Estrogen receptor degraders as treatments for breast cancer

Abstract

The present application relates to treating and / or preventing breast cancer, including locally advanced or metastatic, ER+, HER2- breast cancer, in a subject in need of treatment, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

Description

ESTROGEN RECEPTOR DEGRADERS AS TREATMENTS FOR BREAST CANCER Cross-Reference to Related Applications

[0001] This application claims priority to US Provisional Application Ser. No. 63 / 646,004 filed May 13, 2024, which is incorporated herein in its entirety. Field of the Invention

[0002] The present application relates to treating and / or preventing breast cancer, including locally advanced or metastatic, ER+, HER2- breast cancer, in a subject in need of treatment. Background of the Invention

[0003] Breast cancer accounts for 12.5% of all new annual cancer cases worldwide, making it the most common cancer in the world. In the United States (U.S.), breast cancer is the second leading cause of cancer deaths for women in the United States, after lung cancer. Every year, breast cancer accounts for about 30% of all new cancer cases in U.S. women. In 2023, it is estimated that 43,170 women will die of breast cancer. While breast cancer is less common in men, men account for approximately 1% of all newly diagnosed cases, and almost 530 men are projected to die from their disease in 2023. As of January 2017, approximately 155,000 women with metastatic breast cancer (mBC) were living in the US. It was also reported that the number of women living with mBC is increasing primarily because of improvements in treatment and the aging of the US population. (Siegel, R. L. et al. Cancer statistics, 2023. CA. Cancer J. Clin. 73, 17–48 (2023); "Estimation of the Number of Women Living with Metastatic Breast Cancer in the United States” Cancer Epidemiol. Biomarkers Prev. 2017, 26(6):809-815.)

[0004] Treatment options for advanced breast cancer or mBC depend on many different factors, including whether the tumors express hormone receptors, i.e., estrogen receptor (ER) and / or progesterone receptor, or human epidermal growth factor receptor 2 (HER2). The standard of care for women with mBC is endocrine therapy, chemotherapy and / or targeted therapy alone or in combination. Patients with ER positive (ER+) and HER2 negative (HER2-) mBC are treated with endocrine therapy, sometimes in combination with targeted drugs such asCDK4 / 6 inhibitors (CDKi). In patients with aggressive disease or whose disease continues to progress on endocrine therapy, chemotherapy may be prescribed.

[0005] The current standard of care for women with ER+, HER2-, mBC is endocrine therapy + / - CDKi or mTOR inhibitor. Endocrine therapies include ovarian ablation or suppression (for pre-menopausal women), tamoxifen (a selective ER modulator, a SERM), aromatase inhibitors, fulvestrant (a SERD), and Lasofoxifene (a SERM). Metastatic breast cancer remains incurable, and sequencing of endocrine therapies is the recommended approach for the treatment of ER+ breast cancer. The addition of targeted agents including CDKi and mTOR inhibitors to a backbone of endocrine therapy further improves patient outcomes.

[0006] Fulvestrant is considered the cornerstone component of ER-targeted endocrine regimens in the advanced disease setting, and works via an indirect mechanism of protein degradation, resulting in destabilization of the ER. Single-agent fulvestrant is dosed at 500 mg IM on days 1, 15, and 29 and once monthly thereafter. Efficacy of fulvestrant was established by comparison to the selective aromatase inhibitor anastrozole in 2 randomized, controlled clinical trials in postmenopausal women with locally advanced or mBC (Astra Zeneca Faslodex Full Prescribing Information, revised 03 / 2019). All patients had progressed after previous therapy with an antiestrogen or progestin for breast cancer in the adjuvant or advanced disease setting. In both trials, eligible patients with measurable and / or evaluable disease were randomized to receive either fulvestrant 250 mg IM once a month (28 days + 3 days) or anastrozole 1 mg orally once a day. Results of the trials, after a minimum follow-up duration of 14.6 months, ruled out inferiority of fulvestrant to anastrozole. There was no statistically significant difference in overall survival (OS) between the 2 treatment groups after a follow-up duration 2 years or more. A third study compared fulvestrant 500 mg dose to fulvestrant 250 mg dose. Results of this study after a minimum follow- up duration of 18 months showed that progression free survival (PFS) was statistically significantly superior with fulvestrant 500 mg vs fulvestrant 250 mg (6.5 months versus 5.4 months respectively). There was no statistically significant difference in OS between the 2 treatment groups (25.1 months for fulvestrant 500 mg and 22.8 months for fulvestrant 250 mg). Overall response rates were similar; the response rate for the 500 mg dose was 13.8 %. (95% confidence intervals [CI] 9.7-18.8%) and for the 250 mg dose was 14.6% (CI 10.5-19.4%) (Astra Zeneca Faslodex Full Prescribing Information, revised 03 / 2019).

[0007] Antibody-drug conjugates (ADCs), as new targeted drugs, generally consist of three parts: antibodies or antibody-like ligands, small molecule drugs, and linkers that couple the ligands and drugs. Antibody-drug conjugates utilize the specific recognition of antigens by antibodies to transport drug molecules to the vicinity of target cells and effectively release drug molecules to achieve therapeutic purposes. Compared to the traditional small molecule approaches, ADCs offer enhanced targeting of cancer cells along with potentially minimized dose-limiting toxicities while maximizing desired therapeutic effects.

