Estrogen receptor degraders as therapeutic agents for breast cancer

Abstract

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

Description

[0001] Citations of relevant applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 646,004, filed May 13, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the treatment and / or prevention of breast cancer (breast cancer), including locally advanced or metastatic, ER+, HER2- breast cancer, in subjects requiring treatment. Background Technology

[0004] Breast cancer accounts for 12.5% ​​of all new cancer cases globally each year, making it the most common cancer in the world. In the United States (US), breast cancer is the second leading cause of cancer death among women, after lung cancer. Each year, breast cancer accounts for approximately 30% of all new cancer cases among women in the US. It is estimated that 43,170 women will die from breast cancer in 2023. Although breast cancer is less common in men, men account for about 1% of all new diagnoses, and nearly 530 men are projected to die from the disease in 2023. As of January 2017, approximately 155,000 women in the United States were living with metastatic breast cancer (mBC). There are also reports that the number of women living with mBC is increasing, primarily due to improvements in treatment options 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 BreastCancer in the United States" Cancer Epidemiol. Biomarkers Prev. 2017, 26(6):809-815.)

[0005] Treatment options for advanced breast cancer, or mBC, depend on many different factors, including whether the tumor expresses hormone receptors, namely the estrogen receptor (ER) and / or progesterone receptor, or human epidermal growth factor receptor 2 (HER2). Standard treatment for women with mBC is endocrine therapy, chemotherapy, and / or targeted therapy, which can be used alone or in combination. Patients with ER-positive (ER+) and HER2-negative (HER2-) mBC receive endocrine therapy, sometimes in combination with targeted therapies such as CDK4 / 6 inhibitors (CDKi). Chemotherapy may be prescribed for patients with aggressive disease or those whose disease continues to progress after endocrine therapy.

[0006] Currently, the standard treatment for women with ER+, HER2-, mBC is endocrine therapy plus / - CDKi or mTOR inhibitors. Endocrine therapy includes ovarian ablation or suppression (for premenopausal women), tamoxifen (a selective ER modulator, SERM), aromatase inhibitors, fulvestrant (a SERM), and lasoxifen (a SERM). Metastatic breast cancer remains incurable, and sequential administration of endocrine therapy is the recommended approach for treating ER+ breast cancer. Adding targeted therapies, including CDKi and mTOR inhibitors, to endocrine therapy can further improve patient outcomes.

[0007] Fulvestrant is considered a cornerstone component of ER-targeted endocrine therapy regimens in advanced disease settings, acting through an indirect protein degradation mechanism that leads to ER instability. Fulvestrant monotherapy is administered at a dose of 500 mg, intramuscularly (IM), on days 1, 15, and 29, and monthly thereafter. The efficacy of fulvestrant was established in two randomized, controlled clinical trials in postmenopausal women with locally advanced or mBC, compared to the selective aromatase inhibitor anastrozole (Astra Zeneca Faslodex Full Prescribing Information, 03 / 2019 revised). All patients had progressed on prior anti-estrogen or progestin therapy for breast cancer in adjuvant or advanced disease settings. In both trials, eligible patients with measurable and / or evaluable disease were randomized to receive either fulvestrant 250 mg monthly (28 days + 3 days) IM or anastrozole 1 mg orally once daily. The trial results, after a minimum follow-up of 14.6 months, ruled out the possibility that fulvestrant was inferior to anastrozole. After a follow-up of 2 years or longer, there was no statistically significant difference in overall survival (OS) between the two treatment groups. A third study compared fulvestrant 500 mg with fulvestrant 250 mg. Results from this study, after a minimum follow-up of 18 months, showed that fulvestrant 500 mg had a statistically significant improvement in progression-free survival (PFS) compared to fulvestrant 250 mg (6.5 months vs. 5.4 months, respectively). There was no statistically significant difference in OS between the two treatment groups (25.1 months for fulvestrant 500 mg and 22.8 months for fulvestrant 250 mg). The overall response rate (ORR) was similar; the response rate was 13.8% (95% confidence interval [CI] 9.7–18.8%) at the 500 mg dose and 14.6% (CI 10.5–19.4%) at the 250 mg dose (Astra Zeneca Faslodex FullPrescribing Information, revised 03 / 2019).

[0008] Antibody-drug conjugates (ADCs), as a novel type of targeted therapy, typically consist of three parts: an antibody or antibody-like ligand, a small molecule drug, and a linker (connector) that conjugates the ligand and drug. ADCs utilize the specific recognition of antigens by antibodies to transport drug molecules to the vicinity of target cells and efficiently release the drug molecules to achieve therapeutic goals. Compared to traditional small molecule approaches, ADCs can enhance targeting of cancer cells while potentially minimizing dose-limiting toxicities and maximizing the desired therapeutic effect.

[0009] Mylotarg® (gemtuzumab ozogamicin) was the first ADC approved by the US Food and Drug Administration (FDA) twenty years ago. This early ADC conjugated kazidromycin to an anti-CD33 antibody and was approved as a treatment for acute myeloid leukemia. Additionally, Adcetris® (brentuximab vedotin) conjugated auristatin E to an anti-CD30 antibody and was approved as a treatment for Hodgkin's lymphoma and anaplastic large cell lymphoma. The drugs contained in these early approved ADCs targeted DNA or microtubules.

[0010] The advantages of antibody-drug conjugates (ADCs) lie in increased water solubility, improved targeting, and the fact that the binding of specific antibodies to antigens carries the drug to the vicinity of target cells and releases the drug near the target cells to effectively kill tumor cells and reduce toxic side effects.

[0011] The structure of formula (I) (disclosed herein) comprises structural elements of lasoxifene and cereblon / ligase-binding thalidomide derivatives. These two elements are linked by a novel linker. Summary of the Invention

[0012] In one aspect, this application relates to a method of treating breast cancer in a subject who requires it, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I),

[0013] Or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative or prodrug thereof, wherein the therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg.

[0014] In one aspect, this application relates to a method of treating breast cancer in a subject who requires it, wherein the subject comprises at least one somatic ER tumor mutation; the method includes 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 from about 10 mg to about 1000 mg. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

[0015] In one aspect, this application relates to a compound of formula (I) for use in a method of treating breast cancer in a subject who requires it, 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, and L536X, wherein "X" refers to any amino acid residue at that position other than a wild-type residue. 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.

[0016] In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic or locally advanced.

[0017] In one embodiment, the compound is a compound of formula (I):

[0018] Or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative or prodrug.

[0019] In some embodiments, the compound of formula (I) is administered orally to the subject.

[0020] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered to the subject once daily, twice daily, three times daily, or four times daily. In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered to the subject in a single, complete dose or in two, three, or four unit doses. In some embodiments, a 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, a 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.

[0021] In one aspect, this application relates to a method of treating breast cancer in a subject; the method comprising administering a therapeutically effective amount of a compound of formula (I) to the subject; and further comprising administering a therapeutically effective amount of at least one other anticancer agent to the subject in need of it.

[0022] In some embodiments, the additional anticancer agent is selected from the group consisting of: FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK 4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 agonists, focal adhesion kinase inhibitors, Map kinase inhibitors, and VEGF capture antibodies. In some embodiments, the additional anticancer agent is a CDK 4 / 6 inhibitor.

[0023] In some embodiments, the additional anticancer agents are SHR6390, trilaciclib, lerociclib, AT7519M, denacilib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epothilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, and peptone. Pemetrexed, Erlotinib, Ticilimumab, Ipilimumab, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, 5′-deoxy-5-fluorouridine, Vincristine, Temozolomide, Capecitabine, Camptothecin, PD0325901, Irinotecan, Tamoxifen, Toremifene, Anastrozole, Letrozole, Bevacizumab, Goserelin acetate Acetate, raloxifene, alpelisib, trastuzumab, trastuzumab bemtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (Halaven). In some embodiments, the additional anticancer agent is pebocillin.

[0024] In another aspect, this application relates to conjugating compounds of formula (I) with antibodies to form antibody-drug conjugates (ADCs).

[0025] In one aspect, this application relates to a method of treating breast cancer in a subject in need of it, comprising oral administration once daily of a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is:

[0026] Or a pharmaceutically acceptable salt, solvate, polymorph, isotope 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.

[0027] In one aspect, this application relates to a method of treating breast cancer in a subject who requires it, comprising oral administration once daily of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative, or prodrug thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0028] In one aspect, this application relates to a method of treating breast cancer in a subgroup of breast cancer subjects, comprising: selecting breast cancer subjects for treatment based on the somatic ER tumor biomarker status of the subjects; and administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative or prodrug thereof.

[0029] In one aspect, this application relates to a method of treating breast cancer in a subgroup of breast cancer subjects, comprising: selecting breast cancer subjects for treatment based on the somatic ER tumor biomarker status of the subjects; and administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative or prodrug thereof.

[0030] In some embodiments, the method further includes administering at least one additional anticancer agent. In some embodiments, the additional anticancer agent is selected from the group consisting of: FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK 4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 agonists, focal adhesion kinase inhibitors, Map kinase inhibitors, and VEGF capture antibodies.In some embodiments, the additional anticancer agent is a CDK 4 / 6 inhibitor, such as SHR6390, trilaciclib, lerociclib, AT7519M, denacilib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, or epothilone. B) Fuvestrant, Acolbifene, Lasofoxifene, Idoxifen, Topotecan, Pemetrexed, Erlotinib, Ticilimumab, Ipilimumab, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, 5′-Deoxy- 5-Fluorouracil (5′-deoxy-5-fluorouridine), vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrozole, letrozole, bevacizumab, goserelin acetate Acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (Halaven).

[0031] In some embodiments, the additional anticancer agent is administered before the administration of compound (I). In some embodiments, the additional anticancer agent is administered at least 30 minutes before the administration of compound (I). In some embodiments, the additional anticancer agent is administered after the administration of compound (I). In some embodiments, the additional anticancer agent is administered at least 30 minutes after the administration of compound (I).

