Tetrahydropyranyl cyclopentyl tetrahydroisoquinoline modulators of chemokine receptor activity

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—,

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 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;

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)-(C 3-7 cycloalkyl)-(C 0-6 alkyl), hydroxy, heterocycle, —CN, —NR 20 R 26 , —NHSO 2 R 20 ,—NHCOR 20 , —NHCO 2 R 20 , —CO 2 R 20 , —CR 21 CO 2 R 20 , —CR 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:

(a) halo,

(b) hydroxy,

(c) —O—C 1-3 alkyl,

(d) trifluoromethyl,

(f) C 1-3 alkyl,

(g) —O—C 1-3 alkyl,

(h) —CO 2 R 20 ,

(i) —SO 2 R 20 ,

(j) —NHCOCH 3 ,

(k) —NHSO 2 CH 3 ,

(l) -heterocycle,

(m) ═O,

(n) —CN,

and where the phenyl and pyridyl 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:

(a) hydrogen,

(b) hydroxy,

(c) halo,

(d) C 1-3 alkyl, where the alkyl is unsubstituted or substituted with 1–6 substituents independently selected from: fluoro, and hydroxy,

(e) —NR 20 R 26 ,

(f) —CO 2 R 20 ,

(g) —CONR 20 R 26 ,

(h) —NR 20 COR 21 ,

(i) —OCONR 20 R 26 ,

(j) —NR 20 CONR 20 R 26 ,

(k) -heterocycle,

(l) —CN,

(m) —NR 20 —SO 2 —NR 20 R 26 ,

(n) —NR 20 —SO 2 —R 26 ,

(o) —SO 2 —NR 20 R 26 , and

(p) ═O, where R 2 is connected to the ring via a double bond;

R 3 is selected from:

(a) hydrogen,

(b) hydroxy,

(c) halo,

(d) C 1-6 alkyl,

(e) —O—C 1-6 alkyl,

(f) —NR 20 R 21 ,

(g) —NR 20 CO 2 R 21 ,

(h) —NR 20 CONR 20 R 21 ,

(i) —NR 20 —SO 2 —NR 20 R 21 ,

(j) —NR 20 —SO 2 —R 21 ,

(k) heterocycle,

(l) —CN,

(m) —CONR 20 R 21 ,

(n) —CO 2 R 20 ,

(o) —NO 2 ,

(p) —S—R 20 ,

(q) —SO—R 20 ,

(r) —SO 2 —R 20 , and

(s) —SO 2 —NR 20 R 21 ;

R 4 is selected from:

(a) hydrogen,

(b) C 1-6 alkyl,

(c) trifluoromethyl,

(d) trifluoromethoxy,

(e) chloro,

(f) fluoro,

(g) bromo, and

(h) phenyl;

R 5 is selected from:

(a) C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1–6 fluoro and optionally substituted with hydroxyl,

(b) —O—C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1–6 fluoro,

(c) —CO—C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1–6 fluoro,

(d) —S—C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1–6 fluoro,

(e) -pyridyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, trifluoromethyl, C 1-4 alkyl, and CO 2 R 20 ,

(f) fluoro,

(g) chloro,

(h) bromo,

(i) —C 4-6 cycloalkyl,

(j) —O—C 4-6 cycloalkyl,

(k) phenyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, trifluoromethyl, C 1-4 alkyl, and CO 2 R 20 ,

(l) —O-phenyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, trifluoromethyl, C 1-4 alkyl, and CO 2 R 20 ,

(m) —C 3-6 cycloalkyl, where alkyl may be unsubstituted or substituted with 1–6 fluoro,

(n) —O—C 3-6 cycloalkyl, where alkyl may be unsubstituted or substituted with 1–6 fluoro,

(o) -heterocycle,

(p) —CN, and

(q) —CO 2 R 20 ;

R 6 is selected from:

(a) hydrogen,

(b) C 1-6 alkyl, and

(c) trifluoromethyl

(d) fluoro

(e) chloro, and

(f) bromo;

R 7 is selected from:

(a) hydrogen, and

(b) C 1-6 alkyl, which is unsubstituted or substituted with 1–3 substituents where the substituents are independently selected from: halo, hydroxy, —CO 2 H, —CO 2 C 1-6 alkyl, and —O—C 1-3 alkyl;

R 8 is selected from:

(a) hydrogen,

(b) 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 ,

(c) fluoro,

(d) —O—C 1-3 alkyl, where alkyl may be unsubstituted or substituted with 1–3 fluoro, and

(e) C 3-6 cycloalkyl,

(f) —O—C 3-6 cycloalkyl,

(g) hydroxy,

(h) —CO 2 R 20 ,

(i) —OCOR 20 ,

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:

(a) hydrogen,

(b) 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 ,

(c) CO 2 R 20 ,

(d) hydroxy, and

(e) —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, —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:

(a) hydrogen, and

(b) C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1–6 fluoro,

(c) fluoro,

(d) —O—C 3-6 cycloalkyl, and

(e) —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 2-3 alkyl chain to form a 5–6 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;

n is selected from 0, 1 and 2;

the dashed line represents a single or a double bond;

and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

2. The compound of claim 1 of the formula Ia:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 and X are defined in claim 1 .

