BISARYL (THIO)MORPHOLINE DERIVATIVES AS S1P MODULATORS

The present invention relates to bisaryl (thio)morpholine derivatives of the formula (I) wherein R1 is an aryl substitutent selected from phenyl, pyridyl, pyrimidinyl, biphenyl and naphthyl, each optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl optionally substituted with one or more fluoro atoms, (1-4C)alkoxy optionally substituted with one or more fluoro atoms, amino, di(1-4C)alkylamino, -SO2-(1-4C)alkyl, -CO-(1-4C)alkyl, -CO-O-(1-4C)alkyl and -NH-CO-(1-4C)alkyl, or substituted with phenoxy, benzyl, benzyloxy, phenylethyl or morpholinyl, each optionally substituted with (1-4C)alkyl, and (8-10C)bicyclic group, bicyclic heterocycle, each optionally substituted with (1-4C)alkyl optionally substituted with one or more fluoro atoms or oxo; A is selected from -CO-, -NH-, -O-, -S-, -SO- or -SO2-; ring structure B optionally contains one nitrogen atom; R2 is H, (1-4C)alkyl optionally substituted with one or more fluoro atoms, (1-4C)alkoxy optionally substituted with one or more fluoro atoms, or halogen; and R3 is (1-4C)alkylene-R6 wherein the alkylene group may be substituted with (CH2)2 to form a cyclopropyl moiety or with one or more halogen atoms, or R3 is (3-6C)cycloalkylene-R5 or -CO-CH2-R6, wherein R6 is -OH, -PO3H2, -OPO3H2, -COOH, -COO(1-4C)alkyl or tetrazol-5-yl; R4 is H or (1-4C)alkyl; R5 is one or more substituents independently selected from H, (1-4C)alkyl or oxo; W is -O-, -S-, -SO- or -SO2-; or a pharmaceutically acceptable salt, a solvate or hydrate thereof, with the proviso that the derivative of formula (I) is not 2-[4-(4-chlorophenoxy)-2-chloro-phenyl]-4-morpholineethanol. The compounds of the invention have affinity to S1P receptors and may be used in the treatment, alleviation or prevention of S1P receptor mediated diseases and conditions. La présente invention se rapporte à des dérivés bisaryl (thio)morpholines de formule (I) où R1 est un substituant aryle choisi parmi phényle, pyridyle, pyrimidinyle, biphényle et naphtyle, chacun facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un halogène, un (1-6C) alkyle facultativement substitué par un ou plusieurs atomes de fluor, un (1-4C) alcoxy facultativement substitué par un ou plusieurs atomes de fluor, un amino, di(1-4C)alkylamino, -SO2-(1-4C)alkyle, -CO-(1-4C)alkyle, -CO-O-(1-4C)alkyle et -NH-CO-(1-4C)alkyle, ou substitué par phénoxy, benzyle, benzyloxy, phényléthyle ou morpholinyle, chacun facultativeme