US 11,833,208 B2
PLK1 selective degradation inducing compound
Si Woo Choi, Incheon (KR); Soo Hee Ryu, Incheon (KR); Ji Hoon Ryu, Seoul (KR); San Ha Son, Incheon (KR); Hwa Jin Lee, Incheon (KR); Seong Hoon Kim, Incheon (KR); Boas Nam, Incheon (KR); Im Suk Min, Gyeonggi-do (KR); Hye Guk Ryu, Incheon (KR); and Keum Young Kang, Incheon (KR)
Assigned to UPPTHERA, INC., Incheon (KR)
Appl. No. 17/428,467
Filed by Uppthera, Incheon (KR)
PCT Filed Mar. 27, 2021, PCT No. PCT/KR2021/003807
§ 371(c)(1), (2) Date Aug. 4, 2021,
PCT Pub. No. WO2021/194318, PCT Pub. Date Sep. 30, 2021.
Claims priority of application No. 10-2020-0037875 (KR), filed on Mar. 27, 2020.
Prior Publication US 2023/0104076 A1, Apr. 6, 2023
Int. Cl. A61K 47/55 (2017.01); A61K 47/54 (2017.01); C07D 409/14 (2006.01); C07D 417/14 (2006.01)
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:

OG Complex Work Unit Chemistry
wherein:

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is a ring selected from the group consisting of

OG Complex Work Unit Chemistry
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:

OG Complex Work Unit Chemistry
wherein:
n is an integer from 1 to 3;

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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

OG Complex Work Unit Chemistry
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:

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
and
custom character 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:

OG Complex Work Unit Chemistry
wherein:
custom character and custom character are each independently a bond;
LULM is covalently bonded to the ULM moiety through custom character that is linked thereto,
LPTM is covalently bonded to the PTM moiety through custom character that is linked thereto,
wherein LULM is

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
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.