IMIDAZO [1,2-a]PYRIDINE COMPOUNDS FOR USE IN THERAPY

摘要

The present invention provides novel imidazo[1,2-a]pyridine compounds that are useful in therapy of diseases and disorders. The novel compounds inhibit the activation of Hypoxia Inducible Factor (HIF)-mediated transcription and signaling under hypoxic conditions. In one aspect, the compounds of the present invention are useful for the preparation of a medicament for the treatment or prevention of a disease or disorder selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia-related pathology and a disease characterized by excessive vascularization. Also provided is a pharmaceutical composition, comprising a compound of the invention and a second therapeutic agent or radiation, useful for the treatment or prevention of the mentioned diseases or disorders, wherein X is CH2, CH2CH2 or C═O; R1 is phenyl or C-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R1a which are identical or different; R2 is phenyl or C-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R2a which are identical or different; R3 is hydrogen, C1-C6-alkyl, C1-C4-alkoxy-C1-C4-alkyl, fluorinated C1-C2-alkyl C(O)R4; where R1a, R2a and R4 are as defined in the claims and the specification.;

主权项

1. A method for treating a disorder or disease selected from the group consisting of an inflammatory disease, a hyperproliferative disease or disorder, a hypoxia related pathology and a disease characterized by pathophysiological hypervascularization in a subject in need thereof, comprising administering to the subject an effective amount of an imidazo[1,2-a]pyridine compound of formula (I): wherein X is CH2, CH2CH2 or C═O; R1 is phenyl or C-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R1a which are identical or different;
R1a is selected from the group consisting of halogen, CN, NO2, NH2, OH, SH, C1-C10-alkenyl, C2-C10-alkenyl, C2-C10-alkynyl, C1-C6-alkoxy, C1-C6-alkylthio, hydroxy-C1-C6-alkyl, C1-C4-alkoxy-C1-C4-alkyl, fluorinated C1-C2-alkyl, SF5, fluorinated C1-C2-alkoxy, fluorinated C1-C2-alkylsulfonyl, fluorinated C1-C2-alkylthio, C(O)R4, NR5R6, C(O)NR7R8 and C(O)OR9, or two radicals R1a, which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk-O, wherein Alk is selected from CH2, CH2CH2, CHF, CF2 and CF2CF2; R2 is phenyl or C-bound monocyclic 5- or 6-membered heteroaryl, wherein phenyl and monocyclic 5- or 6-membered heteroaryl are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R2a which are identical or different;
R2a is selected from the group consisting of halogen, CN, NO2, NH2, OH, SH, C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, C1-C6-alkoxy, C1-C6-alkylthio, hydroxy-C1-C6-alkyl, C1-C4-alkoxy-C1-C4-alkyl, fluorinated C1-C2-alkyl, SF5, C1-C4-alkyl-sulfonyl, fluorinated C1-C2-alkoxy, C(O)R4, NR5R6, C(O)NR7R8 and C(O)OR9, or two radicals R2a, which are bound to adjacent carbon atoms, may also form a bridging moiety O-Alk′-O, wherein Alk′ is selected from CH2, CH2CH2, CHF, CF2 and CF2CF2; R3 is hydrogen, C1-C6-alkyl, C1-C4-alkoxy-C1-C4-alkyl, fluorinated C1-C2-alkyl or C(O)R4; R4 is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C3-C7-cycloalkyl, fluorinated C1-C2-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, C3-C7-cycloalkoxy, fluorinated C1-C2-alkoxy; R5 is hydrogen or C1-C6-alkyl; R6 is C1-C6-alkyl, hydroxy-C2-C6-alkyl, C1-C4-alkoxy-C2-C4-alkyl, OH, C1-C4-alkoxy or a radical C(O)Rx, wherein Rx is C1-C4-alkyl; or R5, R6 together with the nitrogen atom, to which they are bound, form an N-bound, 5- or 6-membered saturated nitrogen heterocycle; R7 and R8 independently of one another are hydrogen, OH, C1-C4-alkoxy or C1-C6-alkyl; R9 is hydrogen, C1-C6-alkyl, hydroxy-C2-C6-alkyl or C1-C4-alkoxy-C2-C4-alkyl; or a pharmaceutically acceptable salt thereof, an N-oxide thereof or a pharmaceutically acceptable salt of said N-oxide.