Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors

1. A compound represented by the structural formula

or a pharmaceutically acceptable salt thereof, wherein

R is H or alkyl;

X is O or S;

R 1 is H, alkyl, cycloalkyl, cycloalkyl(C 1 -C 4 )alkyl-, —CH 2 F, —CHF 2 , —CF 3 , —C(O)alkyl or —C(O)NR 18 R 19 ;

R 3 and R 4 are independently selected from the group consisting of H, alkyl, hydroxyalkyl and —C(O)Oalkyl;

R 5 and R 6 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, mercaptoalkyl, —CH 2 F, —CHF 2 , —CF 3 , —C(O)OH, —C(O)Oalkyl and —C(O)NR 43 R 44 ;

t is 1 or 2;

R 7 is H, alkyl, alkenyl, hydroxyalkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, (R 17 -phenyl)alkyl or —CH 2 —C(O)—O-alkyl;

R 8 is H, alkyl, alkenyl, alkoxy, alkoxyalkyl, hydroxyalkyl, dihydroxyalkyl, alkyl-NR 18 R 19 , cyanoalkyl, haloalkyl, R 23 -heteroaryl, R 23 -heteroarylalkyl, R 36 -heterocycloalkyl, (R 36 -heterocycloalkyl)alkyl, R 17 -phenyl, (R 17 -phenyl)alkyl, R 17 -naphthyl, (R 17 -naphthyl)alkyl, R 17 -benzyloxy, -alkyl-C(O)—NR 18 R 19 , -alkyl-C(O)—N(R 30 )—(R 23 -heteroaryl), -alkyl-C(O)—(R 17 -phenyl), -alkyl-C(O)—(R 36 -heterocycloalkyl); -alkyl-N(R 30 )—C(O)Oalkyl, -alkyl-N(R 30 )—C(O)—NR 18 R 19 , -alkyl-N(R 30 )—C(O)alkyl, -alkyl-N(R 30 )—C(O)-(fluoroalkyl), -alkyl-N(R 30 )—C(O)—(R 39 -cycloalkyl), -alkyl-N(R 30 )—C(O)—(R 17 -phenyl), -alkyl-N(R 30 )—C(O)—(R 23 -heteroaryl), -alkyl-N(R 30 )—C(O)-alkylene-(R 23 -heteroaryl), -alkyl-NH—SO 2 —NR 18 R 19 , -alkyl-N(R 30 )—(R 17 -phenyl), -alkyl-N(R 30 )—(R 23 -heteroaryl), -alkyl-O—(R 17 -phenyl), -alkyl-O—(R 23 -heteroaryl), -alkyl-N(R 30 )—SO 2 -alkyl, alkylthioalkyl-, alkyl-SO 2 -alkyl-, (R 35 -phenylalkyl)-S-alkyl-, (hydroxyalkyl)-S-alkyl-, (alkoxyalkyl)-S-alkyl-, -alkyl-CO 2 -alkyl, R 45 -hydroxyalkyl, dihydroxyalkyl substituted by R 17 -benzyloxy, dihydroxyalkyl substituted by R 17 -phenyl, alkoxyalkyl substituted by R 17 -phenyl, (R 17 -phenyl)alkyl substituted by —CO 2 alkyl, (R 17 -phenyl)alkyl substituted by —C(O)N(R 30 ) 2 , alkyl substituted by (R 23 -heteroaryl) and —C(O)NR 37 R 38 , haloalkyl substituted by CO 2 alkyl, R 12 -cycloalkyl, (R 12 -cycloalkyl)alkyl,

or R 7 and R 8 and the nitrogen to which they are attached together form a ring system selected from the group consisting of

comprises an R 35 -substituted 5 or 6-membered heteroaryl group fused to the piperidinyl or pyrrolidinyl ring;

p is 0 or 1;

q is 0 or 1;

the dotted line represents an optional double bond;

R 9 is H, halo, alkyl, cycloalkyl, —CH 2 F, —CHF 2 or CF 3 ;

R 10 , R 11 , and R 13 are independently selected from the group consisting of H and halo;

R 12 is 1-3 substituents independently selected from the group consisting of H, alkyl, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, —C(O)Oalkyl, —(CH 2 ) n —N(R 30 )—C(O)-cycloalkyl, —(CH 2 ) n —N(R 30 )—C(O)alkyl, —(CH 2 ) n —N(R 30 )C(O)Oalkyl, —(CH 2 ) n —N(R 30 )—(R 23 -heteroaryl), —(CH 2 ) n —N(R 30 )—C(O)—NR 18 R 19 , —(CH 2 ) n —C(O)—NR 18 R 19 , R 17 -phenyl, R 35 -heteroarylalkyl, R 35 -heteroaryloxy, —C(O)-heterocycloalkyl, —O—C(O)-heterocycloalkyl, —O—C(O)—NR 18 R 19 , —NH—SO 2 -alkyl, —NH—C(═NH)NH 2 , and

or two R 12 substituents on the same carbon form ═O, ═NOR 30 or ═CH 2 ;

R 14 is 1 or 2 substituents independently selected from the group consisting of H, OH, halo, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, —CF 3 , CN, R 17 -phenyl, (R 17 -phenyl)alkyl, —NR 18 R 19 , alkyl-NR 18 R 19 , —(CH 2 ) n —C(O)OH, —(CH 2 ) n —C(O)Oalkyl, —(CH 2 ) n —C(O)alkyl, —(CH 2 ) n —C(O)(R 35 -phenyl), —(CH 2 ) n —C(O)(R 23 -heteroaryl), —(CH 2 ) n —C(O)NR 18 R 19 , (CH 2 ) n —C(O)N(R 30 )—(CH 2 ) n —(R 23 -heteroaryl), —(CH 2 ) n —N(R 30 )—C(O)alkyl, —(CH 2 ) n —N(R 30 )—C(O)-(fluoroalkyl), —(CH 2 ) n —N(R 30 )—C(O)-(cycloalkyl), —(CH 2 ) n —N(R 30 )—C(O)(R 35 -phenyl), —(CH 2 ) n —N(R 30 )—C(O)(R 23 -heteroaryl), —(CH 2 ) n —N(R 30 )C(O)NR 18 R 19 , —(CH 2 ) n —N(R 30 )—C(O)Oalkyl, —(CH 2 ) n —N(R 30 )cycloalkyl, —(CH 2 ) n —N(R 30 )(R 17 -phenyl), —(CH 2 ) n —N(R 30 )(R 23 -heteroaryl), —(CH 2 ) n —N(R 18 )SO 2 alkyl, —(CH 2 ) n —N(R 20 )SO 2 —(R 17 -phenyl), —(CH 2 ) n —N(R 30 )SO 2 —CF 3 , —CH 2 S(O) 0-2 (R 35 -phenyl), —(CH 2 ) n —OC(O)N(R 30 )alkyl, R 23 -heteroaryl, (R 23 -heteroaryl)alkyl, (R 23 -heteroaryl)oxy, (R 23 -heteroaryl)amino, —CH(OH)—(R 17 -phenyl), —CH(OH)—(R 23 -heteroaryl), —C(═NOR 30 )—(R 17 -phenyl), —C(═NOR 30 )—(R 23 -heteroaryl), morpholinyl, thiomorpholinyl,

w is 0 or 1;

or two R 14 substituents and the carbon to which they are both attached form —C(═NOR 30 )— or —C(O)—;

each n is independently 0, 1, 2 or 3;

R 15 is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, —C(O)Oalkyl, —C(O)O(R 30 -cycloalkyl), -alkyl-C(O)O-alkyl, —C(O)O-alkylene-(R 35 -phenyl), R 17 -phenyl, (R 17 -phenyl)alkyl, —CH—(R 17 -phenyl) 2 , R 23 -heteroaryl, —(CH 2 ) n —C(O)NR 18 R 19 , —SO 2 -alkyl, —SO 2 -cycloalkyl, —SO 2 —CF 3 , —SO 2 —(R 35 -phenyl), —SO 2 —NR 18 R 19 , —C(O)alkyl, —C(O)-(fluoroalkyl), —C(O)—C(CH 3 )(CF 3 ) 2 , —C(O)—(R 17 -phenyl), —C(O)—(R 23 -heteroaryl), —C(O)-hydroxyalkyl, —C(O)alkoxyalkyl, —C(O)—(R 39 -cycloalkyl), —C(O)-alkylene-(R 17 -phenyl), —C(O)-alkylene-R 23 -heteroaryl), —C(O)-alkylene-S—C(O)alkyl, —C(═S)—(R 17 -phenyl), hydroxyalkyl substituted by R 17 -phenyl, hydroxyalkyl substituted by R 23 -heteroaryl, alkoxyalkyl substituted by R 17 -phenyl, alkoxyalkyl substituted by R 23 -heteroaryl,

wherein z is 0, 1 or 2;