3. The compound of claim 1 wherein:

X is selected from the group consisting of: —O—, and —CH 2 —.

4. The compound of claim 1 wherein X is —O—.

5. The compound of claim 1 wherein:

(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1–6 substituents where the substituents are independently selected from:

(a) halo,

(b) hydroxy,

(c) —O—C 1-3 alkyl, and

(d) 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:

(a) halo, and

(b) 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:

(a) halo, and

(b) trifluoromethyl,

(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:

(a) halo,

(b) hydroxy,

(c) —O—C 1-3 alkyl, and

(d) trifluoromethyl.

6. The compound of claim 1 wherein R 1 is C 1-6 alkyl which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:

(a) hydroxy, and

(b) fluoro.

7. The compound of claim 1 wherein:

R 1 is selected from:

(a) isopropyl,

(b) —CH(OH)CH 3 , and

(c) —CH 2 CF 3 .

8. The compound of claim 1 wherein R 1 is isopropyl.

9. The compound of claim 1 wherein:

R 2 is selected from:

(a) hydrogen,

(b) hydroxy,

(c) —NH 2 ,

(d) —CO 2 H,

(e) -triazolyl,

(f) -tetrazolyl,

(g) —CO 2 —C 1-6 alkyl,

(h) —CONH 2 ,

(i) —CONH—C 1-6 alkyl,

(j) —NHCO—C 1-6 alkyl,

(k) —NHCONH 2 ,

(l) —NHCONH—C 1-6 alkyl

(m) —OCONH—C 1-6 alkyl,

(n) —NH—SO 2 —C 1-6 alkyl, and

(o) —SO 2 —NH—C 1-6 alkyl.

10. The compound of claim 1 wherein:

R 2 is selected from:

(a) hydrogen,

(b) hydroxy,

(c) —NH 2 ,

(d) —CO 2 H,

(e) -triazolyl,

(f) -tetrazolyl,

(g) —NHCOCH 3 ,

(h) —NHCONH 2 ,

(i) —CONH 2 ,

(j) —NH—SO 2 —CH 3 , and

(k) —SO 2 —NH—CH 3 .

11. The compound of claim 1 wherein R 2 is hydrogen.

12. The compound of claim 1 wherein R 3 is selected from:

(a) hydrogen,

(b) —NH 2 ,

(c) —NO 2 ,

(c) —NHSO 2 —C 1-6 alkyl,

(d) fluoro,

(e) -triazolyl, and

(f) -tetrazolyl.

13. The compound of claim 1 wherein R 3 is selected from:

(a) hydrogen,

(b) —NH 2 ,

(b) —NO 2 ,

(c) —NHSO 2 —CH 3 , and

(d) fluoro.

14. The compound of claim 1 wherein R 4 is hydrogen.

15. The compound of claim 1 wherein:

R 5 is selected from:

(a) C 1-3 alkyl substituted with 1–6 fluoro,

(b) chloro,

(c) bromo,

(d) —O-phenyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: halo and trifluoromethyl,

(e) phenyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: halo and trifluoromethyl, and

(f) —O—C 1-3 alkyl substituted with 1–6 fluoro.

16. The compound of claim 1 wherein:

R 5 is selected from:

(a) trifluoromethyl,

(b) trifluoromethoxy,

(c) bromo, and

(d) chloro.

17. The compound of claim 1 wherein:

R 5 is trifluoromethyl.

18. The compound of claim 1 wherein R 6 is hydrogen.

19. The compound of claim 1 wherein:

R 7 is hydrogen or methyl.

20. The compound of claim 1 wherein:

R 8 is selected from:

(a) hydrogen,

(b) C 1-3 alkyl, which is unsubstituted or substituted with 1–6 fluoro,

(c) —O—C 1-3 alkyl, and

(d) fluoro, and

(e) hydroxy.

21. The compound of claim 1 wherein:

R 8 is selected from:

(a) hydrogen,

(d) trifluoromethyl,

(c) methyl,

(d) methoxy,

(e) ethoxy,

(f) ethyl,

(g) fluoro, and

(h) hydroxy.

22. The compound of claim 1 wherein:

R 9 is hydrogen and R 10 is hydrogen.

23. The compound of claim 1 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.

24. A compound which is selected from the group consisting of:

and pharmaceutically acceptable salts and individual diastereomers thereof.

25. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 .

26. A method for the treatment of an inflammatory and immunoregulatory disorder or disease which comprises the administration to a patient of an effective amount of the compound of claim 1 .

27. A method for the prevention or treatment of rheumatoid arthritis which comprises the administration to a patient of an effective amount of the compound of claim 1 .