Piperazinylpiperidine derivatives as chemokine receptor antagonists
View Patent ↗The present invention relates to compounds of Formula I: wherein variable substituents are defined herein, that modulate the activity of or bind to chemokine receptors such as CCR5. In some embodiments, the compounds of the invention are selective for CCR5. The compounds can be used, for example, to treat diseases associated with chemokine receptor expression or activity such as inflammatory diseases, immune diseases and viral infections.
1. A compound of Formula I:
or pharmaceutically acceptable salt thereof, wherein:
R 1 is pyrimidinyl optionally substituted by one or more R 6 ;
R 2 is H, halo, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, SOR 7 , SO 2 R 7 , COR 8 , OR 9 , SR 9 , COOR 9 , NR 10 R 11 or NR 10 COR 8 ;
R 3 is F, Cl, Br, I, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or heteroaryl;
R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 haloalkyl;
R 5 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 haloalkyl;
R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, amino, (C 1 -C 6 alkyl)amino or di(C 1 -C 6 alkyl)amino;
R 7 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C 3 -C 7 cycloalkyl)alkyl, heterocycloalkylalkyl, or NR 12 R 13 ;
R 8 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C 3 -C 7 cycloalkyl)alkyl, heterocycloalkylalkyl, or NR 12 R 13 ;
R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, cycloalkyloxyalkyl, heterocycloalkyloxyalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C 3 -C 7 cycloalkyl)alkyl or heterocycloalkylalkyl;
R 10 and R 11 are each, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C 3 -C 7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R 10 and R 11 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
R 12 and R 13 are each, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C 3 -C 7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R 12 and R 13 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
r is 1, 2 or 3.
2. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is:
3. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OR 9 , SR 9 or NR 10 R 11 .
4. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2 is H or OR 9 .
5. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 3 is F, Br, CF 3 , or 6- or 5-membered heteroaryl.
6. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl.
7. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
8. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 5 is C 1 -C 6 alkyl.
9. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
10. The compound of claim 1 , or pharmaceutically acceptable salt thereof, having Formula IIa:
or pharmaceutically acceptable salt form thereof.
11. The compound of claim 10 , or pharmaceutically acceptable salt thereof, wherein R 1 is:
12. The compound of claim 1 selected from:
5-({4-[(3S)-4-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(6-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(7-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
4,6-dimethyl-5-[(4-methyl-4-{(3S)-3-methyl-4-[6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidin-1-yl)carbonyl]pyrimidine;
4,6-dimethyl-5-[(4-methyl-4-{(3S)-3-methyl-4-[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidin-1-yl)carbonyl]pyrimidine;
1-((2S)-4-{1-[(4,6-dimethylpyrimidin-5-yl)carbonyl]-4-methylpiperidin-4-yl}-2-methylpiperazin-1-yl)-5-(trifluoromethyl)inden-2-ol;
5-[(4-{(3S)-4-[2-methoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl) carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl) carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[(1R,2R)-2-(2-Methoxyethoxy)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl) carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[(1R,2R)-5-Bromo-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl) carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[(1R,2R)-5-Bromo-2-(pyridin-2-yloxy)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl) carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(1,3-thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-pyridin-2-yl-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[3-Methoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine, or pharmaceutically acceptable salts thereof.
13. A composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A compound which is 5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 which is 5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride.
16. A compound which is 5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(1,3-thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine, or a pharmaceutically acceptable salt thereof.
17. A compound which is 5-[(4-{4-[2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine, or a pharmaceutically acceptable salt thereof.
18. The compound of claim 17 which is 5-[(4-{4-[2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride.
19. A compound which is 5-[(4-{4-[2-ethoxy-5-(1,3-thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine, or a pharmaceutically acceptable salt thereof.
20. A compound of Formula I:
or pharmaceutically acceptable salt thereof, wherein:
R 1 is pyrimidinyl optionally substituted by one or more R 6 ;
R 2 is H, halo, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, SOR 7 , SO 2 R 7 , COR 8 , OR 9 , SR 9 , COOR 9 , NR 10 R 11 or NR 10 COR 8 ;
R 3 is F, Cl, Br, I or C 1 -C 4 haloalkyl;
R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 haloalkyl;
R 5 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 haloalkyl;
R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, amino, (C 1 -C 6 alkyl)amino or di(C 1 -C 6 alkyl)amino;
R 7 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C 3 -C 7 cycloalkyl)alkyl, heterocycloalkylalkyl,or NR 12 R 13 ;
R 8 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C 3 -C 7 cycloalkyl)alkyl, heterocycloalkylalkyl, or NR 12 R 13 ;
R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, cycloalkyloxyalkyl, heterocycloalkyloxyalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C 3 -C 7 cycloalkyl)alkyl or heterocycloalkylalkyl;
R 10 and R 11 are each, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C 3 -C 7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R 10 and R 11 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
R 12 and R 13 are each, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C 3 -C 7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R 12 and R 13 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
r is 1, 2 or 3.
21. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein R 1 is
22. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein R 2 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OR 9 , SR 9 or NR 10 R 11 .
23. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein R 2 is H or OR 9 .
24. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein R 3 is F, Br or CF 3 .
25. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl.
26. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
27. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein R 5 is C 1 -C 6 alkyl.
28. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
29. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein r is 1.
30. The compound of claim 20 , or pharmaceutically acceptable salt thereof, wherein r is 2.
31. The compound of claim 20 having Formula II:
or pharmaceutically acceptable salt form thereof.
32. The compound of claim 31 , or pharmaceutically acceptable salt thereof, wherein R 1 is
33. The compound of claim 31 , or pharmaceutically acceptable salt thereof, wherein R 2 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OR 9 , SR 9 or NR 10 R 11 .
34. The compound of claim 31 , or pharmaceutically acceptable salt thereof, wherein R 2 is H or OR 9 .
35. The compound of claim 31 , or pharmaceutically acceptable salt thereof, wherein R 3 is F, Br or CF 3 .