[0032] In one aspect, this application relates to compounds of formula (I):

[0033] The compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative, or prodrug thereof, is used in the preparation of a medicament for treating breast cancer in a subject in need of the compound, wherein the subject comprises at least one somatic ER tumor mutation; and wherein the therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0034] The present invention also envisions the conjugation of a compound of formula (I) as an antibody-drug conjugate, wherein the compound of formula (I) is linked, conjugated, or bound to one or more suitable antibodies. Such an ADC would comprise a compound of formula (I) in the form of a drug having therapeutic and / or cytotoxic activity, cross-linked with a monoclonal antibody, targeting an antigen expressed at a higher level on tumor cells than on normal cells. This antibody-drug conjugate (ADC) has a cytotoxic drug conjugated (conjugated, bound) to an antibody whose corresponding antigen is expressed on the surface of cancer cells and which also binds to an antigen capable of internalization, thus allowing selective delivery of the drug to cancer cells, thereby anticipating accumulation of the drug within the cancer cells and killing them.

[0035] These and other aspects will become apparent from the following detailed description of the invention. Attached Figure Description

[0036] Figure 1 The trend of inhibitory effect of compound (I) compared with (racemic) ARV-471 is shown.

[0037] Figure 2A , Figure 2B and Figure 2C The concentrations of compound (I) shown are illustrated. Figure 2A (racemic) ARV-471 Figure 2BWestern blots and graphs of MCF-7 cells treated with vepdegestrant (ARV-471) for 72 hours were generated. Cell lysates were subjected to Western blot analysis, with detection (probe) using an estrogen receptor α antibody and re-probe (re-probe) using an α-tubulin antibody. Detailed Implementation

[0038] In one aspect, this application relates to a method for treating breast cancer in a subject who requires it, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I),

[0039] Or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative or prodrug.

[0040] In one aspect, this application relates to a method for treating breast cancer in a subject who requires treatment, 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).

[0041] Or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative or prodrug.

[0042] In one aspect, this application relates to a method for treating breast cancer in a subject who requires it, wherein the breast cancer comprises at least one somatic ER tumor mutation; the method includes 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 from about 10 mg to about 1000 mg.

[0043] In one aspect, this application relates to a compound of formula (I) for use in a method of treating breast cancer in a subject who requires it, wherein the breast cancer comprises at least one somatic ER tumor mutation. In some embodiments, the method includes administering a therapeutically effective amount of the compound of formula (I) to the subject.

[0044] In one aspect, this application relates to a compound of formula (I) for use in treating breast cancer in a subject in need of treatment, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0045] In one aspect, this application relates to a compound of formula (I) for use in treating breast cancer in a subject in need of treatment, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0046] 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.

[0047] In some implementations, the breast cancer is ER+ or HER2-.

[0048] In some embodiments, the breast cancer is metastatic breast cancer or locally advanced breast cancer.

[0049] In one aspect, this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof in a method of treating breast cancer in a subject who requires it, wherein the subject comprises at least one somatic ER tumor mutation. In some embodiments, the method includes 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.

[0050] In one aspect, this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof in a method of treating breast cancer in a subject in need of it, wherein the breast cancer comprises at least one somatic ER tumor mutation. In some embodiments, the method includes 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.

[0051] In one aspect, this application relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof for use in treating breast cancer in a subject requiring treatment therein, wherein the subject comprises at least one somatic 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.

[0052] In one aspect, this application relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof for use in treating breast cancer in a subject in need of treatment, 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.

[0053] In some embodiments, a therapeutically effective amount of compound (I) is administered to the subject once, twice, three times, or four times daily. In some embodiments, a therapeutically effective amount of compound (I) is administered to the subject in a single dose, or in two, three, or four unit doses.

[0054] 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.

[0055] In some embodiments, the therapeutically effective amount of the compound of formula (I) is about 10 mg to about 1000 mg.

[0056] In some embodiments, the therapeutically effective amount of the compound of formula (I) is about 20 mg to about 700 mg.

[0057] In some embodiments, the therapeutically effective amount of the compound of formula (I) is about 30 mg to about 500 mg.

[0058] In some embodiments, the therapeutically effective amount of the compound of formula (I) is about 30 mg to about 120 mg.

[0059] 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. 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.

[0060] In some embodiments, the compound of formula (I) is formulated into tablets. In some embodiments, the tablets comprise the compound of formula (I) and optionally comprise one or more of the following: an emulsifier; a surfactant; a binder; a disintegrant; a glidant; and a lubricant. In some embodiments, the emulsifier is hydroxypropyl methylcellulose. 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 silica. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the subject requiring treatment is in an eating state. In some embodiments, the subject requiring treatment is in a fasting state.

[0061] In one aspect, this application relates to a method for treating breast cancer in a subject who requires it, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as defined herein, and further comprising administering to the subject a therapeutically effective amount of at least one additional anticancer agent.

[0062] In one aspect, this application relates to the use of a compound of formula (I) as defined herein in a method of treating breast cancer in a subject who requires it, the method further comprising administering a therapeutically effective amount of at least one additional anticancer agent to the subject who requires it. In some embodiments, the method comprises administering a therapeutically effective amount of the compound of formula (I) to the subject.

[0063] In one aspect, this application relates to a compound of formula (I) as defined herein for treating breast cancer in a subject who requires it, said treatment further comprising administering a therapeutically effective amount of at least one additional anticancer agent to the subject who requires it.

[0064] In one aspect, this application relates to a combination comprising a compound of formula (I) as defined herein and a therapeutically effective amount of at least one other anticancer agent for treating breast cancer in a subject in need of it.