[0008] An ADC, Mylotarg® (Gemtuzumab ozogamicin), was the first ADC approved twenty years ago by the U.S. Food and Drug Administration. This early ADC in which calicheamicin is conjugated to an anti-CD33 antibody is approved as a therapeutic agent for acute myeloid leukemia. Further, Adcetris® (Brentuximab vedotin), in which auristatin E is conjugated to an anti-CD30 antibody, is approved as a therapeutic agent for Hodgkin's lymphoma and anaplastic large cell lymphoma. The drugs contained in these early approved ADCs target DNA or tubulin.

[0009] The advantages of antibody-drug conjugates (ADC) drugs are to increase water solubility, improve targeting, and the binding of specific antibodies to antigens to carry the drug around the target cell, and release the drug near the target cell to effectively kill tumor cells, reduce toxic side effects.

[0010] The structure of Formula I (disclosed herein) contain structural elements of Lasofoxifene and cereblon / ligase-binding thalidomide derivatives. These two elements are connected by a novel linker. Summary of the Invention

[0011] In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically accep , , , derivative, or prodrug thereof, wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

[0012] In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation; the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

[0013] In one aspect, this application pertains to a compound of Formula (I) for use in a method of treating breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation. In some embodiments, the subject comprises at least one somatic ER tumor mutation selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, L536X, wherein “X” refers to any amino acid residue, other than the wild-type residue at that position. In some embodiments, the subject comprises at least one somatic ER tumor mutation selected from the group consisting of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P and L536_D538>P.

[0014] In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic or locally advanced.

[0015] In one embodiment, the compound is that of Formula (I): or a pharmaceuticallyderivative, or prodrug thereof.

[0016] In some embodiments, the compound of Formula (I) is administered orally to the subject.

[0017] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is administered to the subject once a day, twice a day, three times a day, or four times a day. In some embodiments, the therapeutically effective amount of the compound of Formula (I) is administered to the subject all at once or is administered in two-, three-, or four- unit doses. In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 40 mg. In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 40 mg.

[0018] In one aspect, this application pertains to a method of treating breast cancer in a subject; the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I); further comprising the administration of a therapeutically effective amount of at least one additional anti-cancer agent to the subject in need thereof.

[0019] In some embodiments, the additional anti-cancer agent is selected from the group consisting of FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK- 1 modulator, Bcl-2 inhibitor, HD AC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4 / 6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORCl / 2 inhibitor, JAK / STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, PD-1 inhibitor, PD-L1 inhibitor, B7-H3 inhibitor, CTLA4 inhibitor, LAG-3 inhibitor, 0X40 agonist, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, and VEGF trap antibody. In some embodiments, the additional anti-cancer agent is a CDK 4 / 6 inhibitor.

[0020] In some embodiments, the additional anti-cancer agent is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5’-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (halaven). In some embodiments, the additional anti-cancer agent is palbociclib,

[0021] In another aspect, this application is directed to the conjugation of the compound of Formula (I) with an antibody to form an antibody-drug conjugate (ADC).

[0022] In one aspect, this application pertains to method of treating breast cancer in a subject in need thereof, comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), wherein the compound of Formula (I) is:or a pharmaceutically acce derivative, or prodrug thereof, wherein the subject comprises at least one somatic ER tumor mutation. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0023] In one aspect, this application pertains to method of treating breast cancer in a subject in need thereof, comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0024] In one aspect, this application pertains to a method of treating breast cancer in a subpopulation of breast cancer subjects, comprising: selecting a breast cancer subject for treatment based on the subject’s somatic ER tumor biomarker status; and administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0025] In one aspect, this application pertains to a method of treating breast cancer in a subpopulation of breast cancer subjects, comprising: selecting a breast cancer subject for treatment based on the subject’s somatic ER tumor biomarker status; and administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0026] In some embodiments, the method further comprises the administration of at least one additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is selected from the group consisting of FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4 / 6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORCl / 2 inhibitor, JAK / STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, PD-1 inhibitor, PD-L1 inhibitor, B7-H3 inhibitor, CTLA4 inhibitor, LAG-3 inhibitor, 0X40 agonist, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, and VEGF trap antibody. In some embodiments, the additional anti-cancer agent is a CDK 4 / 6 inhibitor, the additional anti-cancer agent is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5’-deoxy-5- fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (halaven).

[0027] In some embodiments, the administration of the additional anti-cancer agent occurs before the administration of the compound of Formula (I). In some embodiments, the administration of the additional anti-cancer agent occurs at least 30 minutes before the administration of the compound of Formula (I). In some embodiments, the administration of the additional anti-cancer agent occurs after the administration of the compound of Formula (I). In some embodiments, the administration of the additional anti-cancer agent occurs at least 30 minutes after the administration of the compound of Formula (I).

[0028] In one aspect, this application pertains to a compound of Formula (I):or a pharmaceutically acce derivative, or prodrug thereof, for use in the manufacture of a medicament for the treatment of breast cancer in a subject in need thereof, wherein for use in the treatment of breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation; and wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0029] The instant invention also contemplates the conjugation of a compound of Formula (I) as an antibody-drug conjugate, wherein the compounds of Formula (I) are linked, conjugated, or connected with one or more suitable antibodies. Such an ADC would comprise the compounds of Formula I of a drug with therapeutic and / or cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. This antibody-drug conjugate (ADC) having a drug with cytotoxicity conjugated to an antibody, whose antigen is expressed on a surface of cancer cells and which also binds to an antigen capable of cellular internalization, can therefore deliver the drug selectively to cancer cells and is thus expected to cause accumulation of the drug within cancer cells and to kill the cancer cells.

[0030] These and other aspects will become apparent upon reading the following detailed description of the invention.Brief Description of the Figures

[0031] Figure 1 shows an inhibition effect trend of the compound of Formula (I) as compared to (rac) ARV-471.

[0032] Figures 2A, 2B, and 2C show blots and graphs of MCF-7 cells treated with compound of Formula (1) (Fig. 2A), (racemic) ARV-471 (Fig. 2B), and Vepdegestrant (ARV- 471) with the indicated concentrations for 72 hours. Cell lysates were subjected to Western blot analyses, probed with Estrogen Receptor alpha antibody, and re-probed with α-Tubulin antibody. Detailed Description of the Invention

[0033] In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0034] In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation,the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceuticallyderivative, or prodrug thereof.

[0035] In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation; the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

[0036] In one aspect, this application pertains to a compound of Formula (I) for use in a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).

[0037] In one aspect, this application pertains to a compound of Formula (I) for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0038] In one aspect, this application pertains to a compound of Formula (I) for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0039] In some embodiments, the subject comprises at least one somatic ER tumor mutation selected from the group consisting of D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation selected from the group consisting of D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C.

[0040] In some embodiments, the breast cancer is ER+, HER2−.

[0041] In some embodiments, the breast cancer is metastatic or locally advanced.

[0042] In one aspect, this application pertains to a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof for use in a method of treating breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof. In some embodiments, the compound of Formula (I) is administered orally to the subject. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0043] In one aspect, this application pertains to a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof for use in a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof. In some embodiments, the compound of Formula (I) is administered orally to the subject.

[0044] In one aspect, this application pertains to a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof for use in the treatment of breast cancer in a subject in need thereof, wherein the subject comprises at least onesomatic ER tumor mutation. In some embodiments, the compound of Formula (I) is administered orally to the subject. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0045] In one aspect, this application pertains to a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation. In some embodiments, the compound of Formula (I) is administered orally to the subject.

[0046] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is administered to the subject once a day, twice a day, three times a day, or four times a day. In some embodiments, the therapeutically effective amount of the compound of Formula (I) is administered to the subject all at once or is administered in two-, three-, or four- unit doses.

[0047] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 40 mg.

[0048] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

[0049] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 20 mg to about 700 mg.

[0050] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 30 mg to about 500 mg.

[0051] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 30 mg to about 120 mg.

[0052] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg,about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to about 180 mg, about 160 to about 190 mg, about 170 to about 200 mg, about 180 to about 210 mg, about 190 to about 220 mg, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 230 to about 260 mg, about 240 to about 270 mg, about 250 to about 280 mg, about 260 to about 290 mg, about 270 to about 300 mg, about 280 to about 310 mg, about 290 to about 320 mg, about 300 to about 330 mg, about 310 to about 340 mg, about 320 to about 350 mg, about 330 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, or about 370 to about 400 mg

[0053] In some embodiments, the compound of Formula (I) is formulated as a tablet. In some embodiments, the tablet comprises a compound of Formula (I) and, optionally, one or more of the following: emulsifier; surfactant; binder; disintegrant; glidant; and lubricant. In some embodiments, the emulsifier is hypromellose. In some embodiments, the surfactant is Vitamin E polyethylene glycol succinate. In some embodiments, the binder is microcrystalline cellulose or lactose monohydrate. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the glidant is silicon dioxide. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the subject in need of treatment is in a fed state. In some embodiments, the subject in need of treatment is in a fasted state.

[0054] In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as defined herein, further comprising the administration of a therapeutically effective amount of at least one additional anti-cancer agent to the subject in need thereof.

[0055] In one aspect, this application pertains to a compound of Formula (I) as defined herein for use in a method of treating breast cancer in a subject in need thereof, the method further comprising the administration of a therapeutically effective amount of at least one additional anti-cancer agent to the subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).

[0056] In one aspect, this application pertains to a compound of Formula (I) as defined herein for the treatment of breast cancer in a subject in need thereof, the treatment further comprising the administration of a therapeutically effective amount of at least one additional anti-cancer agent to the subject in need thereof.

[0057] In one aspect, this application pertains to a combination comprising a compound of Formula (I) as defined herein and a therapeutically effective amount of at least one additional anti-cancer agent for the treatment of breast cancer in a subject in need thereof.

[0058] In some embodiments, the at least one additional anti-cancer agent is a FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4 / 6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2 inhibitor, JAK / STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, or VEGF trap antibody.

[0059] In some embodiments, the at least one additional anti-cancer agent is a CDK 4 / 6 inhibitor.

[0060] In some embodiments, the at least one additional anti-cancer agent is a FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4 / 6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2 inhibitor, JAK / STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, VEGF trap antibody, SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (Halaven).

[0061] In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0062] In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

[0063] In one aspect, this application pertains to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation; the method comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0064] In one aspect, this application pertains to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation; the treatment comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0065] In some embodiments, the subject comprises at least one somatic ER tumor mutation selected from the group consisting of D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation selected from the group consisting of D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C.

