Tetrahydropyranyl cyclopentyl tetrahydropyridopyridine modulators of chemokine receptor activity

1. A compound of Formula I:

wherein:

Y is selected from: —O—, —NR 12 —, —S—, —SO—, —SO 2 —, and —CR 12 R 12 —, —NSO 2 R 14 —, —NCOR 13 —, —CR 12 COR 11 —, —CR 12 OCOR 13 — and —CO—;

Z is C or N;

R 1 is selected from:

(a) —SO 2 R 14 ,

(b) —C 0-3 alkyl-S(O)—R 14 ,

(c) —C 1-6 alkyl-NR 12 R 12 ,

(d) —N(CH 3 )—COR 13 ,

(e) —N(CH 3 )—SO 2 R 14 , and

(f) —SO 2 NR 12 R 12 ;

R 2 is selected from:

(a) hydrogen,

(b) hydroxy,

(c) halo,

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

(e) —NR 12 R 12 ,

(f) —COR 11 ,

(g) —CONR 12 R 12 ,

(h) —NR 12 COR 13 ,

(i) —OCONR 12 R 12 ,

(j) —NR 12 CONR 12 R 12 ,

(k) -heterocycle,

(l) —CN,

(m) —NR 12 —SO 2 —NR 12 R 12 ,

(n) —NR 12 —SO 2 —R 12 ,

(o) —SO 2 —NR 12 R 12 , and

(p) ═O;

R 3 is selected from:

(a) hydrogen,

(b) C 1-3 alkyl unsubstituted or substituted with 1-3 fluoro,

(c) —O—C 1-3 alkyl unsubstituted or substituted with 1-3 fluoro,

(d) hydroxy,

(e) chloro,

(f) fluoro,

(g) bromo,

(h) phenyl,

(i) heterocycle,

(j) O, when Z is N, and

(k) nothing, when Z is N;

R 4 is selected from:

(a) hydrogen,

(b) C 1-3 alkyl unsubstituted or substituted with 1-3 fluoro,

(c) —O—C 1-3 alkyl unsubstituted or substituted with 1-3 fluoro,

(d) hydroxy,

(e) chloro,

(f) fluoro,

(g) bromo,

(h) phenyl, and

(i) heterocycle;

R 5 is selected from:

(a) C 1-6 alkyl, unsubstituted or substituted with 1-6 fluoro, hydroxyl, or both,

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

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

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

(e) -pyridyl, unsubstituted or substituted with one or more substituents independently selected from: halo, trifluoromethyl, C 1-4 alkyl, and COR 11 ,

(f) fluoro,

(g) chloro,

(h) bromo,

(i) —C 4-6 cycloalkyl,

(j) —O—C 4-6 cycloalkyl,

(k) phenyl, unsubstituted or substituted with one or more substituents independently selected from: halo, trifluoromethyl, C 1-4 alkyl, and COR 11 ,

(l) —O-phenyl, unsubstituted or substituted with one or more substituents independently selected from: halo, trifluoromethyl, C 1-4 alkyl, and COR 11 ,

(m) —C 3-6 cycloalkyl, unsubstituted or substituted with 1-6 fluoro,

(n) —O—C 3-6 cycloalkyl, unsubstituted or substituted with 1-6 fluoro,

(o) -heterocycle,

(p) —CN, and

(q) —COR 11 ;

R 6 is selected from:

(a) hydrogen,

(b) C 1-3 alkyl, unsubstituted or substituted with 1-3 fluoro,

(c) —O—C 1-3 alkyl, unsubstituted or substituted with 1-3 fluoro,

(d) hydroxy,

(e) chloro,

(f) fluoro,

(g) bromo,

(h) phenyl, and

(i) heterocycle;

R 7 is selected from: hydrogen and C 1-6 alkyl unsubstituted or substituted with 1-3 substituents 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, unsubstituted or substituted with 1-6 substituents independently selected from: fluoro, C 1-3 alkoxy, hydroxy, and —COR 11 ,

