Anti-cancer nuclear hormone receptor-targeting compounds

1. A compound of Formula I, or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof:

wherein:

A 1 is CH or N;

A 2 is CH or N;

A 3 is N or CR 3 ;

A 4 is C and is a double bond, or A 4 is CH and is a single bond, or A 4 is N and is a single bond;

L is

 wherein:

s is 1, 2, or 3,

s′ is 0 or 1,

G 1 , G 2 , G 3 , and G 4 are each independently CH or N, and

L′ and L″ are each independently selected from a bond, CH 2 , CH 2 CH 2 , NHC(O), or C=O;

R 1 is a nuclear receptor-targeting epitope;

R 2 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl;

R 3 is hydrogen or halo; or

R 2 and R 3 together with the atoms to which they are attached form a 6-membered heterocyclyl or 6-membered heteroaryl;

R 4 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one to five R 5 ;

each R 5 is independently halo, cyano, nitro, —OR 10 , —OC(O)R 10 , —C(O)OR 10 , —SR 10 , —NR 10 R 11 , —NR 10 C(O)R 11 , —C(O)NR 10 R 11 , C 1-12 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, or C 2-12 alkynyl; wherein each C 1-12 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, or C 2-12 alkynyl is independently optionally substituted with one to five halo, hydroxyl, or amino;

R 6 is hydrogen, halo, or C 1-6 alkyl; and

each R 10 and R 11 is independently hydrogen or C 1-12 alkyl optionally substituted with oxo, halo, hydroxyl, or amino as valency permits; or R 10 and R 11 are taken together with the atoms to which they are attached to form a heterocyclyl optionally substituted by halo or C 1-12 alkyl optionally substituted by oxo, halo, hydroxyl, or amino;

wherein any hydrogen atom of the moiety in the brackets is replaced with -L-R 1 .

2. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.

3. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula IIA:

4. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula IIB:

5. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R 2 is C 1-6 alkyl, and R 3 is hydrogen.

6. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula IIC:

7. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula IID:

8. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula IIE:

9. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula IIF:

10. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula IIG:

11. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein L is:

where the “*” and the wavy line represent a covalent bond.

12. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R 1 is derived from DHT, testosterone, dienolone, trienolone, drostanolol, stanzolol, JNJ-37654032, LGD-2226, LGD-3303, enzalutamide, apalutamide, darolutamide, bicalutamide, flutamide, nilutamide, enobosarm, BMS-564929, PS178990, LGD-4033 (ligandrol), LGD-2941, JNJ-28330835, JNJ-26146900, LGD-121071, LG-120907, S-40503, RAD-140, acetothiolutamide, andarine (S-4), TFM-4AS-1, YK-11, MK-0773 (PF-05314882), GSK2849466, GSK2881078, GSK8698, GSK4336, ACP-105, TT701, LY2452473, estradiol, fulvestrant, ARN-810 (GDC-810), GW5638, AZD9496, tamoxifen, toremifene, raloxifene, GW7604, bazedoxifene, ospemifene, droloxifene, clomifene, idoxifene, fispemifene, afimoxifene, arzoxifene, zindoxifene, pipendoxifene, GDC9545, lasofoxifene, endoxifen, ormeloxifene, cyclofenil, broparestrol, anordrin, toremifene, mapracorat, flumethasone, loteprednol etabonate, mometasone furoate, methylprednisolone, OP-3633, LLY-2707, CORT-108279, ORIC-101, AL082D06, dagrocorat, fosdagrocorat, megestrol acetate, progesterone, mifepristone (RU-486), telapristone, ulipristal acetate, anordrin, toremifene, or ketodarolutamide, or a stereoisomer or a mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R 1 is

wherein:

Q is

wherein bond a is attached to ring a and bond b is attached to ring b;

R a and R b are each independently CH 3 or CH 2 CH 3 ; or R a and R b together with the atom to which they are attached form a C 3-5 cycloalkyl, oxiranyl, oxetanyl, or tetrahydrofuranyl;