R 16 is 1 to 4 substituents independently selected from the group consisting of H, alkyl, R 17 -phenyl, (R 17 -phenyl)alkyl, (R 23 -heteroaryl)alkyl, hydroxyalkyl, alkoxyalkyl and —(O)Oalkyl, or two R 16 groups and the carbon to which they are both attached form —C(O)—;

R 17 is 1 to 3 substituents independently selected from the group consisting of H, halo, alkyl, cycloalkyl, —OH, hydroxyalkyl, alkoxy, alkoxyalkyl, —CN, —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —C(O)OH, —C(O)Oalkyl, —C(O)O—(R 36 -phenyl), —C(O)alkyl, —C(O)—(R 35 -phenyl), —SOalkyl, —SO 2 alkyl, —O 2 —CF 3 , alkylthio, —NR 43 R 44 , -alkyl-NR 43 R 44 , R 35 -phenyl, R 35 -phenoxy, R 35 -heteroaryl, R 35 -heteroaryloxy, R 36 -heterocycloalkyl, —C(O)—(R 36 -heterocycloalkyl), hydroxyalkyl-NH—, —C(O)N(R 30 ) 2 , —N(R 43 )—(R 35 -cycloalkyl) and —C(═NOR 30 ); or two R 17 substituents on adjacent carbon atoms together form —O—CH 2 —O—, —O—(CH 2 ) 2 —O—, —(CH 2 ) 2 —O— or —O—CH 2 —O—CH 2 —;

R 18 and R 19 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, R 17 -phenyl, (R 17 -phenyl)alkyl, naphthyl and cycloalkyl;

R 20 is H, alkyl, or cycloalkyl;

R 22 is 1 to 4 substituents independently selected from the group consisting of H, alkyl, hydroxy, alkoxy, halo, —CF 3 , —NH 2 and R 35 -phenyl;

R 23 is 1 to 4 substituents independently selected from the group consisting of H, alkyl, hydroxy, alkoxy, halo, —CF 3 , —NR 18 R 19 , —CN, —C(O)Oalkyl, —SO 2 -alkyl, —NHSO 2 -alkyl, R 35 -phenyl, R 35 -heteroaryl, morpholinyl, and —(CH 2 ) n —C(O)—N(R 30 ) 2 ;

R 24 is H, OH or alkoxy; or when the optional double bond is present, R 24 and the adjacent carbon atom form the double bond;

R 25 is H or R 35 -phenyl;

R 27 is 1 to 3 substituents independently selected from the group consisting of H, halo, OH, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, —CN, —C(O)OH, —C(O)Oalkyl, —C(O)N(R 30 )(R 18 ), —C(O)—(R 36 -hetercycloalkyl), R 17 -phenyl, (R 17 -phenyl)-alkyl, R 23 -heteroaryl, (R 23 -heteroaryl)alkyl, (R 23 -heteroaryl)oxy, (R 23 -heteroaryl)amino NR 18 R 19 , NR 18 R 19 -alkyl, —(CH 2 ) n —N(R 30 )—C(O)alkyl, —(CH 2 ) n —N(R 30 )—C(O)-(fluoroalkyl), —(CH 2 ) n —N(R 30 )—C(O)alkoxyalkyl, —(CH 2 ) n —N(R 30 )—C(O)(cycloalkyl), —(CH 2 ) n —N(R 30 )—(R 23 -heteroaryl), —(CH 2 ) n —N(R 30 )—C(O)—(R 23 -heteroaryl), —(CH 2 ) n —N(R 30 )—C(O)O-alkyl, —(CH 2 ) n —N(R 30 )—C(O)O—(CF 3 alkyl), —(CH 2 ) n —N(R 30 )—C(O)O—(R 39 -cycloalkyl), —(CH 2 ) n —N(R 30 )—C(O)O-alkylene-cycloalkyl, —(CH 2 ) n —N(R 30 )—C(O)—N(R 30 )(R 20 ), —(CH 2 ) n —N(R 30 )—SO 2 -alkyl, —(CH 2 ) n —N(R 30 )—SO 2 —CF 3 , —(CH 2 ) n —N(R 30 )—SO 2 —N(R 30 ) 2 and

or two R 27 groups and the carbon to which they are both attached form —C(═NOR 30 )— or —C(O)—;

