Anti-cancer nuclear hormone receptor-targeting compounds

A compound of Formula III, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

• A1-L1-B1 III
• wherein:
• B1 is a nuclear receptor-targeting epitope selected from;
• a) Formula IIB:
• wherein:
• the wavy bond refers to the point of connection to L1;
• R60 is 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 independently substituted with one to five R100 as valency permits;
• R80 is hydrogen, hydroxy, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C1-12 alkoxy, C3-12 cycloalkyl is optionally independently substituted with one to five R100 as valency permits;
• R81 is hydrogen, hydroxy, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, or C3-12 cycloalkyl is optionally independently substituted with one to five R100 as valency permits;
• or R80 and R81 are taken together with the atom to which they are attached to form heterocyclyl optionally substituted by halo or C1-12 alkyl optionally substituted by oxo, halo, hydroxyl, or amino;
• each R100 is independently oxo, halo, cyano, nitro, —OR170, —SR170, —SF5, —NR170R180, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R170, —C(═O)OR170, —OC(═O)OR170, —OC(═O)R170, —C(═O)NR170R180, —OC(═O)NR170R180, —NR170C(═O)NR170R180, —S(═O)1-2R170, —S(═O)1-2NR170R180, —NR170S(═O)1-2R180, —NR170S(═O)1-2NR170R180, —NR170C(═O)R180, —NR170C(═O)OR180, or —C═NOR170, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of R100 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 R170 and R180 is independently hydrogen or C1-12 alkyl optionally substituted with oxo, halo, hydroxyl, or amino as valency permits;
• or R170 and R180 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;
• b) Formula IIA:
• wherein:
• the wavy bond refers to the point of connection to L1;
• R30 is hydrogen, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl is optionally independently substituted with one to five R100 as valency permits;
• R40 is hydrogen, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl is optionally independently substituted with one to five R100 as valency permits;
• each R50 is independently halo, cyano, nitro, —OR170, —SR170, —NR170R180, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, or C2-12 alkynyl;
• wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, or C2-12 alkynyl is independently optionally substituted with one to five halo, hydroxyl, or amino as valency permits;
• each R100 is independently oxo, halo, cyano, nitro, —OR170, —SR170, —SF5, —NR170R180, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R170, —C(═O)OR170, —OC(═O)OR170, —OC(═O)R170, —C(═O)NR170R180, —OC(═O)NR170R180, —NR170C(═O)NR170R180, —S(═O)1-2R170, —S(═O)1-2NR170R180, —NR170S(═O)1-2R180, —NR170S(═O)1-2NR170R180, —NR170C(═O)R180, —NR170C(═O)OR180, or —C═NOR17, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of R100 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 R170 and R180 is independently hydrogen or C1-12 alkyl optionally substituted with oxo, halo, hydroxyl, or amino as valency permits;
• or R170 and R180 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;
• c) Formula IIC:
• wherein:
• the wavy bond refers to the point of connection to L1;
• R60 is 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 independently substituted with one to five R100 as valency permits;
• each R100 is independently oxo, halo, cyano, nitro, —OR170, —SR170, —SF5, —NR170R180, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R170, —C(═O)OR170, —OC(═O)OR170, —OC(═O)R170, —C(═O)NR170R180, —OC(═O)NR170R180, —NR170C(═O)NR170R180, —S(═O)1-2R170, —S(═O)1-2NR170R180, —NR170S(═O)1-2R180, —NR170S(═O)1-2NR170R180, —NR170C(═O)R180, —NR170C(═O)OR180, or —C═NOR17, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of R100 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 R170 and R180 is independently hydrogen or C1-12 alkyl optionally substituted with oxo, halo, hydroxyl, or amino as valency permits;
• or R170 and R180 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;
• or
• d) Formula IID:
• wherein:
• the wavy bond refers to the point of connection to L1;
• A″ and A′″ are each independently O or S;
• Ra and Rb are each independently CH3 or CH2CH3;
• or Ra and Rb together with the atom to which they are attached form a C3-5 cycloalkyl, oxiranyl, oxetanyl, or tetrahydrofuranyl;
• B, B10, B2, B3, B′, B1′, B2′ and B3′ are each independently CRc or N;
• each Rc is independently hydrogen, fluoro, CN, or methyl;
• D is NH, O, S, CH2, or C═O;
• X″ is CN, halo, or NO2;
• Y″ is CH3, CH2Rd, CHF2, or CF3;
• Rd is halo;
• Z′″ is H, C1-2 alkyl, C2 alkenyl, or NO2;
• or
• X″ and Y″ together form a
• wherein the broken lines indicate bonds to the ring;
• or Y″ and Z′″ together form a
• wherein each is a single or double bond, and wherein the broken lines indicate bonds to the ring;
• and
• Z′ is CH or N;
• L1 is a covalent bond or a linking moiety;
• and
• A1 is of Formula IA:
• 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, —NR7C(═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 of Formula IA is replaced by a direct covalent bond L1.