Substituted bicyclic heteroaryl compounds functioning as integrin antagonists and pharmaceutical preparation in which the compounds are comprised

摘要

The invention is directed to physiologically active compounds of general formula (I):wherein Het is an optionally substituted, saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring containing at least one heteroatom selected from O, S or N; R<1 >is optionally substituted aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl; Z<1 >represents a direct bond, an alkylene chain, NR<4>, O or S(O)n; L<1 >is an a -R<5>-R<6>- linkage where R<5 >is alkylene, alkenylene or alkynylene and R<6 >is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, -C(=Z<3>)-NR<4>-, -NR<4>-C(=Z<3>)-, -Z<3>-, -C(=O)-, -C(=NOR<4>)-, -NR<4>-, -NR<4>-C(=Z<3>)-NR<4>-, -SO2-NR<4>-, -NR<4>-SO2-, -O-C(=O)-, -C(=O)-O-, -NR<4>-C(=O)-O- or -O-C(=O)-NR<4>-; L<2 >is a direct bond; an optionally substituted alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage; a -[C(=O)-N(R<9>)-C(R<4>)(R<10>)]p- linkage; a -Z<4>-R<11>- linkage; a -C(=O)-CH2-C(=O)- linkage; a -R<11>-Z<4>-R<11>- linkage; or a -L<3>-L<4>-L<5>- linkage; and Y is carboxy or an acid bioisostere; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs. Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (alpha4beta1).