US 2004/0167156 A1 · TETRAHYDROPYRANYL CYCLOPENTYL TETRAHYDROPYRIDOPYRIDINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

Abstract

The present invention is directed to compounds of the formula I: 1 (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, n and the dashed line 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.

A compound of the formula I:

357
wherein:
X is selected from the group consisting of:
—O—, —NR20—, —S—, —SO—, —SO2—, and —CR21R22—, —NSO2R20—NCOR20—, —NCO2R20—, —CR21 CO2R20—, —CR21 0 COR20—, —CO—,
where R20 is selected from:
hydrogen, C1-6 alkyl, benzyl, phenyl, C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl,
where R21 and R22 are independently selected from:
hydrogen, hydroxy, C1-6 alkyl, —O—C1-6alkyl, benzyl, phenyl, C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl;
R1 is selected from:
—C1-6alkyl, —C0-6alkyl-O—C1-6alkyl-, —C0-6alkyl-S—C 16 alkyl-, —(C0-6alkyl)-(C3-7cycloalkyl)-(C0-6alkyl), hydroxy, —CO2R20, heterocycle, —CN, —NR20R26—, —NSO2R20—, —NCOR20—, —NCO2R20—, —NCOR20—, —CR21 CO2R20—, —CR21 OCOR20—, phenyl and pyridyl,
where R26 is selected from:
hydrogen, C1-6 alkyl, benzyl, phenyl, C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl
where the alkyl and the cycloalkyl are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-3alkyl,
(d) trifluoromethyl,
(f) C1-3alkyl,
(g) —O—C1-3alkyl,
(h) —CO2R20,
(i) —SO2R20,
(j) —NHCOCH3,
(k) —NHSO2CH3,
(l) -heterocycle,
(m) ═O,
(n) —CN,
and where the phenyl and pyridyl are unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, hydroxy, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
R2 is selected from:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) C1-3alkyl, where the alkyl is unsubstituted or substituted with 1-6 substituents independently selected from:
fluoro, and hydroxy,
(e) —NR20R26,
(f) —CO2R20,
(g) —CONR20R26,
(h) —NR20COR21,
(i) —OCONR20R26,
(j) —NR20CONR20R26,
(k) -heterocycle,
(l) —CN,
(m) —NR20—SO2—NR20R26,
(n) —NR20—SO2—R26,
(o) —SO2—NR20R26, and
(p) ═O, where R2 is connected to the ring via a double bond;
R3 is oxygen or is absent;
R4 is selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) trifluoromethyl,
(d) trifluoromethoxy,
(e) chloro,
(f) fluoro,
(g) bromo, and
(h) phenyl;
R5 is selected from:
(a) C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro and optionally substituted with hydroxyl,
(b) —O—C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(c) —CO—C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(d) —S—C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(e) -pyridyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of:
halo, trifluoromethyl, C1-4alkyl, and CO2R20,
(f) fluoro,
(g) chloro,
(h) bromo,
(i) —C4-6cycloalkyl,
(j) —O—C4-6cycloalkyl,
(k) phenyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of:
halo, trifluoromethyl, C1-4alkyl, and CO2R20,
(l) —O-phenyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of:
halo, trifluoromethyl, C1-4alkyl, and CO2R20,
(m) —C3-6cycloalkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(n) —O—C3-6cycloalkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(o) -heterocycle,
(p) —CN, and
(q) —CO2R20;
R6 is selected from:
(a) hydrogen,
(b) C1-6alkyl, and
(c) trifluoromethyl
(d) fluoro
(e) chloro, and
(f) bromo;
R7 is selected from:
(a) hydrogen, and
(b) C1-6alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, hydroxy, —CO2H, —CO2C1-6alkyl, and —O—C1-3alkyl;
R8 is selected from:
(a) hydrogen,
(b) C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 substituents where the substituents are chosen from the group:
fluoro, C1-3alkoxy, hydroxy, —CO2R20,
(c) fluoro,
(d) —O—C1-3alkyl, where alkyl may be unsubstituted or substituted with 1-3 fluoro, and
(e) C3-6 cycloalkyl,
(f) —O—C3-6cycloalkyl,
(g) hydroxy,
(h) —CO2R20,
(i) —OCOR20,
or R7 and R8 may be joined together via a C2-4alkyl or a C0-2alkyl-O—C1-3alkyl chain to form a 5-7 membered ring;
R9 is selected from:
(a) hydrogen,
(b) C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 substituents where the substituents are chosen from the group:
fluoro, C1-3alkoxy, hydroxy, —CO2R20,
(c) CO2R20,
(d) hydroxy, and
(e) —O—C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 substituents where the substituents are chosen from the group:
fluoro, C1-3alkoxy, hydroxy, —CO2R20,
or R8 and R9 may be joined together by a C1-4alkyl chain or a C0-3alkyl-O—C0-3alkyl chain to form a 3-6 membered ring;
R10 is selected from:
(a) hydrogen, and
(b) C1-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(c) fluoro,
(d) —O—C3-6cycloalkyl, and
(e) —O—C1-3alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
or R8 and R10 may be joined together by a C2-3alkyl chain to form a 5-6 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from:
halo, hydroxy, —CO2R20, C1-3alkyl, and C1-3alkoxy, or R8 and R10 may be joined together by a C1-2alkyl-O—C1-2alkyl chain to form a 6-8 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from:
halo, hydroxy, —CO2R20, C1-3alkyl, and C1-3alkoxy,
or R8 and R10 may be joined together by a —O—C1-2alkyl-O-chain to form a 6-7 membered ring, where the alkyl are unsubstituted or substituted with 1-3 substituents where the substiuents are independently selected from:
halo, hydroxy, —CO2R20, C1-3alkyl, and C1-3alkoxy;
n is selected from 0, 1 and 2;
the dashed line represents a single or a double bond;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

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Abstract

Claims28