[0066] In some embodiments, the breast cancer is ER+, HER2−.

[0067] In some embodiments, the breast cancer is metastatic or locally advanced.

[0068] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is administered to the subject all at once or is administered in two-, three-, or four- unit doses.

[0069] In some embodiments, the therapeutically effective amount of the compound of Formula (I) is about 30 mg to about 1000 mg.

[0070] In some embodiments, the compound of Formula (I) is formulated as a tablet.

[0071] In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, further comprising the administration of a therapeutically effective amount of at least one additional anti-cancer agent that is a FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4 / 6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2 inhibitor, JAK / STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, VEGF trap antibody, SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (Halaven).

[0072] In some embodiments, the subject comprises at least one somatic ER tumor mutation selected from the group consisting of D538G, E380Q, V422del, and L536P. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation selected from the group consisting of D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C.

[0073] In some embodiments, the breast cancer is ER+, HER2−.

[0074] In some embodiments, the breast cancer is metastatic or locally advanced.

[0075] In some embodiments, the compound of Formula (I) is an antibody-drug conjugate, wherein the compound of Formula (I) is linked, conjugated, or connected with one or more suitable antibodies. Such an ADC would comprise the compound of Formula I of a drug with therapeutic and / or cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. This antibody-drug conjugate (ADC) having a drug with cytotoxicity conjugated to an antibody, whose antigen is expressed on a surface of cancer cells and which also binds to an antigen capable of cellular internalization, can therefore deliver the drug selectively to cancer cells and is thus expected to cause accumulation of the drug within cancer cells and to kill the cancer cells. Definitions

[0076] “Pharmaceutically acceptable salt” as used herein with respect to a compound of Formula (I), means a salt form of a compound of Formula (I) as well as hydrates of the salt form with one or more water molecules present. Such salt and hydrated forms retain the biological activity of a compound of Formula (I) and are not biologically or otherwise undesirable, i.e., exhibit minimal, if any, toxicological effects. Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4- diaminostilbene-2,2-di sulfonate), benzenesulfonate, benzonate, bicarbonate, bi sulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2- naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0077] The term “isomer” refers to salts and / or compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the salts of a compound of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0078] The compounds of Formula (I) may exist in unsolvated as well as solvated forms such as, for example, hydrates.

[0079] “Solvate” means a solvent addition form that contains either a stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate. In the hydrates, the water molecules are attached through secondary valencies by intermolecular forces, in particular hydrogen bridges. Solid hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalent with respect to their binding state. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally suitable are the hydrates of salts of the compounds of the invention.

[0080] When a compound is crystallized from a solution or slurry, it can be crystallized in a different arrangement lattice of spaces (this property is called “polymorphism”) to form crystals with different crystalline forms, each of which is known as “polymorphs”. “Polymorph”, as used herein, refers to a crystal form of a compound of Formula (I), where the molecules are localized in the three-dimensional lattice sites. Different polymorphs of the compound of Formula (I) may be different from each other in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal form, accumulation mode, flowability and / or solid state stability, etc.

[0081] “Isotopic derivative”, as referred to herein, relates to a compound of Formula (I) that is isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes. Thus, in this application, the compounds of Formula (I) include, for example, compounds that are isotopically enriched or labelled with one or more atoms, such as deuterium (2H or D) or carbon-13 (13C).

[0082] The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds of Formula (I) which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.

[0083] “Prodrug”, as used herein means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the instant invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

[0084] This invention also encompasses pharmaceutical compositions containing, and methods of treating disorders through administering, pharmaceutically acceptable prodrugs of compounds of the invention.

[0085] Metastatic breast cancer, or metastases, refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, e.g., bones, liver, lungs, brain. (https: / / www.cancer.org / cancer / breast-cancer.)

[0086] Locally advanced breast cancer (LABC) is defined by the U.S. National Comprehensive Cancer Network as a subset of breast cancer characterized by the most advanced breast tumors in the absence of distant metastasis, wherein the tumors are more than 5 cm in size with regional lymphadenopathy; tumors of any size with direct extension to the chest wall or skin, or both (including ulcer or satellite nodules), regardless of regional lymphadenopathy; presence of regional lymphadenopathy (clinically fixed or matted axillary lymph nodes, or any of infraclavicular, supraclavicular, or internal mammary lymphadenopathy) regardless of tumor stage. (Garg et al. Curr Oncol. 2015 October; 22(5): e409-e410; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, Pa.: NCCN; 2015. Ver. 2.2015.)

[0087] ER+, estrogen receptor positive, as used herein, refers to breast cancer cells that have a receptor protein that binds the hormone estrogen. Cancer cells that are ER+ may need estrogen to grow, and may stop growing or die when treated with substances that block the binding and actions of estrogen. (https: / / www.cancer.gov / publications / dictionaries / cancer-term s / def / 44404.)

[0088] HER2−, human epidermal growth factor receptor 2, as used herein, refers to breast cancer cells that does not have a large amount of a protein called HER2 on their surface. In normal cells, HER2 helps to control cell growth. Cancer cells that are HER2− may grow more slowly and are less likely to recur or spread to other parts of the body than cancer cells that have a large amount of HER2 on their surface. (https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / her2-negative.)

