US 7,598,243 B2Granted

Heterocyclic cyclopentyl tetrahydroisoquinoline and tetrahydropyridopyridine modulators of chemokine receptor activity

AssigneeMerck & Co., Inc.

InventorsGabor Butora, Stephen D. Goble, Alexander Pasternak, Lihu Yang, Changyou Zhou, Christopher R. Moyes

Life of this patent

Estimating the term…

Abstract

The present invention is directed to compounds of the formula I: Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, n and the broken lines are as 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.

Claims11

Dependent claims

A compound of formula I:

wherein:
X is selected from the group consisting of:
N, O, S and SO2;
Y is N or C;
R1 is selected from the group consisting of:
hydrogen, —C1-6alkyl, —C0-6alkyl-O—C1-6alkyl, —C0-6alkyl-S—C1-6alkyl, —(C0-6alkyl)-(C3-7cycloalkyl)-(C0-6alkyl), hydroxy, heterocycle, —CN, —NR12R12, —NR12COR13, —NR12SO2R14, —COR11, —CONR12R12, and phenyl,
where R11 is independently selected from the group consisting of:
hydroxy, hydrogen, C1-6alkyl, —O—C1-6alkyl, benzyl, phenyl and 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 the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl, and
where R12 is selected from the group consisting of:
hydrogen, C1-6 alkyl, benzyl, phenyl and 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 the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl, and
where R13 is selected from the group consisting of:
hydrogen, C1-6 alkyl, —O—C1-6alkyl, benzyl, phenyl and 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 the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl, and
where R14 is selected from the group consisting of:
hydroxy, C1-6 alkyl, —O—C1-6alkyl, benzyl, phenyl and C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where said substituents are independently selected from the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl, and
where said alkyl and said cycloalkyl are unsubstituted or substituted with 1-7 substituents where said substituents are independently selected from the group consisting of:
(a) halo,
(b) hydroxy,
(c) —O—C1-3alkyl,
(d) trifluoromethyl,
(f) C1-3alkyl,
(g) —O—C1-3alkyl,
(h) —COR11,
(i) —SO2R14,
(j) —NHCOCH3,
(k) —NHSO2CH3,
(l) -heterocycle,
(m) ═O and
(n) —CN,
and where said phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents where said substituents are independently selected from the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
R2 is selected from the group consisting of:
(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) —NR12R12,
(f) —COR11,
(g) —CONR12R12,
(h) —NR12COR13,
(i) —OCONR12R12,
(j) —NR12CONR12R12,
(k) -heterocycle,
(l) —CN,
(m) —NR12—SO2—NR12R12,
(n) —NR12—SO2—R14,
(o) —SO2—NR12R12, and
(p) ═O, where R2 is connected to the ring via a double bond;
R3 is oxygen or is absent when Y is N;
R3 is selected from the following groups when Y is C:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) C1-3alkyl, where said alkyl is unsubstituted or substituted with 1-6 substituents independently selected from:
fluoro, hydroxy, and —COR11,
(e) —NR12R12,
(f) —COR11,
(g) —CONR12R12,
(h) —NR12COR13,
(i) —OCONR12R12,
(j) —NR12CONR12R12,
(k) -heterocycle,
(l) —CN,
(m) —NR12—SO2—NR12R12,
(n) —NR12—SO2—R14,
(o) —SO2—NR12R12 and
(p) nitro;
R4 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl,
(c) trifluoromethyl,
(d) trifluoromethoxy,
(e) chloro,
(f) fluoro,
(g) bromo, and
(h) phenyl;
R5 is selected from the group consisting of:
(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 COR11,
(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 COR11,
(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 COR11,
(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) —COR11;
R6 is selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) trifluoromethyl,
(d) fluoro,
(e) chloro, and
(f) bromo;
R7 is selected from:
hydrogen, (C0-6alkyl)-phenyl, (C0-6alkyl)-heterocycle, (C0-6alkyl)-C3-7cycloalkyl , (C0-6alkyl)-COR11, (C0-6alkyl)-(alkene)-COR11, (C0-6alkyl)-SO3H, (C0-6alkyl)-W—C0-4alkyl, (C0-6alkyl)-CONR12-phenyl, (C0-6alkyl)-CONR15—V—COR11, and nothing (when X is O, S, or SO2), where V is C1-6alkyl or phenyl,
where W is selected from the group consisting of:
a single bond, —O—, —S—, —SO—, —SO2—, —CO—, —CO2—, —CONR12— and —NR12—,
where the R15 can be hydrogen, C1-4alkyl, or where R15 is joined via a 1-5 carbon tether to one of the carbons of V to form a ring,
where the C0-6alkyl is unsubstituted or substituted with 1-5 substituents, where said substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —C0-6alkyl
(d) —O—C1-3alkyl,
(e) trifluoromethyl, and
(f) —C0-2alkyl-phenyl,
where said phenyl, heterocycle, cycloalkyl, and C0-4alkyl is unsubstituted or substituted with 1-5 substituents where said substituents are independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3alkyl,
(e) —O—C1-3alkyl,
(f) —C0-3—COR11,
(g) —CN,
(h) —NR12R12,
(i) —CONR12R12, and
(j) —C0-3-heterocycle,
or where the phenyl and heterocycle may be fused to another heterocycle, which itself may be unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, —COR11, and —C1-3alkyl,
and where alkene is unsubstituted or substituted with 1-3 substituents which are independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) C1-3alkyl,
(d) phenyl, and
(e) heterocycle;
R8 is nothing;
or R7 and R9 may be joined together to form a ring which is heterocycle,
wherein said ring is unsubstituted or substituted with 1-7 substituents where said substituents are independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3alkyl,
(e) —O—C1-3alkyl,
(f) —COR11,
(g) —CN,
(h) —NR12R12, and
(i) —CONR12R12;
R9 and R10 are independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) C1-6alkyl
(d) C1-6alkyl-COR11,
(e) C1-6alkyl-hydroxy,
(f) —O—C1-3alkyl,
(g) ═O, when R9 or R10 is connected to the ring via a double bond, and
(h) halo;
n is 1;
the dashed line represents a single or a double bond;
or a pharmaceutically acceptable salt thereof.

