# US 2019/0375732 A1 · Anti-cancer nuclear hormone receptor-targeting compounds

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- Number: US 2019/0375732 A1
- Document ID: US20190375732A1
- Status: Published application
- Kind: A1
- Application number: 16/412,319
- Filed: 2019-05-14
- Published: 2019-12-12
- Earliest claimed: 2018-05-14
- Inventors: David Hung; Son Minh Pham; Sarvajit Chakravarty; Jiyun Chen; Jayakanth Kankanala; Anup Barde; Anjan Kumar Nayak
- Web page: https://patentgrep.com/patent/US20190375732A1

## CPC

- C07D 403/14: containing three or more hetero rings
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- 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
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 451/02: containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 498/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07J 43/003: {not condensed}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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
- C07J: STEROIDS (seco-steroids C07C)

## Abstract

The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.

## Claims

### Claim 1

A compound comprising at least one nuclear payload and at least one nuclear receptor-targeting epitope; provided that when the compound comprises one nuclear payload and one nuclear receptor-targeting epitope:
the nuclear receptor-targeting epitope is not a peptide, protein, nanoparticle or antibody; and
when the nuclear receptor-targeting epitope is an androgen receptor-targeting epitope or an estrogen receptor-targeting epitope, the nuclear payload is not doxorubicin, or an analog thereof, and is not a hydroxamic acid which binds histone deacetylase (HDAC).

### Claim 2

A compound comprising at least one nuclear payload which binds to a catalytic domain of poly(ADP-ribose) polymerase (PARP) and at least one nuclear receptor-targeting epitope.

### Claim 3 (depends on 1)

The compound of claim 1, wherein at least one nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the nuclear payload is bonded to one nuclear receptor-targeting epitope via a non-biocleavable linking moiety and one or more nuclear receptor-targeting epitope(s) via a biocleavable linking moiety.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound comprises at least one nuclear payload which binds to a protein involved in the DNA damage repair process.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound comprises at least one nuclear payload which binds poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase (DNA-PK), histone deacetylase (HDAC), enhancer of zeste homolog 2 (EZH2), histone acetyl transferase (HAT), methyltransferase, a bromodomain, myelin transcription factor 1 (MYT1), p53, melanocyte-stimulating hormone (MSH), mutL homolog (MLH), ERCC1, apurinic/apyrimidinic endonuclease 1 (APE1), topoisomerase I (Topo I), topoisomerase II (Topo II), Wee1, checkpoint kinase1 (Chk1), checkpoint kinase2 (Chk2), ataxia telangiectasia (ATR), or ataxia-telangiectasia mutated (ATM).

### Claim 7 (depends on 1)

The compound of claim 1, wherein the nuclear payload comprises olaparib (AZD-2281), Olaparib TOPARP-A, rucaparib (AGO 14699, PF-01367338), niraparib, talazoparib (BMN-673), veliparib (ABT-888), CEP 9722, E7016, BGB-290, 3-aminobenzamide, methoxyamine, CC-115, MSC2490484A, AZD6738, VX-970, AZD0156, GDC-0575, MK-8776, LY2606368, AZD1775, belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, topotecan, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide, vorinostat, romidepsin (Istodax), chidamide, panobinostat (Farydak), belinostat (PXD101), panobinostat (LBH589), valproic acid (as Mg valproate), mocetinostat (MGCDO 103), abexinostat (PCI-24781), entinostat (MS-275), SB939, resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), HBI-8000, kevetrin, CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, tazemetostat, MAK638, CPI-1205), DS-3201b, anacardic acid, MG149, C646, S-adenosyl methionine, JQ1, I-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010, CPI-203, CPI-0610, olinone, LY294002, or an analog thereof.

### Claim 8 (depends on 2)

The compound of claim 2, wherein the compound comprises at least one nuclear payload which binds to a catalytic domain of poly(ADP-ribose) polymerase (PARP).

### Claim 9 (depends on 2)

The compound of claim 2, wherein the catalytic domain comprises a conserved HYE motif.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the compound comprises at least one nuclear payload which binds to a poly(ADP-ribose) polymerase (PARP) with an IC50 of less than about 500 nM.

### Claim 11 (depends on 8)

The compound of claim 8, wherein the PARP comprises PARP-1 and/or PARP-2, or a variant thereof.