[0065] In some embodiments, the at least one additional anticancer agent is an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-Met inhibitor, a PARP inhibitor, a CDK 4 / 6 inhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKT inhibitor, an mTORC1 / 2 inhibitor, a JAK / STAT inhibitor, a checkpoint 1 inhibitor, a checkpoint 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase inhibitor, or a VEGF capture antibody.

[0066] In some embodiments, the at least one additional anticancer agent is a CDK 4 / 6 inhibitor.

[0067] In some embodiments, the at least one additional anticancer agent is an 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 capture antibody, SHR6390, trilaciclib, lerociclib, AT7519M, denaciline, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib,GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epothilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy- 5-Fluorouracil (5′-deoxy-5-fluorouridine), vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrozole, letrozole, bevacizumab, goserelin acetate Acetate, raloxifene, alpelisib, trastuzumab, trastuzumab bemtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (Halaven).

[0068] In one aspect, this application relates to a method for treating breast cancer in a subject who requires it, wherein the subject comprises at least one somatic ER tumor mutation, the method comprising oral administration once daily of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative or prodrug thereof.

[0069] In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

[0070] In one aspect, this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof in a method of treating breast cancer in a subject in need of it, wherein the breast cancer comprises at least one somatic ER tumor mutation; the method comprising oral administration once daily of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0071] In one aspect, this application relates to a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof for use in treating breast cancer in a subject in need of treatment, wherein the breast cancer comprises at least one somatic ER tumor mutation; the treatment comprising oral administration once daily of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

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

[0073] In some implementations, breast cancer is ER+, HER2-.

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

[0075] In some implementations, a therapeutically effective amount of the compound of formula (I) is administered to the subject once, or in doses of two, three, or four units.

[0076] In some embodiments, the therapeutically effective amount of the compound of formula (I) is about 30 mg to about 1000 mg.

[0077] In some embodiments, the compound of formula (I) is formulated as a tablet.

[0078] In one aspect, this application relates to a method of treating breast cancer in a subject in need of it, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, the method further comprising administering a therapeutically effective amount of at least one additional anticancer agent, said additional anticancer agent being an 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, or Map kinase inhibitor. kinase inhibitors, VEGF capture antibodies, SHR6390, trilaciclib, lerociclib, AT7519M, denacilib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisibGDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epothilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy- 5-Fluorouracil (5′-deoxy-5-fluorouridine), vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrozole, letrozole, bevacizumab, goserelin acetate Acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (Halaven).

[0079] In some embodiments, the subject contains at least one somatic ER tumor mutation selected from the group consisting of: D538G, E380Q, V422del, and L536P. In some embodiments, the breast cancer contains at least one somatic ER tumor mutation selected from the group consisting of: D538G, E380Q, V422del, L536P, Y537S, Y537N, and Y537C.

[0080] In some implementations, breast cancer is ER+, HER2-.

[0081] In some implementations, the breast cancer is metastatic or locally advanced.

[0082] In some embodiments, the compound of formula (I) is an antibody-drug conjugate (ADC), wherein the compound of formula (I) is linked, conjugated, or bound to one or more suitable antibodies. Such an ADC would comprise a compound of formula (I) having therapeutic and / or cytotoxic activity, cross-linked with a monoclonal antibody that targets an antigen expressed at a higher level on tumor cells than on normal cells. This antibody-drug conjugate (ADC) has a cytotoxic drug conjugated to an antibody whose corresponding antigen is expressed on the surface of cancer cells, and the antibody also binds to an antigen capable of intracellularization, thus allowing selective delivery of the drug to cancer cells, thereby anticipating drug accumulation within the cancer cells and killing them.

[0083] definition

[0084] In this document, the term “pharmaceutically acceptable salt” as used with respect to compounds of formula (I) refers to the salt form of the compound of formula (I) and the hydrate formed when that salt form is present with one or more water molecules. Such salt and hydrate forms retain the biological activity of the compound of formula (I) and are not biologically or otherwise undesirable, i.e., exhibit minimal (if any) toxicological effects.Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetates, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium salts, and calcium edetate (calcium diethylenediaminetetraacetate). edetate), camphor sulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate (ethylenediaminetetraacetic acid), ethylenedisulfonate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycyrrhizinyl arsenate (glycolyl arsenate), hexafluorophosphate, hexylresorcinate, hydrazine arsenate Amines (hydrabamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiocyanate, lactate, lactouronate, laurate, magnesium salt, malate, maleate, mandelate, methanesulfonate, methylbromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine Ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / pyrophosphate (bisphosphonate), picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0085] 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. Structural differences may lie in configuration (geometric isomers) or in the ability to rotate the plane of polarization (stereoisomers). In the case of stereoisomers, salts of compounds of formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0086] Compounds of formula (I) can exist in both unsolvated and solvated forms, such as hydrates.

[0087] A "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming a solvate. If the solvent is water, the formed solvate is a hydrate; when the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by the combination of one or more water molecules with a substance in which water retains its molecular state as H₂O; such combinations can form one or more hydrates. In hydrates, water molecules are linked by intermolecular forces via secondary valences, particularly by hydrogen bridges. Solid hydrates contain water in a stoichiometric form called water of crystallization, where the water molecules need not be identical in their binding states. Examples of hydrates include sesquihydrates, monohydrates, dihydrates, or trihydrates. Hydrates of salts of the compounds of this invention are also suitable.

