CPC A61K 47/55 (2017.08) [A61K 47/545 (2017.08); C07D 409/14 (2013.01); C07D 417/14 (2013.01)] | 8 Claims |
1. A compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
ULM-Linker-PTM [Formula I]
in the Formula I above,
ULM is a CRBN or a VHL E3 ubiquitin ligase binding moiety;
the CRBN E3 ubiquitin ligase binding moiety is represented by Formula A-1:
wherein:
is a ring selected from the group consisting of
X1 is a single bond, —CH2—, —NH—, —O—, —CH2CH2—, —C≡C—, —CO—, —COO—, —NHCO—, or —CONH;
X2 is —CH2—, —CO—, —CH2—CH2—, or —N═N—;
X3 is hydrogen or C1-4 alkyl; and
X4 is hydrogen, halogen, C1-6 alkyl, CN, NH2, NO2, OH, COH, COOH, or CF3;
the VHL E3 ubiquitin ligase binding moiety is represented by Formula B-1:
wherein:
n is an integer from 1 to 3;
is 5- to 6-membered heteroaryl, wherein the heteroaryl contains one to two N or S atoms;
Y1 is hydrogen or C1-4 alkyl;
Y2 is C1-4 alkyl;
Y3
Y4 is C1-4 alkyl, or C3-6 cycloalkyl, optionally substituted by halogen, —OH, or —CN; and
Y5 is hydrogen or C1-4 alkyl;
the PTM is a PLK1 binding moiety represented by Formula II:
wherein
R1 is C1-3 alkyl or C3-6 cycloalkyl;
R1A is hydrogen or C1-3 alkyl;
R2 is hydrogen, halogen, or —OR2A;
R2A is C1-4 alkyl or C3-6 cycloalkyl, optionally substituted by one or more halogen or hydroxy;
R3 is hydrogen or halogen; and
R4 is
and
indicates a covalent bond that links the PTM or the ULM into the Linker, and
the Linker is a chemical group that links the ULM and the PTM, and is represented by Formula L:
wherein:
and are each independently a bond;
LULM is covalently bonded to the ULM moiety through that is linked thereto,
LPTM is covalently bonded to the PTM moiety through that is linked thereto,
wherein LULM is
LU1 is selected from a single bond, —CH2—, —CH2CH2—, —CH═CH—, —C≡C—, —NH—, —NCH3—, —CO—, —NHCO—, or —O—;
LU2 is selected from single bond, —CH2—, —NH—, —O—, —CO—, or —CONH—; and
is a single bond or a ring selected from 3 to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl;
wherein LPTM is
LP1 is selected from single bond, —O—, —S—, —NH—, —N(C1-4 alkyl)-, —CH2—, —CH(C1-4 alkyl)-, —CH2NH—, or —CH2CH2—;
LP2 is selected from a single bond, —CO—, —COCH2—, —NHCO—, —NHCOCH2—, -HET, or -HET-CH2—, wherein HET is a 5- to 6-membered heterocyclyl or heteroaryl containing one or more N, S, or O atoms; and
is a single bond, amino substituted with C1-8 alkyl, or a ring selected from 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl;
wherein
is a single bond or a ring selected from 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl;
LINT1 and LINT2 are each independently selected from —CH2—, —NH—, —NCH3—, —O—, —S—, —SO—, —SO2—, —CO—, —CH2CH2O—, —OCH2CH2—, —CH2CH2S—, —SCH2CH2—, —COO—, —CONH—, or —NHCO—; and
q and r are each independently an integer from 1 to 10.
|