New Homo- and Heterodimeric SMAC Mimetic Compounds as Apoptosis Inducers

摘要

The present invention relates to conformationally constrained homo- and heterodimeric mimetics of Smac with function as inhibitors of Inhibitor of Apoptosis Proteins (IAPs), the invention also relates to the use of these compounds in therapy, wherein the induction of apoptotic cell death is beneficial, especially in the treatment of cancer, alone or in combination with other active ingredients.

主权项

1. A homodimeric compound of formula (I) or pharmaceutically acceptable salt or prodrug thereof, wherein: n is 1 or 2 m is an integer from 0 to 3 A is NR1R2, or N+R1R2R3 R1, R2 and R3 are, each independently,
hydrogen;C1-8 alkyl or heteroalkyl; C2-8 alkenyl or heteroalkenyl; C2-8 alkynyl or heteroalkynyl;optionally substituted aryl, alkylaryl, heteroaryl, alkylheteroaryl; orany two of R1, R2, and R3 taken together with the nitrogen to which they are attached form a heterocyclic group, optionally substituted by one or more oxo, thioxo, and optionally comprising a heteroatom selected from O, S, and N, provided that the heteroatom is separated from the nitrogen atom by a least two carbon atoms; R4 are each independently
hydrogen;optionally substituted C1-18 alkyl or heteroalkyl; C2-18 alkenyl or heteroalkenyl; C2-18 alkynyl or heteroalkynyl;optionally substituted aryl, alkylaryl, heteroaryl, or alkylheteroaryl; B is
C1-4 alkyl; C2-4 alkenyl; C2-4 alkynyl;aryl, alkylaryl, heteroaryl or alkylheteroaryl;all optionally substituted by one or more halogen; Y is selected among OR5, NHR5, NR5R6, NH—S(O)2—R5, N+(R5)3, SR5, N3, C(O)OR5, CN, C(S)OR5, C(S)NHR5, C(NH)NHR5, NH(CNH)NHR5, NH(CS)NHR5, NH(CO)NHR5 or R5 is
hydrogen;optionally substituted C1-8 alkyl; C2-8 alkenyl; C2-8 alkynyl;optionally substituted aryl; alkylaryl; heteroaryl; R6 is
optionally substituted C1-8 alkyl; C2-8 alkenyl; or C2-8 alkynyl;optionally substituted aryl; alkylaryl; or heteroaryl; L is a “linker”L1wherein each n is independently 1-6,L2wherein each n is independently 1-6,L3wherein each n is independently 1-6,L4wherein each n is independently 1-6,L5wherein each n is independently 1-6,L6wherein each n is independently 1-6,L7wherein each n is independently 1-10L8wherein each n is independently 1-10L9wherein each n is independently 1-3,L10wherein each n is independently 1-3,L11wherein each n is independently 1-3,L12wherein each n is independently 1-4L13wherein each n is independently 1-4,L14wherein each n is independently 1-4,L15wherein each n is independently 1-4,L16wherein each n is independently 1-4,L17wherein each n is independently 2-12,L18wherein each n is independently 2-12,L19wherein each n is independently 2-12,L20wherein each n is independently 2-12,L21wherein each n is independently 1-5,L22wherein each n is independently 1-5,L23wherein each n is independently 1-5,L24wherein each n is independently 1-5,L25wherein each n is independently 1-3,L26wherein each n is independently 1-3,L27wherein each n is independently 1-3,L28wherein each n is independently 1-3,L29wherein each n is independently 1-3,L30wherein each n is independently 1-3,L31wherein each n is independently 1-3,L32wherein each n is independently 1-3,L33wherein each n is independently 1-6,L34wherein each n is independently 1-6,L35wherein each n is independently 1-6,L36wherein each n is independently 1-6,L37wherein each n is independently 1-6,L38wherein each n is independently 1-6,L39wherein each n is independently 1-3,L40wherein each n is independently 1-3,L41wherein each n is independently 1-3,L42wherein each n is independently 1-3,L43wherein each n is independently 1-3,L44wherein each n is independently 1-3,L45wherein each n is independently 1-6,L46wherein each n is independently 1-6,L47wherein each n is independently 1-6,L48wherein each n is independently 1-6,L49n, m = 1-6,L50n, m = 1-6,L51n, m = 1-6,L52n, m = 1-6,L53wherein each n is independently 1-6,L54wherein each n is independently 1-6,L55wherein each n is independently 1-6, orL56wherein each n is independently 1-6.