[0088] When a compound crystallizes from a solution or slurry, it can crystallize in different lattice spaces (a property called "polymorphism"), thus forming crystals with different crystalline forms, each of which is called a "polymorph". As used herein, "polymorph" refers to one crystalline form of a compound of formula (I), in which the molecule is located in a three-dimensional lattice site. Different polymorphs of a compound of formula (I) may differ from each other in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal form, packing mode, fluidity, and / or solid-state stability.

[0089] As mentioned herein, “isotope derivatives” refer to compounds of formula (I) that are isotopically enriched or labeled with one or more stable isotopes relative to one or more atoms of the compound. Therefore, in this application, compounds of formula (I) include, for example, compounds that are isotopically enriched or labeled with one or more atoms such as deuterium (2H or D) or carbon-13 (13C) .

[0090] As used herein, the term "pharmaceuticalally acceptable prodrug" refers to those prodrugs of formula (I) that, within reasonable medical judgment, are suitable for contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and are effective for their intended use, and where possible, also relates to the zwitterionic form of the compounds of the present invention.

[0091] As used herein, "prodrug" refers to a compound that can be converted in vivo through metabolism (e.g., by hydrolysis) to obtain any compound defined by the structural formula of this invention. Various forms of prodrugs are known in this art, such as those discussed in the following literature: Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (eds.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen et al. (eds.), “Design and Application of Prodrugs, Textbook of Drug Design and Development”, Chapter 5, pp. 113–191 (1991); Bundgaard et al., Journal of Drug Delivery Reviews, 8:1–38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 ff. (1988); Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa and Joachim Mayer, “Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry and Enzymology,” John Wiley and Sons, Ltd (2002).

[0092] The present invention also covers pharmaceutical compositions comprising a pharmaceutically acceptable prodrug containing a compound of the present invention, and methods of treating a condition by administering the prodrug.

[0093] Metastatic breast cancer, or metastasis, refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body (such as bones, liver, lungs, or brain). (https: / / www.cancer.org / cancer / breast-cancer.)

[0094] Locally advanced breast cancer (LABC) is defined by the National Comprehensive Cancer Network (NCCN) as a subgroup of breast cancer characterized by the most advanced stage of breast tumor in the absence of distant metastasis, wherein the tumor is larger than 5 cm and accompanied by regional lymphadenopathy; tumor of any size extending directly to the chest wall or skin, or both (including ulcers or satellite nodules), regardless of the presence of regional lymphadenopathy; presence of regional lymphadenopathy (clinically fixed or fused axillary lymph nodes, or any subclavian, supraclavicular, or internal mammary lymphadenopathy), regardless of tumor stage. (Garg et al., Curr Oncol. 2015 October; 22(5): e409-e410; NCCN Clinical Practice Guidelines for Oncology: Breast Cancer. Fort Washington, Pa.: NCCN; 2015. Ver. 2.2015.)

[0095] As used in this article, ER+ (estrogen receptor positive) refers to breast cancer cells that possess a receptor protein that binds to the hormone estrogen. ER+ cancer cells may require estrogen to grow and may stop growing or die when treated with substances that block estrogen binding and action. (https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / 44404.)

[0096] As used in this article, HER2- (human epidermal growth factor receptor 2) refers to breast cancer cells that do not have a high concentration of a protein called HER2 on their surface. In normal cells, HER2 helps control cell growth. HER2-negative cancer cells may grow more slowly than cancer cells with a high concentration of HER2 on their surface and are less likely to recur or spread to other parts of the body. (https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / her2-negative.)

[0097] As used in this article, “treatment” describes the management and care of a subject in order to combat a disease, condition, or disorder, and includes reducing or alleviating symptoms or complications, or eliminating the disease, condition, or disorder.

[0098] As used in this article, “prevention” describes preventing the onset of symptoms or complications of a disease, condition, or disorder.

[0099] "Administration" refers to the introduction of a drug, such as a compound of formula (I), into the subject. The related terms "administering" and "administration of" (and their grammatical equivalents) both refer to direct administration (which may be administered to the subject by a medical professional or administered by the subject themselves) and / or indirect administration (which may be the act of prescribing a drug). For example, a physician instructing a patient to administer a drug themselves and / or prescribing a drug for a patient is administering the drug to the patient.

[0100] As used herein, “anticancer agent” is used to describe anticancer agents, or therapeutic agents that are administered concurrently with anticancer agents (such as palonosetron), which may be co-administered and / or co-formulated with compounds of formula (I) to treat cancer and side effects associated with cancer treatment.

[0101] As used herein, a “therapeutic effective amount” refers to an amount of the free base of a compound of formula (I) sufficient to treat, improve, or prevent a particular disease (e.g., breast cancer), disease symptoms, disorders, or conditions, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. The effective amount for a particular subject may depend on the subject’s weight, body type, and health status; the nature and severity of the condition; and whether additional therapeutic agents will be administered to the subject. The therapeutically effective amount for a given situation can be determined through routine laboratory testing within the scope of a clinician’s skill and judgment.

[0102] As used herein, "oral dosage form" refers to a pharmaceutical product containing a specified amount (dosage) of a compound of formula (I) as an active ingredient or a pharmaceutically acceptable salt and / or solvate thereof, and an inactive component (excipient), formulated in a specific form suitable for oral administration and drug delivery, such as tablets, capsules, or liquid oral formulations. In some embodiments, the composition is in the form of a scoreable tablet.