### Claim 12 (depends on 1)

The compound of any-preceding claim 1, wherein the compound is of Formula I or II:
A-(L-B)m I
A-L-(B)m II
wherein:
A is a nuclear payload;
m is 1, 2 or 3;
each B is independently a nuclear receptor-targeting epitope; and
each L is independently a covalent bond or a linking moiety.

### Claim 13

A compound of Formula III, IV, V or VI, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:
wherein:
each R1, R2, R3 and R4 is independently -L-(B)m, hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —S(═O)1-2R5, —S(═O)1-2NR5R6, —NR5S(═O)1-2R6 or —C═NOR5, 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;
m is 1, 2, or 3;
each L is independently a covalent bond or a linking moiety;
each B is independently a nuclear receptor-targeting epitope;
each R10 is independently halo, cyano, nitro, —OR7, —SR7, —SF5, —NR7R8, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R7, —C(═O)OR7, —OC(═O)OR7, —OC(═O)R7, —C(═O)NR7R8, —OC(═O)NR7R8, —NR7C(═O)NR7R8, —S(═O)1-2R7, —S(═O)1-2NR7R8, —NR7S(═O)1-2R8, —NR7S(═O)1-2NR7R8, —NR7C(═O)R8, —NR7C(═O)OR8 or —C═NOR7, 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 R5 and R6 is independently hydrogen, deuterium, C1-12 alkyl or C3-12 cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R5 and R6 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;
each R7 and R8 is independently hydrogen, deuterium or C1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R7 and R8 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
R9 is hydrogen or R2;
provided that at least one R1, R2, R3 and R4 is -L-(B)m.

### Claim 14

A compound of Formula IIIB, IVA, VB or VIA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:
wherein:
R2 is -L-(B)m;
m is 1, 2, or 3;
L is a covalent bond or a linking moiety; and
each B is independently a nuclear receptor-targeting epitope.

### Claim 15 (depends on 12)

The compound of claim 12, wherein at least one L is a non-biocleavable linking moiety.

### Claim 16 (depends on 12)

The compound of claim 12, wherein at least one L is an acid-labile linking moiety.

### Claim 17 (depends on 12)

The compound of claim 12, wherein the linking moiety is alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, may optionally comprise an arylene, heteroarylene, cycloalkylene or heterocycloalkylene; and further wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl.

### Claim 18 (depends on 12)

The compound of claim 12, wherein the linking moiety is of the formula:
—Y1—(CH2)n′—Y2—(CH2)m′—Y3—
wherein:
each of Y1, Y2, and Y3 are independently a bond, —NR11—, —O—, —S(O)0-2—, —NR11C(O)—, —C(O)NR11—, —NR11S(O)2—, —S(O)2NR11—, —CR12═N—NR11—, —NR11—N═CR12—, —C(O)—, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl;
each R11 is independently C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
each R12 is independently C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and
n′ and m′ are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

### Claim 19 (depends on 12)

The compound of claim 12, wherein at least one linking moiety comprises a hydrazone linkage.

### Claim 20 (depends on 1)

The compound of claim 1, wherein the at least one nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope.

### Claim 21 (depends on 1)

The compound of claim 1, wherein the at least one nuclear receptor-targeting epitope is independently selected from an estrogen receptor-targeting epitope, glucocorticoid receptor-targeting epitope, progesterone receptor-targeting epitope or androgen receptor-targeting epitope.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the at least one nuclear receptor-targeting epitope independently comprises an epitope derived from an androgen receptor agonist, an androgen receptor antagonist, a selective androgen-receptor modulator (SARM), an estrogen receptor agonist, an estrogen receptor antagonist, a selective estrogen receptor modulator (SERM), a glucocorticoid receptor antagonist, a glucocorticoid receptor agonist, a selective glucocorticoid receptor modulator (SGRM), a progesterone receptor antagonist, a progesterone receptor agonist, a selective progesterone receptor modulator (SPRM), or a combination thereof.

### Claim 23 (depends on 1)

The compound of claim 1, wherein the at least one nuclear receptor-targeting epitope independently comprises an epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof.

### Claim 24 (depends on 1)

The compound of claim 1, wherein at least one nuclear receptor-targeting epitope is capable of binding to a ligand binding domain of a nuclear steroid receptor.

