Aminocyclopentyl fused heterotricylicamide modulators of chemokine receptor activity
View Patent ↗The present invention is directed to compounds of formulae (I and II)(wherein A, D, E, X, l, m, n and R 1 through R 18 are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.
1. A compound of the formula II
wherein:
A is selected from the group consisting of C and N;
D is independently selected from the group consisting of C, N, O, —SO— and —SO 2 —, E is N;
Y is selected from the group consisting of —CH 2 — and —O—;
R 1 is selected from the group consisting of:
(a) C 1-6 alkyl,
(b) C 1-6 alkyl substituted with hydroxy, and
(c) C 1-6 alkyl substituted with 1-6 fluoro;
if D is C, R 2 is selected from the group consisting of:
(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, and
(i) =O;
if D is N, R 2 is selected from the group consisting of:
(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) phenyl,
(e) O, and
(f) nothing;
if D is O, SO, or SO 2 , R 2 is nothing;
R 3 is selected from the group consisting of:
(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) phenyl,
(e) O, and
(f) nothing;
if E is O, SO, or SO 2 , R 3 is nothing;
R 4 is hydrogen;
R 5 is selected from the group consisting of:
(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;
R 6 is hydrogen;
R 15 is selected from the group consisting of hydrogen and methyl;
R 16 is selected from the group consisting of:
(a) hydrogen,
(b) C 1-3 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(c) —O—C 1-3 alkyl,
(d) fluoro, and
(e) hydroxy;
R 17 is hydrogen;
R 18 is selected from the group consisting of:
(a) hydrogen,
(b) methyl, and
(c) methoxy; and
1 is 1;
or a pharmaceutically acceptable salt or individual diastereomer thereof.
2. The compound of claim 1 of the formula IIa:
or a pharmaceutically acceptable salt or individual diastereomer thereof.
3. The compound of claim 1 of the formula IIb:
or a pharmaceutically acceptable salt or individual diastereomer thereof.
4. A compound selected from
or a pharmaceutically acceptable salt or individual diastereomer thereof.
5. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 .
6. The compound of claim 1 , wherein A is N.
7. The compound of claim 1 , wherein D is selected from the group consisting of C, N, and SO 2 .
8. The compound of claim 1 , wherein R 1 is selected from the group consisting of:
(a) —CH(CH 3 ) 2 ,
(b) —CH(OH)CH 3 , and
(c) —CH 2 CF 3 .
9. The compound of claim 1 , wherein when D is C, R 2 is hydrogen, hydroxy, or oxo.
10. The compound of claim 1 , wherein when D is N, R 2 is hydrogen or is nothing.
11. The compound of claim 1 , wherein R 3 is hydrogen or methyl.
12. The compound of claim 1 , wherein R 5 is selected from the group consisting of:
(a) trifluoromethyl,
(b) trifluoromethoxy,
(c) chloro,
(d) bromo, and
(e) phenyl.
13. The compound of claim 1 , wherein R 5 is trifluoromethyl.
14. The compound of claim 1 , wherein R 16 is selected from the group consisting of:
(a) hydrogen,
(b) trifluoromethyl,
(c) methyl,
(d) methoxy,
(e) ethoxy,
(f) ethyl,
(g) fluoro, and
(h) hydroxy.
15. The compound of claim 1 , wherein R 18 is hydrogen.