[0103] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and refers to materials, compositions, or media that participate in the transport or transfer of a pharmaceutical agent from one organ or body part of a subject to another organ or body part, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0104] 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 value that falls between X-10% and X+10%.

[0105] The terms "comprising" or "comprise" when applied to a particular dosage form, composition, use, method, or process described or claimed herein mean that the dosage form, composition, use, method, or process includes all listed elements in the specific description or claim, but does not exclude other elements. "Consistessentially of" and "consisting essentially of" mean that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not substantially affect the physical, pharmacological, pharmacokinetic properties, or therapeutic effects of the composition, dosage form, method, use, or process. "Consist of" and "consisting of" exclude other component elements beyond trace amounts and substantial method or process steps.

[0106] In this disclosure, the articles “a” and “an” refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, “element” means one or more elements.

[0107] Unless otherwise stated, the term “and / or” as used in this disclosure means “and” or “or”.

[0108] The terms “patient” and “subject” are used interchangeably in this document and refer to mammals such as humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, or non-human primates such as monkeys, chimpanzees, baboons, or rhesus monkeys.

[0109] In some implementations, the subject is a human being.

[0110] In some implementations, the subjects are people diagnosed with breast cancer.

[0111] In some implementations, the subjects are people diagnosed with metastatic breast cancer.

[0112] In some implementations, the subjects are people diagnosed with ER+, HER2- breast cancer.

[0113] In some implementations, the subjects are people diagnosed with metastatic, ER+, HER2- breast cancer.

[0114] Compound of formula (I)

[0115] In one aspect, this application relates to a method of treating and / or preventing cancer, said method comprising administering a compound of formula (I) to a subject in need of it.

[0116] In one aspect, this application relates to the use of the compound of formula (I) in the treatment and / or prevention of breast cancer.

[0117] In one aspect, this application relates to the use of the compound of formula (I) in the preparation of a medicament for the treatment and / or prevention of breast cancer.

[0118] As mentioned herein, compounds of formula (I) refer to compounds having the following structures:

[0119] Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative or prodrug.

[0120] Compounds of formula (I) can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups, including the use of protecting groups. In view of this disclosure, such methods and procedures are available from relevant scientific literature or standard reference textbooks in the field. While not limited to any single or multiple sources, recognized reference textbooks for organic synthesis include: Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 3rd; John Wiley & Sons: New York, 1999.

[0121] Example

[0122] Formula (I) disclosed herein can be prepared according to the synthesis methods described in Schemes A to C.

[0123] Synthesize 3-(4-((4-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione, formula (I):

[0124] Option A

[0125] Methyl 5-amino-4-(4-((tert-butyldimethylsilyl)oxy)-1-oxoisoindoline-2-yl)-5-oxovalerate was prepared (1).

[0126]

[0127] To a stirred suspension of methyl 2-(bromomethyl)-3-(tert-butyldimethylsiloxy)benzoate [1323407-17-5], 90% (4.51 g, 11.3 mmol on a 90% basis) and methyl 4,5-diamino-5-oxovalerate hydrochloride [1323290-64-7] (2.41 g, 12.3 mmol) in acetonitrile (38 mL) at room temperature, diisopropylethylamine (6.0 mL, 34.5 mmol) was added. The stirred suspension was then heated to 40°C and held for 17 hours under N2 protection, cooled, and partitioned between ice-cold 1.0N HCl (aqueous solution) and ethyl acetate. The organic phase was washed with saturated NaCl (aqueous solution), dried (CaSO4), filtered, and pre-adsorbed onto celite. Rapid chromatography (silica gel, EtOAc / hexane) yielded 2.58 g of a light brown solid. Recrystallization from a minimal amount of boiling ethyl acetate gave 1.66 g of a white fine powder. C 20 H 30 N2O5SiLC-MS MH + = 407.1993 (quality error -0.9ppm); 1 H 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. 13 C 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, 172.54ppm.

[0128] Methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxovalerate, namely methyl 4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindolin-2-yl)-butyrate (2).

[0129]

[0130] Potassium hydrofluoric acid methyl ester (1) (2.37 g, 5.8 mmol) in methanol (116 mL) was added to a stirred solution at room temperature with potassium hydrofluoric acid methyl ester (1) at room temperature. The resulting solution was stirred at room temperature for 30 minutes, at which point LC-MS analysis indicated the reaction was complete. The solution was evaporated onto diatomaceous earth and then subjected to rapid chromatography (silica gel, EtOAc / hexane) to give 972.2 mg of a white solid. 14 H 16 N2O5LC-MS MH + = 293.1132 (quality error 0.1ppm).

[0131] Methyl 5-amino-4-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxovalerate was prepared (3).

