US 12,274,697 B2
Compositions and methods for treating EZH2-mediated cancer
Jian Jin, New York, NY (US); Ramon Parsons, Manhasset, NY (US); Ilias Stratikopoulos, New York, NY (US); Xiaobao Yang, New York, NY (US); and Anqi Ma, New York, NY (US)
Assigned to Icahn School of Medicine at Mount Sinai, New York, NY (US)
Filed by Icahn School of Medicine at Mount Sinai, New York, NY (US)
Filed on Nov. 1, 2022, as Appl. No. 17/978,696.
Application 17/978,696 is a division of application No. 16/926,418, filed on Jul. 10, 2020, granted, now 11,510,920.
Application 16/926,418 is a continuation of application No. 16/345,591, abandoned, previously published as PCT/US2017/058718, filed on Oct. 27, 2017.
Claims priority of provisional application 62/414,195, filed on Oct. 28, 2016.
Prior Publication US 2023/0114294 A1, Apr. 13, 2023
Int. Cl. C07D 401/14 (2006.01); A61K 31/437 (2006.01); A61K 31/444 (2006.01); A61K 31/496 (2006.01); A61P 35/00 (2006.01); A61P 35/02 (2006.01); A61P 43/00 (2006.01); C07D 405/12 (2006.01); C07D 405/14 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01)
CPC A61K 31/496 (2013.01) [A61K 31/444 (2013.01); C07D 401/14 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 417/14 (2013.01)] 12 Claims
 
1. A bivalent compound comprising a degrader/disruption tag X″ conjugated to an enhancer of zeste homologue 2 (EZH2) ligand Y″ via a Linker:
X″-Linker-Y″,
and enantiomers and pharmaceutically acceptable salts thereof, wherein:
X″ comprises a degrader/disruption tag selected from the group consisting of adamantane, 1-((4,4,5,5,5-pentafluoropentyl) sulfinyl) nonane, pomalidomide, thalidomide and VHL-1;
Y′″ comprises an EZH2 ligand selected from the group consisting of:

OG Complex Work Unit Chemistry
wherein
the waved bond with * indicates the linker attachment position;
R1 is hydrogen or C1-6 alkyl;
R2 is hydrogen or C1-6 alkyl;
R3 is C1-6 alkyl or methoxy (MeO—); and
G is CH or N; and
the linker is selected from the group consisting of

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

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wherein R is independently —CH2—; —CF2; —CH(C1-3 alkyl)-; —C(C1-3 alkyl)(C1-3 alkyl)-; —CH═CH—; —C(C1-3 alkyl)═C(C1-3 alkyl)-; —C═C—; —O—; —NH—; —N(C1-3 alkyl); —C(O)NH—; —C(O)N(C1-3 alkyl)-; or a 3-13 membered ring, a fused ring, a bridged ring, or a spiro ring with or without one or more heteroatoms selected from the group consisting of —NH—, —N(C1-3 alkyl)-, and —O—;
X and Y are independently O or H2; and
m and n are independently 0-15; and

OG Complex Work Unit Chemistry
wherein X′═NH, O or C1-6 alkyl
m=0-15 and
n″=2-15.