[0089] As used herein, “treating” describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes decreasing or alleviating the symptoms or complications, or eliminating the disease, condition or disorder.

[0090] As used herein, “preventing” describes stopping the onset of the symptoms or complications of the disease, condition or disorder.

[0091] “Administration” refers to introducing an agent, such as a compound of Formula (I) into a subject. The related terms “administering” and “administration of” (and grammaticalequivalents) refer both to direct administration, which may be administration to a subject by a medical professional or by self-administration by the subject, and / or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering the drug to the patient.

[0092] “Anti-cancer agent”, as used herein, is used to describe an anti-cancer agent, or a therapeutic agent administered concurrently with an anti-cancer agent (e.g., palonosetron), with which may be co-administered and / or co-formulated with a compound of Formula (I) to treat cancer, and the side effects associated with the cancer treatment.

[0093] “Therapeutically effective amount”, as used herein means an amount of the free base of a compound of Formula (I) that is sufficient to treat, ameliorate, or prevent a specified disease (e.g., breast cancer), disease symptom, disorder or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective amount for a particular subject may depend upon the subject's body weight, size, and health; the nature and extent of the condition; and whether additional therapeutics are to be administered to the subject. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0094] “Oral dosage form” as used herein refers to a pharmaceutical drug product that contains a specified amount (dose) of a compound of Formula (I) as the active ingredient, or a pharmaceutically acceptable salt and / or solvate thereof, and inactive components (excipients), formulated into a particular configuration that is suitable for oral administration and drug delivery, such as a tablet, capsule or liquid oral formulation. In some embodiments, the compositions are in the form of a tablet that can be scored.

[0095] The term “carrier”, as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0096] The term “about” as part of a quantitative expression such as “about X”, includes any value that is 10% higher or lower than X, and also includes any numerical value that falls between X−10% and X+10%.

[0097] “Comprising” or “comprises” as applied to a particular dosage form, composition, use, method or process described or claimed herein means that the dosage form, composition, use, method, or process includes all of the recited elements in a specific description or claim, but does not exclude other elements. “Consists essentially of” and “consisting essentially of” means that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not materially affect the recited physical, pharmacological, pharmacokinetic properties or therapeutic effects of the composition, dosage form, method, use, or process. “Consists of” and “consisting of” means the exclusion of more than trace elements of other ingredients and substantial method or process steps.

[0098] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0099] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0100] The terms “patient” and “subject” are used interchangeably herein, and refer to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

[0101] In some embodiments, the subject is a human.

[0102] In some embodiments, the subject is a human who has been diagnosed with breast cancer.

[0103] In some embodiments, the subject is a human who has been diagnosed with metastatic breast cancer.

[0104] In some embodiments, the subject is a human who has been diagnosed with ER+, HER2− breast cancer.

[0105] In some embodiments, the subject is a human who has been diagnosed with metastatic, ER+, HER2− breast cancer. Compounds of Formula (I)

[0106] In one aspect, the application pertains to the methods of treating and / or preventing cancer comprising the administration of a compound of Formula (I) to subject in need thereof.

[0107] In one aspect, the application pertains to the use of a compound of Formula (I) in the treatment and / or prevention of breast cancer.

[0108] In one aspect, the application pertains to the use of a compound of Formula (I) in the manufacture of a medicament for the treatment and / or prevention of breast cancer.

[0109] As referred to herein, a compound of Formula (I) refers to a compound with the following structure:or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0110] The compounds of Formula (I), may be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protective groups, as can be obtainedfrom the relevant scientific literature or from standard reference textbooks in the field in view of this disclosure. Although not limited to any one or several sources, recognized reference textbooks of organic synthesis include: Smith, M. B.; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001; and Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd; John Wiley & Sons: New York, 1999. EXAMPLES

[0111] Formula (I) as disclosed herein be prepared according to the synthetic method described in Schemes A through C. Synthesis of 3-(4-((4-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Formula (I):Preparation of methyl 5-amino-4-(4-((tert-butyldimethylsilyl)oxy)-1-oxoisoindolin-2-yl)-5- oxopentanoate (1).

[0112] To an ambient temperature, stirred suspension of methyl 2-(bromomethyl)-3-(tert- butyldimethyl silyloxy)benzoate [1323407-17-5], 90%, (4.51g, 11.3 mmol at 90%) and methyl 4,5-diamino-5-oxopentanoate hydrochloride [1323290-64-7] (2.41g, 12.3 mmol) in acetonitrile (38 mL) contained in 100mL round bottom flask, was added diisopropylethylamine (6.0 mL, 34.5 mmol). The stirred suspension was then heated to 40° C under N2 blanket for 17 hours, cooled, and partitioned between cold 1.0N HCl (aq.) and ethyl acetate. The organic phase was washed with sat. NaCl (aq.), dried (CaSO4), filtered, and preabsorbed onto celite. Flash chromatography (silica gel, EtOAc / hexanes) yielded 2.58g of light brown solid. Recrystallization from minimum boiling ethyl acetate provided 1.66g of white, fine powder. C20H30N2O5Si LC- MS MH+= 407.1993 (mass error -0.9ppm);1H NMR (300 MHz, DMSO-D6) δ 0.24-0.25 (m, 6H), 0.98 (s, 9H), 1.91-2.33 (m, 4H), 3.48 (s, 3H), 4.30-4.52 (m, 2H), 4.72-4.77 (m, 1H), 7.07 (dd, J=7.82, 0.92Hz, 1H), 7.20 (bs, 1H), 7.31-7.33 (m, 1H), 7.38-7.43 (m, 1H), 7.61 (bs, 1H) ppm.13C NMR (75 MHz, DMSO-D6) d -4.52, -4.47, 17.82, 24.82, 25.47, 30.36, 44.71, 51.25, 53.44, 116.03, 121.42, 129.56, 132.40, 133.91, 150.34, 167.87, 171.70, 172.54 ppm. Preparation of methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate 4- Carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (2).

