3-aminocyclopentanecarboxamides as modulators of chemokine receptors

1. A compound of Formula I:

or pharmaceutically acceptable salt, wherein:

a dashed line indicates an optional bond;

W is:

V is N, NO or CR 5 ;

X is N, NO or CR 2 ;

Y is N, NO or CR 3 ;

Z is N, NO or CR 4 ; wherein no more than one of X, Y and Z is NO;

A is S, CR C R D ; or NR F ;

R A , R A1 , R B and R B1 are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl, carbocyclyl, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , 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 12 ;

R C and R D are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 thioalkoxy, heterocyclyl, carbocyclyl, carbocyclyloxy, heterocyclylalkyl, carbocyclylalkyl, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , 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 12 , wherein said C 1-6 alkyl is optionally substituted with 1-5 substituents selected from hydroxyl, OH, C 1-6 alkoxy, and C 1-6 haloalkyl and wherein said heterocyclyl, carbocyclyl, carbocyclyloxy, heterocyclylalkyl, and carbocyclylalkyl are 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 ;

R F is H, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl, carbocyclyl, carbocyclyloxy, heterocyclylalkyl, carbocyclylalkyl, SOR 10 , SO 2 R 10 ; or SO 2 —NR 10 R 12 , wherein said C 1-6 alkyl is optionally substituted with 1-5 substituents selected from hydroxyl, OH, C 1-6 alkoxy, and C 1-6 haloalkyl and wherein said heterocyclyl, carbocyclyl, carbocyclyloxy, heterocyclylalkyl, and carbocyclylalkyl are 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 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —(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, OR 10 , SR 10 , COR 11 , CO 2 R 10 , CONR 10 R 12 , carbocyclyl, heterocyclyl, CN, NR 10 R 12 , NR 10 SO 2 R 10 , NR 10 COR 10 , NR 10 CO 2 R 10 , NR 10 CONR 12 , CR 10 R 11 CO 2 R 10 or CR 10 R 11 OCOR 10 R 10 ;

R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 thioalkoxy, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , heterocyclyl, carbocyclyl, carbocyclyloxy, heterocyclyloxy, CN, NO 2 , COR 11 , CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 ; or SO 2 -NR 10 R 12 ;

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 and R 8′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, halo, 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;

or R 8 and R 8′ together with the carbon atom to which they are attached form a 3-7 membered spirocyclyl group;

R 9 and R 9′ are each, independently, H, C 1-6 alkyl, halo, 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 9 and R 9′ together with the carbon atom to which they are attached form a 3-7 membered spirocyclyl group;

or R 8 and R 9 together with the C atoms to which they are attached form a fused 3-7 membered cycloalkyl group or 3-7 membered heterocycloalkyl group;

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 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CO 2 H, and CO 2 —(C 1-6 alkyl);

R 11 is H, OH, C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C 3-6 cycloalkyl or C 3-6 cycloalkyloxy, wherein said C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C 3-6 cycloalkyl or C 3-6 cycloalkyloxy, 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 selected from halo, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CO 2 H, and CO 2 —(C 1-6 alkyl); 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;

p is 0 or 1; and

with the proviso that when A is O and one of R 8 and R 8′ is H, the other of R 8 and R 8′ is other than C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyloxy or OH.

2. The compound of claim 1 wherein W is

3. The compound of claim 1 wherein W is

4. The compound of claim 1 wherein V is CR 5 .

5. The compound of claim 1 wherein X is CR 2 .

6. The compound of claim 1 wherein Y is CR 3 .

7. The compound of claim 1 wherein Z is CR 4 .

8. The compound of claim 1 wherein X is CR 2 ; Y is CR 3 ; and Z is CR 4 .

9. The compound of claim 1 wherein V is CR 5 , X is CR 2 ; Y is CR 3 ; and Z is CR 4 .

10. The compound of claim 1 wherein A is CR C R D .

11. The compound of claim 1 wherein A is CR C R D , one of R C and R D is OH or C 1-6 alkoxy and the other of R C and R D is heterocyclyl or carbocyclyl wherein said heterocyclyl or carbocyclyl is 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 .

12. The compound of claim 1 wherein R A , R A1 , R B and R B1 are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1- 6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.

13. The compound of claim 1 wherein R A , R A1 , R B and R B1 are each, independently, H, OH or C 1-6 alkoxy.

14. The compound of claim 1 wherein R A , R A1 , R B and R B1 are each, independently, H or OH.

15. The compound of claim 1 wherein R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, —(C 0-6 alkyl)-O—(C 1- 6 alkyl), or heterocyclyl.

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

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

18. The compound of claim 1 wherein one of R 5 and R 6 is other than H.

19. The compound of claim 1 wherein one of R 5 and R 6 is C 1-4 haloalkyl.

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

21. The compound of claim 1 wherein R 6 is CF 3 .

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

23. The compound of claim 1 wherein one of R 8 and R 8′ is H and the other is C 1-6 alkyl, C 1-6 alkyl or halo.

24. The compound of claim 1 wherein one of R 8 and R 8′ is H and the other is C 1-6 alkyl.

25. The compound of claim 1 wherein one of R 8 and R 8 ′ is H and the other is methyl or ethyl.

26. The compound of claim 1 wherein R 9 and R 9′ are both H.

27. The compound of claim 1 having Formula Ia:

28. The compound of claim 1 having Formula Ib, Ic or Id:

29. The compound of claim 1 having Formula Ie or If:

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

31. The compound of claim 1 , wherein

W is:

R B and R B1 are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, carbocyclyl, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , 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 12 ;

R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —(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, OR 10 , SR 10 , COR 11 , CO 2R 10 , CONR 10 R 12 , carbocyclyl, CN, NR 10 R 12 , NR 10 SO 2 R 10 , NR 10 COR 10 , NR 10 C 2 R 10 , NR 10 CONR 12 , CR 10 R 11 C 2 R 10 or CR 10 R 11 OCOR 10 ;

R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 thioalkoxy, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 OCONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , carbocyclyl, carbocyclyloxy, CN, NO 2 , COR 11 , CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 ; or SO 2 —NR 10 R 12 .