US 11,834,458 B2
Anti-cancer nuclear hormone receptor-targeting compounds
David Hung, New York, NY (US); Jayakanth Kankanala, Saint Paul, MN (US); Christopher Paul Miller, San Mateo, CA (US); Jeremy David Pettigrew, Vancouver (CA); Son Minh Pham, San Francisco, CA (US); and Ihab S. Darwish, San Carlos, CA (US)
Assigned to NUVATION BIO INC., New York, NY (US)
Filed by Nuvation Bio Inc., New York, NY (US)
Filed on Mar. 22, 2022, as Appl. No. 17/701,425.
Claims priority of provisional application 63/165,087, filed on Mar. 23, 2021.
Prior Publication US 2022/0340587 A1, Oct. 27, 2022
Int. Cl. C07D 491/22 (2006.01); A61K 31/4745 (2006.01); C07D 471/14 (2006.01)
CPC C07D 491/22 (2013.01) [C07D 471/14 (2013.01)] 34 Claims
 
1. A compound of Formula III, or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof:
A1-L1-B1  III
wherein:
L1 is a covalent bond or a linking moiety;
B1 is a nuclear receptor-targeting epitope selected from the group consisting of;

OG Complex Work Unit Chemistry
 wherein the wavy bond refers to the point of connection to L1; and
A1 is of Formula IA:

OG Complex Work Unit Chemistry
wherein:
Y is a bond, —CH2—, or —CH2—CH2—;
Z is a bond or O;
R1, R2, R3, and R4, are each independently hydrogen, halo, cyano, nitro, —OR15, —SR15, —NR15R16, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R15, —C(═O)OR15, —OC(═O)R15, —C(═O)NR15R16, —NR15C(═O)R16, —NR15C(═O)OR16, —S(═O)1-2R15, —S(═O)1-2NR15R16, —NR15S(═O)1-2R16, —Si(R15)3, or —C═NOR15, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R1, R2, R3, and R4, are independently optionally substituted with one or more R10 as valency permits;
or R1 and R2 are taken together with the atoms to which they are attached to form a C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R10 as valency permits;
or R2 and R3 are taken together with the atoms to which they are attached to form a C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R10 as valency permits;
or R3 and R4 are taken together with the atoms to which they are attached to form a C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R10 as valency permits;
each R10 is independently halo, cyano, nitro, —OR17, —SR17, —SF5, —NR17R18, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R17, —C(═O)OR17, —OC(═O)OR17, —OC(═O)R17, —C(═O)NR17R18, —OC(═O)NR17R18, —NR17C(═O)NR17R18, —S(═O)1-2R17, —S(═O)1-2NR17R18, —NR17S(═O)1-2R18, —NR17S(═O)1-2NR17R18, —NR17C(═O)R18, —NR17C(═O)OR18, —Si(R17)3, or —C═NOR17, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R10 are independently optionally substituted with one or more halo or C1-12 alkyl optionally substituted by oxo, halo, hydroxyl, or amino as valency permits; and
each R15 and R16 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each alkyl, alkenyl, alkynyl, or cycloalkyl is optionally independently substituted with oxo, halo, hydroxyl, or amino as valency permits; or R15 and R16 are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C1-12 alkyl optionally substituted by oxo, halo, hydroxyl, or amino; and
each R17 and R18 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl is optionally substituted with oxo, halo, hydroxyl, or amino as valency permits; or R17 and R18 are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C1-12 alkyl optionally substituted by oxo, halo, hydroxyl, or amino;
wherein one or more atoms in one of R1, R2, and R3 of Formula IA is replaced by a direct covalent bond to L1.