US 12,234,256 B2
Molecular degraders of extracellular proteins
David Caianiello, New Haven, CT (US); Edward DeRamon, New Haven, CT (US); and David Spiegel, New Haven, CT (US)
Assigned to YALE UNIVERSITY, New Haven, CT (US)
Filed by YALE UNIVERSITY, New Haven, CT (US)
Filed on Mar. 8, 2023, as Appl. No. 18/180,634.
Application 18/180,634 is a continuation of application No. PCT/US2022/075527, filed on Aug. 26, 2022.
Claims priority of provisional application 63/237,627, filed on Aug. 27, 2021.
Prior Publication US 2023/0271994 A1, Aug. 31, 2023
Int. Cl. C07H 15/18 (2006.01); A61P 9/00 (2006.01); C07D 225/08 (2006.01)
CPC C07H 15/18 (2013.01) [A61P 9/00 (2018.01); C07D 225/08 (2013.01)] 14 Claims
 
1. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, having the structure:

OG Complex Work Unit Chemistry
wherein:
custom character is a carbon-carbon single or double bond;
A is C6-18 aryl, C6-18 heterocyclyl, C6-18 biaryl, or C6-18 heterobiaryl, wherein each of C6-18 aryl, C6-18 heterocyclyl, C6-18 biaryl, and C6-18 heterobiaryl is independently optionally substituted by 1-6 substituents selected from the group consisting of F, Cl, Br, I, O(RG), OC(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, (RG), N(RG)2, S(RG), SO(RG), SO2(RG), SO2N(RG)2, and SO3(RG);
LA is an asialoglycoprotein receptor (ASGPR) binding moiety with the structure

OG Complex Work Unit Chemistry
LB is an anti-β1AR binding moiety with the structure

OG Complex Work Unit Chemistry
AA is an amino acid sequence at least 80% homologous to SEQ ID NO:1;
each occurrence of RG1′ is independently

OG Complex Work Unit Chemistry
each occurrence of RG1 is independently H or

OG Complex Work Unit Chemistry
each occurrence of ZG is:

OG Complex Work Unit Chemistry
AG is

OG Complex Work Unit Chemistry
RG2 is H;
RG3 is C(═O)CH3;
each occurrence of RG is independently H, unsubstituted or substituted C1-10 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted C6-18 aryl, or unsubstituted or substituted C5-18 heteroaryl;
each occurrence of XG is independently selected from the group consisting of one or more of —CH2—, —C(═O)—, —NH—, and —O—;
m is 2, 3, 4, 5, 6, 7, 8, 9, or 10;
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and
p is 1, 2, 3, or 4.