Triazole derivatives as Wnt signaling pathway inhibitors

摘要

The present invention relates to compounds of formula (I), to processes for their preparation, to pharmaceutical formulations containing such compounds and to their use in therapy: Such compounds find particular use in the treatment and/or prevention of conditions or diseases which are affected by over-activation of signaling in the Wnt pathway and increased presence of nuclear β-catenin. For example, these may be used in preventing and/or retarding proliferation of tumor cells and metastasis, for example carcinomas such as colon carcinomas.;

主权项

1. A compound of general formula I:(wherein
Z1 represents Z2 represents phenyl, pyridyl, pyrimidinyl or oxadiazolyl optionally substituted by one or more groups Ra;
where each Ra may be identical or different and may be selected from F, Cl, Br, I, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, —CN, —NO2, —OR, —SR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)NR2,—NR2, —NR—C(O)R, —NR—C(O)OR, —S(O)R, —S(O)2R, —S(O)OR or —S(O)2NR2 group (where each R is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl or C2-6 alkynyl); R1 represents a phenyl or pyridyl group optionally substituted by one or more groups Rb;
where each Rb may be identical or different and may be selected from F, Cl, Br, I, C1-6 alkyl optionally interrupted by one or more —O—, —S— or —NR— groups, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, —CN, —NO2, —OR, —SR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)NR2, —C(O)NR2, —NR2, —NR—C(O)R, —NR—C(O)OR, —S(O)R, —S(O)2R, —S(O)OR or —S(O)2NR2 group (where each R is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl or C2-6 alkynyl); R2 represents a phenyl group optionally substituted by one or more groups Rc;
where each Rc may be identical or different and may be selected from halogen F, Cl, Br, I, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, —CN, —NO2, —OR, —SR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)NR2, —NR2, —NR—C(O)R, —NR—C(O)OR, —S(O)R, —S(O)2R, or —S(O)OR or group (where each R is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl or C2-6 alkynyl); L1 represents a C1-4 alkylene group optionally substituted by one or more groups Rd, wherein one or more methylene groups are each replaced by a group selected from —CRe═CRf—, —C≡C— and —C═C═C—; and
wherein one or more methylene groups may each additionally be replaced by a group Y1;
where each Y1 is independently selected from —O—, —S—, —NH—, —NR′″—, —NR′″—C(O)—, —C(O)—NR′″—, —C(O)—, —S(O2)—, —S(O)— and —CR′″═N— (where each R′″ is independently hydrogen or C1-6 alkyl);where each Rd may be identical or different and may be selected from C1-6 alkyl, hydroxy, C1-6 alkoxy, F,Cl, Br and I; andwhere Re and Rf are independently selected from H, C1-3 alkyl, halogen, C1-3 haloalkyl, —CN, —NO2, —OR, —SR, —C(O)R, —C(O)OR, —OC(O)R, —OPO3R, —OSO2R and —OSiR4 (where each R is independently H, C1-6 alkyl or C1-6 haloalkyl); L2 represents a bond; and L3 represents a bond)or a stereoisomers or pharmaceutically acceptable salt thereof, wherein said compound is other than