R 28 is H, alkyl, R 35 -benzyl or -alkyl-C(O)O-alkyl;

R 29 is alkyl, haloalkyl, —C(O)Oalkyl, —C(O)alkyl, —C(O)CF 3 , —C(O)—(R 12 -cycloalkyl), —C(O)—(R 17 -phenyl), —C(O)—(R 23 -heteroaryl), —C(O)—(R 36 -hetercycloalkyl), —SO 2 -alkyl, —SO 2 —(R 35 -phenyl), —C(O)NR 18 R 19 , R 35 -phenyl, (R 35 -phenyl)alkyl or R 23 -heteroaryl;

R 30 is independently selected from the group consisting of H, alkyl, R 35 -benzyl and R 35 -phenyl;

R 31 is H, alkyl, R 36 -benzyl or phenoxyalkyl;

R 33 is H, OH or alkoxy;

R 34 is H, alkyl, hydroxyalkyl, alkoxyalkyl or —C(O)Oalkyl;

R 35 is 1 to 3 substituents independently selected from the group consisting of H, halo, alkyl, OH, —CF 3 , alkoxy, —CO 2 alkyl and —N(R 43 )(R 44 );

R 36 is 1 or 2 substituents independently selected from the group consisting of H, alkyl, R 17 -phenyl, —OH, hydroxyalkyl, alkoxyalkyl, —C(O)Oalkyl and —NR 18 R 19 ; or two R 36 groups and the carbon to which they are both attached form —C(═NOR 30 )— or —C(O)—;

R 37 and R 38 are independently selected from the group consisting of H and alkyl, or R 37 and R 38 together are —(CH 2 ) 3 — or —(CH 2 ) 4 —, and together with the nitrogen to which they are attached, form a ring;

R 39 is H, OH, alkyl, alkoxy, or CF 3 ;

R 40 is —OR 30 or —NHC(O)alkyl;

R 41 is H or —SO 2 alkyl;

R 42 is —(CH 2 ) n —(R 35 -phenyl), —(CH 2 ) n —(R 23 -heteroaryl), —C(O)Oalkyl or —C(O)alkyl;

R 43 and R 44 are independently selected from the group consisting of H and alkyl; and

R 45 is 1 or 2 substituents independently selected from the group consisting of halo, alkoxyalkyl, —CO 2 alkyl, R 17 -phenyl, R 23 -heteroaryl and cycloalkyl.

2. A compound of claim 1 wherein X is O.

3. A compound of claim 2 wherein

4. A compound of claim 3 wherein R 10 , R 11 and R 13 are each H; R 1 is H, alkyl, cycloalkyl or —CF 3 ; and R 9 is H, alkyl or —CF 3 .

5. A compound of claim 4 wherein R 10 , R 11 and R 13 are each H, R 1 is alkyl, and R 9 is —CF 3 .

6. A compound of claim 5 wherein t is 1, R 5 is H, R 6 is H, alkyl or hydroxyalkyl, and R 3 and R 4 are each H or alkyl.

7. A compound of claim 6 wherein R 7 is H, alkyl, cycloalkyl, hydroxyalkyl or alkoxyalkyl, and R 8 is R 12 -cycloalkyl, (R 12 -cycloalkyl)alkyl, R 45 -hydroxyalkyl, R 17 -phenyl, (R 17 -phenyl)alkyl, R 23 -heteroaryl, (R 23 -heteroaryl)alkyl, -alkyl-N(R 30 )—C(O)—NR 18 R 19 , -alkyl-N(R 30 )—C(O)alkyl, -alkyl-N(R 30 )—C(O)—(R 17 -phenyl), -alkyl-N(R 30 )—C(O)—(R 23 -heteroaryl), -alkyl-N(R 30 )—(R 23 -heteroaryl),

8. A compound of claim 7 wherein R 8 is R 12 -cycloalkyl, R 45 -hydroxyalkyl, (R 17 -phenyl)alkyl, R 23 -heteroaryl, (R 23 -heteroaryl)alkyl, -alkyl-N(R 30 )—(R 23 -heteroaryl), -alkyl-N(R 30 )—C(O)alkyl,

wherein p is 0, or

wherein p is 1.