[0132]

[0133] To a polymer-loaded suspension of triphenylphosphine, CA 1.6 mmol / g (4.2 g, 6.7 mmol) and methyl 5-amino-4-(4-hydroxy-1-oxoisoindoline-2-yl)-5-oxovalerate (2) (972.2 mg, 3.3 mmol) in THF (33 mL) at 0°C with stirring, diisopropyldiazene-1,2-dicarboxylate (DIAD, 1.3 mL, 6.7 mmol) was added. After stirring at 0°C for 30 min, (4-(chloromethyl)phenyl)methanol (782.3 mg, 5.0 mmol) was added, and the mixture was rapidly stirred for 1.5 h, then filtered through a tightly packed diatomaceous earth filter. The resin bed was thoroughly washed with EtOAc, and the filtrate was evaporated to give 3.1 g of an opaque yellow oil. 1.2 g of white solid was obtained by rapid chromatography (silica gel, EtOAc / hexane). 22 H 23 ClN2O5 LC-MS MH + = 431.1380 (quality 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. 13 C 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.

[0134]

[0135] Option B

[0136] Preparation of 4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (4).

[0137]

[0138] 4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenol [2229713-95-3] (1.6 g, 4.2 mmol, [a]) was added to a 50 mL round-bottom flask. D = -380.55°) and a solution of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride [375-72-4], 96% pure (1.3 g, 4.2 mmol), in 50% (v / v) tetrahydrofuran and acetonitrile (15 mL), with potassium carbonate [584-08-7] (867.2 mg, 6.3 mmol). The reaction mixture was stirred at room temperature under N2 protection for 4 days, after which TLC showed completion of the conversion. The reaction suspension was diluted with EtOAc and adsorbed onto diatomaceous earth for purification. Rapid chromatography (silica gel, EtOAc / hexane) yielded 1.9 g of a milky white (emulsive) viscous oil. 1H NMR (300MHz, 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. 13 C 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.

[0139] Preparation of 4-(4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (5).

[0140]

[0141] Add toluene (20 mL) to a 100 mL round-bottom flask containing a mixture of [4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetrahydronaphthyl-1-yl]phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (4) (1.3 g, 2.0 mmol), piperazine-1-carboxylic acid tert-butyl ester [57260-71-6] (1.12 g, 6.0 mmol), sodium tert-butoxide [865-48-5] (765.4 mg, 8.0 mmol), palladium acetate [3375-31-3] (81.1 mg, 0.4 mmol) and dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl [564483-18-7] (XPhos, 305.5 mg, 0.6 mmol). The rapidly stirred suspension was bubbled with N2 for 15 minutes, the bubbling tube (sparge tube) was removed, and the container was placed under N2 protection. The mixture was stirred at 100°C for 2 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water and EtOAC, and the organic phase was adsorbed onto diatomaceous earth. Rapid chromatography (silica gel, EtOAc / hexane) yielded 837.9 mg of white solid foam. 35 H 44 N2O3 LC-MS MH += 541.3419 (quality error -1.0 ppm); 1 H 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.

[0142] Preparation of (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol hydrochloride (6).

[0143]

[0144] To a 25 mL round-bottom flask containing 752.7 mg (1.4 mmol) of tert-butyl 4-(4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (5), 4.0 M HCl (7.0 mL, 28 mmol) in 1,4-dioxane was added. The solution was stirred at room temperature. After 0.5 hours, LC-MS reported that double deprotection was complete. The reaction solution was evaporated to dryness to give 918.3 mg of a light brown solid, which was used without further purification. 26 H 28 N2O LC-MS MH + = 385.2279 (quality error 1.1 ppm).

[0145]

[0146] Option C

[0147] Methyl 5-amino-4-(4-((4-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxovalerate (7).

[0148]

[0149] To a stirred suspension of (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol hydrochloride (6) (918.3 mg, [1.4 mmol]) and methyl 5-amino-4-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxovalerate (3) (879.7 mg, 2.0 mmol) in methanol (20.0 mL), diisopropylethylamine (2.5 mL, 14.4 mmol) was added. The mixture was stirred under reflux until LC-MS reported the reaction as complete, 17 hours. The cooled reaction mixture was diluted with additional methanol and adsorbed onto diatomaceous earth. Rapid chromatography (silica gel, MeOH / DCM) yielded 1.3 g of white solid foam. 48 H 50 N4O6LC-MS MH + = 779.3829 (quality error 3.3ppm).

[0150] Preparation of 3-(4-((4-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (Formula (I)).

[0151]

[0152] Methyl 5-amino-4-(4-((4-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxovalerate (7) (1.3 g, 1.7 mmol) was added to a stirred solution of 5-amino-4-(4-((4-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxovalerate (7) at room temperature in THF (166 mL) and the solution was stirred under N2 protection until TLC showed complete conversion, 17 h. The reaction solution was then adsorbed onto diatomaceous earth and subjected to rapid chromatography (silica gel, 2-propanol / DCM) to give 0.6 g of white solid, which was recrystallized from boiling EtOAc / heptane to recover 458.6 mg of white powder. C 47 H 46 N4O5LC-MS MH + = 747.3555 (quality 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. 13 C 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: 0.4344 g / 100 cm³ soluble in ethyl acetate, l = 589 nm, 25°C).

