Heterocyclic cyclopentyl tetrahydroisoquinoline and tetrahydropyridopyridine 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 9 , 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.
1. A compound of formula I:
wherein:
X is selected from the group consisting of:
N, O, S and SO 2 ;
Y is N or C;
R 1 is selected from the group consisting of:
hydrogen, —C 1-6 alkyl, —C 0-6 alkyl-O—C 1-6 alkyl, —C 0-6 alkyl-S—C 1-6 alkyl, —(C 0-6 alkyl)-(C 3-7 cycloalkyl)-(C 0-6 alkyl), hydroxy, heterocycle, —CN, —NR 12 R 12 , —NR 12 COR 13 , —NR 12 SO 2 R 14 , —COR 11 , —CONR 12 R 12 , and phenyl,
where R 11 is independently selected from the group consisting of: hydroxy, hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 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, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl, and
where R 12 is selected from the group consisting of: hydrogen, C 1-6 alkyl, benzyl, phenyl and C 3-6 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, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl, and
where R 13 is selected from the group consisting of: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 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, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl, and
where R 14 is selected from the group consisting of: hydroxy, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 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, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 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—C 1-3 alkyl,
(d) trifluoromethyl,
(f) C 1-3 alkyl,
(g) —O—C 1-3 alkyl,
(h) —COR 11 ,
(i) —SO 2 R 14 ,
(j) —NHCOCH 3 ,
(k) —NHSO 2 CH 3 ,
(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, C 1-3 alkyl, C 1-3 alkoxy and trifluoromethyl;
R 2 is selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) C 1-3 alkyl, where the alkyl is unsubstituted or substituted with 1-6 substituents independently selected from fluoro and hydroxy,
(e) —NR 12 R 12 ,
(f) —COR 11 ,
(g) —CONR 12 R 12 ,
(h) —NR 12 COR 13 ,
(i) —OCONR 12 R 12 ,
(j) —NR 12 CONR 12 R 12 ,
(k) -heterocycle,
(l) —CN,
(m) —NR 12 —SO 2 —NR 12 R 12 ,
(n) —NR 12 —SO 2 —R 14 ,
(o) —SO 2 —NR 12 R 12 , and
(p) ═O, where R 2 is connected to the ring via a double bond;
R 3 is oxygen or is absent when Y is N;
R 3 is selected from the following groups when Y is C:
(a) hydrogen,
(b) hydroxy,
(c) halo,
(d) C 1-3 alkyl, where said alkyl is unsubstituted or substituted with 1-6 substituents independently selected from: fluoro, hydroxy, and —COR 11 ,
(e) —NR 12 R 12 ,
(f) —COR 11 ,
(g) —CONR 12 R 12 ,
(h) —NR 12 COR 13 ,
(i) —OCONR 12 R 12 ,
(j) —NR 12 CONR 12 R 12 ,
(k) -heterocycle,
(l) —CN,
(m) —NR 12 —SO 2 —NR 12 R 12 ,
(n) —NR 12 —SO 2 —R 14 ,
(o) —SO 2 —NR 12 R 12 and
(p) nitro;
R 4 is selected from the group consisting of:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) trifluoromethyl,
(d) trifluoromethoxy,
(e) chloro,
(f) fluoro,
(g) bromo, and
(h) phenyl;
R 5 is selected from the group consisting of:
(a) C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro and optionally substituted with hydroxyl,
(b) —O—C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(c) —CO—C 1-6 alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(d) —S—C 1-6 alkyl, 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, C 1-4 alkyl, and COR 11 ,
(f) fluoro,
(g) chloro,
(h) bromo,
(i) —C 4-6 cycloalkyl,
(j) —O—C 4-6 cycloalkyl,
(k) phenyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, trifluoromethyl, C 1-4 alkyl, and COR 11 ,
(l) —O-phenyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, trifluoromethyl, C 1-4 alkyl, and COR 11 ,
(m) —C 3-6 cycloalkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(n) —O—C 3-6 cycloalkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro,
