US 12,264,157 B2
Compounds and methods for the enhanced degradation of targeted proteins
Andrew P. Crew, Guilford, CT (US); Craig M. Crews, New Haven, CT (US); Xin Chen, Trumbull, CT (US); Hanqing Dong, Madison, CT (US); Caterina Ferraro, Stamford, CT (US); Yimin Qian, Plainsboro, NJ (US); Kam Siu, Milford, CT (US); Jing Wang, Milford, CT (US); Meizhong Jin, East Northport, NY (US); Michael Berlin, Flemington, NJ (US); Kurt Zimmermann, Durham, CT (US); and Lawrence Snyder, Killingworth, CT (US)
Assigned to Arvinas Operations, Inc., New Haven, CT (US); and Yale University, New Haven, CT (US)
Filed by Arvinas Operations, Inc., New Haven, CT (US); and Yale University, New Haven, CT (US)
Filed on Sep. 13, 2022, as Appl. No. 17/931,814.
Application 17/931,814 is a continuation of application No. 16/905,641, filed on Jun. 18, 2020, granted, now 11,512,083.
Application 16/905,641 is a continuation of application No. 15/074,820, filed on Mar. 18, 2016, granted, now 10,730,870, issued on Aug. 4, 2020.
Claims priority of provisional application 62/135,125, filed on Mar. 18, 2015.
Prior Publication US 2023/0203030 A1, Jun. 29, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 521/00 (2006.01); A61K 31/422 (2006.01); A61K 31/437 (2006.01); A61K 31/4439 (2006.01); A61K 31/5377 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); C07D 207/16 (2006.01); C07D 207/26 (2006.01); C07D 401/06 (2006.01); C07D 401/10 (2006.01); C07D 401/14 (2006.01); C07D 403/06 (2006.01); C07D 403/14 (2006.01); C07D 405/06 (2006.01); C07D 405/12 (2006.01); C07D 405/14 (2006.01); C07D 413/06 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 417/12 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01); C07D 471/12 (2006.01); C07D 471/14 (2006.01); C07D 495/04 (2006.01)
CPC C07D 471/04 (2013.01) [A61K 45/06 (2013.01); C07D 401/14 (2013.01); C07D 403/06 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 413/14 (2013.01); C07D 417/12 (2013.01); C07D 417/14 (2013.01); C07D 495/04 (2013.01)] 24 Claims
 
1. A compound according to the following structure:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
R is

OG Complex Work Unit Chemistry
and
ULM is

OG Complex Work Unit Chemistry
wherein:
one of R5 and R6 is —OH, and the other is H;
R7 is H;
E is C═O or C═S;
G is C═J;
J is 0;
M is:

OG Complex Work Unit Chemistry
R9 and R10 are each independently H or optionally substituted alkyl;
R11 is optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl;
each R14 is independently H or alkyl;
R15 is optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted heterocyclyl;
each R16 is independently halo, optionally substituted alkyl, CN, or optionally substituted haloalkoxy;
each R25 is H;
R23 is H;
o is 0, 1, 2, 3, or 4; and
L is:
—(A)q—,
wherein:
q is an integer from 1 to 20;
each A is independently selected from a bond, CRL1RL2, O, S, SO2, NRL3, SO2NRL3CONRL3, C0, CRL1CRL2, C═C, C311cycloalkyl optionally substituted with 0-6 RL1, C3-11heteocyclyl optionally substituted with 0-6 RL1, aryl optionally substituted with 0-6 RL1heteroaryl optionally substituted with 0-6 RL1, wherein RL1 or RL2, each independently, can be linked to other groups to form cycloalkyl and/or heterocyclyl; and
RL1, RL2, and RL3 are, each independently, selected from H, halo, C1-8alkyl, OC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OH, NH2, CC—C1-8alkyl, CCH, CH═CH(C1-8alkyl), C(C1-8alkyl)═CH(C1-8alkyl), C(C1-8alkyl)═C(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, and CON(C1-8alkyl)2;
or L is optionally substituted polyethylene glycol that contains between 2 and 10 ethylene glycol units; and
the chemical linker group (L) is covalently attached to the ULM via RS, R10, or R11.