# US 12,006,314 B2 · Anti-cancer nuclear hormone receptor-targeting compounds

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- Number: US 12,006,314 B2
- Document ID: US12006314B2
- Status: Granted
- Kind: B2
- Application number: 17/735,011
- Filed: 2022-05-02
- Published: 2022-12-01
- Granted: 2024-06-11
- Earliest claimed: 2021-05-03
- Assignees: Nuvation Bio Inc.
- Applicants: Nuvation Bio Inc.
- Inventors: David Hung; Jayakanth Kankanala; Christopher Paul Miller; Jeremy David Pettigrew; Son Minh Pham; Ihab S. Darwish
- Web page: https://patentgrep.com/patent/US12006314B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61P 35/00: Antineoplastic agents
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, such as a compound of Formula I: or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, to products containing the same, as well as to methods of their use and preparation.

## Claims

### Claim 1

A compound of Formula I, or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof:
wherein:
A1 is CH or N;
A2 is CH or N;
A3 is N or CR3;
A4 is C and is a double bond, or A4 is CH and is a single bond, or A4 is N and is a single bond;
L is
wherein:
s is 1, 2, or 3,
s′ is 0 or 1,
G1, G2, G3, and G4 are each independently CH or N, and
L′ and L″ are each independently selected from a bond, CH2, CH2CH2, NHC(O), or C=O;
R1 is a nuclear receptor-targeting epitope;
R2 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C3-6 cycloalkyl;
R3 is hydrogen or halo; or
R2 and R3 together with the atoms to which they are attached form a 6-membered heterocyclyl or 6-membered heteroaryl;
R4 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one to five R5;
each R5 is independently halo, cyano, nitro, —OR10, —OC(O)R10, —C(O)OR10, —SR10, —NR10R11, —NR10C(O)R11, —C(O)NR10R11, 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;
R6 is hydrogen, halo, or C1-6 alkyl; and
each R10 and R11 is independently hydrogen or C1-12 alkyl optionally substituted with oxo, halo, hydroxyl, or amino as valency permits; or R10 and R11 are taken together with the atoms to which they are attached to form a heterocyclyl optionally substituted by halo or C1-12 alkyl optionally substituted by oxo, halo, hydroxyl, or amino;
wherein any hydrogen atom of the moiety in the brackets is replaced with -L-R1.

### Claim 2 (depends on 1)

The compound of claim 1, or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.

### Claim 3 (depends on 1)

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:

### Claim 4 (depends on 1)

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:

### Claim 5 (depends on 1)

The compound of claim 1, or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R2 is C1-6 alkyl, and R3 is hydrogen.

### Claim 6 (depends on 1)

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:

### Claim 7 (depends on 1)

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:

### Claim 8 (depends on 1)

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:

### Claim 9 (depends on 1)

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:

### Claim 10 (depends on 1)

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:

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 1)

The compound of claim 1, or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R1 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.

### Claim 13 (depends on 1)

The compound of claim 1, or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R1 is
wherein:
Q is
wherein bond a is attached to ring a and bond b is attached to ring b;
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;
A and A′ are each independently O or S;
B, B1, B2, and B3 are each independently CRc or N, and each Rc is independently hydrogen, halo, CN, or methyl;
B4 is CF, CH, or N;
D is a bond, CH2, C═O, or (C═O)NH;
D′ is NH, O, S, CH2, NH(C═O), C(═O)NH, or C═O;
R′, R″ and R′″ are each independently hydrogen, CN, or C1-2 alkyl;
t is 0, 1, 2, 3 or 4;
each Re is independently halo, cyano, C1-4 alkyl, or C1-4 haloalkyl;
Rf is hydrogen, C1-4 alkyl, or C3-6 cycloalkyl;
X is halo, CN, or NO2;
Y is halo, CH3, CH2F, CHF2, or CF3; or
X and Y together form a
where the broken lines indicate bonds to ring a;
Z is hydrogen, halo, C1-2 alkyl, C2 alkenyl, NO2, CF3; 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.

### Claim 14 (depends on 1)

The compound of claim 1, or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R1 is:
wherein:
R30 is hydrogen, C1-2 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;
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═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;
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;
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, oxirane, oxetane or tetrahydrofuran;
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
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.

### Claim 15 (depends on 1)

The compound of claim 1, or a tautomer, stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein R1 is:
wherein the wavy bond refers to the point of connection to L.

### Claim 16

A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

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.