(o) -heterocycle,
(p) —CN, and
(q) —COR 11 ;
R 6 is selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) trifluoromethyl,
(d) fluoro,
(e) chloro, and
(f) bromo;
R 7 is selected from:
hydrogen, (C 0-6 alkyl)-phenyl, (C 0-6 alkyl)-heterocycle, (C 0-6 alkyl)-C 3-7 cycloalkyl , (C 0-6 alkyl)-COR 11 , (C 0-6 alkyl)-(alkene)-COR 11 , (C 0-6 alkyl)-SO 3 H, (C 0-6 alkyl)-W—C 0-4 alkyl, (C 0-6 alkyl)-CONR 12 -phenyl, (C 0-6 alkyl)-CONR 15 —V—COR 11 , and nothing (when X is O, S, or SO 2 ), where V is C 1-6 alkyl or phenyl,
where W is selected from the group consisting of: a single bond, —O—, —S—, —SO—, —SO 2 —, —CO—, —CO 2 —, —CONR 12 — and —NR 12 —,
where the R 15 can be hydrogen, C 1-4 alkyl, or where R 15 is joined via a 1-5 carbon tether to one of the carbons of V to form a ring,
where the C 0-6 alkyl is unsubstituted or substituted with 1-5 substituents, where said substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —C 0-6 alkyl
(d) —O—C 1-3 alkyl,
(e) trifluoromethyl, and
(f) —C 0-2 alkyl-phenyl,
where said phenyl, heterocycle, cycloalkyl, and C 0-4 alkyl 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) C 1-3 alkyl,
(e) —O—C 1-3 alkyl,
(f) —C 0-3 —COR 11 ,
(g) —CN,
(h) —NR 12 R 12 ,
(i) —CONR 12 R 12 , and
(j) —C 0-3 -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, —COR 11 , and —C 1-3 alkyl,
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) C 1-3 alkyl,
(d) phenyl, and
(e) heterocycle;
R 8 is nothing;
or R 7 and R 9 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) C 1-3 alkyl,
(e) —O—C 1-3 alkyl,
(f) —COR 11 ,
(g) —CN,
(h) —NR 12 R 12 , and
(i) —CONR 12 R 12 ;
R 9 and R 10 are independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) C 1-6 alkyl
(d) C 1-6 alkyl-COR 11 ,
(e) C 1-6 alkyl-hydroxy,
(f) —O—C 1-3 alkyl,
(g) ═O, when R 9 or R 10 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.
2. The compound of claim 1 having formula If:
wherein X is N or O,
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein
X is O;
R 3 is absent when Y is N and hydrogen when Y is C;
R 7 is nothing; and
R 2 is hydrogen;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein R 1 is selected from the group consisting of:
—C 1-6 alkyl, —C 0-6 alkyl-O—C 1-6 alkyl, and
—(C 0-6 alkyl)-(C 3-7 cycloalkyl)-(C 0-6 alkyl),
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—C 1-3 alkyl,
(d) trifluoromethyl,
(f) C 1-3 alkyl,
(g) —O—C 1-3 alkyl,
(h) —COR 11 ,
(i) —CN,
(j) —NR 12 R 12 , and
(k) —CONR 12 R 12 ,
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein R 1 is selected from the group consisting of:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from the group consisting of:
(a) halo,
(b) hydroxy,
(c) —O—C 1-3 alkyl,
(d) trifluoromethyl, and
(e) —COR 11 ,
(2) —C 0-6 alkyl-O—C 1-6 alkyl-, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl, and
(c) —COR 11 ,
(3) and —(C 3-5 cycloalkyl)-(C 0-6 alkyl), which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from the group consisting of:
(a) halo,
(b) hydroxy,
(c) —O—C 1-3 alkyl,
(d) trifluoromethyl, and
(e) —COR 11 ,
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 wherein 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,
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 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 ,
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 .
9. A method for treating rheumatoid arthritis which comprises the administration to a patient of an effective amount of the compound of claim 1 , wherein treating does not include preventing or prophylactic therapy.
10. The compound of claim 1 selected from the following compounds, or a pharmaceutically acceptable salt or individual diastereomer thereof:
11. The compound of claim 1 wherein R 5 is —CF 3 .