### Claim 25 (depends on 24)

The compound of claim 24, wherein the nuclear steroid receptor is an estrogen receptor, a glucocorticoid receptor, a progesterone receptor, or an androgen receptor.

### Claim 26 (depends on 1)

The compound of claim 1, wherein the at least one nuclear receptor-targeting epitope binds to a nuclear steroid receptor with an IC50 of less than about 500 nM or an EC50 of less than about 1 μM.

### Claim 27 (depends on 1)

The compound of claim 1, wherein the at least one nuclear receptor-targeting epitope is not a peptide, protein, nanoparticle or antibody.

### Claim 28 (depends on 12)

A compound as in claim 12, selected from the group consisting of

### Claim 29 (depends on 1)

A pharmaceutical composition comprising a compound as in claim 1 and a pharmaceutically acceptable excipient.

### Claim 30 (depends on 1)

A method for the treatment or prevention of a condition which can be ameliorated by inhibition of PARP in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound or pharmaceutical composition of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

### Claim 31 (depends on 1)

A method of treating or preventing cancer, comprising administering an effective amount of a compound or pharmaceutical composition of claim 1 or a pharmaceutically acceptable salt or solvate thereof to an individual in need thereof.

### Claim 32 (depends on 30)

The method of claim 30, wherein the administering comprises oral administration.

### Claim 33 (depends on 30)

The method of claim 30, further comprising administering an additional chemotherapeutic agent.

### Claim 34 (depends on 33)

The method of claim 33, wherein the additional chemotherapeutic agent is cisplatin or etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, taxotere, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778123, BMS 214662, gefitinib, erlotinib hydrochloride, antibodies to EGFR, matinib, intron, cytarabine, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, vinblastine, vincristine, vindesine, bleomycin, doxorubicin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin, bexxar, velcade, zevalin, trisenox, xeloda, vinorelbine, porfimer, cetuximab, liposomal, Thiotepa, Altretamine, melphalan, Trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab, C225, Campath, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor binding agents, paclitaxel, gemcitabine, navelbine, farnesyl-protein transferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastine and methotrexate, or an analog or derivative thereof.

### Claim 35 (depends on 31)

The method of claim 31, further comprising administering radiotherapy to the patient.

### Claim 36 (depends on 31)

The method of claim 31, wherein the cancer is a BRCA positive cancer.

### Claim 37 (depends on 31)

The method of claim 31, wherein the cancer is a solid tumor.

### Claim 38 (depends on 31)

The method of claim 31, wherein the cancer is a cancer affecting B cells.

### Claim 39 (depends on 31)

The method of claim 31, wherein the cancer is a blood cancer, lung cancer, breast cancer, fallopian tube cancer, brain cancer, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer or skin cancer.

### Claim 40 (depends on 39)

The method of claim 39, wherein the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoide, head neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic carcinoma.

### Claim 41 (depends on 39)

The method of claim 39, wherein the cancer is bladder cancer, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, peritoneal cancer, testicular cancer, endometrial cancer, or uterine cancer.

### Claim 42

A method of treating or preventing an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one androgen receptor-targeting epitope to an individual in need thereof.

### Claim 43 (depends on 42)

The method of claim 42, wherein the cancer is prostate, breast, triple negative breast cancer, bladder, or liver cancer.

### Claim 44 (depends on 42)

The method of claim 42, wherein the androgen receptor-targeting epitope comprises an androgen receptor agonist, a selective androgen-receptor modulator (SARM), an androgen receptor antagonist, a selective estrogen receptor modulator (SERM), an estrogen receptor antagonist, a progestin, or an estrogen.

### Claim 45 (depends on 44)

The method of claim 44, wherein the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estramustine, ketoconazole, abiraterone, darolutamide, or an analog thereof.

### Claim 46

A method of treating or preventing an estrogen and/or progesterone receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one estrogen and/or progesterone receptor-targeting epitope to an individual in need thereof.

### Claim 47 (depends on 46)

The method of claim 46, wherein the cancer is breast, uterine, or ovarian cancer.

### Claim 48

A method of treating or preventing a glucocorticoid receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one glucocorticoid receptor-targeting epitope to an individual in need thereof.

### Claim 49 (depends on 48)

The method of claim 48, wherein the cancer is prostate, breast, uterine, or ovarian cancer.