A and A′ are each independently O or S;

B, B 1 , B 2 , and B 3 are each independently CR c or N, and each R c is independently hydrogen, halo, CN, or methyl;

B 4 is CF, CH, or N;

D is a bond, CH 2 , C═O, or (C═O)NH;

D′ is NH, O, S, CH 2 , NH(C═O), C(═O)NH, or C═O;

R′, R″ and R′″ are each independently hydrogen, CN, or C 1-2 alkyl;

t is 0, 1, 2, 3 or 4;

each R e is independently halo, cyano, C 1-4 alkyl, or C 1-4 haloalkyl;

R f is hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl;

X is halo, CN, or NO 2 ;

Y is halo, CH 3 , CH 2 F, CHF 2 , or CF 3 ; or

X and Y together form a

where the broken lines indicate bonds to ring a;

Z is hydrogen, halo, C 1-2 alkyl, C 2 alkenyl, NO 2 , CF 3 ; or

Y and Z together form a

wherein each is a single or double bond, and where the broken lines indicate bonds to ring a.

14. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R 1 is:

wherein:

R 30 is hydrogen, C 1-2 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, or C 3-12 cycloalkyl, wherein each C 1-12 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, or C 3-12 cycloalkyl is optionally independently substituted with one to five R 100 as valency permits;

R 40 is hydrogen, C 1-12 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, or C 3-12 cycloalkyl, wherein each C 1-12 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, or C 3-12 cycloalkyl is optionally independently substituted with one to five R 100 as valency permits;

each R 50 is independently halo, cyano, nitro, —OR 170 , —SR 170 , —NR 170 R 180 , C 1-12 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, or C 2-12 alkynyl; wherein each C 1-12 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, or C 2-12 alkynyl is independently optionally substituted with one to five halo, hydroxyl, or amino as valency permits;

R 60 is hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, or C 3-12 cycloalkyl, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, or C 3-12 cycloalkyl is optionally independently substituted with one to five R 100 as valency permits;

each R 100 is independently oxo, halo, cyano, nitro, —OR 170 , —SR 170 , —SF 5 , —NR 170 R 180 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R 170 , —C(═O)OR 170 , —OC(═O)OR 170 , —OC(═O)R 170 , —C(═O)NR 170 R 180 , —OC(═O)NR 170 R 180 , —NR 170 C(═O)NR 170 R 180 , —S(═O) 1-2 R 170 , —S(═O) 1-2 NR 170 R 180 , —NR 170 S(═O) 1-2 R 180 , —NR 170 S(═O) 1-2 NR 170 R 180 , —NR 170 C(═O)R 180 , —NR 170 C(═O)OR 180 or —C═NOR 170 , wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 100 are independently optionally substituted with one or more halo or C 1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits;

each R 170 and R 180 is independently hydrogen or C 1-12 alkyl optionally substituted with oxo, halo, hydroxyl, or amino as valency permits; or R 170 and R 180 are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C 1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino;

A″ and A′″ are each independently O or S;

R a and R b are each independently CH 3 or CH 2 CH 3 ; or R a and R b together with the atom to which they are attached form a C 3-5 cycloalkyl, oxirane, oxetane or tetrahydrofuran;

B, B 10 , B 2 , B 3 , B′, B 1′ , B 2′ and B 3′ are each independently CR c or N;

each R c is independently hydrogen, fluoro, CN, or methyl;

D″ is NH, O, S, CH 2 or C═O;

X″ is CN, halo, or NO 2 ;

Y″ is CH 3 , CH 2 R d , CHF 2 , or CF 3 ;

R d is halo;

Z″ is H, C 1-2 alkyl, C 2 alkenyl or NO 2 ; or

X″ and Y″ together form a

where the broken lines indicate bonds to form a fused ring;

or Y″ and Z″ together form a

where is a single or double bond and where the broken lines indicate bonds to form a fused ring;

Z′ is CH or N.

15. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R 1 is:

wherein the wavy bond refers to the point of connection to L.

16. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound as in claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.