158 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/260,008Filed 15 Oct 2004 · continuation in part
Priority: 17 Apr 2003
Published: US 2008/0081803 A13 Apr 2008
Granted: 6 Oct 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 401/08
Containing two hetero rings: linked by a carbon chain containing alicyclic rings
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 35/00
Antineoplastic agents

Family

Application60/463,673Us provisional application · filed 17 Apr 2003
PCT/US2004/011463Parent of this continuation-in-part · filed 14 Apr 2004
US 2008/0081803 A1Pre-grant publication · published 3 Apr 2008
US 7,598,243 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula I:

wherein:
X is selected from the group consisting of:
N, O, S and SO2;
Y is N or C;
R1 is selected from the group consisting of:
hydrogen, —C1-6alkyl, —C0-6alkyl-O—C1-6alkyl, —C0-6alkyl-S—C1-6alkyl, —(C0-6alkyl)-(C3-7cycloalkyl)-(C0-6alkyl), hydroxy, heterocycle, —CN, —NR12R12, —NR12COR13, —NR12SO2R14, —COR11, —CONR12R12, and phenyl,
where R11 is independently selected from the group consisting of:
hydroxy, hydrogen, C1-6alkyl, —O—C1-6alkyl, benzyl, phenyl and 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 the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl, and
where R12 is selected from the group consisting of:
hydrogen, C1-6 alkyl, benzyl, phenyl and 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 the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl, and
where R13 is selected from the group consisting of:
hydrogen, C1-6 alkyl, —O—C1-6alkyl, benzyl, phenyl and 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 the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl, and
where R14 is selected from the group consisting of:
hydroxy, C1-6 alkyl, —O—C1-6alkyl, benzyl, phenyl and C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where said substituents are independently selected from the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl, and
where said alkyl and said cycloalkyl are unsubstituted or substituted with 1-7 substituents where said substituents are independently selected from the group consisting of:
(a) halo,
(b) hydroxy,
(c) —O—C1-3alkyl,
(d) trifluoromethyl,
(f) C1-3alkyl,
(g) —O—C1-3alkyl,
(h) —COR11,
(i) —SO2R14,
(j) —NHCOCH3,
(k) —NHSO2CH3,
(l) -heterocycle,
(m) ═O and
(n) —CN,
and where said phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents where said substituents are independently selected from the group consisting of:
halo, hydroxy, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
R2 is selected from the group consisting of:
(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) —NR12R12,
(f) —COR11,
(g) —CONR12R12,
(h) —NR12COR13,
(i) —OCONR12R12,
(j) —NR12CONR12R12,
(k) -heterocycle,
(l) —CN,
(m) —NR12—SO2—NR12R12,
(n) —NR12—SO2—R14,
(o) —SO2—NR12R12, and
(p) ═O, where R2 is connected to the ring via a double bond;
R3 is oxygen or is absent when Y is N;
R3 is selected from the following groups when Y is C:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) C1-3alkyl, where said alkyl is unsubstituted or substituted with 1-6 substituents independently selected from:
fluoro, hydroxy, and —COR11,
(e) —NR12R12,
(f) —COR11,
(g) —CONR12R12,