[0113] To a stirred, ambientof methyl 5-amino-4-(4-(tert- butyldimethylsilyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1) (2.37g, 5.8 mmol) in methanol (116 mL) was added potassium bifluoride [7789-29-2] (1.36g, 17.4 mmol). The resulting solution was stirred at room temperature for 30 minutes, at which time LC-MS analysis reported the reaction to be complete. Evaporation onto celite and subsequent flash chromatography (silica gel, EtOAc / hexanes) afforded 972.2mg of white solid. C14H16N2O5LC-MS MH+= 293.1132 (mass error 0.1ppm). Preparation of methyl 5-amino-4-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5- oxopentanoate (3).

[0114] Diisopropyl diazene- AD, 1.3mL, 6.7mmol) was added to a stirred, 0° C, suspension of polymer-supported triphenylphosphine, ca. 1.6 mmol / g (4.2g, 6.7 mmol) and methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (2) (972.2mg, 3.3 mmol) in THF (33 mL). After stirring for 30 minutes at 0° C, (4- (chloromethyl)phenyl)methanol (782.3mg, 5.0 mmol) was added and the mixture was rapidly stirred for 1.5h then filtered through tightly packed celite. The resin bed was thoroughly washed with EtOAc and the filtrate evaporated to provide 3.1g of opaque yellow oil. Flash chromatography (silica gel, EtOAc / hexanes) yielded 1.2g of white solid. C22H23ClN2O5LC-MS MH+= 431.1380 (mass error 2.8ppm);1H NMR (300 MHz, DMSO-D6) δ 1.99-2.30 (m, 4H), 3.50 (s, 3H), 4.39-4.58 (m, 2H), 4.74 (dd, J=5.0, 4.5Hz, 1H), 4.78 (s, 2H), 5.26 (s, 2H), 7.21 (bs, 1H), 7.27-7.31 (m, 2H), 7.43-7.53 (m, 5H), 7.60 (bs, 1H) ppm.13C NMR (75 MHz, DMSO-D6) d 25.32, 30.86,45.30,46.36,51.77, 53.90, 69.55, 115.15, 115.70,128.37, 129.53, 130.08, 130.71, 133.97, 137.34, 137.86, 153.79, 168.38, 172.28, 173.00 ppm.Preparation of 4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (4).

[0115] To a solution ofphenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenol [2229713-95-3] (1.6g, 4.2 mmol, [a]D= -380.55°) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonyl fluoride [375-72-4], 96% (1.3g, 4.2 mmol) in 50%(v / v) tetrahydrofuran and acetonitrile (15 mL) contained in a 50 mL round bottomed flask was added potassium carbonate [584-08-7] (867.2mg, 6.3 mmol). The reaction mixture was stirred at ambient temperature for 4 days, under N2 blanket, after which time TLC showed the conversion to be complete. The reaction suspension was diluted with EtOAc and absorbed onto celite in preparation for purification. Flash chromatography (silica gel, EtOAc / hexanes) afforded 1.9g of milky viscous oil.1H NMR (300 MHz, DMSO-D6) δ 1.30 (s, 9H), 1.73-1.76 (m, 1H), 2.93-3.12 (m, 2H), 3.41-3.46 (m,1H), 4.40 (d, J=5.1Hz, 1H), 6.53 (d, J=8.6Hz, 2H),6.69-6.86 (m, 6H), 7.07-7.12 (m, 5H) ppm.13C NMR (75 MHz, DMSO-D6) d 29.1, 29.6, 44.4, 49.9, 78.0, 120.1, 122.1, 123.8, 126.5, 128.1, 128.1, 131.2, 132.2, 133.5, 137.5, 143.8, 144.0, 148.0, 153.9 ppm. Preparation of tert-butyl 4-(4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate (5).