[0153] MCF-7 cell proliferation

[0154] Experimental methods: MCF-7 cells were resuscitated and seeded onto plates after confirming normal growth and viability exceeding 90%. The pretreatment procedure before cell treatment with the test sample was as follows: cell density and viability were measured to determine the appropriate volume of cell culture medium needed to assess the required volume for transferring the desired number of cells. Cells were centrifuged, resuspended in fresh medium (1000 cells / well, 100 μL / well, seeded in a white plate), and mixed. Medium was added to surrounding wells to eliminate edge effects, and the plates were incubated overnight. The next day, the drug was serially diluted with medium, adding 100 μL / well to the corresponding cell wells. The plates were incubated at 37°C, 5% CO2 for 72 hours. When the plates returned to room temperature, 40 μL of CellTiter-Glo was added to each well, and the plates were gently shaken at 80 rpm for 10 minutes to mix. Chemiluminescence was read using a microplate reader. Inhibition curves were plotted using GraphPad Prism.

[0155] Results analysis: Under the same conditions, the inhibitory effect of compound (I) showed a similar trend to that of ARV-471. Figure 1 The inhibitory trend of compound (I) shows higher activity than that of (racemic) ARV-471. Eciruciclib, as a control, shows a stable inhibitory trend as previously observed.

[0156] Western blot analysis: MCF-7 cell line was purchased from the American Type Culture Collection (Manassas, Virginia). Cells were cultured in EMEM medium supplemented with 10% FBS, 100 µg / ml penicillin, and 100 µg / ml streptomycin. Cultures were maintained at 37°C in a humidified atmosphere containing 5% CO2 and 95% air. 7% Tris-acetate gel and nitrocellulose membranes were purchased from Thermo-Fisher Scientific (Waltham, Massachusetts). Estrogen receptor α (Cat#8644S) antibody was purchased from Cell Signaling Technology (Danvers, Massachusetts). Anti-α-tubulin (T9026) antibody was purchased from Sigma (St. Louis, Missouri). Anti-rabbit IgG IRDye 680RD and anti-mouse IgG IRDye 800CW secondary antibodies were purchased from LI-COR (Lincoln, Nebraska).

[0157] program: 1. Take 5x10 5 MCF-7 cells per well were seeded into 12-well plates containing complete culture medium and then incubated overnight.

[0158] 2. The following day, cells were treated with 10 doses of each of the three compounds; the treatment was performed in single 3-fold dilutions starting at 10 μM, using compound (I), (racemic) ARV-471, and vepdegestrant (ARV-471). DMSO was used as a control.

[0159] 3. Incubate the tissue culture plates at 37°C and 5% CO2 for 72 hours.

[0160] 4. Remove the culture medium and wash the cells with ice-cold PBS.

[0161] 5. Lyse cells with 150 µL of 1x SDS sample buffer containing 50 mM DTT.

[0162] 6. Sonicate the sample, then heat it at 95°C for 10 minutes, and then freeze it until it is ready for use.

[0163] 7. Take 20 µL of sample and separate it on a 7% Tris-acetate gel by SDS-PAGE, and then transfer it to a nitrocellulose membrane by iBlot dry blotting system.

[0164] 8. Seal the membrane with 3% milk for 1 hour, then probe overnight with estrogen receptor α antibody in 3% milk.

[0165] 9. Block the membrane with 3% milk for 1 hour, and then re-probe with the anti-α-tubulin antibody in 3% milk.

[0166] 10. Primary antibodies were detected using LI-COR anti-rabbit IgG IRDye 680RD and anti-mouse IgG IRDye 800CW secondary antibodies.

[0167] 11. Scan the membrane using the LI-COR Odyssey Fc imaging system. Quantify the specific bands of interest using LI-COR Image Studio Lite software.

[0168] 12. Use the GraphPad Prism 4 program to draw a bar chart.

[0169] Using the concentration of compound (I) shown ( Figure 2A (racemic) ARV-471 Figure 2B ) and Vepdegestrant (ARV-471) Figure 2C MCF-7 cells were treated for 72 hours. Western blot analysis was performed on the cell lysates. The blots were detected using an estrogen receptor α antibody and then re-detected using an α-tubulin antibody.

Claims

1. A method for treating breast cancer in a subject in need of it, 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 its pharmaceutically acceptable salt.

2. The method according to 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 according to 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 according to claim 1, wherein the breast cancer is estrogen receptor positive (ER+) and 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 administering a therapeutically effective amount of at least one additional anticancer agent to the subject in need of it.

7. The method according to claim 5, wherein the at least one additional anticancer agent is selected from FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK 4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase inhibitors, VEGF capture antibodies, SHR6390, trilacizate, lenosicillin, AT7519M, denaciline, ribociclib, abecilide, pebocillin, everolimus, veneclax, inavolixe (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epothilone B, fulvestrant, azithromycin, etc. The group consists of lasocifen, edoxifene, topotecan, pemetrexed, erlotinib, texilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrozole, letrozole, bevacizumab, goserelin acetate, raloxifene, apeliximab, trastuzumab, emtansine trastuzumab, pertuzumab, fam-trastuzumab, detrastuzumab (Enhertu), or eribulin (Halaven).

8. The method of claim 1, wherein the subject is a human.

9. The method according to claim 1, wherein the compound of formula (I) is conjugated with an antibody to form an antibody-drug conjugate.

10. A compound of formula (I): Or its pharmaceutically acceptable salt.

11. The compound of claim 10, wherein the compound of formula (I) is conjugated with an antibody to form an antibody-drug conjugate.

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

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

14. A method for degrading at least one somatic ER tumor mutation in a human body, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I): 。 15. The method according to 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 administering a therapeutically effective amount of at least one additional anticancer agent to the subject in need of it.

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

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