(c) fluoro,

(d) —O—C 1-3 alkyl, unsubstituted or substituted with 1-3 fluoro,

(e) C 3-6 cycloalkyl,

(f) —O—C 3-6 cycloalkyl,

(g) hydroxy,

(h) —COR 11 , and

(i) —OCOR 13 ,

or R 7 and R 8 together are C 2-4 alkyl or C 0-2 alkyl-O—C 1-3 alkyl, forming a 5-7 membered ring;

R 9 is selected from:

(a) hydrogen,

(b) C 1-6 alkyl, unsubstituted or substituted with 1-6 substituents independently selected from: fluoro, C 1-3 alkoxy, hydroxy, —COR 11 ,

(c) COR 11 ,

(d) hydroxy, and

(e) —O—C 1-6 alkyl, unsubstituted or substituted with 1-6 substituents independently selected from: fluoro, C 1-3 alkoxy, hydroxy, —COR 11 ,

or R 8 and R 9 together are C 1-4 alkyl or C 0-3 alkyl-O—C 0-3 alkyl, forming a 3-6 membered ring;

R 10 is selected from:

(a) hydrogen,

(b) C 1-6 alkyl, unsubstituted or substituted with 1-6 fluoro,

(c) fluoro,

(d) —O—C 3-6 cycloalkyl, and

(e) —O—C 1-3 alkyl, unsubstituted or substituted with 1-6 fluoro,

or R 8 and R 10 together are C 2-3 alkyl, forming 5-6 membered ring, where said C 2-3 alkyl is unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, —COR 11 , C 1-3 alkyl, and C 1-3 alkoxy,

or R 8 and R 10 together are C 1-2 alkyl-O—C 1-2 alkyl, forming a 6-8 membered ring, where said C 1-2 alkyl-O—C 1-2 alkyl is unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, —COR 11 , C 1-3 alkyl, and C 1-3 alkoxy,

or R 8 and R 10 together are —O—C 1-2 alkyl-O—, forming a 6-7 membered ring, where said —O—C 1-2 alkyl-O— is unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, —COR 11 , C 1-3 alkyl, and C 1-3 alkoxy;

R 11 is independently selected from: hydroxy, hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, and C 3-6 cycloalkyl, where said alkyl, phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents 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 12 is independently selected from: hydrogen, C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where said alkyl, phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents 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 13 is independently selected from: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 cycloalkyl, where said alkyl, phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents 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 14 is independently selected from: hydroxy, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 cycloalkyl, where said alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents 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 15 and R 16 are each H, or R 15 and R 16 together are —CH 2 CH(R 2 )—, forming a fused ring;

n is 0, 1 or 2;

a dashed line represents an optional single bond;

or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

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

or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

3. The compound of claim 1 of the Formula Ib:

or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

4. The compound of claim 1 of the Formula Ic:

or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

5. The compound of claim 1 of the Formula Id:

or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

6. The compound of claim 1 wherein when Z is C, R 3 is hydrogen, fluoro or trifluoromethyl, and when Z is N, R 3 is nothing, or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

7. The compound of claim 1 wherein Y is −CH 2 — or −O—, or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

8. The compound of claim 1 wherein R 1 is selected from —SO 2 CH 3 , —SO 2 NH 2 , —SOCH 3 , and —SO 2 NHCH 3 , or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

9. The compound of claim 1 wherein R 5 is selected from C 1-6 alkyl substituted with 1-6 fluoro, —O—C 1-6 alkyl substituted with 1-6 fluoro, chloro, bromo and phenyl, or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

10. The compound of claim 1 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 hydroxyl, or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

11. A compound selected from:

or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

12. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof or an individual diastereomer thereof.

13. A method of treating an inflammatory or immunoregulatory disorder or disease comprising the administration of a therapeutically effective amount of the compound of claim 1 to a patient in need of treatment wherein said disorder or disease is rheumatoid arthritis.