[0116] To a mixture of [4-[phenyl-tetralin-l-yl]phenyl] 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (4) (1.3g, 2.0 mmol), tert-butyl piperazine-1- carboxylate [57260-71-6] (1.12g, 6.0 mmol), sodium tert-butoxide [865-48-5] (765.4mg, 8.0 mmol), palladium acetate [3375-31-3] (81.1mg, 0.4 mmol), and dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl [564483-18-7] (XPhos, 305.5mg, 0.6 mmol) contained in a 100mL round bottomed flask, was added toluene (20 mL). The rapidly stirred suspension was N2 sparged for 15 minutes, the sparge tube removed, the vessel placed under N2 blanket and the mixture stirred at 100 °C for 2 hours. TLC showed the reaction to be complete. The reaction mixture was partitioned between water and EtOAC with the organic phase absorbed onto celite. Flash chromatography (silica gel, EtOAc / hexanes) provided 837.9mg of white solid foam. C35H44N2O3LC-MS MH+= 541.3419 (mass error -1.0 ppm);1H NMR (300 MHz, DMSO-D6) δ 1.29 (s, 9H), 1.40 (s, 9H), 1.71-1.74 (m, 1H), 2.04-2.18 (m, 1H), 2.91-2.95 (m, 4H), 3.02-3.04 (m, 1H), 3.30-3.38 (m, 6H), 4.21-4.22 (m, 1H), 6.22 (d, J=8.64 Hz, 2H), 6.56 (d, J=8.74 Hz, 2H), 6.65-6.69 (m, 1H), 6.73-6.76 (m, 1H), 6.82-6.86 (m, 3H), 7.09-7.19 (m, 3H) ppm.Preparation of (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol hydrochloride (6).

[0117] 4.0M anhydrous HCl28 mmol) was added to tert-butyl 4- (4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1- carboxylate (5) (752.7mg, 1.4 mmol) contained in a 25mL round bottom flask. The solution was allowed to stir at ambient temperature. After 0.5h LC-MS reported the double deprotection to be complete, the reaction solution was evaporated to dryness to obtain 918.3mg of light brown solid, which was used without further purification. C26H28N2O LC-MS MH+= 385.2279 (mass error 1.1 ppm).Preparation of methyl 5-amino-4-(4-((4-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)- 5-oxopentanoate (7).

[0118] Diisopropylethylamine (2.5mL, 14.4 mmol) was added to a stirred suspension of (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol hydrochloride (6) (918.3mg, [1.4 mmol]), and methyl 5-amino-4-(4-((4-(chloromethyl)benzyl)oxy)-1- oxoisoindolin-2-yl)-5-oxopentanoate (3) (879.7mg, 2.0 mmol) in methanol (20.0mL) contained in a 100 mL round bottom flask. The mixture was stirred at reflux until LC-MS reported the reaction to be complete, 17h. The cooled reaction mixture was diluted with additional methanol and absorbed onto celite. Flash chromatography (silica gel, MeOH / DCM) provided 1.3g of white solid foam. C48H50N4O6 LC-MS MH+= 779.3829 (mass error 3.3 ppm). Preparation of 3-(4-((4-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Formula (I)).

[0119] Neat50-6] (2.6g, 8.3 mmol) was added to a stirred, ambient temperature, solution of methyl 5-amino-4-(4-((4-((4-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)- 1-oxoisoindolin-2-yl)-5-oxopentanoate (7) (1.3g, 1.7 mmol) in THF (166mL). The solution was allowed to stir, under N2 blanket, until TLC showed conversion to be complete, 17h. The reaction solution was then absorbed onto celite and flash chromatographed (silica gel, 2-propanol / DCM) to isolate 0.6g of white solid which was recrystallized from boiling EtOAc / heptane to recover 458.6mg of white powder. C47H46N4O5 LC-MS MH+= 747.3555 (mass error = 1.9 ppm).1H NMR (300 MHz, DMSO-D6) δ 1.24-1.32 (m, 1H), 1.68-1.71 (m, 1H), 1.95-1.99 (m, 1H), 2.04-2.16 (m, 1H), 2.40-2.46 (m, 4H), 2.53-2.59 (m, 1H), 2.85-2.96 (m, 7H), 3.25-3.30, 1H), 3.49 (s, 2H), 4.13 (d, J=4.77 Hz, 1H), 4.22-4.28 (m, 1H), 4.38-4.44 (m, 1H), 5.08-5.14 (m, 1H), 5.22 (s, 2H), 6.20 (d, J=8.59 Hz, 2H), 6.46-6.53 (m, 3H), 6.60 (d, J=2.25 Hz, 1H), 6.63 (d,J=8.38 Hz, 1H), 6.82-6.84 (m, 2H), 7.07-7.17 (m, 3H), 7.31-7.34 (m, 4H), 7.42-7.51 (m, 3H), 9.11 (s, 1H), 10.98 (s, 1H) ppm.13C NMR (75 MHz, DMSO-D6) d 22.0, 22.8, 29.8, 31.7, 45.0, 45.6, 48.6, 49.9, 52.0, 53.0, 62.2, 69.9, 114.0, 114.3, 114.8, 115.4, 115.7, 126.2, 128.0, 128.2, 128.3, 129.5, 130.3, 130.4, 130.8, 130.9, 131.6, 133.5, 133.8, 135.7, 137.5, 138.4, 144.7, 149.1, 154.0, 155.7, 168.5, 171.5, 173.4 ppm. [a]D = -244.8° (specific rotation: 0.4344g / 100cm3in ethyl acetate, l = 589nm, 25° C). MCF-7 Cell Proliferation Experimental method:

[0120] MCF-7 cells were resuscitated and plated once normal growth was confirmed and viability exceeded 90%. The processing procedure before treatment of cells with the test article was as follows: measurement of cell density and viability, determination of the corresponding volume of cell culture medium to evaluate the volume required to transfer the required quantity of cells, centrifuge, resuspend the cells with fresh culture medium (1000 cells / well, 100^L / well, plate in white bottom plate) and mix the well, add culture medium to the surrounding wells to eliminate edge effects and culture overnight. The next day, dilute the drug with culture medium gradient, add 100^L / well to the corresponding cell wells. The plates were cultured in a 37°C , 5% CO2 incubator for 72 hours. When the plates returned to room temperature, 40^L of CellTiter-Glo was added to each well, and the plates were gently shaken at 80rpm for 10 minutes to mix. The chemiluminescence was read by an enzyme plate reader. The inhibition curves were drawn with GraphPad Prism. Result analysis:

[0121] Under the same conditions, the inhibition effect trend of the compound of Formula (I) is similar to that of ARV-471 (Figure 1). Inhibition effect trend of the compound of Formula (I) shows greater activity than (rac) ARV-471. Eciruciclib acts as a control and shows the stable suppression trend of previous experiments.Western Blot Assay:

[0122] MCF-7 cell line were purchased from American Type Culture Collection (Manassas, VA). The cells were grown in EMEM medium, which was supplemented with 10% FBS, 100 µg / ml penicillin, and 100 µg / ml streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2and 95% air. 7% Tris-Acetate gel and nitrocellulose membranes were purchased from Thermo-Fisher Scientific (Waltham, MA). The Estrogen Receptor alpha (Cat#8644S) antibody was purchased from Cell Signaling Technology (Danvers, MA). Anti-α-tubulin (T9026) antibody was purchased from Sigma (St. Louis, MO). Anti-rabbit IgG IRDye 680RD and anti-mouse IgG IRDye 800CW secondary antibodies were purchased from LI-COR (Lincoln, NE). Procedure: 1. 5x105cells / well of MCF-7 cells were seeded in 12-well plates with complete culture medium and then incubated overnight. 2. Next day, the cells were treated with 10 doses of each of the three compounds; with compound of Formula (1), (racemic) ARV-471, and Vepdegestrant (ARV-471) starting at 10 µM with 3-fold dilution in singlet. DMSO was used as vehicle control. 3. The tissue culture plates were incubated at 37oC and 5% CO2 for 72 hours. 4. The culture medium was removed, and the cells were washed with ice cold PBS. 5. The cells were lysed with 150 µL 1 x SDS sample buffer supplemented with 50 mM DTT. 6. The samples were sonicated, then heated at 95°C for 10 minutes, then frozen until ready for use. 7. 20 µL of sample was separated by SDS-PAGE on 7% Tris-Acetate gels and transferred onto nitrocellulose membranes by iBlot Dry Blotting system. 8. The membranes were blocked with 3% milk for 1 hour, then probed with Estrogen Receptor alpha antibody in 3% milk overnight. 9. The membranes were blocked with 3% milk for 1 hour and re-probed with anti-α-tubulin antibody in 3% milk. 10. LI-COR anti-rabbit IgG IRDye 680RD and anti-mouse IgG IRDye 800CW secondary antibodies were used to detect the primary antibodies. 11. The membranes were scanned with LI-COR Odyssey Fc Imaging System. The specific bands of interest were quantified by LI-COR Image Studio Lite software. 12. Bar graphs were plotted using the GraphPad Prism 4 program.

[0123] MCF-7 cells were treated with compound of Formula (1) (Fig. 2A), (racemic) ARV-471 (Fig. 2B), and Vepdegestrant (ARV-471) (Fig. 2C) with the indicated concentrationsfor 72 hours. The cell lysates were subjected to Western blot analyses. The blots were probed with Estrogen Receptor alpha antibody and re-probed with α-Tubulin antibody.

Claims

CLAIMS What is claimed is:

1. A method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation; the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the at least one somatic ER tumor mutation is selected from the group consisting of D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C.

3. The method of claim 1, wherein the breast cancer comprises at least one somatic ER tumor mutation selected from the group consisting of D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C.

4. The method of claim 1, wherein the breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−).

5. The method of claim 1, wherein the breast cancer is metastatic or locally advanced.

6. The method of claim 1, further comprising the administration of a therapeutically effective amount of at least one additional anti-cancer agent to the subject in need thereof.

7. The method of claim 5, wherein the at least one additional anti-cancer agent is selected from the group consisting of a FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4 / 6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2 inhibitor, JAK / STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, VEGF trap antibody, SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy-5- fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (halaven).

8. The method of claim 1, wherein the subject is a human 9. The method of claim 1, wherein the compound of Formula (I) is conjugated to an antibody to form an antibody-drug conjugate.

10. A compound of Formula (I):or a pharmaceutically accepta 11. The compound of claim 10, wherein said compound of Formula (I) is conjugated to an antibody to form an antibody drug conjugate.

12. A pharmaceutical composition for treating breast cancer, said pharmaceutical composition comprising a compound of claim 10, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable adjuvants, diluents, and / or carriers.

13. The pharmaceutical composition of claim 12, wherein said composition for treating breast cancer is administered to a subject in need thereof, and wherein the breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation.

14. A method of degrading at least one somatic ER tumor mutation in a human, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

15. The method of claim 14, wherein the at least one somatic ER tumor mutation is selected from the group consisting of D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C.

16. The method of claim 15, further comprising the administration of a therapeutically effective amount of at least one additional anti-cancer agent to the subject in need thereof.

17. The method of claim 14, wherein the compound of Formula (I) is conjugated to an antibody to form an antibody-drug conjugate.

Images