Tetrahydropyranyl cyclopentyl benzylamide modulators of chemokine receptor activity
View Patent ↗The present invention is directed to compounds of the formula (I) (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 27 , R 28 , R 29 , R 30 , R 31 , X, m, n and the dashed line are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2
1. A compound of the formula I:
wherein:
X is selected from the group consisting of:
—O—, —NR 20 —, —S—, —SO—, —SO 2 —, and —CR 21 R 22 —, —NSO 2 R 20 —, —NCOR 20 —, —NCO 2 R 20 —, —CR 21 CO 2 R 20 —, —CR 21 OCOR 20 —, —CO—, —O—C(CH 3 ) 2 —O—,
where R 20 is selected from: hydrogen, C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl,
where R 21 and R 22 are independently selected from: hydrogen, hydroxy, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or subsituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 1 is selected from:
—C 1-6 alkyl, —C 0-6 alkyl—O—C 1-6 alkyl, —C 0-6 alkyl-S—C 1-6 alkyl, —C 0-6 alkyl-SO 1-2 —C 1-6 alkyl, —C 0-6 alkyl-SO 2 —NR 26 —C 1-6 alkyl, —(C 0-6 alkyl)—(C 3-7 cycloalkyl)-(C 0-6 alkyl), hydroxy, —CO 2 R 20 , heterocycle, —CN, —NR 20 R 26 , —NR 26 SO 2 R 20 , —NR 26 COR 21 , —OCOR 20 , and phenyl,
where R 26 is selected from: hydrogen, C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl,
where the alkyl and the cycloalkyl are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from: halo, hydroxy, —O—C 1-3 alkyl, trifluoromethyl, C 1-3 alkyl, —O—C 1-3 alkyl, —CO 2 R 20 , —SO 2 R 20 , —NHCOCH 3 , —NHSO 2 CH 3 , -heterocycle, ═O, and —CN,
and where the phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy and trifluoromethyl;
R 2 is selected from: hydrogen, C 1-6 alkyl, trifluoromethyl trifluoromethoxy, chloro, bromo, and phenyl;
R 3 is selected from: hydrogen, hydroxy, halo, C 1-6 alkyl, —O—C 1-6 alkyl, —NR 20 R 21 , —NR 20 CO 2 R 21 , —NR 20 CONR 20 R 21 , —NR 20 —SO 2 —NR 20 R 21 , —NR 20 —SO 2 —R 21 , heterocycle, —CN, —CONR 20 R 21 , —CO 2 R 20 , —NO 2 , —S—R 20 , —SO—R 20 , —SO 2 —R 20 , and —SO 2 —NR 20 R 21 ;
R 4 is selected from: hydrogen, C 1-6 alkyl, trifluoromethyl, trifluoromethoxy, chloro, bromo, and phenyl;
R 5 is selected from: C 1-6 alkyl substituted with 1-6 fluoro and optionally substituted with hydroxyl, —O—C 1-6 alkyl substituted with 1-6 fluoro, —CO—C 1-6 alkyl substituted with 1-6 fluoro, —S—C 1-6 alkyl, -pyridyl, fluoro, chloro, bromo, and phenyl;
R 6 is selected from: hydrogen, C 1-6 alkyl, trifluoromethyl, trifluoromethoxy, chloro, bromo, and phenyl;
R 7 is selected from: hydrogen, C 1-6 alkyl, and trifluoromethyl;
R 8 is selected from: hydrogen, C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 substituents where the substituents are chosen from the group: fluoro, C 1-3 alkoxy, hydroxy, —CO 2 R 20 , fluoro, —O—C 1-3 alkyl, where alkyl may be unsubstituted or substituted with 1-3 fluoro, and C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —CO 2 R 20 , —OCOR 20 , and phenyl,
or R 7 and R 8 may be joined together via a C 2-4 alkyl or a C 0-2 alkyl-O—C 1-3 alkyl chain to form a 5-7 membered ring;
R 9 is selected from: hydrogen, C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 substituents where the substituents are chosen from the group: fluoro, C 1-3 alkoxy, hydroxy, —CO 2 R 20 , CO 2 R 20 , hydroxy, and —O—C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 substituents where the substituents are chosen from the group: fluoro, C 1-3 alkoxy, hydroxy, and —CO 2 R 20 ,
or R 8 and R 9 may be joined together by a C 1-4 alkyl chain or a C 0-3 alkyl-O—C 0-3 alkyl chain to form a 3-6 membered ring;
R 10 is selected from: hydrogen, and C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro, fluoro, —O—C 3-6 cycloalkyl, and —O—C 1-3 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
or R 8 and R 10 may be joined together by a C 1-3 alkyl chain or a single bond to form a 3-6 membered ring; where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, —CO 2 R 20 , C 1-3 alkyl, and C 1-3 alkoxy,
or R 8 and R 10 may be joined together by a C 1-2 alkyl-O—C 1-2 alkyl chain to form a 6-8 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, —CO 2 R 20 , C 1-3 alkyl, and C 1-3 alkoxy,
or R 8 and R 10 may be joined together by a —O—C 1-2 alkyl-O— chain to form a 6-7 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from: halo, hydroxy, —CO 2 R 20 , C 1-3 alkyl, and C 1-3 alkoxy;
R 11 is selected from: hydrogen, C 1-6 alkyl, and trifluoromethyl;
R 27 and R 28 are independently selected from: ═O, where R 27 , R 28 , or both, is oxygen and is connected via a double bond, hydrogen, phenyl, and C 1-6 alkyl which may be substituted or unsubstituted with 1-6 of the following substituents:
—COR 11 , hydroxy, fluoro, chloro, and —O—C 1-3 alkyl;
R 29 , R 30 , and R 31 are independently selected from: hydrogen, methyl, hydroxyl, trifluoromethyl, methoxy, and trifluoromethoxy;
or R 29 and R 9 are connected by a C 1-3 alkyl bridge;
m is selected from 0, 1, and 2;
n is selected from 0, 1 and 2; and
the dashed line represents a single or a double bond; and
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of the formula Ia:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of: —O—, and —CH 2 —.
4. The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein X is —O—.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from: halo, hydroxy, —O—C 1-3 alkyl, and trifluoromethyl,
(2) —C 0-6 alkyl-O—C 1-6 alkyl-, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from: halo, and trifluoromethyl,
(3) —C 0-6 alkyl-S—C 1-6 alkyl-, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from: halo, and trifluoromethyl, and
(4) —(C 3-5 cycloalkyl)-(C 0-6 alkyl), which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from: halo, hydroxy, —O—C 1-3 alkyl, and trifluoromethyl.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from: hydroxy, and fluoro.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from: isopropyl, —CH(OH)CH 3 , and —CH 2 CF 3 .
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from: hydrogen, hydroxy, and trifluoromethyl.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from: hydrogen, and hydroxy.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 3 is selected from: C 1-6 alkyl unsubstituted or substituted with 1-6 substituents independently selected from fluoro, chloro, and bromo.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 3 is selected from: trifluoromethyl, cyclopropyl, and fluoro.
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 5 is selected from: C 1-6 alkyl unsubstituted or substituted with 1-6 substituents independently selected from fluoro, chloro, and bromo.
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 5 is selected from: trifluoromethyl, cyclopropyl, and fluoro.
14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 5 is trifluoromethyl.
15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.
17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from: hydrogen, C 1-3 alkyl, which is unsubstituted or substituted with 1-6 fluoro, —O—C 1-3 alkyl, fluoro, and hydroxy.
18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from: hydrogen, methyl, ethyl, trifluoromethyl, fluoro, and —O—CH 3 .
19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen and R 10 is hydrogen.
20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 and R 10 are joined together by a —CH 2 CH 2 — chain or a —CH 2 CH 2 CH 2 — chain to form a cyclopentyl ring or a cyclohexyl ring.
21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 27 is ═O, where R 27 is oxygen and is connected via a double bond.
22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 9 and R 29 are joined together by a C 1-3 alkyl chain to form a ring.
23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 29 is hydrogen, R 30 is hydrogen, and R 31 is hydrogen.
24. A compound which is selected from the group consisting of:
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
25. A compound of the formula:
wherin R 7 is F or CF 3 , and wherein R 1 is selected from:
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
26. A compound of the formula:
wherein R 2 is H or OH, wherein R 3 is F or CF 3 , wherein R 4 is CF 3 , Ph, OCF 3 , Cl, or
and wherein R 1 is selected from:
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
27. A compound of the formula:
wherein R is selected from:
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
28. A compound of the formula:
wherein R is selected from:
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
29. A compound of the formula:
wherein R is selected from:
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
30. A compound of the formula:
wherein R is selected from:
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
31. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
32. A method for treating, ameliorating or controlling an inflammatory or immunoregulatory disorder or disease which comprises administering to a patient in need thereof an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
33. A method for reducing the risk of an inflammatory or immunoregulatory disorder or disease which comprises administering to a patient in need thereof an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
34. A method for treating, ameliorating or controlling rheumatoid arthritis which comprises administering to a patient in need thereof an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.