US 6,472,410 B1Granted

N-cyclopentyl modulators of chemokine receptor activity

AssigneeMerck & Co., Inc.

InventorsPaul E. Finke, Kevin T. Chapman, Malcolm Maccoss, Sander G. Mills, Jennifer L. Loebach, Bryan Oates

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Abstract

The present invention is directed to compounds of the formula I: (wherein R1, R3, R4, R5, R6, R7, R8, X, n, x and y are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.

Claims31

Dependent claims

A compound of the formula I:

wherein:
X is —(C0-2 alkyl)-Y—(C0-6 alkyl)-,
where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-3 alkyl, and
(d) trifluoromethyl,
where Y is selected from:
—NR9(CO)O— and —NR9(CO)NR10—,
where R9 is independently selected from:
hydrogen, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkyl-C3-6 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl,
and where R10 is independently selected from:
hydrogen, C1-6 alkyl, benzyl, or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl,
or where R9 and R10 may be joined together to form a 5-8 membered ring which may be unsubstituted or substituted with halo, C1-3 alkyl, and C1-3 alkoxy;
R1 is selected from:
(1) —CO2H,
(2) —NO2,
(3) -tetrazolyl,
(4) -hydroxyisoxazole,
(5) —SO2NHCO—(C0-3 alkyl)-R9, and
(6) —P(O)(OH)2;
R3 is selected from the group consisting of:
phenyl and heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2R9,
(g) —NR9R10, and
(h) —CONR9R10;
R4, R5 and R6 are independently selected from:
hydrogen, C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, —(C1-6 alkyl)-phenyl, —(C1-6 alkyl)-C3-8 cycloalkyl, naphthyl, biphenyl, and heterocycle, which is unsubstituted or substituted with 1-7 of R11 where R11 is independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2R9,
(g) —NR9R10, and
(h) —CONR9R10,
or where R4 and R5 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11,
or where R5 and R6 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11;
R7 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from:
hydroxy, cyano, and halo,
(3) hydroxy, and
(4) halo;
R8 is selected from:
hydrogen, phenyl, naphthyl, biphenyl, and heterocycle, which is unsubstituted or substituted with 1-7 of R12 where R12 is independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from:
halo, cyano, hydroxy, C1-6 alkoxy, —CO2H, —CO2(C1-6 alkyl), phenyl, trifluoromethyl, and —NR9R10,
(e) —O—C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) —CF3,
(g) —CHF2,
(h) —CH2F,
(i) —NO2,
(j) phenyl,
(k) —CO2R9,
(l) tetrazolyl,
(m) —NR9R10,
(n) —NR9—COR10,
(o) —NR9—CO2R10,
(p) —CO—NR9R10,
(q) —OCO—NR9R10,
(r) —NR9CO—NR9R10,
(s) —S(O)m—R9, wherein m is an integer selected from 0, 1 and 2,
(t) —S(O)2—NR9R10,
(u) —NR9S(O)2—R10, and
(v) —NR9S(O)2—NR9R10;
n is an integer selected from 1, 2, 3 and 4;
x is an integer selected from 0, 1 and 2, and y is an integer selected from 0, 1 and 2, with the proviso that the sum of x and y is 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

76 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of the formula I:

wherein:
X is —(C0-2 alkyl)-Y—(C0-6 alkyl)-,
where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-3 alkyl, and
(d) trifluoromethyl,
where Y is selected from:
—NR9(CO)O— and —NR9(CO)NR10—,
where R9 is independently selected from:
hydrogen, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkyl-C3-6 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl,
and where R10 is independently selected from:
hydrogen, C1-6 alkyl, benzyl, or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl,
or where R9 and R10 may be joined together to form a 5-8 membered ring which may be unsubstituted or substituted with halo, C1-3 alkyl, and C1-3 alkoxy;
R1 is selected from:
(1) —CO2H,
(2) —NO2,
(3) -tetrazolyl,
(4) -hydroxyisoxazole,
(5) —SO2NHCO—(C0-3 alkyl)-R9, and
(6) —P(O)(OH)2;
R3 is selected from the group consisting of:
phenyl and heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2R9,
(g) —NR9R10, and
(h) —CONR9R10;
R4, R5 and R6 are independently selected from:
hydrogen, C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, —(C1-6 alkyl)-phenyl, —(C1-6 alkyl)-C3-8 cycloalkyl, naphthyl, biphenyl, and heterocycle, which is unsubstituted or substituted with 1-7 of R11 where R11 is independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2R9,
(g) —NR9R10, and
(h) —CONR9R10,
or where R4 and R5 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11,
or where R5 and R6 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11;
R7 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from:
hydroxy, cyano, and halo,
(3) hydroxy, and
(4) halo;
R8 is selected from:
hydrogen, phenyl, naphthyl, biphenyl, and heterocycle, which is unsubstituted or substituted with 1-7 of R12 where R12 is independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from:
halo, cyano, hydroxy, C1-6 alkoxy, —CO2H, —CO2(C1-6 alkyl), phenyl, trifluoromethyl, and —NR9R10,
(e) —O—C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) —CF3,
(g) —CHF2,
(h) —CH2F,
(i) —NO2,
(j) phenyl,
(k) —CO2R9,
(l) tetrazolyl,
(m) —NR9R10,
(n) —NR9—COR10,
(o) —NR9—CO2R10,
(p) —CO—NR9R10,
(q) —OCO—NR9R10,
(r) —NR9CO—NR9R10,
(s) —S(O)m—R9, wherein m is an integer selected from 0, 1 and 2,
(t) —S(O)2—NR9R10,
(u) —NR9S(O)2—R10, and
(v) —NR9S(O)2—NR9R10;
n is an integer selected from 1, 2, 3 and 4;
x is an integer selected from 0, 1 and 2, and y is an integer selected from 0, 1 and 2, with the proviso that the sum of x and y is 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

76 more elements