US 11,857,519 B2
Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide
Andrew P. Crew, Chester, CT (US); Lawrence B. Snyder, Killingworth, CT (US); Jing Wang, Milford, CT (US); Hanqing Dong, Madison, CT (US); Yimin Qian, Plainsboro, NJ (US); and Michael Berlin, Flemington, NJ (US)
Assigned to Arvinas Operations, Inc., New Haven, CT (US)
Filed by Arvinas Operations, Inc., New Haven, CT (US)
Filed on Jun. 22, 2021, as Appl. No. 17/354,941.
Application 17/354,941 is a continuation of application No. 15/851,053, filed on Dec. 21, 2017, granted, now 11,191,741.
Claims priority of provisional application 62/438,998, filed on Dec. 24, 2016.
Prior Publication US 2022/0378726 A1, Dec. 1, 2022
Int. Cl. A61K 31/166 (2006.01); A61K 31/405 (2006.01); A61K 47/54 (2017.01); A61P 35/00 (2006.01); A61K 38/45 (2006.01); C12N 9/10 (2006.01); A61K 31/351 (2006.01); C07D 471/04 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 405/12 (2006.01); C07D 417/14 (2006.01); C07D 409/14 (2006.01); A61K 47/55 (2017.01)
CPC A61K 31/166 (2013.01) [A61K 31/351 (2013.01); A61K 31/405 (2013.01); A61K 38/45 (2013.01); A61K 47/545 (2017.08); A61K 47/55 (2017.08); A61K 47/555 (2017.08); A61P 35/00 (2018.01); C07D 401/14 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C12N 9/1007 (2013.01); C12Y 201/01043 (2013.01)] 16 Claims
 
1. A compound having the chemical structure:
ULM-L-PTM,
or a pharmaceutically acceptable salt thereof,
wherein:
(a) the ULM is:

OG Complex Work Unit Chemistry
wherein:
W is CH2 or C═O;
A is H;
custom character represents a bond that may be stereospecific or non-stereospecific;
n is 1; and
R is a bond to the chemical linking moiety or NHR′ covalently joined to the chemical linking moiety;
R′ is alkyl;
(b) the L is a chemical linking moiety connecting the ULM and the PTM which comprises (1) a chemical structural unit represented by the formula:
—(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O—, —NH—(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O—;

OG Complex Work Unit Chemistry
 wherein:
each m, o, p, q, and r of the chemical linking moiety are independently 0, 1, 2, 3, 4, 5, 6, with the proviso that when the number is zero, there is no N—O or O—O bond;
n of the chemical linking moiety is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or
(2) a polyethylenoxy group comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ethylene glycol units; and
(c) the PTM is PTM-I-1, PTM-IVa-1, or PTM-IVb-1:

OG Complex Work Unit Chemistry
wherein:
WPTM and XPTM are independently C or N;
YPTM and ZPTM are CH;
XPTM1 is NH or O;
XPTM2 is absent;
RPTM is methyl or methoxy;
RPTM5 is methyl; and
custom character indicates a covalent linkage to the chemical linking moiety.