US 12,479,840 B2
HMG-CoA reductase 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); Eun Bin Lee, Incheon (KR); Hye Guk Ryu, Incheon (KR); Im Suk Min, Gyeonggi-do (KR); and Jun Kyu Lee, Gyeonggi-do (KR)
Assigned to UPPTHERA INC., Incheon (KR)
Appl. No. 17/428,564
Filed by Uppthera, Incheon (KR)
PCT Filed Mar. 30, 2021, PCT No. PCT/KR2021/003955
§ 371(c)(1), (2) Date Aug. 4, 2021,
PCT Pub. No. WO2021/201577, PCT Pub. Date Oct. 7, 2021.
Claims priority of application No. 10-2020-0037908 (KR), filed on Mar. 30, 2020.
Prior Publication US 2023/0078961 A1, Mar. 16, 2023
Int. Cl. C07D 417/14 (2006.01); A61K 47/55 (2017.01); C07D 309/30 (2006.01); C07D 405/14 (2006.01); A61K 31/366 (2006.01); A61K 31/427 (2006.01); A61K 31/454 (2006.01); A61P 3/06 (2006.01); A61P 9/00 (2006.01)
CPC C07D 417/14 (2013.01) [A61K 47/55 (2017.08); C07D 309/30 (2013.01); C07D 405/14 (2013.01)] 3 Claims
 
1. A compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
ULM Linker PTM  [Formula 1]
in the Formula I above,
ULM is a CRBN E3 ubiquitin ligase binding moiety represented by Formula A-2;

OG Complex Work Unit Chemistry
wherein:
X2 is —CH2—, —CO— or —N═N—;
X3 is hydrogen; and
custom character indicates a covalent bond that links ULM into the Linker;
PTM is a HMG-CoA reductase binding moiety represented by Formula II:

OG Complex Work Unit Chemistry
in Formula II above,
R1 is

OG Complex Work Unit Chemistry
RL is a single bond or C1-6 alkylene that is optionally substituted by 1-4 substituents selected from —CH3, —CN, —NH2, —OH, or halogen;
R2 is selected from hydrogen, halogen, —OH, —O(C1-6 alkyl), —O(C3-8 cycloalkyl), —OCO(C1-C6 alkyl),

OG Complex Work Unit Chemistry
 optionally substituted by one or more straight- or branched-C1-4 alkyl, 5- to 6-membered heterocyclyl containing one or two N ring atoms, phenyl, 6-membered heteroaryl containing one or two N ring atoms, NH3, OH, or CF3;
R3 and R4 are each independently —OH or —O(C1-3 alkyl); or R3 and R4 together form —O—;
R3 and R4 are each independently hydrogen, halogen, OH, C1-4 alkyl, C1-4 alkenyl, O(C1-4 alkyl), CF3, NH3, NO2, or CN;
R7 is hydrogen or C1-3 alkyl;
custom character is a single bond or a double bond;
custom character indicates a covalent bond that links PTM into the Linker}; and
the Linker is a chemical group that links ULM and PTM, wherein the Linker 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 a ULM moiety through custom character that is linked thereto,
LPTM is covalently bonded to a PTM moiety through custom character that is linked thereto,
LULM is

OG Complex Work Unit Chemistry
LU1 is selected from —CH2—, —CH2CH2—, —CC—, —NH—, —NHCO—, or —O—;
LU2 is selected from a single bond, —CH2—, —NH—, —O—, —CO—, and —CONH—;

OG Complex Work Unit Chemistry
 is null, C1-3 alkyl, or 4- to 6-membered heterocycloalkyl containing one or two N ring atoms;
LPTM is

OG Complex Work Unit Chemistry
LP1 is selected from a single bond, —NH—, —NCH3, or —CH2NH—;
LP2 is selected from a single bond or —COCH2—;

OG Complex Work Unit Chemistry
 is null or 4- to 6-membered heterocycloalkyl containing one or two N ring atoms;

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
 is null or a ring selected from 4- to 6-membered heterocycloalkyl containing one or two N ring atoms, phenyl, or 5- to 6-membered heteroaryl containing one or two N ring atoms;
LINT1 and LINT2 are each independently selected from —CH2—, —NH—, —CH2CH2O—, or —OCH2CH2—; and
q and r are each independently an integer from 1 to 8.