FUSED HETEROCYCLIC DERIVATIVES AS S1P MODULATORS

摘要

The present invention relates to a fused heterocyclic derivative of the formula (I) The variables R1-R4, z, A, Q, X and Y are as defined in the claims. The following heterocycles are exemplified sub-structures of formula (I): The compounds of formula (I) are modulators of the S1P receptor (Sphingosine-1-phosphate receptor), More specifically, they are agonists of S1P5. The compounds have therapeutic use in treatment of cognitive disorders, age-relate cognitive decline and dementia.

主权项

1. A fused heterocyclic derivative of the formula (I) wherein R1 is selected from
cyano,(2-4C)alkonyl, (2-4C)alkynyl, (1-4C)alkyl, each optionally substituted with CN or one or more fluoro atoms,(3-6C)cycloalkyl, (4-6C)cycloalkenyl or a (8-10C)bicyclic group, each optionally substituted with halogen or (1-4C)alkyl optionally substituted with one or more fluoro atoms,phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from halogen, cyano, (1-4C)alkyl optionally substituted with one or more fluoro atoms, (1-4C)alkoxy optionally substituted with one or more fluoro atoms, amino, dimethylamino, and (3-6C)cycloalkyl optionally substituted with phenyl which may be substituted with (1-4C)alkyl or halogen, andphenyl substituted with phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each optionally substituted with (1-4C)alkyl, Z is a linking group -W-(Cn-alkylene)-T- wherein
W is attached to R1 and selected from a bond, —O—, —CO—, —S—, —SO—, —SO2—, —NH—, —CH═CH—, —C(CF3)=CH—, —C≡C—, —CH2—O—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO— and trans-cyclopropylene;n is an integer from 0 to 10; andT is attached to the phenylene/pyridyl moiety and selected from a bond, —O—, —S—, —SO—, —SO2—, —NH—, —CO—, —C═C—, —C≡C—, and trans-cyclopropylene; R2 is H or one or more substituents independently selected from cyano, halogen, (1-4C)alkyl optionally substituted with one or more halogen atoms, or (1-4C)alkoxy optionally substituted with one or more halogen atoms; ring structure A may contain one nitrogen atom; X is selected from C or N; if X is C, R3 is selected from H and (1-4C)alkyl, otherwise R3 is not present; Y is selected from NH, O and S; structure Q is a 5-, 6- or 7-membered cyclic amine; and R4 is (1-4C)alkylene-R5 wherein one or more carbon atoms in the alkylene group may independently be substituted with one or more halogen atoms or with (CH2)2 to form a cyclopropyl moiety, or R4 is (3-6C)cycloalkylene-R5, —CH2-(3-6C)cycloalkylene-R5, (3-6C)cycloalkylene-CH2—R5 or —CO—CH2—R5, wherein R5 is —OH, —PO3H2, —OPO3H2, —COOH, —COO(1-4C)alkyl or tetrazol-5-yl; or a pharmaceutically acceptable salt, a solvate or hydrate thereof or one or more N-oxides thereof.