3-aminocyclopentanecarboxamides as modulators of chemokine receptors

1. A compound of Formula I:

or pharmaceutically acceptable salt thereof, 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 O;

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 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 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);

p is 0 or 1; and

with the proviso that when 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 , or pharmaceutically accepted salt thereof, wherein W is

3. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein W is

4. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein V is CR 5 .

5. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein X is CR 2 .

6. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein Y is CR 3 .

7. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein Z is CR 4 .

8. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein X is CR 2 ; Y is CR 3 ; and Z is CR 4 .

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

10. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R A , R A1 , R B and a 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.

11. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R A , R A1 , R B and R B1 it are each, independently, H, OH or C 1-6 alkoxy.

12. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R A , R A1 , R B and R B1 are each, independently, H or OH.

13. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, —(C 0-6 alkyl)-O—(C 1-6 alkyl), or heterocyclyl.

14. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R 1 is C 1-6 alkyl.

15. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R 1 is prop-2-yl.

16. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein one of R 5 and R 6 is other than H.

17. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein one of R 5 and R 6 is C 1-4 haloalkyl.

18. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R 6 is C 1-4 haloalkyl.

19. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R 6 is CF 3 .

20. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R 7 is H.

21. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein one of R 8 and R 8′ is H and the other is C 1-6 alkyl, C 1-6 haloalkyl, or halo.

22. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein one of R 8 and R 8′ is H and the other is C 1-6 alkyl.

23. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein one of R 8 and R 8′ is H and the other is methyl or ethyl.

24. The compound of claim 1 , or pharmaceutically accepted salt thereof, wherein R 9 and R 9′ are both H.

25. The compound of claim 1 , or pharmaceutically accepted salt thereof, having Formula Ia:

26. The compound of claim 1 , or pharmaceutically accepted salt thereof, having Formula Ib, Ic or Id:

27. The compound of claim 1 , or pharmaceutically accepted salt thereof, having Formula Ie or If:

28. The compound of claim 1 , or pharmaceutically accepted salt thereof, having the Formula Ig:

29. The compound of claim 1 , or pharmaceutically accepted salt thereof, having the Formula Ih or Ii:

30. The compound of claim 1 which is selected from:

N-[(1R,3S)-3-Isopropyl-3-9{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-Isopropyl-3-({4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-Isopropyl-3-({4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-({4-[3,5-Bis(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-3-isopropylcyclopentyl]tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-Isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

3-Ethyl-N-[(1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-Isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentyl]-3-(methoxymethyl)tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-Isopropyl-3-({4-[4-(trifluoromethyl)pyridine-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

3-Ethyl-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-Isopropyl-3-({4-[5-(trifluoromethyl)pyridin-3-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

3-Ethyl-N-[(1R,3S)-3-isopropyl-3-({4-[5-(trifluoromethyl)pyridin-3-yl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

N-{(1R,3S)-3-Isopropyl-3-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclopentyl}tetrahydro-2H-pyran-4-amine;

N-{(1R,3S)-3-Isopropyl-3-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclopentyl}-3-methyltetrahydro-2H-pyran-4-amine;

N-{(1R,3S)-3-Isopropyl-3-[(4-phenylpiperidin-1-yl)carbonyl]cyclopentyl}tetrahydro-2H-pyran-4-amine;

1-[((1S,3R)-1-Isopropyl-3-{[3-methyltetrahydro-2H-pyran-4-yl]amino}cyclopentyl)carbonyl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol;

1-[((1S,3R)-1-Isopropyl-3-{[3-methyltetrahydro-2H-pyran-4-yl]amino}cyclopentyl)carbonyl]-4-[4-(trifluoromethyl)phenyl]piperidin-4-ol;

N-((1R,3S)-3-Isopropyl-3-{[4-[2-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}cyclopentyl)tetrahydro-2H-pyran-4-amine;

N-((1R,3S)-3-Isopropyl-3-{[4-[3-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}cyclopentyl)tetrahydro-2H-pyran-4-amine;

N-((1R,3S)-3-Isopropyl-3-{[4-[3(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}cyclopentyl)-3-methyltetrahydro-2H-pyran-4-amine;

3-Ethyl-N-((1R,3S)-3-isopropyl-3-{[4-[3-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}cyclopentyl)tetrahydro-2H-pyran-4-amine;

N-((1R,3S)-3-Isopropyl-3-{[4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentyl)-3-methyltetrahydro-2H-pyran-4-amine;

3-Ethyl-N-((1R,3S)-3-isopropyl-3-{[4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentyl)tetrahydro-2H-pyran-4-amine;

N-((1R,3S)-3-Isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentyl)-3-methyltetrahydro-2H-pyran-4-amine;

3-Ethyl-N-((1R,3S)-3-Isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentyl)tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-Isopropyl-3-({-4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

3-Ethyl-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-isopropyl-3-(4-[3(trifluoromethyl)phenyl]piperidin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

N-[(1R,3S)-3-isopropyl-3-(4-[3(trifluoromethyl)phenyl]piperidin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

2-[(1R,3S)-3-[(3-methyltetrahydro-2H-pyran-4-yl)amino]-1-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]propan-2-ol;

2-[(1R,3S)-3-[(4R)-3-methyltetrahydro-2H-pyran-4-yl]amino-1-(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]propan-2-ol;

2-[(1S,3S)-3-[(3-methyltetrahydro-2H-pyran-4-yl)amino]-1-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]propan-2-ol;

N-[(1S,3S)-3-ethyl-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

(4R)-N-[(1R,3S)-3-ethyl-3-(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

N-[(1S,3S)-3-ethyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

(4R)-N-[(1R,3S)-3-methyl-3-(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

(4R)-3-methyl-N-[(1R,3S)-3-(2-methoxyethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

3-methyl-N-[(1S,3S)-3-(2-methoxyethyl)-3-(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

(4R)-N-[(1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

(4R)-N-[(1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-ethyltetrahydro-2H-pyran-4-amine;

(4R)-N-[(1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine;

(4R)-3-methyl-N-[(1R,3S)-3-(methoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

(4R)-3-methyl-N-[(1R,3S)-3-(methoxymethyl)-3-(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine;

(4R)-3-methyl-N-[(1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine; and

(4R)-3-methyl-N-[(1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine; or pharmaceutically acceptable salt thereof.

31. A composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32. A compound which is N-[3-Isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine, or pharmaceutically acceptable salt thereof.

33. The compound of claim 32 which is N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methyltetrahydro-2H-pyran-4-amine, or pharmaceutically acceptable salt thereof.

34. A method of treating a disease associated with expression or activity of a chemokine receptor in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claim 1 , 32 , or 33 , wherein said disease is lupus, or multiple sclerosis.

35. A method of treating a disease associated with expression or activity of a chemokine receptor in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claim 1 , 32 , or 33 , wherein said disease is breast cancer, ovarian cancer or multiple myeloma.