US 7,482,456 B2
8-(3-Biaryl)phenylquinoline phosphodiesterase-4 inhibitors
Daniel Dube, St-Lazare (Canada); Laurence Dube, Ste-Dorothée (Canada); Michel Gallant, Kirkland (Canada); Patrick Lacombe, Montreal (Canada); Denis Deschenes, Dorval (Canada); and Dwight Macdonald, L'lle Bizard (Canada)
Assigned to Merck Frosst Canada, Kirkland, Quebec (US)
Appl. No. 10/554,176
PCT Filed Apr. 27, 2004, PCT No. PCT/CA2004/000622
§ 371(c)(1), (2), (4) Date Oct. 21, 2005,
PCT Pub. No. WO2004/096220, PCT Pub. Date Nov. 11, 2004.
Claims priority of provisional application 60/466542, filed on Apr. 30, 2003.
Prior Publication US 2006/0223850 A1, Oct. 05, 2006
Int. Cl. C07D 215/38 (2006.01)
U.S. Cl. 546—159  [546/153] 25 Claims
 
1. A compound represented by Formula (I):

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt, wherein
S1, S2, and S3 are independently
1. H,
2. —OH,
3. halogen,
4. —C1-C6alkyl,
5. —O—C1-C6alkyl optionally substituted with 1, 2 or 3 halogens, or —CN;
R1 is
1. —(C1-C6alkyl)-SOn—(C1-C6alkyl) group, optionally substituted with 1, 2 or 3 substituents; wherein each substituent is independently a halogen, —OH and —CN,
2. —C(O)—O-aryl,
3. —C(O)—NH-aryl,
4. —C(O)—NH-heterocycle or N-oxide thereof,
5. —C(O)—NH—C1-C6alkyl,
6. —C(O)—NH-cycloC3-C6alkyl,
7. —C1-C6alkyl, optionally substituted with 1 to 6 halogens and 1 hydroxy,
8. —COOH,
9. —C1-C6alkyl-COOH,
10. —O—C1-C6alkyl,
11. -cycloC3-C6alkyl,
12. —C3-C6alkyl-heterocycle,
13. aryl,
14. heterocycle,
15. carbonyl,
16. carbamoyl, or
17. —SOn—(C1-C6alkyl);
each n is independently 0, 1, or 2;
Ar1 and Ar2 are each independently an aryl or heterocycle or an N-oxide thereof;
R2 is
1. Hydrogen,
2. aryl optionally substituted with 1, 2 or 3 substituents selected from halogen,
3. heterocycle optionally substituted with 1, 2 or 3 halogens,
4. —C1-C6alkyl optionally substituted with 1, 2 or 3 substituents selected from hydroxy and halogen,
5. —COOH,
6. 1, 2 or 3 halogens,
7. —SOn—(C1-C6alkyl),
8. —N(H)—S(O)n—C1-C6alkyl,
9. —O—C1-C6alkyl substituents each optionally substituted with 1, 2 or 3 halogens,
10. —C(O)—N(H)—C3-C6cycloalkyl, or
11. —C(O)—C1-C6alkyl;
R3 is
1. Hydrogen,
2. —C1-C6alkyl optionally substituted with hydroxy, —S(O)nC1-C6alkyl, heterocycle, or 1, 2, 3, 4, 5 or 6 halogens,
3. aryl or C6-C12cycloalkyl optionally substituted with phenyl, —C1-C6alkyl, —S(O)nC1-C6alkyl, —C(O)—O—C1-C6alkyl, —COOH, hydroxy-C1-C6alkyl- or 1, 2 or 3 halogens,
4. heterocycle or optionally substituted with 1, 2 or 3 substituents independently selected from phenyl, halogen, C1-C6alkyl, hydroxyC1-C6alkyl, —COOH, —C(O)—O—C1-C6alkyl,
5. amino,
6. —C(O)—O—C1-C6alkyl,
7. —C1-C6alkyl-O-phenyl optionally substituted with 1, 2 or 3 halogens,
8. —C1-C6alkyl-phenyl optionally substituted with 1 or 2 substituents selected from hydroxy and halo,
9. —COOH,
10. Halogen,
11. —SOn—(C1-C6alkyl),
12. —N(H)—S(O)n—C1-C6alkyl optionally substituted with 1, 2 or 3 halogen,
13. —N(H)—C(O)—C1-C6alkyl,
14. —N(H)-heterocycle optionally substituted with 1, 2 or 3 halogens,
15. —N(H)-aryl optionally substituted with 1, 2 or 3 halogens,
16. —N(H)—C1-C6alkyl optionally substituted with 1, 2 or 3 halogens,
17. —C(O)—N(H)—C1-C6alkyl optionally substituted with 1, 2 or 3 halogens,
18. —C(O)—NH—C3-C6cycloalkyl,
19. —O—C1-C6alkyl optionally substituted with 1, 2 or 3 halogens or phenyl optionally substituted with 1, 2, or 3 halogen;
R4 is
1. H,
2. Halogen,
3. —CN
4. —C1-C6alkyl,
5. —O—C1-C6alkyl optionally substituted with 1, 2 or 3 halogens,
6. —C1-C6alkyl-phenyl with phenyl optionally substituted with halogen, or
7. Oxo.