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 —C 3-4 cycloalkyl(C 1-4 alkyl) m —COOH, wherein the C 3-4 cycloalkyl 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, m is 0, 1 or 2;

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 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. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Y is cyclopropyl-COOH;

Ar is phenyl,

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.

3. 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.

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

R is hydrogen.

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

R 2 is hydrogen or —C 1-3 alkyl.

6. 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.

7. 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.

8. A compound represented by Formula (I):

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;

R 2 is hydrogen or halo; and

Y is —CH 3 —C 3-4 cycloalkyl —COOH or —C 3-4 cycloalkyl —COOH.

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

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 1-6 alkyl, —SO n′ NH(C 0-6 alkyl), or —(C 1-6 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.

10. A compound which is:

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising

a therapeutically effective amount of the compound according to claim 10 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

12. A compound which is

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

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising

a therapeutically effective amount of the compound according to claim 12 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

14. A compound which is

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

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising

a therapeutically effective amount of the compound according to claim 14 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.