Amino cyclobutylamide modulators of chemokine receptor activity

1. A compound of formula IIa:

wherein:

X is C;

R 11 is 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 groups are unsubstituted or substituted with 1-3 substituents, and where said 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 12 is selected from: hydrogen, 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, and where said 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 13 is 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 groups are unsubstituted or substituted with 1-3 substituents, and where said 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 14 is 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, and where said 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;

Z is selected from C and N;

R 1 is selected from:

(a) hydrogen,

(b) —C 1-6 alkyl,

(c) —C 0-6 alkyl-O—C 1-6 alkyl,

(d) —C 0-6 alkyl-S—C 1-6 alkyl,

(e) —(C 0-6 alkyl)-(C 3-7 cycloalkyl)-(C 0-6 alkyl),

(f) hydroxy,

(g) heterocycle,

(h) —CN,

(i) —NR 12 R 12 ,

(j) —NR 12 COR 13 ,

(k) —NR 12 SO 2 R 14 ,

(l) —COR 11 ,

(m) —CONR 12 R 12 , and

(n) phenyl;

where said alkyl and cycloalkyl are unsubstituted or substituted with 1-7 substituents, and where said substituents are independently selected from: halo, hydroxy, —O—C 1-3 alkyl, trifluoromethyl, C 1-3 alkyl, —O—C 1-3 alkyl, —COR 11 , —SO 2 R 14 , —NHCOCH 3 , —NHSO 2 CH 3 , -heterocycle, ═O, —CN, and where said phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, —COR 11 , C 1-3 alkyl, C 1-3 alkoxy and trifluoromethyl;

R 3 is selected from:

(a) hydrogen,

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

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

(d) hydroxy,

(e) chloro,

(f) fluoro,

(g) bromo,

(h) phenyl,

(i) heterocycle, and

(j) nothing or O (when the Z bonded to R 3 is N);

R 5 is selected from:

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

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

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

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

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

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

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

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

(o) -heterocycle,

(p) —CN, and

(q) —COR 11 ;

R 7 and R 8 are joined together to form a ring which is selected from:

(a) 1H-indene,

(b) 2,3-dihydro-1H-indene,

(c) 2,3-dihydro-benzofuran,

(d) 1,3-dihydro-isobenzofuran,

(e) 2,3-dihydro-benzothiofuran,

(f) 1,3-dihydro-isobenzothiofuran,

(g) 6H-cyclopenta[d]isoxazol-3-ol

(h) cyclopentane, and

(i) cyclohexane,

where the ring formed is unsubstituted or substituted with 1-5 substituents independently selected from: halo, trifluoromethyl, hydroxy, C 1-3 alkyl, —O—C 1-3 alkyl, —C 0-3 —COR 11 , —CN, —NR 12 R 12 , —CONR 12 R 12 , and —C 0-3 -heterocycle, and

R 9 and R 10 are independently selected from:

(a) hydrogen,

(b) hydroxy,

(c) C 1-6 alkyl,

(d) C 1-6 alkyl-COR 11 ,

(e) C 1-6 alkyl-hydroxy,

(f) —O—C 1-3 alkyl, and

(g) halo;

or a pharmaceutically acceptable salt or individual diastereomer thereof.

2. The compound of claim 1 of formula IId:

wherein the dashed line represents a single or a double bond, and R 23 and R 24 are independently selected from:

(a) hydrogen,

(b) halo,

(c) trifluoromethyl,

(d) hydroxy,

(e) C 1-3 alkyl,

(f) —O—C 1-3 alkyl,

(g) —C 0-3 —CO 2 H,

(h) —C 0-3 —CO 2 C 1-3 alkyl,

(i) —CN, and

(j) —C 0-3 —heterocycle,

or a pharmaceutically acceptable salt or individual diastereomer thereof.

3. The compound of claim 2 of formula IIf:

or a pharmaceutically acceptable salt or individual diastereomer thereof.

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

hydrogen, phenyl, heterocycle, —C 1-6 alkyl, —C 0-6 alkyl-O—C 1-6 alkyl, and —(C 0-6 alkyl)-(C 3-7 cycloalkyl)-(C 0-6 alkyl),

where said alkyl, phenyl, heterocycle, and cycloalkyl are unsubstituted or substituted with 1-7 substituents, where said 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) —COR 11 ,

(i) —CN,

(j) —NR 12 R 12 , and

(k) —CONR 12 R 12 .

5. The compound of claim 4 wherein R 1 is selected from:

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

(a) halo,

(b) hydroxy,

(c) —O—C 1-3 alkyl,

(d) trifluoromethyl, and

(e) —COR 11 ,

(2) —C 0-6 alkyl-O—C 1-6 alkyl-, which is unsubstituted or substituted with 1-6 substituents where said substituents are independently selected from:

(a) halo,

(b) trifluoromethyl, and

(c) —COR 11 ,

(3) —(C 3-5 cycloalkyl)-(C 0-6 alkyl), which is unsubstituted or substituted with 1-7 substituents where said substituents are independently selected from:

(a) halo,

(b) hydroxy,

(c) —O—C 1-3 alkyl,

(d) trifluoromethyl, and

(e) —COR 11 ,

(4) phenyl or heterocycle which is unsubstituted or substituted with 1-3 substituents where said substituents are independently selected from:

(a) halo,

(b) hydroxy,

(c) —O—C 1-3 alkyl,

(d) trifluoromethyl, and

(e) —COR 11 .

6. The compound of claim 5 wherein R 1 is selected from:

(a) hydrogen,

(b) C -1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents independently selected from: fluoro and hydroxyl

(c) phenyl, and

(d) pyridyl.

7. The compound of claim 2 wherein Z is C and R 3 is selected from:

(a) hydrogen

(b) halo

(c) hydroxy

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

(e) —COR 11 ,

(f) —CONR 12 R 12 ,

(g) -heterocycle,

(h) —NR 12 —SO 2 —NR 12 R 12 ,

(i) —NR 12 —SO 2 —R 14 ,

(j) —SO 2 —NR 12 R 12 ,

(k) -nitro, and

(l) —NR12R12.

8. The compound of claim 7 wherein Z is C and R 3 is selected from:

(a) fluoro,

(b) trifluoromethyl, and

(c) hydrogen.

9. The compound of claim 2 wherein R 5 is selected from:

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

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

(c) chloro,

(d) bromo, and

(e) phenyl.

10. The compound of claim 1 , which is selected from the following compounds, or a pharmaceutically acceptable salt or individual diastereomer thereof:

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

12. A method for treating rheumatoid arthritis which comprises the administration to a patient of an effective amount of the compound of claim 1 .