Gamma-aminoamide modulators of chemokine receptor activity
View Patent ↗The present invention is directed to compounds of the formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , W, X, and n 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 Ib:
wherein the dashed line represents a single or a double bond and wherein
R 1 is selected from:
and positional and stereo isomers thereof;
R 2 is selected from: (C 0-6 alkyl)-phenyl and (C 0-6 alkyl)-heterocycle, where the alkyl is unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-3 alkyl,
(d) trifluoromethyl,
(e) —C 1-3 alkyl,
(f) —CO 2 R 9 , and
(g) oxo;
and where the phenyl and the heterocycle may be unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl
(c) trifluoromethoxy,
(d) hydroxy,
(e) C 1-6 alkyl,
(f) C 3-7 cycloalkyl,
(g) —O—C 1-6 alkyl,
(h) —O—C 3-7 cycloalkyl,
(i) —SCF 3 ,
(j) —S—C 1-6 alkyl,
(k) —SO 2 —C 1-6 alkyl,
(l) phenyl,
(m) hetreocycle,
(n) —CO 2 R 9 ,
(o) —CN,
(p) —NR 9 R 10 ,
(q) —NR 9 —SO 2 —R 10 ,
(r) —SO 2 —NR 9 R 10 ,
(s) —ONR 9 R 10 , and
(t) —O -phenyl;
R 5 is selected from:
(a) hydrogen,
(b) hydroxy,
(c) C 1-6 alkyl,
(d) C 1-6 alkyl-hydroxy,
(e) —O—C 1-3 alkyl,
(f) oxo, and
(g) halo,
(h) C 0-4 CO 2 R 9 , and
(i) CF 3 ,
R 15 and R 16 are independently selected from:
(a) hydrogen,
(b) halo,
(c) trifluoromethyl,
(d) hydroxy,
(e) C 1-3 alkyl,
(f) —O—C 1-3 alkyl,
(g) —CO 2 H,
(h) –CO 2 C 1-3 alkyl,
(i) —CN, and
(j) heterocycle;
and pharmaceutically acceptable salts and individual diastereomers thereof.
2. The compound of claim 1 wherein R 2 is selected from:
(1) —CH 2 -(phenyl),
(2) —CH 2 -(4-bromophenyl),
(3) —CH 2 -(3-chlorophenyl),
(4) —CH 2 -(3,5-difluorophenyl),
(5) —CH 2 -((2-trifluoromethyl)phenyl),
(6) —CH 2 -((3-trifluoromethyl)phenyl),
(7) —CH 2 -((4-trifluoromethyl)phenyl),
(8) —CH 2 -((3-trifluoromethoxy)phenyl),
(9) —CH 2 -((3-trifluoromethylthio)phenyl),
(10) —CH 2 -((3-trifluoromethoxy-5-thiomethyl)phenyl),
(11) —CH 2 -((3-trifluoromethoxy-5-methoxy)phenyl),
(12) —CH 2 -((3-trifluoromethoxy-5-methanesulfonyl)phenyl),
(13) —CH 2 -((3-trifluoromethoxy-5-amino)phenyl),
(14) —CH 2 -((3-trifluoromethoxy-5-aminomethanesulfonyl)phenyl),
(15) —CH 2 -((3-trifluoromethoxy-5-sulfonylamino)phenyl),
(16) —CH 2 -((3,5-bis-trifluoromethyl)phenyl),
(17) —CH 2 -((3-fluoro-5-trifluoromethyl)phenyl),
(18) —CH(CH 3 )-((3,5-bis-trifluoromethyl)phenyl),
(19) —C(CH 3 )2-((3,5-bis-trifluoromethyl)phenyl),
(20) —CH 2 -(4-(2-trifluoromethyl)pyridyl),
(21) —CH 2 -(5-(3-trifluoromethyl)pyridyl),
(22) —CH 2 -(5-(3-trifluoromethyl)pyridazinyl),
(23) —CH 2 -(4-(2-trifluoromethyl)pyridyl-N-oxide), and
(24) —CH 2 -(5-(3-trifluoromethyl)pyridyl-N-oxide).
3. The compound of claim 1 of the formula:
wherein the dashed line represents a single or a double bond,
R 5 is hydrogen or methyl;
and pharmaceutically acceptable salts and individual diastereomers thereof.