9. A compound of claim 8 wherein R 12 is OH, —(CH 2 ) n —N(R 30 )—C(O)-cycloalkyl Or —(CH 2 ) n —N(R 30 )—(R 23 -heteroaryl), R 45 is R 17 -phenyl, or R 29 is heteroaryl, —C(O)alkyl or —C(O)cycloalkyl.

10. A compound of claim 6 wherein R 7 and R 8 and the nitrogen to which they are attached form

11. A compound of claim 10 wherein R 7 and R 8 form

the optional double bond is not present, and R 14 is selected from the group consisting of H, OH, alkoxy, —(CH 2 ) n —N(R 30 )(R 23 -heteroaryl), R 23 -heteroaryl and (R 23 -heteroaryl)-alkyl; or wherein R 7 and R 8 form

R 15 is selected from the group consisting of alkyl, R 17 -phenyl, R 23 -heteroaryl, —C(O)alkyl, —C(O)(fluoroalkyl), —C(O)—(R 23 -heteroaryl), —C(O)-alkoxyalkyl, —C(O)—(R 38 -cycloalkyl), —SO 2 -alkyl, —SO 2 —NR 18 R 19 and

and R 16 is selected from the group consisting of H and alkyl, or two R 16 groups and the carbon to which they are attached form —C(O)—.

12. A compound of claim 10 wherein R 7 and R 8 form

q is 1, and R 27 is 1, 2 or 3 substituents independently selected from the group consisting of H, OH, alkyl, alkoxy, alkoxyalkyl, R 17 -phenyl, —C(O)OH, —C(O)Oalkyl, R 23 -heteroaryl, (R 23 -heteroaryl)amino and —(CH 2 ) n —N(R 30 )—C(O)(cycloalkyl) wherein n is 0.

13. A compound of claim 10 wherein R 7 and R 8 form

wherein p is 0, R 34 is H, and R 35 is 1 or 2 substituents independently selected from the group consisting of H, OH, halo and alkyl.

14. A compound of claim 10 wherein R 7 and R 8 form

wherein p is 0, B is a pyrazolyl or thiazolyl ring, and R 35 is 1 or 2 substituents independently selected from the group consisting of H and alkyl.

15. A compound of claim 7 wherein R 7 is H or alkyl and R 8 is (R 17 -phenyl)alkyl, R 45 -hydroxyalkyl or -alkyl-N(R 30 )—(R 23 -heteroaryl), wherein R 45 is R 17 -phenyl; heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzothienyl or benzofuranyl; R 17 is 1 to 3 substituents independently selected from the group consisting of halogen, OH, alkoxy and alkyl; and R 23 is 1 or 2 substituents independently selected from the group consisting of H, alkyl, alkoxy and halogen.

16. A compound of claim 1 selected from the group consisting of

17. The compound of claim 1 having the formula

18. The compound of claim 1 having the formula

19. The compound of claim 1 having the formula

20. The compound of claim 1 having the formula

21. The compound of claim 1 having the formula

22. The compound of claim 1 having the formula

23. The compound of claim 1 having the formula

24. The compound of claim 1 having the formula

25. The compound of claim 1 having the formula

26. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

27. A method of treating a PDE4 mediated disease, where the disease is selected from COPD asthma, depression or multiple sclerosis comprising administering an effective amount of a compound of claim 1 to a patient in need of such treatment.

28. The method of claim 27 for treating dermatitis in dogs.

29. The method of claim 27 further comprising administering to said patient the compound of formula I in combination with at least one other medicament selected from the group consisting of disease modifying antirheumatic drugs, nonsteroidal anitinflammatory drugs, COX-2 selective inhibitors, COX-1 inhibitors, Immunosuppressives, steroids, biological response modifiers and other anti-inflammatory agents or therapeutics useful for the treatment of PDE4 mediated diseases.