Biaryl derivatives
The invention is concerned with novel biaryl derivatives of formula (I), wherein m, R 1 , R 2 , R 3 , X 1 , X 2 and X 3 are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds are antagonists of CCR-2 receptor, CCR-5 receptor and/or CCR-3 receptor and can be used as medicaments.
1. A compound of formula (I)
wherein
R 1 is halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, heteroalkyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl C 1-6 alkyl;
R 2 is hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, trimethylsilanyl C 1-6 alkyl, heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 3-6 alkenyl, hydroxy C 3-6 alkynyl, C 1-6 alkoxy C 3-6 alkenyl, C 1-6 alkoxy C 3-6 alkynyl, trimethylsilanyl C 2-6 alkynyl, hydroxy, C 1-6 alkoxy, halo C 1-6 alkoxy, heteroalkoxy, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 cycloalkyl C 1-6 alkyl, halogen, cyano, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted phenylmethoxy-C 1-6 alkoxy,
provided that the optionally substituted phenyl does not have nitro as a substituent;
R 3 is, when attached to a ring carbon atom, independently hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 3-6 alkenyl, hydroxy C 3-6 alkynyl, C 1-6 alkoxy C 3-6 alkenyl, C 1-6 alkoxy C 3-6 alkynyl, hydroxy, C 1-6 alkoxy, halo C 1-6 alkoxy, heteroalkoxy, halogen, cyano, optionally substituted phenyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 cycloalkyl C 1-6 alkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted phenyl-C 1-6 alkyl, optionally substituted heteroaryl-C 1-6 alkyl, optionally substituted heterocyclyl-C 1-6 alkyl, nitro, carboxy, formyl, acyl, C 1-6 alkoxycarbonyl, carbamoyl, mono- or di-C 1-6 alkyl substituted aminocarbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl or C 1-6 alkylsulfonyl or amino optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, heteroalkyl, optionally substituted C 3-7 cycloalkyl and optionally substituted heterocyclyl; or
m is 0, 1, 2, 3 or 4;
is piperidin-1-yl;
X 2 is C—R 4 wherein R 4 is phenyl or pyridyl, said phenyl and pyridyl being substituted by halo C 1-6 alkyl or halo C 1-6 alkyoxy;
and both X 1 and X 3 are N or C—R 5 wherein R 5 is hydrogen;
or pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein m is 1.
3. The compound of claim 1 wherein R 3 is optionally substituted heterocyclyl or heteroalkyl.
4. The compound of claim 1 wherein R 3 is hydroxy C 1-6 alkyl, optionally substituted pyrrolidin-1-yl or optionally substituted piperidin-1-yl.
5. The compound of claim 1 wherein R 3 is piperidin-1-yl or pyrrolidin-1-yl, said piperidin-1-yl and pyrrolidin-1-yl being optionally substituted by hydroxyl C 1-6 alkyl or hydroxy.
6. The compound of claim 1 wherein R 3 is pyrrolidin-1-yl, 2-hydroxymethyl-pyrrolidin-1-yl or 4-hydroxy-piperidin-1-yl.
7. The compound of claim 1 wherein
is 4-pyrrolidin-1-yl-piperidin-1-yl, 4-(2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl or 4-hydroxy-[1,4′]bipiperidinyl-1′-yl.
8. The compound of claim 1 wherein R 1 is halogen or C 1-6 alkyl and R 2 is hydrogen, hydroxy, halogen, C 1-6 alkyl, optionally substituted heteroaryl, heteroalkoxy or cyclopropyl.
9. The compound of claim 8 wherein R 1 is fluorine or methyl and R 2 is hydrogen, hydroxy, fluorine, methyl, pyrimidinyl, pyridinyl, hydroxyethoxy or cyclopropyl.
10. The compound of claim 8 wherein R 1 is C 1-6 alkyl and R 2 is hydrogen, C 1-6 alkyl or cyclopropyl.
11. The compound of claim 10 , wherein R 1 is methyl and R 2 is methyl or cyclopropyl.
12. The compound of claim 1 , selected from the group consisting of
(3,5-Dimethyl-3′-trifluoromethoxy-biphenyl-4-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
(3,5-Dimethyl-3′-trifluoromethyl-biphenyl-4-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
(3,5-Dimethyl-3′-trifluoromethyl-biphenyl-4-yl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone,
[2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-3-yl)-phenyl]-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone,
[4-Cyclopropyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
(3,5-Dimethyl-3′-trifluoromethyl-biphenyl-4-yl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone,
[2,4-Dimethyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
(3,5-Difluoro-3′-trifluoromethyl-biphenyl-4-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
(5-Methyl-3-pyrimidin-5-yl-3′-trifluoromethyl-biphenyl-4-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
(5-Methyl-3-pyridin-3-yl-3′-trifluoromethyl-biphenyl-4-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[2-Hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 4-Methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromethyl-phenyl)-1H-pyridin-2-one, and
[2-(2-Hydroxy-ethoxy)-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone.
13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable excipient.