3-(4-heteroarylcyclohexylamino)cyclopentanecarboxamides as modulators of chemokine receptors

1. A compound of Formula I:

or pharmaceutically acceptable salt or prodrug thereof, wherein:

a dashed line indicates an optional bond;

X is N, NO or CR 3 ;

R 1 is 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), OH, CO 2 R 10 , heterocyclyl, CN, NR 10 R 12 , NSO 2 R 10 , NCOR 10 , NCO 2 R 10 , NCOR 10 , CR 11 CO 2 R 10 , CR 11 OCOR 10 , or phenyl;

R 2 is H, OH, halo, C 1-3 alkyl, NR 10 R 12 , CO 2 R 10 , CONR 10 R 12 , NR 10 COR 11 ; OCONR 10 R 12 , NR 10 CONR 10 R 12 , heterocyclyl, CN, NR 10 —SO 2 —NR 10 R 12 , NR 10 —SO 2 —R 12 , SO 2 —NR 10 R 12 , or oxo; wherein said C 1-3 alkyl is optionally substituted with 1-6 substituents selected from F and OH;

R 3 is H, OH, halo, C 1-6 alkyl, C 1-6 alkoxy, NR 10 R 11 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 11 , NR 10 SO 2 NR 10 R 11 , NR 10 —SO 2 —R 11 , heterocyclyl, CN, CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 ; or SO 2 —NR 10 R 11 ;

R 4 is H, C 1-6 alkyl, CF 3 , OCF 3 , Cl, F, Br or phenyl;

R 5 is C 1-6 alkyl, C 1-6 alkoxy, CO—(C 1-6 alkyl), C 1-6 thioalkoxy, pyridyl, F, Cl, Br, C 4-6 cycloalkyl, C 4-6 cycloalkyloxy, phenyl, phenyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, heterocyclyl, CN, or CO 2 R 10 ; wherein said C 1-6 alkyl is optionally substituted with one or more OH or F; wherein said C 1-6 alkoxy, CO—(C 1-6 alkyl), or C 1-6 thioalkoxy are optionally substituted with one or more F; wherein said pyridyl, phenyl or phenyloxy is optionally substituted with one or more substituents selected from halo, CF 3 , C 1-4 alkyl and CO 2 R 10 ; wherein said C 3-6 cycloalkyl or C 3-6 cycloalkyloxy is optionally substituted with one or more F;

R 6 is H, CF 3 , C 1-6 alkyl, F, Cl, or Br;

R 7 is H or C 1-6 alkyl optionally substituted by 1-3 substituents selected from halo, OH, CO 2 H, CO 2 -(C 1-6 alkyl), or C 1-3 alkoxy;

R 8 is H, C 1-6 alkyl, F, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, OH, CO 2 R 10 , OCOR 10 ; wherein said C 1-6 alkyl is optionally substituted with one or more substituents selected from F, C 1-3 alkoxy, OH or CO 2 R 10 ;

or R 7 and R 8 together form a bridging C 2-4 alkylene or -(C 0-2 alkyl)-O-(C 1-3 alkyl)-group to form a 5-7 membered ring;

R 9 is heterocyclyl optionally substituted with 1-4 substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-4 haloalkyl, CN, NO 2 , OR 13 , SR 13 , C(O)R 14 , C(O)OR 13 , C(O)NR 15 R 16 , NR 15 R 16 , NR 15 CONHR 16 , NR 15 C(O)R 14 , NR 15 C(O)OR 13 , S(O)R 14 , S(O) 2 R 14 , S(O)NR 15 R 16 or SO 2 NR 15 R 16 ;

R 10 is H, C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, CO 2 —(C 1-6 alkyl) and CF 3 ;

R 11 is H, OH, C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 substituents selected from halo, OH, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, CO 2 —(C 1-6 alkyl) and CF 3 ;

R 12 is H, C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 substituents selected from halo, OH, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, CO 2 —(C 1-6 alkyl) and CF 3 ;

R 13 and R 14 are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;

R 15 and R 16 are each, independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;

or R 15 and R 16 together with the N atom to which they are attached form a 4-6 membered heterocyclyl group.

2. The compound of claim 1 wherein X is N or NO.

3. The compound of claim 1 wherein X is CR 3 .

4. The compound of claim 1 wherein R 1 is C 1-6 alkyl.

5. The compound of claim 1 wherein R 1 is prop-2-yl.

6. The compound of claim 1 wherein R 2 is H, OH, halo, or C 1-3 alkyl.

7. The compound of claim 1 wherein R 2 is H.

8. The compound of claim 1 wherein R 3 is H, OH, halo or C 1-6 alkyl.

9. The compound of claim 1 wherein R 3 is H.

10. The compound of claim 1 wherein R 4 is H.

11. The compound of claim 1 wherein R 5 is C 1-6 alkyl substituted with 1-4 F.

12. The compound of claim 1 wherein R 5 is CF 3 .

13. The compound of claim 1 wherein R 6 is H.

14. The compound of claim 1 wherein R 7 is H.

15. The compound of claim 1 wherein R 8 is H.

16. The compound of claim 1 wherein R 9 is heteroaryl optionally substituted with 1-4 substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-4 haloalkyl, CN, NO 2 , OR 13 , SR 13 , C(O)R 14 , C(O)OR 13 , C(O)NR 15 R 16 , NR 15 R 16 , NR 15 CONHR 16 , NR 15 C(O)R 14 , NR 15 C(O)OR 13 , S(O)R 14 , S(O) 2 R 14 , S(O)NR 15 R 16 or SO 2 NR 15 R 16 .

17. The compound of claim 16 wherein said heteroaryl is a 5- or 6-membered heteroaryl optionally substituted with 1-4 substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-4 haloalkyl, CN, NO 2 , OR 13 , SR 13 , C(O)R 14 , C(O)OR 13 , C(O)NR 15 R 16 , NR 15 R 16 , NR 15 CONHR 16 , NR 15 C(O)R 14 , NR 15 C(O)OR 13 , S(O)R 14 , S(O) 2 R 14 , S(O)NR 15 R 16 or SO 2 NR 15 R 16 .

18. The compound of claim 16 wherein said heteroaryl is pyridyl, pyimidinyl, pyrazinyl, pyridazinyl or triazinyl, each optionally substituted with 1-4 substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-4 haloalkyl, CN, NO 2 , OR 13 , SR 13 , C(O)R 14 , C(O)OR 13 , C(O)NR 15 R 16 , NR 15 R 16 , NR 15 CONHR 16 , NR 15 C(O)R 14 , NR 15 C(O)OR 13 , S(O)R 14 , S(O) 2 R 14 , S(O)NR 15 R 16 or SO 2 NR 15 R 16 .

19. The compound of claim 16 wherein said heteroaryl is thienyl, furanyl, thiazoyl, oxazolyl, or imidazolyl, each optionally substituted with 1-4 substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-4 haloalkyl, CN, NO 2 , OR 13 , SR 13 , C(O)R 14 , C(O)OR 13 , C(O)NR 15 R 16 , NR 15 R 16 , NR 15 CONHR 16 , NR 15 C(O)R 14 , NR 15 C(O)OR 13 , S(O)R 14 , S(O) 2 R 14 , S(O)NR 15 R 16 or SO 2 NR 15 R 16 .

20. The compound of claim 16 wherein said heteroaryl is thiazolyl, oxazolyl, pyrimidinyl, or pyridyl, each optionally substituted by 1-3 F, Cl, Br, I, methyl, ethyl, methoxy, ethoxy or trifluoromethyl.

21. The compound of claim 1 having Formula II:

22. The compound of claim 1 having Formula IIIa, IIIb or IIIc:

23. The compound of claim 1 selected from:

4-[((1R,3 S)-3-Isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)amino]-1-pyridin-2-ylcyclohexanol;

4-[((1R,3 S)-3-Isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)amino]-1-(1,3-oxazol-2-yl)cyclohexanol;

4-[((1R,3 S)-3-Isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)amino]-1-pyrimidin-2-ylcyclohexanol;

4-[((1R,3S)-3-Isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)amino]-1-(1,3-thiazol-2-yl)cyclohexanol;

4-[((1R,3 S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)amino]-1-(1,3-thiazol-2-yl)cyclohexanol;

4-[((1R,3S)-3-Isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)amino]-1-(4-methyl-1,3-thiazol-2-yl)cyclohexanol;

4-[((1R,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)amino]-1-(4-methyl-1,3-thiazol-2-yl)cyclohexanol;

4-[((1R,3 S)-3-Isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)amino]-1-(5-methyl-1,3-thiazol-2-yl)cyclohexanol;

4-[((1R,3 S)-3-Isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)amino]-1-(1,3-thiazol-5-yl)cyclohexanol;

4-[((1R,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)amino]-1-(1,3-thiazol-5-yl)cyclohexanol;

4-[((1R,3 S)-3-Isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentyl)amino]-1-(2-methyl-1,3-thiazol-5-yl)cyclohexanol; and

4-[((1R,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)amino]-1-(2-methyl-1,3-thiazol-5-yl)cyclohexanol; or

pharmaceutically acceptable salt thereof.

24. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.