(h) —NR12COR13,
(i) —OCONR12R12,
(j) —NR12CONR12R12,
(k) -heterocycle,
(l) —CN,
(m) —NR12—SO2—NR12R12,
(n) —NR12—SO2—R14,
(o) —SO2—NR12R12 and
(p) nitro;
R4 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl,
(c) trifluoromethyl,
(d) trifluoromethoxy,
(e) chloro,
(f) fluoro,
(g) bromo, and
(h) phenyl;
R5 is selected from the group consisting of:
(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 COR11,
(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 COR11,
(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 COR11,
(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) —COR11;
R6 is selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) trifluoromethyl,
(d) fluoro,
(e) chloro, and
(f) bromo;
R7 is selected from:
hydrogen, (C0-6alkyl)-phenyl, (C0-6alkyl)-heterocycle, (C0-6alkyl)-C3-7cycloalkyl , (C0-6alkyl)-COR11, (C0-6alkyl)-(alkene)-COR11, (C0-6alkyl)-SO3H, (C0-6alkyl)-W—C0-4alkyl, (C0-6alkyl)-CONR12-phenyl, (C0-6alkyl)-CONR15—V—COR11, and nothing (when X is O, S, or SO2), where V is C1-6alkyl or phenyl,
where W is selected from the group consisting of:
a single bond, —O—, —S—, —SO—, —SO2—, —CO—, —CO2—, —CONR12— and —NR12—,
where the R15 can be hydrogen, C1-4alkyl, or where R15 is joined via a 1-5 carbon tether to one of the carbons of V to form a ring,
where the C0-6alkyl is unsubstituted or substituted with 1-5 substituents, where said substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —C0-6alkyl
(d) —O—C1-3alkyl,
(e) trifluoromethyl, and
(f) —C0-2alkyl-phenyl,
where said phenyl, heterocycle, cycloalkyl, and C0-4alkyl is unsubstituted or substituted with 1-5 substituents where said substituents are independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3alkyl,
(e) —O—C1-3alkyl,
(f) —C0-3—COR11,
(g) —CN,
(h) —NR12R12,
(i) —CONR12R12, and
(j) —C0-3-heterocycle,
or where the phenyl and heterocycle may be fused to another heterocycle, which itself may be unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, —COR11, and —C1-3alkyl,
and where alkene is unsubstituted or substituted with 1-3 substituents which are independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) C1-3alkyl,
(d) phenyl, and
(e) heterocycle;
R8 is nothing;
or R7 and R9 may be joined together to form a ring which is heterocycle,
wherein said ring is unsubstituted or substituted with 1-7 substituents where said substituents are independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3alkyl,
(e) —O—C1-3alkyl,
(f) —COR11,
(g) —CN,
(h) —NR12R12, and
(i) —CONR12R12;
R9 and R10 are independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) C1-6alkyl
(d) C1-6alkyl-COR11,
(e) C1-6alkyl-hydroxy,
(f) —O—C1-3alkyl,
(g) ═O, when R9 or R10 is connected to the ring via a double bond, and
(h) halo;
n is 1;
the dashed line represents a single or a double bond;
or a pharmaceutically acceptable salt thereof.

158 more elements

Facts

Application

10/260,008Filed 15 Oct 2004 · continuation in part

Priority

17 Apr 2003

Published

US 2008/0081803 A13 Apr 2008

Granted

6 Oct 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 401/08
Containing two hetero rings: linked by a carbon chain containing alicyclic rings
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 35/00
Antineoplastic agents