-2-{3′-[3-[(cyclobutylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

3-{3′-]3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}bicycio[1.1.1]pentane-1-carboxylic acid;

4-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}-4-hydroxypentanoic acid;

(trans)-2-{3′-[3-{[(±)-cis-(2-fluorocyclopropyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H)yl]-(+)-biphenyl-4-yl}cyclopropanecarboxylic acid;

(+)-(trans)-2-{3′-[3-{[(dicyclopropylmethyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

4-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}-2,2-dimethylbutanoic acid;

(+)-(trans)-2-{3′-[3-{[(1-hydroxycyclopropyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

(+)-(trans)-2-{3′-[4-oxo-3-{[(1-phenylcyclopropyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

4-{3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}-3,3-dimethylbutanoic acid;

(+)-(trans)-2-{3′-[3-{[(1-cyclopropyl-1-methylethyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

1-({3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}methyl)cyclobutanecarboxylic acid;

(+)-(trans)-2-{3′-[3-{[(cyclopropylmethyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

(−)-(trans)-2-{3-fluoro-3′-[3-{[(1-hydroxycyclopropyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

(trans)-2-{3′-[4-oxo-3-{[((±)-2,2,2-trifluoro-1-methylethyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]-(+)-biphenyl-4-yl}cyclopropanecarboxylic acid;

(+)-(trans)-2-{3′-[3-{[(1-methylcyclopropyl)amino]carbonyl}-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid;

2,2-dimethyl-4-{3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}butanoic acid;

2,2-dimethyl-3-{3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}propanoic acid;

(−)-(trans)-2-{3-chloro-3′-[3-[(cyclopropylamino)carbonyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]biphenyl-4-yl}cyclopropanecarboxylic acid; or

(+)-(trans)-2-{3′-[4-oxo-3-{[(2,2,2-trifluoroethyl)amino]carbonyl}-1,8-naphthyridin-1(4H) -yl]biphenyl-4-yl}cyclopropanecarboxylic acid, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition

comprising

a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.