Inhibitors of kinases and cancer stem cells, and methods of preparation and use thereof

摘要

The invention provides novel inhibitors of cancer stem cells as well as cancer stem cell pathway kinase and other related kinases, pharmaceutical compositions and uses thereof in the treatment of cancer or a related disorder in a mammal, and methods of making such compounds and compositions.

主权项

1. A compound of Formula I,or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein:
R1 is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, ORa, SRa, S(═O)2Re, S(═O)2ORe, C(═O)ORd, C(═O)Ra, or C(═O)NRbRc; R2 is monocyclic or bicyclic heterocycle or substituted heterocycle; R3 is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, halogen, ORa, C(═O)Ra, C(═O)ORa, NRaRb, or S(═O)2NRaRb; R4, R5, R6, and R7 are each independently hydrogen, halogen, cyano, nitro, trihalomethyl, OCF3, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORe, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRdC(═O)NRbRc, NRdS(═O)2NRbRc, NRdP(═O)2NRbRc, NRbC(═O)Ra, or NRbP(═O)2Re; T is O, S or Ra; U and V are each independently carbon; W is N; X, Y, Z, and A are each independently carbon; with the provision that one of R4, R5, R6, and R7 iswherein:
Q-2 is a 5- or 6-membered aromatic or non-aromatic ring or ring system having at least one ring carbon atom substituted with a heteroatom selected from N, O and S; Rn′ and Rn″ are each independently hydrogen, halogen, cyano, nitro, trihalomethyl, OCF3, alkyl or substituted alkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, or ORa; Ra is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; Rb, Rc and Rd are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle; and Re is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl.