MULTITARGET HEDGEHOG PATHWAY INHIBITORS AND USES THEREOF

摘要

The present invention concerns compounds that selectively inhibit the activity of the Hedgehog (Hh) pathway, their preparation and uses thereof. The compounds of the present invention are useful in treating Hh-dependent tumors, such as medulloblastoma (MB).

主权项

1. A compound having the general formula I: wherein R1 is hydrogen; halogen; acyclic branched or straight, saturated or unsaturated aliphatic chain having from 1 to 10 carbon atoms; acyclic branched or straight, saturated or unsaturated aliphatic chain containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulphur and having from one to ten carbon atoms; ORA; C(═O)RA; C(═O)ORA; OC(═O)RA; OSO3; OSO2RA; SO2RA; SO3RA; N(RA)2; NHC(═O)RA; C(═O)N(RA)2; or C(RA)3; wherein each occurrence of RA is independently hydrogen, branched or straight, saturated or unsaturated aliphatic chain having from 1 to 10 carbon atoms or branched or straight, saturated or unsaturated aliphatic chain containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulphur and having from one to ten carbon atoms, acyl, C1-C10 alkoxy, C1-C10 alkylthio, amino, C1-C10 alkylamino, C1-C10 dialkylamino; R2 is hydrogen; halogen; acyclic branched or straight, saturated or unsaturated aliphatic chain having from 1 to 10 carbon atoms; acyclic branched or straight, saturated or unsaturated aliphatic chain containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulphur and having from one to ten carbon atoms; ORB; C(═O)RB; C(═O)ORB; OC(═O)RB; OSO3; OSO2RB; SO2RB; SO3RB; N(RB)2; NHC(O)RB; C(═O)N(RB)2; or C(RB)3; wherein each occurrence of RB is independently hydrogen, branched or straight, saturated or unsaturated aliphatic chain having from 1 to 10 carbon atoms or branched or straight, saturated or unsaturated aliphatic chain containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulphur and having from one to ten carbon atoms, acyl, C1-C10 alkoxy, C1-C10 alkylthio, amino, C1-C10 alkylamino, C1-C10 dialkylamino; R3 is hydrogen; ORC; C(═O)RC; C(═O)ORC; OC(═O)RC; N(RC)2; NHC(═O)RC; C(═O)N(RC)2; SRC; CH2RC or C(RC)3; wherein RC is independently, methyl, ethyl, propyl, isopropyl, prenyl, geranyl, farnesyl, benzyl; O(CH2)n-phenyl wherein n is 1, 2 or 3, O(CH═CH)Phenyl, O(CH═CH—CH2)Phenyl, O(CH2—CH═CH)Phenyl, O(CH═CH═CH)Phenyl; wherein the phenyl of O(CH2)n-phenyl, O(CH═CH)Phenyl, O(CH═CH—CH2)Phenyl, O(CH2—CH═CH)Phenyl, O(CH═CH═CH)Phenyl or the phenyl of the benzyl group may be substituted by halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, amino, C1-C6 alkylamino, C1-C6 dialkylamino; R4 is hydrogen; ORD; C(═O)RD; C(═O)ORD; OC(═O)RD; N(RD)2; NHC(═O)RD; C(═O)N(RD)2; SRD; CH2RD or C(RD)3 wherein RD is independently, methyl, ethyl, propyl, isopropyl, prenyl, geranyl, farnesyl, benzyl; O(CH2)n-phenyl wherein n is 1, 2 or 3, O(CH═CH)Phenyl, O(CH═CH—CH2)Phenyl, O(CH2—CH═CH)Phenyl, O(CH═CH═CH)Phenyl; wherein the phenyl of O(CH2)n-phenyl, O(CH═CH)Phenyl, O(CH═CH—CH2)Phenyl, O(CH2—CH═CH)Phenyl, O(CH═CH═CH)Phenyl or the phenyl of the benzyl group may be substituted by halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C1-C6 alkylthio, amino, C1-C6 alkylamino, C1-C6 dialkylamino; or stereoisomers or a pharmaceutically acceptable salt thereof.